Sample records for neuroendocrine gnrh1 cells

  1. Specification of GnRH-1 neurons by antagonistic FGF and retinoic acid signaling. (United States)

    Sabado, Virginie; Barraud, Perrine; Baker, Clare V H; Streit, Andrea


    A small population of neuroendocrine cells in the rostral hypothalamus and basal forebrain is the key regulator of vertebrate reproduction. They secrete gonadotropin-releasing hormone (GnRH-1), communicate with many areas of the brain and integrate multiple inputs to control gonad maturation, puberty and sexual behavior. In humans, disruption of the GnRH-1 system leads to hypogonadotropic gonadism and Kallmann syndrome. Unlike other neurons in the central nervous system, GnRH-1 neurons arise in the periphery, however their embryonic origin is controversial, and the molecular mechanisms that control their initial specification are not clear. Here, we provide evidence that in chick GnRH-1 neurons originate in the olfactory placode, where they are specified shortly after olfactory sensory neurons. FGF signaling is required and sufficient to induce GnRH-1 neurons, while retinoic acid represses their formation. Both pathways regulate and antagonize each other and our results suggest that the timing of signaling is critical for normal GnRH-1 neuron formation. While Kallmann's syndrome has generally been attributed to a failure of GnRH-1 neuron migration due to impaired FGF signaling, our findings suggest that in at least some Kallmann patients these neurons may never be specified. In addition, this study highlights the intimate embryonic relationship between GnRH-1 neurons and their targets and modulators in the adult. Copyright © 2011 Elsevier Inc. All rights reserved.

  2. The frequency of neuroendocrine cell hyperplasia in patients with pulmonary neuroendocrine tumours and non-neuroendocrine cell carcinomas. (United States)

    Rizvi, Selim M H; Goodwill, Joseph; Lim, Eric; Yap, Yoong K; Wells, Athol U; Hansell, David M; Davis, Peter; Selim, Abdel-Ghani; Abdel-Ghani, Syed; Goldstraw, Peter; Nicholson, Andrew G


    To evaluate the frequency of neuroendocrine cell hyperplasia (NEH) in resected neuroendocrine tumours and non-neuroendocrine cell carcinomas and to study its relationship to selected clinical parameters. Random blocks without tumour from resected typical carcinoids (TCs, n = 46), atypical carcinoids (ACs, n = 14), large cell neuroendocrine carcinomas (LCNECs, n = 18), small cell carcinomas (SCLCs, n = 22), adenocarcinomas (ADENOs, n = 26) and squamous cell carcinomas (SCCs, n = 18) were stained for CD56 and evaluated for linear proliferations, cell aggregates (>4 CD56+ cells), and tumourlets (<5 mm with basement membrane invasion). There was a statistically significant difference between the frequency of NEH in all neuroendocrine tumours (TC/AC/LCNEC/SCLC, 35/100, 35%) (P = 0.009) when compared with non-neuroendocrine carcinomas (ADENO/SCC, 6/44, 14%) and in the frequency of NEH in TC (21/46, 46%) versus all other tumours (AC/LCNEC/SCLC/SCC/ADENO, 20/98, 20%) (P = 0.001). There was increased frequency of NEH in peripheral TCs (8/13, 62%) compared with central TCs (14/33, 43%) (P = 0.33). There was no association between smoking history and NEH. Clinical and imaging data showed no evidence of an increased frequency of obliterative bronchiolitis in patients with NEH. NEH is significantly increased in the background lung of neuroendocrine tumours when compared with non-neuroendocrine carcinomas, supportive data for NEH having neoplastic potential.

  3. [EGFR-expression in pulmonary neuroendocrine cell hyperplasia]. (United States)

    Kuhnen, C; Winter, B U


    15 cases of pulmonary neuroendocrine cell hyperplasia (carcinoid-tumorlets, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia/DIPNECH) and 20 neuroendocrine pulmonary tumors (10 carcinoid tumors, 5 large cell neuroendocrine, and 5 small cell neuroendocrine lung carcinomas) were immunohistochemically analyzed for the expression of epidermal growth factor receptor (EGFR, = HER-1). All cases of neuroendocrine cell hyperplasia exhibited a maximum EGFR expression (score 3 in 100% of cells) showing predominantly membranous, partly cytoplasmic staining. 4 ot the 10 carcinoid tumors were strongly positive for EGFR, whereas the other 6 were EGFR-negative. A total of 90% of large cell neuroendocrine and small cell neuroendocrine carcinomas were negative for EGFR. Overexpression of EGFR in pulmonary neuroendocrine cell hyperplasia might be significant for the pathogenesis of these lesions. As DIPNECH is characterized by clinical signs and symptoms including mild cough and obstructive functional impairment, a specific antagonistic therapeutic trial could aim at blocking EGFR/HER-1 or its subsequent signal transduction pathway.

  4. Large cell neuroendocrine carcinoma of the ampulla of Vater.

    LENUS (Irish Health Repository)

    Beggs, Rachel E


    Large cell neuroendocrine carcinomas of the ampulla of Vater are rare and confer a very poor prognosis despite aggressive therapy. There are few case reports of large cell neuroendocrine carcinomas of the ampulla of Vater in the literature and to date no studies have been done to establish optimal management. We describe a pooled case series from published reports of neuroendocrine carcinomas of the ampulla of Vater including a case which presented to our institution.

  5. Diffuse Neuroendocrine Cell Hyperplasia: Report of Two Cases

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    Cevriye Cansız Ersöz


    Full Text Available Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH is a rare pulmonary disorder characterised by a proliferation of neuroendocrine cells within the lung. It is believed that a minority of the patients with DIPNECH can develop carcinoid tumors. Here, we report two new cases of DIPNECH with coexisting carcinoid tumors.

  6. Social Crowding during Development Causes Changes in GnRH1 DNA Methylation. (United States)

    Alvarado, Sebastian G; Lenkov, Kapa; Williams, Blake; Fernald, Russell D


    Gestational and developmental cues have important consequences for long-term health, behavior and adaptation to the environment. In addition, social stressors cause plastic molecular changes in the brain that underlie unique behavioral phenotypes that also modulate fitness. In the adult African cichlid, Astatotilapia burtoni, growth and social status of males are both directly regulated by social interactions in a dynamic social environment, which causes a suite of plastic changes in circuits, cells and gene transcription in the brain. We hypothesized that a possible mechanism underlying some molecular changes might be DNA methylation, a reversible modification made to cytosine nucleotides that is known to regulate gene function. Here we asked whether changes in DNA methylation of the GnRH1 gene, the central regulator of the reproductive axis, were altered during development of A. burtoni. We measured changes in methylation state of the GnRH1 gene during normal development and following the gestational and developmental stress of social crowding. We found differential DNA methylation within developing juveniles between 14-, 28- and 42-day-old. Following gestational crowding of mouth brooding mothers, we saw differential methylation and transcription of GnRH1 in their offspring. Taken together, our data provides evidence for social control of GnRH1 developmental responses to gestational cues through DNA methylation.

  7. Concomitant Small Cell Neuroendocrine Carcinoma of Gallbladder and Breast Cancer

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    Paolo Aiello


    Full Text Available The neuroendocrine carcinoma is defined as a high-grade malignant neuroendocrine neoplasm arising from enterochromaffin cells, usually disposed in the mucosa of gastric and respiratory tracts. The localization in the gallbladder is rare. Knowledge of these gallbladder tumors is limited and based on isolated case reports. We describe a case of an incidental finding of small cell neuroendocrine carcinoma of the gallbladder, observed after cholecystectomy for cholelithiasis, in a 55-year-old female, who already underwent quadrantectomy and sentinel lymph-node biopsy for breast cancer. The patient underwent radiotherapy for breast cancer and six cycles of chemotherapy with cisplatin and etoposide. Eighteen months after surgery, the patient was free from disease. Small cell neuroendocrine carcinoma of the gallbladder has poor prognosis. Because of the rarity of the reported cases, specific prognostic factors have not been identified. The coexistence of small cell neuroendocrine carcinoma of the gallbladder with another malignancy has been reported only once. The contemporary presence of the two neoplasms could reflect that bioactive agents secreted by carcinoid can promote phenotypic changes in susceptible cells and induce neoplastic transformation.

  8. Large-cell Neuroendocrine Carcinoma of the Lung: Unusual Presentation

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    Miguel Ángel Serra Valdés


    Full Text Available Lung cancer is the leading cause of death among malignant tumors. Pulmonary neuroendocrine tumors encompass a broad spectrum of tumors including the large-cell neuroendocrine carcinoma. The case of a 57-year-old white housewife with a history of smoking, diabetes, hypothyroidism and hypertension who sought medical attention because of headache, vomiting, weight loss, neuropsychiatric symptoms and metastatic inguinal lymphadenopathy is presented. The symptoms resulted from the extrapulmonary metastases found. Imaging studies, histology and immunohistochemistry confirmed the diagnosis of large-cell carcinoma of the lung with neuroendocrine pattern. This type of highly aggressive tumor is usually diagnosed when there are already multiple metastases, which affects the short-term prognosis. The aim of this paper is to inform the medical community of this case due to the scarce reports in the literature.

  9. Large-cell neuroendocrine carcinoma of the uterine cervix- a ...

    African Journals Online (AJOL)

    Objective. The present study describes 5 cases of large-cell neuroendocrine carcinoma (LCNEC) of the uterine cervix, evaluating their clinical features and pathological profiles. Methods. Clinical data were obtained from the patients' clinical files at the combined gynaecological-oncology unit of Johannesburg Hospital and ...

  10. A Rare Case of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia

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    Godwin Ofikwu


    Full Text Available Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH is a rare clinical condition with only about 100 cases reported in the literature. It is characterized by primary hyperplasia of pulmonary neuroendocrine cells (PNECs which are specialized epithelial cells located throughout the entire respiratory tract, from the trachea to the terminal airways. DIPNECH appears in various forms that include diffuse proliferation of scattered neuroendocrine cells, small nodules, or a linear proliferation. It is usually seen in middle-aged, nonsmoking women with symptoms of cough, dyspnea, and wheezing. We present a 45-year-old, nonsmoking woman who presented with symptoms of DIPNECH associated with bilateral pulmonary nodules and left hilar adenopathy. Of interest, DIPNECH in our patient was associated with metastatic pulmonary carcinoids, papillary carcinoma of the left breast, oncocytoma and angiomyolipoma of her left kidney, and cortical nodules suggestive of tuberous sclerosis. She had video assisted thoracoscopic surgery (VATS, modified radical mastectomy with reconstruction, and radical nephrectomy. She is currently symptom-free most of the time with over two years of follow-up.

  11. Clonality analysis of neuroendocrine cells in gastric adenocarcinoma (United States)

    Wang, Ling-Ling; Yao, Gen-You; Zhao, Zhong-Sheng; Wei, Xiao-Li; Xu, Ru-Jun


    AIM: To achieve a better understanding of the origination of neuroendocrine (NE) cells in gastric adenocarcinoma. METHODS: In this study, 120 cases of gastric adenocarcinoma were obtained. First, frozen section-immunohistochemistrical samples were selected from a large quantity of neuroendocrine cells. Second, laser capture microdissection was used to get target cells from gastric adenocarcinoma and whole genome amplification was applied to get a large quantity of DNA for further study. Third, genome-wide microsatellite abnormalities [microsatellite instability (MSI), loss of heterozygosity (LOH)] and p53 mutation were detected by polymerase chain reaction (PCR)-single-strand conformation polymer- phism-silver staining and PCR-sequencing in order to identify the clonality of NE cells. RESULTS: The total incidence rate of MSI was 27.4%, while LOH was 17.9%. Ten cases had a highest concordance for the two types of cells. The other samples had similar microsatellite changes, except for cases 7 and 10. Concordant p53 mutations exhibited in sample 4, 14, 21 and 27, and there were different mutations between two kinds of cells in case 7. In case 17, mutation took place only in adenocarcinoma cells. p53 mutation was closely related with degree of differentiation, tumor-node-metastasis stage, vessel invasion and lymph node metastasis. In brief, NE and adenocarcinoma cells showed the same MSI, LOH or p53 mutation in most cases (27/30). In the other three cases, different MSI, LOH or p53 mutation occurred. CONCLUSION: NE and the gastric adenocarcinoma cells may mainly derive from the same stem cells, but the remaining cases showing different origin needs further investigation. PMID:23983439

  12. Rb Loss is Characteristic of Prostatic Small Cell Neuroendocrine Carcinoma (United States)

    Tan, Hsueh-Li; Sood, Akshay; Rahimi, Hameed A.; Wang, Wenle; Gupta, Nilesh; Hicks, Jessica; Mosier, Stacy; Gocke, Christopher D.; Epstein, Jonathan I.; Netto, George J.; Liu, Wennuan; Isaacs, William B.; De Marzo, Angelo M.; Lotan, Tamara L.


    Purpose Small cell neuroendocrine carcinoma of the prostate is likely to become increasingly common with recent advances in pharmacologic androgen suppression. Thus, developing molecular markers of small cell differentiation in prostate cancer will be important to guide diagnosis and therapy of this aggressive tumor. Experimental Design We examined the status of RB1, TP53 and PTEN in prostatic small cell and acinar carcinomas via immunohistochemistry (IHC), copy number alteration analysis and sequencing of formalin fixed paraffin-embedded specimens. Results We found Rb protein loss in 90% (26/29) of small cell carcinoma cases with RB1 allelic loss in 85% (11/13) of cases. Of acinar tumors occurring concurrently with prostatic small cell carcinoma, 43% (3/7) showed Rb protein loss. In contrast, only 7% (10/150) of primary high grade acinar carcinomas, 11% (4/35) of primary acinar carcinomas with neuroendocrine differentiation, and 15% (2/13) of metastatic castrate resistant acinar carcinomas showed Rb protein loss. Loss of PTEN protein was seen in 63% (17/27) of small cell carcinomas, with 38% (5/13) showing allelic loss. By IHC, accumulation of p53 was observed in 56% (14/25) of small cell carcinomas, with 60% (6/10) of cases showing TP53 mutation. Conclusions Loss of RB1 by deletion is a common event in prostatic small cell carcinoma and can be detected by validated IHC assay. As Rb protein loss rarely occurs in high grade acinar tumors, these data suggest that Rb loss is a critical event in the development of small cell carcinomas and may be a useful diagnostic and potential therapeutic target. PMID:24323898

  13. Chemotherapy for pulmonary large cell neuroendocrine carcinomas : Does the regimen matter?

    NARCIS (Netherlands)

    Derks, Jules L.; van Suylen, Robert Jan; Thunnissen, Erik; den Bakker, Michael A.; Groen, Harry J.; Smit, Egbert F.; Damhuis, Ronald A.; van den Broek, Esther C.; Speel, Ernst-Jan M.; Dingemans, Anne-Marie C.

    Pulmonary large cell neuroendocrine carcinoma (LCNEC) is rare. Chemotherapy for metastatic LCNEC ranges from small cell lung carcinoma (SCLC) regimens to nonsmall cell lung carcinoma (NSCLC) chemotherapy regimens. We analysed outcomes of chemotherapy treatments for LCNEC. The Netherlands Cancer

  14. Transformation of Nonfunctioning Pancreatic Neuroendocrine Carcinoma Cells into Insulin Producing Cells after Treatment with Sunitinib

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    Jung Hun Ohn


    Full Text Available We report a rare case of severe hypoglycemia after sunitinib treatment for pancreatic neuroendocrine carcinoma. We describe the initial clinical presentation, laboratory results, pathologic findings, and managment in a patient with a nonfunctioning pancreatic neuroendocrine carcinoma with liver metastases who developed life threatening hypoglycemia after 2 months of sunitinib therapy. A 46-year-old woman presented to the emergency department with loss of consciousness from hypoglycemia. Serum C-peptide and insulin levels at fasting state revealed that the hypoglycemia resulted from endogenous hyperinsulinemia. She had been diagnosed with nonfunctioning pancreatic neuroendocrine carcinoma based on a biopsy of metastatic cervical lymph node and was being treated with sunitinib, a small molecule tyrosine kinase inhibitor. Immunohistochemical stain of the metastatic liver mass demonstrated that the initially nonfunctioning neuroendocrine carcinoma cells had changed into insulin-producing cells after sunitinib therapy. Transarterial chemoembolization of the liver masses and systemic chemotherapy with streptozotocin/adriamycin relieved the hypoglycemia. A nonfunctioning pancreatic neuroendocrine carcinoma was transformed into an insulin-producing tumor after treatment with sunitinib, causing endogenous hyperinsulinemia and severe hypoglycemia.

  15. Genetic and molecular coordinates of neuroendocrine lung tumors, with emphasis on small-cell lung carcinomas

    National Research Council Canada - National Science Library

    Koutsami, Marilena K; Doussis-Anagnostopoulou, Ipatia; Papavassiliou, Athanasios G; Gorgoulis, Vassilis G


    .... Current information on established and putative diagnostic and prognostic markers of neuroendocrine tumors are evaluated, with a special reference to small-cell lung carcinoma, due to its higher...

  16. Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP.


    Bang, Y J; Pirnia, F; Fang, W G; Kang, W K; Sartor, O; Whitesell, L; Ha, M J; Tsokos, M.; Sheahan, M D; Nguyen, P.


    Recent clinicopathologic studies have shown that many prostatic adenocarcinomas express focal neuroendocrine differentiation and that neuroendocrine differentiation is most apparent in advanced anaplastic tumors. While studying growth-regulatory signal transduction events in human prostate carcinoma cell lines, we found that in two of four cell lines, the androgen-sensitive line LNCaP and the highly metastatic androgen-independent line PC-3-M, elevation of cAMP through addition of cAMP analog...

  17. Evaluation of neuroendocrine markers in renal cell carcinoma

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    Kauppila Saila


    Full Text Available Abstract Background The purpose of the study was to examine serotonin, CD56, neurone-specific enolase (NSE, chromogranin A and synaptophysin by immunohistochemistry in renal cell carcinomas (RCCs with special emphasis on patient outcome. Methods We studied 152 patients with primary RCCs who underwent surgery for the removal of kidney tumours between 1990 and 1999. The mean follow-up was 90 months. The expression of neuroendocrine (NE markers was determined by immunohistochemical staining using commercially available monoclonal antibodies. Results were correlated with patient age, clinical stage, Fuhrman grade and patient outcome. Results Eight percent of tumours were positive for serotonin, 18% for CD56 and 48% for NSE. Chromogranin A immunostaining was negative and only 1% of the tumours were synaptophysin immunopositive. The NSE immunopositivity was more common in clear cell RCCs than in other subtypes (p = 0.01. The other NE markers did not show any association with the histological subtype. Tumours with an immunopositivity for serotonin had a longer RCC-specific survival and tumours with an immunopositivity for CD56 and NSE had a shorter RCC-specific survival but the difference was not significant. There was no relationship between stage or Fuhrman grade and immunoreactivity for serotonin, CD56 and NSE. Conclusions Serotonin, CD56 and NSE but not synaptophysin and chromogranin A are expressed in RCCs. However, the prognostic potential of these markers remains obscure.

  18. New model for gastroenteropancreatic large-cell neuroendocrine carcinoma: establishment of two clinically relevant cell lines.

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    Andreas Krieg

    Full Text Available Recently, a novel WHO-classification has been introduced that divided gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN according to their proliferation index into G1- or G2-neuroendocrine tumors (NET and poorly differentiated small-cell or large-cell G3-neuroendocrine carcinomas (NEC. Our knowledge on primary NECs of the GEP-system is limited due to the rarity of these tumors and chemotherapeutic concepts of highly aggressive NEC do not provide convincing results. The aim of this study was to establish a reliable cell line model for NEC that could be helpful in identifying novel druggable molecular targets. Cell lines were established from liver (NEC-DUE1 or lymph node metastases (NEC-DUE2 from large cell NECs of the gastroesophageal junction and the large intestine, respectively. Morphological characteristics and expression of neuroendocrine markers were extensively analyzed. Chromosomal aberrations were mapped by array comparative genomic hybridization and DNA profiling was analyzed by DNA fingerprinting. In vitro and in vivo tumorigenicity was evaluated and the sensitivity against chemotherapeutic agents assessed. Both cell lines exhibited typical morphological and molecular features of large cell NEC. In vitro and in vivo experiments demonstrated that both cell lines retained their malignant properties. Whereas NEC-DUE1 and -DUE2 were resistant to chemotherapeutic drugs such as cisplatin, etoposide and oxaliplatin, a high sensitivity to 5-fluorouracil was observed for the NEC-DUE1 cell line. Taken together, we established and characterized the first GEP large-cell NEC cell lines that might serve as a helpful tool not only to understand the biology of these tumors, but also to establish novel targeted therapies in a preclinical setup.


    Danza, Giovanna; Di Serio, Claudia; Rosati, Fabiana; Lonetto, Giuseppe; Sturli, Niccolò; Kacer, Doreen; Pennella, Antonio; Ventimiglia, Giuseppina; Barucci, Riccardo; Piscazzi, Annamaria; Prudovsky, Igor; Landriscina, Matteo; Marchionni, Niccolò; Tarantini, Francesca


    Prostate carcinoma is among the most common causes of cancer-related death in men, representing 15% of all male malignancies in developed countries. Neuroendocrine differentiation has been associated with tumor progression, poor prognosis and with the androgen-independent status. Currently, no successful therapy exists for advanced, castration-resistant disease. Because hypoxia has been linked to prostate cancer progression and unfavourable outcome, we sought to determine whether hypoxia would impact the degree of neuroendocrine differentiation of prostate cancer cells, in vitro. Results exposure of LNCaP cells to low oxygen tension induced a neuroendocrine phenotype, associated with an increased expression of the transcription factor neurogenin3 and neuroendocrine markers, such as neuron-specific enolase, chromogranin A and β3-tubulin. Moreover, hypoxia triggered a significant decrease of Notch 1 and Notch 2 mRNA and protein expression, with subsequent down regulation of Notch-mediated signalling, as demonstrated by reduced levels of the Notch target genes, Hes1 and Hey1. Neuroendocrine differentiation was promoted by attenuation of Hes1 transcription, as cells expressing a dominant negative form of Hes1 displayed increased levels of neuroendocrine markers under normoxic conditions. Although hypoxia down regulated Notch 1 and Notch 2 mRNA transcription and receptor activation also in the androgen independent cell lines, PC3 and Du145, it did not change the extent of NE differentiation in these cultures, suggesting that androgen sensitivity may be required for transdifferentiation to occur. Conclusions hypoxia induces neuroendocrine differentiation of LNCaP cells in vitro, which appears to be driven by the inhibition of Notch signalling with subsequent down-regulation of Hes1 transcription. PMID:22172337

  20. Large cell neuroendocrine carcinoma of the kidney with cardiac metastasis: a case report

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    Moeka Shimbori


    Full Text Available Abstract Background Primary large cell neuroendocrine carcinoma of the kidney is a rare and generally very aggressive disease. We present a case of a patient with primary large cell neuroendocrine carcinoma of the kidney with cardiac metastasis. Case presentation A 59-year-old Japanese man presented to his previous physician with hematuria. Computed tomography revealed masses in the heart and right kidney, and fluorodeoxyglucose-positron emission tomography showed abnormal uptake in the heart. A cardiac biopsy under transesophageal echocardiographic guidance revealed a metastatic tumor. Subsequently, multiple lung lesions were detected, and a right nephrectomy was performed after these metastases were suspected to have originated from renal carcinoma. Large cell neuroendocrine carcinoma of the kidney was ultimately diagnosed. Pancreatic metastasis was detected on computed tomography postoperatively. Three courses of chemotherapy with carboplatin and irinotecan were administered, and were temporarily effective against the metastatic lesions in the lungs and pancreas. However, our patient’s general condition deteriorated with the progression of the lesions, and he died 9 months after his initial examination. Conclusions Multi-agent chemotherapy, including platinum-based drugs was effective against large cell neuroendocrine carcinoma metastases, albeit only temporarily. This is the first reported case of large cell neuroendocrine carcinoma with cardiac metastasis.

  1. [Small cell neuroendocrine tumour of the bladder: with reference to a case and bibliographical revision]. (United States)

    Lahoz Tornos, A; Marrón Penón, Maria C; Pardo López, Maria L; Nogueras Gimeno, M A; Pujol Obis, E; Del Villar Sordo, V


    The small cell neuroendocrine tumour is an infrecuent neoplasia, with inmunohistochemistry being the key to diagnosis. We present a new case making reference to treatment and its evolution there after. The clinic, diagnosis and treatment of this tumour is described. Bibliographical revision follours. The neuroendocrine tumour of small cell is an infrecuent neoplasia, in which the inmunohistochemistry study is key in the diagnosis. The differential diagnosis includes the high degree diferentiation transitionals cells carcinoma and primary and secondary linfoma. The standard treatment is based on chemotherapy plus surgery.

  2. Survival of egg-laying controlling neuroendocrine cells during reproductive senescence of a mollusc

    NARCIS (Netherlands)

    Janse, C.


    During brain aging neuronal degradation occurs. In some neurons this may result in degeneration and cell death, still other neurons may survive and maintain their basic properties. The present study deals with survival of the egg-laying controlling neuroendocrine caudodorsal cells (CDCs) during

  3. [Neuroendocrine tumors of digestive system: morphologic spectrum and cell proliferation (Ki67 index)]. (United States)

    Delektorskaia, V V; Kushliskiĭ, N E


    This review deals with the analysis of up-to-date concepts ofdiferent types of human neuroendocrine tumors of the digestive system. It summarizes the information on the specifics of recent histological classifications and criteria of morphological diagnosis accounting histological, ultrastructural and immunohistochemical parameters. Current issues of the nomenclature as well as various systems of grading and staging are discussed. In the light of these criteria the results of the own research clinical value of the determination of cell proliferation in primary and metastatic gastroenteropancreatic neuroendocrine neoplasms on the basis of evaluation of the Ki67 antigen expression are also presented.

  4. The forebrain-midbrain acts as functional endocrine signaling pathway of Kiss2/Gnrh1 system controlling the gonadotroph activity in the teleost fish European sea bass (Dicentrarchus labrax). (United States)

    Espigares, Felipe; Carrillo, Manuel; Gómez, Ana; Zanuy, Silvia


    Some teleost species, including European sea bass, harbor two different kisspeptin coding genes: kiss1 and kiss2. Both genes are expressed in the brain, but their differential roles in the central control of fish reproduction are only beginning to be elucidated. In this study, we have examined the effects of intracerebroventricular injections of the highly active sea bass peptides Kiss1-15 and Kiss2-12 on spermiating male sea bass. Physiological saline, Kiss1-15, or Kiss2-12 was injected into the third ventricle. To establish the gene expression cascade involved in the action of kisspeptins, the expression of the two sea bass kisspeptin receptor genes (kiss1r and kiss2r) and the three sea bass Gnrh genes (gnrh1, gnrh2, and gnrh3) were analyzed in the forebrain-midbrain and the hypothalamus. In addition, the protein levels of hypothalamic and pituitary Gnrh1 were measured. Blood samples were collected at different times after injection to analyze the effects of kisspeptins on the release of gonadotropins (Lh and Fsh) and androgens (testosterone and 11-ketotestosterone). The present results provide the first evidence that the effects of Kiss2 on central regulation of reproductive function involve the neuroendocrine areas of the forebrain-midbrain in teleost fish. The marked effect of Kiss2 on kiss2r and gnrh1 expression in the forebrain-midbrain and on Gnrh1 release suggest that this neuronal system is involved in the neuroendocrine regulation of gonadotroph activity. This hypothesis was confirmed by a surge of plasma Lh in response to Kiss2, which presumably has a strong stimulatory effect on testosterone release, and thus on sperm quality parameters. © 2015 by the Society for the Study of Reproduction, Inc.

  5. Does Fetal antigen 1 (FA1) identify cells with regenerative, endocrine and neuroendocrine potentials?

    DEFF Research Database (Denmark)

    Jensen, Charlotte Floridon; Jensen, Charlotte Harken; Thorsen, Poul


    in the subcellular localisation indicating differential post-translational/post-transcriptional modifications during fetal development. FA1 may be a new marker of cellular subtypes with a regenerative potential and of specific cells with endocrine or neuroendocrine functions. Udgivelsesdato: 2000-Aug...

  6. Large Cell Neuroendocrine Carcinoma of the Rectum Presenting with Extensive Metastatic Disease

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    Vinay Minocha


    Full Text Available Introduction. Rectal large cell neuroendocrine carcinoma (LCNEC is a poorly differentiated neoplasm that is very rare and belongs within the poorest prognostic subgroup among primary colorectal neoplasms. Here, we describe a case of LCNEC of the rectum, which highlights the aggressive clinical course and poor prognosis associated with this disease. Case Presentation. We report a case of a 63-year-old male who presented to our hospital with a one-month history of lower abdominal pain, constipation, and weight loss. A computed tomography (CT scan of the chest, abdomen, and pelvis revealed a rectal mass as well as metastatic disease of the liver and lung. Flexible sigmoidoscopy revealed a fungating, ulcerated and partially obstructing rectal mass located 6 cm from the anal verge. This mass was biopsied and pathological examination of the resected specimen revealed features consistent with a large cell neuroendocrine carcinoma. Conclusion. Rectal large cell neuroendocrine carcinomas are rare and have a significantly worse prognosis than adenocarcinomas. At diagnosis, a higher stage and metastatic disease are likely to be found. It is important to differentiate large cell, poorly differentiated neuroendocrine carcinomas from adenocarcinomas of the colon and rectum pathologically because patients may benefit from alternative cytotoxic chemotherapeutic regimens.

  7. Combined choriocarcinoma, neuroendocrine cell carcinoma and tubular adenocarcinoma in the stomach (United States)

    Hirano, Yasumitsu; Hara, Takuo; Nozawa, Hiroshi; Oyama, Kaeko; Ohta, Naohiro; Omura, Kenji; Watanabe, Go; Niwa, Hideki


    We described a patient with adenocarcinoma of the stomach combined with choriocarcinoma and neuroendocrine cell carcinoma. An 85-year-old man visited our hospital because of appetite loss. Gastric fiberscopy revealed a large tumor occupying the cardial region and anterior wall of the gastric body. The patient underwent total gastrectomy with lymphnode dissection and partial resection of the liver. Choriocarcinoma, small cell carcinoma and tubular adenocarcinoma existed in the gastric tumor. The choriocarcinomatous foci contained cells positive for beta-subunit of human chorionic gonadotropin (B-hCG) and human placental lactogen mainly in syncytiotrophoblastic cells. The small cell carcinomatous foci contained cells positive for synaptophysin, neuron-specific enolase (NSE), and chromogranin A. The prognosis for gastric adenocarcinoma with choriocarcinoma and neuroendocrine cell carcinoma is exceedingly poor. This patient died about 2 mo after the first complaint from hepatic failure. This is the first reported case of gastric cancer with these three pathological features. PMID:18506939

  8. Primary small cell neuroendocrine carcinoma of the breast: a report of two cases and review of the literature

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    Spinelli C


    Full Text Available Primary neuroendocrine carcinomas of the breast are extremely rare. Neuroendocrine tumors mainly occur in the broncopolmonary system and gastrointestinal tract. The diagnosis of small cell neuroendocrine carcinoma (SCNC of the breast can only be made if a non mammary site is excluded or if an in situ component can be found. We are going to describe two cases and to discuss their clinical, radiological and pathological manifestations. Introduction: Neuroendocrine tumors are rare and slow-growing neoplasias derived from neuroendocrine cells. We describe two cases of small cell neuroendocrine carcinoma of the breast and discuss their clinical, radiological and pathological manifestations. Case report: Our patients are two Italian females (38 and 36 year-old with no family history of breast disease. In both cases the diagnosis was confirmed after surgery, when immunohistochemistry revealed a neuroendocrine differentiation of the tumor. The patients are alive and disease free after more than ten years of follow-up. Conclusion: Primary neuroendocrine carcinomas of the breast are extremely rare. The diagnosis of SCNC of the breast can only be made if a non mammary site is excluded or if an in situ component can be found. After surgery, a strict follow-up including octreotide scan should be performed and this doesn’t differ from the one of the usual breast carcinoma.

  9. Notch signaling modulates hypoxia-induced neuroendocrine differentiation of human prostate cancer cells. (United States)

    Danza, Giovanna; Di Serio, Claudia; Rosati, Fabiana; Lonetto, Giuseppe; Sturli, Niccolò; Kacer, Doreen; Pennella, Antonio; Ventimiglia, Giuseppina; Barucci, Riccardo; Piscazzi, Annamaria; Prudovsky, Igor; Landriscina, Matteo; Marchionni, Niccolò; Tarantini, Francesca


    Prostate carcinoma is among the most common causes of cancer-related death in men, representing 15% of all male malignancies in developed countries. Neuroendocrine differentiation (NED) has been associated with tumor progression, poor prognosis, and with the androgen-independent status. Currently, no successful therapy exists for advanced, castration-resistant disease. Because hypoxia has been linked to prostate cancer progression and unfavorable outcome, we sought to determine whether hypoxia would impact the degree of neuroendocrine differentiation of prostate cancer cells in vitro. Exposure of LNCaP cells to low oxygen tension induced a neuroendocrine phenotype, associated with an increased expression of the transcription factor neurogenin3 and neuroendocrine markers, such as neuron-specific enolase, chromogranin A, and β3-tubulin. Moreover, hypoxia triggered a significant decrease of Notch 1 and Notch 2 mRNA and protein expression, with subsequent downregulation of Notch-mediated signaling, as shown by reduced levels of the Notch target genes, Hes1 and Hey1. NED was promoted by attenuation of Hes1 transcription, as cells expressing a dominant-negative form of Hes1 displayed increased levels of neuroendocrine markers under normoxic conditions. Although hypoxia downregulated Notch 1 and Notch 2 mRNA transcription and receptor activation also in the androgen-independent cell lines, PC-3 and Du145, it did not change the extent of NED in these cultures, suggesting that androgen sensitivity may be required for transdifferentiation to occur. Hypoxia induces NED of LNCaP cells in vitro, which seems to be driven by the inhibition of Notch signaling with subsequent downregulation of Hes1 transcription. ©2011 AACR.

  10. Cutaneous squamous and neuroendocrine carcinoma: genetically and immunohistochemically different from Merkel cell carcinoma (United States)

    Pulitzer, Melissa P; Brannon, A Rose; Berger, Michael F; Louis, Peter; Scott, Sasinya N; Jungbluth, Achim A; Coit, Daniel G; Brownell, Isaac; Busam, Klaus J


    Cutaneous neuroendocrine (Merkel cell) carcinoma most often arises de novo in the background of a clonally integrated virus, the Merkel cell polyomavirus, and is notable for positive expression of retinoblastoma 1 (RB1) protein and low expression of p53 compared with the rare Merkel cell polyomavirus-negative Merkel cell carcinomas. Combined squamous and Merkel cell tumors are consistently negative for Merkel cell polyomavirus. Little is known about their immunophenotypic or molecular profile. Herein, we studied 10 combined cutaneous squamous cell and neuroendocrine carcinomas for immunohistochemical expression of p53, retinoblastoma 1 protein, neurofilament, p63, and cytokeratin 20 (CK20). We compared mutation profiles of five combined Merkel cell carcinomas and seven ‘pure’ Merkel cell carcinomas using targeted next-generation sequencing. Combined tumors were from the head, trunk, and leg of Caucasian males and one female aged 52–89. All cases were highly p53- and p63-positive and neurofilament-negative in the squamous component, whereas RB1-negative in both components. Eight out of 10 were p53-positive, 3/10 p63-positive, and 3/10 focally neurofilament-positive in the neuroendocrine component. Six out of 10 were CK20-positive in any part. By next-generation sequencing, combined tumors were highly mutated, with an average of 48 mutations per megabase compared with pure tumors, which showed 1.25 mutations per megabase. RB1 and p53 mutations were identified in all five combined tumors. Combined tumors represent an immunophenotypically and genetically distinct variant of primary cutaneous neuroendocrine carcinomas, notable for a highly mutated genetic profile, significant p53 expression and/or mutation, absent RB1 expression in the context of increased RB1 mutation, and minimal neurofilament expression. PMID:26022453

  11. Expression of developing neural transcription factors in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). (United States)

    Escudero, Antonio García; Zarco, Enrique Rodríguez; Arjona, Juan Carlos Girón; Moreno, María José Ríos; Rodríguez, Katherine Gallardo; Benítez, Ana Vallejo; Cámpora, Ricardo González


    DIPNECH is characterized by neuroendocrine cell hyperplasia, tumorlets, and eventually carcinoid tumors. Although it is regarded by some authors as a preneoplastic condition, this issue is controversial. New pathologic criteria have recently been proposed for the diagnosis of DIPNECH, and a subgroup of carcinoid tumors expressing developing neural transcription factors (DNTFs), with clinicopathologic features similar to those of DIPNECH, has been recognized. This paper reports on the clinical and pathological findings in three cases of DIPNECH and investigates the expression of three DNTFs (TTF1, ASCL1, and POU3F2). All patients were female, with a mean age of 63 years, and all lesions were located in the periphery of the lung. In two cases, typical carcinoids were associated with a spindle-cell component. All neuroendocrine proliferations were DNTF positive. The morphologic (spindle-cell component), phenotypic (DNTF expression), and clinicopathologic (peripheral tumors, female predominance) similarities suggest that DIPNECH may be a preneoplastic lesion for peripheral carcinoids.

  12. Intravenous injection of Evans Blue labels magnocellular neuroendocrine cells of the rat supraoptic nucleus in situ and after dissociation. (United States)

    Weiss, M L; Cobbett, P


    Previous work has demonstrated that intravenous injection of neuronal tracers, e.g. horseradish peroxidase or Fast Blue, can retrogradely label neurons in brain areas that project outside the blood-brain barrier, e.g. magnocellular neuroendocrine neurons of the hypothalamus. Here we have shown that 24 h after intravenous injection of the fluorescent retrograde tracer Evans Blue, the same population of magnocellular neuroendocrine neurons is labeled in the paraventricular, supraoptic and accessory magnocellular nuclei. Parvicellular neuroendocrine cells in the paraventricular nuclei are also labeled. Most Evans Blue-labeled magnocellular neuroendocrine cells in the supraoptic nucleus could be stained immunocytochemically for neurophysins, suggesting that these neurons continue to produce their peptide hormones after taking up the fluorescent dye. Ultrastructural observation of supraoptic cells retrogradely labeled with Evans Blue shows that 95% of the neurons appeared healthy. There was no ultrastructural evidence of degeneration, hyperstimulation, or interruption of the axoplasmic flow. Labeling the neuroendocrine cells with Evans Blue did not alter the size of magnocellular cells, the animal's fluid balance or ingestive behavior. Following enzymatic/mechanical dissociation of the supraoptic nucleus from animals that had been injected with Evans Blue 24 h previously, phase-bright neurons that often contained fluorescent material were observed, thus identifying these neurons as neuroendocrine. Recording from identified neuroendocrine cells showed that these neurons generated spontaneous or current-evoked overshooting action potentials with an afterhyperpolarization and had negative resting membrane potentials. Action potential broadening, a feature of magnocellular neurons, was observed during bursts of action potentials elicited by depolarizing current injection. Taken together, this work would suggest that Evans Blue is non-toxic at the doses used and that it

  13. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia diagnosed by tranbronchoscopic cryoprobe biopsy technique


    Patel, Ravi; Collazo‐Gonzalez, Carolina; Andrews, Arthur; Johnson, Jean; Rumbak, Mark; Smith, Maxwell


    Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) remains a poorly understood clinical entity. It is currently classified as a premalignant condition by the World Health Organization (WHO). Symptoms are similar to those associated with obstructive lung disease, including breathlessness and cough. The presentation is often initially ascribed to other diseases such as asthma or chronic obstructive pulmonary disease. Here, we present what we believe is the first described ca...

  14. Primary small cell neuroendocrine carcinoma of the breast: The histogenetic diatribe

    Directory of Open Access Journals (Sweden)

    Cabibi D


    Full Text Available The article entitled “Primary small cell neuroendocrine carcinoma of the breast: a report of two cases and review of the literature” by Spinelli et al. [1]. The authors stated that “the histogenesis is still unclear because the presence of neuroendocrine cells in normal breast has not been proved conclusively”. Moreover they reported two histogenetic hypotheses, the first one stating that “small cell neuroendocrine carcinoma (SCNC is a variant of metaplastic carcinoma arising from a lobular or ductal carcinoma”, the second one claiming that “it is a distinct type of breast carcinoma different from the usual type”. We appreciate this case report and we agree with the authors on the histogenetic diatribe of this rare type of breast neoplasia. In this background, we would highlight our previous case report about a solid variant of mammary adenoid cystic carcinoma merging with "small cell carcinoma" [2] in which we found positivity for CD10 and S100 and negativity for estrogen receptors, both in sbACC and in SCC, in keeping with a myoepithelial origin of both neoplastic areas [3] supporting the hypothesis that the “two components share the same histogenetic myoepithelial origin and represent an example of dedifferentiation along neuroendocrine phenotype lines occurring in a multipotential neoplastic stem line, already committed towards a myoepithelial phenotype”. These findings are in keeping with the first hypothesis about the metaplastic, divergent histogenetic nature of SNSC and we think that this rare SNSC, albeit arising from a different tumor, could be introduced in this case review of the literature, also for its contribute to the histogenetic diatribe.

  15. INSL5 may be a unique marker of colorectal endocrine cells and neuroendocrine tumors

    Energy Technology Data Exchange (ETDEWEB)

    Mashima, Hirosato, E-mail: [Department of Gastroenterology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543 (Japan); Ohno, Hideki [Division of Advanced Medical Science, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 (Japan); Yamada, Yumi; Sakai, Toshitaka; Ohnishi, Hirohide [Department of Gastroenterology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543 (Japan)


    Highlights: ► INSL5 is expressed in enteroendocrine cells along the colorectum. ► INSL5 is expressed increasingly from proximal colon to rectum. ► INSL5 co-localizes rarely with chromogranin A. ► All rectal neuroendocrine tumors examined expressed INSL5. -- Abstract: Insulin-like peptide 5 (INSL5) is a member of the insulin superfamily, and is a potent agonist for RXFP4. We have shown that INSL5 is expressed in enteroendocrine cells (EECs) along the colorectum with a gradient increase toward the rectum. RXFP4 is ubiquitously expressed along the digestive tract. INSL5-positive EECs have little immunoreactivity to chromogranin A (CgA) and might be a unique marker of colorectal EECs. CgA-positive EECs were distributed normally along the colorectum in INSL5 null mice, suggesting that INSL5 is not required for the development of CgA-positive EECs. Exogenous INSL5 did not affect the proliferation of human colon cancer cell lines, and chemically-induced colitis in INSL5 null mice did not show any significant changes in inflammation or mucosal healing compared to wild-type mice. In contrast, all of the rectal neuroendocrine tumors examined co-expressed INSL5 and RXFP4. INSL5 may be a unique marker of colorectal EECs, and INSL5–RXFP4 signaling might play a role in an autocrine/paracrine fashion in the colorectal epithelium and rectal neuroendocrine tumors.

  16. Chromophobe renal cell carcinoma with neuroendocrine differentiation/morphology: A clinicopathological and genetic study of three cases

    Directory of Open Access Journals (Sweden)

    Chisato Ohe, MD


    Full Text Available Chromophobe renal cell carcinoma (ChRCC with neuroendocrine differentiation/morphology (NED/NEM is exceedingly rare. We present three cases of ChRCC with NED/NEM, two of which showed positivity for neuroendocrine markers on immunohistochemical analysis. Patients ranged in age from 49 to 79 years (mean: 64.3 years. One of the three patients died of metastatic disease to multiple organs. Of the remaining two patients, one is currently alive without disease and the other is alive with disease. Histologically, all three tumors were composed of conventional ChRCC and NEM showed glandular and rosette formation. Immunohistochemically, tumor cells were positive for CK7, KAI1, E-cadherin, and c-kit in both ChRCC and neuroendocrine areas in three cases. CD56 and synaptophysin immunoreactivity were detected in two cases; in only the neuroendocrine area in one case and in both components in the other. Neuroendocrine granules were ultrastructurally observed at both neuroendocrine and conventional areas of ChRCC. Array comparative genomic hybridization (CGH study indicated losses of chromosomes 1, 2, 6, 10, 17, 21, and Y in both conventional ChRCC and NED in one case. In addition, losses of chromosomes 1, 2, 4, 6, 9, 10, 13, 16p, 17, and 21 were observed in both components of the remaining one tumor. Furthermore, loss of chromosome 5 was identified only in the neuroendocrine area in this case. We concluded that the neuroendocrine area may reflect dedifferentiation within ChRCC. It is possible that losses of chromosomes 4, 5, and 16p may be involved in the neuroendocrine differentiation or progression of ChRCC.

  17. A case of large cell neuroendocrine carcinoma of the bladder with prolonged spontaneous remission. (United States)

    Chong, Vincent; Zwi, Jonathan; Hanning, Fritha; Lim, Remy; Williams, Andrew; Cadwallader, Jon


    Large cell neuroendocrine carcinoma (LCNEC) of the urinary bladder are rare. We present a case of a 72-year-old man who presented with back pain and acute renal failure. Ultrasound showed a soft tissue mass in the base of the bladder causing bilateral ureteric obstruction. Subsequent biopsy of this mass demonstrated neuroendocrine carcinoma. He was commenced on neoadjuvant chemotherapy (carboplatin/etoposide) and proceeded to a radical cysto-prostatectomy. Histology revealed a LCNEC involving the bladder, T4a with invasion through to adipose tissue and posteriorly at perivesical resection margins. In addition, there was a Gleason score 9 prostatic adenocarcinoma, distinct from the neuroendocrine carcinoma. Following surgery, the patient developed gross local-regional recurrence and refused further systemic therapy. However, 1 year following referral to palliative care, a further CT-PET showed complete spontaneous remission of his disease. There are only few case reports of LCNEC of the urinary bladder therefore the pathogenesis and treatment protocol are still unclear. This case report highlights the unpredictable nature of this disease.

  18. Postembryonic proliferation of neuroendocrine cells expressing adipokinetic hormone peptides in the corpora cardiaca of the locust. (United States)

    Kirschenbaum, S R; O'Shea, M


    Neuroendocrine glands that synthesize and secrete peptide hormones regulate the levels of these peptide messengers during development. In this article we describe a mechanism for regulating neuropeptide levels in the corpora cardiaca of the locust Schistocerca gregaria, a neuroendocrine gland structurally analogous to the vertebrate adenohypophysis. A set of five colocalized peptide hormones of the adipokinetic hormone family is synthesized in intrinsic neurosecretory cells in the corpora cardiaca. During postembryonic development there are progressive changes in the absolute and relative levels of these five peptide hormones. We show that the ability of the gland to increase peptide synthesis is due to a 100-fold increase in the number of cells which make up the gland. The gland grows by the addition of new cells derived from symmetrical division of undifferentiated precursor cells within the corpora cardiaca. We show, using double-label immunocytochemistry, that cells born in the glandular lobe mature into cells that express adipokinetic hormone peptides. The pattern of cell birth and peptide expression can account for the dramatic increase in postembryonic peptide levels.

  19. Treatment Option Overview (Pancreatic Neuroendocrine Tumors / Islet Cell Tumors) (United States)

    ... Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer Leukemia Liver Cancer Lung Cancer Lymphoma Pancreatic Cancer Prostate Cancer Skin Cancer Thyroid Cancer Uterine Cancer All ...

  20. Neuroendocrine regulation of frog adrenocortical cells by neurotensin

    NARCIS (Netherlands)

    Sicard, F.; D, D.E.G.; Gras, M.; Leprince, J.; Conlon, J.M.; Roubos, E.W.; Vaudry, H.; Delarue, C.


    We previously characterized the primary structure of neurotensin (NT) from an extract of the intestine of the frog Rana esculenta. In this study, we provide evidence for the involvement of NT in the neurocrine regulation of the secretory activity of frog adrenocortical cells. Immunohistochemical

  1. Functional Implications of Neuroendocrine Differentiated Cells in Prostate Cancer

    NARCIS (Netherlands)

    J. Jongsma (Johan)


    textabstractThis thesis focuses on NE differentiation in prostate cancer, especially in prostate cancer models. We studied the effects of androgen depletion on the NE differentiated status of in vivo and in vitro prostatic tumor models. Knowledge concerning the function of NE cells in the normal

  2. Somatic currents contribute to frequency-dependent spike-broadening in supraoptic neuroendocrine cells. (United States)

    O'Regan, M H; Cobbett, P


    Voltage-gated K and Ca currents were recorded in acutely dissociated neuroendocrine cells of the supraoptic nucleus. The effect of repeated activation of the currents by trains of (10) voltage pulses over a range of pulse-repetition frequencies were examined. There was a significant reduction of K-current amplitude and a significant increase of Ca-current amplitude during trains with high repetition frequencies. Frequency-dependent changes in K and Ca conductances may contribute to frequency-dependent spike-broadening which is exhibited during bursts of action potentials generated by these neurons.

  3. The Function of Neuroendocrine Cells in Prostate Cancer (United States)


    with 10% fetal bovine serum , 2 mM L-glutamine, penicillin (100 U/ml), and streptomycin (100 mg/ml) in a humidified atmosphere of 5% CO2 maintained at 37...cells were in McCoy’s 5Amedium, and all were supplementedwith 10% fetal calf serum , 2 mM glutamine, penicillin, and streptomycin at 37 °C with 5% CO2...mortality risk and decreased serum prostate specific antigen. J Urol 2010;184:2303–7. 2. Andriole GL, Crawford ED, Grubb RL III, Buys SS, Chia D, Church TR

  4. Early life allergen-induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion. (United States)

    Barrios, Juliana; Patel, Kruti R; Aven, Linh; Achey, Rebecca; Minns, Martin S; Lee, Yoonjoo; Trinkaus-Randall, Vickery E; Ai, Xingbin


    Pulmonary neuroendocrine cells (PNECs) are the only innervated airway epithelial cells. To what extent neural innervation regulates PNEC secretion and function is unknown. Here, we discover that neurotrophin 4 (NT4) plays an essential role in mucus overproduction after early life allergen exposure by orchestrating PNEC innervation and secretion of GABA. We found that PNECs were the only cellular source of GABA in airways. In addition, PNECs expressed NT4 as a target-derived mechanism underlying PNEC innervation during development. Early life allergen exposure elevated the level of NT4 and caused PNEC hyperinnervation and nodose neuron hyperactivity. Associated with aberrant PNEC innervation, the authors discovered that GABA hypersecretion was required for the induction of mucin Muc5ac expression. In contrast, NT4-/- mice were protected from allergen-induced mucus overproduction and changes along the nerve-PNEC axis without any defects in inflammation. Last, GABA installation restored mucus overproduction in NT4-/- mice after early life allergen exposure. Together, our findings provide the first evidence for NT4-dependent neural regulation of PNEC secretion of GABA in a neonatal disease model. Targeting the nerve-PNEC axis may be a valid treatment strategy for mucus overproduction in airway diseases, such as childhood asthma.-Barrios, J., Patel, K. R., Aven, L., Achey, R., Minns, M. S., Lee, Y., Trinkaus-Randall, V. E., Ai, X. Early life allergen-induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion. © FASEB.

  5. Isoform 1 of TPD52 (PC-1) promotes neuroendocrine transdifferentiation in prostate cancer cells

    KAUST Repository

    Moritz, Tom


    The tumour protein D52 isoform 1 (PC-1), a member of the tumour protein D52 (TPD52) protein family, is androgen-regulated and prostate-specific expressed. Previous studies confirmed that PC-1 contributes to malignant progression in prostate cancer with an important role in castration-resistant stage. In the present work, we identified its impact in mechanisms leading to neuroendocrine (NE) transdifferentiation. We established for long-term PC-1 overexpression an inducible expression system derived from the prostate carcinoma cell line LNCaP. We observed that PC-1 overexpression itself initiates characteristics of neuroendocrine cells, but the effect was much more pronounced in the presence of the cytokine interleukin-6 (IL-6). Moreover, to our knowledge, this is the first report that treatment with IL-6 leads to a significant upregulation of PC-1 in LNCaP cells. Other TPD52 isoforms were not affected. Proceeding from this result, we conclude that PC-1 overexpression enhances the IL-6-mediated differentiation of LNCaP cells into a NE-like phenotype, noticeable by morphological changes and increased expression of typical NE markers, like chromogranin A, synaptophysin or beta-3 tubulin. Immunofluorescent staining of IL-6-treated PC-1-overexpressing LNCaP cells indicates a considerable PC-1 accumulation at the end of the long-branched neuron-like cell processes, which are typically formed by NE cells. Additionally, the experimentally initiated NE transdifferentiation correlates with the androgen receptor status, which was upregulated additively. In summary, our data provide evidence for an involvement of PC-1 in NE transdifferentiation, frequently associated with castration resistance, which is a major therapeutic challenge in the treatment of advanced prostate cancer.

  6. Breast metastasis and lung large-cell neuroendocrine carcinoma: first clinical observation. (United States)

    Papa, Anselmo; Rossi, Luigi; Verrico, Monica; Di Cristofano, Claudio; Moretti, Valentina; Strudel, Martina; Zoratto, Federica; Minozzi, Marina; Tomao, Silverio


    The lung large-cell neuroendocrine carcinoma (LCNEC) is a very rare aggressive neuroendocrine tumor with a high propensity to metastasize and very poor prognosis. We report an atypical presentation of lung LCNEC was diagnosed from a metastatic nodule on the breast. Our patient is a 59-years-old woman that presented in March 2014 nonproductive cough. A CT scan showed multiple brain, lung, adrenal gland and liver secondary lesions; moreover, it revealed a breast right nodule near the chest measuring 1.8 cm. The breast nodule and lung lesions were biopsied and their histology and molecular diagnosis were LCNEC of the lung. To our knowledge, this is the first documented case of breast metastasis from LCNEC of the lung. Furthermore, breast metastasis from extramammary malignancy is uncommon and its diagnosis is difficult but important for proper management and prediction of prognosis. Therefore, a careful clinical history with a thorough clinical examination is needed to make the correct diagnosis. Moreover, metastasis to the breast should be considered in any patient with a known primary malignant tumor history who presents with a breast lump. Anyhow, pathological examination should be performed to differentiate the primary breast cancer from metastatic tumor. Therefore, an accurate diagnosis of breast metastases may not only avoid unnecessary breast resection, more importantly it is crucial to determine an appropriate and systemic treatment. © 2015 John Wiley & Sons Ltd.

  7. Atypical carcinoid and large cell neuroendocrine carcinoma of the lung: a proteomic dataset from formalin-fixed archival samples

    Directory of Open Access Journals (Sweden)

    Alessandro Tanca


    Full Text Available Here we present a dataset generated using formalin-fixed paraffin-embedded archival samples from two rare lung neuroendocrine tumor subtypes (namely, two atypical carcinoids, ACs, and two large-cell neuroendocrine carcinomas, LCNECs. Samples were subjected to a shotgun proteomics pipeline, comprising full-length protein extraction, SDS removal through spin columns, in solution trypsin digestion, long gradient liquid chromatography peptide separation and LTQ-Orbitrap mass spectrometry analysis. A total of 1260 and 2436 proteins were identified in the AC and LCNEC samples, respectively, with FDR <1%. MS data are available in the PeptideAtlas repository at


    NARCIS (Netherlands)



    The current study describes the presence of neuroendocrine antigens of peripheral and central neural tumors using eight monoclonal antibodies raised to small cell lung carcinoma (SCLC), which recognize "neural/neuroendocrine" or "neural" antigens, as defined by their reaction pattern in normal

  9. Annual gonadal cycles in birds: modeling the effects of photoperiod on seasonal changes in GnRH-1 secretion. (United States)

    Dawson, Alistair


    This paper reviews current knowledge of photoperiod control of GnRH-1 secretion and proposes a model in which two processes act together to regulate GnRH1 secretion. Photo-induction controls GnRH1 secretion and is directly related to prevailing photoperiod. Photo-inhibition, a longer term process, acts through GnRH1 synthesis. It progresses each day during daylight hours, but reverses during darkness. Thus, photo-inhibition gradually increases when photoperiods exceed 12h, and reverses under shorter photoperiods. GnRH1 secretion on any particular day is the net result of these two processes acting in tandem. The only difference between species is their sensitivity to photo-inhibition. This can potentially explain differences in timing and duration of breeding seasons between species, why some species become absolutely photorefractory and others relatively photorefractory, why breeding seasons end at the same time at different latitudes within species, and why experimental protocols sometimes produce results that appear counter to what happens naturally. Copyright © 2014 The Author. Published by Elsevier Inc. All rights reserved.

  10. Benign Endometrial Polyp and Primary Endometrial Small Cell Neuroendocrine Carcinoma Confined to the Polyp: A Rare Association

    Directory of Open Access Journals (Sweden)

    Pembe Oltulu


    Full Text Available Neuroendocrine tumors (NETs are a heterogeneous group of tumoral lesions originating from diffuse endo­crine system cells. They occur mostly in the gastrointes­tinal system and the lung. Primary NETs of the female reproductive tract are rare. In a widely used classification, primary small cell neuroendocrine carcinomas (SCNECs and large cell neuroendocrine carcinomas (LCNECs of the endometrium were included in a subgroup of poorly differentiated neuroendocrine carcinomas. SCNECs of the endometrium are very rare and they are often com­bined with other epithelial neoplasms. Their myometrial and extrauterine invasions are common during the initial diagnosis due to their aggressive behaviors. In this ar­ticle, we present a rare case of primary endometrial SC­NEC detected within the benign endometrial polyp and without invasion of myometrium and extrauterine tissues in a 70-year-old female patient presenting with post­menopausal bleeding. Histopathologically, the tumor cells showed positive staining with Synaptophysin, the Ki-67 labeling index was 80-90%, the mitotic index was 15/10 per HPF and there was no necrosis and lymphovascular invasion. J Clin Exp Invest 2016; 7 (1: 107-110

  11. Gene expression signatures of neuroendocrine prostate cancer and primary small cell prostatic carcinoma. (United States)

    Tsai, Harrison K; Lehrer, Jonathan; Alshalalfa, Mohammed; Erho, Nicholas; Davicioni, Elai; Lotan, Tamara L


    Neuroendocrine prostate cancer (NEPC) may be rising in prevalence as patients with advanced prostate cancer potentially develop resistance to contemporary anti-androgen treatment through a neuroendocrine phenotype. While prior studies comparing NEPC and prostatic adenocarcinoma have identified important candidates for targeted therapy, most have relied on few NEPC patients due to disease rarity, resulting in thousands of differentially expressed genes collectively and offering an opportunity for meta-analysis. Moreover, past studies have focused on prototypical NEPC samples with classic immunohistochemistry profiles, whereas there is increasing recognition of atypical phenotypes. In the primary setting, small cell prostatic carcinoma (SCPC) is frequently admixed with adenocarcinomas that may be clonally related, and a minority of SCPCs express markers typical of prostatic adenocarcinoma while rare cases do not express neuroendocrine markers. We derived a meta-signature of prototypical high-grade NEPC, then applied it to develop a classifier of primary SCPC incorporating disease heterogeneity. Prototypical NEPC samples from 15 patients across 6 frozen tissue microarray datasets were assessed for genes with consistent outlier expression relative to adenocarcinomas. Resulting genes were used to determine subgroups of primary SCPCs (N=16) and high-grade adenocarcinomas (N=16) profiled by exon arrays using formalin-fixed paraffin-embedded (FFPE) material from our institutional archives. A subgroup classifier was developed using differential expression for feature selection, and applied to radical prostatectomy cohorts. Sixty nine and 375 genes demonstrated consistent outlier expression in at least 80% and 60% of NEPC patients, with close resemblance in expression between NEPC and small cell lung cancer. Clustering by these genes generated 3 subgroups among primary samples from our institution. Nearest centroid classification based on the predominant phenotype from each

  12. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia diagnosed by tranbronchoscopic cryoprobe biopsy technique (United States)

    Patel, Ravi; Collazo‐Gonzalez, Carolina; Johnson, Jean; Rumbak, Mark; Smith, Maxwell


    Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) remains a poorly understood clinical entity. It is currently classified as a premalignant condition by the World Health Organization (WHO). Symptoms are similar to those associated with obstructive lung disease, including breathlessness and cough. The presentation is often initially ascribed to other diseases such as asthma or chronic obstructive pulmonary disease. Here, we present what we believe is the first described case of DIPNECH diagnosed by transbronchoscopic cryoprobe biopsy. The patient presented with chronic cough, dyspnoea, pulmonary function tests consistent with obstruction, and a computed tomography (CT) scan of chest with multiple nodules. The patient went on to have transbronchoscopic cryoprobe biopsies of the lung, which confirmed the diagnosis of DIPNECH. PMID:29026608

  13. Voltage-clamp recordings from identified dissociated neuroendocrine cells of the adult rat supraoptic nucleus. (United States)

    Cobbett, P; Weiss, M L


    In vitro intracellular recordings of membrane potential obtained from the oxytocin and vasopressin neurons of the mammalian hypothalamo-neurohypophysial system in slices (1-3) and expiants (4, 5) have demonstrated many of the intrinsic properties of these magnocellular neuroendocrine cells (MNCs). Voltage-clamp techniques, which are required to study directly the currents underlying intrinsic or transmitter-evoked potential changes, have been applied to cultured embryonic (6) or neonatal supraoptic neurons (7-9) and have been successfully applied to adult supraoptic neurons in situ in only one laboratory (10, 11). We have modified a technique for dissociation of viable adult guineapig hippocampal neurons (12) to dissociate supraoptic MNCs from adult rats for voltage-clamp studies. MNCs were selectively labelled with a fluorescent dye in vivo so that they could be identified after dissociation and prior to making recordings. These data have been published in abstract form elsewhere (13, 14).

  14. Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia of the Lung (DIPNECH): Current Best Evidence. (United States)

    Wirtschafter, Eric; Walts, Ann E; Liu, Sandy T; Marchevsky, Alberto M


    Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is recognized as a preneoplastic condition by the World Health Organization. We reviewed our experience with 30 patients and performed a systematic review of the English literature to collect best evidence on the clinical features and disease course in 169 additional patients. Some patients presented with one or more carcinoid tumors associated with multiple small pulmonary nodules on imaging studies and showed DIPNECH as a somewhat unexpected pathologic finding. Others presented with multiple small pulmonary nodules that raised suspicion of metastatic disease on imaging. A third subset was presented with previously unexplained respiratory symptoms. In most patients, DIPNECH was associated with a good prognosis, with chronological progression into a subsequent carcinoid tumor noted in only one patient and death attributed directly to DIPNECH in only two patients. There is no best evidence to support the use of octreotide, steroids, or bronchodilators in DIPNECH patients.

  15. Specification of Drosophila corpora cardiaca neuroendocrine cells from mesoderm is regulated by Notch signaling.

    Directory of Open Access Journals (Sweden)

    Sangbin Park


    Full Text Available Drosophila neuroendocrine cells comprising the corpora cardiaca (CC are essential for systemic glucose regulation and represent functional orthologues of vertebrate pancreatic α-cells. Although Drosophila CC cells have been regarded as developmental orthologues of pituitary gland, the genetic regulation of CC development is poorly understood. From a genetic screen, we identified multiple novel regulators of CC development, including Notch signaling factors. Our studies demonstrate that the disruption of Notch signaling can lead to the expansion of CC cells. Live imaging demonstrates localized emergence of extra precursor cells as the basis of CC expansion in Notch mutants. Contrary to a recent report, we unexpectedly found that CC cells originate from head mesoderm. We show that Tinman expression in head mesoderm is regulated by Notch signaling and that the combination of Daughterless and Tinman is sufficient for ectopic CC specification in mesoderm. Understanding the cellular, genetic, signaling, and transcriptional basis of CC cell specification and expansion should accelerate discovery of molecular mechanisms regulating ontogeny of organs that control metabolism.

  16. Specification of Drosophila corpora cardiaca neuroendocrine cells from mesoderm is regulated by Notch signaling. (United States)

    Park, Sangbin; Bustamante, Erika L; Antonova, Julie; McLean, Graeme W; Kim, Seung K


    Drosophila neuroendocrine cells comprising the corpora cardiaca (CC) are essential for systemic glucose regulation and represent functional orthologues of vertebrate pancreatic α-cells. Although Drosophila CC cells have been regarded as developmental orthologues of pituitary gland, the genetic regulation of CC development is poorly understood. From a genetic screen, we identified multiple novel regulators of CC development, including Notch signaling factors. Our studies demonstrate that the disruption of Notch signaling can lead to the expansion of CC cells. Live imaging demonstrates localized emergence of extra precursor cells as the basis of CC expansion in Notch mutants. Contrary to a recent report, we unexpectedly found that CC cells originate from head mesoderm. We show that Tinman expression in head mesoderm is regulated by Notch signaling and that the combination of Daughterless and Tinman is sufficient for ectopic CC specification in mesoderm. Understanding the cellular, genetic, signaling, and transcriptional basis of CC cell specification and expansion should accelerate discovery of molecular mechanisms regulating ontogeny of organs that control metabolism.

  17. Neuroendocrine Tumors of the Lung

    Energy Technology Data Exchange (ETDEWEB)

    Fisseler-Eckhoff, Annette, E-mail:; Demes, Melanie [Department of Pathology und Cytology, Dr. Horst-Schmidt-Kliniken (HSK), Wiesbaden 65199 (Germany)


    Neuroendocrine tumors may develop throughout the human body with the majority being found in the gastrointestinal tract and bronchopulmonary system. Neuroendocrine tumors are classified according to the grade of biological aggressiveness (G1–G3) and the extent of differentiation (well-differentiated/poorly-differentiated). The well-differentiated neoplasms comprise typical (G1) and atypical (G2) carcinoids. Large cell neuroendocrine carcinomas as well as small cell carcinomas (G3) are poorly-differentiated. The identification and differentiation of atypical from typical carcinoids or large cell neuroendocrine carcinomas and small cell carcinomas is essential for treatment options and prognosis. Pulmonary neuroendocrine tumors are characterized according to the proportion of necrosis, the mitotic activity, palisading, rosette-like structure, trabecular pattern and organoid nesting. The given information about the histopathological assessment, classification, prognosis, genetic aberration as well as treatment options of pulmonary neuroendocrine tumors are based on own experiences and reviewing the current literature available. Most disagreements among the classification of neuroendocrine tumor entities exist in the identification of typical versus atypical carcinoids, atypical versus large cell neuroendocrine carcinomas and large cell neuroendocrine carcinomas versus small cell carcinomas. Additionally, the classification is restricted in terms of limited specificity of immunohistochemical markers and possible artifacts in small biopsies which can be compressed in cytological specimens. Until now, pulmonary neuroendocrine tumors have been increasing in incidence. As compared to NSCLCs, only little research has been done with respect to new molecular targets as well as improving the classification and differential diagnosis of neuroendocrine tumors of the lung.

  18. [Inhibitory effects of Notch1 overexpression on proliferation and neuroendocrine marker expression in a small cell lung cancer cell line]. (United States)

    Wang, Jie-Xin; Zhang, Xiu-ming; Wang, Ling-ling; Cheng, Hui; Yao, Gen-you


    To investigate the effects of Notch1 signal activation on proliferation and neuroendocrine marker expression in small cell lung cancer cells. The active form of Notch1 (NIC) was over-expressed in NCI-H446 cells by constitutive transfection and a stable transfected cell line was established. Proliferation of NCI-H446 cells was analysed by MTT assay on 6 successive days. Expression of neuroendocrine markers (CgA, NSE) was observed by immunohistochemistry and Western blot analysis. Statistical analysis was conducted to compare the results in cells with NIC transfected and those in control groups. MTT assay showed that absorbance (A) of cells overexpressing Notch1 was significantly depressed compared with that of the control cells (PNIC transfected group, sham group and negative control group were 8.81 +/- 0.77, 38.10 +/- 1.55, 38.97 +/- 0.80, respectively, the former one was significantly smaller than that of the latter two (PNIC transfected group, sham group and negative control group were 7.21 +/- 0.59, 28.25 +/- 1.46, 30.57 +/- 1.31, respectively, the former one was significantly smaller than that in the latter two (PNIC transfected group and sham group were 0.54 +/- 0.03 and 0.99 +/- 0.05, respectively, (gray scale of the negative control set as 1.00), the former one was significantly smaller than that of the other two groups (PNIC transfected group and sham group were 0.43 +/- 0.02 and 1.07 +/- 0.09, respectively (gray scale of the negative control set as 1.00), the former one was significantly smaller than that of the other two groups (P<0.01). Notch1 may behave as a tumor suppressor in small cell lung cancer. Notch1 signal activation can inhibit the proliferation and neuroendocrine marker expression in small cell lung cancer cells, suggesting that Notch1 gene could be a new target for small cell lung cancer treatment and probable relief of paraneoplastic syndrome.

  19. Acute damage by naphthalene triggers expression of the neuroendocrine marker PGP9.5 in airway epithelial cells

    DEFF Research Database (Denmark)

    Poulsen, T.T.; Naizhen, X.; Linnoila, R.I.


    Protein Gene Product 9.5 (PGP9.5) is highly expressed in nervous tissue. Recently PGP9.5 expression has been found to be upregulated in the pulmonary epithelium of smokers and in non-small cell lung cancer, suggesting that it also plays a role in carcinogen-inflicted lung epithelial injury...... neuroendocrine markers was found in the non-neuroendocrine epithelial cells after naphthalene exposure. In contrast, immunostaining for the cell cycle regulator p27(Kip1), which has previously been associated with PGP9.5 in lung cancer cells, revealed transient downregulation of p27(Kip1) in naphthalene exposed...... and further strengthens the accumulating evidence of PGP9.5 as a central player in lung epithelial damage and early carcinogenesis Udgivelsesdato: 2008/9/26...

  20. Mixed Large Cell Neuroendocrine Carcinoma and Adenocarcinoma with Spindle Cell and Clear Cell Features in the Extrahepatic Bile Duct

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    John Wysocki


    Full Text Available Mixed adenoneuroendocrine carcinomas, spindle cell carcinomas, and clear cell carcinomas are all rare tumors in the biliary tract. We present the first case, to our knowledge, of an extrahepatic bile duct carcinoma composed of all three types. A 65-year-old man with prior cholecystectomy presented with painless jaundice, vomiting, and weight loss. CA19-9 and alpha-fetoprotein (AFP were elevated. Cholangioscopy revealed a friable mass extending from the middle of the common bile duct to the common hepatic duct. A bile duct excision was performed. Gross examination revealed a 3.6 cm intraluminal polypoid tumor. Microscopically, the tumor had foci of conventional adenocarcinoma (CK7-positive and CA19-9-postive surrounded by malignant-appearing spindle cells that were positive for cytokeratins and vimentin. Additionally, there were separate areas of large cell neuroendocrine carcinoma (LCNEC. Foci of clear cell carcinoma merged into both the LCNEC and the adenocarcinoma. Tumor invaded through the bile duct wall with extensive perineural and vascular invasion. Circumferential margins were positive. The patient’s poor performance status precluded adjuvant therapy and he died with recurrent and metastatic disease 5 months after surgery. This is consistent with the reported poor survival rates of biliary mixed adenoneuroendocrine carcinomas.

  1. Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms. (United States)

    Zitzmann, Kathrin; Vlotides, George; Brand, Stephan; Lahm, Harald; Spöttl, Gerald; Göke, Burkhard; Auernhammer, Christoph J


    The majority of neuroendocrine tumors (NETs) of the gastroenteropancreatic system show aberrant Akt activity. Several inhibitors of the phosphoinositide 3-kinase (PI(3)K)-Akt-mTOR signaling pathway are currently being evaluated in clinical phase II and III studies for the treatment of NETs with promising results. However, the molecular mechanisms and particularly the role of different Akt isoforms in NET signaling are not fully understood. In this study, we examine the effect of Akt inhibition on NET cells of heterogeneous origin. We show that the Akt inhibitor perifosine effectively inhibits Akt phosphorylation and cell viability in human pancreatic (BON1), bronchus (NCI-H727), and midgut (GOT1) NET cells. Perifosine treatment suppressed the phosphorylation of Akt downstream targets such as GSK3α/β, MDM2, and p70S6K and induced apoptosis. To further investigate the role of individual Akt isoforms for NET cell function, we specifically blocked Akt1, Akt2, and Akt3 via siRNA transfection. In contrast to Akt2 knockdown, knockdown of Akt isoforms 1 and 3 decreased phosphorylation levels of GSK3α/β, MDM2, and p70S6K and suppressed NET cell viability and colony-forming capacity. The inhibitory effect of simultaneous downregulation of Akt1 and Akt3 on tumor cell viability was significantly stronger than that caused by downregulation of all Akt isoforms, suggesting a particular role for Akt1 and Akt3 in NET signaling. Akt3 siRNA-induced apoptosis while all three isoform-specific siRNAs impaired BON1 cell invasion. Together, our data demonstrate potent antitumor effects of the pan-Akt inhibitor perifosine on NET cells in vitro and suggest that selective targeting of Akt1 and/or Akt3 might improve the therapeutic potential of Akt inhibition in NET disease.

  2. Public speaking stress-induced neuroendocrine responses and circulating immune cell redistribution in irritable bowel syndrome. (United States)

    Elsenbruch, Sigrid; Lucas, Ayscha; Holtmann, Gerald; Haag, Sebastian; Gerken, Guido; Riemenschneider, Natalie; Langhorst, Jost; Kavelaars, Annemieke; Heijnen, Cobi J; Schedlowski, Manfred


    Augmented neuroendocrine stress responses and altered immune functions may play a role in the manifestation of functional gastrointestinal (GI) disorders. We tested the hypothesis that IBS patients would demonstrate enhanced psychological and endocrine responses, as well as altered stress-induced redistribution of circulating leukocytes and lymphocytes, in response to an acute psychosocial stressor when compared with healthy controls. Responses to public speaking stress were analyzed in N = 17 IBS patients without concurrent psychiatric conditions and N = 12 healthy controls. At baseline, immediately following public speaking, and after a recovery period, state anxiety, acute GI symptoms, cardiovascular responses, serum cortisol and plasma adrenocorticotropic hormone (ACTH) were measured, and numbers of circulating leukocytes and lymphocyte subpopulations were analyzed by flow cytometry. Public speaking led to significant cardiovascular activation, a significant increase in ACTH, and a redistribution of circulating leukocytes and lymphocyte subpopulations, including significant increases in natural killer cells and cytotoxic/suppressor T cells. IBS patients demonstrated significantly greater state anxiety both at baseline and following public speaking. However, cardiovascular and endocrine responses, as well as the redistribution of circulating leukocytes and lymphocyte subpopulations after public speaking stress, did not differ for IBS patients compared with controls. In IBS patients without psychiatric comorbidity, the endocrine response as well as the circulation pattern of leukocyte subpopulations to acute psychosocial stress do not differ from healthy controls in spite of enhanced emotional responses. Future studies should discern the role of psychopathology in psychological and biological stress responses in IBS.


    African Journals Online (AJOL)

    INTRODUCTION. Neuroendocrine tumors comprise heterogeneous group of neoplasms which originate from endocrine cells, both within endocrine organs and within the cells of diffuse endocrine system. These tumors have vari- able clinical behavior ranging from well-differentiated, slow growing tumors to ...

  4. Clinical analysis of 50 Eastern Asian patients with primary pulmonary large-cell neuroendocrine carcinoma

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    Zhang XK


    Full Text Available Xin-ke Zhang,1,* Tao Qin,1,* Yin-duo Zeng,1,2,* Yuan-yuan Zhao,1 Xue Hou,1 Wen-feng Fang,1 Shao-dong Hong,1 Ting Zhou,1 Zhi-huang Hu,1 Yun-peng Yang,1 Yu-xiang Ma,1 Cong Xue,1 Yan Huang,1 Hong-yun Zhao,1 Li Zhang1 1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 2Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Background: To understand the clinicopathological features of patients with primary pulmonary large-cell neuroendocrine carcinoma (LCNEC, including the frequency of epidermal growth factor receptor (EGFR mutation, and to explore prognostic factors.Methods: We investigated a cohort of 50 individuals from our center database who were diagnosed with operable pulmonary LCNEC and treated in Sun Yat-sen University Cancer Center. Serum albumin (ALB and neuron-specific enolase (NSE were also collected. Survival curves were obtained with the Kaplan–Meier method, and the differences between groups in survival were tested by the log-rank test.Results: The median age was 59 years (range, 40–80 years. Fourteen patients underwent mutational analysis of EGFR; of these, 12 had wild-type EGFR and the remaining two had EGFR mutations in exons. The median disease-free survival (DFS of pulmonary LCNEC was 49.3 months and that of overall survival (OS was not reached. DFS and OS were shorter for patients with decreased serum ALB than for patients with normal serum ALB (P=0.003 and P=0.004, respectively. Meanwhile, a high level of NSE was also significantly associated with short DFS and OS (P=0.005 and P=0.000, respectively. Multivariate analysis showed that decrease in serum ALB was an independent prognostic factor for OS (P=0.046.Conclusion: The frequency of EGFR mutation in LCNEC patients is low. Serum ALB and NSE levels are

  5. Oligophrenin-1 Connects Exocytotic Fusion to Compensatory Endocytosis in Neuroendocrine Cells. (United States)

    Houy, Sébastien; Estay-Ahumada, Catherine; Croisé, Pauline; Calco, Valérie; Haeberlé, Anne-Marie; Bailly, Yannick; Billuart, Pierre; Vitale, Nicolas; Bader, Marie-France; Ory, Stéphane; Gasman, Stéphane


    Oligophrenin-1 (OPHN1) is a protein with multiple domains including a Rho family GTPase-activating (Rho-GAP) domain, and a Bin-Amphiphysin-Rvs (BAR) domain. Involved in X-linked intellectual disability, OPHN1 has been reported to control several synaptic functions, including synaptic plasticity, synaptic vesicle trafficking, and endocytosis. In neuroendocrine cells, hormones and neuropeptides stored in large dense core vesicles (secretory granules) are released through calcium-regulated exocytosis, a process that is tightly coupled to compensatory endocytosis, allowing secretory granule recycling. We show here that OPHN1 is expressed and mainly localized at the plasma membrane and in the cytosol in chromaffin cells from adrenal medulla. Using carbon fiber amperometry, we found that exocytosis is impaired at the late stage of membrane fusion in Ophn1 knock-out mice and OPHN1-silenced bovine chromaffin cells. Experiments performed with ectopically expressed OPHN1 mutants indicate that OPHN1 requires its Rho-GAP domain to control fusion pore dynamics. On the other hand, compensatory endocytosis assessed by measuring dopamine-β-hydroxylase (secretory granule membrane) internalization is severely inhibited in Ophn1 knock-out chromaffin cells. This inhibitory effect is mimicked by the expression of a truncated OPHN1 mutant lacking the BAR domain, demonstrating that the BAR domain implicates OPHN1 in granule membrane recapture after exocytosis. These findings reveal for the first time that OPHN1 is a bifunctional protein that is able, through distinct mechanisms, to regulate and most likely link exocytosis to compensatory endocytosis in chromaffin cells. Copyright © 2015 the authors 0270-6474/15/3511045-11$15.00/0.

  6. Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD. (United States)

    Cortez, Eliane; Gladh, Hanna; Braun, Sebastian; Bocci, Matteo; Cordero, Eugenia; Björkström, Niklas K; Miyazaki, Hideki; Michael, Iacovos P; Eriksson, Ulf; Folestad, Erika; Pietras, Kristian


    Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis.

  7. An Extremely Rare Case of Advanced Metastatic Small Cell Neuroendocrine Carcinoma of Sinonasal Tract

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    Yu Yu Thar


    Full Text Available Small cell neuroendocrine carcinoma (SNEC is a rare form of malignancy. It mainly presents as bronchogenic neoplasm, and the extrapulmonary form accounts for only 0.1% to 0.4% of all cancers. These extrapulmonary tumors have been described most frequently in the urinary bladder, prostate, esophagus, stomach, colon and rectum, gall bladder, head and neck, cervix, and skin. Primary SNEC of the sinonasal tract is extremely rare with only less than 100 cases reported in the literature. Because of extreme rarity and aggressiveness of the tumor, the management for this entity varies considerably mandating multimodality approach. In this paper, we report a patient presented with left-sided facial swelling, and the histopathologic examination confirmed primary SNEC of left sinonasal tract. The tumor involved multiple paranasal sinuses with invasion into the left orbit and left infratemporal fossa and metastasized to cervical lymph nodes and bone. The patient encountered devastating outcome in spite of optimal medical management and treatment with palliative chemotherapy highlighting the necessity for further research of primary SNEC of head and neck.

  8. Pancreatic neuroendocrine cell tumor secreting parathyroid hormone-related protein and gastrin: Report of a case. (United States)

    Morita, Yoshifumi; Suzuki, Shohachi; Sakaguchi, Takanori; Oishi, Kosuke; Suzuki, Atsushi; Fukumoto, Kazuhiko; Inaba, Keisuke; Baba, Satoshi; Takehara, Yasuo; Konno, Hiroyuki


    This report presents a case of pancreatic neuroendocrine cell carcinoma with multiple liver metastases secreting gastrin and parathyroid hormone-related protein (PTHrP) related to lumbar bone fracture and hypercalcemia. A 58-year-old woman visited an affiliated hospital with a chief complaint of lumbago without any evidence of trauma. She was diagnosed with hepatic dysfunction and hypercalcemia as well as multiple lumbar compression fractures without osteolytic lesions. Abdominal computed tomography (CT) showed a hypervascular mass in the pancreatic tail and multiple liver tumors. Duodenal ulcers were found with gastrointestinal endoscopy. There was a marked increase in the serum gastrin level. She was diagnosed as gastrinoma with multiple liver metastases and was admitted to the hospital. She had an increase in serum PTHrP level without the elevation of intact parathyroid hormone at the time of admission. She underwent an extended right hepatectomy in addition to a distal pancreatectomy with a regional lymphadenectomy and splenectomy. The postoperative course was uneventful, and serum gastrin and PTHrP activities reduced to normal levels. She remained symptom-free, and serum calcium, gastrin, and PTHrP levels remain within the normal ranges 19 months after surgery without adjuvant therapy.

  9. Wnt-11 promotes neuroendocrine-like differentiation, survival and migration of prostate cancer cells

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    Diez Soraya


    Full Text Available Abstract Background Wnt-11 is a secreted protein that modulates cell growth, differentiation and morphogenesis during development. We previously reported that Wnt-11 expression is elevated in hormone-independent prostate cancer and that the progression of prostate cancer from androgen-dependent to androgen-independent proliferation correlates with a loss of mutual inhibition between Wnt-11- and androgen receptor-dependent signals. However, the prevalence of increased expression of Wnt-11 in patient tumours and the functions of Wnt-11 in prostate cancer cells were not known. Results Wnt-11 protein levels in prostate tumours were determined by immunohistochemical analysis of prostate tumour tissue arrays. Wnt-11 protein was elevated in 77/117 of tumours when compared with 27 benign prostatic hypertrophy specimens and was present in 4/4 bone metastases. In addition, there was a positive correlation between Wnt-11 expression and PSA levels above 10 ng/ml. Androgen-depleted LNCaP prostate cancer cells form neurites and express genes associated with neuroendocrine-like differentiation (NED, a feature of prostate tumours that have a poor prognosis. Since androgen-depletion increases expression of Wnt-11, we examined the role of Wnt-11 in NED. Ectopic expression of Wnt-11 induced expression of NSE and ASCL1, which are markers of NED, and this was prevented by inhibitors of cyclic AMP-dependent protein kinase, consistent with the known role of this kinase in NED. In contrast, Wnt-11 did not induce NSE expression in RWPE-1 cells, which are derived from benign prostate, suggesting that the role of Wnt-11 in NED is specific to prostate cancer. In addition, silencing of Wnt-11 expression in androgen-depleted LNCaP cells prevented NED and resulted in apoptosis. Silencing of Wnt-11 gene expression in androgen-independent PC3 cells also reduced expression of NSE and increased apoptosis. Finally, silencing of Wnt-11 reduced PC3 cell migration and ectopic

  10. A confocal microscopic study of solitary pulmonary neuroendocrine cells in human airway epithelium

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    Sparrow Malcolm P


    Full Text Available Abstract Background Pulmonary neuroendocrine cells (PNEC are specialized epithelial cells that are thought to play important roles in lung development and airway function. PNEC occur either singly or in clusters called neuroepithelial bodies. Our aim was to characterize the three dimensional morphology of PNEC, their distribution, and their relationship to the epithelial nerves in whole mounts of adult human bronchi using confocal microscopy. Methods Bronchi were resected from non-diseased portions of a lobe of human lung obtained from 8 thoracotomy patients (Table 1 undergoing surgery for the removal of lung tumors. Whole mounts were stained with antibodies to reveal all nerves (PGP 9.5, sensory nerves (calcitonin gene related peptide, CGRP, and PNEC (PGP 9.5, CGRP and gastrin releasing peptide, GRP. The analysis and rendition of the resulting three-dimensional data sets, including side-projections, was performed using NIH-Image software. Images were colorized and super-imposed using Adobe Photoshop. Results PNEC were abundant but not homogenously distributed within the epithelium, with densities ranging from 65/mm2 to denser patches of 250/mm2, depending on the individual wholemount. Rotation of 3-D images revealed a complex morphology; flask-like with the cell body near the basement membrane and a thick stem extending to the lumen. Long processes issued laterally from its base, some lumenal and others with feet-like processes. Calcitonin gene-related peptide (CGRP was present in about 20% of PNEC, mainly in the processes. CGRP-positive nerves were sparse, with some associated with the apical part of the PNEC. Conclusion Our 3D-data demonstrates that PNEC are numerous and exhibit a heterogeneous peptide content suggesting an active and diverse PNEC population.

  11. Insulin/IGF-regulated size scaling of neuroendocrine cells expressing the bHLH transcription factor Dimmed in Drosophila.

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    Jiangnan Luo

    Full Text Available Neurons and other cells display a large variation in size in an organism. Thus, a fundamental question is how growth of individual cells and their organelles is regulated. Is size scaling of individual neurons regulated post-mitotically, independent of growth of the entire CNS? Although the role of insulin/IGF-signaling (IIS in growth of tissues and whole organisms is well established, it is not known whether it regulates the size of individual neurons. We therefore studied the role of IIS in the size scaling of neurons in the Drosophila CNS. By targeted genetic manipulations of insulin receptor (dInR expression in a variety of neuron types we demonstrate that the cell size is affected only in neuroendocrine cells specified by the bHLH transcription factor DIMMED (DIMM. Several populations of DIMM-positive neurons tested displayed enlarged cell bodies after overexpression of the dInR, as well as PI3 kinase and Akt1 (protein kinase B, whereas DIMM-negative neurons did not respond to dInR manipulations. Knockdown of these components produce the opposite phenotype. Increased growth can also be induced by targeted overexpression of nutrient-dependent TOR (target of rapamycin signaling components, such as Rheb (small GTPase, TOR and S6K (S6 kinase. After Dimm-knockdown in neuroendocrine cells manipulations of dInR expression have significantly less effects on cell size. We also show that dInR expression in neuroendocrine cells can be altered by up or down-regulation of Dimm. This novel dInR-regulated size scaling is seen during postembryonic development, continues in the aging adult and is diet dependent. The increase in cell size includes cell body, axon terminations, nucleus and Golgi apparatus. We suggest that the dInR-mediated scaling of neuroendocrine cells is part of a plasticity that adapts the secretory capacity to changing physiological conditions and nutrient-dependent organismal growth.

  12. Pulmonary Neuroendocrine Cell Hyperplasia in Hemoglobin Bart-induced Hydrops Fetalis: A model for Chronic Intrauterine Hypoxia. (United States)

    Taweevisit, Mana; Theerasantipong, Boochit; Taothong, Kanlaya; Thorner, Paul Scott


    The pulmonary neuroendocrine system includes pulmonary neuroendocrine cells (PNECs) and neuroepithelial bodies (NEBs) that are distributed throughout respiratory epithelium and regulate lung growth and maturation antenatally. Abnormalities in this system have been linked to many hypoxia-associated pediatric pulmonary disorders. Hemoglobin (Hb) Bart disease is a severe form of α-thalassemia resulting in marked intrauterine hypoxia with hydrops fetalis (HF) and usually death in utero. Affected fetuses can serve as a naturally occurring human model for the effects of intrauterine hypoxia, and we postulated that these effects should include changes in the pulmonary neuroendocrine system. Bombesin immunostaining was used to assess PNECs and NEBs in stillborn fetuses with Hb Bart HF ( n = 16) and with HF from other causes ( n = 14) in comparison to non-HF controls. Hb Bart HF showed a significant increase in the proportion of PNECs in respiratory epithelium ( P = .002), mean number of NEB nuclei ( P = .03), and mean size of NEBs ( P = .002), compared to normal non-HF controls. Significant differences were not observed between HF due to other causes and non-HF controls with normal lungs. Non-HF controls with pulmonary hypoplasia showed significant increases in PNECs compared to HF cases not due to Hb Bart HF, implying HF alone does not cause such increases. In contrast, no significant differences were noted between non-HF controls with pulmonary hypoplasia and Hb Bart cases. Hb Bart HF may provide a useful model for studying the pulmonary neuroendocrine system under chronic intrauterine hypoxia.

  13. Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258 and its Therapeutic Implications

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    Shalini S. Yadav


    Full Text Available Prostate cancer (PCa remains the second-leading cause of cancer-related deaths in American men with an estimated mortality of more than 26,000 in 2016 alone. Aggressive and metastatic tumors are treated with androgen deprivation therapies (ADT; however, the tumors acquire resistance and develop into lethal castration resistant prostate cancer (CRPC. With the advent of better therapeutics, the incidences of a more aggressive neuroendocrine prostate cancer (NEPC variant continue to emerge. Although de novo occurrences of NEPC are rare, more than 25% of the therapy-resistant patients on highly potent new-generation anti-androgen therapies end up with NEPC. This, along with previous observations of an increase in the number of such NE cells in aggressive tumors, has been suggested as a mechanism of resistance development during prostate cancer progression. Dovitinib (TKI-258/CHIR-258 is a pan receptor tyrosine kinase (RTK inhibitor that targets VEGFR, FGFR, PDGFR, and KIT. It has shown efficacy in mouse-model of PCa bone metastasis, and is presently in clinical trials for several cancers. We observed that both androgen receptor (AR positive and AR-negative PCa cells differentiate into a NE phenotype upon treatment with Dovitinib. The NE differentiation was also observed when mice harboring PC3-xenografted tumors were systemically treated with Dovitinib. The mechanistic underpinnings of this differentiation are unclear, but seem to be supported through MAPK-, PI3K-, and Wnt-signaling pathways. Further elucidation of the differentiation process will enable the identification of alternative salvage or combination therapies to overcome the potential resistance development.

  14. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia in a patient with multiple pulmonary nodules: case report and literature review

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    Yamin HS


    Full Text Available Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH is a rare pulmonary disease, where carcinoid tumorlets invade the pulmonary parenchyma and bronchioles. These nests of cells release a variety of mediators including bombesin and gastrin releasing peptide that cause heterogeneous bronchoconstriction, creating a mosaic appearance on chest imaging studies, especially on expiratory scans. Clinically patients usually have long standing symptoms of shortness of breath (SOB and cough that are difficult to distinguish from asthma. In this article we describe a case of DIPNECH in a patient with several years’ history of SOB and cough, and review 179 cases of DIPNECH reported in the literature since 1992.

  15. Genetic polymorphisms of the GNRH1 and GNRHR genes and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3

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    Lund Eiliv


    Full Text Available Abstract Background Gonadotropin releasing hormone (GNRH1 triggers the release of follicle stimulating hormone and luteinizing hormone from the pituitary. Genetic variants in the gene encoding GNRH1 or its receptor may influence breast cancer risk by modulating production of ovarian steroid hormones. We studied the association between breast cancer risk and polymorphisms in genes that code for GNRH1 and its receptor (GNRHR in the large National Cancer Institute Breast and Prostate Cancer Cohort Consortium (NCI-BPC3. Methods We sequenced exons of GNRH1 and GNRHR in 95 invasive breast cancer cases. Resulting single nucleotide polymorphisms (SNPs were genotyped and used to identify haplotype-tagging SNPs (htSNPS in a panel of 349 healthy women. The htSNPs were genotyped in 5,603 invasive breast cancer cases and 7,480 controls from the Cancer Prevention Study-II (CPS-II, European Prospective Investigation on Cancer and Nutrition (EPIC, Multiethnic Cohort (MEC, Nurses' Health Study (NHS, and Women's Health Study (WHS. Circulating levels of sex steroids (androstenedione, estradiol, estrone and testosterone were also measured in 4713 study subjects. Results Breast cancer risk was not associated with any polymorphism or haplotype in the GNRH1 and GNRHR genes, nor were there any statistically significant interactions with known breast cancer risk factors. Polymorphisms in these two genes were not strongly associated with circulating hormone levels. Conclusion Common variants of the GNRH1 and GNRHR genes are not associated with risk of invasive breast cancer in Caucasians.

  16. Evaluation of somatostatin receptors in large cell pulmonary neuroendocrine carcinoma with 99mTc-EDDA/HYNIC-TOC scintigraphy. (United States)

    Nocuń, Anna; Chrapko, Beata; Gołębiewska, Renata; Stefaniak, Bogusław; Czekajska-Chehab, Elżbieta


    Large cell pulmonary neuroendocrine carcinoma (LCNEC) is a poorly differentiated and high-grade neoplasm. It is positioned between an atypical carcinoid and small cell neuroendocrine carcinoma of the lung in a distinct family of pulmonary neuroendocrine tumors. The aim of our study was to detect somatostatin receptors in this uncommon malignancy and to evaluate the sensitivity of somatostatin receptor scintigraphy (SRS) in LCNEC staging. We analyzed data of 26 patients (mean age: 61.5±7.9 years) with histologically confirmed diagnosis of LCNEC, including 18 cases not treated surgically and eight patients after the resection of the primary tumor. SRS was carried out with technetium-99m ethylene diamine-diacetic acid/hydrazinonicotinyl-Tyr3-octreotide (Tc-TOC). A visual analysis of scintigraphic images was done with reference to conventional imaging modalities (computed tomography and bone sicintigraphy). SRS sensitivity for the detection of primary lesions, supradiaphragmatic metastases, and infradiaphragmatic metastases was 100, 83.3%, and 0%, respectively. Five out of 13 metastases to the liver appeared on SRS as photopenic foci, visible on the background of physiological hepatic activity. Only one of the nine metastases to the skeletal system was found by SRS with sensitivity as low as 11.1%. The overall SRS sensitivity for the detection of secondary lesions and of all lesions was 54.8 and 62.2%, respectively. Within a rather large series of LCNEC, the primary tumor showed an uptake of Tc-TOC in all cases, whereas some metastases did show Tc-TOC uptake and some others did not.

  17. Neuroendocrine Tumor, diagnostic difficulties

    Directory of Open Access Journals (Sweden)

    Pedro Oliveira


    Full Text Available Ectopic adrenocorticotropic hormone (ACTH secretion is a rare disease. A 51 years old woman, with a Cushing syndrome secondary to ectopic ACTH secretion, diagnosed in 2009, with mediastinal lymphadenopathy, whose biopsy was compatible with lung small cell carcinoma, staged as IIIB using TNM classification. No other lesions were found in patient study. The patient was submitted to chemotherapy, associated to ketoconazole 200 mg twice daily, with partial remission of both conditions. Three years later was admitted with an aggravation of Cushing syndrome. There was no evidence of progression of pulmonary disease. A cystic lesion in the pancreatic uncinated process was found by abdominal CT scan and with avid uptake by DOTANOC PET discreet in anterior mediastinal lymphadenopathy. Biopsy of pancreatic mass revealed a neuroendocrine tumor. Pulmonary masses were biopsied again and was in favor of neuroendocrine tumor. It was assumed the diagnosis of pancreatic neuroendocrine tumor with mediastinal metastasis. The patient initiated lanreotid (120 mg, monthly, subcutaneous in association with ketoconazole. After 5 months of therapy, patient died with sepsis secondary to pneumonia. Neuroendocrine tumours are rare, difficult to diagnose and with poor prognosis when associated with ectopic ACTH secreting Cushing syndrome.

  18. The prognostic influence of neuroendocrine cells in prostate cancer: Results of a long-term follow-up study with patients treated by radical prostatectomy

    NARCIS (Netherlands)

    M.A. Noordzij (Marinus); Th.H. van der Kwast (Theo); G.J. van Steenbrugge (Gert Jan); W.C.J. Hop (Wim); F.H. Schröder (Fritz)


    textabstractThe distribution of immunohistochemically defined neuroen-docrine (NE) cells in benign, pre-cancerous and neoplastic prostatic tissues and the prognostic value of these cells in prostate cancer were studied in the radical prostatectomy specimens of 90 patients from whom complete

  19. CD200 Expression in Neuroendocrine Neoplasms. (United States)

    Love, Jason E; Thompson, Kimberly; Kilgore, Mark R; Westerhoff, Maria; Murphy, Claire E; Papanicolau-Sengos, Antonios; McCormick, Kinsey A; Shankaran, Veena; Vandeven, Natalie; Miller, Faith; Blom, Astrid; Nghiem, Paul T; Kussick, Steven J


    CD200 expression has been well studied in hematopoietic malignancies; however, CD200 expression has not been well-characterized in neuroendocrine neoplasms. We examined CD200 expression in 391 neuroendocrine neoplasms from various anatomic sites. Tissue blocks containing pulmonary small cell carcinoma, pulmonary carcinoid, large cell neuroendocrine carcinoma, pancreatic neuroendocrine tumor, gastrointestinal carcinoid, and Merkel cell carcinoma were evaluated for CD200 expression by immunohistochemistry. A set of nonneuroendocrine carcinomas was stained for comparison. CD200 was expressed in 87% of the neuroendocrine neoplasms studied, including 60 of 72 (83%) pulmonary small cell carcinomas, 15 of 22 (68%) pulmonary carcinoids, three of four (75%) pulmonary large cell neuroendocrine carcinomas, 125 of 146 (86%) Merkel cell carcinomas, 79 of 83 (95%) gastrointestinal luminal carcinoids, and 56 of 60 (93%) pancreatic neuroendocrine tumors. Thirty-two of 157 (20%) nonneuroendocrine carcinomas expressed CD200. In gastrointestinal carcinoid and pancreatic neuroendocrine neoplasms, CD200 negativity correlated with higher grade. CD200 is a relatively sensitive marker of neuroendocrine neoplasms and represents a potential therapeutic target in these difficult-to-treat malignancies.

  20. Treatment Outcomes, Growth Height, and Neuroendocrine Functions in Patients With Intracranial Germ Cell Tumors Treated With Chemoradiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Odagiri, Kazumasa, E-mail: [Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama (Japan); Department of Radiology, Kanagawa Children' s Medical Center, Yokohama (Japan); Omura, Motoko [Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama (Japan); Department of Radiology, Kanagawa Children' s Medical Center, Yokohama (Japan); Hata, Masaharu [Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama (Japan); Aida, Noriko; Niwa, Tetsu [Department of Radiology, Kanagawa Children' s Medical Center, Yokohama (Japan); Ogino, Ichiro [Department of Radiology, Yokohama City University Medical Center, Yokohama (Japan); Kigasawa, Hisato [Division of Hemato-oncology/Regeneration Medicine, Kanagawa Children' s Medical Center, Yokohama (Japan); Ito, Susumu [Department of Neurosurgery, Kanagawa Children' s Medical Center, Yokohama (Japan); Adachi, Masataka [Department of Endocrinology, Kanagawa Children' s Medical Center, Yokohama (Japan); Inoue, Tomio [Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama (Japan)


    Purpose: We carried out a retrospective review of patients receiving chemoradiation therapy (CRT) for intracranial germ cell tumor (GCT) using a lower dose than those previously reported. To identify an optimal GCT treatment strategy, we evaluated treatment outcomes, growth height, and neuroendocrine functions. Methods and Materials: Twenty-two patients with GCT, including 4 patients with nongerminomatous GCT (NGGCT) were treated with CRT. The median age at initial diagnosis was 11.5 years (range, 6-19 years). Seventeen patients initially received whole brain irradiation (median dose, 19.8 Gy), and 5 patients, including 4 with NGGCT, received craniospinal irradiation (median dose, 30.6 Gy). The median radiation doses delivered to the primary site were 36 Gy for pure germinoma and 45 Gy for NGGCT. Seventeen patients had tumors adjacent to the hypothalamic-pituitary axis (HPA), and 5 had tumors away from the HPA. Results: The median follow-up time was 72 months (range, 18-203 months). The rates of both disease-free survival and overall survival were 100%. The standard deviation scores (SDSs) of final heights recorded at the last assessment tended to be lower than those at initial diagnosis. Even in all 5 patients with tumors located away from the HPA, final height SDSs decreased (p = 0.018). In 16 patients with tumors adjacent to the HPA, 8 showed metabolic changes suggestive of hypothalamic obesity and/or growth hormone deficiency, and 13 had other pituitary hormone deficiencies. In contrast, 4 of 5 patients with tumors away from the HPA did not show any neuroendocrine dysfunctions except for a tendency to short stature. Conclusions: CRT for GCT using limited radiation doses resulted in excellent treatment outcomes. Even after limited radiation doses, insufficient growth height was often observed that was independent of tumor location. Our study suggests that close follow-up of neuroendocrine functions, including growth hormone, is essential for all patients with

  1. Primary small-cell neuroendocrine carcinoma of the male breast: a rare case report with review of the literature

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    Jiang J


    Full Text Available Jian Jiang,1 Guixin Wang,1 Li Lv,2 Caigang Liu,1 Xi Liang,1 Haidong Zhao11Department of Breast Surgery, 2Department of Pathology, the Second Affiliated Hospital of Dalian Medical University, Dalian, People's Republic of ChinaAbstract: In this case study and review, we present a case of a primary small-cell neuroendocrine carcinoma (SCNC of the male breast. Primary SCNC of the breast is a rare tumor with less than 30 cases reported in the literature. Most cases are found in women. Another exceptional point is that human epidermal growth factor receptor-2 (Her-2 immunoreactivity was positive in our recent case, which differed to previous reports detailing SCNC in women. We have no evidence to demonstrate the differences between treatment and prognoses for males and females, because we do not have sufficient cases to undertake an evidence-based investigation. We provide this rare case history; review the literature on SCNC of the breast; and discuss detailed information regarding epidemiology, histogenesis, clinical and histologic diagnosis criteria, surgical and adjuvant treatment, and prognosis.Keywords: small-cell carcinoma, SMCC, neuroendocrine, male breast cancer, SCNC neoplasm

  2. Neuroendocrine breast cancer. (United States)

    Graça, Susana; Esteves, Joana; Costa, Sílvia; Vale, Sílvio; Maciel, Jorge


    Neuroendocrine breast cancer is thought to account for about 1% of all breast cancers. This rare type of breast malignancy is more common in older women and presents as a low-grade, slow-growing cancer. The most definitive markers that indicate neuroendocrine carcinoma are the presence of chromogranin, synaptophysin or neuron-specific enolase, in at least 50% of malignant tumour cells. The authors present a case report of an 83-year-old woman, admitted to their institution with right breast lump. Physical examination, mammography and ultrasonography showed a 2.4 cm nodule, probably a benign lesion (BI-RADS 3). A fine needle aspiration biopsy was performed and revealed proliferative epithelial papillary lesion. She was submitted to excisional biopsy and histology showed endocrine breast cancer well differentiated (G1). Immunohistochemically, tumour cells were positive for synaptophysin. These breast cancers are characterised for their excellent prognosis and conservative treatment is almost always enough to obtain patient cure.

  3. Immune-Neuroendocrine Interactions and Autoimmune Diseases

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    Luis J. Jara


    Full Text Available The relationship between immune-neuroendocrine system is firmly established. The messengers of this connection are hormones, neuropeptides, neurotransmitters and cytokines. The immune-neuroendocrine system have the capacity to synthesize and release these molecules, which, in turn, can stimulate or suppress the activity of immune or neuroendocrine cells by binding to receptors. In fact, hormones, neuropeptides and neurotransmitters participate in innate and adaptive immune response.

  4. Neuroendocrine Role for VGF

    Directory of Open Access Journals (Sweden)

    Jo Edward Lewis


    Full Text Available The vgf gene (non-acronymic is highly conserved and was identified on the basis of its rapid induction in vitro by nerve growth factor, although can also be induced by brain derived neurotrophic factor, and glial derived growth factor. The VGF gene gives rise to a 68kDa precursor polypeptide which is induced robustly, relatively selectively and is synthesized exclusively in neuronal and neuroendocrine cells. Post-translational processing by neuroendocrine specific pro-hormone convertases in these cells results in the production of a number of smaller peptides. The VGF gene and peptides are widely expressed throughout the brain, particularly the hypothalamus and hippocampus, and in peripheral tissues including the pituitary gland, the adrenal glands and the pancreas, and in the gastrointestinal tract in both the myenteric plexus and in endocrine cells. VGF peptides have been associated with a number of neuroendocrine roles and in this mini-review we aim to describe these roles to highlight the importance of VGF as therapeutic target for a number of disorders, particularly those associated with energy metabolism, pain, reproduction and cognition.

  5. Secretagogin is a novel marker for neuroendocrine differentiation

    DEFF Research Database (Denmark)

    Birkenkamp-Demtröder, Karin; Wagner, Ludwig; Brandt Sørensen, Flemming


    , synaptophysin) in neuroendocrine cells in crypts of normal mucosa, and in tumor cells of carcinoids. Secretagogin was strongly expressed in the cytosol and the nucleus of 19 well-differentiated neuroendocrine carcinoids and carcinoid metastases, as well as in neuroendocrine tumors from the lung, pancreas...

  6. Small cell neuroendocrine carcinoma of tracheostomy site in a patient with a history of juvenile laryngeal papillomatosis. (United States)

    Violet Wilmot, Victoria; Nixon, Iain James; Nixon, Ioanna Fragkandrea


    Juvenile laryngeal papillomatosis is the commonest cause of benign epithelial tumours of the larynx. Following diagnostic biopsy, surgical debulking is the mainstay of therapy. The condition is often recurrent with further papillomas forming after debridement, requiring serial procedures and occasionally demanding tracheostomy. Rarely, the disease can undergo malignant transformation; most commonly to squamous cell carcinoma. We describe the first reported case of small cell neuroendocrine carcinoma occurring in the previous tracheostomy site of a 29-year-old male with a history of juvenile laryngeal papillomatosis. The patient, with a background of multiple treatments for juvenile papillomas, presented with voice change, breathing difficultly and erythema at the site of previous tracheostomy. Induction chemotherapy followed by chemoradiation was used to treat the lesion with a good response to initial therapy. 2016 BMJ Publishing Group Ltd.

  7. HPV positive neuroendocrine cervical cancer cells are dependent on Myc but not E6/E7 viral oncogenes (United States)

    Yuan, Hang; Krawczyk, Ewa; Blancato, Jan; Albanese, Christopher; Zhou, Dan; Wang, Naidong; Paul, Siddartha; Alkhilaiwi, Faris; Palechor-Ceron, Nancy; Dakic, Aleksandra; Fang, Shuang; Choudhary, Sujata; Hou, Tung-Wei; Zheng, Yun-Ling; Haddad, Bassem R.; Usuda, Yukari; Hartmann, Dan; Symer, David; Gillison, Maura; Agarwal, Seema; Wangsa, Danny; Ried, Thomas; Liu, Xuefeng; Schlegel, Richard


    Using conditional cell reprogramming, we generated a stable cell culture of an extremely rare and aggressive neuroendocrine cervical cancer. The cultured cells contained HPV-16, formed colonies in soft agar and rapidly produced tumors in immunodeficient mice. The HPV-16 genome was integrated adjacent to the Myc gene, both of which were amplified 40-fold. Analysis of RNA transcripts detected fusion of the HPV/Myc genes, arising from apparent microhomologous recombination. Spectral karyotyping (SKY) and fluorescent-in-situ hybridization (FISH) demonstrated coordinate localization and translocation of the amplified Myc and HPV genes on chromosomes 8 and 21. Similar to the primary tumor, tumor cell cultures expressed very high levels of the Myc protein and, in contrast to all other HPV-positive cervical cancer cell lines, they harbored a gain-of-function mutation in p53 (R273C). Unexpectedly, viral oncogene knockdown had no effect on the growth of the cells, but it did inhibit the proliferation of a conventional HPV-16 positive cervical cancer cell line. Knockdown of Myc, but not the mutant p53, significantly inhibited tumor cell proliferation. On the basis of these data, we propose that the primary driver of transformation in this aggressive cervical cancer is not HPV oncogene expression but rather the overexpression of Myc. PMID:28378747

  8. Primary Small Cell Neuroendocrine Carcinoma of the Nasal Cavity After Successful Curative Therapy of Nasopharyngeal Carcinoma: A Case Report

    Directory of Open Access Journals (Sweden)

    Chien-Heng Lin


    Full Text Available Patients with head and neck cancer have a greater risk of developing second primary malignant neoplasms than patients with any other type of malignancy. Small cell neuroendocrine carcinoma (SNEC mainly occurs in the lung, and is rarely found in the head and neck region. Only a few cases of sinonasal SNEC have been reported in the English literature. A woman aged 53 years, who had undergone successful curative radiotherapy for nasopharyngeal carcinoma 10 years earlier, presented with a history of bleeding from the left nostril for several weeks. A computed tomography scan of the head and neck showed a mass in the left nasal cavity with extension into the maxillary sinus. A biopsy specimen was taken and pathology revealed SNEC. The patient underwent a full course of concurrent chemoradiotherapy. No local recurrence or distant metastasis was noted during the 12 months of follow-up.

  9. Flow cytometry analysis of hormone receptors on human peripheral blood mononuclear cells to identify stress-induced neuroendocrine effects (United States)

    Meehan, R. T.


    Understanding the role of circulating peptide hormones in the pathogenesis of space-flight induced disorders would be greatly facilitated by a method which monitors chronic levels of hormones and their effects upon in vivo cell physiology. Single and simultaneous multiparameter flow cytometry analysis was employed to identify subpopulations of mononuclear cells bearing receptors for ACTH, Endorphin, and Somatomedin-C using monoclonal antibodies and monospecific antisera with indirect immunofluorescence. Blood samples were obtained from normal donors and subjects participating in decompression chamber studies (acute stress), medical student academic examination (chronic stress), and a drug study (Dexamethasone). Preliminary results indicate most ACTH and Endorphin receptor positive cells are monocytes and B-cells, exhibit little diurnal variation but the relative percentages of receptor positive cells are influenced by exposure to various stressors and ACTH inhibition. This study demonstrates the capability of flow cytometry analysis to study cell surface hormone receptor regulation which should allow insight into neuroendocrine modulation of the immune and other cellular systems during exposure to stress or microgravity.

  10. Neuroendocrine Cell Carcinoma of Unknown Primary Arising in Long Standing History of Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Stergios Boussios


    Full Text Available Multiple sclerosis (MS is a chronic autoimmune disease that targets myelinated axons in the central nervous system (CNS. Cancer of unknown primary site (CUP is a well-recognised clinical disorder, accounting for 3–5% of all malignant epithelial tumors. CUP is clinically characterised as an aggressive disease with early dissemination. Studies of cancer risk in MS patients have shown inconsistent findings. An increased risk of malignancy in patients with MS has been suggested, but recently serious questions have been raised regarding this association. Use of disease-modifying therapies might contribute to an increased cancer risk in selected MS patients. The concurrence of MS and CUP is exceptionally rare. Here we describe the case of a neuroendocrine carcinoma of unknown primary diagnosed in a male patient with a nine-year history of MS. The discussion includes data from all available population-based register studies with estimates of certain malignancies in patients with MS.

  11. [Nontraditional "large-cell" neuroendocrine formations (accessory nuclei) in the brain of Anamnia and Amniota]. (United States)

    Grinevich, V V; Polenov, A L; Danilova, O A; Kuzik, V V; Romanova, I V


    Using immunochemical PAP-method nonapeptidergic neuroendocrine formations in the hypothalamus and adjacent brain areas of fishes (the sterlet Acipenser ruthenus, the shark Scylliorhinus canicula), amphibians (the frog Rana temporaria), reptiles (the snake Natrix natrix), mammals (rats and dogs) and human have been studied. In Amniota and human accessory nuclei (AN) in addition to main "magnocellular" nuclei (supraoptic, postoptic and paraventricular) were discovered. Two AN, circular and dorsolateral ones, were found in snakes, and circular, dorsolateral, forniceal and extrahypothalamic AN were revealed in rat, dog and human brain. In Anamnia, sharks and frogs, in contrast to sterlets, the dorsolateral sub-nucleus inside preoptic nucleus was identified. AN similarity in the phylogenetic row of vertebrates and mechanisms of AN creation in phylo- and ontogenesis were discussed.

  12. Autophagy pathway is required for IL-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer LNCaP cells.

    Directory of Open Access Journals (Sweden)

    Pei-Ching Chang

    Full Text Available Prostate cancer (PCa cells undergoing neuroendocrine differentiation (NED are clinically relevant to the development of relapsed castration-resistant PCa. Increasing evidences show that autophagy involves in the development of neuroendocrine (NE tumors, including PCa. To clarify the effect of autophagy on NED, androgen-sensitive PCa LNCaP cells were examined. Treatment of LNCaP cells with IL-6 resulted in an induction of autophagy. In the absence of androgen, IL-6 caused an even stronger activation of autophagy. Similar result was identified in NED induction. Inhibition of autophagy with chloroquine (CQ markedly decreased NED. This observation was confirmed by beclin1 and Atg5 silencing experiments. Further supporting the role of autophagy in NED, we found that LC3 was up-regulated in PCa tissue that had relapsed after androgen-deprivation therapy when compared with their primary tumor counterpart. LC3 staining in relapsed PCa tissue showed punctate pattern similar to the staining of chromogranin A (CgA, a marker for NED cells. Moreover, autophagy inhibition induced the apoptosis of IL-6 induced NE differentiated PCa cells. Consistently, inhibition of autophagy by knockdown of beclin1 or Atg5 sensitized NE differentiated LNCaP cells to etoposide, a chemotherapy drug. To identify the mechanisms, phosphorylation of IL-6 downstream targets was analyzed. An increase in phospho-AMPK and a decrease in phospho-mTOR were found, which implies that IL-6 regulates autophagy through the AMPK/mTOR pathway. Most important to this study is the discovery of REST, a neuronal gene-specific transcriptional repressor that is involved in autophagy activation. REST was down-regulated in IL-6 treatment. Knockdown experiments suggest that REST is critical to NED and autophagy activation by IL-6. Together, our studies imply that autophagy is involved in PCa progression and plays a cytoprotective role when NED is induced in PCa cells by IL-6 treatment. These results

  13. Unusual presentation of high-grade neuroendocrine carcinoma of the Urinary bladder with small-cell and large-cell features

    Directory of Open Access Journals (Sweden)

    Vitor Fiorin de Vasconcellos


    Full Text Available High-grade neuroendocrine carcinoma of the urinary bladder comprehends small-cell and large-cell variants. It is a rare and aggressive neoplasm, mostly diagnosed in advanced stages. It is more frequently encountered among Caucasian men in the sixth decade of life. Urinary symptoms are the most common clinical presentation. Diagnosis is generally not troublesome once the lesions are easily detectable by imaging exams and cystoscopy. This neoplasia is associated with tobacco smoking, and is frequently associated with other carcinomatous components such as urothelial carcinoma, adenocarcinoma, and sarcomatoid carcinoma. The authors report a case of an apparently healthy female patient who presented cervical lymph node enlargement not accompanied by systemic symptoms. The supraclavicular lymph node biopsy revealed metastatic small cell carcinoma. The computed tomography scan showed a bladder wall nodular thickening, enlarged lymph nodes along the iliac, periaortic, mediastinal, cervical and supraclavicular chains, as well as an insufflating lytic bone lesion in the right iliac wing. The positron emission tomography-fluorodeoxyglucose (PET-FDG added to these findings, the presence of a paraesophageal lymph node, lymphadenomegaly in the gluteal region and a vertebral lytic lesion in T10. Resected specimen of the bladder tumor revealed a high-grade neuroendocrine carcinoma with small-cell and large-cell features.

  14. Neuroendocrine Tumor: Statistics (United States)

    ... Tumor > Neuroendocrine Tumor: Statistics Request Permissions Neuroendocrine Tumor: Statistics Approved by the Cancer.Net Editorial Board , 11/ ... the body. It is important to remember that statistics on the survival rates for people with a ...

  15. A methodology for distinguishing divergent cell fates within a common progenitor population: adenoma- and neuroendocrine-like cells are confounders of rat ileal epithelial cell (IEC-18 culture

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    Paxton Jessica B


    Full Text Available Abstract Background IEC-18 cells are a non-transformed, immortal cell line derived from juvenile rat ileal crypt cells. They may have experimental advantages over tumor-derived gastrointestinal lineages, including preservation of phenotype, normal endocrine responses and retention of differentiation potential. However, their proclivity for spontaneous differentiation / transformation may be stereotypical and could represent a more profound experimental confounder than previously realized. We hypothesized that IEC-18 cells spontaneously diverge towards a uniform mixture of epigenetic fates, with corresponding phenotypes, rather than persist as a single progenitor lineage. Results IEC-18 cells were cultured for 72 hours in serum free media (SFM, with and without various insulin-like growth factor agonists to differentially boost the basal rate of proliferation. A strategy was employed to identify constitutive genes as markers of divergent fates through gene array analysis by cross-referencing fold-change trends for individual genes against crypt cell abundance in each treatment. We then confirmed the cell-specific phenotype by immunolocalization of proteins corresponding to those genes. The majority of IEC-18 cells in SFM alone had a loss in expression of the adenomatous polyposis coli (APC gene at the mRNA and protein levels, consistent with adenoma-like transformation. In addition, a small subset of cells expressed the serotonin receptor 2A gene and had neuroendocrine-like morphology. Conclusions IEC-18 cells commonly undergo a change in cell fate prior to reaching confluence. The most common fate switch that we were able to detect correlates with a down regulation of the APC gene and transformation into an adenoma-like phenotype.

  16. Midgut neuroendocrine tumor presenting with acute intestinal ischemia. (United States)

    Mantzoros, Ioannis; Savvala, Natalia Antigoni; Ioannidis, Orestis; Parpoudi, Styliani; Loutzidou, Lydia; Kyriakidou, Despoina; Cheva, Angeliki; Intzos, Vasileios; Tsalis, Konstantinos


    Neuroendocrine tumors represent a heterogeneous group of neoplasms that arise from neuroendocrine cells and secrete various peptides and bioamines. While gastrointestinal neuroendocrine tumors, commonly called carcinoids, account for about 2/3 of all neuroendocrine tumors, they are relatively rare. Small intestine neuroendocrine tumors originate from intestinal enterochromaffin cells and represent about 1/4 of small intestine neoplasms. They can be asymptomatic or cause nonspecific symptoms, which usually leads to a delayed diagnosis. Imaging modalities can aid diagnosis and surgery remains the mainstay of treatment. We present a case of a jejunal neuroendocrine tumor that caused nonspecific symptoms for about 1 year before manifesting with acute mesenteric ischemia. Abdominal X-rays revealed pneumatosis intestinalis and an abdominal ultrasound and computed tomography confirmed the diagnosis. The patient was submitted to segmental enterectomy. Histopathological study demonstrated a neuroendocrine tumor with perineural and arterial infiltration and lymph node metastasis. The postoperative course was uneventful and the patient denied any adjuvant treatment.

  17. The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells. (United States)

    Zitzmann, Kathrin; de Toni, Enrico; von Rüden, Janina; Brand, Stephan; Göke, Burkhard; Laubender, Rüdiger P; Auernhammer, Christoph J


    The tumour-selective death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for the treatment of human cancer. However, many tumours have evolved mechanisms to resist TRAIL-induced apoptosis. A number of studies have demonstrated that aberrant PI(3)K-Akt-mTOR survival signalling may confer TRAIL resistance by altering the balance between pro- and anti-apoptotic proteins. Here, we show that neuroendocrine tumour (NET) cell lines of heterogeneous origin exhibit a range of TRAIL sensitivities and that TRAIL sensitivity correlates with the expression of FLIP(S), caspase-8, and Bcl-2. Neither single mTOR inhibition by everolimus nor dual mTOR/PI(3)K inhibition by NVP-BEZ235 was able to enhance TRAIL susceptibility in any of the tested cell lines. In contrast, dual PI(3)K-Akt-mTOR and Raf-MEK-Erk pathway inhibition by the IGF-1R inhibitor NVP-AEW541 effectively restored TRAIL sensitivity in NCI-H727 bronchus carcinoid cells. Furthermore, blocking Raf-MEK-Erk signalling by the novel Raf inhibitor Raf265 significantly enhanced TRAIL sensitivity in NCI-H727 and CM insulinoma cells. While having no effect on FLIP(S) or caspase-8 expression, Raf265 strongly decreased Bcl-2 levels in those cell lines susceptible to its TRAIL-sensitizing action. Taken together, our findings suggest that combinations of Raf-MEK-Erk pathway inhibitors and TRAIL might offer a novel therapeutic strategy in NET disease.

  18. The cannabinoid WIN 55,212-2 prevents neuroendocrine differentiation of LNCaP prostate cancer cells. (United States)

    Morell, C; Bort, A; Vara, D; Ramos-Torres, A; Rodríguez-Henche, N; Díaz-Laviada, I


    Neuroendocrine (NE) differentiation represents a common feature of prostate cancer and is associated with accelerated disease progression and poor clinical outcome. Nowadays, there is no treatment for this aggressive form of prostate cancer. The aim of this study was to determine the influence of the cannabinoid WIN 55,212-2 (WIN, a non-selective cannabinoid CB1 and CB2 receptor agonist) on the NE differentiation of prostate cancer cells. NE differentiation of prostate cancer LNCaP cells was induced by serum deprivation or by incubation with interleukin-6, for 6 days. Levels of NE markers and signaling proteins were determined by western blotting. Levels of cannabinoid receptors were determined by quantitative PCR. The involvement of signaling cascades was investigated by pharmacological inhibition and small interfering RNA. The differentiated LNCaP cells exhibited neurite outgrowth, and increased the expression of the typical NE markers neuron-specific enolase and βIII tubulin (βIII Tub). Treatment with 3 μM WIN inhibited NK differentiation of LNCaP cells. The cannabinoid WIN downregulated the PI3K/Akt/mTOR signaling pathway, resulting in NE differentiation inhibition. In addition, an activation of AMP-activated protein kinase (AMPK) was observed in WIN-treated cells, which correlated with a decrease in the NE markers expression. Our results also show that during NE differentiation the expression of cannabinoid receptors CB1 and CB2 dramatically decreases. Taken together, we demonstrate that PI3K/Akt/AMPK might be an important axis modulating NE differentiation of prostate cancer that is blocked by the cannabinoid WIN, pointing to a therapeutic potential of cannabinoids against NE prostate cancer.

  19. Up-Regulated Expression of LAMP2 and Autophagy Activity during Neuroendocrine Differentiation of Prostate Cancer LNCaP Cells. (United States)

    Morell, Cecilia; Bort, Alicia; Vara-Ciruelos, Diana; Ramos-Torres, Ágata; Altamirano-Dimas, Manuel; Díaz-Laviada, Inés; Rodríguez-Henche, Nieves


    Neuroendocrine (NE) prostate cancer (PCa) is a highly aggressive subtype of prostate cancer associated with resistance to androgen ablation therapy. In this study, we used LNCaP prostate cancer cells cultured in a serum-free medium for 6 days as a NE model of prostate cancer. Serum deprivation increased the expression of NE markers such as neuron-specific enolase (NSE) and βIII tubulin (βIII tub) and decreased the expression of the androgen receptor protein in LNCaP cells. Using cDNA microarrays, we compared gene expression profiles of NE cells and non-differentiated LNCaP cells. We identified up-regulation of 155 genes, among them LAMP2, a lysosomal membrane protein involved in lysosomal stability and autophagy. We then confirmed up-regulation of LAMP2 in NE cells by qRT-PCR, Western blot and confocal microscopy assays, showing that mRNA up-regulation correlated with increased levels of LAMP2 protein. Subsequently, we determined autophagy activity in NE cells by assessing the protein levels of SQSTM/p62 and LC3 by Western blot and LC3 and Atg5 mRNAs content by qRT-PCR. The decreased levels of SQSTM/p62 was accompanied by an enhanced expression of LC3 and ATG5, suggesting activation of autophagy in NE cells. Blockage of autophagy with 1μM AKT inhibitor IV, or by silencing Beclin 1 and Atg5, prevented NE cell differentiation, as revealed by decreased levels of the NE markers. In addition, AKT inhibitor IV as well as Beclin1 and Atg5 kwockdown attenuated LAMP2 expression in NE cells. On the other hand, LAMP2 knockdown by siRNA led to a marked blockage of autophagy, prevention of NE differentiation and decrease of cell survival. Taken together, these results suggest that LAMP2 overexpression assists NE differentiation of LNCaP cells induced by serum deprivation and facilitates autophagy activity in order to attain the NE phenotype and cell survival. LAMP2 could thus be a potential biomarker and potential target for NE prostate cancer.

  20. [Neuroendocrine neoplasms of the breast]. (United States)

    Anlauf, M; Neumann, M; Bomberg, S; Luczak, K; Heikaus, S; Gustmann, C; Antke, C; Ezziddin, S; Fottner, C; Pavel, M; Pape, U-F; Rinke, A; Lahner, H; Schott, M; Cremer, B; Hörsch, D; Baum, R P; Groh, U; Alkatout, I; Rudlowski, C; Scheler, P; Zirbes, T K; Hoffmann, J; Fehm, T; Gabbert, H E; Baldus, S E


    Neuroendocrine neoplasms (NEN) of the breast are specific tumor entities. According to the literature up to 5% of breast neoplasms are malignant epithelial neoplasms of the breast. They are defined by a neuroendocrine (NE) architecture and cytology combined with an expression of the neuroendocrine vesicle markers chromogranin A and/or synaptophysin. The diagnosis is supplemented by the receptor status and the proliferative activity. According to the World Health Organization (WHO) classification of 2012 the following groups of NEN are distinguished: (1) invasive breast carcinoma with NE differentiation, (2) well-differentiated neuroendocrine tumor (NET) and (3) poorly differentiated small cell carcinoma (NEC). This review article focuses on (1) the definition and basic principles of diagnostics, (2) the history, nomenclature and WHO classification from 2003 and 2012, (3) the frequency of breast NEN, (4) the hereditary background and functional activity, (5) the expression of receptors and (6) the possible clinical implications. In addition, the first results of a retrospective single center study (n = 465 patients with breast cancer over a time period of 4 years) on the frequency of NEN of the breast at the Breast Center of the University Hospital Düsseldorf are presented. In this study a frequency of 4.5% of NEN was found based on a diagnostic cut-off of > 50% Chromogranin A and/or synaptophysin positive tumor cells.

  1. 1α,25(OH)2D3Analog, MART-10, Inhibits Neuroendocrine Tumor Cell Metastasis After VEGF-A Stimulation. (United States)

    Chiang, Kun-Chun; Yeh, Chun-Nan; Pang, Jong-Hwei S; Hsu, Jun-Te; Yeh, Ta-Sen; Chen, Li-Wei; Kuo, Sheng-Fong; Takano, Masashi; Chen, Tai C; Kittaka, Atsushi; Hsieh, Po-Jen; Juang, Horng-Heng


    Pancreatic neuroendocrine tumors (PanNETs) are usually diagnosed in an advanced stage. Most patients with PanNETs die of metastasis. Vascular endothelial growth factor-A (VEGF-A) is a strong stimulator of angiogenesis and tumor metastasis. We aimed to investigate the effect of MART-10 [19-nor-2α-(3-hydroxypropyl)-1α,25(OH) 2 D 3 ], a 1α,25-dihydroxy-vitamin D3 (1α,25(OH) 2 D 3 ) analog, on PanNET cell metastasis after VEGF-A stimulation. Migration and invasion assays, western blot, and immunofluorescent staining were applied in this study. VEGF-A increased PanNET cell migration and invasion, which was attenuated by 1α,25(OH) 2 D 3 and MART-10. VEGF-A treatment stimulated epithelial-mesenchymal transition (EMT) of PanNET cells. During this process, expression of snail family transcriptional repressor 1 and 2, and fibronectin was up-regulated. 1α,25(OH) 2 D 3 and MART-10 counteracted VEGF-A-induced EMT. In addition, expression of neuropilin 1, a key protein in VEGF-A signaling, was down-regulated by 1α,25(OH) 2 D 3 and MART-10. Furthermore, synthesis of F-actin was increased by VEGF-A and reduced by 1α,25(OH) 2 D 3 and MART-10. Our data indicate that MART-10 could be deemed a promising drug for PanNET treatment. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  2. Renal cell carcinoma metastasizing to pancreatic neuroendocrine neoplasm - the second case described in the world literature. (United States)

    Bednarek-Rajewska, Katarzyna; Zalewski, Przemysław; Bręborowicz, Danuta; Woźniak, Aldona

    Tumor-to-tumor metastases are very rare events. We report a case of a 64-year-old man who presented with a tumor of the pancreas. The patient underwent partial pancreatectomy. Frozen section diagnosis of the tumor was an endocrine neoplasm. Paraffin block slide examination revealed a tumor consisting of two components: pancreatic endocrine neoplasm at the periphery of the tumor and the central part composed of clear cells with delicate vessels. The results of immunohistochemical stains revealed renal cell carcinoma surrounded by pancreatic endocrine neoplasm, therefore representing an unusual case of renal cell carcinoma metastasizing to a pancreatic endocrine neoplasm.

  3. Expression and physiological regulation of BDNF receptors in the neuroendocrine melanotrope cell of Xenopus laevis

    NARCIS (Netherlands)

    Kidane, A.H.; Dooren, S.H. van; Roubos, E.W.; Jenks, B.G.


    Brain-derived neurotrophic factor (BDNF) and alpha-melanophore-stimulating hormone (alpha-MSH) are co-sequestered in secretory granules in melanotrope cells of the pituitary pars intermedia of the amphibian Xenopus laevis. alpha-MSH is responsible for pigment dispersion in dermal melanophores during

  4. Genomic profiling of a combined large cell neuroendocrine carcinoma of the submandibular gland

    DEFF Research Database (Denmark)

    Andreasen, Simon; Persson, Marta; Kiss, Katalin


    A 69-year-old female with no previous medical history presented with a rapidly growing submandibular mass. Fine needle aspiration cytology suggested a small-cell carcinoma and PET-CT showed increased 18-FDG uptake in the submandibular mass as well as in a lung mass. Submandibular resection...

  5. Identification of deregulation of apoptosis and cell cycle in neuroendocrine tumors of the lung via NanoString nCounter expression analysis. (United States)

    Walter, Robert Fred Henry; Werner, Robert; Ting, Saskia; Vollbrecht, Claudia; Theegarten, Dirk; Christoph, Daniel Christian; Schmid, Kurt Werner; Wohlschlaeger, Jeremias; Mairinger, Fabian Dominik


    Neuroendocrine tumors of the lung comprise typical (TC) and atypical carcinoids (AC), large-cell neuroendocrine cancer (LCNEC) and small-cell lung cancer (SCLC). Cell cycle and apoptosis are key pathways of multicellular homeostasis and deregulation of these pathways is associated with cancerogenesis. Sixty representative FFPE-specimens (16 TC, 13 AC, 16 LCNEC and 15 SCLC) were used for mRNA expression analysis using the NanoString technique. Eight genes related to apoptosis and ten genes regulating key points of cell cycle were investigated. ASCL1, BCL2, CASP8, CCNE1, CDK1, CDK2, CDKN1A and CDKN2A showed lower expression in carcinoids compared to carcinomas. In contrast, CCNE1 and CDK6 showed elevated expression in carcinoids compared to carcinomas. The calculated BCL2/BAX ratio showed increasing values from TC to SCLC. Between SCLC and LCNEC CDK2, CDKN1B, CDKN2A and PNN expression was significantly different with higher expression in SCLC. Carcinoids have increased CDK4/6 and CCND1 expression controlling RB1 phosphorylation via this signaling cascade. CDK2 and CCNE1 were increased in carcinomas showing that these use the opposite way to control RB1. BAX and BCL2 are antagonists in regulating apoptosis. BCL2 expression increased over BAX expression with increasing malignancy of the tumor from TC to SCLC.

  6. Non-conducting function of the Kv2.1 channel enables it to recruit vesicles for release in neuroendocrine and nerve cells. (United States)

    Feinshreiber, Lori; Singer-Lahat, Dafna; Friedrich, Reut; Matti, Ulf; Sheinin, Anton; Yizhar, Ofer; Nachman, Rachel; Chikvashvili, Dodo; Rettig, Jens; Ashery, Uri; Lotan, Ilana


    Regulation of exocytosis by voltage-gated K(+) channels has classically been viewed as inhibition mediated by K(+) fluxes. We recently identified a new role for Kv2.1 in facilitating vesicle release from neuroendocrine cells, which is independent of K(+) flux. Here, we show that Kv2.1-induced facilitation of release is not restricted to neuroendocrine cells, but also occurs in the somatic-vesicle release from dorsal-root-ganglion neurons and is mediated by direct association of Kv2.1 with syntaxin. We further show in adrenal chromaffin cells that facilitation induced by both wild-type and non-conducting mutant Kv2.1 channels in response to long stimulation persists during successive stimulation, and can be attributed to an increased number of exocytotic events and not to changes in single-spike kinetics. Moreover, rigorous analysis of the pools of released vesicles reveals that Kv2.1 enhances the rate of vesicle recruitment during stimulation with high Ca(2+), without affecting the size of the readily releasable vesicle pool. These findings place a voltage-gated K(+) channel among the syntaxin-binding proteins that directly regulate pre-fusion steps in exocytosis.

  7. Anti-Ri-associated paraneoplastic brainstem cerebellar syndrome with coexisting limbic encephalitis in a patient with mixed large cell neuroendocrine lung carcinoma. (United States)

    Mitchell, Amber N; Bakhos, Charles T; Zimmerman, Earl A


    Paraneoplastic neurologic syndromes (PNS) can be the first manifestations of occult malignancies. If left untreated, PNS often lead to significant morbidity and mortality. Anti-Ri (anti-neuronal nuclear antibody type 2 [ANNA-2]) autoantibodies are commonly associated with breast and small cell lung cancers. Cases of anti-Ri paraneoplastic cerebellar degeneration are reported, but few describe severe nausea and coexisting limbic encephalitis as the major presenting features. We report a 75-year-old woman with medically-intractable emesis, encephalopathy, diplopia, vertigo, and gait ataxia for 3 months. Examination revealed rotary nystagmus, ocular skew deviation, limb dysmetria, and gait ataxia. After two courses of intravenous immunoglobulin, there was minimal improvement. Anti-Ri antibodies were positive in serum only. CT scan identified a 2.0 cm left lung mass, and histopathology revealed large cell neuroendocrine carcinoma with admixed adenocarcinoma non-small cell lung carcinoma (NCSLC). Though the patient achieved nearly complete clinical recovery after tumor resection, anti-Ri levels remained high at 20 months post-resection. To our knowledge this is the first report of a paraneoplastic brainstem cerebellar syndrome with coexisting limbic encephalitis involving anti-Ri positivity and associated mixed neuroendocrine/NSCLC of the lung with marked improvement after tumor resection. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. High glucose induces N-linked glycosylation-mediated functional upregulation and overexpression of Cav3.2 T-type calcium channels in neuroendocrine-like differentiated human prostate cancer cells. (United States)

    Fukami, Kazuki; Asano, Erina; Ueda, Mai; Sekiguchi, Fumiko; Yoshida, Shigeru; Kawabata, Atsufumi


    Given that Cav3.2 T-type Ca(2+) channels were functionally regulated by asparagine (N)-linked glycosylation, we examined effects of high glucose on the function of Cav3.2, known to regulate secretory function, in neuroendocrine-like differentiated prostate cancer LNCaP cells. High glucose accelerated the increased channel function and overexpression of Cav3.2 during neuroendocrine differentiation, the former prevented by enzymatic inhibition of N-glycosylation and cleavage of N-glycans. Hyperglycemia thus appears to induce N-linked glycosylation-mediated functional upregulation and overexpression of Cav3.2 in neuroendocrine-like differentiated prostate cancer cells. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  9. High glucose induces N-linked glycosylation-mediated functional upregulation and overexpression of Cav3.2 T-type calcium channels in neuroendocrine-like differentiated human prostate cancer cells

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    Kazuki Fukami


    Full Text Available Given that Cav3.2 T-type Ca2+ channels were functionally regulated by asparagine (N-linked glycosylation, we examined effects of high glucose on the function of Cav3.2, known to regulate secretory function, in neuroendocrine-like differentiated prostate cancer LNCaP cells. High glucose accelerated the increased channel function and overexpression of Cav3.2 during neuroendocrine differentiation, the former prevented by enzymatic inhibition of N-glycosylation and cleavage of N-glycans. Hyperglycemia thus appears to induce N-linked glycosylation-mediated functional upregulation and overexpression of Cav3.2 in neuroendocrine-like differentiated prostate cancer cells.

  10. Pulmonary neuroendocrine (carcinoid) tumors

    DEFF Research Database (Denmark)

    Caplin, M E; Baudin, E; Ferolla, P


    BACKGROUND: Pulmonary carcinoids (PCs) are rare tumors. As there is a paucity of randomized studies, this expert consensus document represents an initiative by the European Neuroendocrine Tumor Society to provide guidance on their management. PATIENTS AND METHODS: Bibliographical searches were...... carried out in PubMed for the terms 'pulmonary neuroendocrine tumors', 'bronchial neuroendocrine tumors', 'bronchial carcinoid tumors', 'pulmonary carcinoid', 'pulmonary typical/atypical carcinoid', and 'pulmonary carcinoid and diagnosis/treatment/epidemiology/prognosis'. A systematic review...... of the relevant literature was carried out, followed by expert review. RESULTS: PCs are well-differentiated neuroendocrine tumors and include low- and intermediate-grade malignant tumors, i.e. typical (TC) and atypical carcinoid (AC), respectively. Contrast CT scan is the diagnostic gold standard for PCs...

  11. The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models.

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    Svenja Nölting

    Full Text Available The therapeutic options for metastatic neuroendocrine tumors (NETs are limited. As PI3K signaling is often activated in NETs, we have assessed the effects of selective PI3Kp110α inhibition by the novel agent BYL719 on cell viability, colony formation, apoptosis, cell cycle, signaling pathways, differentiation and secretion in pancreatic (BON-1, QGP-1 and pulmonary (H727 NET cell lines.Cell viability was investigated by WST-1 assay, colony formation by clonogenic assay, apoptosis by caspase3/7 assay, the cell cycle by FACS, cell signaling by Western blot analysis, expression of chromogranin A and somatostatin receptors 1/2/5 by RT-qPCR, and chromogranin A secretion by ELISA.BYL719 dose-dependently decreased cell viability and colony formation with the highest sensitivity in BON-1, followed by H727, and lowest sensitivity in QGP-1 cells. BYL719 induced apoptosis and G0/G1 cell cycle arrest associated with increased p27 expression. Western blots showed inhibition of PI3K downstream targets to a varying degree in the different cell lines, but IGF1R activation. The most sensitive BON-1 cells displayed a significant, and H727 cells a non-significant, GSK3 inhibition after BYL719 treatment, but these effects do not appear to be mediated through the IGF1R. In contrast, the most resistant QGP-1 cells showed no GSK3 inhibition, but a modest activation, which would partially counteract the other anti-proliferative effects. Accordingly, BYL719 enhanced neuroendocrine differentiation with the strongest effect in BON-1, followed by H727 cells indicated by induction of chromogranin A and somatostatin receptor 1/2 mRNA-synthesis, but not in QGP-1 cells. In BON-1 and QGP-1 cells, the BYL719/everolimus combination was synergistic through simultaneous AKT/mTORC1 inhibition, and significantly increased somatostatin receptor 2 transcription compared to each drug separately.Our results suggest that the agent BYL719 could be a novel therapeutic approach to the

  12. A short history of neuroendocrine tumours and their peptide hormones

    DEFF Research Database (Denmark)

    de Herder, Wouter W; Rehfeld, Jens F; Kidd, Mark


    The discovery of neuroendocrine tumours of the gastrointestinal tract and pancreas started in 1870, when Rudolf Heidenhain discovered the neuroendocrine cells, which can lead to the development of these tumours. Siegfried Oberndorfer was the first to introduce the term carcinoid in 1907. The panc...

  13. Neuroendocrine Merkel cell carcinoma is associated with mutations in key DNA repair, epigenetic and apoptosis pathways: a case-based study using targeted massively parallel sequencing. (United States)

    Graves, Christian A; Jones, Ashley; Reynolds, Justin; Stuart, Jeremy; Pirisi, Lucia; Botrous, Peter; Wells, James


    Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma with a poorly understood molecular etiology. We implemented a comprehensive deep sequencing approach to identify mutations in the tumor DNA from a cohort of patients treated at our institution over the past 15 years. Our results indicate mutations that may constitute therapeutic targets in MCC. Five patients were treated for MCC within the study interval. Patients with adequate tissue (n = 4), positive neuroendocrine differentiation (chromogranin, synaptophysin, and cytokeratin 20), and histopathological confirmation of MCC were included in the study. DNA was extracted from archival tumor tissue samples and analyzed by massively parallel sequencing using a targeted, multiplex PCR approach followed by semiconductor sequencing. We demonstrate high-penetrance nonsense mutations in PDE4DIP (n = 4) as well as various missense mutations in the DNA damage response (PRKDC, AURKB, ERCC5, ATR, and ATRX) and epigenetic modulating enzymes (MLL3). We describe several mutations in potential disease-relevant genes and pathways. These targets should be evaluated in a larger cohort to determine their role in the molecular pathogenesis of MCC. © 2015 S. Karger AG, Basel.

  14. PET/CT in Neuroendocrine Tumors. (United States)

    Castellucci, Paolo; Ambrosini, Valentina; Montini, Giancarlo


    Neuroendocrine tumors (NETs) are a rare group of neoplasms that originate from pluripotent stem cells or differentiated neuroendocrine cells, mostly localized in the bronchus, lungs, or gastroenteropancreatic tract. This issue reviews the results achieved with PET. The potential applications of the most commonly used receptor or metabolic positron-emitter radiopharmaceuticals in the field of NET to stage or restage disease, to detect unknown primary tumor, and to assess and monitor therapy response to different kind of treatments are analyzed. Copyright © 2008 Elsevier Inc. All rights reserved.

  15. Neuroendocrine differentiation in prostate cancer – a review

    Directory of Open Access Journals (Sweden)

    R. Popescu


    Full Text Available Objectives: This review aims to provide practicing clinicians with the most recent knowledge of the biological nature of prostate cancer especially the information regarding neuroendocrine differentiation. Methods: Review of the literature using PubMed search and scientific journal publications. Results: Much progress has been made towards an understanding of the development and progression of prostate cancer. The prostate is a male accessory sex gland which produces a fraction of seminal fluid. The normal human prostate is composed of a stromal compartment (which contains: nerves, fibroblast, smooth muscle cells, macrophages surrounding glandular acins – epithelial cells. Neuroendocrine cells are one of the epithelial populations in the normal prostate and are believed to provide trophic signals trough the secretion of neuropeptides that diffuse and influence surrounding epithelial cells. Prostate cancer is the most frequently diagnosed malignancy in men. In prostate cancer, neuroendocrine cells can stimulate growth of surrounding prostate adenocarcinoma cells (proliferation of neighboring cancer cells in a paracrine manner by secretion of neuroendocrine products. Neuroendocrine prostate cancer is an aggressive variant of prostate cancer that commonly arises in later stages of castration resistant prostate cancer. The detection of neuroendocrine prostate cancer has clinical implications. These patients are often treated with platinum chemotherapy rather than with androgen receptor targeted therapies. Conclusion: This review shows the need to improve our knowledge regarding diagnostic and treatment methods of the Prostate Cancer, especially cancer cells with neuroendocrine phenotype.

  16. Melatonin Inhibits GnRH-1, GnRH-3 and GnRH Receptor Expression in the Brain of the European Sea Bass, Dicentrarchus labrax

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    José Antonio Muñoz-Cueto


    Full Text Available Several evidences supported the existence of melatonin effects on reproductive system in fish. In order to investigate whether melatonin is involved in the modulation of GnRH systems in the European sea bass, we have injected melatonin (0.5 µg/g body mass in male specimens. The brain mRNA transcript levels of the three GnRH forms and the five GnRH receptors present in this species were determined by real time quantitative PCR. Our findings revealed day–night variations in the brain expression of GnRH-1, GnRH-3 and several GnRH receptors (dlGnRHR-II-1c, -2a, which exhibited higher transcript levels at mid-light compared to mid-dark phase of the photocycle. Moreover, an inhibitory effect of melatonin on the nocturnal expression of GnRH-1, GnRH-3, and GnRH receptors subtypes 1c, 2a and 2b was also demonstrated. Interestingly, the inhibitory effect of melatonin affected the expression of hypophysiotrophic GnRH forms and GnRH receptors that exhibit day–night fluctuations, suggesting that exogenous melatonin reinforce physiological mechanisms already established. These interactions between melatoninergic and GnRH systems could be mediating photoperiod effects on reproductive and other rhythmic physiological events in the European sea bass.

  17. Synchronous Quadruple Primary Neoplasms: Colon Adenocarcinoma, Collision Tumor of Neuroendocrine Tumor and Schwann Cell Hamartoma and Sessile Serrated Adenoma of the Appendix. (United States)

    Meeks, Marshall W; Grace, Shane; Chen, Yongxin; Petterchak, James; Bolesta, Edward; Zhou, Yihua; Lai, Jin-Ping


    Quadruple synchronous primary neoplasms are very rare with only three cases reported in the English-speaking literature to date. Collision tumors are also rare entities, especially of the appendix. We herein report a case of synchronous quadruple primary neoplasm in a 95-year-old female. She was diagnosed with colon adenocarcinoma, sessile serrated adenoma of the appendix and a collision tumor composed of a well-differentiated neuroendocrine tumor and Schwann cell hamartoma. Histological examination and immunohistochemistry supported these four lesions as separate entities. This case is unique because we report the diagnosis of quadruple synchronous primary, an extremely rare occurrence, in addition to a collision tumor of the appendix. We also provide a review of the literature for synchronous neoplasms and collision tumors. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  18. ERCC1 and Ki67 in Small Cell Lung Carcinoma and Other Neuroendocrine Tumors of the Lung Distribution and Impact on Survival

    DEFF Research Database (Denmark)

    Skov, Birgit Guldhammer; Holm, B.; Erreboe, A.


    ), typical carcinoid (TC), atypical carcinoid (AC), and large cell neuroendocrine carcinoma (LCNEC) were determined. Materials and Methods: We included a consecutive series of 186 patients with SCLC treated with platinum-based chemotherapy and surgically treated patients with TC (n = 48), AC (n = 15......) and LCNEC (n = 27). ERCC1 and Ki 67 were measured by immunohistochemistry and scored using published criteria. Results: The expression of ERCC1 was different among the different tumor types (p disease as well as extensive disease SCLC, no association of ERCC1 expression.......001). The difference between TC and AC was significant (p = 0.02), as was the difference between low grade (TC + AC) and high grade NE (LCNEC + SCLC) (p treated...

  19. Neuroendocrine-immune interaction

    NARCIS (Netherlands)

    Kemenade, van Lidy; Cohen, Nicholas; Chadzinska, Magdalena


    It has now become accepted that the immune system and neuroendocrine system form an integrated part of our physiology. Immunological defense mechanisms act in concert with physiological processes like growth and reproduction, energy intake and metabolism, as well as neuronal development. Not only

  20. Nuclear Image Analysis Study of Neuroendocrine Tumors


    Park, Meeja; Baek, Taehwa; Baek, Jongho; Son, Hyunjin; Kang, Dongwook; Kim, Jooheon; Lee, Hyekyung


    Background There is a subjective disagreement about nuclear chromatin in the field of pathology. Objective values of red, green, and blue (RGB) light intensities for nuclear chromatin can be obtained through a quantitative analysis using digital images. Methods We examined 10 cases of well differentiated neuroendocrine tumors of the rectum, small cell lung carcinomas, and moderately differentiated squamous cell lung carcinomas respectively. For each case, we selected 30 representative cells a...

  1. EGF Prevents the Neuroendocrine Differentiation of LNCaP Cells Induced By Serum Deprivation: The Modulator Role of P13K/Akt

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    Rosa M. Martín-Orozco


    Full Text Available The primary focus of this investigation was to study the relationship between neuroendocrine (NE differentiation, epidermal growth factor (EGF because both have been implicated in the progression of prostate cancer. For this purpose, we used gefitinib, trastuzumab, which are inhibitors of EGF receptor (EGFR, ErbB2, respectively. EGF prevents NE differentiation induced by androgen depletion. This effect is prevented by gefitinib, which blocks the activation of EGFR, ErbB2, stimulation of mitogen-activated protein kinase (MAPK, cell proliferation induced by EGF. Conversely, trastuzumab does not inhibit the effect of EGF on EGFR phosphorylation, MAPK activity, cell proliferation, NE differentiation, although it reduces ErbB2 levels specifically, suggesting that ErbB2 is not necessary to inhibit NE differentiation. Prevention of NE differentiation by EGF is mediated by a MAPK-dependent mechanism, requires constitutive Akt activation. The abrogation of the PI3K/Akt pathway changes the role of EGF from inhibitor to inductor of NE differentiation. We show that EGFR tyrosine kinase, MAPK, PI3K inhibitors inhibit the cell proliferation stimulated by EGF but induce the acquisition of NE phenotype. Altogether, the present data should be borne in mind when designing new clinical schedules for the treatment of prostate cancer, including the use of ErbB receptors, associated signaling pathway inhibitors.

  2. Small cell neuroendocrine carcinoma of the endometrium with pulmonary metastasis: A clinicopathologic study of a case and a brief review of the literature

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    Antonio D'Antonio


    Full Text Available Neuroendocrine carcinomas (NEC of the female genital tract are aggressive and rare tumors that usually involve the cervix and ovary, and are seen rarely in the endometrium in perimenopausal or postmenopausal women. We presented a case of a73 year-old postmenopausal woman with vaginal bleeding and abdominal pain. A subsequent computerized tomography (CT scan of pelvis showed an enlarged uterus (20,0 × 12,0 cm with para-aortic and pelvic lymph node metastases. She underwent surgical debulking and staging of an endometrial tumor with omental metastasis and positive lymph nodes. The pathological diagnosis was primary small cell carcinoma (SCC combined with endometrioid carcinoma of uterine corpus. Her final FIGO stage was IVB. Three months after surgery CT-total body showed a metastasis to left lung of SCC. Because the small-cell component of endometrial tumor showed a strong positivity for TTF1 as pulmonary counterpart a differential diagnosis with a primary small cell carcinoma of the lung should be made. Identifying an appropriate therapeutic management for SCC of endometrium is challenging since these are extremely rare tumors. An optimal initial therapeutic approach to this rare disease, especially at an advanced stage, has not yet been clearly defined. However, in these a multidisciplinary therapy, including surgery, chemotherapy, and radiotherapy represent until this time the only therapeutic option.

  3. Benign gastric neuroendocrine tumors in three snow leopards (Panthera uncia). (United States)

    Dobson, Elizabeth C; Naydan, Dianne K; Raphael, Bonnie L; McAloose, Denise


    Neuroendocrine tumors are relatively rare neoplasms arising from neuroendocrine cells that are distributed throughout the body and are predominant in the gastrointestinal tract. This report describes benign, well-differentiated gastric neuroendocrine tumors in three captive snow leopards (Panthera uncia). All tumors were well circumscribed, were within the gastric mucosa or submucosa, and had histologic and immunohistochemical features of neuroendocrine tumors. Histologic features included packeted cuboidal to columnar epithelial cells that were arranged in palisades or pseudorosettes and contained finely granular cellular cytoplasm with centrally placed, round nuclei. Cytoplasmic granules of neoplastic cells strongly expressed chromogranin A, variably expressed neuron-specific enolase, and did not express synaptophysin or gastrin. Each leopard died or was euthanatized for reasons unrelated to its tumor.

  4. Primary neuroendocrine carcinoma of the breast: report of 2 cases and literature review

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    Fernando Collado-Mesa, MD


    Full Text Available Neuroendocrine tumors of the breast are very rare accounting for less than 0.1% of all breast cancers and less than 1% of all neuroendocrine tumors. Focal neuroendocrine differentiation can be found in different histologic types of breast carcinoma including in situ and invasive ductal or invasive lobular. However, primary neuroendocrine carcinoma of the breast requires the expression of neuroendocrine markers in more than 50% of the cell population, the presence of ductal carcinoma in situ, and the absence of clinical evidence of concurrent primary neuroendocrine carcinoma of any other organ. Reports discussing the imaging characteristics of this rare carcinoma in different breast imaging modalities are scarce. We present 2 cases of primary neuroendocrine carcinoma of the breast for which mammography, ultrasound, and magnetic resonance imaging findings and pathology findings are described. A review of the medical literature on this particular topic was performed, and the results are presented.

  5. The Expression of Serum Antibodies against Gonadotropin-releasing Hormone (GnRH1, Progonadoliberin-2, Luteinizing Hormone (LH, and Related Receptors in Patients with Gastrointestinal Dysfunction or Diabetes Mellitus

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    Bodil Roth


    Full Text Available Gonadotropin-releasing hormone (GnRH 1 and 2 and luteinizing hormone (LH receptors have been described in the gastrointestinal tract. We have previously demonstrated antibodies in serum against GnRH1 in patients with gastrointestinal dysfunction and diabetes mellitus, and antibodies against GnRH receptor, LH, and LH receptor in patients with infertility. The aim of this study was to search for the expression of serum antibodies against GnRH1 with an improved enzyme-linked immune sorbent assay (ELISA, and antibodies against progonadoliberin-2, GnRH2, GnRH receptor, LH, and LH receptor with newly developed ELISAs, in patients with gastrointestinal dysfunction or diabetes mellitus. Healthy blood donors served as controls. Medical records were scrutinized. Our conclusion was that IgM antibodies against GnRH1, progonadoliberin-2, and/or GnRH receptors were more prevalent in patients with functional gastrointestinal disorders, gastrointestinal dysmotility, and/or diabetes mellitus, whereas IgG antibodies against these peptides, and LH- and LH receptor antibodies, were expressed in the same magnitude as in controls.

  6. Mixed adenocarcinoma and neuroendocrine prostate cancer: a case report

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    Rittu Hingorani


    Full Text Available Background: Neuroendocrine prostate cancer is rare but lethal. It is one of the most common extra pulmonary manifestations of small cell cancer. Case presentation: Here we present a case report of a 53-year-old male who presents with a mixed adenocarcinoma and neuroendocrine prostate tumor on a background of previously normal prostate-specific antigen (PSA. His initial symptoms prior to diagnosis included decreased urine output and acute kidney injury (AKI. Conclusion: Neuroendocrine tumor does not elevate the PSA level and hence is often a late finding with a poor prognosis. Special staining on histopathogy is required to reveal this diagnosis.

  7. Development of the Neuroendocrine Hypothalamus. (United States)

    Burbridge, Sarah; Stewart, Iain; Placzek, Marysia


    The neuroendocrine hypothalamus is composed of the tuberal and anterodorsal hypothalamus, together with the median eminence/neurohypophysis. It centrally governs wide-ranging physiological processes, including homeostasis of energy balance, circadian rhythms and stress responses, as well as growth and reproductive behaviours. Homeostasis is maintained by integrating sensory inputs and effecting responses via autonomic, endocrine and behavioural outputs, over diverse time-scales and throughout the lifecourse of an individual. Here, we summarize studies that begin to reveal how different territories and cell types within the neuroendocrine hypothalamus are assembled in an integrated manner to enable function, thus supporting the organism's ability to survive and thrive. We discuss how signaling pathways and transcription factors dictate the appearance and regionalization of the hypothalamic primordium, the maintenance of progenitor cells, and their specification and differentiation into neurons. We comment on recent studies that harness such programmes for the directed differentiation of human ES/iPS cells. We summarize how developmental plasticity is maintained even into adulthood and how integration between the hypothalamus and peripheral body is established in the median eminence and neurohypophysis. Analysis of model organisms, including mouse, chick and zebrafish, provides a picture of how complex, yet elegantly coordinated, developmental programmes build glial and neuronal cells around the third ventricle of the brain. Such conserved processes enable the hypothalamus to mediate its function as a central integrating and response-control mediator for the homeostatic processes that are critical to life. Early indications suggest that deregulation of these events may underlie multifaceted pathological conditions and dysfunctional physiology in humans, such as obesity. Copyright © 2016 John Wiley & Sons, Inc.

  8. Perinatal exposure to organohalogen pollutants decreases vasopressin content and its mRNA expression in magnocellular neuroendocrine cells activated by osmotic stress in adult rats (United States)

    Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are environmental pollutants that produce neurotoxicity and neuroendocrine disruption. They affect the vasopressinergic system but their disruptive mechanisms are not well understood. Our group reported t...

  9. Neuroendocrine tumors in the urinary bladder: a literature review

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    Monika Ulamec


    Full Text Available Neuroendocrine tumors (NETs can be found in most organs, as well as in the urinary bladder. Some of the clinical and pathologic features of these tumors may be characteristic of the organ of origin, but most of the properties are shared by neuroendocrine neoplasms regardless of their anatomic site. In the bladder, NETs comprise less than 1% of all bladder tumors and can be found in a pure form or intermixed with urothelial carcinoma and its variants. Bladder NETs are classified into 2 subtypes: carcinoid tumor and neuroendocrine carcinoma, which is further subdivided into small cell and large cell neuroendocrine carcinoma. Characteristics of bladder NETs and its differential diagnosis are discussed herein.

  10. Large cell neuroendocrine carcinoma originating from the uterine endometrium: a report on magnetic resonance features of 2 cases with very rare and aggressive tumor

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    Natsuko Makihara


    Full Text Available Neuroendocrine carcinomas (NEC of the female genital tract are aggressive and uncommon tumors, which usually involve the uterine cervix and ovary, and are seen very rarely in the endometrium. Only less than 10 cases of large cell NEC (LCNEC of the endometrium have been reported in the literature and their radiological findings are not well described. We report here two cases of pathologically proven LCNEC of the uterine endometrium. In both cases, the uterine body was enlarged and the tumor occupied part of the uterine cavity. Endometrial mass exhibited heterogeneous high intensity on T2-weighted magnetic resonance (MR images, and diffusion-weighted MR images revealed high intensity throughout the tumor, consistent with malignancy. LCNEC is a highly malignant neoplasm without particular findings in terms of diagnostic imaging and pathology, so its preoperative definitive diagnosis is very difficult. However, when laboratory test, pathologic diagnosis and MR imaging suggest a poorly differentiated uterine malignancy, positron emission tomography-computed tomography scan should be performed as a general assessment to help with diagnosis.

  11. Programming of neuroendocrine self in the thymus and its defect in the development of neuroendocrine autoimmunity (United States)

    Geenen, Vincent; Bodart, Gwennaëlle; Henry, Séverine; Michaux, Hélène; Dardenne, Olivier; Charlet-Renard, Chantal; Martens, Henri; Hober, Didier


    For centuries after its first description by Galen, the thymus was considered as only a vestigial endocrine organ until the discovery in 1961 by Jacques FAP Miller of its essential role in the development of T (thymo-dependent) lymphocytes. A unique thymus first appeared in cartilaginous fishes some 500 million years ago, at the same time or shortly after the emergence of the adaptive (acquired) immune system. The thymus may be compared to a small brain or a computer highly specialized in the orchestration of central immunological self-tolerance. This was a necessity for the survival of species, given the potent evolutionary pressure imposed by the high risk of autotoxicity inherent in the stochastic generation of the diversity of immune cell receptors that characterize the adaptive immune response. A new paradigm of “neuroendocrine self-peptides” has been proposed, together with the definition of “neuroendocrine self.” Neuroendocrine self-peptides are secreted by thymic epithelial cells (TECs) not according to the classic model of neuroendocrine signaling, but are processed for presentation by, or in association with, the thymic major histocompatibility complex (MHC) proteins. The autoimmune regulator (AIRE) gene/protein controls the transcription of neuroendocrine genes in TECs. The presentation of self-peptides in the thymus is responsible for the clonal deletion of self-reactive T cells, which emerge during the random recombination of gene segments that encode variable parts of the T cell receptor for the antigen (TCR). At the same time, self-antigen presentation in the thymus generates regulatory T (Treg) cells that can inhibit, in the periphery, those self-reactive T cells that escaped negative selection in the thymus. Several arguments indicate that the origin of autoimmunity directed against neuroendocrine glands results primarily from a defect in the intrathymic programming of self-tolerance to neuroendocrine functions. This defect may be genetic

  12. [The role of endoscopy in gastroenteropancreatic neuroendocrine tumors]. (United States)

    Magno, L; Sivero, L; Napolitano, V; Ruggiero, S; Fontanarosa, G; Massa, S


    Versione italiana Riassunto: Il ruolo dell'endoscopia nei tumori neuroendocrini gastroenteropancreatici. L. Magno, L. Sivero, V. Napolitano, S. Ruggiero, G. Fontanarosa, S. Massa I tumori neuroendocrini (NET) gastro-entero-pancreatici (GEP) sono neoplasie rare che originano dalle cellule neuroendocrine del tubo digerente e del pancreas. L'endoscopia digestiva e l'ecoendoscopia rivestono un ruolo importante nella diagnosi, stadiazione e sorveglianza dei pazienti con NET. Inoltre, in casi selezionati, le tecniche endoscopiche operative consentono il trattamento di queste neoplasie in fase precoce. English version Summary: The role of endoscopy in gastroenteropancreatic neuroendocrine tumors. L. Magno, L. Sivero, V. Napolitano, S. Ruggiero, G. Fontanarosa, S. Massa Gastroenteropancreatic (GEP) neuroendocrine tumors (NET) are rare neoplasia arisen from neuroendocrine cells present in the gut mucosa and pancreas. Digestive endoscopy and endoscopic ultrasonography play a relevant role in NET diagnosis, stadiation and surveillance. Moreover, in selected patients, surgical endoscopy allows the tratment of these cancers at an early stage.

  13. Taurine, energy drinks, and neuroendocrine effects. (United States)

    Caine, Jonathan J; Geracioti, Thomas D


    Taurine is an amino acid found abundantly in brain, retina, heart, and reproductive organ cells, as well as in meat and seafood. But it is also a major ingredient in popular "energy drinks," which thus constitute a major source of taurine supplementation. Unfortunately, little is known about taurine's neuroendocrine effects. The authors review the sparse data and provide a basic background on the structure, synthesis, distribution, metabolism, mechanisms, effects, safety, and currently proposed therapeutic targets of taurine. Copyright © 2016 Cleveland Clinic.

  14. Acute Disseminated Intravascular Coagulation in Neuroendocrine Carcinoma


    Ru-Wen Teh; Tsoi, Daphne T.


    Malignancy is a common cause of disseminated intravascular coagulation and usually presents as a chronic disorder in solid organ tumours. We present a rare case of recurrent acute disseminated intravascular coagulation in neuroendocrine carcinoma after manipulation, firstly, by core biopsy and, later, by cytotoxic therapy causing a release of procoagulants and cytokines from lysed tumour cells. This is reminiscent of tumour lysis syndrome where massive quantities of intracellular electrolytes...

  15. Neuroendocrine carcinoma of the prostate gland. (United States)

    Hoof, Pamela; Tsai-Nguyen, Ginger; Paulson, Scott; Syed, Almas; Mora, Adam


    Small cell prostate carcinoma (SCPC) has a clinical course and prognosis that is markedly different from that of common adenocarcinoma of the prostate. The patient in this case presented with fever of unknown origin, dyspnea, and near spinal cord compression. He was subsequently found to have widely metastatic high-grade neuroendocrine carcinoma of prostatic origin. This case emphasizes that despite the commonality of prostate cancer, there are rare presentations of this common disease.

  16. High grade neuroendocrine neoplasm of the antrum and orbit. (United States)

    MacIntosh, Peter W; Jakobiec, Frederick A; Stagner, Anna M; Gilani, Sapideh; Fay, Aaron


    Neuroendocrine malignancies-tumors characterized by the production of dense-core secretory granules-are most often encountered in the lungs and can also be found in extrapulmonary sites. Our patient had a primary neuroendocrine tumor of the antrum with an elusive cell of origin that secondarily invaded the inferior orbit. In the sinuses, neuroendocrine tumors may be confused with infectious sinusitis or squamous cell carcinoma. There are no known pathognomonic clinical or radiographic signs to distinguish these tumors from other conditions. Diagnosis depends on a biopsy with histopathologic and immunohistochemical analysis to identify biomarkers such as synaptophysin, chromogranin, CD56 and neuron specific enolase. Our patient's tumor defied precise immunohistochemical characterization because of its primitive character and erratic biomarker expression. The diagnosis oscillated between a neuroendocrine carcinoma and an ectopic esthesioneuroblastoma grade IV-hence the use of the more generic nosologic category of neuroendocrine neoplasm without specifying a neuronal or epithelial origin. Data to guide management are limited, particularly in the ophthalmic literature, and derive from experience with tumors of the sinonasal compartments. In the present case of a sino-orbital high grade neuroendocrine neoplasm, regional lymph node metastases developed shortly after presentation. The tumor has responded well to chemotherapy and radiation, but recurrence is often encountered within 2 years in this class of neoplasms. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Neuroendocrine Carcinoma: Immunohistochemistry Department Of Cancer Institute 1996 - 2000

    Directory of Open Access Journals (Sweden)

    Yazdani F


    Full Text Available Dispersed neuroendocrine system (D.N.S consists of a wide variety of cells that are present in the central and peripheral nervous system and in many classic endocrine organs and different tissues such as respiratory and gastrointestinal tracts, skin, prostate, breast and also their neoplasm show neuroendocrine differentiation by electron microscopy, immunohistochemistry or biochemical techniques:"nMaterials and Methods: The present study has been carried out by case-series method in order to evaluating the characteristics of all types of neuroendocrine carcinoma: different anatomical locations during 5 years period in immunohistochemistry department of cancer institute."nResults: The diagnosis of 109 cases of neuroendocrine carcinoma consisting of neuroendocrine carcinoma, small cell carcinoma, medullary carcinoma of thyroid, carcinoid tumor and merkel cell carcinoma are confirmed that among them the most common diagnosis was related to neuroendocrine carcinoma (50.5 percent. The most prevalent age group was 40-49 years and male to female distribution were 56 percent and 44 percent respectively. Anatomical distribution of tumor show that about 30 percent of cases were metastatic carcinoma, 30 percent in thyroid, respiratory tract and head and neck region and remainder in a variety of tissues. In over 50 percent of cases one of endocrinoid patterns as trabecular, organoid or mixed of them were seen."nConclusion: Immunohistochemically N.S.E (Neuron Specific Enolase show high sensitivity with 96 percent positive reaction and more specific endocrine markers as chromogranin A in 80 percent and synaptophysin only in 24 percent because of lesser application of the latter. Also epithelial markers such as cytokeratin and E.M.A."n(Epithelial Membrane Antigen were positive in 69 percent and 74 percent respectively. Mean survival rate of all neuroendocrine carcinoma reached to 4.8 years with lowest survival of 4.3 years among small cell carcinoma and

  18. Molecular basis for vulnerability to mitochondrial and oxidative stress in a neuroendocrine CRI-G1 cell line.

    Directory of Open Access Journals (Sweden)

    Natasha Chandiramani


    Full Text Available Many age-associated disorders (including diabetes, cancer, and neurodegenerative diseases are linked to mitochondrial dysfunction, which leads to impaired cellular bioenergetics and increased oxidative stress. However, it is not known what genetic and molecular pathways underlie differential vulnerability to mitochondrial dysfunction observed among different cell types.Starting with an insulinoma cell line as a model for a neuronal/endocrine cell type, we isolated a novel subclonal line (named CRI-G1-RS that was more susceptible to cell death induced by mitochondrial respiratory chain inhibitors than the parental CRI-G1 line (renamed CRI-G1-RR for clarity. Compared to parental RR cells, RS cells were also more vulnerable to direct oxidative stress, but equally vulnerable to mitochondrial uncoupling and less vulnerable to protein kinase inhibition-induced apoptosis. Thus, differential vulnerability to mitochondrial toxins between these two cell types likely reflects differences in their ability to handle metabolically generated reactive oxygen species rather than differences in ATP production/utilization or in downstream apoptotic machinery. Genome-wide gene expression analysis and follow-up biochemical studies revealed that, in this experimental system, increased vulnerability to mitochondrial and oxidative stress was associated with (1 inhibition of ARE/Nrf2/Keap1 antioxidant pathway; (2 decreased expression of antioxidant and phase I/II conjugation enzymes, most of which are Nrf2 transcriptional targets; (3 increased expression of molecular chaperones, many of which are also considered Nrf2 transcriptional targets; (4 increased expression of β cell-specific genes and transcription factors that specify/maintain β cell fate; and (5 reconstitution of glucose-stimulated insulin secretion.The molecular profile presented here will enable identification of individual genes or gene clusters that shape vulnerability to mitochondrial dysfunction and

  19. Current Concepts in Neuroendocrine Disruption (United States)


    In the last few years, it has become clear that a wide variety of environmental contaminants have specific effects on neuroendocrine systems in fish, amphibians, birds and mammals. While it is beyond the scope of this review to provide a comprehensive examination of all of these neuroendocrine disruptors, we will focus on select representative examples. Organochlorine pesticides bioaccumulate in neuroendocrine areas of the brain that directly regulate GnRH neurons, thereby altering the expression of genes downstream of GnRH signaling. Organochlorine pesticides can also agonize or antagonize hormone receptors, adversely affecting crosstalk between neurotransmitter systems. The impacts of polychlorinated biphenyls are varied and in many cases subtle. This is particularly true for neuroedocrine and behavioral effects of exposure. These effects impact sexual differentiation of the hypothalamic-pituitary-gonadal axis, and other neuroendocrine systems regulating the thyroid, metabolic, and stress axes and their physiological responses. Weakly estrogenic and anti-androgenic pollutants such as bisphenol A, phthalates, phytochemicals, and the fungicide vinclozolin can lead to severe and widespread neuroendocrine disruptions in discrete brain regions, including the hippocampus, amygdala, and hypothalamus, resulting in behavioral changes in a wide range of species. Behavioral features that have been shown to be affected by one or more these chemicals include cognitive deficits, heightened anxiety or anxiety-like, sociosexual, locomotor, and appetitive behaviors. Neuroactive pharmaceuticals are now widely detected in aquatic environments and water supplies through the release of wastewater treatment plant effluents. The antidepressant fluoxetine is one such pharmaceutical neuroendocrine disruptor. Fluoxetine is a selective serotonin reuptake inhibitor that can affect multiple neuroendocrine pathways and behavioral circuits, including disruptive effects on reproduction and

  20. Prolactin and natural killer cells: evaluating the neuroendocrine-immune axis in women with primary infertility and recurrent spontaneous abortion. (United States)

    Triggianese, Paola; Perricone, Carlo; Perricone, Roberto; De Carolis, Caterina


    An association between serum prolactin (PRL) and peripheral blood natural killer (NK) cells has been described in healthy women. We explored for the first time the PRL response to the thyrotrophin-releasing hormone (TRH) test and the association between PRL and NK cells in women with reproductive failure. A total of 130 women [31 primary infertility, 69 recurrent spontaneous abortion (RSA), and 30 fertile women] were evaluated by a TRH test to analyze the following: basal PRL (bPRL), peak-time PRL, PRL absolute and relative increase, decline-time PRL. Hyperprolactinaemia (HPRL) was defined as bPRL ≥15 ng/mL. NK cells were characterized by immunophenotyping. Significantly higher bPRL levels were found in the infertile women than in controls. Both the infertile and the RSA women showed significantly elevated NK levels. bPRL levels correlated with NK cells in HPRL-infertile women. In patients with HPRL, an association between NK cell and bPRL results. The dynamic test in the infertile women would help in the management of the pregnancy impairment. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Interplay of CREB and ATF2 in Ionizing Radiation-Induced Neuroendocrine Differentiation of Prostate Cancer Cells (United States)


    regulatory networks in Saccharomyces cerevisiae . Science 298, 799–804 Second NES in N Terminus of ATF2 8632 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 287...C4-2B or LN3) or VCaP cells were cultured in androgen-free medium in the presence or absence of the Hh inhibitor, cyclopamine. Smoothened (Smo) siRNA...To determine how these clones respond to androgen depletion treatment, we treated cells in phenol-free medium supplemented with 10% CD-FBS for 3

  2. Calnuc plays a role in dynamic distribution of Gαi but not Gβ subunits and modulates ACTH secretion in AtT-20 neuroendocrine secretory cells

    Directory of Open Access Journals (Sweden)

    Huang Haining


    Full Text Available Abstract In AtT-20 cells ACTH secretion is regulated by both Ca2+ and G proteins. We previously demonstrated that calnuc, an EF-hand Ca2+ binding protein which regulates Alzheimer's β-amyloid precursor protein (APP biogenesis, binds both Ca2+ as well as Gα subunits. Here we investigate calnuc's role in G protein-mediated regulation of ACTH secretion in AtT-20 neuroendocrine secretory cells stably overexpressing calnuc-GFP. Similar to endogenous calnuc, calnuc-GFP is mainly found in the Golgi, on the plasma membrane (PM, and associated with regulated secretion granules (RSG. By deconvolution immunofluorescence, calnuc-GFP partially colocalizes with Gαi1/2 and Gαi3 at the PM and on RSG. Cytosolic calnuc(ΔSS-CFP with the signal sequence deleted also partially colocalizes with RSG and partially cosediments with Gαi1/2 in fractions enriched in RSG. Overexpression of calnuc-GFP specifically increases the distribution of Gαi1/2 on the PM whereas the distribution of Gβ subunits and synaptobrevin 2 (Vamp 2 is unchanged. Overexpression of calnuc-GFP or cytosolic calnuc(ΔSS-CFP enhances ACTH secretion two-fold triggered by mastoparan or GTPγS but does not significantly affect glycosaminoglycan (GAG chain secretion along the constitutive pathway or basal secretion of ACTH. Calnuc's facilitating effects on ACTH secretion are decreased after introducing anti-Gαi1/2, Gαi3, Gβ or calnuc IgG into permeabilized cells but not when Gα12 or preimmune IgG is introduced. The results suggest that calnuc binds to Gα subunits on the Golgi and on RSG and that overexpression of calnuc causes redistribution of Gαi subunits to the PM and RSG, indicating that calnuc plays a role in dynamic distribution of only Gα but not Gβ subunits. Thus calnuc may connect G protein signaling and calcium signaling during regulated secretion.

  3. Tracer development for detection and characterization of neuroendocrine tumors with PET

    NARCIS (Netherlands)

    Neels, Olivier Christiaan


    Neuroendocrine tumors are slowly growing tumors which originate from neuroendocrine cells. These tumors can secrete several products. In case of overproduction of serotonin, symptoms such as flushing, diarrhea and right-sided heart disease can occur. Next to serotonin, other well known products are

  4. Is neuroendocrine cell differentiation detected using chromogranin A from patients with bone metastatic prostate cancer a prognostic factor for outcome? (United States)

    Yamada, Yoshiaki; Nakamura, Kogenta; Aoki, Shigeyuki; Taki, Tomohiro; Matsubara, Hiroyuki; Sai, Shotoku; Naruse, Katsuya; Tobiume, Motoi; Katsuda, Remi; Zennami, Kenji; Honda, Nobuaki; Nakagawa, Atsuko; Ikeda, Hiroshi


    We evaluated the usefulness of overexpression of neuroendrocrine (NE) cell differentiation determined by immunohistochemical staining for chromogranin A (Cg A) in diagnostic needle biopsy specimens of bone metastatic prostate cancers. A total of 50 patients diagnosed as having bone metastatic prostate cancer were studied. The period of observation was between 6.9 and 79.4 months (median 48.7 months). Cg A was detected by immunostaining using the labeled streptavidin biotin method. Cg A-positivity was defined as the presence of immunostained cells in 10% or more of the tumor. All statistical analyses were carried out using the Statistical Package for Social Sciences Software, version 10.0 for Windows. Eleven patients (22%) were classified into the Cg A-positive group. There were no significant differences in clinical data between the Cg A-positive and Cg A-negative groups. The 5-year cause-specific survival rate was 34.1% for the Cg A-positive group and 55.2% for the Cg A-negative group (p=0.3763). The 3-year non-recurrence rate was 9.1% for the Cg A-positive group and 35.9% for the Cg A-negative group, and this difference was significant (p=0.0253). The 3-year cause-specific survival rates after recurrence were 38.4% and 42.3% respectively (p=0.8125). We consider that NE cell differentiation of the primary tumor in cases of bone metastatic prostate cancer is not a prognostic factor for outcome.

  5. Neuroendocrine Immunoregulation in Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Nathalie Deckx


    Full Text Available Currently, it is generally accepted that multiple sclerosis (MS is a complex multifactorial disease involving genetic and environmental factors affecting the autoreactive immune responses that lead to damage of myelin. In this respect, intrinsic or extrinsic factors such as emotional, psychological, traumatic, or inflammatory stress as well as a variety of other lifestyle interventions can influence the neuroendocrine system. On its turn, it has been demonstrated that the neuroendocrine system has immunomodulatory potential. Moreover, the neuroendocrine and immune systems communicate bidirectionally via shared receptors and shared messenger molecules, variously called hormones, neurotransmitters, or cytokines. Discrepancies at any level can therefore lead to changes in susceptibility and to severity of several autoimmune and inflammatory diseases. Here we provide an overview of the complex system of crosstalk between the neuroendocrine and immune system as well as reported dysfunctions involved in the pathogenesis of autoimmunity, including MS. Finally, possible strategies to intervene with the neuroendocrine-immune system for MS patient management will be discussed. Ultimately, a better understanding of the interactions between the neuroendocrine system and the immune system can open up new therapeutic approaches for the treatment of MS as well as other autoimmune diseases.

  6. The cell non-autonomous function of ATG-18 is essential for neuroendocrine regulation of Caenorhabditis elegans lifespan. (United States)

    Minnerly, Justin; Zhang, Jiuli; Parker, Thomas; Kaul, Tiffany; Jia, Kailiang


    Dietary restriction (DR) and reduced insulin growth factor (IGF) signaling extend lifespan in Caenorhabditis elegans and other eukaryotic organisms. Autophagy, an evolutionarily conserved lysosomal degradation pathway, has emerged as a central pathway regulated by various longevity signals including DR and IGF signaling in promoting longevity in a variety of eukaryotic organisms. However, the mechanism remains unclear. Here we show that the autophagy protein ATG-18 acts cell non-autonomously in neuronal and intestinal tissues to maintain C. elegans wildtype lifespan and to respond to DR and IGF-mediated longevity signaling. Moreover, ATG-18 activity in chemosensory neurons that are involved in food detection sufficiently mediates the effect of these longevity pathways. Additionally, ATG-18-mediated cell non-autonomous signaling depends on the release of neurotransmitters and neuropeptides. Interestingly, our data suggest that neuronal and intestinal ATG-18 acts in parallel and converges on unidentified neurons that secrete neuropeptides to regulate C. elegans lifespan through the transcription factor DAF-16/FOXO in response to reduced IGF signaling.

  7. Dynamin-2 regulates fusion pore expansion and quantal release through a mechanism that involves actin dynamics in neuroendocrine chromaffin cells.

    Directory of Open Access Journals (Sweden)

    Arlek M González-Jamett

    Full Text Available Over the past years, dynamin has been implicated in tuning the amount and nature of transmitter released during exocytosis. However, the mechanism involved remains poorly understood. Here, using bovine adrenal chromaffin cells, we investigated whether this mechanism rely on dynamin's ability to remodel actin cytoskeleton. According to this idea, inhibition of dynamin GTPase activity suppressed the calcium-dependent de novo cortical actin and altered the cortical actin network. Similarly, expression of a small interfering RNA directed against dynamin-2, an isoform highly expressed in chromaffin cells, changed the cortical actin network pattern. Disruption of dynamin-2 function, as well as the pharmacological inhibition of actin polymerization with cytochalasine-D, slowed down fusion pore expansion and increased the quantal size of individual exocytotic events. The effects of cytochalasine-D and dynamin-2 disruption were not additive indicating that dynamin-2 and F-actin regulate the late steps of exocytosis by a common mechanism. Together our data support a model in which dynamin-2 directs actin polymerization at the exocytosis site where both, in concert, adjust the hormone quantal release to efficiently respond to physiological demands.

  8. Tracking Ca2+-dependent and Ca2+-independent conformational transitions in syntaxin 1A during exocytosis in neuroendocrine cells. (United States)

    Greitzer-Antes, Dafna; Barak-Broner, Noa; Berlin, Shai; Oron, Yoram; Chikvashvili, Dodo; Lotan, Ilana


    A key issue for understanding exocytosis is elucidating the various protein interactions and the associated conformational transitions underlying soluble N-ethylmeleimide-sensitive factor attachment protein receptor (SNARE) protein assembly. To monitor dynamic changes in syntaxin 1A (Syx) conformation along exocytosis, we constructed a novel fluorescent Syx-based probe that can be efficiently incorporated within endogenous SNARE complexes, support exocytosis, and report shifts in Syx between 'closed' and 'open' conformations by fluorescence resonance energy transfer analysis. Using this probe we resolve two distinct Syx conformational transitions during membrane depolarization-induced exocytosis in PC12 cells: a partial 'opening' in the absence of Ca(2+) entry and an additional 'opening' upon Ca(2+) entry. The Ca(2+)-dependent transition is abolished upon neutralization of the basic charges in the juxtamembrane regions of Syx, which also impairs exocytosis. These novel findings provide evidence of two conformational transitions in Syx during exocytosis, which have not been reported before: one transition directly induced by depolarization and an additional transition that involves the juxtamembrane region of Syx. The superior sensitivity of our probe also enabled detection of subtle Syx conformational changes upon interaction with VAMP2, which were absolutely dependent on the basic charges of the juxtamembrane region. Hence, our results further suggest that the Ca(2+)-dependent transition in Syx involves zippering between the membrane-proximal juxtamembrane regions of Syx and VAMP2 and support the recently implied existence of this zippering in the final phase of SNARE assembly to catalyze exocytosis.

  9. Pitfalls in the diagnosis of neuroendocrine tumors: atypical clinical and radiological findings as cause of medical mistakes. (United States)

    Bajetta, Emilio; Catena, Laura; Ducceschi, Monika; Pusceddu, Sara; Milione, Massimo; Maccauro, Marco; Bajetta, Roberto; Procopio, Giuseppe; Buzzoni, Roberto; Formisano, Barbara; Di Guardo, Lorenza; Platania, Marco


    Carcinoids are infrequent neoplasms arising from neuroendocrine cells. Due to blurred symptoms and the presence of equivocal diagnostic findings, these tumors are sometimes misdiagnosed. Therefore, increased rates of false neuroendocrine tumors represent an emerging problem in clinical practice. Our aim is to alert clinicians on this matter by supplying them with useful warnings. In the specialized neuroendocrine tumor study Center Centro di Riferimento per lo Studio e la Cura dei Carcinoidi e dei Tumori Neuroendocrini (Ce.Ri.Ca), some patients highly suspected to have a neuroendocrine tumor have been recognized as having false neuroendocrine tumors. The related clinical and instrumental findings leading to a previous wrong neuroendocrine tumor diagnosis are reported. From July 2006 to December 2008, 88 consecutive cases of neuroendocrine tumors (Nets) were referred at Ce.Ri.Ca. In the former group, 8 cases of false Nets were discovered while in the remaining 80 cases a correct Net diagnosis was carried out. Watchful differential diagnoses and skill appraisal of laboratory investigations resulted in: chronic atrophic gastritis with enterochromaffin-like cell hyperplasia (4 cases), estrogen-deprivation syndrome (1), hypochondriac disorder (1), metabolic syndrome (1), and sarcoidosis (1). Neuroendocrine tumors are still relatively known clinical entities. To discriminate false neuroendocrine tumors from neuroendocrine tumors requires a good expertise and a large daily practice with the disease. Good knowledge and skillfulness in identifying biochemical alterations and false radiological positive results could avoid both patient inconvenience and very expensive workup. The importance of a multidisciplinary approach in specialized centers is emphasized.

  10. Neuroendocrine control of ionic balance in zebrafish. (United States)

    Kwong, Raymond W M; Kumai, Yusuke; Perry, Steve F


    Zebrafish (Danio rerio) is an emerging model for integrative physiological research. In this mini-review, we discuss recent advances in the neuroendocrine control of ionic balance in this species, and identify current knowledge gaps and issues that would benefit from further investigation. Zebrafish inhabit a hypo-ionic environment and therefore are challenged by a continual loss of ions to the water. To maintain ionic homeostasis, they must actively take up ions from the water and reduce passive ion loss. The adult gill or the skin of larvae are the primary sites of ionic regulation. Current models for the uptake of major ions in zebrafish incorporate at least three types of ion transporting cells (also called ionocytes); H(+)-ATPase-rich cells for Na(+) uptake, Na(+)/K(+)-ATPase-rich cells for Ca(2+) uptake, and Na(+)/Cl(-)-cotransporter expressing cells for both Na(+) and Cl(-) uptake. The precise molecular mechanisms regulating the paracellular loss of ions remain largely unknown. However, epithelial tight junction proteins, including claudins, are thought to play a critical role in reducing ion losses to the surrounding water. Using the zebrafish model, several key neuroendocrine factors were identified as regulators of epithelial ion movement, including the catecholamines (adrenaline and noradrenaline), cortisol, the renin-angiotensin system, parathyroid hormone and prolactin. Increasing evidence also suggests that gasotransmitters, such as H2S, are involved in regulating ion uptake. Copyright © 2016 Elsevier Inc. All rights reserved.


    Directory of Open Access Journals (Sweden)

    Pasupuleti Prathima


    Full Text Available BACKGROUND Neuroendocrine tumours occur at various sites in the human body. They are considered as one of the close differentials for many tumours. Various benign and malignant tumours undergo neuroendocrine differentiation. Its incidence is slightly increasing due to advanced imaging modalities. Although rare, they can be seen in breast, gallbladder and skin. The aim of the study is to study the spectrum of neuroendocrine tumours from various sites, their clinical presentation, histomorphological features with immunohistochemistry and review of literature. MATERIALS AND METHODS This is a retrospective study for a period of 3 years (June 2013-June 2016. Surgical resection specimens were included in the study. Out of the total specimens received, 24 cases were of neuroendocrine tumours. Differential diagnosis of small round cell tumours also was considered and a panel of immunohistochemical markers were included to rule out them. Biopsy specimens were excluded from the study. RESULTS Out of the 24 cases, 18 cases were benign lesions. 6 cases were malignant lesions. Female preponderance was noted. Peak incidence was seen in 20-30 years of age group. CONCLUSION Neuroendocrine tumours can occur anywhere in the body and it should be considered in one of the differential diagnosis. Diagnosis must be accurately made.

  12. Immune-Neuroendocrine Interactions: Evolution, Ecology, and Susceptibility to Illness. (United States)

    Blom, Johanna M C; Ottaviani, Enzo


    The integration between immune and neuroendocrine systems is crucial for maintaining homeostasis from invertebrates to humans. In the first, the phagocytic cell, i.e., the immunocyte, is the main actor, while in the latter, the principle player is the lymphocyte. Immunocytes are characterized by the presence of pro-opiomelanocortin (POMC) peptides, CRH, and other molecules that display a significant similarity to their mammalian counterparts regarding their functions, as both are mainly involved in fundamental functions such as immune (chemotaxis, phagocytosis, cytotoxicity, etc.) and neuroendocrine (stress) responses. Furthermore, the immune-neuroendocrine system provides vital answers to ecological and immunological demands in terms of economy and efficiency. Finally, susceptibility to disease emerges as the result of a continuous dynamic interaction between the world within and the world outside. New fields such as ecological immunology study the susceptibility to pathogens in an evolutionary perspective while the field of neuro-endocrine-immunology studies the susceptibility from a more immediate perspective.

  13. Unusual apocrine carcinoma with neuroendocrine differentiation: a cutaneous neoplasm may be analogous to neuroendocrine carcinoma with apocrine differentiation of breast. (United States)

    Li, Yang; Chen, Li-li; Li, Bin; Tian, Xiao-ying; Li, Zhi


    Cutaneous apocrine carcinoma (AC) is a rare adnexal neoplasm that histologically can mimic breast carcinoma metastatic to the skin or apocrine carcinoma arising in ectopic breast tissue. As extremely rare condition, neuroendocrine differentiation may be observed in AC although its etiology and pathogenesis is still unclear. We report here a case of unusual AC with neuroendocrine differentiation in right labium majus pudenda. A 43-year-old woman presented with a 6-month history of an asymptomatic pea-sized brownish nodule in right labium majus pudenda without enlargement of inguinal lymph nodes and bilateral breast nodules. The mass was totally resected. Microscopically, the tumor was solitary and located in the deep dermis without epidermal connection. Tumor cells were arranged in a micronodular or formed massive solid nests separated by densely fibroblastic stroma. Scattered glandular or rosette-like structures were identified within the tumor nodules. Immunohistochemically, the tumor cells were diffusely positive to CK7, CEA, GCDFP-15, synaptophysin, estrogen and progesterone receptors. Part of tumor cells expressed androgen receptor, but they were negative to CK20, CK5/6, p63 and S-100. Because of its rarity and histogenesis complexity, there exist diagnostic challenges for pathologists to differentiate cutaneous AC with neuroendocrine differentiation from other carcinomas with apocrine or neuroendocrine features. Our case demonstrates that the tumor shares some features with mammary carcinoma and might originate from mammary-like sweat gland in anogenital region. The results suggest that, for the first time, primary cutaneous AC with neuroendocrine differentiation may be analogous to the mammary neuroendocrine carcinoma with apocrine differentiation in histological feature and biological behavior. Virtual Slides: The virtual slide(s) for this article can be found here:

  14. Neuroendocrine effects of cytokines in the rat. (United States)

    Rivier, C


    The necessity ot maintain and/or restore homeostasis is an essential feature of mammals. This requires complex interactions between body cells, such as those from the immune and neuroendocrine systems, and in particular implies that the occurrence of immune activation be conveyed to the brain. It is now widely recognized that following infection, injury or inflammation, some immune cells (particularly macrophages) produce polypeptides called cytokines, interleukins or lymphokines /48/. These proteins provide the basis for intercellular communication between leukocytes (hence the name "interleukins") and mediate the immunoinflammatory responses (in particular T and B lymphocyte proliferation) /4,177/. In addition, interleukins (IL) can enter the general circulation and reach cells of the neuroendocrine axes, a phenomenon which represents one arm of the bidirectional communication links between the immune and the endocrine systems /25/. The early events which take place after presentation of an antigen (the so-called "acute-phase response" /89/) include metabolic and endocrine changes, such as changes in the circulating levels of insulin, TSH, GH, LH and ACTH, as well as adrenal and gonadal steroids /7,14/. This article reviews our present state of knowledge with regard to the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes of the rodent in response to interleukins.

  15. Neuroendocrine differentiation in a case of cervical cancer | Rashed ...

    African Journals Online (AJOL)

    tumor; that further showed neuroendocrine differentiation, as demonstrated by chromogranin-A positivity. It is important to differentiate small cell carcinoma from other malignant tumors of the uterine cervix. Morphological features play an important role in making a diagnosis and the immunohistochemistry study can offer an ...

  16. Reclassification of neuroendocrine tumors improves the separation of carcinoids and the prediction of survival

    DEFF Research Database (Denmark)

    Skov, B.G.; Krasnik, M.; Lantuejoul, S.


    INTRODUCTION: The classification of neuroendocrine lung tumors has changed over the last decades. Reliable diagnoses are crucial for the quality of clinical databases. The purpose of this study is to determine to which extent the use of different diagnostic criteria of neuroendocrine lung tumors.......03). However, the number of removed lymph nodes were insufficient for definitive determination of the prognostic impact of node metastases. Regarding the revised diagnoses, a significant difference in survival between typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma and small cell...

  17. Diffuse endocrine system, neuroendocrine tumors and immunity: what's new? (United States)

    Ameri, Pietro; Ferone, Diego


    During the last two decades, research into the modulation of immunity by the neuroendocrine system has flourished, unravelling significant effects of several neuropeptides, including somatostatin (SRIH), and especially cortistatin (CST), on immune cells. Scientists have learnt that the diffuse neuroendocrine system can regulate the immune system at all its levels: innate immunity, adaptive immunity, and maintenance of immune tolerance. Compelling studies with animal models have demonstrated that some neuropeptides may be effective in treating inflammatory disorders, such as sepsis, and T helper 1-driven autoimmune diseases, like Crohn's disease and rheumatoid arthritis. Here, the latest findings concerning the neuroendocrine control of the immune system are discussed, with emphasis on SRIH and CST. The second part of the review deals with the immune response to neuroendocrine tumors (NETs). The anti-NET immune response has been described in the last years and it is still being characterized, similarly to what is happening for several other types of cancer. In parallel with investigations addressing the mechanisms by which the immune system contrasts NET growth and spreading, ground-breaking clinical trials of dendritic cell vaccination as immunotherapy for metastatic NETs have shown in principle that the immune reaction to NETs can be exploited for treatment. Copyright © 2012 S. Karger AG, Basel.

  18. Safety and Tolerability of Everolimus as Second-line Treatment in Poorly Differentiated Neuroendocrine Carcinoma / Neuroendocrine Carcinoma G3 (WHO 2010) and Neuroendocrine Tumor G3 - an Investigator Initiated Phase II Study (United States)


    Poorly Differentiated Malignant Neuroendocrine Carcinoma; Neuroendocrine Carcinoma, Grade 3; Neuroendocrine Carcinoma, Grade 1 [Well-differentiated Neuroendocrine Carcinoma] That Switched to G3; Neuroendocrine Carcinoma, Grade 2 [Moderately Differentiated Neuroendocrine Carcinoma] That Switched to G3; Neuroendocrine Tumor, Grade 3 and Disease Progression as Measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1.)

  19. Functional imaging of neuroendocrine tumors

    DEFF Research Database (Denmark)

    Binderup, Tina; Knigge, Ulrich; Loft, Annika


    UNLABELLED: Functional techniques are playing a pivotal role in the imaging of cancer today. Our aim was to compare, on a head-to-head basis, 3 functional imaging techniques in patients with histologically verified neuroendocrine tumors: somatostatin receptor scintigraphy (SRS) with (111)In......-diethylenetriaminepentaacetic acid-octreotide, scintigraphy with (123)I-metaiodobenzylguanidine (MIBG), and (18)F-FDG PET. METHODS: Ninety-six prospectively enrolled patients with neuroendocrine tumors underwent SRS, (123)I-MIBG scintigraphy, and (18)F-FDG PET on average within 40 d. The functional images were fused with low......-positive, of which 3 were also (123)I-MIBG scintigraphy-positive, giving a combined overall sensitivity of 96%. SRS also exceeded (123)I-MIBG scintigraphy and (18)F-FDG PET based on the number of lesions detected (393, 185, and 225, respectively) and tumor subtypes. (123)I-MIBG scintigraphy was superior to (18)F...

  20. Towards a unified model of neuroendocrine-immune interaction. (United States)

    Petrovsky, N


    Although the neuroendocrine system has immunomodulating potential, studies examining the relationship between stress, immunity and infection have, until recently, largely been the preserve of behavioural psychologists. Over the last decade, however, immunologists have begun to increasingly appreciate that neuroendocrine-immune interactions hold the key to understanding the complex behaviour of the immune system in vivo. The nervous, endocrine and immune systems communicate bidirectionally via shared messenger molecules variously called neurotransmitters, cytokines or hormones. Their classification as neurotransmitters, cytokines or hormones is more serendipity than a true reflection of their sphere of influence. Rather than these systems being discrete entities we would propose that they constitute, in reality, a single higher-order entity. This paper reviews current knowledge of neuroendocrine-immune interaction and uses the example of T-cell subset differentiation to show the previously under-appreciated importance of neuroendocrine influences in the regulation of immune function and, in particular, Th1/Th2 balance and diurnal variation there of.

  1. Cowden Syndrome and Concomitant Pulmonary Neuroendocrine Tumor

    DEFF Research Database (Denmark)

    Langer, Seppo W; Ringholm, Lene; Dali, Christine I


    Cowden Syndrome is a rare autosomal dominantly inherited disorder. Patients with Cowden Syndrome are at increased risk of various benign and malignant neoplasms in breast, endometrium, thyroid, gastrointestinal tract, and genitourinary system. Neuroendocrine tumors are ubiquitous neoplasms that may...... occur anywhere in the human body. Bronchopulmonary neuroendocrine tumors include four different histological subtypes, among these, typical and atypical pulmonary carcinoids. No association between Cowden Syndrome and neuroendocrine tumors has previously been described. We present two cases of Cowden...

  2. Androgen deprivation of the PC-310 [correction of prohormone convertase-310] human prostate cancer model system induces neuroendocrine differentiation

    NARCIS (Netherlands)

    J. Jongsma (Johan); M.H. Oomen; M.A. Noordzij (Marinus); W.M. van Weerden (Wytske); G.J. Martens; Th.H. van der Kwast (Theo); F.H. Schröder (Fritz); G.J. van Steenbrugge (Gert Jan)


    textabstractNeuroendocrine (NE) cells are androgen-independent cells and secrete growth-modulating neuropeptides via a regulated secretory pathway (RSP). We studied NE differentiation after androgen withdrawal in the androgen-dependent prostate cancer xenograft PC-310.

  3. An In Vitro System Comprising Immortalized Hypothalamic Neuronal Cells (GT1–7 Cells for Evaluation of the Neuroendocrine Effects of Essential Oils

    Directory of Open Access Journals (Sweden)

    Dai Mizuno


    Full Text Available Aromatherapy and plant-based essential oils are widely used as complementary and alternative therapies for symptoms including anxiety. Furthermore, it was reportedly effective for the care of several diseases such as Alzheimer’s disease and depressive illness. To investigate the pharmacological effects of essential oils, we developed an in vitro assay system using immortalized hypothalamic neuronal cells (GT1–7 cells. In this study, we evaluated the effects of essential oils on neuronal death induced by hydrogen peroxide (H2O2, aluminum, zinc, or the antagonist of estrogen receptor (tamoxifen. Among tests of various essential oils, we found that H2O2-induced neuronal death was attenuated by the essential oils of damask rose, eucalyptus, fennel, geranium, ginger, kabosu, mandarin, myrrh, and neroli. Damask rose oil had protective effects against aluminum-induced neurotoxicity, while geranium and rosemary oil showed protective activity against zinc-induced neurotoxicity. In contrast, geranium oil and ginger oil enhanced the neurotoxicity of tamoxifen. Our in vitro assay system could be useful for the neuropharmacological and endocrine pharmacological studies of essential oils.

  4. INSM1 Demonstrates Superior Performance to the Individual and Combined Use of Synaptophysin, Chromogranin and CD56 for Diagnosing Neuroendocrine Tumors of the Thoracic Cavity. (United States)

    Rooper, Lisa M; Sharma, Rajni; Li, Qing Kay; Illei, Peter B; Westra, William H


    Despite the importance of recognizing neuroendocrine differentiation when diagnosing tumors of the thoracic cavity, the sensitivity of traditional neuroendocrine markers is suboptimal, particularly for high-grade neuroendocrine carcinomas such as small cell lung carcinoma and large cell neuroendocrine carcinoma. To increase sensitivity, neuroendocrine markers are routinely ordered as panels of multiple immunostains where any single positive marker is regarded as sufficient evidence of neuroendocrine differentiation. Insulinoma-associated protein 1 (INSM1) is a well-validated transcription factor of neuroendocrine differentiation that has only recently been evaluated for diagnostic use. We performed INSM1 immunohistochemistry on a large series of thoracic neuroendocrine and non-neuroendocrine tumors and compared its performance to synaptophysin, chromogranin, and CD56. INSM1 was positive in 94.9% of small cell lung carcinomas and 91.3% of large cell neuroendocrine carcinomas, compared with 74.4% and 78.3% with the combined panel of traditional markers. INSM1 also stained all (100%) of the atypical carcinoids, typical carcinoids and mediastinal paragangliomas, but only 3.3% of adenocarcinomas and 4.2% of squamous cell carcinomas. Overall, INSM1 demonstrated a sensitivity of 96.4% across all grades of thoracic neuroendocrine tumors, significantly more than the 87.4% using the panel of traditional markers (P=0.02). INSM1 is sufficiently sensitive and specific to serve as a standalone first-line marker of neuroendocrine differentiation. A more restrained approach to immunohistochemical analysis of small thoracic biopsies is appropriate given the expanding demand on this limited material for therapeutic biomarker analysis.

  5. A Neuroendocrine Carcinoma of Undetermined Origin in a Dog


    Kuwata, Kazunori; Shibutani, Makoto; Kemmochi, Yusuke; Taniai, Eriko; Morita, Reiko; Ogawa, Bunichiro; Mitsumori, Kunitoshi


    In this report, we describe a case of neuroendocrine carcinoma of undetermined origin in a dog. Necropsy revealed scattered small neoplastic nodules in the bilateral lungs and a small nodule in the parapancreatic lymph node. Histopathologically, both pulmonary and lymph nodal nodules showed a similar histologic pattern, with neoplastic cells being arranged in diffusely proliferating sheet-like cellular nests separated by variable amounts of fibrous septa, sometimes forming rosettes and duct-l...

  6. Gastrointestinal Surgery of Neuroendocrine Neoplasms

    DEFF Research Database (Denmark)

    Hansen, Carsten Palnæs; Olsen, Ingrid Marie Holst; Knigge, Ulrich


    Surgery is the only treatment that may cure the patient with gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) and should always be considered as the first-line treatment if radical resection can be achieved. Even in cases where radical surgery is not possible, palliative resection may...... be performed to reduce local or hormone-induced symptoms and to improve quality of life. The surgical procedures for GEP-NENs are accordingly described below. In most patients life-long follow-up is required, even following radical surgery, as recurrence may occur several years later....

  7. A neuroendocrine carcinoma of undetermined origin in a dog. (United States)

    Kuwata, Kazunori; Shibutani, Makoto; Kemmochi, Yusuke; Taniai, Eriko; Morita, Reiko; Ogawa, Bunichiro; Mitsumori, Kunitoshi


    In this report, we describe a case of neuroendocrine carcinoma of undetermined origin in a dog. Necropsy revealed scattered small neoplastic nodules in the bilateral lungs and a small nodule in the parapancreatic lymph node. Histopathologically, both pulmonary and lymph nodal nodules showed a similar histologic pattern, with neoplastic cells being arranged in diffusely proliferating sheet-like cellular nests separated by variable amounts of fibrous septa, sometimes forming rosettes and duct-like structures. Scattered small necrotic foci and invasion to fibrous septa were typically observed. Neoplastic cells showed round to oval-shaped nuclei with prominent nucleoli and abundant eosinophilic cytoplasm that were positive for Grimelius' silver impregnation staining and immunostaining with cytokeratin, synaptophysin, vasoactive intestinal peptide and chromogranin A, indicative of the development of a neuroendocrine carcinoma. However, judging from the distribution of tumors lacking the portion suggestive of the primary site in any organ examined, as well as no further indication of differentiation potential of neoplastic cells, this tumor has so far been diagnosed as neuroendocrine carcinoma of undetermined origin.

  8. A Case of Focal Small-cell Neuroendocrine Carcinoma in the Vicinity of the Extrahepatic Bile Duct, Adjacent to an Extensive Biliary Intraepithelial Neoplasm: A Diagnostic Challenge with Major Clinical Implications. (United States)

    Aigner, Birgit; Kornprat, Peter; Schöllnast, Helmut; Kasparek, Anne-Katrin; Mischinger, Hans-Jörg; Haybaeck, Johannes


    Gastroenteropancreatic neuroendocrine tumors are known for their aggressiveness. Diagnosis of various bile duct pathologies, like biliar intraepithelial neoplasm, mixed adenoneuroendocrine carcinomas or small cell carcinomas, is challenging. This case report focuses on a rare case of a focal primary minute small cell carcinoma in the vicinity of the extrahepatic bile duct, presenting itself next to an extensive biliar intraepithelial neoplasm. This finding led to adjuvant chemotherapy, followed by major surgery. Therapeutic approach was based on CT and MRI scans but most importantly on immunohistochemistry and histological evaluation. Initially CR seemed achievable, but metastases were to be found rapidly. The authors want to underline the fact that major clinical decisions are based on sometimes tiny specimens; as literature shows it is absolutely advisable to use markers to differentiate the dignity of investigated areas. The authors call for keeping collision of tumors in mind and adding KOC staining and using it in a routine manner examining biliary duct lesions. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  9. Contemporary Incidence and Mortality Rates of Neuroendocrine Prostate Cancer. (United States)

    Alanee, Shaheen; Moore, Aaron; Nutt, Max; Holland, Bradley; Dynda, Danuta; El-Zawahry, Ahmed; McVary, Kevin T


    The purpose of the study was to provide an update ever the incidence and mortality for neuroendocrine prostate cancer (NEPC) in the United States. Using a large national database, we examined changes in age-adjusted incidence (AAIR), mortality rates (MR) and 5-year cancer-specific survival (CSS) for 378 patients diagnosed with NEPC between 1992 and 2011. Analysis was performed for all NEPC and for its two major sub-groups [small cell carcinoma (SCC) and neuroendocrine carcinoma (NEC)]. AAIR of NEPC continues to rise in recent years (2004-2011:+6.8%/year, p>0.05). AAIR of SCC has been increasing significantly by 6.94%/year since 2001 (from 0.470 to 0.582/1,000,000 person years, pAAIR of SCC is increasing with no change in the MR of NEPC over the past 20 years. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  10. Altered Neuroendocrine Immune Responses, a Two-Sword Weapon against Traumatic Inflammation. (United States)

    Yang, Ce; Gao, Jie; Du, Juan; Yang, Xuetao; Jiang, Jianxin


    During the occurrence and development of injury (trauma, hemorrhagic shock, ischemia and hypoxia), the neuroendocrine and immune system act as a prominent navigation leader and possess an inter-system crosstalk between the reciprocal information dissemination. The fundamental reason that neuroendocrinology and immunology could mix each other and permeate toward the field of traumatology is owing to their same biological languages or chemical information molecules (hormones, neurotransmitters, neuropeptides, cytokines and their corresponding receptors) shared by the neuroendocrine and immune systems. The immune system is not only modulated by the neuroendocrine system, but also can modulate the biological functions of the neuroendocrine system. The interactive linkage of these three systems precipitates the complicated space-time patterns for the courses of traumatic inflammation. Recently, compelling evidence indicates that the network linkage pattern that initiating agents of neuroendocrine responses, regulatory elements of immune cells and effecter targets for immune regulatory molecules arouse the resistance mechanism disorders, which supplies the beneficial enlightenment for the diagnosis and therapy of traumatic complications from the view of translational medicine. Here we review the alternative protective and detrimental roles as well as possible mechanisms of the neuroendocrine immune responses in traumatic inflammation.

  11. High grade neuroendocrine lung tumors: pathological characteristics, surgical management and prognostic implications. (United States)

    Grand, Bertrand; Cazes, Aurélie; Mordant, Pierre; Foucault, Christophe; Dujon, Antoine; Guillevin, Elizabeth Fabre; Barthes, Françoise Le Pimpec; Riquet, Marc


    Among non-small cell lung cancers (NSCLC), large cell carcinoma (LCC) is credited of significant adverse prognosis. Its neuroendocrine subtype has even a poorer diagnosis, with long-term survival similar to small cell lung cancer (SCLC). Our purpose was to review the surgical characteristics of those tumors. The clinical records of patients who underwent surgery for lung cancer in two French centers from 1980 to 2009 were retrospectively reviewed. We more particularly focused on patients with LCC or with high grade neuroendocrine lung tumors. High grade neuroendocrine tumors were classified as pure large cell neuroendocrine carcinoma (pure LCNEC), NSCLC combined with LCNEC (combined LCNEC), and SCLC combined with LCNEC (combined SCLC). There were 470 LCC and 155 high grade neuroendocrine lung tumors, with no difference concerning gender, mean age, smoking habits. There were significantly more exploratory thoracotomies in LCC, and more frequent postoperative complications in high grade neuroendocrine lung tumors. Pathologic TNM and 5-year survival rates were similar, with 5-year ranging from 34.3% to 37.6% for high grade neuroendocrine lung tumors and LCC, respectively. Induction and adjuvant therapy were not associated with an improved prognosis. The subgroups of LCNEC (pure NE, combined NE) and combined SCLC behaved similarly, except visceral pleura invasion, which proved more frequent in combined NE and less frequent in combined SCLC. Survival analysis showed a trend toward a lower 5-year survival in case of combined SCLC. Therefore, LCC, LCNEC and combined SCLC share the same poor prognosis, but surgical resection is associated with long-term survival in about one third of patients. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  12. Breast Carcinoma With Unrecognized Neuroendocrine Differentiation Metastasizing to the Pancreas

    DEFF Research Database (Denmark)

    Christensen, Lene Svendstrup; Mortensen, Michael Bau; Detlefsen, Sönke


    , a second panel revealed positivity for estrogen receptors and GATA3. On review of the lumpectomy specimen, a significant neuroendocrine component was found, leading to the final diagnosis of breast carcinoma with neuroendocrine features metastasizing to the pancreas. Neuroendocrine markers...... are not routinely analyzed in breast tumors. Hence, metastases from breast carcinomas with unrecognized neuroendocrine features may lead to false diagnoses of primary neuroendocrine tumors at different metastatic sites, such as the pancreas....

  13. Unusual Paraneoplastic Syndrome Accompanies Neuroendocrine Tumours of the Pancreas

    Directory of Open Access Journals (Sweden)

    Helga Bertani


    Full Text Available Neuroendocrine tumours comprise a small percentage of pancreatic neoplasia (10% (1. Diagnosis of neuroendocrine tumours is difficult, especially if the tumours are small and nonfunctional. CT scans, MRI, and nuclear scans are sufficiently sensitive assessment tools for tumours with diameters of at least 2 cm; otherwise, the sensitivity and specificity of these techniques is less than 50% (2. Myasthenia gravis (MG is a heterogeneous neuromuscular junction disorder that is primarily caused when antibodies form against the acetylcholine receptors (Ab-AchR. MG can develop in conjunction with neoplasia, making MG a paraneoplastic disease. In those cases, MG is most commonly associated with thymomas and less frequently associated with extrathymic malignancies. The mechanism underlying this paraneoplastic syndrome has been hypothesized to involve an autoimmune response against the tumour cells (3. No published reports have linked malignant pancreatic diseases with MG. Here, we report the case of a young woman, negative for Ab-AchR, with a neuroendocrine tumour in the pancreatic head, who experienced a complete resolution of her MG-like syndrome after surgical enucleation of the tumour.

  14. Mucinous Carcinoma with Neuroendocrine Differentiation of Salivary Gland Origin. (United States)

    Wong, Frankie K; Zumsteg, Zachary S; Langevin, Claude-Jean; Ali, Nabilah; Maclary, Shawn; Balzer, Bonnie L; Ho, Allen S


    Primary mucinous adenocarcinomas of the salivary gland are rare malignancies defined by aggregates of epithelial cells suspended in large pools of extracellular mucin. We report a case of a giant mucinous adenocarcinoma of salivary gland origin, with low-grade cytoarchitectural features and neuroendocrine differentiation arising in the submental region. Grossly, the tumor measured 12.5 × 13.4 × 8.2 cm and replaced the bone and soft tissues of the anterior oral cavity. Microscopically, the neoplasm was composed of large extracellular pools of mucin, which contained papillary and acinar aggregates, and small nodules of ductal type epithelium with minimal nuclear enlargement, powdery chromatin and little pleomorphism. The nodules comprised 20 % of the tumor and showed morphologic and immunohistochemical evidence of neuroendocrine differentiation. Examination revealed histologic features comparable to mammary gland analogues in mucin predominance, ductal type morphology, expression of estrogen and progesterone receptors, and GATA-3 positivity. This is the first case reported of mucin-rich carcinoma of salivary gland origin exhibiting neuroendocrine differentiation.

  15. Neuroendocrine and Immune System Responses with Spaceflights (United States)

    Tipton, Charles M.; Greenleaf, John E.; Jackson, Catherine G. R.


    -lymphocytes and natural killer cells are decreased with post-flight conditions. Of the lymphokines, interleukin-2 production, lymphocyte responsiveness, and the activity of natural killer cells are consistently reduced post-flight. Limited head-down tilt (HDT) data suggest it is an effective simulation model for microgravity investigations. Neuroendocrine and pharmacological countermeasures are virtually nonexistent arid should become high priority items for future research. Although exercise has the potential to be an effective countermeasure for various neuroen-docrine-immune responses in microgravity, this concept must be tested before flights to Mars are scheduled.

  16. Minichromosome Maintenance Expression Defines Slow-Growing Gastroenteropancreatic Neuroendocrine Neoplasms

    Directory of Open Access Journals (Sweden)

    Simon Schimmack


    Full Text Available BACKGROUND: Small intestinal neuroendocrine neoplasm (SI-NEN proliferation is quantified by Ki67 measurements which capture G1-G2M phases of the cell cycle. G0 and early G1 phases, typical of slow-growing cells, can be detected by minichromosome maintenance protein (MCM expression. We hypothesized that these replication licensing markers may provide clinically relevant information to augment Ki67 in low-grade neuroendocrine neoplasia. METHODS: Immunohistochemical staining (IHC, Western blot analysis, quantitative polymerase chain reaction, and copy number variations of MCM2, MCM3, and Ki67 were undertaken in SI-NENs (n = 22. MCM and Ki67 expression was compared by Kaplan-Meier survival analysis (tissue microarray, independent set [n = 55]. Forty-three pancreatic NENs and 14 normal tissues were included as controls. RESULTS: In SI-NENs, MCM2 (mean: 21.2%: range: 16%-25% and MCM3 (28.7%: 22%-34% were detected in significantly more cells than Ki67 (2.3%: 0%-7%, P < .01. MCM2 mRNA correlated with Ki67 IHC (P < .05. MCM3 protein expression was higher in metastases (38-fold than in normal small intestine (P = .06 and was largely absent in normal neuroendocrine cells. There was considerable variation at the MCM copy number level (0-4 copies. MCM3 expression in proliferating cells significantly predicted overall survival (P < .002. Combinations of Ki67 and MCM2/3 in algorithms differentiated low and higher proliferative lesions (overall survival: 12 vs 6.1 years, P = .06. MCM expression was not informative in pancreatic NENs. CONCLUSION: MCMs are expressed in a higher proportion of NEN cells than Ki67 in slow-growing small intestinal lesions and correlate with survival. Assessment can be used to augment Ki67 to improve prognostic classification in these low-grade tumors.

  17. Somatostatin-Immunoreactive Pancreaticoduodenal Neuroendocrine Neoplasms

    DEFF Research Database (Denmark)

    Engelund Luna, Iben; Monrad, Nina; Binderup, Tina


    OBJECTIVE: Neuroendocrine neoplasms in the pancreas and duodenum with predominant or exclusive immunoreactivity for somatostatin (p-dSOMs) are rare, and knowledge on tumour biology, treatment, survival and prognostic factors is limited. This study aimes to describe clinical, pathological, and bio......OBJECTIVE: Neuroendocrine neoplasms in the pancreas and duodenum with predominant or exclusive immunoreactivity for somatostatin (p-dSOMs) are rare, and knowledge on tumour biology, treatment, survival and prognostic factors is limited. This study aimes to describe clinical, pathological...

  18. Contemporary nuclear medicine diagnostics of neuroendocrine tumors


    Todorović-Tirnanić Mila; Artiko Vera; Pavlović Smiljana; Šobić-Šaranović Dragana; Obradović Vladimir


    The new positron emission tomography (PET/CT) methods for neuroendocrine tumors detection are presented and compared with classic, conventional methods. Conventional methods use a gamma scintillation camera for patients with neuroendocrine tumor imaging, after intravenous injection of one of the following radiopharmaceuticals: 1) somatostatin analogues labeled with indium-111 (111In-pentetreotide) or technetium-99m (99mTc-EDDA/HYNIC-TOC); 2) noradrenaline a...

  19. Primary Neuroendocrine Carcinoma of Ocular Adnexa

    Directory of Open Access Journals (Sweden)

    Daisuke Yamanouchi


    Full Text Available We present our findings in a case of primary neuroendocrine carcinoma (NEC of the lacrimal gland and a case of primary Merkel cell carcinoma (MCC of the eyelid. An 86-year-old man noticed a swelling of the left upper eyelid three months earlier. We performed excision biopsy and histopathological examination indicated that he had a primary NEC of the left lacrimal gland. He underwent chemotherapy followed by excision including the clinically visible margins and 50 Gy radiotherapy of the surgical margins. He had neither recurrence nor metastasis for 6 months since the last radiotherapy. An 80-year-old man noticed a nodule in the right upper eyelid and was referred to our hospital because the size was increasing rapidly. A complete surgical excision of the margins of the tumor was performed with histopathological confirmation of negative margins. The final diagnosis was a primary MCC of the right upper eyelid. After surgery, he underwent 50 Gy radiotherapy on the neck to prevent metastasis. No recurrence or metastasis was found for two years. Although primary NEC of the ocular adnexa is extremely rare, the tumor has high malignancy and readily metastasizes. Thus, combined therapy including surgery, radiotherapy, and/or chemotherapy is needed for complete management of NEC.

  20. Locally-advanced primary neuroendocrine carcinoma of the breast: case report and review of the literature. (United States)

    Angarita, Fernando A; Rodríguez, Jorge L; Meek, Eugenio; Sánchez, Jesus O; Tawil, Mauricio; Torregrosa, Lilian


    Primary neuroendocrine carcinoma of the breast is a heterogeneous group of rare tumors with positive immunoreactivity to neuroendocrine markers in at least 50% of cells. Diagnosis also requires that other primary sites be ruled out and that the same tumor show histological evidence of a breast in situ component. Primary neuroendocrine carcinoma of the breast rarely presents as locally advanced disease and less frequently with such widespread metastatic disease as described herein. The review accompanying this case report is the first to provide an overview of all the cases of primary neuroendocrine carcinoma of the breast published in the literature and encompasses detailed information regarding epidemiology, histogenesis, clinical and histologic diagnosis criteria, classification, surgical and adjuvant treatment, as well as prognosis. We also provide recommendations for common clinical and histologic pitfalls associated with this tumor. We describe a case of a 51-year-old Hispanic woman initially diagnosed with locally-advanced invasive ductal carcinoma that did not respond to neoadjuvant treatment. After undergoing modified radical mastectomy the final surgical pathology showed evidence of alveolar-type primary neuroendocrine carcinoma of the breast. The patient was treated with cisplatin/etoposide followed by paclitaxel/carboplatinum. Thirteen months after surgery the patient is alive, but developed pulmonary, bone, and hepatic metastasis. The breast in situ component of primary neuroendocrine carcinoma of the breast may prevail on a core biopsy samples increasing the probability of underdiagnosing this tumor preoperatively. Being aware of the existence of this disease allows for timely diagnosis and management. Optimal treatment requires simultaneous consideration of both the neuroendocrine and breast in situ tumor features.

  1. Assessment of functional changes in nanoparticle-exposed neuroendocrine cells with amperometry: exploring the generalizability of nanoparticle-vesicle matrix interactions. (United States)

    Love, Sara A; Haynes, Christy L


    Using two of the most commonly synthesized noble metal nanoparticle preparations, citrate-reduced Au and Ag, the impacts of short-term accidental nanoparticle exposure are examined in primary culture murine adrenal medullary chromaffin cells. Transmission electron microscopy (TEM), inductively coupled plasma atomic emission spectroscopy (ICP-AES) and Alamar Blue viability studies revealed that nanoparticles are taken up by cells but do not decrease cell viability within 48 hours of exposure. Carbon-fiber microelectrode amperometry (CFMA) examination of exocytosis in nanoparticle-exposed cells revealed that nanoparticle exposure does lead to decreased secretion of chemical messenger molecules, of up to 32.5% at 48 hours of Au exposure. The kinetics of intravesicular species liberation also slows after nanoparticle exposure, between 30 and 50% for Au and Ag, respectively. Repeated stimulation of exocytosis demonstrated that these effects persisted during subsequent stimulations, meaning that nanoparticles do not interfere directly with the vesicle recycling machinery but also that cellular function is unable to recover following vesicle content expulsion. By comparing these trends with parallel studies done using mast cells, it is clear that similar exocytosis perturbations occur across cell types following noble metal nanoparticle exposure, supporting a generalizable effect of nanoparticle-vesicle interactions.

  2. A fish model for the study of the relationship between neuroendocrine and immune cells in the intestinal epithelium: Silurus glanis infected with a tapeworm. (United States)

    Dezfuli, B Sayyaf; DePasquale, J A; Castaldelli, G; Giari, L; Bosi, G


    Immunohistochemical, immunofluorescence and ultrastructural studies were conducted on a sub-population of 20 wels catfish Silurus glanis from a tributary of the River Po (Northern Italy). Fish were examined for the presence of ecto- and endo-parasites; in the intestine of 5 fish, 11 specimens of cestode Glanitaenia osculata were noted and was the only helminth species encountered. The architecture of intestine and its cellular features were nearly identical in either the uninfected S. glanis or in those harboring G. osculata. Near the site of worm's attachment, mucous cells, several mast cells (MCs), few neutrophils and some endocrine cells (ECs) were found to co-occur within the intestinal epithelium. MCs and neutrophils were abundant also in the submucosa. Immunohistochemical staining revealed that enteric ECs were immunoreactive to met-enkephalin, galanin and serotonin anti-bodies. The numbers of ECs, mucous cells and MCs were significantly higher in infected wels catfish (Mann-Whitney U test, p < 0.05). Dual immunofluorescence staining with the biotinylated lectin Sambucus nigra Agglutinin and the rabbit polyclonal anti-met-enkephalin or anti-serotonin, with parallel transmission electron microscopy, showed that ECs often made intimate contact with the mucous cells and epithelial MCs. The presence of numerous MCs in intestinal epithelium shows S. glanis to be an interesting model fish to study processes underlying intestinal inflammation elicited by an enteric worm. Immune cells, ECs and mucous cells of the intestinal epithelium have been described at the ultrastructural level and their possible functions and interactions together will be discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. A Drosophila LexA Enhancer-Trap Resource for Developmental Biology and Neuroendocrine Research. (United States)

    Kockel, Lutz; Huq, Lutfi M; Ayyar, Anika; Herold, Emma; MacAlpine, Elle; Logan, Madeline; Savvides, Christina; Kim, Grace E S; Chen, Jiapei; Clark, Theresa; Duong, Trang; Fazel-Rezai, Vahid; Havey, Deanna; Han, Samuel; Jagadeesan, Ravi; Kim, Eun Soo Jackie; Lee, Diane; Lombardo, Kaelina; Piyale, Ida; Shi, Hansen; Stahr, Lydia; Tung, Dana; Tayvah, Uriel; Wang, Flora; Wang, Ja-Hon; Xiao, Sarah; Topper, Sydni M; Park, Sangbin; Rotondo, Cheryl; Rankin, Anne E; Chisholm, Townley W; Kim, Seung K


    Novel binary gene expression tools like the LexA-LexAop system could powerfully enhance studies of metabolism, development, and neurobiology in Drosophila However, specific LexA drivers for neuroendocrine cells and many other developmentally relevant systems remain limited. In a unique high school biology course, we generated a LexA-based enhancer trap collection by transposon mobilization. The initial collection provides a source of novel LexA-based elements that permit targeted gene expression in the corpora cardiaca, cells central for metabolic homeostasis, and other neuroendocrine cell types. The collection further contains specific LexA drivers for stem cells and other enteric cells in the gut, and other developmentally relevant tissue types. We provide detailed analysis of nearly 100 new LexA lines, including molecular mapping of insertions, description of enhancer-driven reporter expression in larval tissues, and adult neuroendocrine cells, comparison with established enhancer trap collections and tissue specific RNAseq. Generation of this open-resource LexA collection facilitates neuroendocrine and developmental biology investigations, and shows how empowering secondary school science can achieve research and educational goals. Copyright © 2016 Kockel et al.

  4. A Drosophila LexA Enhancer-Trap Resource for Developmental Biology and Neuroendocrine Research (United States)

    Kockel, Lutz; Huq, Lutfi M.; Ayyar, Anika; Herold, Emma; MacAlpine, Elle; Logan, Madeline; Savvides, Christina; Kim, Grace E. S.; Chen, Jiapei; Clark, Theresa; Duong, Trang; Fazel-Rezai, Vahid; Havey, Deanna; Han, Samuel; Jagadeesan, Ravi; Kim, Eun Soo Jackie; Lee, Diane; Lombardo, Kaelina; Piyale, Ida; Shi, Hansen; Stahr, Lydia; Tung, Dana; Tayvah, Uriel; Wang, Flora; Wang, Ja-Hon; Xiao, Sarah; Topper, Sydni M.; Park, Sangbin; Rotondo, Cheryl; Rankin, Anne E.; Chisholm, Townley W.; Kim, Seung K.


    Novel binary gene expression tools like the LexA-LexAop system could powerfully enhance studies of metabolism, development, and neurobiology in Drosophila. However, specific LexA drivers for neuroendocrine cells and many other developmentally relevant systems remain limited. In a unique high school biology course, we generated a LexA-based enhancer trap collection by transposon mobilization. The initial collection provides a source of novel LexA-based elements that permit targeted gene expression in the corpora cardiaca, cells central for metabolic homeostasis, and other neuroendocrine cell types. The collection further contains specific LexA drivers for stem cells and other enteric cells in the gut, and other developmentally relevant tissue types. We provide detailed analysis of nearly 100 new LexA lines, including molecular mapping of insertions, description of enhancer-driven reporter expression in larval tissues, and adult neuroendocrine cells, comparison with established enhancer trap collections and tissue specific RNAseq. Generation of this open-resource LexA collection facilitates neuroendocrine and developmental biology investigations, and shows how empowering secondary school science can achieve research and educational goals. PMID:27527793

  5. Mucinous Carcinoma with Neuroendocrine Differentiation of Salivary Gland Origin


    Wong, Frankie K.; Zumsteg, Zachary S.; Langevin, Claude-Jean; Ali, Nabilah; Maclary, Shawn; Balzer, Bonnie L.; Ho, Allen S.


    Primary mucinous adenocarcinomas of the salivary gland are rare malignancies defined by aggregates of epithelial cells suspended in large pools of extracellular mucin. We report a case of a giant mucinous adenocarcinoma of salivary gland origin, with low-grade cytoarchitectural features and neuroendocrine differentiation arising in the submental region. Grossly, the tumor measured 12.5 × 13.4 × 8.2 cm and replaced the bone and soft tissues of the anterior oral cavity. Microscopically, the neo...

  6. Pulmonary neuroendocrine tumor in a female wolf (Canis lupus lupus). (United States)

    Shiraki, Ayako; Yoshida, Toshinori; Kawashima, Masahi; Murayama, Hirotada; Nagahara, Rei; Ito, Nanao; Shibutani, Makoto


    A 17-year-old female wolf (Canis lupus lupus) had a right lung mass that was adhered to the thoracic cavity. Histopathological examination revealed that the mass consisted of sheets, cord or ribbon-like structures of monotonous, small, cuboidal cells with round, oval or short-spindle nuclei and scant clear cytoplasm, demarcated by a fine fibrovascular stroma. Focal necrosis, congestion and thrombi were observed. Immunohistochemically, the tumor cells diffusely expressed cytokeratin AE1/AE3, and some expressed chromogranin A, neural cell adhesion molecule (CD56) and thyroid transcription factor-1. The number of proliferating cell nuclear antigen-positive tumor cells was low. A diagnosis of pulmonary neuroendocrine tumor was based on the resemblance to carcinoids.


    Directory of Open Access Journals (Sweden)

    I. V. Trigolosova


    early disability and death of patients with neuroendocrine diseases.

  8. Endoscopic diagnosis and treatment of neuroendocrine tumors of the digestive system

    Directory of Open Access Journals (Sweden)

    Sivero Luigi


    Full Text Available The authors evaluated the role of endoscopic techniques in the diagnosis and in the potential treatment of neuroendocrine tumors (NET localized in the gastro-entero-pancreatic system, on the basis of their experience and of the international literature. NET are rare tumors that arise from neuroendocrine cells of the gastrointestinal tract and pancreas. It is a possibility that both the digestive endoscopy and EUS play an important role in the diagnosis, staging and surveillance of this disease. In some cases, especially in the early stages, surgical endoscopy allows the treatment of such tumors.

  9. Primary neuroendocrine tumour of the breast: a case report and review of the literature. (United States)

    Tato-Varela, Sara; Albalat-Fernández, Rosa; Pabón-Fernández, Sara; Zarco, Enrique Rodríguez; Calle-Marcos, Manolo La


    Primary neuroendocrine tumour of the breast is a rare entity that first appeared in the 2003 World Health Organisation (WHO) classification of breast tumours. The data currently available on its prognosis are contradictory, although it seems clear that histological varieties such as small cell neuroendocrine carcinoma have a worse prognosis, due to their low degree of differentiation. The treatment of choice is surgery, and the indications for chemotherapy or radiotherapy do not differ greatly from those used for other breast tumours. It is crucial to underline the difficulty of establishing treatment protocols due to the low incidence of this histological type.

  10. Incidental neuroendocrine tumor of the appendiceal base less ...

    African Journals Online (AJOL)

    Incidental neuroendocrine tumor of the appendiceal base less than20 mm in diameter: is appendectomy enough? Landolsi Sana, Mannai Saber. Abstract. The appendixis the second primary site for neuroendocrine tumors. The management of incidentelly discovered neuroendocrine tumor of the appendiceal base less ...

  11. Effect of reserpine on development and its neuro-endocrine regulation in Galleria mellonella

    DEFF Research Database (Denmark)

    Cymborowski, B.; Sørensen, Ilona Kryspin


    1. Studies were made on the effect of reserpine on development and its neuro-endocrine regulation in Galleria mellonella. It was shown that resperine greatly restricts the development of this insect. 2. Reserpine causes inhibition of the activity of the neurosecretory cells of pars intercerebralis...

  12. Increased percentages of regulatory T cells are associated with inflammatory and neuroendocrine responses to acute psychological stress and poorer health status in older men and women. (United States)

    Ronaldson, Amy; Gazali, Ahmad M; Zalli, Argita; Kaiser, Frank; Thompson, Stephen J; Henderson, Brian; Steptoe, Andrew; Carvalho, Livia


    The percentage of regulatory T cells (TRegs)-a subtype of T lymphocyte that suppresses the immune response-appears to be reduced in a number of stress-related diseases. The role of the TReg in stress-disease pathways has not yet been investigated. The aim of the study was to investigate the association between biological responsivity to acute psychosocial stress and the percentage of TRegs in healthy older adults. The secondary purpose was to measure the associations between TReg percentage and psychological and physical well-being in the participants. Salivary cortisol and plasma interleukin (IL)-6 samples were obtained from 121 healthy older men and women from the Whitehall II cohort following acute psychophysiological stress testing. Three years later at a follow-up visit, we measured TReg percentages and psychological and physical well-being were recorded using the Short Form 36 Health Survey and the Center for Epidemiologic Studies Depression Scale. Blunted cortisol responses (p = 0.004) and elevated IL-6 responses (p = 0.027) to acute psychophysiological stress were associated with greater TReg percentage independently of age, sex, BMI, smoking status, employment grade, time of testing, and baseline measures of cortisol and IL-6, respectively. Percentage of TRegs was associated cross-sectionally with lower physical (p = 0.043) and mental health status (p = 0.008), and higher levels of depressive symptoms (p = 0.002), independently of covariates. Increased levels of TRegs may act as a defence against increased inflammation and may be a pre-indication for chronically stressed individuals on the cusp of clinical illness.

  13. Gastroduodenal neuroendocrine neoplasms, including gastrinoma - management guidelines (recommended by the Polish Network of Neuroendocrine Tumours). (United States)

    Lipiński, Michał; Rydzewska, Grażyna; Foltyn, Wanda; Andrysiak-Mamos, Elżbieta; Bałdys-Waligórska, Agata; Bednarczuk, Tomasz; Blicharz-Dorniak, Jolanta; Bolanowski, Marek; Boratyn-Nowicka, Agnieszka; Borowska, Małgorzata; Cichocki, Andrzej; Ćwikła, Jarosław B; Falconi, Massimo; Handkiewicz-Junak, Daria; Hubalewska-Dydejczyk, Alicja; Jarząb, Barbara; Junik, Roman; Kajdaniuk, Dariusz; Kamiński, Grzegorz; Kolasińska-Ćwikła, Agnieszka; Kowalska, Aldona; Król, Robert; Królicki, Leszek; Kunikowska, Jolanta; Kuśnierz, Katarzyna; Lampe, Paweł; Lange, Dariusz; Lewczuk-Myślicka, Anna; Lewiński, Andrzej; Londzin-Olesik, Magdalena; Marek, Bogdan; Nasierowska-Guttmejer, Anna; Nowakowska-Duława, Ewa; Pilch-Kowalczyk, Joanna; Poczkaj, Karolina; Rosiek, Violetta; Ruchała, Marek; Siemińska, Lucyna; Sowa-Staszczak, Anna; Starzyńska, Teresa; Steinhof-Radwańska, Katarzyna; Strzelczyk, Janusz; Sworczak, Krzysztof; Syrenicz, Anhelli; Szawłowski, Andrzej; Szczepkowski, Marek; Wachuła, Ewa; Zajęcki, Wojciech; Zemczak, Anna; Zgliczyński, Wojciech; Kos-Kudła, Beata


    This paper presents the updated Polish Neuroendocrine Tumour Network expert panel recommendations on the management of neuroendocrine neoplasms (NENs) of the stomach and duodenum, including gastrinoma. The recommendations discuss the epidemiology, pathogenesis, and clinical presentation of these tumours as well as their diagnosis, including biochemical, histopathological, and localisation diagnoses. The principles of treatment are discussed, including endoscopic, surgical, pharmacological, and radionuclide treatments. Finally, there are also recommendations on patient monitoring.

  14. Irritable bowel syndrome: the role of gut neuroendocrine peptides. (United States)

    El-Salhy, Magdy; Seim, Inge; Chopin, Lisa; Gundersen, Doris; Hatlebakk, Jan Gunnar; Hausken, Trygve


    Irritable bowel syndrome (IBS) is a common chronic disorder with a prevalence ranging from 5 to 10 percent of the world's population. This condition is characterised by abdominal discomfort or pain, altered bowel habits, and often bloating and abdominal distension. IBS reduces quality of life in the same degree of impairment as major chronic diseases such as congestive heart failure and diabetes and the economic burden on the health care system and society is high. Abnormalities have been reported in the neuroendocrine peptides/amines of the stomach, small- and large intestine in patients with IBS. These abnormalities would cause disturbances in digestion, gastrointestinal motility and visceral hypersensitivity, which have been reported in patients with IBS. These abnormalities seem to contribute to the symptom development and appear to play a central role in the pathogenesis of IBS. Neuroendocrine peptides/amines are potential tools in the treatment and diagnosis of IBS. In particular, the cell density of duodenal chromogranin A expressing cells appears to be a good histopathological marker for the diagnosis of IBS with high sensitivity and specificity.

  15. PICK1 expression in the Drosophila central nervous system primarily occurs in the neuroendocrine system

    DEFF Research Database (Denmark)

    Jansen, Anna M; Nässel, Dick R; Madsen, Kenneth L


    in the adult and larval Drosophila central nervous system. PICK1 was found in cell bodies in the subesophageal ganglion, the antennal lobe, the protocerebrum, and the neuroendocrine center pars intercerebralis. The cell types that express PICK1 were identified using GAL4 enhancer trap lines. The PICK1...... (AMPA) receptor subunit GluR2 and the dopamine transporter. PICK1 is strongly implicated in GluR2 trafficking and synaptic plasticity. In mammals, PICK1 has been characterized extensively in cell culture studies. To study PICK1 in an intact system, we characterized PICK1 expression immunohistochemically...... neurons in the neuroendocrine system, which express the transcription factor DIMM and the amidating enzyme peptidylglycine-alpha-hydroxylating monooxygenase (PHM). The PICK1-positive cells include neurosecretory cells that produce the insulin-like peptide dILP2. PICK1 expression in insulin-producing cells...

  16. Medical Treatment of Gastroenteropancreatic Neuroendocrine Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Rinke, Anja, E-mail:; Michl, Patrick; Gress, Thomas [Department of Gastroenterology, University Hospital Marburg, Baldinger Strasse, Marburg D-35043 (Germany)


    Treatment of the clinically and prognostically heterogeneous neuroendocrine neoplasms (NEN) should be based on a multidisciplinary approach, including surgical, interventional, medical and nuclear medicine-based therapeutic options. Medical therapies include somatostatin analogues, interferon-α, mTOR inhibitors, multikinase inhibitors and systemic chemotherapy. For the selection of the appropriate medical treatment the hormonal activity, primary tumor localization, tumor grading and growth behaviour as well as the extent of the disease must be considered. Somatostatin analogues are mainly indicated in hormonally active tumors for symptomatic relief, but antiproliferative effects have also been demonstrated, especially in well-differentiated intestinal NET. The efficacy of everolimus and sunitinib in patients with pancreatic neuroendocrine tumors (pNET) has been demonstrated in large placebo-controlled clinical trials. pNETs are also chemosensitive. Streptozocin-based chemotherapeutic regimens are regarded as current standard of care. Temozolomide in combination with capecitabine is an alternative that has shown promising results that need to be confirmed in larger trials. Currently, no comparative studies and no molecular markers are established that predict the response to medical treatment. Therefore the choice of treatment for each pNET patient is based on individual parameters taking into account the patient’s preference, expected side effects and established response criteria such as proliferation rate and tumor load. Platin-based chemotherapy is still the standard treatment for poorly differentiated neuroendocrine carcinomas. Clearly, there is an unmet need for new systemic treatment options in patients with extrapancreatic neuroendocrine tumors.

  17. FDA Approves Lutathera for Neuroendocrine Tumors (United States)

    FDA has approved Lutathera® for some people with neuroendocrine tumors (NETs) that affect the digestive tract. On January 29, FDA approved Lutathera® for adult patients with advanced NETs that affect the pancreas or gastrointestinal tract, known as GEP-NETs.

  18. A pancreatic neuroendocrine tumor diagnosed during the ...

    African Journals Online (AJOL)

    Pancreatic neuroendocrine tumors (PNET) are increasingly being discovered. A case of PNET diagnosed and treated during the management of acute appendicitis is presented and discussed. The importance of imaging modalities in patients with acute abdominal pain is emphasized. To the best our knowledge, this is the ...

  19. Nuclear Medicine Imaging of Neuroendocrine Tumors

    NARCIS (Netherlands)

    Brabander, Tessa; Kwekkeboom, Dik J.; Feelders, Richard A.; Brouwers, Adrienne H.; Teunissen, Jaap J. M.; Papotti, M; DeHerder, WW


    An important role is reserved for nuclear imaging techniques in the imaging of neuroendocrine tumors (NETs). Somatostatin receptor scintigraphy (SRS) with In-111-DTPA-octreotide is currently the most important tracer in the diagnosis, staging and selection for peptide receptor radionuclide therapy

  20. Molecular neuroendocrine targets for obesity therapy. (United States)

    de Kloet, Annette D; Woods, Stephen C


    Although energy balance is tightly regulated in order to maintain a specific level of adiposity, the incidence of obesity continues to increase. Consequently, it is essential that effective therapeutics for the treatment and prevention of obesity be developed. This review provides a brief update on some recent advances in the characterization of neuroendocrine targets for obesity therapy. During the review period, considerable progress occurred in the understanding of previously described neuroendocrine regulators of energy balance, and several novel targets have been identified. Moreover, the understanding of the neural circuitry and molecular mechanisms of the neuroendocrine regulation of energy homeostasis has been expanded. Energy balance is maintained by neuroendocrine signals arising from many tissues including the gastrointestinal tract and adipose tissue. These signals are integral to the cessation of meals and to the ability of the brain to monitor energy status and respond accordingly. Many current targets for obesity therapy are based on manipulating the activity of these signals and their receptors; however, to date, clinical-weight loss based on this strategy has been minimal and alternative approaches such as combinatorial therapies are emerging.

  1. Other PET tracers for neuroendocrine tumors

    NARCIS (Netherlands)

    Koopmans, Klaas Pieter; Glaudemans, Andor W J M

    In this article the applicability of (124)I-MIBG and (11)C-5-HTP PET for the detection of abdominal gastro-enteropancreatic neuroendocrine tumors is discussed. (124)I-MIBG is a positron-emitting variant of (123)I-MIBG and therefore suited for PET imaging. Due to the better intrinsic characteristics

  2. Molecular neuroendocrine targets for obesity therapy (United States)

    de Kloet, Annette D.; Woods, Stephen C.


    Purpose of review Although energy balance is tightly regulated in order to maintain a specific level of adiposity, the incidence of obesity continues to increase. Consequently, it is essential that effective therapeutics for the treatment and prevention of obesity be developed. This review provides a brief update on some recent advances in the characterization of neuroendocrine targets for obesity therapy. Recent findings During the review period, considerable progress occurred in the understanding of previously-described neuroendocrine regulators of energy balance, and several novel targets have been identified. Moreover, the understanding of the neural circuitry and molecular mechanisms of neuroendocrine regulators of energy homeostasis has been expanded. Summary Energy balance is maintained by neuroendocrine signals arising from many tissues including the gastrointestinal tract and adipose tissue. These signals are integral to the cessation of meals and to the ability of the brain to monitor energy status and respond accordingly. Many current targets for obesity therapy are based on manipulating the activity of these signals and their receptors; however, to date, clinical weight loss based on this strategy has been minimal and alternative approaches such as combinatorial therapies are emerging. PMID:20585249

  3. Medical Treatment of Gastroenteropancreatic Neuroendocrine Tumors

    Directory of Open Access Journals (Sweden)

    Thomas Gress


    Full Text Available Treatment of the clinically and prognostically heterogeneous neuroendocrine neoplasms (NEN should be based on a multidisciplinary approach, including surgical, interventional, medical and nuclear medicine-based therapeutic options. Medical therapies include somatostatin analogues, interferon-a, mTOR inhibitors, multikinase inhibitors and systemic chemotherapy. For the selection of the appropriate medical treatment the hormonal activity, primary tumor localization, tumor grading and growth behaviour as well as the extent of the disease must be considered. Somatostatin analogues are mainly indicated in hormonally active tumors for symptomatic relief, but antiproliferative effects have also been demonstrated, especially in well-differentiated intestinal NET. The efficacy of everolimus and sunitinib in patients with pancreatic neuroendocrine tumors (pNET has been demonstrated in large placebo-controlled clinical trials. pNETs are also chemosensitive. Streptozocin-based chemotherapeutic regimens are regarded as current standard of care. Temozolomide in combination with capecitabine is an alternative that has shown promising results that need to be confirmed in larger trials. Currently, no comparative studies and no molecular markers are established that predict the response to medical treatment. Therefore the choice of treatment for each pNET patient is based on individual parameters taking into account the patient’s preference, expected side effects and established response criteria such as proliferation rate and tumor load. Platin-based chemotherapy is still the standard treatment for poorly differentiated neuroendocrine carcinomas. Clearly, there is an unmet need for new systemic treatment options in patients with extrapancreatic neuroendocrine tumors.

  4. First-line treatment of patients with disseminated poorly differentiated neuroendocrine carcinomas with carboplatin, etoposide, and vincristine: a single institution experience

    DEFF Research Database (Denmark)

    Olsen, Ingrid Holst; Langer, Seppo W; Jepsen, Ida


    Poorly differentiated neuroendocrine carcinomas (PDECs) represent highly malignant tumors with an immense tendency to metastasize and with a poor prognosis. The treatment consists of palliative chemotherapy and corresponds to the treatment of extensive stage small cell lung cancer....

  5. Contemporary nuclear medicine diagnostics of neuroendocrine tumors

    Directory of Open Access Journals (Sweden)

    Todorović-Tirnanić Mila


    Full Text Available The new positron emission tomography (PET/CT methods for neuroendocrine tumors detection are presented and compared with classic, conventional methods. Conventional methods use a gamma scintillation camera for patients with neuroendocrine tumor imaging, after intravenous injection of one of the following radiopharmaceuticals: 1 somatostatin analogues labeled with indium-111 (111In-pentetreotide or technetium-99m (99mTc-EDDA/HYNIC-TOC; 2 noradrenaline analogue labeled with iodine-131 or -123 (131I/123I-MIBG; or 3 99mTc(V-DMSA. Contemporary methods use PET/CT equipment for patients with neuroendocrine tumor imaging, after intravenous injection of pharmaceuticals labeled with positron emitters [fluorine-18 (18F, galium-68 (68Ga, or carbon-11 (11C]: 1 glucose analogue (18FDG; 2 somatostatin analogue (68Ga-DOTATOC/68Ga-DOTATATE/68Ga-DOTANOC; 3 aminoacid precursors of bioamines: [a dopamine precursor 18F-DOPA (6-18F-dihydroxyphenylalanine, b serotonin precursor 11C-5HTP (11C-5-hydroxytryptophan]; or 4 dopamine analogue 18F-DA (6-18F-fluorodopamine. Conventional and contemporary (PET/ CT somatostatin receptor detection showed identical high specificity (92%, but conventional had very low sensitivity (52% compared to PET/CT (97%. It means that almost every second neuroendocrine tumor detected by contemporary method cannot be discovered using conventional (classic method. In metastatic pheochromocytoma detection contemporary (PET/ CT methods (18F-DOPA and 18F-DA have higher sensitivity than conventional (131I/123I-MIBG. In medullary thyroid carcinoma diagnostics contemporary method (18F-DOPA is more sensitive than conventional 99mTc(V-DMSA method, and is similar to 18FDG, computed tomography and magnetic resonance. In carcinoid detection contemporary method (18F-DOPA shows similar results with contemporary somatostatin receptor detection, while for gastroenteropancreatic neuroendocrine tumors it is worse. To conclude, contemporary (PET/CT methods for

  6. Stages of Pancreatic Neuroendocrine Tumors (United States)

    ... Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer Leukemia Liver Cancer Lung Cancer Lymphoma Pancreatic Cancer Prostate Cancer Skin Cancer Thyroid Cancer Uterine Cancer All ...

  7. Colonic neuroendocrine carcinoma in a child

    Energy Technology Data Exchange (ETDEWEB)

    Sasi, Omai Al; Rifai, Ayman; Hugosson, Claes [King Faisal Specialist Hospital and Research Centre, Department of Radiology, MBC 28, Riyadh (Saudi Arabia); Sathiapalan, Rajeev; Kofide, Amani [King Faisal Specialist Hospital and Research Centre, Department of Paediatric Haematology and Oncology, Riyadh (Saudi Arabia); Tulbah, Asthma Mahmoud Mohamed [King Faisal Specialist Hospital and Research Centre, Department of Pathology, Riyadh (Saudi Arabia); Al-Mehaidib, Ali [King Faisal Specialist Hospital and Research Centre, Department of Paediatrics, Riyadh (Saudi Arabia)


    A 10-year-old boy with congenital immunodeficiency (X-linked agammaglobulinaemia) presented with loss of appetite and weight, right-sided abdominal pain, diarrhoea and low-grade fever. Radiological investigations with barium follow-through, CT, PET and octreotide scans revealed a primary caecal/ascending proximal colonic mass with liver and bony metastases. Urine screen for 5HIAA was positive. Percutaneous liver biopsy confirmed the diagnosis of neuroendocrine carcinoma. The radiological work-up and the usefulness of various imaging modalities in the diagnosis of this rare paediatric tumour are discussed. The PET scan demonstrated the primary tumour and the metastatic locations more vividly than the octreotide scan, which is currently considered to be the most specific imaging modality for neuroendocrine masses. (orig.)

  8. Interventional treatment of neuroendocrine liver metastases

    DEFF Research Database (Denmark)

    Knigge, U.; Hansen, C.P.; Stadil, F.


    Neuroendocrine gastroenteropancreatic tumours are rare with an incidence of 2-4/100.000 per year. More than 75% of the patients develop hepatic metastases, which reduce the five year survival from 70-80% to 30-40%. In addition to chemo- and biotherapy, interventional therapy of liver metastases s....... The symptomatic response rate is 90% with a mean duration of two years. Liver transplantation should be restricted to very few and highly selected patients without extrahepatic disease. Recurrence is inevitable in nearly all patients Udgivelsesdato: 2008/8......Neuroendocrine gastroenteropancreatic tumours are rare with an incidence of 2-4/100.000 per year. More than 75% of the patients develop hepatic metastases, which reduce the five year survival from 70-80% to 30-40%. In addition to chemo- and biotherapy, interventional therapy of liver metastases...

  9. Tissue microarray analysis as a screening tool for neuroendocrine carcinoma of the breast. (United States)

    Brask, Julie Benedicte; Talman, Maj-Lis Møller; Wielenga, Vera Timmermans


    Neuroendocrine carcinoma of the breast (NCB) is a fairly recent diagnostic entity added by WHO in 2003. Since then, studies have indicated that NCB potentially displays a worse prognosis than invasive ductal carcinoma. However, due to a lack of standard use of immunohistochemical staining for neuroendocrine markers and the fact that NCB may only show slight neuroendocrine morphology that can easily be overlooked, NCB is often underdiagnosed. Consequently, there is a need for fast and reliable detection method for NCB. Here, we take a first step toward finding an easy way of identifying NCB by investigating the usefulness of tissue microarray (TMA) analysis as a screening tool. We present our findings with regard to sensitivity and specificity compared with whole-mount sections. The material consists of 240 cases of breast cancer divided into 20 TMA blocks that were all immunohistochemically stained for the neuroendocrine markers chromogranin A and synaptophysin. Cases positive in more than 50% of the tumor cells were accepted in accordance with WHO (2003) standards of NCB. Sensitivity and specificity for TMA sections vs whole-mount sections were found to be 100% and 97.8%, respectively, suggesting that TMA analysis is a reliable method for NCB detection. © 2013 APMIS. Published by John Wiley & Sons Ltd.

  10. [Surgical approach of gastroduodenal neuroendocrine neoplasms]. (United States)

    Fendrich, V; Bartsch, D K


    Gastroduodenal neuroendocrine tumors are rare but an increase in incidence has been recognized worldwide over the past 35 years. At the same time the prognosis of patients has substantially improved because the majority of these tumors can now be detected at an early stage. Neuroendocrine neoplasms (NENs) of the stomach are the most frequent neoplasms of neuroendocrine origin in the gastrointestinal tract. The therapeutic management of these tumors is complicated by the fact that they must be classified not only by staging and grading but also according to their pathophysiological background (types). These types differ in biological behavior and therefore have an influence on the therapeutic concept. Because more than 90 % of duodenal NENs are often asymptomatic and are as a rule identified at a curable stage, resection of the tumor should always be the first line of therapy. The therapeutic strategies vary from local endoscopic resection (duodenotomy with excision) up to pancreas retaining duodenectomy and pylorus retaining or classical Whipple procedures. This article presents the various surgical approaches to gastric and duodenal NENs.

  11. Reproductive disturbances in multiple neuroendocrine tumor syndromes. (United States)

    Lytras, Aristides; Tolis, George


    In the context of multiple neuroendocrine tumor syndromes, reproductive abnormalities may occur via a number of different mechanisms, such as hyperprolactinemia, increased GH/IGF-1 levels, hypogonadotropic hypogonadism, hypercortisolism, hyperandrogenism, hyperthyroidism, gonadotropin hypersecretion, as well as, tumorigenesis or functional disturbances in gonads or other reproductive organs. Precocious puberty and/or male feminization is a feature of McCune-Albright syndrome (MAS), neurofibromatosis type 1 (NF1), Carney complex (CNC), and Peutz-Jeghers syndrome (PJS), while sperm maturation and ovulation defects have been described in MAS and CNC. Although tumorigenesis of reproductive organs due to a multiple neuroendocrine tumor syndrome is very rare, certain lesions are characteristic and very unusual in the general population. Awareness leading to their recognition is important especially when other endocrine abnormalities coexist, as occasionally they may even be the first manifestation of a syndrome. Lesions such as certain types of ovarian cysts (MAS, CNC), pseudogynecomastia due to neurofibromas of the nipple-areola area (NF1), breast disease (CNC and Cowden disease (CD)), cysts and 'hypernephroid' tumors of the epididymis or bilateral papillary cystadenomas (mesosalpinx cysts) and endometrioid cystadenomas of the broad ligament (von Hippel-Lindau disease), testicular Sertoli calcifying tumors (CNC, PJS) monolateral or bilateral macroochidism and microlithiasis (MAS) may offer diagnostic clues. In addition, multiple neuroendocrine tumor syndromes may be complicated by reproductive malignancies including ovarian cancer in CNC, breast and endometrial cancer in CD, breast malignancies in NF1, and malignant sex-cord stromal tumors in PJS.

  12. ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs

    Directory of Open Access Journals (Sweden)

    Mark D. Borromeo


    Full Text Available Small cell lung carcinoma (SCLC is a high-grade pulmonary neuroendocrine tumor. The transcription factors ASCL1 and NEUROD1 play crucial roles in promoting malignant behavior and survival of human SCLC cell lines. Here, we find that ASCL1 and NEUROD1 identify heterogeneity in SCLC, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1, but not NEUROD1, is present in mouse pulmonary neuroendocrine cells, and only ASCL1 is required in vivo for tumor formation in mouse models of SCLC. ASCL1 targets oncogenic genes including MYCL1, RET, SOX2, and NFIB while NEUROD1 targets MYC. ASCL1 and NEUROD1 regulate different genes that commonly contribute to neuronal function. ASCL1 also regulates multiple genes in the NOTCH pathway including DLL3. Together, ASCL1 and NEUROD1 distinguish heterogeneity in SCLC with distinct genomic landscapes and distinct gene expression programs.

  13. The many faces of neuroendocrine differentiation in prostate cancer progression

    Directory of Open Access Journals (Sweden)

    Stephane eTerry


    Full Text Available In normal prostate, neuroendocrine (NE cells are rare and interspersed among the epithelium. These cells are believed to provide trophic signals to epithelial cell populations through the secretion of an abundance of neuropeptides that can diffuse to influence surrounding cells. In the setting of prostate cancer (PC, NE cells can also stimulate surrounding prostate adenocarcinoma cell growth, but in some cases adenocarcinoma cells themselves acquire NE characteristics. This epithelial plasticity is associated with decreased androgen receptor (AR signaling and the accumulation of neuronal and stem cell characteristics. Transformation to a NE phenotype is one proposed mechanism of resistance to contemporary AR targeted treatments, is associated with poor prognosis, and thought to represent up to 25% of lethal PCs. Importantly, the advent of high-throughput technologies has started to provide clues for understanding the complex molecular profiles of tumors exhibiting NE differentiation. Here, we discuss these recent advances, the multifaceted manner by which a NE-like state may arise during the different stages of disease progression, and the potential benefit of this knowledge for the management of patients with advanced PC

  14. [Advances of circulating biomarkers in gastroenteropancreatic neuroendocrine neoplasms]. (United States)

    Chen, Luohai; Chen, Minhu; Chen, Jie


    Gastroenteropancreatic neuroendocrine neoplam (GEP-NEN) is a rare group of tumors with its incidence rising significantly in recent decades. Because of the late presentation of the disease and limitations in conventional biomarkers, about 50% of GEP-NEN patients manifests advanced disease when diagnosed. Therefore, it is vital to identify circulating biomarkers which can not only be used for early diagnosis but also accurately evaluating the biological behavior of GEP-NEN. This review summarizes the advances of circulating biomarkers in diagnosing and evaluating efficacy of treatment in GEP-NEN. Well-known circulating biomarkers include chromogranin A (CgA), pancreastatin (PST), chromogranin B (CgB), neuron-specific enolase (NSE) and pancreatic peptide(PP). Novel biomarkers including circulating tumor cell(CTC), microRNA and NETest are promising biomarkers with potential clinical benefit, but further researches are needed before their clinical applications.

  15. Neuroendocrine Tumour of the Prostate: A Rare Variant

    Directory of Open Access Journals (Sweden)

    Ozer Ural Cakici


    Full Text Available About 95% of prostate cancers are adenocarcinomas. Neuroendocrine differentiation (NED is seen in virtually all cases of prostatic carcinoma, mostly in a focal pattern. Extensive NED is associated to aggressive disease with a poor prognosis and most cases are diagnosed in advanced stages.We present a 79-year- old male who was admitted to our department with severe lower urinary tract obstructive symptoms and weight loss. On digital rectal examination, the prostate was fixed to the rectum with irregular margins. Serum prostate-specific antigen (PSA level was 1.9 ng/ml.Transrectal ultrasound-guided prostate biopsies revealed small-cell carcinoma of the prostate. Multiple metastatic lesions in vertebral bones and iliac lymph nodes were detected by nuclear bone scan and abdominal computerised tomography CT. Thereafter, the patient was treated with cisplatin-based chemotherapy and palliative radiotherapy.

  16. Immunohistochemical detection of dopamine D2 receptors in neuroendocrine tumours. (United States)

    Pawlikowski, Marek; Pisarek, Hanna; Winczyk, Katarzyna


    Recently, dopamine D2 receptors (RD2) have been found to be expressed in neuroendocrine tumours (NET), the tumours which arise from the diffuse neuroendocrine cells. Moreover, successful trials of the treatment of NET with cabergoline - D2 agonist, have been reported. These findings increase the interest of investigating RD2 expression in NET. The expression of RD2 was investigated immunohistochemically using the antibody which recognises both short (S) and long (L) isoforms of the receptor in 17 NET samples taken from 15 patients. In 17 NET samples, a positive reaction with the anti-RD2 antibody occurred in 11 cases. In six cases, the localisation of the immunostaining was cytoplasmic and in nine cases it was nuclear. Only in one case was the receptor cell membrane-located, and in two cases the immunoreaction was also localised in the blood vessels walls. The relation between RD2 expression and the grade of malignancy examined by means of Ki-67 antigen expression needs further study. However, preliminary observations indicate that the nuclear localisation of RD2 is linked to higher tumour malignancy. The next investigated question was the co-expression of somatostatin and dopamine receptors. This question seems important because of the perspectives of somatostatin-dopamine chimeras application in NET treatment. In the samples examined by us, RD2 were co-expressed in 5/10 cases with sstr1, in 3/10 with sstr2A, in 2/9 with sstr2B, in 3/10 with sstr3, and in 5/10 with sstr5. Dopamine D2 receptors are revealed by means of immunohistochemistry in the majority of NET. They exhibit cytoplasmic and/or nuclear localisations, the latter being possibly linked to a higher grade of malignancy, and are often co-expressed with somatostatin receptors (mostly with subtypes1 and 5).

  17. Neuroendocrine Tumor, Well Differentiated, of the Breast: A Relatively High-Grade Case in the Histological Subtype

    Directory of Open Access Journals (Sweden)

    Shogo Tajima


    Full Text Available Primary neuroendocrine carcinoma of the breast is a rare entity, comprising <1% of breast carcinomas. Described here is the case of a 78-year-old woman who developed an invasive tumor in the left breast measuring 2.0 cm x 1.5 cm x 1.2 cm. The tumor was composed of only endocrine elements in the invasive part. It infiltrated in a nested fashion with no tubular formation. Intraductal components were present both inside and outside of the invasive portion. Almost all carcinoma cells consisting of invasive and intraductal parts were positive for synaptophysin and neuron-specific enolase. According to the World Health Organization classification 2012, this tumor was subclassified as neuroendocrine tumor, well-differentiated. Among the subgroup, this tumor was relatively high-grade because it was grade 3 tumor with a few mitotic figures. Vascular and lymphatic permeation and lymph node metastases were noted. In the lymph nodes, the morphology of the tumor was similar to the primary site. No distant metastasis and no relapse was seen for one year after surgery. The prognosis of neuroendocrine carcinomas is thought to be worse than invasive mammary carcinomas, not otherwise specified. Therefore, immunohistochemistry for neuroendocrine markers is important in the routine practice to prevent overlooking neuroendocrine carcinomas.

  18. Common Diagnostic Challenges in the Histopathologic Diagnosis of Neuroendocrine Lung Tumors: A Case Report

    Directory of Open Access Journals (Sweden)

    Monica Valente


    Full Text Available Bronchopulmonary neuroendocrine tumors are an uncommon group of neoplasms, accounting for about 20% of all lung carcinomas, arising from stem cells of the bronchial epithelium known as Kulchitsky cells. In the past, these tumors were grouped among benign or less aggressive malignant pulmonary tumors. Currently, according to the 2004 World Health Organization categorization, these tumors are separated into 4 subtypes characterized by increasing biologic aggressiveness: low-grade (typical carcinoid; TC, intermediate-grade (atypical carcinoid; AC and high-grade (large-cell neuroendocrine carcinoma, LCNEC, and small-cell lung carcinoma, SCLC. They differ by morphologic, immunohistochemical and structural features. At histopathologic analysis, these tumors share progressive increase in a number of mitotic figures per 10 high-power fields and in the extent of necrosis, with TC having the lowest values and SCLC having the highest. TCs and ACs make up approximately 1–2% of all primary lung tumors. Differentiating ACs from TCs or LCNEC and SCLC is clinically important because the treatment modalities and prognoses for these types of tumors are different. We report a case of misdiagnosis of bronchopulmonary neuroendocrine tumor in a young woman which has heavily influenced her clinical history.

  19. Neuroendocrine tumour in a patient with neurofibromatosis type 1 ...

    African Journals Online (AJOL)


    Jun 26, 2015 ... concomitant gastrin-producing neuroendocrine tumour was found. Neuroendocrine tumours. (NETs) are very rare neoplasms originating from a wide variety of endocrine and nervous system tissue with the ability to produce different hormones. A somatostatin- and gastrin- secreting NET in a patient with HIV ...

  20. Recognition memory tasks in neuroendocrine research. (United States)

    Luine, Victoria


    The recognition memory tasks, novel object and novel object location, have been beneficial to neuroendocrine research concerning the effects of gonadal and adrenal hormones on cognitive function. This review discusses the advantages of these tasks in comparison with other learning and memory tasks. Experiments conducted across a number of laboratories show that gonadal hormones, both estradiol and testosterone, promote memory while the adrenal hormone, corticosterone, impairs memory. The effects of these steroid hormones on spine density in the prefrontal cortex and hippocampus are also briefly presented. Overall, results show that these steroid hormones are potent modulators of memory consolidation in rodent models. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Neuroendocrine-immune (NEI) circuitry from neuron-glial interactions to function: Focus on gender and HPA-HPG interactions on early programming of the NEI system. (United States)

    Morale, M C; Gallo, F; Tirolo, C; Testa, N; Caniglia, S; Marletta, N; Spina-Purrello, V; Avola, R; Caucci, F; Tomasi, P; Delitala, G; Barden, N; Marchetti, B


    Bidirectional communication between the neuroendocrine and immune systems during ontogeny plays a pivotal role in programming the development of neuroendocrine and immune responses in adult life. Signals generated by the hypothalamic-pituitary-gonadal axis (i.e. luteinizing hormone-releasing hormone, LHRH, and sex steroids), and by the hypothalamic-pituitary-adrenocortical axis (glucocorticoids (GC)), are major players coordinating the development of immune system function. Conversely, products generated by immune system activation exert a powerful and long-lasting regulation on neuroendocrine axes activity. The neuroendocrine-immune system is very sensitive to preperinatal experiences, including hormonal manipulations and immune challenges, which may influence the future predisposition to several disease entities. We review our work on the ongoing mutual regulation of neuroendocrine and immune cell activities, both at a cellular and molecular level. In the central nervous system, one chief compartment is represented by the astroglial cell and its mediators. Hence, neuron-glial signalling cascades dictate major changes in response to hormonal manipulations and pro-inflammatory triggers. The interplay between LHRH, sex steroids, GC and pro-inflammatory mediators in some physiological and pathological states, together with the potential clinical implications of these findings, are summarized. The overall study highlights the plasticity of this intersystem cross-talk for pharmacological targeting with drugs acting at the neuroendocrine-immune interface.

  2. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects

    DEFF Research Database (Denmark)

    Zhu, Xiaorong; Zhou, An; Dey, Arunangsu


    The subtilisin-like proprotein convertases PC1/3 (SPC3) and PC2 (SPC2) are believed to be the major endoproteolytic processing enzymes of the regulated secretory pathway. They are expressed together or separately in neuroendocrine cells throughout the brain and dispersed endocrine system in both ...

  3. Dissociative symptoms and neuroendocrine dysregulation in depression. (United States)

    Bob, Petr; Fedor-Freybergh, Peter; Jasova, Denisa; Bizik, Gustav; Susta, Marek; Pavlat, Josef; Zima, Tomas; Benakova, Hana; Raboch, Jiri


    Dissociative symptoms are traditionally attributed to psychological stressors that produce dissociated memories related to stressful life events. Dissociative disorders and dissociative symptoms including psychogenic amnesia, fugue, dissociative identity-disorder, depersonalization, derealization and other symptoms or syndromes have been reported as an epidemic psychiatric condition that may be coexistent with various psychiatric diagnoses such as depression, schizophrenia, borderline personality disorder or anxiety disorders. According to recent findings also the somatic components of dissociation may occur and influence brain, autonomic and neuroendocrine functions. At this time there are only few studies examining neuroendocrine response related to dissociative symptoms that suggest significant dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis. The aim of the present study is to perform examination of HPA axis functioning indexed by basal cortisol and prolactin and test their relationship to psychic and somatoform dissociative symptoms. Basal cortisol and prolactin and psychic and somatoform dissociative symptoms were assessed in 40 consecutive inpatients with diagnosis of unipolar depression mean age 43.37 (SD=12.21). The results show that prolactin and cortisol as indices of HPA axis functioning manifest significant relationship to dissociative symptoms. Main results represent highly significant correlations obtained by simple regression between psychic dissociative symptoms (DES) and serum prolactin (R=0.55, p=0.00027), and between somatoform dissociation (SDQ-20) and serum cortisol (R=-0.38, p=0.015). These results indicate relationship between HPA-axis reactivity and dissociative symptoms in unipolar depressive patients that could reflect passive coping behavior and disengagement.

  4. A novel approach in the treatment of neuroendocrine gastrointestinal tumors: Additive antiproliferative effects of interferon-γ and meta-iodobenzylguanidine

    Directory of Open Access Journals (Sweden)

    Ahnert-Hilger Gudrun


    Full Text Available Abstract Background Therapeutic options to effectively inhibit growth and spread of neuroendocrine gastrointestinal tumors are still limited. As both meta-iodobenzylguanidine (MIBG and interferon-γ (IFNγ cause antineoplastic effects in neuroendocrine gastrointestinal tumor cells, we investigated the antiproliferative effects of the combination of IFNγ and non-radiolabeled MIBG in neuroendocrine gut STC-1 and pancreatic carcinoid BON tumor cells. Methods and results IFNγ receptors were expressed in both models. IFNγ dose- and time-dependently inhibited the growth of both STC-1 and of BON tumor cells with IC50-values of 95 ± 15 U/ml and 135 ± 10 U/ml, respectively. Above 10 U/ml IFNγ induced apoptosis-specific caspase-3 activity in a time-dependent manner in either cell line and caused a dose-dependent arrest in the S-phase of the cell cycle. Furthermore, IFNγ induced cytotoxic effects in NE tumor cells. The NE tumor-targeted drug MIBG is selectively taken up via norepinephrine transporters, thereby specifically inhibiting growth in NE tumor cells. Intriguingly, IFNγ treatment induced an upregulation of norepinephrine transporter expression in neuroendocrine tumors cells, as determined by semi-quantitative RT-PCR. Co-application of sub-IC50 concentrations of IFNγ and MIBG led to additive growth inhibitory effects, which were mainly due to increased cytotoxicity and S-phase arrest of the cell cycle. Conclusion Our data show that IFNγ exerts antiproliferative effects on neuroendocrine gastrointestinal tumor cells by inducing cell cycle arrest, apoptosis and cytotoxicity. The combination of IFNγ with the NE tumor-targeted agent MIBG leads to effective growth control at reduced doses of either drug. Thus, the administration of IFNγ alone and more so, in combination with MIBG, is a promising novel approach in the treatment of neuroendocrine gastrointestinal tumors.


    Directory of Open Access Journals (Sweden)

    Smaranda DIACONESCU


    Full Text Available Gastroenteropancreatic neuroendocrine tumors (GEP NET represent a heterogenous group of neoplasms: carcinoids (serotoninomas and gastroenteropancreatic (insulinomas, gastrinomas, VIPomas, glucagonomas, somatostatinomas respectively, unified by their origin (neuroendocrine cells, histology and immunohistochemical profile. Unlike their frequency in adults, the rarity of these lesions in childhood makes difficult their early diagnosis. Many tumors can be asymptomatic or may show non-specific features, the diagnosis being nevertheless based on clinical signs, dosage of hormonal specific peptides, nuclear medicine imaging and pathology confirmation. Baseline tests should also include chromogranine A and sinaptophysine. Localising studies comprise CT, MRI, somatostatine receptor scintigraphy and ultrasonography completed by endoscopy. Surgery is the mainstay therapy of GEP NET, as a complete removal can potentially cure the disease; debulking and metastasis surgery, together with adjuvant medical therapy can alleviate some symptoms, sometimes for a long period. Survival is variable, depending on tumour’s type, stage, histology and also on the completeness of the treatment.

  6. Tissue microarray analysis as a screening tool for neuroendocrine carcinoma of the breast

    DEFF Research Database (Denmark)

    Brask, Julie Benedicte; Talman, Maj-Lis Møller; Wielenga, Vera Timmermans


    by investigating the usefulness of tissue microarray (TMA) analysis as a screening tool. We present our findings with regard to sensitivity and specificity compared with whole-mount sections. The material consists of 240 cases of breast cancer divided into 20 TMA blocks that were all immunohistochemically stained...... for the neuroendocrine markers chromogranin A and synaptophysin. Cases positive in more than 50% of the tumor cells were accepted in accordance with WHO (2003) standards of NCB. Sensitivity and specificity for TMA sections vs whole-mount sections were found to be 100% and 97.8%, respectively, suggesting that TMA......Neuroendocrine carcinoma of the breast (NCB) is a fairly recent diagnostic entity added by WHO in 2003. Since then, studies have indicated that NCB potentially displays a worse prognosis than invasive ductal carcinoma. However, due to a lack of standard use of immunohistochemical staining...

  7. The special relationship: glia-neuron interactions in the neuroendocrine hypothalamus. (United States)

    Clasadonte, Jerome; Prevot, Vincent


    Natural fluctuations in physiological conditions require adaptive responses involving rapid and reversible structural and functional changes in the hypothalamic neuroendocrine circuits that control homeostasis. Here, we discuss the data that implicate hypothalamic glia in the control of hypothalamic neuroendocrine circuits, specifically neuron-glia interactions in the regulation of neurosecretion as well as neuronal excitability. Mechanistically, the morphological plasticity displayed by distal processes of astrocytes, pituicytes and tanycytes modifies the geometry and diffusion properties of the extracellular space. These changes alter the relationship between glial cells of the hypothalamus and adjacent neuronal elements, especially at specialized intersections such as synapses and neurohaemal junctions. The structural alterations in turn lead to functional plasticity that alters the release and spread of neurotransmitters, neuromodulators and gliotransmitters, as well as the activity of discrete glial signalling pathways that mediate feedback by peripheral signals to the hypothalamus. An understanding of the contributions of these and other non-neuronal cell types to hypothalamic neuroendocrine function is thus critical both to understand physiological processes such as puberty, the maintenance of bodily homeostasis and ageing and to develop novel therapeutic strategies for dysfunctions of these processes, such as infertility and metabolic disorders.

  8. PET tracers for somatostatin receptor imaging of neuroendocrine tumors

    DEFF Research Database (Denmark)

    Johnbeck, Camilla Bardram; Knigge, Ulrich; Kjær, Andreas


    Neuroendocrine tumors have shown rising incidence mainly due to higher clinical awareness and better diagnostic tools over the last 30 years. Functional imaging of neuroendocrine tumors with PET tracers is an evolving field that is continuously refining the affinity of new tracers in the search...... for the perfect neuroendocrine tumor imaging tracer. (68)Ga-labeled tracers coupled to synthetic somatostatin analogs with differences in affinity for the five somatostatin receptor subtypes are now widely applied in Europe. Comparison of sensitivity between the most used tracers - (68)Ga-DOTA-Tyr3-octreotide...

  9. Neuroendocrine tumor of the inguinal node: A very rare presentation

    Directory of Open Access Journals (Sweden)

    Niharika Bisht


    Full Text Available Neuroendocrine tumors are a broad family of tumors arising most commonly in the gastrointestinal tract and the bronchus pulmonary tree. The other common sounds are the parathyroid, pituitary and adrenal gland. Inguinal node as a primary presentation of a neuroendocrine tumor is an extremely rare presentation. We present the case of a 43-year-old-male who presented with the complaints of an inguinal node swelling without any other symptoms and on further evaluation was diagnosed to have a non-metastatic neuroendocrine tumor of the inguinal node. He was treated with a combination of chemotherapy and surgery and is presently awaiting completion chemotherapy.

  10. Neuroendocrine tumor presenting like lymphoma: a case report

    Directory of Open Access Journals (Sweden)

    Vincenzi Bruno


    Full Text Available Abstract Introduction Neuroendocrine tumors are a rare but diverse group of malignancies that arise in a wide range of organ systems, including the mediastinum. Differential diagnosis includes other masses arising in the middle mediastinum such as lymphoma, pericardial, bronchogenic and enteric cysts, metastatic tumors, xanthogranuloma, systemic granuloma, diaphragmatic hernia, meningocele and paravertebral abscess. Case presentation We present a case of 42-year-old Caucasian man with a neuroendocrine tumor of the middle-posterior mediastinum and liver metastases, which resembled a lymphoma on magnetic resonance imaging. Conclusion The differential diagnosis in patients with mediastinal masses and liver lesions should include neuroendocrine tumor.

  11. Synchronous gastric neuroendocrine carcinoma and hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Ewertsen, Caroline; Henriksen, Birthe Merete; Hansen, Carsten Palnæs


    UNLABELLED: Gastric neuroendocrine carcinomas (NECs) are rare tumours that are divided into four subtypes depending on tumour characteristics. Patients with NECs are known to have an increased risk of synchronous and metachronous cancers mainly located in the gastrointestinal tract. A case...... of synchronous gastric NEC and hepatocellular carcinoma in a patient with several other precancerous lesions is presented. The patient had anaemia, and a gastric tumour and two duodenal polyps were identified on upper endoscopy. A CT scan of the abdomen revealed several lesions in the liver. The lesions were...... invisible on B-mode sonography and real-time sonography fused with CT was used to identify and biopsy one of the lesions. Histology showed hepatocellular carcinoma. A literature search showed that only one case of a hepatocellular carcinoma synchronous with a gastric NEC has been reported previously. TRIAL...

  12. Immunohistochemical study of the neural development transcription factors (TTF1, ASCL1 and BRN2) in neuroendocrine prostate tumours. (United States)

    Rodríguez-Zarco, E; Vallejo-Benítez, A; Umbría-Jiménez, S; Pereira-Gallardo, S; Pabón-Carrasco, S; Azueta, A; González-Cámpora, R; Espinal, P S; García-Escudero, A


    Prostatic small-cell neuroendocrine carcinoma is an uncommon malignancy that constitutes 0.5-1% of all prostate malignancies. The median cancer-specific survival of patients with prostatic small-cell neuroendocrine carcinoma is 19 months, and 60.5% of the patients have metastatic disease. Neural development transcription factors are molecules involved in the organogenesis of the central nervous system and of neuroendocrine precursors of various tissues, including the suprarenal gland, thyroid glands, lungs and prostate. We present 3 cases of this uncommon condition, applying the new World Health Organisation criteria. We conducted studies through haematoxylin and eosin staining and analysed the expression of the neural development transcription factors achaete-scute homolog like 1, thyroid transcription factor 1 and the class III/IV POU transcription factors, as a new research line in the carcinogenesis of prostatic neuroendocrine tumours. In case 1, there was no TTF1 immunoexpression. Cases 2 and 3 had positive immunostaining for ASCL1, and Case 1 had negative immunostaining. BRN2 immunostaining was negative in case 1 and positive in cases 2 and 3. The World Health Organisation does not recognise any molecular or genetic marker with prognostic value. ASCL-1 is related to the NOTCH and WNT signalling pathways. ASCL-1, TTF1 and BRN2 could be used for early diagnosis and as prognostic factors and therapeutic targets. Copyright © 2017 AEU. All rights reserved.

  13. Pancreatic Neuroendocrine Neoplasms: Basic Biology, Current Treatment Strategies and Prospects for the Future

    Directory of Open Access Journals (Sweden)

    Akihiro Ohmoto


    Full Text Available Pancreatic neuroendocrine neoplasms (pNENs are rare tumors accounting for only 1%–2% of all pancreatic tumors. pNENs are pathologically heterogeneous and are categorized into three groups (neuroendocrine tumor: NET G1, NET G2; and neuroendocrine carcinoma: NEC on the basis of the Ki-67 proliferation index and the mitotic count according to the 2010 World Health Organization (WHO classification of gastroenteropancreatic NENs. NEC in this classification includes both histologically well-differentiated and poorly differentiated subtypes, and modification of the WHO 2010 classification is under discussion based on genetic and clinical data. Genomic analysis has revealed NETs G1/G2 have genetic alterations in chromatin remodeling genes such as MEN1, DAXX and ATRX, whereas NECs have an inactivation of TP53 and RB1, and these data suggest that different treatment approaches would be required for NET G1/G2 and NEC. While there are promising molecular targeted drugs, such as everolimus or sunitinib, for advanced NET G1/G2, treatment stratification based on appropriate predictive and prognostic biomarkers is becoming an important issue. The clinical outcome of NEC is still dismal, and a more detailed understanding of the genetic background together with preclinical studies to develop new agents, including those already under investigation for small cell lung cancer (SCLC, will be needed to improve the prognosis.

  14. Gastric non-secreting neuroendocrine tumor and hypochlorhydria-related hypergastrinemia: a case report. (United States)

    Biolato, Marco; Alfieri, Sergio; Ianiro, Gianluca; Pizzoferrato, Marco; Gasbarrini, Giovanni


    Zollinger-Ellison syndrome is characterized by recurrent peptic ulcers and diarrhea that result from gastrin-secreting neuroendocrine tumors of the gastrointestinal tract; nevertheless, severe hypergastrinemia may also have alternative pathogenetic explanations. A 61-year-old woman of Caucasian origin presented with a history of epigastric pain and early satiety, severe hypergastrinemia (approximately 2000 pg/mL) and a neuroendocrine polyp in the corpus of her stomach. Chronic atrophic gastritis and intestinal metaplasia was present, but she denied use of acid suppressant drugs and the results of tests for Helicobacter pylori as well as gastric parietal cell and intrinsic factor antibodies were negative. She underwent a radical gastric tangential resection. Six months later, serum gastrin was still elevated despite lack of recurrence of tumor. The clinical picture was suggestive for a hypochlorhydria-related hypergastrinemia with subsequent development of a non-secreting carcinoid. We suggest a periodic endoscopic follow-up in patients with severe hypochlorhydria-related hypergastrinemia in order to earlier detect neuroendocrine polyps.

  15. Occult Primary Neuroendocrine Tumor Metastasis to the Breast Detected on Screening Mammogram

    Directory of Open Access Journals (Sweden)

    Fabiana Policeni


    Full Text Available Metastatic tumors are rare in the breast. Well-differentiated neuroendocrine tumors (WDNETs are slow-growing neoplasms that arise from neuroendocrine cells, particularly in the gastrointestinal tract and bronchial tree. Metastatic WDNET to the breast is a rare entity. We present a case report of ileal WDNET metastatic to the breast which was initially identified as a small mass in the patient′s left breast on screening mammography. Targeted ultrasound identified a suspicious mass, and ultrasound-guided percutaneous core biopsy was performed. Pathology revealed metastatic WDNET. Breast magnetic resonance imaging (MRI was then performed and demonstrated left axillary Level 2 lymphadenopathy, and liver lesions were suspicious for metastasis. The patient underwent abdominal computed tomography (CT to evaluate for distant metastatic disease. A spiculated mass was found near the ileocecal valve, suggestive of primary ileal WDNET. In addition, CT identified multiple liver lesions, most compatible with metastasis. Indium 111 OctreoScan confirmed radiotracer uptake in the ileum consistent with primary neuroendocrine tumor. In this report, we review the imaging characteristics of metastatic WDNET to the breast by different imaging modalities including mammogram, ultrasound, and breast MRI.

  16. Characterization of prostate neuroendocrine cancers and therapeutic management: a literature review. (United States)

    Sargos, P; Ferretti, L; Gross-Goupil, M; Orre, M; Cornelis, F; Henriques de Figueiredo, B; Houédé, N; Merino, C; Roubaud, G; Dallaudiére, B; Richaud, P; Fléchon, A


    Neuroendocrine prostate cancers (NEPCs) are rare. The current lack of consensus for clinical, biological and pathological characterization as well as therapeutic approach makes the management of those tumors a clinical challenge. This literature review aims to summarize available data on the characterization and management of patients with prostate cancer with a neuroendocrine element. We try to identify major controversies and uncertainties in order to understand all aspects of this particular entity. We searched for all articles published and registered in the MEDLINE database before 31 November 2013 with the following search terms: (('prostatic neoplasms' (MeSH Terms)) AND ('carcinoma, neuroendocrine' (MeSH Terms)) OR ('carcinoma, small cell' (MeSH Terms))) AND (English (Language)). Case reports, letters or comments were excluded. We then selected relevant articles from titles and abstracts. Overall, 278 articles published between 1976 and November 2013 were identified. No definition of NEPC seems to be clearly established. Natural history of the disease reveals poor prognosis with median survival of up to 10 to 13 months. Histological characterization appears difficult. Serum markers could be helpful with some controversies in terms of prognostic significance. Concerning management, the majority of patients received local treatment combined with chemotherapy in case of early and localized disease. Few clinical trials described strategy for metastatic disease. The exploration of the different pathways implicated in the neuroendocrine differentiation of prostate cancers is essential for the comprehension of castration-resistance mechanisms. It will enable the identification of optimal therapeutic strategies for which no recommendation is currently established. Inclusion in prospective clinical trials appears necessary to identify the adequate strategy.

  17. Targeted Therapies Improve Survival for Patients with Pancreatic Neuroendocrine Tumors (United States)

    In 2011, based on initial findings from two clinical trials, the Food and Drug Administration approved sunitinib and everolimus for patients with pancreatic neuroendocrine tumors. Updated results from the everolimus trial were published in September 2016.

  18. Neuroendocrine, immune and oxidative stress in shift workers. (United States)

    Faraut, Brice; Bayon, Virginie; Léger, Damien


    Shift work is commonly associated with disturbed life rhythms, resulting in chronic exposure to circadian desynchronization and sleep restriction. Epidemiological data have shown that shift workers are at an increased risk of cardiovascular disease and breast cancer. In this review, we will explore how observed increases in neuroendocrine stress, non-specific immune responses and pro-oxidative status could act as biological mediators for these damaging health risks in shift workers. To explain these risks, compelling evidence from laboratory studies links circadian misalignment but also sleep restriction to disruptions in the neuroendocrine, immune and oxidative stress systems. Assessment of neuroendocrine, oxidative and immune stress in the shift worker population is still a limited and novel field, which may have considerable clinical relevance. Finally, we will consider the potential benefits of a countermeasure, such as napping, in minimizing the neuroendocrine and immune stress and cardiovascular risk imposed by shift work. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Gastroenteropancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1

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    Tonelli, Francesco, E-mail:; Giudici, Francesco [Department of Clinical Physiopathology, Surgical Unit, Medical School, University of Florence, Largo Brambilla n° 3, Florence 50134 (Italy); Giusti, Francesca; Brandi, Maria Luisa [Department of Internal Medicine, Medical School and Regional Centre for Hereditary Endocrine Tumors, University of Florence, Largo Brambilla n° 3, Florence 50134 (Italy)


    We reviewed the literature about entero-pancreatic neuroendocrine tumors in Multiple Endocrine Neoplasia type 1 syndrome (MEN1) to clarify their demographic features, localization imaging, practice, and appropriate therapeutical strategies, analyzing the current approach to entero-pancreatic neuroendocrine tumors in MEN1. Despite the fact that hyperparathyroidism is usually the first manifestation of MEN1, the penetrance of these tumors is similar. They are characterized by multiplicity of lesions, variable expression of the tumors, and propensity for malignant degeneration. Both the histological type and the size of MEN1 neuroendocrine tumors correlate with malignancy. Monitoring of pancreatic peptides and use of imaging exams allow early diagnosis and prompt surgical treatment, resulting in prevention of metastatic disease and improvement of long-term survival. Surgery is often the treatment of choice for MEN1-neuroendocrine tumors. The rationale for surgical approach is to curtail malignant progression of the disease, and to cure the associated biochemical syndrome, should it be present.

  20. Primary Neuroendocrine Carcinoma of Breast: A Rare Case Report

    African Journals Online (AJOL)

    Department of Pathology, ESIC Medical College and PGIMSR, Rajajinagar, Bangalore, India. Abstract. Primary neuroendocrine carcinoma (PNEC) of breast was an unknown pathologic entity till recently due ... whole body computed tomography and magnetic resonance imaging revealed no extra mammary primary tumor.

  1. Differential Diagnosis in Neuroendocrine Neoplasms of the Larynx

    NARCIS (Netherlands)

    Hunt, Jennifer L; Ferlito, Alfio; Hellquist, Henrik; Rinaldo, Alessandra; Skálová, Alena; Slootweg, Pieter J; Willems, Stefan M; Cardesa, Antonio


    The differential diagnosis of neuroendocrine neoplasms of the larynx is broad and includes lesions of epithelial, mesenchymal, and neuroectodermal origin. These lesions have overlapping clinical and pathologic aspects and must be carefully considered in the differential diagnosis of laryngeal

  2. Calcitonin-negative primary neuroendocrine tumor of the thyroid ...

    African Journals Online (AJOL)

    nonmedullary" in humans is a rare tumor that arises primarily in the thyroid gland and may be mistaken for medullary thyroid carcinoma; it is characterized by the immunohistochemical (IHC) expression of neuroendocrine markers and the absence of ...

  3. Anxiety, Family Functioning and Neuroendocrine Biomarkers in Obese Children

    Directory of Open Access Journals (Sweden)

    Inês Pinto


    Conclusion: These results highlight the importance of taking into account family functioning, parental mental state and gender, when investigating neuroendocrine biomarkers in obese children associated with symptoms of anxiety and depression.

  4. Ghrelin and pre-proghrelin immunoreactive cells in gastric neuroendocrine tumors associated with atrophic body gastritis Grelina e pré-progrelina em tumores neuroendócrinos do estômago associados à gastrite atrófica do corpo

    Directory of Open Access Journals (Sweden)

    Letícia Figueiredo Moreira


    Full Text Available INTRODUCTION: Ghrelin is a 28 amino acid peptide secreted mainly by endocrine cells present in the gastric mucosa and acknowledged as an endogenous releaser of growth hormone. The immunohistochemical expression of ghrelin has been described in neuroendocrine tumors, and it is believed that may exert modulating action related to the growth of these tumors. OBJECTIVE: To study the presence of ghrelin and preproghrelin immunoreactive cells in gastric neuroendocrine tumors associated with atrophic body gastritis. METHODS: Endoscopic biopsies from 15 patients with neuroendocrine tumor of the gastric mucosa associated with atrophic body gastritis were performed for immunohistochemistry, and specific chromogranin, ghrelin and preproghrelin antibodies were applied. The immunohistochemical expression was assessed in tumor cells and endocrine micronodular hyperplasia present in mucosa adjacent to the tumor, and it was classified in relation to the number of stained cells. RESULTS: Chromogranin was positive in 14 out of 15 tumors. Ghrelin and preproghrelin immunoreactive cells were detected in 11 (73% and 13 (87% tumors, respectively. There was a significant correlation between the immunohistochemical results of both antigen expressions (kappa = 81%. Ghrelin and preproghrelin expression was detected in hyperplastic nodules present in the mucosa adjacent to the tumor in seven and eight cases, respectively. There was no correlation between these results and those observed in neoplastic cells. CONCLUSION: Ghrelin and preproghrelin immunoreactive cells may be found in variable number in Type I neuroendocrine gastric tumors and in hyperplastic nodules associated with these tumors. However, it remains unclear what role these peptides play on the development of these tumors.INTRODUÇÃO: Grelina é um peptídeo de 28 aminoácidos, reconhecido como liberador endógeno do hormônio do crescimento, sendo secretado principalmente por células endócrinas da mucosa g

  5. Pulmonary neuroendocrine carcinoma mimicking neurocysticercosis: a case report. (United States)

    Lam, John C; Robinson, Stephen R; Schell, Andrew; Vaughan, Stephen


    Neurocysticercosis occurs when the eggs of the pork tapeworm (Taenia solium) migrate and hatch into larvae within the central nervous system. Neurocysticercosis is the most common cause of seizures in the developing world and is characterized on brain imaging by cysts in different stages of evolution. In Canada, cases of neurocysticercosis are rare and most of these patients acquire the disease outside of Canada. We report the case of a patient with multiple intracranial lesions whose history and diagnostic imaging were consistent with neurocysticercosis. Pathological investigations ultimately demonstrated that her brain lesions were secondary to malignancy. Brain metastases are considered to be the most common cause of intracranial cystic lesions. We present the case of a 60-year-old Canadian-born Caucasian woman with a subacute history of ataxia, lower extremity hyper-reflexia, and otalgia who resided near a pig farm for most of her childhood. Computed tomography and magnetic resonance imaging showed that she had multiple heterogeneous intracranial cysts, suggestive of neurocysticercosis. Despite a heavy burden of disease, serological tests for cysticercosis were negative. This result and a lack of the central scolices on neuroimaging that are pathognomonic of neurocysticercosis prompted whole-body computed tomography imaging to identify another etiology. The whole-body computed tomography revealed right hilar lymphadenopathy associated with soft tissue nodules in her chest wall and abdomen. A biopsy of an anterior chest wall nodule demonstrated high-grade poorly differentiated carcinoma with necrosis, which stained strongly positive for thyroid transcription factor-1 and synaptophysin on immunohistochemistry. A diagnosis of stage 4 metastatic small cell neuroendocrine carcinoma was made and our patient was referred for oncological palliative treatment. This case illustrates the importance of the diagnostic approach to intracranial lesions. Our patient

  6. An unusual association of neuroendocrine tumors in MEN 1A. (United States)

    Varsavsky, Mariela; Reyes-García, Rebeca; Alonso García, Guillermo; Muñoz-Torres, Manuel


    Multiple Endocrine Neoplasia type 1 is an autonomic dominant disease with a high degree of penetrance. It is characterized by combinations of over 20 different endocrine and nonendocrine tumors. A 25-year-old woman was referred for 1 year-evolution amenorrhea and bilateral galactorrhea. She also had fasting hypoglycaemia and hypercalcemia, and she was diagnosed of Multiple Endocrine Neoplasia type 1A. Resection of three parathyroid glands was performed showing hyperplasia of principal cells. Post-parathyroidectomy serum levels of calcium and intact PTH were normal but 3 years later serum calcium levels rose again. A 99mTc-sestamibi scan showed increased uptake in the low right area compatible with adenoma. After biochemical test showing probable insulinoma, somatostatin receptor scintigraphy showed a focal captation in head and body of pancreas. MRI found two nodules in the same localization. An antral gastrectomy, total pancreatoduodenectomy, colecistectomy and truncal vagotomy was performed and histopathologic examination revealed a combination of neuroendocrine tumors: gastrinomas, somastotinomas, glucagonomas and insulinomas. After surgery she started with tingling in fingers, toes and lips, and calcium levels was 5.9 mg/dl and PTH intact 3 pg/ml. A new 99m Tc-sestamibi scan showed no captation and cervical ultrasonography was normal. Now, 2 years later, she continues with normal calcium and i-PTH levels. This report represents an unusual case of MEN 1A with association of insulinomas, gastrinomas glucagonomas and somatostatinomas in the same patient.

  7. Psychological and neuroendocrine reactivity to ostracism. (United States)

    Zwolinski, Jennifer


    This study used the ostracism detection theory to investigate how ostracism impacts individuals in two ways: (1) immediate poststressor needs, mood, ruminative thoughts, and desire to affiliate, and (2) short-term affective and cortisol reactivity. A total of 58 college students were randomly assigned to the inclusion or ostracism conditions of Cyberball, a virtual ball-tossing game. Immediately following the experimental manipulation, ostracized participants reported more thwarted psychological need states, more negative mood, and fewer positive ruminative thoughts, relative to their included counterparts. Ostracized participants reported a greater interest in affiliating with others in online or in-person settings. In the short-term, ostracized males reported more hostility than included males, although the scores were within expected norms for most males. There was no relation between Cyberball condition and gender across time for depression, anxiety, or positive affect. Approximately 20 min after the onset of the stressor, women in the luteal phase and women taking oral contraceptives in the ostracized group displayed higher cortisol than their counterparts in the included group. Relative to baseline, however, cortisol did not reliably increase after the onset of the stressor. Ostracized females taking oral contraceptives showed the greatest decline in cortisol, compared to included oral contraceptive users. Overall, results suggest that most of the negative effects of ostracism are immediate and limited to psychological, not neuroendocrine, responses. © 2012 Wiley Periodicals, Inc.

  8. [Neuroendocrine factors in hypertension during pregnancy]. (United States)

    Diaconu, Minodora; Ghiciuc, Cristina-Mihaela; Tarţău, Liliana; Lupuşoru, Cătălina-Elena


    Pregnancy induced hypertension is a condition of high blood pressure during early and mid-pregnancy. This type of hypertension is much like the chronic type, but it occurs only when the woman is pregnant and resolves completely after delivery. to evaluate some stress hormones in both normotensive and hypertensive pregnant women. The study investigated the correlation between pregnancy induced hypertension and different immune/inflammatory and other markers. This exploratory investigation was performed on pregnant women diagnosed with pregnancy-induced hypertension, admitted to the lasi Cuza Voda Hospital. The psychometric assessment was performed by using the daily stress test, daily hassle scale, blood pressure measurements, and determination of anthropometrical parameters. Some parameters, such as the neuroendocrine and immune/inflammatory ones, and specific parameters for pregnancy hypertension were determined. Our study revealed that blood pressure values presented significant differences between systolic, but not diastolic blood pressure values (p < 0.05). In 75% of subjects blood cortisol levels were not changed. Daily stress level assessment proved that low potential factors and an annoying environment had a high influence on both normotensive and hypertensive pregnant women. Hypertensive women also presented leukocytosis and thrombocytopenia. The research results showed that plasma cortisol level was higher in hypertensive pregnant women, compared with normotensives.

  9. Management of neuroendocrine tumors of unknown primary. (United States)

    Alexandraki, Krystallenia; Angelousi, Anna; Boutzios, Georgios; Kyriakopoulos, Georgios; Rontogianni, Dimitra; Kaltsas, Gregory


    Neuroendocrine neoplams (NENs) are mostly relatively indolent malignancies but a significant number have metastatic disease at diagnosis mainly to the liver. Although in the majority of such cases the primary origin of the tumor can be identified, in approximately 11-22% no primary tumor is found and such cases are designated as NENs of unknown primary origin (UPO). This has significant therapeutic implications with respect to potentially resectable hepatic disease and/or application of appropriate medical therapy, either chemotherapeutic agents or targeted treatment, as the response to various treatments varies according to the origin of the primary tumor. This lack of tumor specific orientated treatment may also account for the relatively poorer prognosis of NENs of UPO compared to metastatic NENs with a known primary site. In the majority of cases the primary tumors are located in the small bowel and the lung, but a number may still elude detection. Occasionally the presence of a functional syndrome may direct to the specific tissue of origin but in the majority of cases a number of biochemical, imaging, histopathological and molecular modalities are utilized to help identify the primary origin of the tumor and direct treatment accordingly. Several diagnostic algorithms have recently been developed to help localize an occult primary tumor; however, in a number of cases no lesion is identified even after prolonged follow-up. It is expected that the delineation of the molecular signature of the different NENs may help identify such cases and provide appropriate treatment.

  10. Pancreatic neuroendocrine neoplasms; Neuroendokrine Neoplasien des Pankreas

    Energy Technology Data Exchange (ETDEWEB)

    Beiderwellen, K.; Lauenstein, T.C. [Universitaetsklinikum Essen, Institut fuer Diagnostische und Interventionelle Radiologie und Neuroradiologie, Essen (Germany); Sabet, A.; Poeppel, T.D. [Universitaetsklinikum Essen, Klinik fuer Nuklearmedizin, Essen (Germany); Lahner, H. [Universitaetsklinikum Essen, Klinik fuer Endokrinologie und Stoffwechselerkrankungen, Essen (Germany)


    Pancreatic neuroendocrine neoplasms (NEN) account for 1-2 % of all pancreatic neoplasms and represent a rare differential diagnosis. While some pancreatic NEN are hormonally active and exhibit endocrine activity associated with characteristic symptoms, the majority are hormonally inactive. Imaging techniques such as ultrasound, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) or as combined PET/CT play a crucial role in the initial diagnosis, therapy planning and control. Endoscopic ultrasound (EUS) and multiphase CT represent the reference methods for localization of the primary pancreatic tumor. Particularly in the evaluation of small liver lesions MRI is the method of choice. Somatostatin receptor scintigraphy and somatostatin receptor PET/CT are of particular value for whole body staging and special aspects of further therapy planning. (orig.) [German] Neuroendokrine Neoplasien (NEN) des Pankreas stellen mit einem Anteil von 1-2 % aller pankreatischen Tumoren eine seltene Differenzialdiagnose dar. Ein Teil der Tumoren ist hormonell aktiv und faellt klinisch durch charakteristische Symptome auf, wohingegen der ueberwiegende Anteil hormonell inaktiv ist. Bildgebende Verfahren wie Sonographie, Computertomographie (CT), Magnetresonanztomographie (MRT) und nicht zuletzt Positronenemissionstomographie (PET oder kombiniert als PET/CT) spielen eine zentrale Rolle fuer Erstdiagnose, Therapieplanung und -kontrolle. Die Endosonographie und die multiphasische CT stellen die Referenzmethoden zur Lokalisation des Primaertumors dar. Fuer die Differenzierung insbesondere kleiner Leberlaesionen bietet die MRT die hoechste Aussagekraft. Fuer das Ganzkoerperstaging und bestimmte Aspekte der Therapieplanung lassen sich die Somatostatinrezeptorszintigraphie und v. a. die Somatostatinrezeptor-PET/CT heranziehen. (orig.)

  11. Effect of yoga on sleep quality and neuroendocrine immune response in metastatic breast cancer patients

    Directory of Open Access Journals (Sweden)

    Raghavendra Mohan Rao


    Full Text Available Background: Studies have shown that distress and accompanying neuroendocrine stress responses as important predictor of survival in advanced breast cancer patients. Some psychotherapeutic intervention studies have shown have modulation of neuroendocrine-immune responses in advanced breast cancer patients. In this study, we evaluate the effects of yoga on perceived stress, sleep, diurnal cortisol, and natural killer (NK cell counts in patients with metastatic cancer. Methods: In this study, 91 patients with metastatic breast cancer who satisfied selection criteria and consented to participate were recruited and randomized to receive “integrated yoga based stress reduction program” (n = 45 or standard “education and supportive therapy sessions” (n = 46 over a 3 month period. Psychometric assessments for sleep quality were done before and after intervention. Blood draws for NK cell counts were collected before and after the intervention. Saliva samples were collected for three consecutive days before and after intervention. Data were analyzed using the analysis of covariance on postmeasures using respective baseline measure as a covariate. Results: There was a significant decrease in scales of symptom distress (P < 0.001, sleep parameters (P = 0.02, and improvement in quality of sleep (P = 0.001 and Insomnia Rating Scale sleep score (P = 0.001 following intervention. There was a decrease in morning waking cortisol in yoga group (P = 0.003 alone following intervention. There was a significant improvement in NK cell percent (P = 0.03 following intervention in yoga group compared to control group. Conclusion: The results suggest modulation of neuroendocrine responses and improvement in sleep in patients with advanced breast cancer following yoga intervention.

  12. Impact of Prenatal Stress on Neuroendocrine Programming

    Directory of Open Access Journals (Sweden)

    Odile Viltart


    programming strongly, notably when hormonal surges occur during sensitive periods of development, so-called developmental windows of vulnerability. Stressful events occurring during the perinatal period may impinge on various aspects of the neuroendocrine programming, subsequently amending the offspring's growth, metabolism, sexual maturation, stress responses, and immune system. Such prenatal stress-induced modifications of the phenotypic plasticity of the progeny might ultimately result in the development of long-term diseases, from metabolic syndromes to psychiatric disorders. Yet, we would like to consider the outcome of this neuroendocrine programming from an evolutionary perspective. Early stressful events during gestation might indeed shape internal parameters of the developing organisms in order to adapt the progeny to its everyday environment and thus contribute to an increased reproductive success, or fitness, of the species. Moreover, parental care, adoption, or enriched environments after birth have been shown to reverse negative long-term consequences of a disturbed gestational environment. In this view, considering the higher potential for neonatal plasticity within the brain in human beings as compared to other species, long-term consequences of prenatal stress might not be as inexorable as suggested in animal-based studies published to date.

  13. Bronchopulmonary Neuroendocrine Neoplasms and Their Precursor Lesions in Multiple Endocrine Neoplasia Type 1. (United States)

    Bartsch, Detlef K; Albers, Max B; Lopez, Caroline L; Apitzsch, Jonas C; Walthers, Eduard M; Fink, Ludger; Fendrich, Volker; Slater, Emily P; Waldmann, Jens; Anlauf, Martin


    The prevalence and clinical behavior of bronchopulmonary neuroendocrine tumors (bNET) associated with multiple endocrine neoplasia type 1 (MEN1) are not well defined. This study aimed to determine the prevalence, potential precursor lesions and prognosis of bNET in patients with MEN1. A database of 75 prospectively collected MEN1 cases was retrospectively analyzed for bNET. Patient characteristics, imaging and treatment were evaluated. Resection specimens of operated patients were reassessed by two specialized pathologists. Available CT scans of the whole cohort were reviewed to determine the prevalence of bronchopulmonary nodules. Five of the 75 MEN1 patients (6.6%; 2 male, 3 female) developed histologically confirmed bNET after a median follow-up of 134 months. The median age at diagnosis of bNET was 47 years (range 31-67), and all patients were asymptomatic. Four patients underwent anatomic lung resections with lymphadenectomy; the remaining patient with multiple lesions had only a wedge resection of the largest bNET. Tumor sizes ranged from 7 to 32 mm in diameter, and all bNET were well differentiated. Two patients had lymph node metastases. Two of 4 reevaluated resection specimens revealed multifocal bNET, and 3 specimens showed tumorlets (up to 3) associated with multifocal areas of a neuroendocrine cell hyperplasia within the subsegmental bronchi. One bNET-related death (1.3%) occurred during long-term follow-up. Review of the available CT scans of the patients without proven bNET revealed small bronchopulmonary lesions (≥3 mm) in 16 of 53 cases (30.2%). bNET in MEN1 might be more common than previously recognized. Their natural course seems to be rather benign. Multifocal tumorlets and multifocal neuroendocrine cell hyperplasia might represent their precursor lesions. © 2015 S. Karger AG, Basel.

  14. Neuroendocrine and Immune Responses Undertake Different Fates following Tryptophan or Methionine Dietary Treatment: Tales from a Teleost Model


    Azeredo, Rita; Machado, Marina; Afonso, António; Fierro-Castro, Camino; Reyes-López, Felipe E.; Tort, Lluis; Gesto, Manuel; Conde-Sieira, Marta; Míguez, Jesús M.; José L. Soengas; Kreuz, Eva; Wuertz, Sven; Peres, Helena; Oliva-Teles, Aires; Costas, Benjamin


    Methionine and tryptophan appear to be fundamental in specific cellular pathways involved in the immune response mechanisms, including stimulation of T-regulatory cells by tryptophan metabolites or pro-inflammatory effects upon methionine supplementation. Thus, the aim of this study was to evaluate the immunomodulatory effect of these amino acids on the inflammatory and neuroendocrine responses in juveniles of European seabass, Dicentrarchus labrax. To achieve this, goal fish were fed for 14 ...

  15. Neuroendocrine and immune responses undertake different fates following tryptophan or methionine dietary treatment: Tales from a teleost model


    Azeredo, Rita; Machado, Marina; Afonso, António; Fierro-Castro, Camino; Reyes-López, Felipe E.; Tort, Lluis; Gesto, Manuel; Conde-Sieira, Marta; Míguez, Jesús M.; José L. Soengas; Kreuz, Eva; Wuertz, Sven; Peres, Helena; Oliva-Teles, Aires; Costas, Benjamin


    Methionine and tryptophan appear to be fundamental in specific cellular pathways involved in the immune response mechanisms, including stimulation of T-regulatory cells by tryptophan metabolites or pro-inflammatory effects upon methionine supplementation. Thus, the aim of this study was to evaluate the immunomodulatory effect of these amino acids on the inflammatory and neuroendocrine responses in juveniles of European seabass, Dicentrarchus labrax. To achieve this, goal fish were fed for 14 ...

  16. Neuroendocrine and immune responses undertake different fates following tryptophan or methionine dietary treatment: tales from a teleost model


    Rita Azeredo; Marina Machado; António Afonso; Camino Fierro-Castro; Reyes-López, Felipe E.; Lluis Tort; Manuel Gesto; Marta Conde-Sieira; Míguez, Jesús M.; José L. Soengas; Eva Kreuz; Sven Wuertz; Helena Peres; Aires Oliva-Teles; Benjamin Costas


    Methionine and tryptophan appear to be fundamental in specific cellular pathways involved in the immune response mechanisms, including stimulation of T-regulatory cells by tryptophan metabolites or pro-inflammatory effects upon methionine supplementation. Thus, the aim of this study was to evaluate the immunomodulatory effect of these amino acids on the inflammatory and neuroendocrine responses in juveniles of European seabass, Dicentrarchus labrax. To achieve this, goal fish were fed for 14 ...

  17. [Role of somatostatin analogs in the treatment of neuroendocrine tumours]. (United States)

    Cuccurullo, V; Cascini, G L; Rambaldi, P F; Mansi, L


    Current therapeutic approaches in neuroendocrine tumours include surgery, radiotherapy and polychemotherapy. Different metabolic patterns of neuroendocrine tumours allow the use of a wide range of diagnostic options in nuclear medicine, due to the presence of a wide spectrum of radiotracers electively concentrating in these neoplasms. Nuclear medicine, and in particular 111In Octreotide (OCT) scintigraphy, 123I Methaiodobenzylguanidine (MIBG) and pentavalent 99mTc-DMSA (V-DMSA), together with biohumoral markers, are currently able to locate tumours also not detectable using traditional diagnostic techniques. Somatostatin analogs, such as octreotide have become increasingly important over the years in the treatment of patients with neuroendocrine tumours. At present the therapeutic use of somatostatin analogs can be schematised as 1) pharmacological treatment (with cold octreotide); 2) surgical treatment (radioguided surgery); 3) radiometabolic treatment (with marked octreotide). The development of new synthetic molecules and new radiocompounds will probably open up interesting scenarios in the near future.

  18. HER2-Positive Neuroendocrine Breast Cancer: Case Report and Review of Literature. (United States)

    Gevorgyan, Arpine; Bregni, Giacomo; Galli, Giulia; Zanardi, Elisa; de Braud, Filippo; Di Cosimo, Serena


    Neuroendocrine carcinoma is an uncommon histology for breast cancer. Our patient underwent right quadrantectomy for a neuroendocrine carcinoma in 1984 and had a bone relapse 30 years later. After thorough pathological and immunohistochemical analysis the diagnosis was confirmed and HER2 amplification was observed. Here we discuss the management, rationale and results of HER2-targeted therapy in advanced neuroendocrine breast carcinoma.

  19. Post-traumatic intrahepatic splenosis mimicking a neuroendocrine tumour. (United States)

    Leong, Chee Weng; Menon, Tulsi; Rao, Sudhakar


    A 52-year-old man presented with abdominal pain with a background of splenectomy 25 years previously. Initial investigations lead to suspicion of a neuroendocrine tumour. Positron emission tomography octreotide scanning and chromogranin were raised. He subsequently underwent a lateral segmentectomy. The histopathology was consistent with splenosis. 1. Splenosis must be considered as differential in any patient with abdominal symptoms post-traumatic splenectomy. 2. Positron emission tomography (PET) octreotide scanning can detect splenosis giving false positives for a neuroendocrine tumour. This is the first case to describe such an association.

  20. Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism (United States)

    Park, Hyeong-Kyu; Ahima, Rexford S.


    Leptin is secreted by adipose tissue and regulates energy homeostasis, neuroendocrine function, metabolism, immune function and other systems through its effects on the central nervous system and peripheral tissues. Leptin administration has been shown to restore metabolic and neuroendocrine abnormalities in individuals with leptin-deficient states, including hypothalamic amenorrhea and lipoatrophy. In contrast, obese individuals are resistant to leptin. Recombinant leptin is beneficial in patients with congenital leptin deficiency or generalized lipodystrophy. However, further research on molecular mediators of leptin resistance is needed for the development of targeted leptin sensitizing therapies for obesity and related metabolic diseases. PMID:25199978

  1. Metastatic breast cancer presenting as a primary hindgut neuroendocrine tumour. (United States)

    Okines, Alicia F C; Hawkes, Eliza A; Rao, Sheela; VAN As, Nicholas; Marsh, Henry; Riddell, Angela; Wilson, Philip O G; Osin, Peter; Wotherspoon, Andrew C; Wetherspoon, Andrew C


    The examination of limited, potentially non-representative fragments of tumour tissue from a core biopsy can be misleading and misdirect subsequent treatment, especially in cases where a primary tumour has not been identified. This case report is of a 65-year-old woman presenting with a destructive sacral mass, diagnosed on radiological imaging and core biopsy as a hindgut neuroendocrine tumour, which on histopathological review of the subsequently resected tumour was found instead to represent a metastasis from an occult hormone-positive breast cancer with neuroendocrine features.

  2. Nasal neuroendocrine carcinoma in a free-living Japanese raccoon dog (Nyctereutes procyonoides viverrinus). (United States)

    Kubo, M; Matsuo, Y; Okano, T; Sakai, H; Masegi, T; Asano, M; Uchida, K; Yanai, T


    Neuroendocrine carcinoma was diagnosed in the left nasal cavity of a free-living Japanese raccoon dog (Nyctereutes procyonoides viverrinus). Microscopically, the tumour consisted of sheets of anaplastic cells separated by narrow zones of fibrovascular stroma. The neoplastic cells had varying numbers of cytoplasmic granules stained by the Grimelius method. Immunohistochemically, the neoplastic cells were variably labelled for cytokeratin AE1/AE3, vimentin, chromogranin A and S-100. Ultrastructurally, some of the neoplastic cells had cytoplasmic membrane-bound dense-core granules of approximate diameter 140-240nm. The tumour had infiltrated the cerebrum and metastasized to the pituitary gland, mandibular and pulmonary lymph nodes, lungs, thyroid gland and adrenal glands.

  3. Neuroendocrine aspects of the response to stress. (United States)

    Miller, Diane B; O'Callaghan, James P


    Disruptions in homeostasis (ie, stress) place demands on the body that are met by the activation of 2 systems, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). Stressor-induced activation of the HPA axis and the SNS results in a series of neural and endocrine adaptations known as the "stress response" or "stress cascade." The stress cascade is responsible for allowing the body to make the necessary physiological and metabolic changes required to cope with the demands of a homeostatic challenge. Here we discuss the key elements of the HPA axis and the neuroendocrine response to stress. A challenge to homeostasis (a stressor) initiates the release of corticotropin-releasing hormone (CRH) from the hypothalamus, which in turn results in release of adrenocortiotropin hormone (ACTH) into general circulation. ACTH then acts on the adrenal cortex resulting in release of a species-specific glucocorticoid into blood. Glucocorticoids act in a negative feedback fashion to terminate the release of CRH. The body strives to maintain glucocorticoid levels within certain boundaries and interference at any level of the axis will influence the other components via feedback loops. Over- or underproduction of cortisol can result in the devastating diseases of Cushing's and Addison's, respectively, but less severe dysregulation of the HPA axis can still have adverse health consequences. These include the deposition of visceral fat as well as cardiovascular disease (eg, atherosclerosis). Thus, chronic stress with its physical and psychological ramifications remains a persistent clinical problem for which new pharmacological treatment strategies are aggressively sought. To date, treatments have been based on the existing knowledge concerning the brain areas and neurobiological substrates that subserve the stress response. Thus, the CRH blocker, antalarmin, is being investigated as a treatment for chronic stress because it prevents CRH from having its

  4. Neuroendocrine tumors of the lung: major radiologic findings in a series of 22 histopathologically confirmed cases

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    Santos, Marcel Koenigkam, E-mail: [Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo (HCFMRP-USP), SP (Brazil); Department of Diagnostic and Interventional Radiology, Heidelberg University (Germany); Barreto, Andre Rodrigues Facanha [Clinica Radius, Clinica Sao Carlos Imagem and Santa Casa de Misericordia de Fortaleza, Fortaleza, CE (Brazil); Chagas Neto, Francisco Abaete [Program of Health Sciences Applied to the Locomotor System - Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo (FMRP-USP), Ribeirao Preto, SP (Brazil); Muglia, Valdair Francisco; Elias Junior, Jorge [Division of Radiology, Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo (FMRPUSP), Ribeirao Preto, SP (Brazil)


    Objective: To describe key imaging findings in a series of cases of primary neuroendocrine tumors of the lung (NTLs), with emphasis on computed tomography changes. Materials And Methods: Imaging studies of 22 patients (12 men, mean age 60 years) with histopathologically confirmed diagnosis, evaluated in the author's institution during the last five years were retrospectively reviewed by two radiologists, with findings being consensually described focusing on changes observed at computed tomography. Results: The authors have described five typical carcinoids, three atypical carcinoids, three large-cell neuroendocrine carcinomas (LCNCs), and 11 small-cell lung cancers (SCLCs). Only one typical carcinoid presented the characteristic appearance of central endobronchial nodule with distal pulmonary atelectasis, while the others were pulmonary nodules or masses. The atypical carcinoids corresponded to peripheral heterogeneous masses. One out of the three LCNCs was a peripheral homogeneous mass, while the others were ill-defined and heterogeneous. The 11 SCLCs corresponded to central, infiltrating and heterogeneous masses with secondary pleuropulmonary changes. Calcifications were absent both in LGNCs and SCLCs. Metastases were found initially and also at follow-up of all the cases of LCNCs and SCLCs. Conclusion: Although some imaging features may be similar, radiologic findings considered together with clinical information may play a relevant role in the differentiation of histological types of NTLs. (author)

  5. Genetic analysis of an orbital metastasis from a primary hepatic neuroendocrine carcinoma

    DEFF Research Database (Denmark)

    Rasmussen, Jacob Ø; von Holstein, Sarah L; Prause, Jan U


    hepatic neuroendocrine carcinoma. Primary hepatic neuroendocrine tumours are extremely rare, and the orbit is an extremely rare location for a neuroendocrine carcinoma metastasis. This is the first reported case of an orbital metastasis with origin from a primary hepatic neuroendocrine carcinoma.......A 71-year-old female with a known history of primary hepatic neuroendocrine carcinoma, presented with a visual defect, proptosis and restricted eye movements of the right eye. Biopsies from the orbit and from the primary hepatic neuroendocrine carcinoma showed similar morphological...... and immunohistochemical features, and high-resolution, array-based comparative genomic hybridization demonstrated loss of one copy each of chromosomes 3 and 18, and gain of 1q both in the primary hepatic neuroendocrine carcinoma and in the orbital tumour. The orbital mass was diagnosed as a metastasis from the primary...

  6. Everolimus Effect on Gastrin and Glucagon in Pancreatic Neuroendocrine Tumors

    NARCIS (Netherlands)

    Pavel, Marianne E.; Chen, David; He, Wei; Cushman, Stephanie; Voi, Maurizio; de Vries, Elisabeth G. E.; Baudin, Eric; Yao, James C.

    Objectives: The pharmacodynamic effects of everolimus on gastrointestinal hormone levels have not been described in patients with pancreatic neuroendocrine tumors (pNETs). We report the effects of everolimus on gastrin and glucagon levels in patients with progressive pNETin RADIANT-1 (a single-arm

  7. Surgical Treatment of an Isolated Metastatic Myocardial Neuroendocrine Tumor. (United States)

    Caldeira, Christiano C B; Sayad, Dany; Strosberg, Jonathan; Faber, Cristiano; Saouma, Samer; Michaud, Tabitha


    We describe a patient diagnosed with a neuroendocrine tumor of the small intestine metastatic to the heart who underwent successful cardiac metastasectomy. The tumor was located on the right ventricle free wall, obstructing the right ventricular outflow tract. There was no valvular involvement. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  8. Is human papillomavirus involved in laryngeal neuroendocrine carcinoma?

    NARCIS (Netherlands)

    Halmos, Gyorgy B; van der Laan, Tom P; van Hemel, Bettien M; Dikkers, Frederik G; Slagter-Menkema, Lorian; van der Laan, Bernard F A M; Schuuring, Ed

    The purpose of this study was to detect human papillomavirus (HPV) infection in laryngeal neuroendocrine carcinoma (LNEC) and to explore the possible relationship between HPV-induced malignant transformation and prognosis in LNEC. Ten cases of LNEC from a tertiary referral hospital were

  9. Neuroendocrine Tumour in a Patient with Neurofibromatosis Type 1 ...

    African Journals Online (AJOL)

    We report the case of an HIV-positive female patient with neurofibromatosis type 1 who was treated for recurrent peptic ulcer disease and later developed diabetes mellitus and chronic diarrhoea. A metastasising somatostatinoma was histologically proven and evidence of a concomitant gastrin-producing neuroendocrine ...

  10. Neuroendocrine neoplasms of the pancreas at dynamic enhanced CT: comparison between grade 3 neuroendocrine carcinoma and grade 1/2 neuroendocrine tumour

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Dong Wook; Kim, Hyoung Jung; Kim, Kyung Won; Byun, Jae Ho [University of Ulsan College of Medicine, Department of Radiology and Research Institute of Radiology, Asan Medical Center, Seoul (Korea, Republic of); Song, Ki Byung [University of Ulsan College of Medicine, Department of Surgery, Asan Medical Center, Seoul (Korea, Republic of); Kim, Ji Hoon; Hong, Seung-Mo [University of Ulsan College of Medicine, Department of Pathology, Asan Medical Center, Seoul (Korea, Republic of)


    To identify the CT features in differentiating grade 3 neuroendocrine carcinomas from grade 1/2 neuroendocrine tumours. This study included 161 patients with surgically confirmed pancreatic neuroendocrine neoplasms. Pathology slides were reviewed to determine the tumour grade. CT image analysis included size, pattern, calcification, margin, pancreatic duct dilatation, bile duct dilatation, vascular invasion, arterial enhancement ratio, and portal enhancement ratio. We used 2 cm, 3 cm, and 4 cm as cutoff values of tumour size and 0.9 and 1.1 of enhancement ratio to determine the sensitivity and specificity. Pathology analysis identified 167 lesions in 161 patients. 154 lesions (92 %) were grade 1/2 and 13 (8 %) were grade 3. Portal enhancement ratio (< 1.1) showed high sensitivity and specificity 92.3 % and 80.5 %, respectively in differentiating grade 3 from grade 1/2. It showed the highest odds ratio (49.60), followed by poorly defined margin, size (> 3 cm), bile duct dilatation, and vascular invasion. When at least two of these five criteria were used in combination, the sensitivity and specificity for diagnosing grade 3 were 92.3 % (12/13) and 87.7 % (135/154), respectively. By using specific CT findings, grade 3 can be differentiated from grade 1/2 with a high diagnostic accuracy leading to an appropriate imaging staging. (orig.)

  11. Diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours). (United States)

    Kos-Kudła, Beata; Blicharz-Dorniak, Jolanta; Strzelczyk, Janusz; Bałdys-Waligórska, Agata; Bednarczuk, Tomasz; Bolanowski, Marek; Boratyn-Nowicka, Agnieszka; Borowska, Małgorzata; Cichocki, Andrzej; Ćwikła, Jarosław B; Falconi, Massimo; Foltyn, Wanda; Handkiewicz-Junak, Daria; Hubalewska-Dydejczyk, Alicja; Jarząb, Barbara; Junik, Roman; Kajdaniuk, Dariusz; Kamiński, Grzegorz; Kolasińska-Ćwikła, Agnieszka; Kowalska, Aldona; Król, Robert; Królicki, Leszek; Krzakowski, Maciej; Kunikowska, Jolanta; Kuśnierz, Katarzyna; Lampe, Paweł; Lange, Dariusz; Lewczuk-Myślicka, Anna; Lewiński, Andrzej; Lipiński, Michał; Londzin-Olesik, Magdalena; Marek, Bogdan; Nasierowska-Guttmejer, Anna; Nawrocki, Sergiusz; Nowakowska-Duława, Ewa; Pilch-Kowalczyk, Joanna; Rosiek, Violetta; Ruchała, Marek; Siemińska, Lucyna; Sowa-Staszczak, Anna; Starzyńska, Teresa; Steinhof-Radwańska, Katarzyna; Sworczak, Krzysztof; Syrenicz, Anhelli; Szawłowski, Andrzej; Szczepkowski, Marek; Wachuła, Ewa; Zajęcki, Wojciech; Zemczak, Anna; Zgliczyński, Wojciech; Zieniewicz, Krzysztof


    Progress in the diagnostics and therapy of gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NEN), the published results of new randomised clinical trials, and the new guidelines issued by the European Neuroendocrine Tumour Society (ENETS) have led the Polish Network of Neuroendocrine Tumours to update the 2013 guidelines regarding management of these neoplasms. We present the general recommendations for the management of NENs, developed by experts during the Third Round Table Conference - Diagnostics and therapy of gastro-entero-pancreatic neuroendocrine neoplasms: Polish recommendations in view of current European recommenda-tions, which took place in December 2016 in Żelechów near Warsaw. Drawing from the extensive experience of centres dealing with this type of neoplasms, we hope that we have managed to develop the optimal management system, applying the most recent achievements in the field of medicine, for these patients, and that it can be implemented effectively in Poland. These management guidelines have been arranged in the following order: gastric and duodenal NENs (including gastrinoma); pancreatic NENs; NENs of the small intestine and appendix, and colorectal NENs.

  12. Duodenal neuroendocrine tumor and the onset of severe diabetes mellitus in a US veteran

    Directory of Open Access Journals (Sweden)

    Lauren Murray


    Full Text Available Objective: Neuroendocrine tumors are neoplasms derived from endocrine cells, most commonly occurring in the gastrointestinal tract. Duodenal neuroendocrine tumors are rare tumors averaging 1.2–1.5 cm, and most are asymptomatic. Common presentation is abdominal pain, upper gastrointestinal bleed, constipation, anemia, and jaundice. Methods: An adult, Black, male patient with newly diagnosed diabetes mellitus presented to the emergency department with elevated liver function test and fatigue. Results: Magnetic resonance cholangiopancreatography demonstrated a large obstructing mass (3.6 cm × 4.4 cm × 3 cm within the second and third portions of the duodenum at the ampulla. Esophagogastroduodenoscopy demonstrated an ulcerated duodenal mass that was biopsied. Immunohistochemical stains were positive for synaptophysin, chromogranin B, and CK7. Chromogranin A was in normal range. Post-Whipple procedure demonstrated a 5.5 cm × 4.1 cm × 2.9 cm duodenal mass with invasion of the subserosal tissue of the small intestine, a mitotic rate of 2 per high-power field, and antigen Ki-67 of 2%–5%. Conclusion: This case raises the question as to if the patient developed diabetes mellitus due to the tumor size and location or if the new onset of diabetes was coincidental. This case also demonstrates the importance of a proficient history and physical.

  13. Primary ovarian neuroendocrine tumor arising in association with a mature cystic teratoma: A case report

    Directory of Open Access Journals (Sweden)

    Nicolas M. Orsi


    Full Text Available Primary ovarian carcinoid tumors are exceptionally rare entities accounting for approximately 0.1% of all ovarian neoplasms. This report describes a primary ovarian neuroendocrine tumor arising in association with a mature cystic teratoma in a 65 year-old woman. Macroscopically, the unilateral adnexal tumor was composed of cystic, solid and mucinous elements which resolved into a dual component lesion histologically. The majority of the tumor displayed an organoid architecture with mild to moderate pleomorphism and no discernible mitotic activity, while approximately 10% consisted of sheets and groups of cells with highly pleomorphic nuclei, necrosis and occasional mitoses. Features of a mature cystic teratoma were seen very focally. Immunohistochemistry revealed strong, diffuse positivity for CD56 and synaptophysin. Chromogranin immunonegativity was noted and there was an absence of nuclear β-catenin accumulation. Ki-67 index was 10–12%. Although there is no established diagnostic framework for primary ovarian carcinoid tumors, this case was diagnosed as a well-differentiated neuroendocrine tumor, Grade 2 (intermediate grade, arising in association with a mature cystic teratoma/dermoid cyst. This case highlights the need to develop ovarian diagnostic criteria in this area.

  14. Genomic alterations in neuroendocrine cancers of the ovary. (United States)

    Yaghmour, George; Prouet, Philippe; Wiedower, Eric; Jamy, Omer Hassan; Feldman, Rebecca; Chandler, Jason C; Pandey, Manjari; Martin, Mike G


    As we have previously reported, small cell carcinoma of the ovary (SCCO) is a rare, aggressive form of ovarian cancer associated with poor outcomes. In an effort to identify new treatment options, we utilized comprehensive genomic profiling to assess the potential for novel therapies in SCCO. Patients with SCCO, SCCO-HT (hypercalcemic type), neuroendocrine tumors of the ovary (NET-O), and small cell carcinoma of the lung (SCLC) profiled by Caris Life Sciences between 2007-2015 were identified. Tumors were assessed with up to 21 IHC stains, in situ hybridization of cMET, EGFR, HER2 and PIK3CA, and next-generation sequencing (NGS) as well as Sanger sequencing of selected genes. Forty-six patients with SCCO (10 SCCO, 18 SCCO-HT, 18 NET-O) were identified as well as 58 patients with SCLC for comparison. Patients with SCCO and SCCO-HT were younger (median 42 years [range 12-75] and 26 years [range 8-40], respectively) than patients with NET-O 62 [range 13-76] or SCLC 66 [range 36-86]. SCCO patients were more likely to be metastatic (70 %) than SCCO-HT (50 %) or NET-O (33 %) patients, but at a similar rate to SCLC patients (65 %). PD1 expression varied across tumor type with SCCO (100 %), SCCO-HT (60 %), NET-O (33 %) vs SCLC (42 %). PDL1 expression also varied with SCCO (50 %), SCCO-HT (20 %), NET-O (33 %) and SCLC (0 %). No amplifications were identified in cMET, EGFR, or HER2 and only 1 was found in PIK3CA (NET-O). Actionable mutations were rare with 1 patient with SCCO having a BRCA2 mutation and 1 patient with NET-O having a PIK3CA mutation. No other actionable mutations were identified. No recurrent actionable mutations or rearrangements were identified using this platform in SCCO. IHC patterns may help guide the use of chemotherapy in these rare tumors.

  15. Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer. (United States)

    Archetti, Marco; Ferraro, Daniela A; Christofori, Gerhard


    The extensive intratumor heterogeneity revealed by sequencing cancer genomes is an essential determinant of tumor progression, diagnosis, and treatment. What maintains heterogeneity remains an open question because competition within a tumor leads to a strong selection for the fittest subclone. Cancer cells also cooperate by sharing molecules with paracrine effects, such as growth factors, and heterogeneity can be maintained if subclones depend on each other for survival. Without strict interdependence between subclones, however, nonproducer cells can free-ride on the growth factors produced by neighboring producer cells, a collective action problem known in game theory as the "tragedy of the commons," which has been observed in microbial cell populations. Here, we report that similar dynamics occur in cancer cell populations. Neuroendocrine pancreatic cancer (insulinoma) cells that do not produce insulin-like growth factor II (IGF-II) grow slowly in pure cultures but have a proliferation advantage in mixed cultures, where they can use the IGF-II provided by producer cells. We show that, as predicted by evolutionary game theory, producer cells do not go extinct because IGF-II acts as a nonlinear public good, creating negative frequency-dependent selection that leads to a stable coexistence of the two cell types. Intratumor cell heterogeneity can therefore be maintained even without strict interdependence between cell subclones. Reducing the amount of growth factors available within a tumor may lead to a reduction in growth followed by a new equilibrium, which may explain relapse in therapies that target growth factors.

  16. Neuroendocrine stimulatory tests of hypothalamus-pituitary-adrenal axis in psoriasis and correlative implications with psychopathological and immune parameters. (United States)

    Karanikas, Evangelos; Harsoulis, Faidon; Giouzepas, Ioannis; Griveas, Ioannis; Chrisomallis, Fotios


    Psoriasis constitutes one of the most representative examples of psychosomatic disorders. The published work investigating the psychological parameters and the way they interact during the course of the disease is extensive, whereas only a few studies have focused on the neuroendocrine framework of psoriasis. In the present study, the objective was to investigate the neuroendocrine parameters of psoriasis and the way they interact with psychopathological and immune variables. Patients with psoriasis (n=24) and the same number of matched healthy controls underwent psychiatric evaluation with interviews and psychometric questionnaires. Both of the groups underwent the corticotropin-releasing hormone (CRH) test and the dexamethasone suppression test (DST) to investigate functional parameters of the hypothalamus-pituitary-adrenal (HPA) axis. The evaluation of immune variables included the estimation of the distribution of T-cell and natural killer lymphocytes. Levels of depressive and anxiety features were increased within subjects with psoriasis and they were significantly correlated with stressful life events and the extent of the disease. The adrenocorticotrophic hormone and cortisol levels increased after CRH infusion without significant differences between the two groups and the psoriatic subjects' cortisol suppression after DST was within normal range, though relatively blunted. No significant correlations were identified among neuroendocrine, psychopathological and immune parameters. No particular neuroendocrine profile has been identified among psoriatic patients and the hypothesized interaction with psychopathological and immune parameters was not replicated. Nevertheless, it is still premature to exclude the possibility that a subtle latent alteration of the HPA axis function might exist, in psoriasis, either stemming from the psychopathology or from the disease per se.

  17. Treatment Options for Pancreatic Neuroendocrine Tumors (United States)

    ... Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer Leukemia Liver Cancer Lung Cancer Lymphoma Pancreatic Cancer Prostate Cancer Skin Cancer Thyroid Cancer Uterine Cancer All ...

  18. Neuroendocrine-type prostatic adenocarcinoma with microsatellite instability in a patient with lynch syndrome. (United States)

    Wagner, David G; Gatalica, Zoran; Lynch, Henry T; Kohl, Shane; Johansson, Sonny L; Lele, Subodh M


    Lynch syndrome is an autosomal-dominant cancer syndrome that can be identified with microsatellite instability molecular tests or immunohistochemical stains on pathologic material from patients who meet the Amsterdam Criteria II. The development of prostatic carcinoma in situ or invasive small cell carcinoma (SCC) of the prostate has not been previously reported in a patient with this syndrome. In this report, an 87-year-old White man with the Lynch syndrome had a prostate biopsy that revealed a mixed high-grade conventional adenocarcinoma and SCC of the prostate with high-grade prostatic intraepithelial neoplasia of the small cell neuroendocrine-type (HGPIN-NE), all showing MSH2 microsatellite instability and loss of MSH2 expression, a finding not previously published. These findings suggest that HGPIN-NE is a precursor of invasive SCC and also that prostatic SCC can develop in a patient with the Lynch syndrome.

  19. [Surgical treatment of gastroentero-pancreatic neuroendocrine tumor]. (United States)

    Ohtsuka, Takao; Takahata, Shunichi; Ueda, Junji; Ueki, Takashi; Nagai, Eishi; Mizumoto, Kazuhiro; Shimizu, Shuji; Tanaka, Masao


    The treatment of choice for gastroentero-pancreatic neuroendocrine tumor(NET)is resection. Because it is difficult to determine the histological grade of NET before operation, the treatment strategy is usually made based on an imaging study including the tumor's size. Some selected gastrointestinal NETs are indicated for endoscopic resection, while others are resected surgically with lymph node dissection. The types of resections for pancreatic NETs vary from enucleation to pancreatectomy with or without regional lymph node dissection, based on the type of excessive hormone, tumor size, distance from the main pancreatic duct, and the presence of type 1 multiple endocrine neoplasia. Hepatic metastases are also resected, if indicated, and even in patients having unresectable metastatic lesions, multidisciplinary therapy including reduction surgery of over 90% of tumor volume might lead to a favorable prognosis. Postoperative adjuvant therapy is recommended for neuroendocrine carcinoma, while there is no evidence to support adjuvant therapy for curatively resected well-differentiated NET.

  20. Insulinoma and gastrinoma syndromes from a single intrapancreatic neuroendocrine tumor. (United States)

    Lodish, Maya B; Powell, Anathea C; Abu-Asab, Mones; Cochran, Craig; Lenz, Petra; Libutti, Steven K; Pingpank, James F; Tsokos, Maria; Gorden, Phillip


    The insulinoma syndrome is marked by fasting hypoglycemia and inappropriate elevations of insulin. The gastrinoma syndrome is characterized by hypergastrinemia, ulcer disease, and/or diarrhea. Rarely, insulinoma and gastrinoma coexist in the same patient simultaneously. Our objective was to determine the cause of a patient's hypoglycemic episodes and peptic ulcer disease. This is a clinical case report from the Clinical Research Center of the National Institutes of Health. One patient with hypoglycemic episodes and peptic ulcer disease had a surgical resection of neuroendocrine tumor. The patient was found to have a single tumor cosecreting both insulin and gastrin. Resection of this single tumor was curative. A single pancreatic neuroendocrine tumor may lead to the expression of both the hyperinsulinemic and hypergastrinemic syndromes.

  1. Neuropsychology of Neuroendocrine Dysregulation after Traumatic Brain Injury

    Directory of Open Access Journals (Sweden)

    Josef Zihl


    Full Text Available Endocrine dysfunction is a common effect of traumatic brain injury (TBI. In addition to affecting the regulation of important body functions, the disruption of endocrine physiology can significantly impair mental functions, such as attention, memory, executive function, and mood. This mini-review focuses on alterations in mental functioning that are associated with neuroendocrine disturbances in adults who suffered TBI. It summarizes the contribution of hormones to the regulation of mental functions, the consequences of TBI on mental health and neuroendocrine homeostasis, and the effects of hormone substitution on mental dysfunction caused by TBI. The available empirical evidence suggests that comprehensive assessment of mental functions should be standard in TBI subjects presenting with hormone deficiency and that hormone replacement therapy should be accompanied by pre- and post-assessments.

  2. Primary Malignant Neuroendocrine Tumour of Pleura: First Case Report

    Directory of Open Access Journals (Sweden)

    Anirban Das


    Full Text Available Metastatic tumours of pleura are the most common malignant tumours causing malignant pleural effusion. Lungs are the most common primary sites. Primary pleural tumours are rarely seen and diffuse malignant mesothelioma is the most common malignant tumour of pleura. Primary malignant neuroendocrine tumour of pleura is not reported in the literature. Here, we report a rare case of primary malignant neuroendocrine tumour of pleura in a fifty-two-year-old, nonsmoker female who presented with right-sided pleural effusion and ipsilateral, dull aching chest pain. Clinical presentations of inflammatory lesions like tuberculous pleuritis and benign and malignant neoplasms of pleura are indistinguishable; hence, fluid cytology, pleural biopsy, and immunohistochemistry are necessary for exact tissue diagnosis of the tumours, which is mandatory for correct treatment and prognostic assessment.

  3. Massive gastrointestinal bleed due to multiple gastric neuroendocrine tumors

    Directory of Open Access Journals (Sweden)

    Vishal Sharma


    Full Text Available Gastric neuroendocrine tumors (G-NETs are uncommon lesions which are usually diagnosed on histological evaluation of gastric polyps. These may occur sporadically or due to hypergastrinemia in the setting of atrophic gastritis or Zollinger-Ellison Syndrome. Large lesions may ulcerate and result in gastrointestinal bleeding. However, massive gastrointestinal bleeding is rare in patients with NETs. We report a 60-year-old lady who presented with massive gastrointestinal bleeding due to multiple G-NETs.

  4. Assessment of intracranial metastases from neuroendocrine tumors/carcinoma

    Directory of Open Access Journals (Sweden)

    Ahmed M Ragab Shalaby


    Full Text Available Background: The most common sites of origin for neuroendocrine carcinoma are gastrointestinal tract and its accessory glands, and lungs. Materials and Methods: One-hundred fifty cases diagnosed with metastatic brain lesions were retrieved from hospital records within 5 years. For these cases, the primary neoplasm, histopathological classification, metastasis, treatment, and fate all were studied. Results: Intracranial deposits were detected in 10%. The primary lesion was in the lungs in 87% of patients, and 1 patient in the breast and 1 in esophagus. Pathological classification of the primary lesion was Grade 2 (MIB-1: 3–20% in 1 patient and neuroendocrine carcinoma (MIB-1: ≥21% in 14 patients. The median period from onset of the primary lesion up to diagnosis of brain metastasis was 12.8 months. About 33% of patients had a single metastasis whereas 67% patients had multiple metastases. Brain metastasis was extirpated in 33% of patients. Stereotactic radiotherapy alone was administered in 20% of patients, and brain metastasis was favorably controlled in most of the patients with coadministration of cranial irradiation as appropriate. The median survival period from diagnosis of brain metastasis was 8.1 months. Conclusion: Most of patients with brain metastasis from neuroendocrine carcinoma showed the primary lesion in the lungs, and they had multiple metastases to the liver, lymph nodes, bones, and so forth at the time of diagnosis of brain metastasis. The guidelines for accurate diagnosis and treatment of neuroendocrine carcinoma should be immediately established based on further analyses of those patients with brain metastasis.

  5. The Neuroendocrine Functions of the Parathyroid Hormone 2 Receptor

    Directory of Open Access Journals (Sweden)

    Arpad eDobolyi


    Full Text Available The G-protein coupled parathyroid hormone 2 receptor (PTH2R is concentrated in endocrine and limbic regions in the forebrain. Its endogenous ligand,tuberoinfundibular peptide of 39 residues (TIP39, is synthesized in only 2 brain regions, within the posterior thalamus and the lateral pons. TIP39-expressing neurons have a widespread projection pattern, which matches the PTH2R distribution in the brain. Neuroendocrine centers including the preoptic area, the periventricular, paraventricular, and arcuate nuclei contain the highest density of PTH2R-positive networks. The administration of TIP39 and an antagonist of the PTH2R as well as the investigation of mice that lack functional TIP39 and PTH2R revealed the involvement of the PTH2R in a variety of neural and neuroendocrine functions. TIP39 acting via the PTH2R modulates several aspects of the stress response. It evokes corticosterone release by activating corticotropin-releasing hormone-containing neurons in the hypothalamic paraventricular nucleus. Block of TIP39 signaling elevates the anxiety state of animals and their fear response, and increases stress-induced analgesia. TIP39 has also been suggested to affect the release of additional pituitary hormones including arginine vasopressin and growth hormone. A role of the TIP39-PTH2R system in thermoregulation was also identified. TIP39 may play a role in maintaining body temperature in a cold environment via descending excitatory pathways from the preoptic area. Anatomical and functional studies also implicated the TIP39-PTH2R system in nociceptive information processing. Finally, TIP39 induced in postpartum dams may play a role in the release of prolactin during lactation. Potential mechanisms leading to the activation of TIP39 neurons and how they influence the neuroendocrine system are also described. The unique TIP39-PTH2R neuromodulator system provides the possibility for developing drugs with a novel mechanism of action to control

  6. Perinatal programming of neuroendocrine mechanisms connecting feeding behavior and stress

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    Sarah J Spencer


    Full Text Available Feeding behavior is closely regulated by neuroendocrine mechanisms that can be influenced by stressful life events. However, the feeding response to stress varies among individuals with some increasing and others decreasing food intake after stress. In addition to the impact of acute lifestyle and genetic backgrounds, the early life environment can have a life-long influence on neuroendocrine mechanisms connecting stress to feeding behavior and may partially explain these opposing feeding responses to stress. In this review I will discuss the perinatal programming of adult hypothalamic stress and feeding circuitry. Specifically I will address how early life (prenatal and postnatal nutrition, early life stress, and the early life hormonal profile can program the hypothalamic-pituitary-adrenal (HPA axis, the endocrine arm of the body’s response to stress long-term and how these changes can, in turn, influence the hypothalamic circuitry responsible for regulating feeding behavior. Thus, over- or under-feeding and / or stressful events during critical windows of early development can alter glucocorticoid (GC regulation of the HPA axis, leading to changes in the GC influence on energy storage and changes in GC negative feedback on HPA axis-derived satiety signals such as corticotropin-releasing-hormone. Furthermore, peripheral hormones controlling satiety, such as leptin and insulin are altered by early life events, and can be influenced, in early life and adulthood, by stress. Importantly, these neuroendocrine signals act as trophic factors during development to stimulate connectivity throughout the hypothalamus. The interplay between these neuroendocrine signals, the perinatal environment, and activation of the stress circuitry in adulthood thus strongly influences feeding behavior and may explain why individuals have unique feeding responses to similar stressors.

  7. Neuroendocrine brake for the treatment of morbid obesity. Preliminary report

    Directory of Open Access Journals (Sweden)

    Aureo Ludovico de Paula


    Full Text Available Objectives: To demonstrate the preliminary results of a newtechnique named neuroendocrine brake, for surgical treatment ofmorbid obesity. Methods: In November 2003, three patientsunderwent the neuroendocrine brake operation performed by thelaparoscopic approach. The mean age was 46.4 years; all patientswere female. Mean BMI was 42.3 kg/m2. The patients selectedpresented some relative or absolute contraindications to the useof gastrointestinal bypass techniques, including gastric ulcer anda family history of gastric malignancy(1 and chronic anemia (2.All patients had associated diseases, including type II diabetesmellitus (2, hypertension (2, obstructive sleep apnea (1,dyslipidemia (3, cholecystolithiasis (1, gastric ulcer (1 andchronic anemia (2. The laparoscopic technique consisted of anileal interposition at the proximal jejunum and longitudinalgastrectomy. Results: There was no conversion to open surgery orpostoperative complications. Sixteen months later, the meanpercentage of initial body weight loss was 44.6% and the meanBMI was 24.3 kg/m2. Glucose, triglyceride and cholesterol levelswere normalized, and sleep apnea showed remission. Conclusion:In spite of the reduced number of patients and short term followup, the good results suggest that the neuroendocrine brake maybecome an option for surgical treatment of morbid obesity in thenear future.

  8. Staging of gastroenteropancreatic neuroendocrine tumors: how we do it based on an evidence-based approach.

    LENUS (Irish Health Repository)

    McDermott, Shaunagh


    In contrast to other common types of malignant tumors, the vast majority of gastroenteropancreatic neuroendocrine tumors are well differentiated and slowly growing with only a minority showing aggressive behavior. It is important to accurately stage patients radiologically so the correct treatment can be implemented and to improve prognosis. In this article, we critically appraise the current literature in an effort to establish the current role of radiologic imaging in the staging of neuroendocrine tumors. We also discuss our protocol for staging neuroendocrine tumors.

  9. Temozolomide as second or third line treatment of patients with neuroendocrine carcinomas

    DEFF Research Database (Denmark)

    Olsen, Ingrid Marie Holst; Sørensen, Jens B; Federspiel, Birgitte


    Knowledge of the clinical efficacy in recurrent neuroendocrine carcinomas is sparse. Treatment with temozolomide alone or in combination with capecitabine and bevacizumab has recently shown promising results....

  10. Expression of PD-1 and PD-L1 in poorly differentiated neuroendocrine carcinomas of the digestive system: a potential target for anti-PD-1/PD-L1 therapy. (United States)

    Roberts, Jordan A; Gonzalez, Raul S; Das, Satya; Berlin, Jordan; Shi, Chanjuan


    Poorly-differentiated neuroendocrine carcinoma of the digestive system has a dismal prognosis with limited treatment options. This study aimed to investigate expression of the PD-1/PD-L1 pathway in these tumors. Thirty-seven patients with a poorly-differentiated neuroendocrine carcinoma of the digestive system were identified. Their electronic medical records, pathology reports and pathology slides were reviewed for demographics, clinical history and pathologic features. Tumor sections were immunohistochemically labeled for PD-1 and PD-L1 and expression of PD-1 and PD-L1 on tumor and tumor-associated immune cells was analyzed and compared between small cell and large cell neuroendocrine carcinomas. The mean age of patients was 61years old with 18 males and 19 females. The colorectum (n=20) was the most common primary site, other primary sites included the pancreaticobiliary system, esophagus, stomach, duodenum, and ampulla. Expression of PD-1 was detected on tumor cells (n=6, 16%) as well as on tumor-associated immune cells (n=23, 63%). The 6 cases with PD-1 expression on tumor cells also had the expression on immune cells. Expression of PD-L1 was visualized on tumor cells in 5 cases (14%), and on tumor-associated immune cells in 10 cases (27%). There was no difference in PD-1 and PD-L1 expression between small cell and large cell neuroendocrine carcinomas. In conclusion, PD-1/PD-L1 expression is a frequent occurrence in poorly-differentiated neuroendocrine carcinomas of the digestive system. Checkpoint blockade targeting the PD-1/PD-L1 pathway may have a potential role in treating patients with this disease. Copyright © 2017. Published by Elsevier Inc.

  11. Effect of antidepressants on neuroendocrine axis in humans. (United States)

    Meltzer, H Y; Fang, V S; Tricou, B J; Robertson, A


    Unlike neuroleptic drugs, the effect of antidepressant drugs on the neuroendocrine axis in man is highly variable and may or may not be intimately related to their antidepressant action. However, the limited neuroendocrine data available does shed some light on the mechanism of action of these agents and raises some important questions, particularly about the regulation of PRL secretion and the interaction between various neurotransmitter systems. At one end of the spectrum, the ability of nomifensine and buproprion to lower serum PRL levels, presumably due to their ability to block the reuptake of DA by tuberoinfundibular DA neurons, suggests that it may be necessary to reconsider the conclusion that these neurons lack a DA reuptake mechanism or that these two agents are antidepressant by virtue of their ability to block DA uptake. Similarly, the inability of amphetamine or methylphenidate to decrease serum PRL levels in man suggests important differences between the tuberoinfundibular DA neurons in man and the rat. These findings also call into question the ability of these agents to block DA uptake or increase DA release in the tuberoinfundibular DA neurons. The finding that fluoxetine raises serum PRL levels, even in one subject, whereas zimelidine has not yet been shown to do so, and that fluoxetine does not potentiate the ability of 5-HTP to stimulate PRL secretion, has raised important questions about the role of 5-HT in PRL and GH regulation in man and the relationship between 5-HT and DA neurons in man. The occasional increase in serum PRL levels found in patients treated with lithium or the MAO inhibitor phenelzine are suggestive of important interindividual differences which may be revealed by neuroendocrine studies, differences which could be valuable in understanding the mechanism of action of these agents - e.g., does lithium decrease DA receptor sensitivity? - and fundamental aspects of neuroendocrine regulation - e.g., do the MAO inhibitors

  12. Predicting neuroendocrine tumor (carcinoid) neoplasia using gene expression profiling and supervised machine learning. (United States)

    Drozdov, Ignat; Kidd, Mark; Nadler, Boaz; Camp, Robert L; Mane, Shrikant M; Hauso, Oyvind; Gustafsson, Bjorn I; Modlin, Irvin M


    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. Seventy-three clinically and World Health Organization pathologically classified NET samples (primary tumor, n = 44 samples; liver metastases, n = 29 samples) and 30 normal human enterochromaffin (EC) cell preparations were analyzed using real-time polymerase chain reaction. Transcript levels were normalized to 3 NET housekeeping genes (asparagine-linked glycosylation 9 or ALG9, transcription factor CP2 or TFCP2, and zinc finger protein 410 or ZNF410) using geNorm analysis. A predictive gene-based model was constructed using supervised learning algorithms from the transcript expression levels. Primary SI NETs could be differentiated from normal human EC cell preparations with 100% specificity and 92% sensitivity. Well differentiated NETs (WDNETs), well differentiated neuroendocrine carcinomas, and poorly differentiated NETs (PDNETs) were classified with a specificity of 78%, 78%, and 71%, respectively; whereas poorly differentiated neuroendocrine carcinomas were misclassified as either WDNETs or PDNETs. Metastases were predicted in all cases with 100% sensitivity and specificity. The current results indicated that gene expression profiling and supervised machine learning can be used to classify SI NET subtypes and accurately predict metastasis

  13. Alternative polyadenylation of tumor suppressor genes in small intestinal neuroendocrine tumors

    DEFF Research Database (Denmark)

    Rehfeld, Anders Aagaard; Plass, Mireya; Døssing, Kristina


    The tumorigenesis of small intestinal neuroendocrine tumors (SI-NETs) is poorly understood. Recent studies have associated alternative polyadenylation (APA) with proliferation, cell transformation, and cancer. Polyadenylation is the process in which the pre-messenger RNA is cleaved at a polyA site...... and a polyA tail is added. Genes with two or more polyA sites can undergo APA. This produces two or more distinct mRNA isoforms with different 3' untranslated regions. Additionally, APA can also produce mRNAs containing different 3'-terminal coding regions. Therefore, APA alters both the repertoire...... and the expression level of proteins. Here, we used high-throughput sequencing data to map polyA sites and characterize polyadenylation genome-wide in three SI-NETs and a reference sample. In the tumors, 16 genes showed significant changes of APA pattern, which lead to either the 3' truncation of mRNA coding regions...

  14. Cholinergic regulation of the vasopressin neuroendocrine system

    Energy Technology Data Exchange (ETDEWEB)

    Michels, K.M.


    To clarify the physical and functional relationship between the cholinergic system, and the neurodocrine cells of the supraoptic nucleus, a combination of experiments on receptor binding, localization and function were carried out. The putative nicotinic receptor probe (/sup 125/I)alpha bungarotoxin ((/sup 125/I)alpha BTX) bound with high affinity and specificity to the vasopressin and oxytocin magnocellular neurons of the supraoptic nucleus, nucleus circularis, and paraventricular nucleus. Binding of (/sup 125/I)alpha BTX within the neural lobe was very low. In contrast, the muscarinic cholinergic receptor probe (/sup 3/H)quinuclidinylbenzilate ((/sup 3/H)QNB) did not bind to magnocellular vasopressin and oxytocin cell groups. The median eminence, which contains the neurosecretory axons, and the neural lobe of the pituitary contain low levels of (/sup 3/H)QNB binding. The physiological significance of these cholinergic receptors in regulation of vasopressin release was tested using an in vitro preparation of the supraoptic - neural lobe system.

  15. Autonomic, neuroendocrine, and immunological effects of ayahuasca: a comparative study with d-amphetamine. (United States)

    Dos Santos, Rafael G; Valle, Marta; Bouso, José Carlos; Nomdedéu, Josep F; Rodríguez-Espinosa, José; McIlhenny, Ethan H; Barker, Steven A; Barbanoj, Manel J; Riba, Jordi


    Ayahuasca is an Amazonian psychotropic plant tea combining the 5-HT2A agonist N,N-dimethyltryptamine (DMT) and monoamine oxidase-inhibiting β-carboline alkaloids that render DMT orally active. The tea, obtained from Banisteriopsis caapi and Psychotria viridis, has traditionally been used for religious, ritual, and medicinal purposes by the indigenous peoples of the region. More recently, the syncretistic religious use of ayahuasca has expanded to the United States and Europe. Here we conducted a double-blind randomized crossover clinical trial to investigate the physiological impact of ayahuasca in terms of autonomic, neuroendocrine, and immunomodulatory effects. An oral dose of encapsulated freeze-dried ayahuasca (1.0 mg DMT/kg body weight) was compared versus a placebo and versus a positive control (20 mg d-amphetamine) in a group of 10 healthy volunteers. Ayahuasca led to measurable DMT plasma levels and distinct subjective and neurophysiological effects that were absent after amphetamine. Both drugs increased pupillary diameter, with ayahuasca showing milder effects. Prolactin levels were significantly increased by ayahuasca but not by amphetamine, and cortisol was increased by both, with ayahuasca leading to the higher peak values. Ayahuasca and amphetamine induced similar time-dependent modifications in lymphocyte subpopulations. Percent CD4 and CD3 were decreased, whereas natural killer cells were increased. Maximum changes occurred around 2 hours, returning to baseline levels at 24 hours. In conclusion, ayahuasca displayed moderate sympathomimetic effects, significant neuroendocrine stimulation, and a time-dependent modulatory effect on cell-mediated immunity. Future studies on the health impact of long-term ayahuasca consumption should consider the assessment of immunological status in regular users.

  16. Global gene expression in neuroendocrine tumors from patients with the MEN1 syndrome

    Directory of Open Access Journals (Sweden)

    Laramie Jason M


    Full Text Available Abstract Background Multiple Endocrine Neoplasia type 1 (MEN1, OMIM 131100 is an autosomal dominant disorder characterized by endocrine tumors of the parathyroids, pancreatic islets and pituitary. The disease is caused by the functional loss of the tumor suppressor protein menin, coded by the MEN1 gene. The protein sequence has no significant homology to known consensus motifs. In vitro studies have shown menin binding to JunD, Pem, Smad3, NF-kappaB, nm23H1, and RPA2 proteins. However, none of these binding studies have led to a convincing theory of how loss-of-menin leads to neoplasia. Results Global gene expression studies on eight neuroendocrine tumors from MEN1 patients and 4 normal islet controls was performed utilizing Affymetrix U95Av2 chips. Overall hierarchical clustering placed all tumors in one group separate from the group of normal islets. Within the group of tumors, those of the same type were mostly clustered together. The clustering analysis also revealed 19 apoptosis-related genes that were under-expressed in the group of tumors. There were 193 genes that were increased/decreased by at least 2-fold in the tumors relative to the normal islets and that had a t-test significance value of p Conclusion This is the first analysis of global gene expression in MEN1-associated neuroendocrine tumors. Many genes were identified which were differentially expressed in neuroendocrine tumors arising in patients with the MEN1 syndrome, as compared with normal human islet cells. The expression of a group of apoptosis-related genes was significantly suppressed, suggesting that these genes may play crucial roles in tumorigenesis in this syndrome. We identified a number of genes which are attractive candidates for further investigation into the mechanisms by which menin loss causes tumors in pancreatic islets. Of particular interest are: FGF9 which may stimulate the growth of prostate cancer, brain cancer and endometrium; and IER3 (IEX-1, PHLDA2

  17. The Function of Neuroendocrine Cells in Prostate Cancer (United States)


    University of Rochester Medical Center School of Medicine and Dentistry , Rochester, NY. Corresponding Authors: Jiaoti Huang, UCLA David Geffen School of...and transcribed as part of the miR-106b25 poly- cistron. It is overexpressed in several human cancers, including pediatric brain tumors (28...Handler MH, Vibhakar R, Foreman NK. Survey of MicroRNA expression in pediatric brain tumors. Pediatr Blood Cancer 2011;56:211–6. 29. Petrocca F, Visone R

  18. The Function of Neuroendocrine Cells in Prostate Cancer (United States)


    weighs and measures the prostate, inks its surface with Indian ink (to assess the status of surgical margins on histologic sections) and slices the...for pathologic diagnosis. Slices 2 and 4 are divided into 4 quadrants and additional ink of different colors is used for orientation indicating right vs...medium (DMEM), sodium pyru- vate, L-glutamine, penicillin, and streptomycin were purchased from Hyclone; charcoal /dextran-treated FBS medium was

  19. General Information about Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) (United States)

    ... History Committees of Interest Legislative Resources Recent Public Laws Careers Visitor Information Search Search Home Cancer Types Pancreatic Cancer Patient Pancreatic Cancer Patient Pancreatic ...

  20. Nordic guidelines 2014 for diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms

    DEFF Research Database (Denmark)

    Janson, Eva Tiensuu; Sorbye, Halfdan; Welin, Staffan


    BACKGROUND: The diagnostic work-up and treatment of patients with neuroendocrine neoplasms (NENs) has undergone major recent advances and new methods are currently introduced into the clinic. An update of the WHO classification has resulted in a new nomenclature dividing NENs into neuroendocrine...

  1. Neuroendocrine dysregulations in sexually abused children and adolescents: a systematic review

    NARCIS (Netherlands)

    Bicanic, I. A. E.; Meijer, M.; Sinnema, G.; van de Putte, E. M.; Olff, M.


    Several studies provided evidence for neuroendocrine dysregulations in adults with a history of child sexual abuse. This review focuses on neuroendocrine studies in sexually abused children and adolescents, dating from January 1, 1990 to January 1, 2007 and obtained from a systematic Medline Indexed

  2. Neuroendocrine reactivity and recovery from work with different physical and mental demands

    NARCIS (Netherlands)

    Sluiter, JK; Frings-Dresen, MHW; van der Beek, AJ; Meijman, TF; Heisterkamp, SH

    Objectives The purpose of this study was to examine the extent to which the type or nature (physical, mental or mixed mental and physical) of work and work characteristics is related to the course of neuroendocrine reactivity and recovery from work. Methods Neuroendocrine reactivity and recovery

  3. Neuroendocrine Tumors of the Lung: Current Challenges and Advances in the Diagnosis and Management of Well-Differentiated Disease. (United States)

    Hendifar, Andrew E; Marchevsky, Alberto M; Tuli, Richard


    Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies that arise from neuroendocrine cells throughout the body, most commonly originating from the lungs and gastrointestinal tract. Lung NETs can be classified as well differentiated (low-grade typical carcinoids [TCs] and intermediate-grade atypical carcinoids [ACs]) and poorly differentiated (high-grade large cell neuroendocrine carcinoma or SCLC). The incidence of these tumors is increasing, but disease awareness remains low among thoracic specialists, who are often involved in the diagnosis and early treatment for these patients. An accurate and timely diagnosis can ensure the implementation of appropriate treatment and have a substantial impact on prognosis. However, lung NET classification and diagnosis, particularly for TCs/ACs, are complicated by several factors, including a variable natural history and nonspecific symptoms. Surgery remains the only curative option for TCs/ACs, but there is a lack of consensus between lung NET management guidelines regarding optimal treatment approaches in the unresectable/metastatic setting on account of the limited availability of high-level clinical evidence. As a result, a multidisciplinary approach to management of lung NETs is required to ensure a consistent and optimal level of care. RADIANT-4 is the first phase III trial involving a large subpopulation of patients with advanced well-differentiated lung NETs to report reductions in the risk for disease progression and death with everolimus over placebo. This led to the recent U.S. approval of everolimus-the first agent approved for advanced lung TCs/ACs. To further improve evidence-based care, additional randomized controlled trials in patients with lung carcinoids are needed. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  4. Neuroendocrine and Immune Responses Undertake Different Fates following Tryptophan or Methionine Dietary Treatment: Tales from a Teleost Model

    Directory of Open Access Journals (Sweden)

    Rita Azeredo


    Full Text Available Methionine and tryptophan appear to be fundamental in specific cellular pathways involved in the immune response mechanisms, including stimulation of T-regulatory cells by tryptophan metabolites or pro-inflammatory effects upon methionine supplementation. Thus, the aim of this study was to evaluate the immunomodulatory effect of these amino acids on the inflammatory and neuroendocrine responses in juveniles of European seabass, Dicentrarchus labrax. To achieve this, goal fish were fed for 14 days methionine and tryptophan-supplemented diets (MET and TRP, respectively, 2× dietary requirement level or a control diet meeting the amino acids requirement levels (CTRL. Fish were sampled for immune status assessment and the remaining fish were challenged with intraperitoneally injected inactivated Photobacterium damselae subsp. piscicida and sampled either 4 or 24 h post-injection. Respiratory burst activity, brain monoamines, plasma cortisol, and immune-related gene expression showed distinct and sometimes opposite patterns regarding the effects of dietary amino acids. While neuroendocrine intermediates were not affected by any dietary treatment at the end of the feeding trial, both supplemented diets led to increased levels of plasma cortisol after the inflammatory insult, while brain monoamine content was higher in TRP-fed fish. Peripheral blood respiratory burst was higher in TRP-fed fish injected with the bacteria inoculum but only compared to those fed MET. However, no changes were detected in total antioxidant capacity. Complement factor 3 was upregulated in MET-fed fish but methionine seemed to poorly affect other genes expression patterns. In contrast, fish fed MET showed increased immune cells numbers both before and after immune challenge, suggesting a strong enhancing effect of methionine on immune cells proliferation. Differently, tryptophan effects on inflammatory transcripts suggested an inhibitory mode of action. This, together

  5. Neuroendocrine and Immune Responses Undertake Different Fates following Tryptophan or Methionine Dietary Treatment: Tales from a Teleost Model. (United States)

    Azeredo, Rita; Machado, Marina; Afonso, António; Fierro-Castro, Camino; Reyes-López, Felipe E; Tort, Lluis; Gesto, Manuel; Conde-Sieira, Marta; Míguez, Jesús M; Soengas, José L; Kreuz, Eva; Wuertz, Sven; Peres, Helena; Oliva-Teles, Aires; Costas, Benjamin


    Methionine and tryptophan appear to be fundamental in specific cellular pathways involved in the immune response mechanisms, including stimulation of T-regulatory cells by tryptophan metabolites or pro-inflammatory effects upon methionine supplementation. Thus, the aim of this study was to evaluate the immunomodulatory effect of these amino acids on the inflammatory and neuroendocrine responses in juveniles of European seabass, Dicentrarchus labrax. To achieve this, goal fish were fed for 14 days methionine and tryptophan-supplemented diets (MET and TRP, respectively, 2× dietary requirement level) or a control diet meeting the amino acids requirement levels (CTRL). Fish were sampled for immune status assessment and the remaining fish were challenged with intraperitoneally injected inactivated Photobacterium damselae subsp. piscicida and sampled either 4 or 24 h post-injection. Respiratory burst activity, brain monoamines, plasma cortisol, and immune-related gene expression showed distinct and sometimes opposite patterns regarding the effects of dietary amino acids. While neuroendocrine intermediates were not affected by any dietary treatment at the end of the feeding trial, both supplemented diets led to increased levels of plasma cortisol after the inflammatory insult, while brain monoamine content was higher in TRP-fed fish. Peripheral blood respiratory burst was higher in TRP-fed fish injected with the bacteria inoculum but only compared to those fed MET. However, no changes were detected in total antioxidant capacity. Complement factor 3 was upregulated in MET-fed fish but methionine seemed to poorly affect other genes expression patterns. In contrast, fish fed MET showed increased immune cells numbers both before and after immune challenge, suggesting a strong enhancing effect of methionine on immune cells proliferation. Differently, tryptophan effects on inflammatory transcripts suggested an inhibitory mode of action. This, together with a high

  6. Spontaneous rupture of thymic neuroendocrine carcinoma: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Park, Chan Yeong; Lee, In Jae; Min, Soo Kee [Hallym University College of Medicine, Chuncheon (Korea, Republic of)


    Thymic neuroendocrine carcinoma (NEC) is a rare neoplasm with tendencies of local invasion and metastasis. Usually, it is detected incidentally or by its symptoms caused by mass effect. Rupture of the tumor is extremely rare. In this study, we report a case of a ruptured thymic NEC that was combined with a potentially fatal hemorrhage. This lesion was manifested as a progressive bulging of the right cardiac border on serial chest radiographs, and on CT as a large anterior mediastinal mass with heterogeneous enhancement, internal necrosis, and hematoma.

  7. Update on the management of neuroendocrine hepatic metastases. (United States)

    Madoff, David C; Gupta, Sanjay; Ahrar, Kamran; Murthy, Ravi; Yao, James C


    Neuroendocrine tumors (NETs) are rare and represent a diverse collection of malignancies that occur in many organ systems throughout the body, including the gastrointestinal and respiratory tracts. Unfortunately, the majority of patients with NETs have hepatic metastases at the time of diagnosis. Although some patients may be asymptomatic, others have unusual clinical presentations and variable tumor growth patterns. Although many patients have long indolent courses, without treatment, most patients die within 5 years of diagnosis. This article reviews the care of patients with NETs and hepatic metastases, with emphasis on the increasingly important role of oncologic image-guided interventions.

  8. Treatment of pancreatic neuroendocrine tumor with liver metastases

    Directory of Open Access Journals (Sweden)

    LI Zhao


    Full Text Available Pancreatic neuroendocrine tumor (pNET is a rare type of pancreatic tumors. The incidence of pNET shows a gradually increasing trend in recent years. The most common organ of distant metastases is the liver. Surgical resection is still the optimal treatment for resectable, well-differentiated liver metastases with no evidence of extrahepatic spread. For unresectable patients, a combination of multiple modalities, such as transarterial chemoembolization, radiofrequency ablation, systemic chemotherapy, and molecular targeted therapy, can prolong the survival time of patients. Liver transplantation should be strictly evaluated on an individual basis.

  9. Psychoneuroendocrine research in depression. I. Hormone levels of different neuroendocrine axes and the dexamethasone suppression test. (United States)

    Rupprecht, R; Lesch, K P


    Psychoneuroendocrinology is of major importance in the biological research of depression. Most studies have focussed on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis but other endocrine systems such as the hypothalamic-pituitary-thyroid (HPT), hypothalamic-pituitary-somatotropic (HPS), and the hypothalamic-pituitary-gonadal (HPG) axis have also been shown to be involved in the psychobiology of depression. There are close interrelations between various endocrine axes which possibly are affected during depressive illness. A variety of neuroendocrine abnormalities has been detected in depressive disorder but the pathophysiology of these derangements remains still unclear. Although the currently used neuroendocrine tests are not of diagnostic validity they may help to clarify the pathophysiological significance of the complex regulatory mechanisms of different neuroendocrine axes in affective disorders. Neuroendocrine regulation is determined both by peripheral and central mechanisms which both have to be adequately considered as well as potent interactions between various endocrine systems in further neuroendocrine depression research.

  10. Methylmercury-induced changes in gene transcription associated with neuroendocrine disruption in largemouth bass (Micropterus salmoides) (United States)

    Richter, Catherine A.; Martyniuk, Christopher J.; Annis, Mandy L.; Brumbaugh, William G.; Chasar, Lia C.; Denslow, Nancy D.; Tillitt, Donald E.


    Methyl-mercury (MeHg) is a potent neuroendocrine disruptor that impairs reproductive processes in fish. The objectives of this study were to (1) characterize transcriptomic changes induced by MeHg exposure in the female largemouth bass (LMB) hypothalamus under controlled laboratory conditions, (2) investigate the health and reproductive impacts of MeHg exposure on male and female largemouth bass (LMB) in the natural environment, and (3) identify MeHg-associated gene expression patterns in whole brain of female LMB from MeHg-contaminated habitats. The laboratory experiment was a single injection of 2.5 μg MeHg/g body weight for 96 h exposure. The field survey compared river systems in Florida, USA with comparably lower concentrations of MeHg (Wekiva, Santa Fe, and St. Johns Rivers) in fish and one river system with LMB that contained elevated concentrations of MeHg (St. Marys River). Microarray analysis was used to quantify transcriptomic responses to MeHg exposure. Although fish at the high-MeHg site did not show overt health or reproductive impairment, there were MeHg-responsive genes and pathways identified in the laboratory study that were also altered in fish from the high-MeHg site relative to fish at the low-MeHg sites. Gene network analysis suggested that MeHg regulated the expression targets of neuropeptide receptor and steroid signaling, as well as structural components of the cell. Disease-associated gene networks related to MeHg exposure, based upon expression data, included cerebellum ataxia, movement disorders, and hypercalcemia. Gene responses in the CNS are consistent with the documented neurotoxicological and neuroendocrine disrupting effects of MeHg in vertebrates.

  11. Succinate Dehydrogenase (SDH)-Deficient Pancreatic Neuroendocrine Tumor Expands the SDH-Related Tumor Spectrum. (United States)

    Niemeijer, Nicolasine D; Papathomas, Thomas G; Korpershoek, Esther; de Krijger, Ronald R; Oudijk, Lindsey; Morreau, Hans; Bayley, Jean-Pierre; Hes, Frederik J; Jansen, Jeroen C; Dinjens, Winand N M; Corssmit, Eleonora P M


    Mutations in genes encoding the subunits of succinate dehydrogenase (SDH) can lead to pheochromocytoma/paraganglioma formation. However, SDH mutations have also been linked to nonparaganglionic tumors. The objective was to investigate which nonparaganglionic tumors belong to the SDH-associated tumor spectrum. This was a retrospective cohort study. The setting was a tertiary referral center. Patients included all consecutive SDHA/SDHB/SDHC and SDHD mutation carriers followed at the Department of Endocrinology of the Leiden University Medical Center who were affected by non-pheochromocytoma/paraganglioma solid tumors. Main outcome measures were SDHA/SDHB immunohistochemistry, mutation analysis, and loss of heterozygosity analysis of the involved SDH-encoding genes. Twenty-five of 35 tumors (from 26 patients) showed positive staining on SDHB and SDHA immunohistochemistry. Eight tumors showed negative staining for SDHB and positive staining for SDHA: a pancreatic neuroendocrine tumor, a macroprolactinoma, two gastric gastrointestinal stromal tumors, an abdominal ganglioneuroma, and three renal cell carcinomas. With the exception of the abdominal ganglioneuroma, loss of heterozygosity was detected in all tumors. A prolactinoma in a patient with a germline SDHA mutation was the only tumor immunonegative for both SDHA and SDHB. Sanger sequencing of this tumor revealed a somatic mutation (p.D38V) as a likely second hit leading to biallelic inactivation of SDHA. One tumor (breast cancer) showed heterogeneous SDHB staining, positive SDHA staining, and retention of heterozygosity. This study strengthens the etiological association of SDH genes with pituitary neoplasia, renal tumorigenesis, and gastric gastrointestinal stromal tumors. Furthermore, our results indicate that pancreatic neuroendocrine tumor also falls within the SDH-related tumor spectrum.

  12. Neuroendocrine Function After Hypothalamic Depletion of Glucocorticoid Receptors in Male and Female Mice. (United States)

    Solomon, Matia B; Loftspring, Matthew; de Kloet, Annette D; Ghosal, Sriparna; Jankord, Ryan; Flak, Jonathan N; Wulsin, Aynara C; Krause, Eric G; Zhang, Rong; Rice, Taylor; McKlveen, Jessica; Myers, Brent; Tasker, Jeffrey G; Herman, James P


    Glucocorticoids act rapidly at the paraventricular nucleus (PVN) to inhibit stress-excitatory neurons and limit excessive glucocorticoid secretion. The signaling mechanism underlying rapid feedback inhibition remains to be determined. The present study was designed to test the hypothesis that the canonical glucocorticoid receptors (GRs) is required for appropriate hypothalamic-pituitary-adrenal (HPA) axis regulation. Local PVN GR knockdown (KD) was achieved by breeding homozygous floxed GR mice with Sim1-cre recombinase transgenic mice. This genetic approach created mice with a KD of GR primarily confined to hypothalamic cell groups, including the PVN, sparing GR expression in other HPA axis limbic regulatory regions, and the pituitary. There were no differences in circadian nadir and peak corticosterone concentrations between male PVN GR KD mice and male littermate controls. However, reduction of PVN GR increased ACTH and corticosterone responses to acute, but not chronic stress, indicating that PVN GR is critical for limiting neuroendocrine responses to acute stress in males. Loss of PVN GR induced an opposite neuroendocrine phenotype in females, characterized by increased circadian nadir corticosterone levels and suppressed ACTH responses to acute restraint stress, without a concomitant change in corticosterone responses under acute or chronic stress conditions. PVN GR deletion had no effect on depression-like behavior in either sex in the forced swim test. Overall, these findings reveal pronounced sex differences in the PVN GR dependence of acute stress feedback regulation of HPA axis function. In addition, these data further indicate that glucocorticoid control of HPA axis responses after chronic stress operates via a PVN-independent mechanism.

  13. The interplay between neuroendocrine activity and psychological stress-induced exacerbation of allergic asthma. (United States)

    Miyasaka, Tomomitsu; Dobashi-Okuyama, Kaori; Takahashi, Tomoko; Takayanagi, Motoaki; Ohno, Isao


    Psychological stress is recognized as a key factor in the exacerbation of allergic asthma, whereby brain responses to stress act as immunomodulators for asthma. In particular, stress-induced enhanced type 2 T-helper (Th2)-type lung inflammation is strongly associated with asthma pathogenesis. Psychological stress leads to eosinophilic airway inflammation through activation of the hypothalamic-pituitary-adrenal pathway and autonomic nervous system. This is followed by the secretion of stress hormones into the blood, including glucocorticoids, epinephrine, and norepinephrine, which enhance Th2 and type 17 T-helper (Th17)-type asthma profiles in humans and rodents. Recent evidence has shown that a defect of the μ-opioid receptor in the brain along with a defect of the peripheral glucocorticoid receptor signaling completely disrupted stress-induced airway inflammation in mice. This suggests that the stress response facilitates events in the central nervous and endocrine systems, thus exacerbating asthma. In this review, we outline the recent findings on the interplay between stress and neuroendocrine activities followed by stress-induced enhanced Th2 and Th17 immune responses and attenuated regulatory T (Treg) cell responses that are closely linked with asthma exacerbation. We will place a special focus on our own data that has emphasized the continuity from central sensing of psychological stress to enhanced eosinophilic airway inflammation. The mechanism that modulates psychological stress-induced exacerbation of allergic asthma through neuroendocrine activities is thought to involve a series of consecutive pathological events from the brain to the lung, which implies there to be a "neuropsychiatry phenotype" in asthma. Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

  14. Neuropeptide Receptor Transcriptome Reveals Unidentified Neuroendocrine Pathways (United States)

    Yamanaka, Naoki; Yamamoto, Sachie; Žitňan, Dušan; Watanabe, Ken; Kawada, Tsuyoshi; Satake, Honoo; Kaneko, Yu; Hiruma, Kiyoshi; Tanaka, Yoshiaki; Shinoda, Tetsuro; Kataoka, Hiroshi


    Neuropeptides are an important class of molecules involved in diverse aspects of metazoan development and homeostasis. Insects are ideal model systems to investigate neuropeptide functions, and the major focus of insect neuropeptide research in the last decade has been on the identification of their receptors. Despite these vigorous efforts, receptors for some key neuropeptides in insect development such as prothoracicotropic hormone, eclosion hormone and allatotropin (AT), remain undefined. In this paper, we report the comprehensive cloning of neuropeptide G protein-coupled receptors from the silkworm, Bombyx mori, and systematic analyses of their expression. Based on the expression patterns of orphan receptors, we identified the long-sought receptor for AT, which is thought to stimulate juvenile hormone biosynthesis in the corpora allata (CA). Surprisingly, however, the AT receptor was not highly expressed in the CA, but instead was predominantly transcribed in the corpora cardiaca (CC), an organ adjacent to the CA. Indeed, by using a reverse-physiological approach, we purified and characterized novel allatoregulatory peptides produced in AT receptor-expressing CC cells, which may indirectly mediate AT activity on the CA. All of the above findings confirm the effectiveness of a systematic analysis of the receptor transcriptome, not only in characterizing orphan receptors, but also in identifying novel players and hidden mechanisms in important biological processes. This work illustrates how using a combinatorial approach employing bioinformatic, molecular, biochemical and physiological methods can help solve recalcitrant problems in neuropeptide research. PMID:18725956

  15. Genetic associations with neuroendocrine tumor risk: results from a genome-wide association study. (United States)

    Du, Yeting; Ter-Minassian, Monica; Brais, Lauren; Brooks, Nichole; Waldron, Amanda; Chan, Jennifer A; Lin, Xihong; Kraft, Peter; Christiani, David C; Kulke, Matthew H


    The etiology of neuroendocrine tumors remains poorly defined. Although neuroendocrine tumors are in some cases associated with inherited genetic syndromes, such syndromes are rare. The majority of neuroendocrine tumors are thought to be sporadic. We performed a genome-wide association study (GWAS) to identify potential genetic risk factors for sporadic neuroendocrine tumors. Using germline DNA from blood specimens, we genotyped 909,622 SNPs using the Affymetrix 6.0 GeneChip, in a cohort comprising 832 neuroendocrine tumor cases from Dana-Farber Cancer Institute and Massachusetts General Hospital and 4542 controls from the Harvard School of Public Health. An additional 241 controls from Dana-Farber Cancer Institute were used for quality control. We assessed risk associations in the overall cohort, and in neuroendocrine tumor subgroups. We identified no potential risk associations in the cohort overall. In the small intestine neuroendocrine tumor subgroup, comprising 293 cases, we identified risk associations with three SNPs on chromosome 12, all in strong LD. The three SNPs are located upstream of ELK3, a transcription factor implicated in angiogenesis. We did not identify clear risk associations in the bronchial or pancreatic neuroendocrine subgroups. This large-scale study provides initial evidence that presumed sporadic small intestine neuroendocrine tumors may have a genetic etiology. Our results provide a basis for further exploring the role of genes implicated in this analysis, and for replication studies to confirm the observed associations. Additional studies to evaluate potential genetic risk factors for sporadic pancreatic and bronchial neuroendocrine tumors are warranted. © 2016 Society for Endocrinology.

  16. Neuroendocrine regulation of salt and water metabolism

    Directory of Open Access Journals (Sweden)

    S.M. McCann


    Full Text Available Neurons which release atrial natriuretic peptide (ANPergic neurons have their cell bodies in the paraventricular nucleus and in a region extending rostrally and ventrally to the anteroventral third ventricular (AV3V region with axons which project to the median eminence and neural lobe of the pituitary gland. These neurons act to inhibit water and salt intake by blocking the action of angiotensin II. They also act, after their release into hypophyseal portal vessels, to inhibit stress-induced ACTH release, to augment prolactin release, and to inhibit the release of LHRH and growth hormone-releasing hormone. Stimulation of neurons in the AV3V region causes natriuresis and an increase in circulating ANP, whereas lesions in the AV3V region and caudally in the median eminence or neural lobe decrease resting ANP release and the response to blood volume expansion. The ANP neurons play a crucial role in blood volume expansion-induced release of ANP and natriuresis since this response can be blocked by intraventricular (3V injection of antisera directed against the peptide. Blood volume expansion activates baroreceptor input via the carotid, aortic and renal baroreceptors, which provides stimulation of noradrenergic neurons in the locus coeruleus and possibly also serotonergic neurons in the raphe nuclei. These project to the hypothalamus to activate cholinergic neurons which then stimulate the ANPergic neurons. The ANP neurons stimulate the oxytocinergic neurons in the paraventricular and supraoptic nuclei to release oxytocin from the neural lobe which circulates to the atria to stimulate the release of ANP. ANP causes a rapid reduction in effective circulating blood volume by releasing cyclic GMP which dilates peripheral vessels and also acts within the heart to slow its rate and atrial force of contraction. The released ANP circulates to the kidney where it acts through cyclic GMP to produce natriuresis and a return to normal blood volume

  17. Epithelial-Mesenchymal Transition Is a Critical Step in Tumorgenesis of Pancreatic Neuroendocrine Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Fendrich, Volker, E-mail:; Maschuw, Katja; Waldmann, Jens [Department of Surgery, Philipps University Marburg, Baldingerstraße, Marburg D-35043 (Germany); Buchholz, Malte [Department of Gastroenterology and Endocrinology, Philipps-University Marburg, Baldingerstraße, Marburg D-35043 (Germany); Rehm, Johannes [Department of Surgery, Philipps University Marburg, Baldingerstraße, Marburg D-35043 (Germany); Gress, Thomas M. [Department of Gastroenterology and Endocrinology, Philipps-University Marburg, Baldingerstraße, Marburg D-35043 (Germany); Bartsch, Detlef K. [Department of Surgery, Philipps University Marburg, Baldingerstraße, Marburg D-35043 (Germany); König, Alexander [Department of Gastroenterology and Endocrinology, Philipps-University Marburg, Baldingerstraße, Marburg D-35043 (Germany)


    The transcription factors Snail, Slug and Twist repress E-cadherin and induce epithelial-mesenchymal transition (EMT), a process exploited by invasive cancer cells. In this study, we evaluated the role of EMT in the tumorgenesis of neuroendocrine tumors of the pancreas (PNETs) in vitro, in vivo and human tumor specimen. Expression of EMT markers was analyzed using immunohistochemistry and real-time PCR. For in vitro studies, BON-1 cells were analyzed regarding expression of EMT markers before and after transfection with siRNA against Slug or Snail, and cell aggregation assays were performed. To asses in vivo effects, Rip1Tag2 mice were treated with vehicle or the snail-inhibitor polythlylenglykol from week 5-10 of age. The resected pancreata were evaluated by weight, tumor cell proliferation and apoptosis. Snail and Twist was expressed in 61 % and 64% of PNETs. This was associated with loss of E-cadherin. RT-PCR revealed conservation of the EMT markers Slug and Snail in BON-1 cells. Transfection with siRNA against Slug was associated with upregulation of E-cadherin, enhanced cell-cell adhesion and inhibition of cell proliferation. Snail-inhibition in vivo by PEG was associated with increased apoptosis, decreased tumor cell proliferation and dramatic reduced tumor volume in Rip1Tag2 mice. The presented data show that EMT plays a key role in tumorgenesis of PNETs. The activation of Snail in a considerable subset of human PNETs and the successful effect of Snail inhibition by PEG in islet cell tumors of transgenic mice provides first evidence of Snail as a drug target in PNETs.

  18. Neuroendocrine Tumours : From Radiomolecular Imaging to Radionuclide Therapy

    Directory of Open Access Journals (Sweden)



    Full Text Available Transhepatic radionuclide infusion (THRI has been introduced as a new treatment approach for unresectable liver neuroendocrine metastatic lesions with the prerequisite of a positive In-111 Pentetreotide (Octreoscan. Patients with multiple liver neuroendocrine metastases can be locally treated after selective hepatic artery catheterization and infusion of radiolabelled somatostatin analogues, and in case of extra-hepatic secondary spread, after simple i.v. application. According to the world wide references, the average dose per session to each patient is 6.3±0.3 GBq (~ 160-180 mCi of In-111-DTPA-Phe1- Pentetreotide, 10-12 fold in total, administered monthly or of 4.1± 0.2 GBq (~105-116 mCi of Y-90 DOTA TOC, 3 fold in total or of 7.0 ± 0.4 GBq (~178-200 mCi of Lu-177 DOTA TATE, 4-6 fold in total (the choice of which being based on the tumor size, assessed by CT or MRI . Follow-up at monthly intervals has to be performed by means of ultrasonography (US. Treat- ment response has to be assessed according to the WHO criteria (RECIST or SWOG.

  19. Current Status of Radiopharmaceuticals for the Theranostics of Neuroendocrine Neoplasms

    Directory of Open Access Journals (Sweden)

    Melpomeni Fani


    Full Text Available Abstract: Nuclear medicine plays a pivotal role in the management of patients affected by neuroendocrine neoplasms (NENs. Radiolabeled somatostatin receptor analogs are by far the most advanced radiopharmaceuticals for diagnosis and therapy (radiotheranostics of NENs. Their clinical success emerged receptor-targeted radiolabeled peptides as an important class of radiopharmaceuticals and it paved the way for the investigation of other radioligand-receptor systems. Besides the somatostatin receptors (sstr, other receptors have also been linked to NENs and quite a number of potential radiolabeled peptides have been derived from them. The Glucagon-Like Peptide-1 Receptor (GLP-1R is highly expressed in benign insulinomas, the Cholecystokinin 2 (CCK2/Gastrin receptor is expressed in different NENs, in particular medullary thyroid cancer, and the Glucose-dependent Insulinotropic Polypeptide (GIP receptor was found to be expressed in gastrointestinal and bronchial NENs, where interestingly, it is present in most of the sstr-negative and GLP-1R-negative NENs. Also in the field of sstr targeting new discoveries brought into light an alternative approach with the use of radiolabeled somatostatin receptor antagonists, instead of the clinically used agonists. The purpose of this review is to present the current status and the most innovative strategies for the diagnosis and treatment (theranostics of neuroendocrine neoplasms using a cadre of radiolabeled regulatory peptides targeting their receptors.

  20. MRI findings of small cell neuroendocrime carcinoma of the uterine cervix: A case report

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    Won, You Sun; Yi, Boem Ha; Lee, Hae Kyung; Lee, Min Hee; Choi, Seo Youn; Kwak, Jeong Ja [Soonchunhyang University College of Medicine, Bucheon Hospital, Bucheon (Korea, Republic of)


    Small cell neuroendocrine carcinoma of the uterine cervix is a rare primary neoplasm, accounting for less than 5% of all uterine cervical cancers. The tumor is known to have an aggressive behavior and poor prognosis. In this article, we present the MRI findings of 5 cases of pathologically-proven small cell neuroendocrine carcinoma of the uterine cervix, including diffusion-weighted images.

  1. Immune Reactivity and Pseudoprogression or Tumor Flare in a Serially Biopsied Neuroendocrine Patient Treated with the Epigenetic Agent RRx-001

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    Corey A. Carter


    Full Text Available Neuroendocrine tumors (NETs are grouped together as a single class on the basis of histologic appearance, immunoreactivity for the neuroendocrine markers chromogranin A and synaptophysin, and potential secretion of hormones, neurotransmitters, neuromodulators and neuropeptides. Nevertheless, despite these common characteristics, NETs differ widely in terms of their natural histories: high-grade NETs are clinically aggressive and, like small cell lung cancer, which they most closely resemble, tend to respond to cisplatin and etoposide. In contrast, low-grade NETs, which as a rule progress and behave indolently, do not. In either case, the treatment strategy, apart from potentially curative surgical resection, is very poorly defined. This report describes the case of a 28-year-old white male with a diagnosis of high-grade NET of undetermined primary site metastatic to the lymph nodes, skin and paraspinal soft tissues, treated with the experimental anticancer agent RRx-001, in the context of a phase II clinical trial called TRIPLE THREAT (NCT02489903; serial sampling of tumor material through repeat biopsies demonstrated an intratumoral inflammatory response, including the amplification of infiltrating T cells, which correlated with clinical and symptomatic benefit. This case suggests that pseudoprogression or RRx-001-induced enlargement of tumor lesions, which has been previously described for several RRx-001-treated patients, is the result of tumoral lymphocyte infiltration.

  2. MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus. (United States)

    Blanchet, Patricia; Bebin, Martina; Bruet, Shaam; Cooper, Gregory M; Thompson, Michelle L; Duban-Bedu, Benedicte; Gerard, Benedicte; Piton, Amelie; Suckno, Sylvie; Deshpande, Charu; Clowes, Virginia; Vogt, Julie; Turnpenny, Peter; Williamson, Michael P; Alembik, Yves; Glasgow, Eric; McNeill, Alisdair


    Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms "mental retardation". To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus.

  3. Mixed Mesonephric Adenocarcinoma and High-grade Neuroendocrine Carcinoma of the Uterine Cervix: Case Description of a Previously Unreported Entity With Insights Into Its Molecular Pathogenesis. (United States)

    Cavalcanti, Marcela S; Schultheis, Anne M; Ho, Caleb; Wang, Lu; DeLair, Deborah F; Weigelt, Britta; Gardner, Ginger; Lichtman, Stuart M; Hameed, Meera; Park, Kay J


    Human papillomavirus (HPV)-negative cervical carcinomas are uncommon and typically encompass unusual histologic subtypes. Mesonephric adenocarcinoma is one such subtype. Mesonephric tumors in the female genital tract are thought to arise from Wolffian remnants, and are extremely rare tumors with widely variable morphology. Sarcomatoid dedifferentiation has been previously described in a few cases, but other forms of dedifferentiation have not been reported. Neuroendocrine carcinoma of the cervix (e.g. small cell carcinoma) is associated with HPV infection, typically HPV 18. These tumors often arise in association with a conventional epithelial component such as squamous cell carcinoma or usual-type endocervical adenocarcinoma. We describe a case of mesonephric adenocarcinoma of the uterine cervix associated with an HPV-negative high-grade neuroendocrine carcinoma at the morphologic and immunophenotypic level, for which we performed targeted massively parallel sequencing analysis of the 2 elements. Both components shared identical mutations in U2AF1 p.R156H (c.467G>A) and GATA3 p.M422fs (c.1263dupG), as well as MYCN amplification. In addition, the neuroendocrine carcinoma harbored TP53 and MST1R mutations not present in the mesonephric carcinoma. Our data suggest a clonal origin of the 2 components of this rare entity, rather than a collision tumor.

  4. Cognitive Performance and the Alteration of Neuroendocrine Hormones in Chronic Tension-Type Headache. (United States)

    Qu, Ping; Yu, Jin-Xia; Xia, Lan; Chen, Gui-Hai


    Tension-type headache (TTH) is the most prevalent primary headache. Chronic TTH (CTTH), the most serious form of TTH, is refractory, with a high socio-economic burden. Research studies have shown patients with migraine often had cognitive impairment, but few studies have focused on the cognition in patients with CTTH. In this study, we assumed that patients with CTTH also have cognitive impairments, which are modulated by the neuroendocrine state. Participants were recruited, including patients with CTTH and healthy controls. Cognitive ability was evaluated using the Montreal Cognitive Assessment and the Nine Box Maze Test. The administration of neuroendocrine hormones has been established to be associated with cognitive performance, and we detected the hormonal changes in the hypothalamus-pituitary-adrenal axis, the hypothalamus-pituitary-thyroid axis, and gonadotropin-releasing hormone. These results showed that compared to the controls, significant cognitive impairment and neuroendocrine dysfunction were present in the patients with CTTH. We also assessed the correlations between the neuroendocrine hormones and Pittsburgh Sleep Quality Index score, 17-term Hamilton's Depression Scale score, pain intensity, and duration of pain to determine whether the neuroendocrine hormones had any associations with these symptoms of CTTH. These results showed that changes in neuroendocrine hormones were involved in these symptoms of CTTH. Intervention with the neuroendocrine state may be a strategy for CTTH treatment. © 2017 World Institute of Pain.

  5. Inhibition of mTOR's Catalytic Site by PKI-587 Is a Promising Therapeutic Option for Gastroenteropancreatic Neuroendocrine Tumor Disease. (United States)

    Freitag, Helma; Christen, Friederike; Lewens, Florentine; Grass, Irina; Briest, Franziska; Iwaszkiewicz, Sara; Siegmund, Britta; Grabowski, Patricia


    The characteristic clinical heterogeneity and mostly slow-growing behavior of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) cause problems in finding appropriate treatments. Thus, the current therapy options are not satisfactory. PKI-587 is a highly potent, novel dual inhibitor of PI3K and mTORC1/C2. We assessed the effects of PKI-587 in different GEP-NEN tumor models, including the poorly differentiated cell line LCC-18, and compared them with those of the established mTORC1 inhibitor everolimus. We treated BON, QGP-1, KRJ-I, and LCC-18 cell lines with increasing concentrations of the inhibitor PKI-587, and compared the results with those of everolimus and DMSO. We assessed the impact of the treatments on viability (WST-1 assay), on apoptotic processes (caspase 3/7 assay, JC-1), and on cell cycle regulation (flow cytometry). We determined alterations in signaling mediators by phosphor-specific Western blot analysis and conducted multiplexed gene expression analysis (nCounter® technology). In all cell lines, PKI-587 dose-dependently inhibited proliferation, whereas everolimus was less effective. Treatment with PKI-587 led to cell cycle arrest and induction of apoptosis and successfully suppressed activity of the direct mTORC1 target 4E-BP1, a crucial factor for tumor genesis only partially inhibited by everolimus. Gene expression analyses revealed relevant changes of RAS, MAPK, STAT, and PI3K pathway genes after treatment. Treatment-dependent and cell line-characteristic effects on AKT/Rb/E2F signaling regarding cell cycle control and apoptosis are extensively discussed in this paper. PI3K/mTOR dual targeting is a promising new therapeutic approach in neuroendocrine tumor disease that should be evaluated in further clinical trials. © 2016 The Author(s) Published by S. Karger AG, Basel.

  6. Infection with multidrug-resistant Campylobacter coli mimicking recurrence of carcinoid syndrome: a case report of a neuroendocrine tumor patient with repeated diarrhea. (United States)

    Lagler, Heimo; Kiesewetter, Barbara; Raderer, Markus


    Campylobacteriosis caused by Gram-negative bacteria of the genus Campylobacter (mainly C. jejuni and C. coli) is one of the most common gastrointestinal zoonotic infections with increased incidence in humans worldwide. The typical symptoms are severe abdominal cramps, diarrhea and sometimes fever. The clinical course of Campylobacter infection is mainly mild and after one week self-limiting, but can take several weeks in some rare cases. However, patients with neuroendocrine tumors in the gastrointestinal tract, a neoplasm of enterochromaffin/neuroendocrine cell origin, can develop severe diarrhea during progression of tumor growth caused by hormonal excess due to the tumor. Both diseases have very similar clinical symptoms and this case report elaborates the differences. So far it is known in the literature that the clinical symptoms of campylobacteriosis can mimic appendicitis or acute colitis of inflammatory bowel disease but a mimicking of recurrence of carcinoid syndrome in a patient with neuroendocrine tumor is not reported. A 72-year-old man with already diagnosed and treated metastatic neuroendocrine tumor of the terminal ileum (G1 rated, Ki-67 index 1 %) was again suffering from increasing diarrhea, abdominal cramps and weight lost. These symptoms were similar to the initial symptoms due to the tumor which improved at the time after total resection of the primary in the terminal ileum and regular therapy with long-acting release depot octreotide intramuscularly. As progression/tachyphylaxis in symptomatic patients with carcinoid syndrome undergoing therapy, reassessment of disease and analysis of tumor markers was initiated, and the interval of intramuscular injections was shortened. Radiological findings and tumor marker levels disclosed no evidence of neuroendocrine tumor progression and the symptoms continued. After 4 weeks with symptoms the patient developed additionally fever. Due to impaired renal function and elevated signs of systemic

  7. Peptide receptor radionuclide therapy in the management of gastrointestinal neuroendocrine tumors: efficacy profile, safety, and quality of life

    Directory of Open Access Journals (Sweden)

    Severi S


    Full Text Available Stefano Severi,1 Ilaria Grassi,1 Silvia Nicolini,1 Maddalena Sansovini,1 Alberto Bongiovanni,2 Giovanni Paganelli1 1Nuclear Medicine Unit, 2Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST IRCCS, Meldola, Italy Abstract: Peptide receptor radionuclide therapy (PRRT, developed over the last two decades, is carried out using radiopharmaceuticals such as 90Y-DOTA-Tyr3-octreotide and 177Lu-DOTA-Tyr3-octreotate (177Lu-Dotatate. These radiocompounds are obtained by labeling a synthetic somatostatin analog with a β-emitting radioisotope. The compounds differ from each other in terms of their energetic features (due to the radionuclide and peptide receptor affinity (due to the analog but share the common characteristic of binding specific membrane somatostatin receptors that are (generally overexpressed in neuroendocrine neoplasms (NENs and their metastases. NENs are tumors arising from diffuse neuroendocrine system cells that are classified according to grading based on Ki67 percentage values (Grades 1 and 2 are classed as neuroendocrine tumors [NETs] and to the anatomical site of occurrence (in this paper, we only deal with gastroenteropancreatic [GEP]-NETs, which account for 60%–70% of all NENs. They are also characterized by specific symptoms such as diarrhea and flushing (30% of cases. Despite substantial experience gained in the area of PRRT and its demonstrable effects in terms of efficacy, safety, and improvement in quality of life, these compounds are still not registered (registration of 177Lu-Dotatate for the treatment of midgut NETs is expected soon. Thus, PRRT can only be used in experimental protocols. We provide an overview of the work of leading groups with wide-ranging experience and continuity in data publication in the area of GEP-NET PRRT and report our own personal experience of using different dosage schedules based on the presence of kidney and bone marrow risk factors

  8. Endocrine and neuroendocrine regulation of fathering behavior in birds. (United States)

    Lynn, Sharon E


    This article is part of a Special Issue "Parental Care". Although paternal care is generally rare among vertebrates, care of eggs and young by male birds is extremely common and may take on a variety of forms across species. Thus, birds provide ample opportunities for investigating both the evolution of and the proximate mechanisms underpinning diverse aspects of fathering behavior. However, significant gaps remain in our understanding of the endocrine and neuroendocrine influences on paternal care in this vertebrate group. In this review, I focus on proximate mechanisms of paternal care in birds. I place an emphasis on specific hormones that vary predictably and/or unpredictably during the parental phase in both captive and wild birds: prolactin and progesterone are generally assumed to enhance paternal care, whereas testosterone and corticosterone are commonly-though not always correctly-assumed to inhibit paternal care. In addition, because endocrine secretions are not the sole mechanistic influence on paternal behavior, I also explore potential roles for certain neuropeptide systems (specifically the oxytocin-vasopressin nonapeptides and gonadotropin inhibitory hormone) and social and experiential factors in influencing paternal behavior in birds. Ultimately, mechanistic control of fathering behavior in birds is complex, and I suggest specific avenues for future research with the goal of narrowing gaps in our understanding of this complexity. Such avenues include (1) experimental studies that carefully consider not only endocrine and neuroendocrine mechanisms of paternal behavior, but also the ecology, phylogenetic history, and social context of focal species; (2) investigations that focus on individual variation in both hormonal and behavioral responses during the parental phase; (3) studies that investigate mechanisms of maternal and paternal care independently, rather than assuming that the mechanistic foundations of care are similar between the sexes; (4

  9. Update on neuroendocrine regulation and medical intervention of reproduction in birds. (United States)

    Mans, Christoph; Taylor, W Michael


    In avian species, reproductive disorders and undesirable behaviors commonly reflect abnormalities in the neuroendocrine regulation of the reproductive system. Current treatment options are often disappointing, show no long-lasting effect, or have significant side effects. A possible reason for our lack of success is a dearth of knowledge of the underlying neuroendocrine, behavioral, and autonomous physiology of the reproductive processes. Tremendous progress has been made in the last few years in our understanding of the neuroendocrine control of reproduction in birds. Advantage should be taken of these experimentally derived data to develop appropriate and safe treatment protocols for avian patients suffering from reproductive disorders.

  10. [Radioguided surgery in neuroendocrine tumors. A review of the literature]. (United States)

    García-Talavera, P; Ruano, R; Rioja, M E; Cordero, J M; Razola, P; Vidal-Sicart, S


    Radioguided surgery can be a useful technique in the localization of neuroendocrine tumors. It detects more and smaller lesions compared to pre-surgical imaging and intraoperative digital palpation by the surgeon. It detects residual lesions and also indicates the shortest access route to the lesion. Nevertheless, its use has not become widespread because of technical difficulties. There is a limited number of published series, a lack of standardized protocol because of the great variability regarding type of radiopharmaceutical, dose of radiotracer, timing between injection and surgery. In this paper, we review these issues, describing the experience of different authors in diverse tumors. Copyright © 2014 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

  11. Leptin as immune mediator: Interaction between neuroendocrine and immune system. (United States)

    Procaccini, Claudio; La Rocca, Claudia; Carbone, Fortunata; De Rosa, Veronica; Galgani, Mario; Matarese, Giuseppe


    Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. Initially described as an anti-obesity hormone, leptin has subsequently been shown to exert pleiotropic effects, being also able to influence haematopoiesis, thermogenesis, reproduction, angiogenesis, and more importantly immune homeostasis. As a cytokine, leptin can affect both innate and adaptive immunity, by inducing a pro-inflammatory response and thus playing a key role in the regulation of the pathogenesis of several autoimmune/inflammatory diseases. In this review, we discuss the most recent advances on the role of leptin as immune-modulator in mammals and we also provide an overview on its main functions in non-mammalian vertebrates. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Circadian neuroendocrine physiology and electromagnetic field studies: Precautions and complexities

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    Warman, G.R.; Tripp, H.M.; Harman, V.L.; Arendt, J


    The suppression of melatonin by exposure to low frequency electromagnetic fields (EMFs) 'the melatonin hypothesis' has been invoked as a possible mechanism through which exposure to these fields may result in an increased incidence of cancer. While the effect of light on melatonin is well established, data showing a similar effect due to EMF exposure are sparse and, where present, are often poorly controlled. The current review focuses on the complexities associated with using melatonin as a marker and the dynamic nature of normal melatonin regulation by the circadian neuroendocrine axis. These are issues which the authors believe contribute significantly to the lack of consistency of results in the current literature. Recommendations on protocol design are also made which, if followed, should enable researchers to eliminate or control for many of the confounding factors associated with melatonin being an output from the circadian clock. (author)

  13. Neonatal testosterone suppresses a neuroendocrine pulse generator required for reproduction (United States)

    Israel, Jean-Marc; Cabelguen, Jean-Marie; Le Masson, Gwendal; Oliet, Stéphane H.; Ciofi, Philippe


    The pituitary gland releases hormones in a pulsatile fashion guaranteeing signalling efficiency. The determinants of pulsatility are poorly circumscribed. Here we show in magnocellular hypothalamo-neurohypophyseal oxytocin (OT) neurons that the bursting activity underlying the neurohormonal pulses necessary for parturition and the milk-ejection reflex is entirely driven by a female-specific central pattern generator (CPG). Surprisingly, this CPG is active in both male and female neonates, but is inactivated in males after the first week of life. CPG activity can be restored in males by orchidectomy or silenced in females by exogenous testosterone. This steroid effect is aromatase and caspase dependent, and is mediated via oestrogen receptor-α. This indicates the apoptosis of the CPG network during hypothalamic sexual differentiation, explaining why OT neurons do not burst in adult males. This supports the view that stereotypic neuroendocrine pulsatility is governed by CPGs, some of which are subjected to gender-specific perinatal programming.

  14. Imaging of neuroendocrine tumours with gamma-emitting radiopharmaceuticals. (United States)

    Bombardieri, E; Coliva, A; Maccauro, M; Seregni, E; Orunesu, E; Chiti, A; Lucignani, G


    Nuclear medicine can image some tumors by means of receptor specific radiopharmaceuticals, and offers the possibility to characterize cancer through the detection of its receptor expression. This is the case of neuroendocrine tumours (NETs), that are visualized by different radiolabelled somatostatin analogues that bind 5 distinct somatostatin receptor types (named sstr1-5) that show different tissue distribution. The subtypes sstr2 and sstr5 are the most commonly expressed in NETs. Until now the most widely used radiolabelled somatostatin analogue for planar and single photon emission computed tomography (SPECT) has been [(111)In]pentetreotide, because of its commercial availability. Other analogues labelled with gamma emitting radionuclides are [(99m)Tc]EDDA/HYNIC-TOC, [(99m)Tc]P829, [(111)In]DOTA-lanreotide, [(111)In]DOTA-NOC-ATE, [(111)In]DOTA-BOC-ATE. However, these compounds have not been successful for the routine use. Moreover, NETs express various receptors that can be depicted by different radiopharmaceuticals, such as [(123)I]VIP and [(111)In]GLP-1. Besides this, some precursors of the catecholamines metabolism, as meta-iodo-benzyl-guanidine (MIBG), labelled with (123)I or (131)I, accumulates in neuroendocrine tissues, in particular those of sympathoadrenal lineage. MIBG scintigraphy is currently indicated for neuroblastoma, paraganglioma and phaeocromocitoma. An impressive technological progress has been achieved recently with PET and, in particular, with the development of hybrid instrumentations (PET/CT) combining nuclear imaging with radiological imaging providing both functional and morphologic information. Among positron emitting tracers, the [(18)F]FDG is the most diffuse in oncology, but other more effective tracers are available for NETs, such as the analogues labelled with 68Ga. The diagnostic sensitivity and accuracy of these technology is superior to that of gamma emitting radiopharmaceuticals, but the fact that they are not still registered

  15. Social stress contagion in rats: Behavioural, autonomic and neuroendocrine correlates. (United States)

    Carnevali, Luca; Montano, Nicola; Statello, Rosario; Coudé, Gino; Vacondio, Federica; Rivara, Silvia; Ferrari, Pier Francesco; Sgoifo, Andrea


    The negative emotional consequences associated with life stress exposure in an individual can affect the emotional state of social partners. In this study, we describe an experimental rat model of social stress contagion and its effects on social behaviour and cardiac autonomic and neuroendocrine functions. Adult male Wistar rats were pair-housed and one animal (designated as "demonstrator" (DEM)) was submitted to either social defeat stress (STR) by an aggressive male Wild-type rat in a separate room or just exposed to an unfamiliar empty cage (control condition, CTR), once a day for 4 consecutive days. We evaluated the influence of cohabitation with a STR DEM on behavioural, cardiac autonomic and neuroendocrine outcomes in the cagemate (defined "observer" (OBS)). After repeated social stress, STR DEM rats showed clear signs of social avoidance when tested in a new social context compared to CTR DEM rats. Interestingly, also their cagemate STR OBSs showed higher levels of social avoidance compared to CTR OBSs. Moreover, STR OBS rats exhibited a higher heart rate and a larger shift of cardiac autonomic balance toward sympathetic prevalence (as indexed by heart rate variability analysis) immediately after the first reunification with their STR DEMs, compared to the control condition. This heightened cardiac autonomic responsiveness habituated over time. Finally, STR OBSs showed elevated plasma corticosterone levels at the end of the experimental protocol compared to CTR OBSs. These findings demonstrate that cohabitation with a DEM rat, which has experienced repeated social defeat stress, substantially disrupts social behaviour and induces short-lasting cardiac autonomic activation and hypothalamic-pituitary-adrenal axis hyperactivity in the OBS rat, thus suggesting emotional state-matching between the OBS and the DEM rats. We conclude that this rodent model may be further exploited for investigating the neurobiological bases of negative affective sharing between

  16. Morphological and immunohistochemical profile of pancreatic neuroendocrine neoplasms. (United States)

    Simtniece, Zane; Vanags, Andrejs; Strumfa, Ilze; Sperga, Maris; Vasko, Ervins; Prieditis, Peteris; Trapencieris, Peteris; Gardovskis, Janis


    The study represents a comprehensive retrospective morphological and immunohistochemical profiling of pancreatic neuroendocrine neoplasms (PNENs) in order to reveal the associations between morphological and molecular parameters. The local tumour spread (T), presence of metastases in regional lymph nodes (N) and distant organs (M), tumour grade (G) and resection line status (R) by pathology findings (pTNMGR), mitotic activity, perineural, vascular and lymphatic invasion were assessed in 16 surgically resected PNENs. By immunohistochemistry, expression of Ki-67, p53, p27, p21, cyclin D1, Bcl-2, E-cadherin, CD44, vimentin, cyclooxygenase 2 (COX-2), microvascular density, and cytokeratin (CK) spectrum, along with neuroendocrine, intestinal and squamous markers were detected. Descriptive statistics, Chi-square test, Spearman's rank correlation, Mann-Whitney and Kruskal-Wallis methods were applied; p<0.05 was considered significant. Ki-67, CK19, p63, vimentin and COX-2 were significantly up-regulated in PNENs in comparison to benign pancreatic islets. A complex network of morphological and molecular associations was identified. Ki-67 correlated with PNEN size (p=0.022), the World Health Organization 2004 and 2010 classification grades (p=0.021 and p=0.002), stage (p=0.028) and mitotic count (p=0.007) but among molecular markers--with CK19 (p=0.033) and vimentin (p=0.045). CK19 was significantly up-regulated in PNENs, having higher pT (p=0.018), pR (p=0.025), vascular (p=0.020), perineural (p=0.026) and lymphatic invasion (p=0.043). In conclusion, proliferation activity (by Ki-67), E-cadherin, vimentin and CK19 are important molecular characteristics of PNENs due to significant associations with morphological tumour characteristics, pTNMGR and invasive growth.

  17. Malnutrition Predicts Clinical Outcome in Patients with Neuroendocrine Neoplasia. (United States)

    Maasberg, Sebastian; Knappe-Drzikova, Barbora; Vonderbeck, Dorothée; Jann, Henning; Weylandt, Karsten H; Grieser, Christian; Pascher, Andreas; Schefold, Jörg C; Pavel, Marianne; Wiedenmann, Bertram; Sturm, Andreas; Pape, Ulrich-Frank


    Malnutrition is a common problem in oncological diseases, influencing treatment outcomes, treatment complications, quality of life and survival. The potential role of malnutrition has not yet been studied systematically in neuroendocrine neoplasms (NEN), which, due to their growing prevalence and additional therapeutic options, provide an increasing clinical challenge to diagnosis and management. The aim of this cross-sectional observational study, which included a long-term follow-up, was therefore to define the prevalence of malnutrition in 203 patients with NEN using various methodological approaches, and to analyse the short- and long-term outcome of malnourished patients. A detailed subgroup analysis was also performed to define risk factors for poorer outcome. When applying malnutrition screening scores, 21-25% of the NEN patients were at risk of or demonstrated manifest malnutrition. This was confirmed by anthropometric measurements, by determination of serum surrogate parameters such as albumin as well as by bioelectrical impedance analysis (BIA), particularly phase angle α. The length of hospital stay was significantly longer in malnourished NEN patients, while long-term overall survival was highly significantly reduced. Patients with high-grade (G3) neuroendocrine carcinomas, progressive disease and undergoing chemotherapy were at particular risk of malnutrition associated with a poorer outcome. Multivariate analysis confirmed the important and highly significant role of malnutrition as an independent prognostic factor for NEN besides proliferative capacity (G3 NEC). Malnutrition is therefore an underrecognized problem in NEN patients which should systematically be diagnosed by widely available standard methods such as Nutritional Risk Screening (NRS), serum albumin assessment and BIA, and treated to improve both short- and long-term outcomes. © 2015 S. Karger AG, Basel.

  18. Massive parallel sequencing and digital gene expression analysis reveals potential mechanisms to overcome therapy resistance in pulmonary neuroendocrine tumors. (United States)

    Walter, Robert Fred Henry; Vollbrecht, Claudia; Christoph, Daniel; Werner, Robert; Schmeller, Jan; Flom, Elena; Trakada, Georgia; Rapti, Aggeliki; Adamidis, Vasilis; Hohenforst-Schmidt, Wolfgang; Kollmeier, Jens; Mairinger, Thomas; Wohlschlaeger, Jeremias; Zarogoulidis, Paul; Porpodis, Konstantinos; Schmidt, Kurt Werner; Mairinger, Fabian Dominik


    Background : Lung cancer is the leading cause of cancer-related deaths worldwide. 25% show neuroendocrine differentiation (typical/atypical carcinoids, large-/small-cell neuroendocrine carcinomas). Carcinoids present with long survival rates, but metastatic carcinoids correlate with decreased survival and are commonly insensitive to standard chemotherapy or radiation. Therefore, novel therapeutic strategies are urgently needed. Material and methods : 70 representative tumor specimens were used for next-generation sequencing analysis of 14 genes related to therapy response. Additionally, mRNA-expression profiles of 60 matching samples were determined for 13 selected drug targets by using the NanoString nCounter technology. Results : A number of features known to sensitize tumors for different targeted therapies could be identified, which hopefully improve the clinical management of this subgroup of lung neoplasias. In particular, EGFR expression was observed in the investigated tumors in a noteworthy manner. Additionally, MDM2 was strongly expressed in the majority of all samples whereas the expression of its physiological inhibitor, CDKN2A , was nearly absent in all low-grade tumors. TP53 showed a high frequency of variants in high-grade tumors but mutations were rare in carcinoids. Conclusion : Based on our results, therapeutic approaches with MDM2-inhibitors and monoclonal anti-EGFR antibodies may be promising in pulmonary carcinoid tumors.

  19. A novel injectable formulation of 6-fluoro-l-DOPA imaging agent for diagnosis of neuroendocrine tumors and Parkinson's disease. (United States)

    Trapani, Adriana; Tricarico, Domenico; Mele, Antonietta; Maqoud, Fatima; Mandracchia, Delia; Vitale, Paola; Capriati, Vito; Trapani, Giuseppe; Dimiccoli, Vincenzo; Tolomeo, Anna; Scilimati, Antonio


    Two [19F]F-l-DOPA (F-DOPA) new β-cyclodextrin (CD)-based dosage forms (FA and FB, respectively) have been studied and their physico-chemical and pharmacological features determined to overcome the administration site reactions showed by the currently used [18F]F-l-DOPA formulation (IASOdopa(®)) to perform PET-CT diagnosis in oncology (neuroendocrine tumors) and neurological (Parkinson's disease) field. Chemical stability of FA and FB was found to be longer than IASOdopa(®) by adding the thiol-antioxidant agent, L-Cysteine. (1)H and (19)F NMR investigations suggest the formation of an inclusion complex of F-DOPA with β-CD. In vitro experiments on the effects of FA and FB on mouse skeletal muscle fibers and on the human neuroblastoma SH-SY5Y and embryonal kidney tsA201 cell lines viability showed that FA was the most performant formulation compared to F-DOPA solutions. In vivo tolerability tests of FA on adult male rat showed no significant effects on body weight and no change in their dried organs weight. In addition, their metabolic and physiological parameters were not affected. In conclusion, [18F]F-l-DOPA, formulated as FA, constitutes a promising dosage form for PET-CT diagnosis of both neuroendocrine tumors and Parkinson's disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. High expression of dopamine receptor subtype 2 in a large series of neuroendocrine tumors. (United States)

    Grossrubatscher, Erika; Veronese, Silvio; Ciaramella, Paolo Dalino; Pugliese, Raffaele; Boniardi, Marco; De Carlis, Luciano; Torre, Massimo; Ravini, Mario; Gambacorta, Marcello; Loli, Paola


    To evaluate by immumohistochemistry the presence of DR subtype 2 (D2R) in well differentiated NETs of different sites and in normal islet cells. Recent data in vitro and in vivo support that dopaminergic drugs might exert an inhibitory effect on hormone secretion and, possibly, on tumor growth in neuroendocrine tumors (NET)s. Their potential therapeutic role needs the demonstration of dopamine receptors (DR) in tumor cells. Little is known on the expression of DR in NETs. 85% of samples (100% of bronchial carcinoids and 93% of islet cell tumors) showed positivity for D2R; intensity of immunoreaction in NETs was similar or higher than in pituitary (54% and respectively 31% of cases). D2R positivity in more than 70% of tumor cells was observed in 46% of samples. Same intensity of D2R-immunoreactivity was found in pituitary and normal islet cells. No differences in D2R expression were recorded on considering tumor grading, size, proliferative activity, presence of metastases, endocrine activity and gender. A significant difference (62.5% vs 96.4%, p = 0.039) was observed in the prevalence of D2R expression between patients with more aggressive tumors and patients without recurrence/progression of disease during follow-up. 46 NET samples from 44 patients and normal endocrine pancreatic tissue were studied. D2R-staining was performed on NETs and compared with six non-secreting pituitary adenomas and related to clinical-pathological data. The present data demonstrate a high expression of D2R in NETs; this finding is of clinical relevance in view of the potential role of dopaminergic drugs in inhibiting secretion and/or cell proliferation in NETs.

  1. A Delphic consensus assessment : imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management

    NARCIS (Netherlands)

    Oberg, Kjell; Krenning, Eric; Sundin, Anders; Bodei, Lisa; Kidd, Mark; Tesselaar, Margot; Ambrosini, Valentina; Baum, Richard P.; Kulke, Matthew; Pavel, Marianne; Cwikla, Jaroslaw; Drozdov, Ignat; Falconi, Massimo; Fazio, Nicola; Frilling, Andrea; Jensen, Robert; Koopmans, Klaus; Korse, Tiny; Kwekkeboom, Dik; Maecke, Helmut; Paganelli, Giovanni; Salazar, Ramon; Severi, Stefano; Strosberg, Jonathan; Prasad, Vikas; Scarpa, Aldo; Grossman, Ashley; Walenkamp, Annemiek; Cives, Mauro; Virgolini, Irene; Kjaer, Andreas; Modlin, Irvin M.


    The complexity of the clinical management of neuroendocrine neoplasia (NEN) is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging modalities reflect difficulties in measuring an intrinsically indolent disease,

  2. Epigenetic programming of the neuroendocrine stress response by adult life stress

    NARCIS (Netherlands)

    Dirven, B.C.J.; Homberg, J.R.; Kozicz, L.T.; Henckens, M.J.A.G.


    The hypothalamic-pituitary-adrenal (HPA) axis is critically involved in the neuroendocrine regulation of stress adaptation, and the restoration of homeostasis following stress exposure. Dysregulation of this axis is associated with stress-related pathologies like major depressive disorder,

  3. Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma

    DEFF Research Database (Denmark)

    Ali, Abir Salwa; Grönberg, Malin; Federspiel, Birgitte


    BACKGROUND: Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are aggressive, rapidly proliferating tumors. Therapeutic response to current chemotherapy regimens is usually short lasting. The aim of this study was to examine the expression and potential clinical importance of immunoreac...

  4. Middle ear adenoma with neuroendocrine differentiation: relate of two cases and literature review

    Directory of Open Access Journals (Sweden)

    Bittencourt, Aline Gomes


    Full Text Available Introduction: Adenomas with neuroendocrine differentiation are defined as neuroendocrine neoplasms, and they are rarely found in the head and neck. Objective: To describe two cases of a middle ear adenoma with neuroendocrine differentiation, with a literature review. Case Report: Patient 1 was a 41-year-old woman who presented with a 3-year history of left aural fullness associated with ipsilateral “hammer beating” tinnitus. Patient 2 was a 41-year-old male who presented with unilateral conductive hearing loss. Conclusion: Adenoma with neuroendocrine differentiation of the middle ear is a rare entity, but it should be considered in patients with tinnitus, aural fullness, and a retrotympanic mass and remembered as a diferential diagnosis of tympanic paraganglioma.

  5. Middle ear adenoma with neuroendocrine differentiation: relate of two cases and literature review (United States)

    Bittencourt, Aline Gomes; Tsuji, Robinson Koji; Cabral, Francisco; Pereira, Larissa Vilela; Fonseca, Anna Carolina de Oliveira; Alves, Venâncio; Bento, Ricardo Ferreira


    Summary Introduction: Adenomas with neuroendocrine differentiation are defined as neuroendocrine neoplasms, and they are rarely found in the head and neck. Objective: To describe two cases of a middle ear adenoma with neuroendocrine differentiation, with a literature review. Case Report: Patient 1 was a 41-year-old woman who presented with a 3-year history of left aural fullness associated with ipsilateral “hammer beating” tinnitus. Patient 2 was a 41-year-old male who presented with unilateral conductive hearing loss. Conclusion: Adenoma with neuroendocrine differentiation of the middle ear is a rare entity, but it should be considered in patients with tinnitus, aural fullness, and a retrotympanic mass and remembered as a diferential diagnosis of tympanic paraganglioma. PMID:25992031

  6. A case of neuroendocrine carcinoma developing from the broad ligament of the uterus

    Directory of Open Access Journals (Sweden)

    Yui Itonaga


    Full Text Available Neuroendocrine carcinoma (NEC, also called small cell carcinoma or large cell carcinoma, is a rare and aggressive tumor that develops mainly in the lung and intestine. More rarely, NEC develops in gynecologic organs, with poor prognoses. We experienced a case of NEC in the broad ligament of the uterus. The patient was a 74-year-old woman with symptoms of abdominal distension and constipation. Ultrasound sonography detected an abdominal tumor larger than 10 cm. She was then admitted to our hospital. She underwent surgery under the diagnosis of ovarian cancer, but the bilateral ovaries and uterus were normal in appearance, and a tumor was developing instead from the broad ligament of the uterus. The patient then received a hysterectomy, salpingo- oophorectomies, and lymphadenectomy, and the peritoneal membrane was stripped around the pelvic space. Despite our suggestion, she never accepted the adjuvant treatment. She discontinued her periodic follow-up with us and was followed in another hospital. Generally, the prognosis of NEC is poor, and there is no established treatment for a tumor in a gynecologic lesion. However, we anticipate that the accumulation of experience treating such cases will eventually lead to a standard treatment for NEC.

  7. Octreotide-functionalized and resveratrol-loaded unimolecular micelles for targeted neuroendocrine cancer therapy (United States)

    Xu, Wenjin; Burke, Jocelyn F.; Pilla, Srikanth; Chen, Herbert; Jaskula-Sztul, Renata; Gong, Shaoqin


    Medullary thyroid cancer (MTC) is a neuroendocrine tumor (NET) that is often resistant to standard therapies. Resveratrol suppresses MTC growth in vitro, but it has low bioavailability in vivo due to its poor water solubility and rapid metabolic breakdown, as well as lack of tumor-targeting ability. A novel unimolecular micelle based on a hyperbranched amphiphilic block copolymer was designed, synthesized, and characterized for NET-targeted delivery. The hyperbranched amphiphilic block copolymer consisted of a dendritic Boltorn® H40 core, a hydrophobic poly(l-lactide) (PLA) inner shell, and a hydrophilic poly(ethylene glycol) (PEG) outer shell. Octreotide (OCT), a peptide that shows strong binding affinity to somatostatin receptors, which are overexpressed on NET cells, was used as the targeting ligand. Resveratrol was physically encapsulated by the micelle with a drug loading content of 12.1%. The unimolecular micelles exhibited a uniform size distribution and spherical morphology, which were determined by both transmission electron microscopy (TEM) and dynamic light scattering (DLS). Cellular uptake, cellular proliferation, and Western blot analyses demonstrated that the resveratrol-loaded OCT-targeted micelles suppressed growth more effectively than non-targeted micelles. Moreover, resveratrol-loaded NET-targeted micelles affected MTC cells similarly to free resveratrol in vitro, with equal growth suppression and reduction in NET marker production. These results suggest that the H40-based unimolecular micelle may offer a promising approach for targeted NET therapy.

  8. A case of pancreatic neuroendocrine tumor in a patient with neurofibromatosis-1

    Directory of Open Access Journals (Sweden)

    Nishi Takeshi


    Full Text Available Abstract Patients with neurofibromatosis-1 (NF-1 sometime develop neuroendocrine tumors (NET. Although these NETs usually occur in the duodenum or peri-ampullary region, they occasionally grow in the pancreas (PNET. A 62-year-old man with NF-1 had mild liver dysfunction and was admitted to our hospital for further examination. An abdominal contrast-enhanced computed tomography scan demonstrated a 30-mm tumor in the head of the pancreas. The scan showed an invasion of the tumor into the duodenum, and biopsy under an endoscopic ultrasonography indicated that the tumor was a NET. A subtotal stomach-preserving pancreaticoduodenectomy was performed. Macroscopically, the pancreatic tumor was white and elastic hard. Microscopically, tumor cells were composed of ribbons, cords, and solid nests with an acinus-like structure. The tumor was diagnosed as NET G2 according to the WHO classification (2010. The product of theNF-1 gene, i.e., neurofibromin, was weakly positive in the tumor cells, suggesting that the tumor was induced by a mutation in the NF-1 gene. This is the seventh case of PNET arising in NF-1 patients worldwide.

  9. Expression of Neuroendocrine Markers in Normal and Neoplastic Tissue with an Emphasis on Ghrelin and Obestatin


    Grönberg, Malin


    The aim of this thesis was to characterize the expression of the peptides ghrelin and obestatin, as well as other neuroendocrine markers in human normal tissues, in invasive breast cancer and a wide panel of neuroendocrine tumors (NETs). In normal tissues the expression of ghrelin and obestatin was mainly localized to the gastric mucosa, and in lesser extent in the remaining gastrointestinal tract, endocrine pancreas and mammary glands. Double immunofluorescence studies demonstrated that ghre...

  10. Carcinome neuroendocrine du sein: à propos d'un cas et revue de ...

    African Journals Online (AJOL)

    Le carcinome neuroendocrine primitif du sein est une tumeur rare qui a été reconnue par la dernière édition de la classification OMS du cancer du sein publiée en 2003. Le diagnostic est évoqué sur des critères morphologiques et confirmé par l'expression des marqueurs neuroendocrines (chromogranine et ...

  11. The Structure of the Neuroendocrine Hypothalamus: The Neuroanatomical Legacy of Geoffrey Harris (United States)

    Watts, Alan G.


    In November 1955 Geoffrey Harris published a paper based on the Christian A. Herter Lecture he had given earlier that year at Johns Hopkins University in Baltimore. The paper reviewed the contemporary research that was starting to explain how the hypothalamus controlled the pituitary gland. In the process of doing this Harris introduced a set of properties that would help define the neuroendocrine hypothalamus. They included: a) three criteria that putative releasing factors for adenohypophysial hormones would have to fulfill; b) an analogy between the representation of body parts in sensory and motor cortices and the spatial localization of neuroendocrine function in the hypothalamus; and c) the idea that neuroendocrine neurons were motor neurons, with the pituitary stalk functioning as a Sherringtonian final common pathway through which the impact of sensory and emotional events on neuroendocrine neurons had to pass to control pituitary hormone release. Were these properties a sign that the major neuroscientific discoveries being made in the early 1950s were beginning to influence neuroendocrinology? The present article discusses two main points: the context and significance of Harris's Herter Lecture for how our understanding of neuroendocrine anatomy (particularly as it relates to the control of the adenohypophysis) has developed since 1955; and within this framework, how novel and powerful techniques are taking our understanding of the structure of the neuroendocrine hypothalamus to new levels. PMID:25994006

  12. A fluorescence-coupled assay for gamma aminobutyric acid (GABA reveals metabolic stress-induced modulation of GABA content in neuroendocrine cancer.

    Directory of Open Access Journals (Sweden)

    Joseph E Ippolito

    Full Text Available Pathways involved in the synthesis of the neurotransmitter gamma-aminobutyric acid (GABA have been implicated in the pathogenesis of high grade neuroendocrine (NE neoplasms as well as neoplasms from a non-NE lineage. Using The Cancer Genome Atlas, overexpression of the GABA synthetic enzyme, glutamate decarboxylase 1 (GAD1, was found to be associated with decreased disease free-survival in prostate adenocarcinoma and decreased overall survival in clear cell renal cell carcinomas. Furthermore, GAD1 was found to be expressed in castrate-resistant prostate cancer cell lines, but not androgen-responsive cell lines. Using a novel fluorescence-coupled enzymatic microplate assay for GABA mediated through reduction of resazurin in a prostate neuroendocrine carcinoma (PNEC cell line, acid microenvironment-induced stress increased GABA levels while alkaline microenvironment-induced stress decreased GABA through modulation of GAD1 and glutamine synthetase (GLUL activities. Moreover, glutamine but not glucose deprivation decreased GABA through modulation of GLUL. Consistent with evidence in prokaryotic and eukaryotic organisms that GABA synthesis mediated through GAD1 may play a crucial role in surviving stress, GABA may be an important mediator of stress survival in neoplasms. These findings identify GABA synthesis and metabolism as a potentially important pathway for regulating cancer cell stress response as well as a potential target for therapeutic strategies.

  13. Neuroendocrine and behavioral implications of endocrine disrupting chemicals in quail (United States)

    Ottinger, M.A.; Abdelnabi, M.A.; Henry, P.; McGary, S.; Thompson, N.; Wu, J.M.


    Studies in our laboratory have focused on endocrine, neuroendocrine, and behavioral components of reproduction in the Japanese quail. These studies considered various stages in the life cycle, including embryonic development, sexual maturation, adult reproductive function, and aging. A major focus of our research has been the role of neuroendocrine systems that appear to synchronize both endocrine and behavioral responses. These studies provide the basis for our more recent research on the impact of endocrine disrupting chemicals (EDCs) on reproductive function in the Japanese quail. These endocrine active chemicals include pesticides, herbicides, industrial products, and plant phytoestrogens. Many of these chemicals appear to mimic vertebrate steroids, often by interacting with steroid receptors. However, most EDCs have relatively weak biological activity compared to native steroid hormones. Therefore, it becomes important to understand the mode and mechanism of action of classes of these chemicals and sensitive stages in the life history of various species. Precocial birds, such as the Japanese quail, are likely to be sensitive to EDC effects during embryonic development, because sexual differentiation occurs during this period. Accordingly, adult quail may be less impacted by EDC exposure. Because there are a great many data available on normal development and reproductive function in this species, the Japanese quail provides an excellent model for examining the effects of EDCs. Thus, we have begun studies using a Japanese quail model system to study the effects of EDCs on reproductive endocrine and behavioral responses. In this review, we have two goals: first, to provide a summary of reproductive development and sexual differentiation in intact Japanese quail embryos, including ontogenetic patterns in steroid hormones in the embryonic and maturing quail. Second, we discuss some recent data from experiments in our laboratory in which EDCs have been tested in

  14. Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms). Part II-specific NE tumour types

    DEFF Research Database (Denmark)

    Oberg, Kjell; Astrup, Lone Bording; Eriksson, Barbro


    Part II of the guidelines contains a description of epidemiology, histopathology, clinical presentation, diagnostic procedure, treatment, and survival for each type of neuroendocrine tumour. We are not only including gastroenteropancreatic tumours but also bronchopulmonary and thymic neuroendocrine...... tumours. These guidelines essentially cover basic knowledge in the diagnosis and management of the different forms of neuroendocrine tumour. We have, however, tried to give more updated information about the epidemiology and histopathology, which is essential for the clinical management of these tumours....

  15. Clinical and functional implication of the components of somatostatin system in gastroenteropancreatic neuroendocrine tumors. (United States)

    Herrera-Martínez, Aura D; Gahete, Manuel D; Pedraza-Arevalo, Sergio; Sánchez-Sánchez, Rafael; Ortega-Salas, Rosa; Serrano-Blanch, Raquel; Luque, Raúl M; Gálvez-Moreno, María A; Castaño, Justo P


    Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) comprise a heterogeneous group of malignancies often presenting with metastasis at diagnosis and whose clinical outcome is difficult to predict. Somatostatin (SST) analogs (SSAs) provide a valuable pharmacological tool to palliate hormonal symptoms, and control progression in some NETs. However, many patients do not respond to SSAs or develop resistance, and there are many uncertainties regarding pathophysiology of SST and its receptors (sst1-sst5) in GEP-NETs. The expression of SST system components in GEP-NETs was determined, compared with that of non-tumor adjacent and normal tissues and correlated with clinical and histological characteristics. Specifically, 58 patients with GEP-NETs and 14 normal samples were included. Cell viability in NET cell lines was determined in response to specific SSAs. Normal samples and non-tumor adjacent tissues presented a similar expression profile, with appreciable expression of sst2 and sst3, and a lower expression of the other receptors. In contrast, cortistatin, sst1, sst4, and sst5 were overexpressed in tumors, while sst3 and sst4 seemed overexpressed in less differentiated tumors. Some SST system components were related to vascular/nerve invasion and metastasis. In vitro, sst1 and sst3 agonists reduced viability in BON-1 cells, while they, similar to octreotide and pasireotide, increased viability in QGP-1 cells. These results provide novel information on SST system pathophysiology in GEP-NETs, including relevant associations with clinical-histological parameters, which might help to better understand the intrinsic heterogeneity of NETs and to identify novel biomarkers and/or targets with potential prognostic and/or therapeutic value for GEP-NETs patients.

  16. Spectrum of malignant somatostatin-producing neuroendocrine tumors. (United States)

    Moayedoddin, Baback; Booya, Fargol; Wermers, Robert A; Lloyd, Ricardo V; Rubin, Joseph; Thompson, Geoffrey B; Fatourechi, Vahab


    To evaluate the clinical manifestations and outcome of patients with somatostatinomas--rare neuroendocrine tumors of pancreaticoduodenal origin. We searched the medical archives and tumor registry of our institution for somatostatinomas or somatostatin-staining tumors for the 12-year period from January 1990 to February 2002. In addition, we reviewed laboratory databases for patients who had an elevated serum somatostatin level. Patients with a neuroendocrine tumor and an elevated serum somatostatin level or somatostatin-positive tumor immunostaining were included in this study. Eleven patients qualified (9 men and 2 women; median age at diagnosis, 45 years; age range, 22 to 73). The diagnosis of a somatostatinoma was made by immunostaining of the tumor in 9 patients and by finding elevated serum somatostatin levels in 2. Five primary tumors were of duodenal and 6 of pancreatic origin. Psammoma body formation and association with neurofibromatosis were seen only in the duodenal tumors. The known primary tumor sizes varied from 2 to 6 cm. Liver metastatic lesions were present in 6 patients, abdominal lymph node involvement was found in 10 patients, and lung, spleen, and ovarian metastatic involvement was noted in 1 patient each. Diabetes was present in 4 patients (36%) and cholelithiasis in 7 (64%). The presence of a mass led to the diagnosis in most patients with primary duodenal tumors, whereas patients with pancreatic tumors were more likely to have endocrine manifestations. A Whipple procedure was performed in 6 patients, distal pancreatectomy in 3, hepatic artery embolization or ligation in 3, and partial hepatectomy in 1. Cancer-related death occurred in 4 patients, 1 to 8 years after diagnosis (median, 4.5 years). At last follow-up, 2 patients were alive without evidence of disease (8 and 10 years after diagnosis), and 3 were alive with liver metastatic lesions. The status of 2 patients was unclear. Somatostatinomas occurred with approximately equal frequency


    Directory of Open Access Journals (Sweden)

    N. V. Lyubimova


    Full Text Available Background: Neuroendocrine tumors (NET is a heterogeneous group of neoplasms characterized by hypersecretion of biologically active sub- stances that manifests by specific syndromes and determines the clinical course of the disease. The most common NET types are those of gastrointestinal tract. The obligatory biochemical marker used in the examination of NET patients is chromogranin A (CgA.Aim: Evaluation of the CgA value for diagnostics and monitoring of gastrointestinal NETs.Materials and methods: A comparative study of plasma CgA levels was performed in 146 patients with gastroenteropancreatic neuroendocrine tu- mors and 66 healthy individuals using the enzyme immunoassay “Chromogranin A ELISA kit” (Dako A/S, Denmark.Results: CgA levels were significantly higher in patients with NETs of all localizations, such as pancreas, stomach, gut, small and large bowel, than in the healthy subjects (р < 0.000001. In NET patients, CgA secretion was highly variable, with the highest value in the group of patients with gastric NETs (102000 U/l. The highest CgA medians were detected in patients with small intestinal (183.9 U/l, colon (148.4 U/l and pancreatic (135.9 U/l NETs. There was an association between CgA secretion and extension or activity of NETs, with the highest median values in patients with hepatic metastases (395 U/l and those with carcinoid syndrome (352 U/l. The clinical significance of CgA as a NET marker was assessed using the cut-off value of 33 U/l, calculated according to the results in the control group. Overall diagnostic sensitivity of CgA in NET patients was high (85.8% with a specificity of 98.5%. Conclusion: The results obtained confirm a high sensitivity of CgA as a NET marker whose determination helps to improve accuracy of diagnostics and to assess NET prevalence.

  18. MR imaging features and staging of neuroendocrine carcinomas of the uterine cervix with pathological correlations

    Energy Technology Data Exchange (ETDEWEB)

    Duan, Xiaohui; Zhang, Xiang; Hu, Huijun; Li, Guozhao; Wang, Dongye; Zhang, Fang; Shen, Jun [Sun Yat-Sen University, Department of Radiology, Sun Yat-Sen Memorial Hospital, Guangzhou (China); Ban, Xiaohua [Sun Yat-Sen University, Medical Imaging and Minimally Invasive Interventional Center and State Key Laboratory of Oncology in Southern China, Cancer Center, Guangzhou, Guangdong (China); Wang, Charles Qian [Sun Yat-Sen University, Department of Radiology, Sun Yat-Sen Memorial Hospital, Guangzhou (China); University of New South Wales, JMO, Westmead Hospital, Sydney (Australia)


    To determine MR imaging features and staging accuracy of neuroendocrine carcinomas (NECs) of the uterine cervix with pathological correlations. Twenty-six patients with histologically proven NECs, 60 patients with squamous cell carcinomas (SCCs), and 30 patients with adenocarcinomas of the uterine cervix were included. The clinical data, pathological findings, and MRI findings were reviewed retrospectively. MRI features of cervical NECs, SCCs, and adenocarcinomas were compared, and MRI staging of cervical NECs was compared with the pathological staging. Cervical NECs showed a higher tendency toward a homogeneous signal intensity on T2-weighted imaging and a homogeneous enhancement pattern, as well as a lower ADC value of tumour and a higher incidence of lymphadenopathy, compared with SCCs and adenocarcinomas (P < 0.05). An ADC value cutoff of 0.90 x 10{sup -3} mm{sup 2}/s was robust for differentiation between cervical NECs and other cervical cancers, with a sensitivity of 63.3 % and a specificity of 95 %. In 21 patients who underwent radical hysterectomy and lymphadenectomy, the overall accuracy of tumour staging by MR imaging was 85.7 % with reference to pathology staging. Homogeneous lesion texture and low ADC value are likely suggestive features of cervical NECs and MR imaging is reliable for the staging of cervical NECs. (orig.)

  19. From the brain-skin connection: the neuroendocrine-immune misalliance of stress and itch. (United States)

    Arck, Petra; Paus, Ralf


    Perceived stress has long been allied with disturbances of the dynamic equilibrium established between the nervous, endocrine and immune systems, thus triggering or aggravating disease manifestation. Several common skin diseases are now acknowledged to be worsened by psychological stress, particularly immunodermatoses such as atopic dermatitis, psoriasis, seborrheic eczema, prurigo nodularis, lichen planus, chronic urticaria, alopecia areata and pruritus sine materia. Itch (pruritus) is perhaps the most common symptom associated with a majority of these inflammatory skin diseases, and acute as well as chronic stress perceptions are recognized to trigger or enhance pruritus. A wealth of mediators released systemically or locally in the skin in response to stress increase sensory innervation, upregulate the production of other pruritogenic agents, perpetuate (neurogenic) inflammation and lower the itch threshold. In the present review, we explore recent frontiers in both stress and pruritus research and portray the perpetuation of chronic skin inflammation and itch as a neuroendocrine-immune 'misalliance'. We argue that key candidate molecules of the stress response with strong pruritogenic potential, such as nerve growth factor, corticotropin-releasing hormone and substance P, and mast cells, which may be considered as 'central cellular switchboards of pruritogenic inflammation', need to be further explored systematically in order to develop more effective therapeutic combination strategies for itch management in chronic, stress-vulnerable inflammatory skin diseases. Copyright (c) 2006 S. Karger AG, Basel.

  20. Interaction and developmental activation of two neuroendocrine systems that regulate light-mediated skin pigmentation. (United States)

    Bertolesi, Gabriel E; Song, Yi N; Atkinson-Leadbeater, Karen; Yang, Jung-Lynn J; McFarlane, Sarah


    Lower vertebrates use rapid light-regulated changes in skin colour for camouflage (background adaptation) or during circadian variation in irradiance levels. Two neuroendocrine systems, the eye/alpha-melanocyte-stimulating hormone (α-MSH) and the pineal complex/melatonin circuits, regulate the process through their respective dispersion and aggregation of pigment granules (melanosomes) in skin melanophores. During development, Xenopus laevis tadpoles raised on a black background or in the dark perceive less light sensed by the eye and darken in response to increased α-MSH secretion. As embryogenesis proceeds, the pineal complex/melatonin circuit becomes the dominant regulator in the dark and induces lightening of the skin of larvae. The eye/α-MSH circuit continues to mediate darkening of embryos on a black background, but we propose the circuit is shut down in complete darkness in part by melatonin acting on receptors expressed by pituitary cells to inhibit the expression of pomc, the precursor of α-MSH. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Drug effects on neuroendocrine regulation; Proceedings of the International Symposium, Snowmass-at-Aspen, Colo., July 17-19, 1972 (United States)

    Zimmermann, E. (Editor); Gispen, W. H.; Marks, B. H.; De Wied, D.


    Subjects related to the characterization of neuroendocrine systems are discussed, taking into account the need for the precise identification and rigorous description of their operations. Steroid effects on neuroendocrine system performance are considered along with biogenic amine effects on neuroendocrine systems and the influence of drugs of abuse on neuroendocrine behavior. Other topics explored include pituitary-adrenal influences on avoidance and approach behavior of the rat, the adrenocortical mediation of the effects of early life experiences, and the implication of noradrenaline in avoidance learning in the rat. Individual items are announced in this issue.

  2. VGF: an inducible gene product, precursor of a diverse array of neuro-endocrine peptides and tissue-specific disease biomarkers. (United States)

    Ferri, Gian-Luca; Noli, Barbara; Brancia, Carla; D'Amato, Filomena; Cocco, Cristina


    The vgf gene (non-acronymic) is induced in vivo by neurotrophins including Nerve Growth Factor (NGF), Brain Derived Growth Factor (BDNF) and Glial Derived Growth Factor (GDNF), by synaptic activity and by homeostatic and other stimuli. Post-translational processing of a single VGF precursor gives raise to a varied multiplicity of neuro-endocrine peptides, some of which are secreted upon stimulation both in vitro and in vivo. Several VGF peptides, accounting for ∼20% of the VGF precursor sequence, have shown biological roles including regulation of food intake, energy balance, reproductive and homeostatic mechanisms, synaptic strengthening, long-term potentiation (LTP) and anti-depressant activity. From a further ∼50% of VGF derive multiple "fragments", largely identified in the human cerebro-spinal fluid by proteomic studies searching for disease biomarkers. These represent an important starting point for discovery of further VGF products relevant to neuronal brain functions, as well as to neurodegenerative and psychiatric disease conditions. A distinct feature of VGF peptides is their cell type specific diversity in all neuroendocrine organs studied so far. Selective differential profiles are found across the cell populations of pituitary, adrenal medulla and pancreatic islets, and in gastric neuroendocrine as well as some further mucosal cells, and are yet to be investigated in neuronal systems. At the same time, specific VGF peptide/s undergo selective modulation in response to organ or cell population relevant stimuli. Such pattern argues for a multiplicity of roles for VGF peptides, including endocrine functions, local intercellular communication, as well as the possible mediation of intracellular mechanisms. Copyright © 2011 Elsevier B.V. All rights reserved.

  3. Differential expression of the PTEN tumor suppressor protein in fetal and adult neuroendocrine tissues and tumors: progressive loss of PTEN expression in poorly differentiated neuroendocrine neoplasms. (United States)

    Wang, Luoquan; Ignat, Ana; Axiotis, Constantine A


    Genetic alteration and loss of expression of tumor suppressor gene PTEN has been found in carcinomas of the breast, prostate, and endometrium, as well as in gliomas. PTEN expression in neural crest/neuroendocrine (NC/NE) tissues and in neoplasms has not been reported. This study examines PTEN expression in embryonal, fetal, and adult tissues by immunohistochemistry. The authors found high PTEN expression in embryonal, fetal, and adult NC/NE tissues. The authors also study the PTEN expression in NC/NE neoplasms (N = 37), including 5 melanocytic nevi, 2 melanomas, 9 carcinoids, 2 moderately differentiated neuroendocrine carcinomas, 13 poorly differentiated neuroendocrine carcinomas, 2 paragangliomas, 2 pheochromocytomas, 2 medullary thyroid carcinomas, and 1 neuroblastoma. All carcinoid tumors and melanocytic nevi showed moderate or strong immunostaining for PTEN. In contrast, the majority of poorly differentiated neuroendocrine carcinomas (7 of 13) were negative for PTEN (54%); the remainder showed diminished reactivity. The two melanomas studied were also negative for PTEN immunostaining. The paragangliomas, pheochromocytomas, medullary thyroid carcinomas, and neuroblastoma all showed a strong PTEN stain. The authors postulate that PTEN is a differentiation marker for NC/NE tissue and tumors and that loss of PTEN expression may represent an important step in the progression of NE tumors.

  4. Goblet cell carcinoid in a patient with neurofibromatosis type 1-a rare combination

    DEFF Research Database (Denmark)

    Gregersen, Tine; Holt, Nanna; Gronbaek, Henning


    Neuroendocrine tumors are rare tumors primarily located in the gastrointestinal tract. Goblet cell carcinoid is a rare subgroup of neuroendocrine tumors located in the appendix. Neurofibromatosis type 1 is an autosomal dominant disorder caused by a mutation in the NF1 gene. Patients...... with neurofibromatosis type 1 have an increased incidence of typical neuroendocrine tumors, but it is unknown if this is the case with goblet cell carcinoids. We describe a patient with both neurofibromatosis type 1 and goblet cell carcinoid, that according to literature would occur in 0.00017 per million per year....... This may suggest a previously unknown association between neurofibromatosis type 1 and goblet cell carcinoids....

  5. Epidemiology of neuroendocrine cancers in an Australian population. (United States)

    Luke, Colin; Price, Timothy; Townsend, Amanda; Karapetis, Christos; Kotasek, Dusan; Singhal, Nimit; Tracey, Elizabeth; Roder, David


    The aim was to explore incidence, mortality and case survivals for invasive neuroendocrine cancers in an Australian population and consider cancer control implications. Directly age-standardised incidence and mortality rates were investigated from 1980 to 2006, plus disease-specific survivals. Annual incidence per 100,000 increased from 1.7 in 1980-1989 to 3.3 in 2000-2006. A corresponding mortality increase was not observed, although numbers of deaths were low, reducing statistical power. Increases in incidence affected both sexes and were more evident for female lung, large bowel (excluding appendix), and unknown primary site. Common sites were lung (25.9%), large bowel (23.3%) (40.9% were appendix), small intestine (20.6%), unknown primary (15.0%), pancreas (6.5%), and stomach (3.7%). Site distribution did not vary by sex (p = 0.260). Younger ages at diagnosis applied for lung (p = 0.002) and appendix (p colon (excluding appendix). Incidence rates are increasing. Research is needed into possible aetiological factors for lung and large-bowel sites, including tobacco smoking, and excess body weight and lack of exercise, respectively; and Crohn's disease as a possible precursor condition.

  6. [Genetic and neuroendocrine aspects in autism spectrum disorder]. (United States)

    Oviedo, Norma; Manuel-Apolinar, Leticia; de la Chesnaye, Elsa; Guerra-Araiza, Christian

    The autism spectrum disorder (ASD) was described in 1943 and is defined as a developmental disorder that affects social interaction and communication. It is usually identified in early stages of development from 18 months of age. Currently, autism is considered a neurological disorder with a spectrum covering cases of different degrees, which is associated with genetic factors, not genetic and environmental. Among the genetic factors, various syndromes have been described that are associated with this disorder. Also, the neurobiology of autism has been studied at the genetic, neurophysiological, neurochemical and neuropathological levels. Neuroimaging techniques have shown multiple structural abnormalities in these patients. There have also been changes in the serotonergic, GABAergic, catecholaminergic and cholinergic systems related to this disorder. This paper presents an update of the information presented in the genetic and neuroendocrine aspects of autism spectrum disorder. Copyright © 2014 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

  7. Ileal neuroendocrine tumors and heart: not only valvular consequences. (United States)

    Calissendorff, Jan; Maret, Eva; Sundin, Anders; Falhammar, Henrik


    Ileal neuroendocrine tumors (NETs) often progress slowly, but because of their generally nonspecific symptoms, they have often metastasized to local lymph nodes and to the liver by the time the patient presents. Biochemically, most of these patients have increased levels of whole blood serotonin, urinary 5-hydroxyindoleacetic acid, and chromogranin A. Imaging work-up generally comprises computed tomography or magnetic resonance imaging and somatostatin receptor scintigraphy, or in recent years positron emission tomography with 68Ga-labeled somatostatin analogs, allowing for detection of even sub-cm lesions. Carcinoid heart disease with affected leaflets, mainly to the right side of the heart, is a well-known complication and patients routinely undergo echocardiography to diagnose and monitor this. Multitasking surgery is currently recognized as first-line treatment for ileal NETs with metastases and carcinoid heart disease. Open heart surgery and valve replacement are advocated in patients with valvular disease and progressive heart failure. When valvulopathy in the tricuspid valve results in right-sided heart failure, a sequential approach, performing valve replacement first before intra-abdominal tumor-reductive procedures are conducted, reduces the risk of bleeding. Metastases to the myocardium from ileal NETs are seen in heart metastases are detected, with the addition of diuretics and fluid restriction in cases of heart failure. Myocardial metastases are rarely treated by surgical resection.

  8. Genetic and epigenetic drivers of neuroendocrine tumours (NET). (United States)

    Di Domenico, Annunziata; Wiedmer, Tabea; Marinoni, Ilaria; Perren, Aurel


    Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. The molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well-differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging. Indeed, mutations in genes encoding for proteins directly involved in chromatin remodelling, such as DAXX and ATRX are a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. Molecular profiles derived from omics data including DNA mutation, methylation, gene and miRNA expression have already shown promising results in distinguishing clinically and molecularly different subtypes of NET. In this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal NET and the affected pathways. We also discuss potential epigenetic mechanisms leading to NET development. © 2017 Society for Endocrinology.

  9. Blunted neuroendocrine stress reactivity in young women with eating disorders. (United States)

    Het, Serkan; Vocks, Silja; Wolf, Jutta M; Hammelstein, Philipp; Herpertz, Stephan; Wolf, Oliver T


    Stress is known to influence risk and progression of eating disorders (EDs). However, studies investigating physiological and psychological stress responses under laboratory conditions in patients with Anorexia nervosa or Bulimia nervosa are scarce and often produce conflicting findings. We therefore aimed to compare the neuroendocrine and affective stress response in ED inpatients and healthy controls. Twenty-eight female inpatients with Anorexia or Bulimia nervosa and 26 healthy women were exposed to the Trier Social Stress Test (TSST). Salivary cortisol and alpha-amylase (sAA) levels were assessed before as well as repeatedly after stress exposure, while heart rate and heart rate variability were determined before and during the TSST. Negative affective state was assessed at baseline and post-TSST. Compared to healthy controls, ED patients showed blunted cortisol stress responses combined with overall attenuated sAA levels. The latter was reflected in generally enhanced parasympathetic activity indicated by lower heart rate and stronger high-frequency heart rate variability throughout the TSST. Although patients reported more negative affect overall, they did not differ in their affective stress response. In summary, patients suffering from eating disorders show a blunted HPA axis reactivity to stress exposure and a generally reduced sympathetic/exaggerated parasympathetic nervous system activity. This combination may contribute to elevated health risks seen in eating disorder patients, such as enhanced inflammatory activity, and thus provide insight into the underlying stress-related mechanisms. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Outcome and CT differentiation of gallbladder neuroendocrine tumours from adenocarcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Tae-Hyung [Seoul National University Hospital, Department of Radiology, Seoul (Korea, Republic of); Kim, Se Hyung [Seoul National University Hospital, Department of Radiology, Seoul (Korea, Republic of); Seoul National University Hospital and Seoul National University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Seoul National University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Lee, Kyoung Boon [Seoul National University Hospital, Department of Pathology, Seoul (Korea, Republic of); Han, Joon Koo [Seoul National University Hospital, Department of Radiology, Seoul (Korea, Republic of); Seoul National University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Seoul National University Medical Research Center, Institute of Radiation Medicine, Seoul (Korea, Republic of)


    To retrospectively investigate clinical outcome and differential CT features of gallbladder (GB) neuroendocrine tumours (NETs) from adenocarcinomas (ADCs). Nineteen patients with poorly-differentiated (PD) NETs and 19 patients with PD ADCs were enrolled. Clinical outcome was compared by the Kaplan-Meier method. We assessed qualitative and quantitative CT features to identify significant differential CT features of PD NETs from ADCs using univariate and multivariate analyses. Receiver operating characteristic (ROC) analysis was used for quantitative CT features. PD NETs showed poorer prognosis with significantly shorter median survival days than ADCs (363 vs. 590 days, P = 0.03). On univariate analysis, NETs more frequently manifested as GB-replacing type and showed well-defined margins accompanied with intact overlying mucosa. On multivariate analysis, well-defined margin was the sole significant CT differentiator (odds ratio = 27.817, P = 0.045). Maximum size of hepatic and lymph node (LN) metastases was significantly larger in NETs (11.0 cm and 4.62 cm) than ADCs (2.40 cm and 2.41 cm). Areas under ROC curves for tumour-to-mucosa ratio, maximum size of hepatic and LN metastasis were 0.772, 0.932 and 0.919, respectively (P < 0.05). GB PD NETs show poorer prognosis than ADCs. Well-defined margin, larger hepatic and LN metastases are useful CT differentiators of GB NETs from ADCs. (orig.)

  11. Metabonomic profiling: a novel approach in neuroendocrine neoplasias. (United States)

    Kinross, James M; Drymousis, Panagiotis; Jiménez, Beatriz; Frilling, Andrea


    A metabonomic phenotyping strategy was developed as part of a pilot study to define a diagnostic metabolic phenotype for neuroendocrine neoplasms (NEN). Twenty-eight patients with NEN were prospectively recruited: small bowel NEN, n = 8; pancreatic NEN, n = 10; and others, n = 10 (mean age 49.4 years [26–81] male/female ratio 17:11). There were 17 healthy control patients. Urine samples were subjected to 1H nuclear magnetic resonance spectroscopic profiling via the use of a Bruker Avance 600-MHz spectrometer (Bruker, Rheinstetten, Germany). Acquired spectral data were imported into SIMCA and MATLAB for supervised and unsupervised multivariate analysis. Partial least squares-discriminant analysis differentiated between NEN and healthy samples with accuracy (R(2)Y = 0.79, Q2Y = 0.53, area under the curve [AUC] 0.90). Orthogonal partial least squares-discriminant analysis was able to distinguish between small bowel NEN and pancreatic NEN (R2Y = 0.91, Q2Y = 0.35). Subclass analysis also demonstrated class separation between functional and nonfunctional NEN (R2Y = 0.98, Q2Y = 0.77, AUC 0.6) and those with metastases (R2Y = 0.72 , Q2 Y = 0.41, AUC 0.86) due to variations in hippurate metabolism (P < .0001). Metabonomic analysis suggests that subgroups of NEN may possess a stratified metabolic phenotype. Metabolic profiling could provide novel biomarkers for NEN.

  12. MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus.

    Directory of Open Access Journals (Sweden)

    Patricia Blanchet


    Full Text Available Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense. The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms "mental retardation". To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus.

  13. Meta-type analysis of dopaminergic effects on gene expression in the neuroendocrine brain of female goldfish

    Directory of Open Access Journals (Sweden)

    Jason T Popesku


    Full Text Available Dopamine (DA is a major neurotransmitter important for neuroendocrine control and recent studies have described genomic signalling pathways activated and inhibited by DA agonists and antagonists in the goldfish brain. Here we perform a meta-type analysis using microarray datasets from experiments conducted with female goldfish to characterize the gene expression responses that underlie dopaminergic signalling. Sexually mature, pre-spawning (GSI 4.5 ± 1.3% or sexually regressing ( GSI 3 ± 0.4% female goldfish (15-40 g injected intraperitoneally with either SKF 38393, LY 171555, SCH 23390, sulpiride, or a combination of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and α-methyl-p-tyrosine. Microarray meta-type analysis identified 268 genes in the telencephalon and hypothalamus as having reciprocal (i.e. opposite between agonism and antagonism/depletion fold change responses, suggesting that these transcripts are likely targets for DA-mediated regulation. Noteworthy genes included ependymin, vimentin, and aromatase, genes that support the significance of DA in neuronal plasticity and tissue remodelling. Sub-network enrichment analysis (SNEA was used to identify common gene regulators and binding proteins associated with the differentially expressed genes mediated by DA. SNEA analysis identified gene expression targets that were related to three major categories that included cell signalling (STAT3, SP1, SMAD, Jun/Fos, immune response (IL6, IL1β, TNFs, cytokine, NF-κB, and cell proliferation and growth (IGF1, TGFβ1. These gene networks are also known to be associated with neurodegenerative disorders such as Parkinsons’ disease, well-known to be associated with loss of dopaminergic neurons. This study identifies genes and networks that underlie DA signalling in the vertebrate CNS and provides targets that may be key neuroendocrine regulators. The results provide a foundation for future work on dopaminergic regulation of gene expression in fish

  14. Neuronal, neurohormonal, and autocrine control of Xenopus melanotrope cell activity

    NARCIS (Netherlands)

    Roubos, E.W.; Scheenen, W.J.J.M.; Jenks, B.G.


    Amphibian pituitary melanotropes are used to investigate principles of neuroendocrine translation of neural input into hormonal output. Here, the steps in this translation process are outlined for the melanotrope cell of Xenopus laevis, with attention to external stimuli, neurochemical messengers,

  15. Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the alpha-subunit of glycoprotein hormones

    NARCIS (Netherlands)

    F.R.E. Nobels (Frank); D.J. Kwekkeboom (Dirk Jan); W. Coopmans; C.H.H. Schoenmakers (Christian); J. Lindemans (Jan); E.P. Krenning (Eric); R. Bouillon (Roger); S.W.J. Lamberts (Steven); W.W. de Herder (Wouter)


    textabstractChromogranin A (CgA) is gaining acceptance as a serum marker of neuroendocrine tumors. Its specificity in differentiating between neuroendocrine and nonneuroendocrine tumors, its sensitivity to detect small tumors, and its clinical value, compared with other

  16. CT differentiation of poorly-differentiated gastric neuroendocrine tumours from well-differentiated neuroendocrine tumours and gastric adenocarcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Seong Ho; Kim, Se Hyung; Shin, Cheong-il; Han, Joon Koo; Choi, Byung Ihn [Seoul National University Hospital, Department of Radiology, Jongno-gu, Seoul (Korea, Republic of); Seoul National University Hospital, Institute of Radiation Medicine, Jongno-gu, Seoul (Korea, Republic of); Kim, Min-A [Seoul National University Hospital, Department of Pathology, Jongno-gu, Seoul (Korea, Republic of)


    To evaluate the differential CT features of gastric poorly-differentiated neuroendocrine tumours (PD-NETs) from well-differentiated NETs (WD-NETs) and gastric adenocarcinomas (ADCs) and to suggest differential features of hepatic metastases from gastric NETs and ADCs. Our study population was comprised of 36 patients with gastric NETs (18 WD-NETs, 18 PD-NETs) and 38 patients with gastric ADCs who served as our control group. Multiple CT features were assessed to identify significant differential CT findings of PD-NETs from WD-NETs and ADCs. In addition, CT features of hepatic metastases including the metastasis-to-liver ratio were analyzed to differentiate metastatic NETs from ADCs. The presence of metastatic lymph nodes was the sole differentiator of PD-NETs from WD-NETs (P =.001, odds ratio = 56.67), while the presence of intact overlying mucosa with mucosal tenting was the sole significant CT feature differentiating PD-NETs from ADCs (P =.047, odds ratio = 15.3) For hepatic metastases, metastases from NETs were more hyper-attenuated than those from ADCs. The presence of metastatic LNs and intact overlying mucosa with mucosal tenting are useful CT discriminators of PD-NETs from WD-NETs and ADCs, respectively. In addition, a higher metastasis-to-liver ratio may help differentiate hepatic metastases of gastric NETs from those of gastric ADCs with high accuracy. (orig.)

  17. Poorly-differentiated colorectal neuroendocrine tumour: CT differentiation from well-differentiated neuroendocrine tumour and poorly-differentiated adenocarcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Ji Hee [Seoul National University Hospital, Department of Radiology, Seoul (Korea, Republic of); Kim, Se Hyung [Seoul National University Hospital, Department of Radiology, Seoul (Korea, Republic of); Seoul National University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Han, Joon Koo [Seoul National University Hospital, Department of Radiology, Seoul (Korea, Republic of); Seoul National University College of Medicine, Department of Radiology, Seoul (Korea, Republic of); Seoul National University Medical Research Center, Institute of Radiation Medicine, Seoul (Korea, Republic of)


    The differentiation of poorly-differentiated neuroendocrine tumours (PD-NETs), well-differentiated NETs (WD-NETs), and adenocarcinomas (ADCs) is important due to different management options and prognoses. This study is to find the differential CT features of colorectal PD-NETs from WD-NETs and ADCs. CT features of 25 colorectal WD-NETs, 36 PD-NETs, and 36 ADCs were retrospectively reviewed. Significant variables were assessed using univariate and multivariate analyses. Receiver operating characteristics analysis determined the optimal cut-off value of tumour and lymph node (LN) size. Large size, rectum location, ulceroinfiltrative morphology without intact overlying mucosa, heterogeneous attenuation with necrosis, presence of ≥3 enlarged LNs, and metastasis were significant variables to differentiate PD-NETs from WD-NETs (P < 0.05). High attenuation on arterial phase, persistently high enhancement pattern, presence of ≥6 enlarged LNs, large LN size, and wash-in/wash-out enhancement pattern of liver metastasis were significant variables to differentiate PD-NETs from ADCs (P < 0.05). Compared to WD-NETs, colorectal PD-NETs are usually large, heterogeneous, and ulceroinfiltrative mass without intact overlying mucosa involving enlarged LNs and metastasis. High attenuation on arterial phase, presence of enlarged LNs with larger size and greater number, and wash-in/wash-out enhancement pattern of liver metastasis can be useful CT discriminators of PD-NETs from ADCs. (orig.)

  18. SOX4, SOX11 and PAX6 mRNA expression was identified as a (prognostic) marker for the aggressiveness of neuroendocrine tumors of the lung by using next-generation expression analysis (NanoString). (United States)

    Walter, Robert Fred Henry; Mairinger, Fabian Dominik; Werner, Robert; Ting, Saskia; Vollbrecht, Claudia; Theegarten, Dirk; Christoph, Daniel Christian; Zarogoulidis, Konstantinos; Schmid, Kurt Werner; Zarogoulidis, Paul; Wohlschlaeger, Jeremias


    Neuroendocrine tumors of the lung (NELC) account for 25% of all lung cancer cases and transcription factors may drive dedifferentiation of these tumors. This study was conducted to identify supportive diagnostic and prognostic biomarkers. A total of 16 TC, 13 AC, 16 large cell neuroendocrine carcinomas and 15 small cell lung cancer were investigated for the mRNA expression of 11 transcription factors and related genes (MYB, MYBBP1A, OCT4, PAX6, PCDHB, RBP1, SDCBP, SOX2, SOX4, SOX11, TEAD2). SOX4 (p = 0.0002), SOX11 (p < 0.0001) and PAX6 (p = 0.0002) were significant for tumor type. Elevated PAX6 and SOX11 expression correlated with poor outcome in large cell neuroendocrine carcinomas and small cell lung cancer (p < 0.0001 and p = 0.0232, respectively) based on survival data of 34 patients (57%). Aggressiveness of NELC correlated with increasing expression of transcription factors. SOX11 seems to be a highly valuable diagnostic and prognostic marker for aggressive NELC.

  19. Molecular Imaging Radiotherapy: Theranostics for Personalized Patient Management of Neuroendocrine Tumors (NETs). (United States)

    Oberg, Kjell


    Neuroendocrine tumors (NETs) possess unique features including expression of peptide hormone receptors as well as the capacity to concentrate and take up precursor forms of amines and peptides making hormones that are stored in secretory granules within the tumor cells (APUD). The expression of somatostatin receptors on tumor cells have been widely explored during the last two decades starting with (111)In-DTPA-Octreotide as an imaging agent followed by (68)Ga-DOTATOC/TATE positron emission tomography scanning. The new generation of treatment includes (90)Yttrium-DOTATOC/DOTATATE as well as (177)Lutetium-DOTATOC/DOTATATE/DOTANOC treatment of various subtypes of NETs. The objective response rate by these types of PRRT is in the range of 30-45% objective responses with 5-10% grade 3/4 toxicity mainly hematologic and renal toxicity. The APUD mechanism is another unique feature of NETs which have generated an interest over the last two decades to develop specific tracers including (11)C-5HTP, (18)F-DOPA and (11)C-hydroxyefedrin. These radioactive tracers have been developed in centres with specific interest in NETs and are not available everywhere. (111)In-DTPA-Octreotide is still the working horse in diagnosis and staging of metastatic NETs, but will in the future be replaced by (68)Ga-DOTATOC/DOTATATE PET/CT scanning which provide higher sensitivity and specificity and is also more convenient for the patient because it is a one-stop-procedure. Both (90)Yttrium-DOTATOC/DOTATATE as well as (177)Lutetium-DOTATOC/DOTATATE are important new therapies for malignant metastatic NETs. However, the precise role in the treatment algorithm has to be determined in forthcoming randomized trials.

  20. Comparative Analysis of Clinical, Hormonal and Morphological Studies in Patients with Neuroendocrine ACTH-Producing Tumours

    Directory of Open Access Journals (Sweden)

    G. S. Kolesnikova


    Full Text Available This paper highlights the problem of neuroendocrine tumours (NETs with clinical symptoms of hypercorticism caused by hypersecretion of adrenocorticotropic hormone (ACTH by tumour cells. In most cases (85%, the tumours were localized in the pituitary gland (Cushing's disease; 15% of the patients had an extrapituitary tumour that manifest as an ectopic ACTH secretion (EAS. Comparative analysis of clinical, hormonal, histological, and immunohistochemical characteristics of pituitary and extrapituitary ACTH-secreting NET was performed. It included 46 patients with CD and 38 ones exhibiting ectopic ACTH secretion (EAS. Results of the study suggest differences between CD and EAS in terms of the severity of clinical manifestations and duration of the disease. Hormonal studies showed that EAS unlike CD was associated with high plasma ACTH and cortisol levels, late-evening salivary cortisol and daily urinary free cortisol, the absence of a 60% or greater reduction of cortisol in the HDDST test, and the presence of a low (less than 2 ACTH gradient in response to desmopressin administration with catheterization of cavernous sinuses. The study of morphofunctional characteristics of the removed NET demonstrated the ability of both pituitary and extrapituitary NETs to express ACTH as well as GH, PRL, LH, and FSH. The angiogenic markers (CD31 and VEGF were detected with equal frequency regardless of the NET localization. The histological structure of all corticotropinomas suggested their benign origin, but extrapituitary NETs were represented by different morphological types with varying malignancy, invasiveness, and metastatic properties. A higher cell proliferation potential (Ki-67 was documented for NET in patients presenting with an ectopic ACTH secretion compared to those having corticotropinomas.

  1. The Neuroendocrine System and Stress, Emotions, Thoughts and Feelings** (United States)

    Vaillant, George E.


    The philosophy of mind is intimately connected with the philosophy of action. Therefore, concepts like free will, motivation, emotions (especially positive emotions), and also the ethical issues related to these concepts are of abiding interest. However, the concepts of consciousness and free will are usually discussed solely in linguistic, ideational and cognitive (i.e. “left brain”) terms. Admittedly, consciousness requires language and the left-brain, but the aphasic right brain is equally conscious; however, what it “hears” are more likely to be music and emotions. Joy can be as conscious as the conscious motivation produced by the left-brain reading a sign that says, “Danger mines!!” However, look in the index of a Western textbook of psychology, psychiatry or philosophy for positive emotions located in the limbic system. Notice how discussion of positive spiritual/emotional issues in consciousness and motivation are scrupulously ignored. For example, the popular notions of “love” being either Eros (raw, amoral instinct) or agape (noble, non-specific valuing of all other people) miss the motivational forest for the trees. Neither Eros (hypothalamic) nor agape (cortical) has a fraction of the power to relieve stress as attachment (limbic love), yet until the 1950s attachment was neither appreciated nor discussed by academic minds. This paper will point out that the prosocial, “spiritual” positive emotions like hope, faith, forgiveness, joy, compassion and gratitude are extremely important in the relief of stress and in regulation of the neuroendocrine system, protecting us against stress. The experimental work reviewed by Antonio Damasio and Barbara Fredrickson, and the clinical example of Alcoholics Anonymous, will be used to illustrate these points. PMID:21694965

  2. Maternal neuroendocrine serum levels in exclusively breastfeeding mothers. (United States)

    Stuebe, Alison M; Meltzer-Brody, Samantha; Pearson, Brenda; Pedersen, Cort; Grewen, Karen


    Low milk supply is a common cause of early weaning, and supply issues are associated with dysregulation of thyroid function and prolactin. However, hormone levels compatible with successful breastfeeding are not well defined, limiting interpretation of clinical lab results. In this study we sought to quantify ranges for thyroid-stimulating hormone (TSH), free thyroxine (T4), total T4, and prolactin in a cohort of exclusively breastfeeding women. Women planning to breastfeed were recruited in the third trimester of pregnancy. Maternal endocrine function was assessed before and after a breastfeeding session at 2 and 8 weeks postpartum. We used paired t tests to determine whether values changed from the 2- to 8-week visit. Of 52 study participants, 28 were exclusively breastfeeding, defined as only breastmilk feeds in the prior 7 days, at both the 2- and 8-week study visits. Endocrine function changed with time since delivery: the TSH level was higher, whereas total T4, free T4, and prolactin levels were lower, at the 8-week visit than at the 2-week visit (by paired t test, p≤0.01). We found a wide range of prolactin values at the 8-week visit, with a 5th percentile value of 9 ng/dL before feeding and 74 ng/dL at 10 minutes after feeding. Neuroendocrine function changes during the first 8 weeks after birth, and a wide range of values is compatible with successful breastfeeding. Further studies are needed to define reference values in breastfeeding women.

  3. Lu-177 DOTATATE dosimetry for neuroendocrine tumor: single center experience (United States)

    Said, MA; Masud, MA; Zaini, MZ; Salleh, RA; Lee, BN; Zainon, R.


    Lu-177 labelled with DOTATE is widely acceptable to treat Neuroendocrine Tumor (NET) disease and it better improvement of quality of patients’ life since few years ago. However, the radionuclide toxicity becomes the main limitation of the (NET) treatment. Therefore, we performed a pilot study aimed to estimate radiation absorbed doses to dose-limiting organs to develop a systemic therapy with Lu-177 in NET patients. In this study, five set of planar whole body images was acquired every 0.5 hour, 4 hours, 24 hours, 48 hours and 72 hours after Lu-177 administrations. The planar image acquisition was done using Philip Brightview X with Medium Energy General Purpose Collimator (MEGP) collimator. All patients’ images in Conjugate View (CV) format were transferred into PMOD 3.7 Software for Region of Interest (ROI) analysis. The ROI were drawn at selected organs such as kidneys, liver, spleen and bladder. This study found that the mean absorbed dose for kidneys 0.62 ± 0.26 Gy/GBq, liver 0.63 ± 0.28 Gy/GBq, spleen 0.83 ± 0.73 Gy/GBq and bladder 0.14 ± 0.07 Gy/GBq. The radionuclide kinetic for the whole body 99.7 ± 0.1 percent at 0.5 hours, 79.5 ± 10.7 percent at 4 hours, 56.6 ± 10.3 percent at 24 hours, 43.2 ± 7.9 percent at 48 hours and 37.1 ± 9.0 percent at 72 hours. This study verifies that this planar quantitative method able to determine organ at risk and the result line with other published data.

  4. Neuroendocrine and immune characteristics of aging in avian species. (United States)

    Ottinger, M A; Lavoie, E


    Avian species show a remarkable diversity in lifespan. The differing lifespan patterns are found across a number of birds, in spite of higher body temperature and apparent increased metabolic rate. These characteristics make study of age-related changes of great interest, especially for understanding the biology of aging associated with surprisingly long lifespan in some birds. Our studies have focused on a short-lived avian model, the Japanese quail in order to describe reproductive aging and the neuroendocrine characteristics leading to reproductive senescence. Biomarkers of aging used in mammalian species include telomere length, oxidative damage, and selected metabolic indicators. These markers provide confirming evidence that the long-lived birds appear to age more slowly. A corollary area of interest is that of immune function and aging. Immune responses have been studied in selected wild birds and there has been a range of studies that have considered the effects of stress in wild and domestic species. Our laboratory studies have specifically tested response to immune challenge relative to aging in the quail model and these studies indicate that there is an age-related change in the qualitative aspects of the response. However, there are also intriguing differences in the ability of the aging quail to respond that differ from mammalian data. Finally, another approach to understanding aging is to attempt to develop or test strategies that may extend lifespan and presumably health. One area of great interest has been to consider the effect of calorie restriction, which is a treatment shown to extend lifespan in a variety of species. This approach is routinely used in domestic poultry as a means for extending reproductive function and enhancing health. Our data indicate that moderate calorie restriction has beneficial effects, and that physiological and endocrine responses reflect these benefits. Copyright 2007 S. Karger AG, Basel.

  5. The neuroendocrine system and stress, emotions, thoughts and feelings. (United States)

    Vaillant, George E


    The philosophy of mind is intimately connected with the philosophy of action. Therefore, concepts like free will, motivation, emotions (especially positive emotions), and also the ethical issues related to these concepts are of abiding interest. However, the concepts of consciousness and free will are usually discussed solely in linguistic, ideational and cognitive (i.e. "left brain") terms. Admittedly, consciousness requires language and the left-brain, but the aphasic right brain is equally conscious; however, what it "hears" are more likely to be music and emotions. Joy can be as conscious as the conscious motivation produced by the left-brain reading a sign that says, "Danger mines!!" However, look in the index of a Western textbook of psychology, psychiatry or philosophy for positive emotions located in the limbic system. Notice how discussion of positive spiritual/emotional issues in consciousness and motivation are scrupulously ignored. For example, the popular notions of "love" being either Eros (raw, amoral instinct) or agape (noble, non-specific valuing of all other people) miss the motivational forest for the trees. Neither Eros (hypothalamic) nor agape (cortical) has a fraction of the power to relieve stress as attachment (limbic love), yet until the 1950s attachment was neither appreciated nor discussed by academic minds. This paper will point out that the prosocial, "spiritual" positive emotions like hope, faith, forgiveness, joy, compassion and gratitude are extremely important in the relief of stress and in regulation of the neuroendocrine system, protecting us against stress. The experimental work reviewed by Antonio Damasio and Barbara Fredrickson, and the clinical example of Alcoholics Anonymous, will be used to illustrate these points.

  6. Similar cold stress induces sex-specific neuroendocrine and working memory responses. (United States)

    Solianik, Rima; Skurvydas, Albertas; Urboniene, Daiva; Eimantas, Nerijus; Daniuseviciute, Laura; Brazaitis, Marius


    Men have higher cold-induced neuroendocrine response than women; nevertheless, it is not known whether a different stress hormone rise elicits different effects on cognition during whole body cooling. The objective was to compare the effect of cold-induced neuroendocrine responses on the performance of working memory sensitive tasks between men and women. The cold stress continued until rectal temperature reached 35.5 degree C or for a maximum of 170 min. Working memory performance and stress hormone concentrations were monitored. During cold stress, body temperature variables dropped in all subjects (P stress raised plasma epinephrine and serum cortisol levels only in men (P stress adversely affected memory performance in men but not in women (P stress in men and women induces sex-specific neuroendocrine and working memory responses.

  7. Failed Lactation and Perinatal Depression: Common Problems with Shared Neuroendocrine Mechanisms? (United States)

    Grewen, Karen; Pedersen, Cort A.; Propper, Cathi; Meltzer-Brody, Samantha


    Abstract In the early postpartum period, mother and infant navigate a critical neuroendocrine transition from pregnancy to lactation. Two major clinical problems that occur during this transition are failed lactation and perinatal mood disorders. These disorders often overlap in clinical settings. Failed lactation is common. Although all major medical organizations recommend 6 months of exclusive breastfeeding, only 13% of women in the United States achieve this recommendation. Perinatal mood disorders affect 10% of mothers, with substantial morbidity for mother and child. We hypothesize that shared neuroendocrine mechanisms contribute to both failed lactation and perinatal mood disorders. In this hypothesis article, we discuss data from both animal models and clinical studies that suggest neuroendocrine mechanisms that may underlie these two disorders. Research to elucidate the role of these underlying mechanisms may identify treatment strategies both to relieve perinatal depression and to enable women to achieve their infant feeding goals. PMID:22204416

  8. Standardisation of imaging in neuroendocrine tumours: results of a European delphi process

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    Ricke, J. E-mail:; Klose, K.-J.; Mignon, M.; Oeberg, K.; Wiedenmann, B


    In 1998 and 1999, a delphi consensus procedure was performed to establish guidelines for standardised diagnostic imaging of neuroendocrine tumours. The procedure included four consecutive workshops of a European group of experts in neuroendocrine tumours as well as feedback given by specialists from the departments of radiology, nuclear medicine, surgery and internal medicine of the according home institutions. Diverging approaches among the centres, which became apparent during the discussion, reflect a lack of controlled studies specifically for rare subgroups of neuroendocrine tumours. This paper summarises the standards for diagnostic imaging as developed during the delphi process. In particular, the diagnostic workflows as well as the technical properties of different imaging modalities are described in detail.

  9. [Aldehyde reductase activity and blood aldo-keto reductase spectrum in adolescents with neuroendocrine obesity]. (United States)

    Kuleshova, D K; Davydov, V V; Shvets, V N


    Investigation of aldehyde-reductase activity and blood aldo-keto reductase spectrum has been performed in 13-15 and 16-18-years old adolescents with obesity to clear up the mechanisms of neuroendocrine obesity at the age of puberty. It has been established that basal aldehyde reductase activity and blood aldo-keto reductase spectrum of healthy adolescents in early puberty do not differ from those of healthy adolescents in late puberty. A decreased aldehyde reductase activity and some alterations in blood aldo-keto reductase spectrum have been observed in late puberty in adolescents with neuroendocrine obesity. In adolescents with obesity there have been registered some changes in blood aldo-keto reductase spectrum which are not accompanied by any alterations in its aldehyde reductase activity. The results obtained suggest that certain prerequisites are formed in late puberty to complicate the course of neuroendocrine obesity.

  10. Nintedanib Is a Highly Effective Therapeutic for Neuroendocrine Carcinoma of the Pancreas (PNET) in the Rip1Tag2 Transgenic Mouse Model. (United States)

    Bill, Ruben; Fagiani, Ernesta; Zumsteg, Adrian; Antoniadis, Helena; Johansson, David; Haefliger, Simon; Albrecht, Imke; Hilberg, Frank; Christofori, Gerhard


    Pancreatic neuroendocrine tumors (PNET) represent a rare but challenging heterogeneous group of cancers with an increasing incidence over the last number of decades. Herein, we report an in-depth evaluation of the new antiangiogenic small-molecule tyrosine kinase inhibitor (TKI) nintedanib in the preclinical Rip1Tag2 transgenic mouse model of neuroendocrine carcinoma of the pancreas (insulinoma). We have assessed the antiangiogenic and antitumor activity of nintedanib, in comparison with other antiangiogenic TKI, by treating Rip1Tag2 transgenic mice with different treatment schedules complemented with histopathologic, cell biologic, and biochemical analyses. Prolonged nintedanib treatment of Rip1Tag2 mice has led to a strong suppression of angiogenesis, accompanied by a reduced tumor burden, which translated into a significant prolongation of survival. Despite nintedanib's inhibitory action on perivascular cells, the blood vessels remaining after therapy displayed a considerably mature phenotype with tight perivascular cell coverage and preserved perfusion. Nintedanib treatment did not increase local tumor invasiveness or metastasis to the liver and pancreatic lymph nodes--a phenomenon that has been observed with antiangiogenic treatments of Rip1Tag2 transgenic mice in other laboratories. In contrast with the strong reduction in blood microvessel densities, nintedanib did not have any impact on tumor lymphangiogenesis. Based on our findings, we propose the clinical evaluation of the antiangiogenic drug nintedanib as a new treatment modality for PNET patients, notably in a direct comparison with already established therapeutic regimens, such as sunitinib. ©2015 American Association for Cancer Research.

  11. Small cell carcinoma of the vulva: case report

    Directory of Open Access Journals (Sweden)

    Ana Correia


    Full Text Available Neuroendocrine tumours are rare in the gynaecologic tract, comprising approximately 2% of all gynaecological tumours. They have an aggressive behaviour and are a diagnostic and clinical challenge, due to their rarity and the lack of standardized therapeutic approaches. There are a few case reports. It is defined as a high-grade carcinoma exhibiting neuroendocrine differentiation. The authors describe the case of a 70-year-old woman, with vulvar neuroendocrine small cell carcinoma after superficial vulvectomy. The patient was submitted to a surgery with wide local excision and adjuvant radiation therapy. A review of the literature on this topic is also presented.

  12. Splenosis Mimicking Relapse of a Neuroendocrine Tumor at Gallium-68-DOTATOC PET/CT

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    Treglia, Giorgio; Luca, Giovanella [Oncology Institute of Southern Switzerland, Bellinzona (Switzerland); Barbara, Muoio; Carmelo, Caldarella [Catholic Univ., Rome (Italy)


    A 48-year-old female patient underwent splenopancreasectomy for a 4-cm pancreatic neuroendocrine tumor (pNET), grade G2, located in the pancreatic tail. One year after surgery, the patient presented an increased serum level of the tumor marker chromogranin A (value: 160 U/l). Therefore, she underwent somatostatin receptor PET/CT using gallium-68-DOTATOC for restaging. This imaging method showed a focal area of increased radiopharmaceutical uptake corresponding to a 2.5-cm nodule located in the left superior abdomen near a clip from the previous surgery, suggesting a possible relapse of pNET. Based on this PET/CT finding, the patient underwent ultrasonography-guided core biopsy of this nodule. Histology did not reveal findings suggestive of pNET but identified spleen tissue most likely caused by splenosis accidentally seeded at the previous operation. It is likely that the increased serum level of the tumor marker chromogranin A was due to the chronic proton-pump inhibitors use. Somatostatin receptor PET/CT is an accurate imaging method for staging and restaging pNET, presenting high sensitivity and specificity in this setting. Nevertheless, possible sources of false-negative and -positive findings with this method should be taken into account. Inflammatory lesions represent the most frequent causes of false-positive findings for pNET at somatostatin receptor imaging because inflammatory cellsmay overexpress somatostatin receptors on their cell surface. In our case, we showed that splenosis may represent a possible cause of false-positive findings for pNET relapse due to the physiological uptake of somatostatin analogs by the spleen tissue.

  13. mTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors. (United States)

    Falletta, Simona; Partelli, Stefano; Rubini, Corrado; Nann, Dominik; Doria, Andrea; Marinoni, Ilaria; Polenta, Vanessa; Di Pasquale, Carmelina; Degli Uberti, Ettore; Perren, Aurel; Falconi, Massimo; Zatelli, Maria Chiara


    Medical therapy of pancreatic neuroendocrine tumors (P-NET) may take advantage of Everolimus treatment. However, the extent of therapeutic response cannot be predicted. This study was aimed to identify the possible predictive markers of response to Everolimus in P-NET. We found that Everolimus reduced the cell viability and induced apoptosis in primary cultures of 6 P-NET (P-NET-R), where the proliferative and antiapoptotic effects of IGF1 were blocked by Everolimus. On the contrary, 14 P-NET primary cultures (P-NET-NR) were resistant to Everolimus and IGF1, suggesting an involvement of PI3K/AKT/mTOR pathway in the mechanism of resistance. The response to Everolimus in vitro was associated with an active AKT/mTOR pathway and seemed to be associated with a greater clinical aggressiveness. In addition, a patient sensitive to Everolimus in vitro was sensitive to this drug in vivo also and showed a positive p-AKT immunohistochemistry (IHC) at tissue level. Similarly, a patient resistant to Everolimus treatment after surgery was not sensitive to the drug in vitro and had a negative p-AKT IHC staining. Therefore, present data confirm that P-NET primary cultures may be considered a model for testing medical treatment efficacy and that IHC characterization of p-AKT might help in identifying human P-NET who can benefit from Everolimus treatment. These data encourage conducting a prospective multicenter study involving different groups of P-NET patients treated with Everolimus. © 2016 Society for Endocrinology.

  14. Impact of the gut microbiota on the neuroendocrine and behavioural responses to stress in rodents

    Directory of Open Access Journals (Sweden)

    Rabot Sylvie


    Full Text Available The gastro-intestinal tract hosts a complex microbial ecosystem, the gut microbiota, whose collective genome coding capacity exceeds that of the host genome. The gut microbiota is nowadays regarded as a full organ, likely to contribute to the development of pathologies when its dynamic balance is disrupted (dysbiosis. In the last decade, evidence emerged that the gut microbiota influences brain development and function. In particular, comparisons between germ-free and conventional laboratory rodents showed that the absence of the gut microbiota exacerbates the hypothalamic pituitary adrenal (HPA system reactivity to stress and alters the anxiety-like behaviour. Furthermore, the dysfunctions observed in germ-free animals can be corrected if the gut microbiota is restored in early life but not in adulthood, suggesting a critical period for microbiota imprinting on the responsiveness to stress. The modes of action are still to be deciphered. They may involve transport of neuroactive bacterial metabolites to the brain through the bloodstream, stimulation of the vagus nerve or of entero-endocrine cells, or modulation of the immune system and, consequently, of the inflammatory status. The discovery that the gut microbiota regulates the neuroendocrine and behavioural responses to stress paves the way for the hypothesis that gut microbiota dysbioses could contribute to the pathophysiology of anxiety-related disorders. In this regard, treatments of anxiety-prone rodent strains with probiotics or antibiotics aimed at modifying their gut microbiota have shown an anxiolytic-like activity. Clinical trials are now needed to know if results obtained in preclinical studies can translate to humans.

  15. [Structural plasticity of the adult central nervous system: insights from the neuroendocrine hypothalamus]. (United States)

    Girardet, Clémence; Bosler, Olivier


    Accumulating evidence renders the dogma obsolete according to which the structural organization of the brain would remain essentially stable in adulthood, changing only in response to a need for compensatory processes during increasing age and degeneration. It has indeed become clear from investigations on various models that the adult nervous system can adapt to physiological demands by altering reversibly its synaptic circuits. This potential for structural and functional modifications results not only from the plastic properties of neurons but also from the inherent capacity of the glial cellular components to undergo remodeling as well. This is currently known for astrocytes, the major glial cells in brain which are well-recognized as dynamic partners in the mechanisms of synaptic transmission, and for the tanycytes and pituicytes which contribute to the regulation of neurosecretory processes in neurohemal regions of the hypothalamus. Studies on the neuroendocrine hypothalamus, whose role is central in homeostatic regulations, have gained good insights into the spectacular neuronal-glial rearrangements that may subserve functional plasticity in the adult brain. Following pioneering works on the morphological reorganizations taking place in the hypothalamo-neurohypophyseal system under certain physiological conditions such as dehydration and lactation, studies on the gonadotropic system that orchestrates reproductive functions have re-emphasized the dynamic interplay between neurons and glia in brain structural plasticity processes. This review summarizes the major contributions provided by these researches in the field and also addresses the question of the morphological rearrangements that occur on a 24-h basis in the central component of the circadian clock responsible for the temporal aspects of endocrine regulations. Taken together, the reviewed data highlight the close cooperation between neurons and glia in developing strategies for functional adaptation

  16. The neuroendocrine response of luteinizing hormone to estrogen administration in heterosexual, homosexual, and transsexual subjects. (United States)

    Gooren, L


    The neuroendocrine response of LH to estrogen administration may be related to sexual dimorphism of the brain, and therefore, homosexual and especially transsexual individuals may differ from heterosexual individuals in their responses. This study failed to find such differences among groups of female heterosexuals, homosexuals, and transsexuals. Specifically, after single dose estrogen administration, all subjects had an initial decline in serum LH levels, followed by a brisk rise of equal magnitude. Among males, the type of response was less uniform. After an initial fall in serum LH levels, the individual responses varied. In 12 of 23 male homosexuals, 10 of 15 male heterosexuals, and all 6 genetic male transsexuals studied, serum LH levels remained below pretreatment levels. In the remaining 11 male homosexuals and 5 of the heterosexuals, serum LH levels increased to values exceeding those before treatment, resembling the response found in the 3 groups of women. Those homosexual and heterosexual men with a rise in serum LH levels to above pretreatment values also had the greatest fall in testosterone levels after estrogen administration, while these same men had the lowest testosterone response to hCG stimulation. I conclude from these results that 1) the similarity of LH responses to estrogen administration in all groups of women studied does not support a theory of brain androgenization as a factor in the establishment of gender identity of sexual orientation; and 2) individual differences in men in the type of LH response to estrogen administration can be satisfactorily explained by endocrine factors, such as Leydig cell function, and need not be related to gender identity, sexual orientation, or other possible causes.

  17. Analysis of 320 gastroenteropancreatic neuroendocrine tumors identifies TS expression as independent biomarker for survival. (United States)

    Lee, Hye Seung; Chen, Min; Kim, Ji Hun; Kim, Woo Ho; Ahn, Soyeon; Maeng, Kyungah; Allegra, Carmen J; Kaye, Frederic J; Hochwald, Steven N; Zajac-Kaye, Maria


    Thymidylate synthase (TS), a critical enzyme for DNA synthesis and repair, is both a potential tumor prognostic biomarker as well as a tumorigenic oncogene in animal models. We have now studied the clinical implications of TS expression in gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) and compared these results to other cell cycle biomarker genes. Protein tissue arrays were used to study TS, Ki-67, Rb, pRb, E2F1, p18, p21, p27 and menin expression in 320 human GEP-NETs samples. Immunohistochemical expression was correlated with univariate and multivariate predictors of survival utilizing Kaplan Meier and Cox proportional hazards models. Real time RT-PCR was used to validate these findings. We found that 78 of 320 GEP-NETs (24.4%) expressed TS. NETs arising in the colon, stomach and pancreas showed the highest expression of TS (47.4%, 42.6% and 37.3%, respectively), whereas NETs of the appendix, rectum and duodenum displayed low TS expression (3.3%, 12.9% and 15.4%, respectively). TS expression in GEP-NETs was associated with poorly differentiated endocrine carcinoma, angiolymphatic invasion, lymph node metastasis and distant metastasis (p TS-positive NETs had markedly worse outcomes than TS-negative NETs as shown by univariate (p TS-positive patients that received chemotherapy (p = 0.015). In conclusion, TS protein expression was an independent prognostic biomarker for GEP-NETs. The strong association of increased TS expression with aggressive disease and early death supports the role of TS as a cancer promoting agent in these tumors. © 2013 UICC.

  18. Impact of scorpion venom as an acute stressor on the neuroendocrine-immunological network. (United States)

    Santhosh, K N; Pavana, D; Thippeswamy, N B


    Although immunomodulatory property and many other pharmaceutical applications of scorpion venom have been addressed before, no studies were reported about its application as a neuroimmunomodulator at therapeutic dose. In this study, we conceptualized the property of scorpion venom, capable of inducing the acute pain and neurotoxicity can cause acute stress resulting in the modulation of immune cells through HPA axis. The whole venom from Hottentotta rugiscutis, a widely seen scorpion in the region of eastern Karnataka, was extracted and injected a single dose of 1 mg/kg b.w. to Swiss albino mice and then erythrocytes and leukogram were measured. Whole brain AChE activity, corticosterone, cytokines and NO levels in plasma were also evaluated at various time points. Hrv didn't show any histopathological changes in the lymphoid organs and at the site of injection. However, lymphocytes and neutrophils did get altered at 2 h post-injection. Plasma corticosterone, cytokine levels such as IL-1β, IL-6, TNF-α and IL-10 and the AChE activity were significantly increased in a time-dependent manner. Based on these results, it may be predicted, Hrv's ability to cause acute stress resulted in the activation of HPA axis, which stimulates the release of glucocorticoid hormones which in turn elicits the immunomodulation of leukocytes by altering the levels of pro and anti-inflammatory cytokines. Thus, we can conclude, the impact of acute stress induced by Hrv can intercommunicate the signals between neuroendocrine-immune systems. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Diagnosis and Prognosis of Neuroendocrine Tumours of the Lung by Means of High Resolution Image Analysis

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    Uta Jütting


    Full Text Available Neuroendocrine tumours (NET of the lung are divided in subtypes with different malignant potential. The first is the benign or low‐grade malignant tumours, well‐differentiated, called typical carcinoids (TC and the second is the high‐grade malignant tumours, poorly differentiated of small (SCLC or large cell type (LCLC. Between these tumour types lies the well‐differentiated carcinoma with a lower grade of malignancy (WDNEC. In clinical routine it is very important with regard to prognosis to distinguish patients with low malignant potential from those with higher ones. In this study 32 cases of SCLC, 13 of WDNEC and 14 of TC with a follow‐up time up to 7 years were collected. Sections 4 μm thick from paraffin embedded tissue were Feulgen stained. By means of high resolution image analysis 100 nuclei per case were randomly gathered to extract morphometric, densitometric and textural quantitative features. To investigate the ploidy status of the tumour the corrected DNA distribution was calculated. Stepwise linear discriminant analysis to differentiate the classes and Cox regression analysis for the survival time analysis were applied. Using chromatin textural and morphometric features in two two‐class discriminations, 11 of the 14 TC cases and 8 of the 13 WDNEC cases were correctly classified and 11/13 WDNEC cases and 28/32 SCLC cases, respectively. The WDNEC cases are more similar in chromatin structure to TC than to SCLC. For the survival analysis, only chromatin features were selected to differentiate patients with better and worse prognosis independent of staging and tumour type.

  20. Endoscopic treatment of sporadic small duodenal and ampullary neuroendocrine tumors. (United States)

    Gincul, Rodica; Ponchon, Thierry; Napoleon, Bertrand; Scoazec, Jean-Yves; Guillaud, Olivier; Saurin, Jean-Christophe; Ciocirlan, Mihai; Lepilliez, Vincent; Pioche, Mathieu; Lefort, Christine; Adham, Mustapha; Pialat, Jean; Chayvialle, Jean-Alain; Walter, Thomas


    Background and study aim: As duodenal neuroendocrine tumors (NETs) are rare, their optimal management has not been clearly established. The aim of this study was to evaluate the feasibility and outcome of endoscopic treatment of duodenal NETs. Patients and methods: We reviewed the files of all patients who underwent endoscopic resection of a sporadic duodenal or ampullary NET between 1996 and 2014 at two centers. Results: A total of 29 patients with 32 uT1N0M0 NETs < 20 mm were included. Treatment consisted of endoscopic mucosal resection in 19 cases, and cap aspiration in 13 cases. Prior submucosal saline injection was used in 15 cases. Mortality was 3 % (one severe bleeding). Morbidity was 38 % (11/29). At post-resection analysis, mean tumor size was 8.9 mm (range 3 - 17 mm), 29 lesions were stage pT1, one was pT2, and 2 were pTx because of piecemeal resection. All NETs were well differentiated. A total of 27 lesions were classified as grade 1 and 5 were grade 2. The resection was R0, R1, and Rx for 16, 14, and 2 lesions, respectively. Three R1 patients underwent additional surgical treatment, with no residual tumor on the surgical specimen but with positive metastatic lymph nodes in two cases. One patient was lost to follow-up. Finally, 24 patients were included in the follow-up analysis. The median follow-up period was 56 months (range 6 - 175 months). Two patients presented a tumor recurrence during the follow-up period. Conclusions: Endoscopic treatment of small duodenal NETs was associated with significant morbidity, a difficulty in obtaining an R0 specimen, and the risk of lymph node metastasis. Nevertheless, it represents an interesting alternative in small grade 1 duodenal lesions and in patients at high surgical risk. © Georg Thieme Verlag KG Stuttgart · New York.

  1. Aspectos neuroendocrinos de la obesidad Neuroendocrine aspects of obesity

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    Mario Perello


    Full Text Available En la fisiopatología de la obesidad intervienen factores genéticos, sociales, metabólicos, endocrinos y neurológicos. Esta multifactoriedad junto al hecho que estos factores se interrelacionan a través de mecanismos muy complejos, que son sólo parcialmente conocidos, ha llevado a que la comprensión íntima de este trastorno resulte una tarea sumamente ardua. Por estos motivos, el conocimiento integral de esta afección plantea un desafío al que actualmente están abocados numerosos grupos de investigadores. El análisis de la obesidad como un trastorno neuroendocrino, propone el estudio de este fenómeno desde una visión particular que implica disfunciones en casi todos los órganos endocrinos y en el sistema nervioso central, fundamentalmente en la actividad hipotalámica. Estas alteraciones afectan principalmente a los ejes neuroendocrinos hipotálamo-hipofiso-adrenal, adipo-insular y al control hipotalámico, tanto de la ingesta de alimento como del almacenamiento y gasto energético. Este artículo plantea una actualización en este campo; en primer lugar, se realiza una breve descripción, en forma independiente, de los principales sistemas antes mencionados y luego una descripción de su funcionamiento normal integrado. Finalmente, se describen desregulaciones de estos mecanismos y se discute como ellas contribuirían al desarrollo y/o mantenimiento de la obesidad.Genetic, social, metabolic, endocrine and neural events participate in the physiopathological development of obesity. Because of the multifactorial background of obesity, up to now, it has been very difficult to fully understand the whole disease. In fact, the relationship between several signals, through very complex mechanisms, is only partially known. Obesity, from a neuroendocrine point of view, implies taking into account abnormalities in both hypothalamic and endocrine functions. Among altered functions in obesity, namely those involving the hypothalamo

  2. Circadian Tick-Talking Across the Neuroendocrine System and Suprachiasmatic Nuclei Circuits: The Enigmatic Communication Between the Molecular and Electrical Membrane Clocks. (United States)

    Belle, M D C


    As with many processes in nature, appropriate timing in biological systems is of paramount importance. In the neuroendocrine system, the efficacy of hormonal influence on major bodily functions, such as reproduction, metabolism and growth, relies on timely communication within and across many of the brain's homeostatic systems. The activity of these circuits is tightly orchestrated with the animal's internal physiological demands and external solar cycle by a master circadian clock. In mammals, this master clock is located in the hypothalamic suprachiasmatic nucleus (SCN), where the ensemble activity of thousands of clock neurones generates and communicates circadian time cues to the rest of the brain and body. Many regions of the brain, including areas with neuroendocrine function, also contain local daily clocks that can provide feedback signals to the SCN. Although much is known about the molecular processes underpinning endogenous circadian rhythm generation in SCN neurones and, to a lesser extent, extra-SCN cells, the electrical membrane clock that acts in partnership with the molecular clockwork to communicate circadian timing across the brain is poorly understood. The present review focuses on some circadian aspects of reproductive neuroendocrinology and processes involved in circadian rhythm communication in the SCN, aiming to identify key gaps in our knowledge of cross-talk between our daily master clock and neuroendocrine function. The intention is to highlight our surprisingly limited understanding of their interaction in the hope that this will stimulate future work in these areas. © 2015 The Author. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of The British Society for Neuroendocrinology.

  3. Goblet cell carcinoids

    DEFF Research Database (Denmark)

    Olsen, Ingrid Holst; Holt, Nanna; Langer, Seppo W


    BACKGROUND: Appendiceal goblet cell carcinoids (GCCs) exhibit neuroendocrine and adenocarcinoma features. PATIENTS AND METHODS: Analysis of demography, pathology, prognostic markers, treatment and survival in 83 GCC patients (f/m: 56/27) diagnosed 1992-2013. RESULTS: Median age for f/m was 59...

  4. Prognostic value of 18F-FLT PET in patients with neuroendocrine neoplasms

    DEFF Research Database (Denmark)

    Johnbeck, Camilla B.; Knigge, Ulrich; Langer, Seppo W.


    Neuroendocrine neoplasms (NENs) constitute a heterogeneous group of tumors arising in various organs and with a large span of aggressiveness and survival rates. The Ki-67 proliferation index is presently used as the key marker of prognosis, and treatment guidelines are largely based on this index...

  5. Occurrence of second primary malignancies in patients with neuroendocrine tumors of the digestive tract and pancreas

    NARCIS (Netherlands)

    K. Kamp (Kimberly); R.A. Damhuis (Ronald); R.A. Feelders (Richard); W.W. de Herder (Wouter)


    textabstractAn increased association between neuroendocrine tumors of the gastrointestinal tract and pancreas (GEP-NET) and other second primary malignancies has been suggested. We determined whether there is indeed an increased risk for second primary malignancies in GEP-NET patients compared with

  6. Neuroendocrine and cardiovascular reactions to acute psychological stress are attenuated in smokers

    NARCIS (Netherlands)

    Ginty, Annie T; Jones, Alexander; Carroll, Douglas; Roseboom, Tessa J; Phillips, Anna C; Painter, Rebecca; de Rooij, Susanne R


    A number of studies have now examined the association between smoking and the magnitude of physiological reactions to acute psychological stress. However, no large-scale study has demonstrated this association incorporating neuroendocrine in addition to cardiovascular reactions to stress. The

  7. Topotecan Monotherapy in Heavily Pretreated Patients with Progressive Advanced Stage Neuroendocrine Carcinomas

    DEFF Research Database (Denmark)

    Olsen, Ingrid Marie Holst; Knigge, Ulrich; Federspiel, Birgitte


    neuroendocrine carcinomas (Ki67>20%, G3) successively treated with oral topotecan 2.3 mg/m(2) d1-5 every 3 weeks. All patients had previously received treatment with carboplatin/etoposide. Demographic, clinical and pathological features were recorded. CT-evaluations according to RECIST 1.1 were performed after...

  8. Neuro-endocrine control of reproduction in hermaphroditic freshwater snails: mechanisms and evolution.

    NARCIS (Netherlands)

    Koene, J.M.


    Invertebrates are used extensively as model species to investigate neuro-endocrine processes regulating behaviors, and many of these processes may be extrapolated to vertebrates. However, when it comes to reproductive processes, many of these model species differ notably in their mode of

  9. Octreotide long-acting repeatable in the treatment of neuroendocrine tumors: patient selection and perspectives

    Directory of Open Access Journals (Sweden)

    Yau H


    Full Text Available Hanford Yau,1 Mustafa Kinaan,2 Suzanne L Quinn,3 Andreas G Moraitis3 1Division of Endocrinology, Diabetes, and Metabolism, University of California, San Francisco (Fresno Division, Fresno, CA, USA; 2Division of Internal Medicine, University of Central Florida College of Medicine, Orlando, FL, USA; 3Division of Endocrinology, Diabetes, and Metabolism, Orlando VA Medical Center, Orlando, FL, USA Abstract: Over the past three decades, the incidence and prevalence of neuroendocrine tumors have gradually increased. Due to the slow-growing nature of these tumors, most cases are diagnosed at advanced stages. Prognosis and survival are associated with location of primary lesion, biochemical functional status, differentiation, initial staging, and response to therapy. Octreotide, the first synthetic somatostatin analog, was initially used for the management of gastrointestinal symptoms associated with functional carcinoid tumors. Its commercial development over time led to long-acting repeatable octreotide acetate, a long-acting version that provided greater administration convenience. Recent research demonstrates that octreotide’s efficacy has evolved beyond symptomatic management to targeted therapy with antitumoral effects. This review examines the history and development of octreotide, provides a synopsis on the classification, grading, and staging of neuroendocrine tumors, and reviews the evidence of long-acting repeatable octreotide acetate as monotherapy and in combination with other treatment modalities in the management of non-pituitary neuroendocrine tumors with special attention to recent high-quality Phase III trials. Keywords: carcinoid, everolimus, neuroendocrine tumor, octreotide LAR, somatostatin analog, ITMO, NETTER-1, PROMID, RADIANT-2

  10. Paraneoplastic syndromes in patients with laryngeal neuroendocrine carcinomas : clinical manifestations and prognostic significance

    NARCIS (Netherlands)

    Ferlito, Alfio; Rinaldo, Alessandra; Bishop, Justin A.; Hunt, Jennifer L.; Vander Poorten, Vincent; Williams, Michelle D.; Triantafyllou, Asterios; Devaney, Kenneth O.; Gnepp, Douglas R.; Kusafuka, Kimihide; Halmos, Gyorgy B.; Westra, William H.; Takes, Robert P.; Thompson, Lester D. R.

    Paraneoplastic syndromes are associated with a variety of malignant neoplasms and are systemic and non-metastatic manifestations that develop in a minority of cancer patients. This review examines all published cases of paraneoplastic syndromes associated with neuroendocrine carcinomas of the

  11. Paraneoplastic syndromes in patients with laryngeal neuroendocrine carcinomas: clinical manifestations and prognostic significance

    NARCIS (Netherlands)

    Ferlito, A.; Rinaldo, A.; Bishop, J.A.; Hunt, J.L.; Poorten, V. Van der; Williams, M.D.; Triantafyllou, A.; Devaney, K.O.; Gnepp, D.R.; Kusafuka, K.; Halmos, G.B.; Westra, W.H.; Takes, R.P.; Thompson, L.D.


    Paraneoplastic syndromes are associated with a variety of malignant neoplasms and are systemic and non-metastatic manifestations that develop in a minority of cancer patients. This review examines all published cases of paraneoplastic syndromes associated with neuroendocrine carcinomas of the

  12. The combination of neuroendocrine tumor and mucinous neoplasm of the appendix: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Suh, Hie Bum; Lee, Nam Kyung; Kim, Suk; Park, Won Young; Kim, Jae Hun [Pusan National University Hospital, Pusan National University School of Medicine, Busan (Korea, Republic of)


    Primary neoplasm of the appendix is an uncommon pathology, representing 0.5-1% of all appendix specimens. Especially, simultaneous occurrence of two tumors of the appendix was rarely documented. We report a case of the concomitant neuroendocrine tumor and the mucinous neoplasm of the appendix on abdominal computed tomography, in a 62-year-old female who came for a check-up.

  13. Rare neuroendocrine tumours : Results of the surveillance of rare cancers in Europe project

    NARCIS (Netherlands)

    van der Zwan, Jan Maarten; Trama, Annalisa; Otter, Renee; Larranaga, Nerea; Tavilla, Andrea; Marcos-Gragera, Rafael; Dei Tos, Angelo Paolo; Baudin, Eric; Poston, Graeme; Links, Thera

    Because of the low incidence, and limited opportunities for large patient volume experiences, there are very few relevant studies of neuroendocrine tumours (NETs). A large population-based database (including cancer patients diagnosed from 1978 to 2002 and registered in 76 population-based cancer

  14. Interrelation between Neuroendocrine Disturbances and Medical Complications Encountered during Rehabilitation after TBI

    Directory of Open Access Journals (Sweden)

    Caroline I. E. Renner


    Full Text Available Traumatic brain injury is not a discrete event but an unfolding sequence of damage to the central nervous system. Not only the acute phase but also the subacute and chronic period after injury, i.e., during inpatient rehabilitation, is characterized by multiple neurotransmitter alterations, cellular dysfunction, and medical complications causing additional secondary injury. Neuroendocrine disturbances also influence neurological outcome and are easily overlooked as they often present with diffuse symptoms such as fatigue, depression, poor concentration, or a decline in overall cognitive function; these are also typical sequelae of traumatic brain injury. Furthermore, neurological complications such as hydrocephalus, epilepsy, fatigue, disorders of consciousness, paroxysmal sympathetic hyperactivity, or psychiatric-behavioural symptoms may mask and/or complicate the diagnosis of neuroendocrine disturbances, delay appropriate treatment and impede neurorehabilitation. The present review seeks to examine the interrelation between neuroendocrine disturbances with neurological complications frequently encountered after moderate to severe TBI during rehabilitation. Common neuroendocrine disturbances and medical complications and their clinical implications are discussed.

  15. Giant type III well-differentiated neuroendocrine tumor of the stomach: A case report

    Directory of Open Access Journals (Sweden)

    Omar Bellorin


    Conclusion: The incidence of gastric neuroendocrine tumors has been increasing during the last decade, underscoring the need to improve our understanding of their biology and behavior. When identified histologically, patient outcomes depend on appropriate determination of tumor biology and subsequent choice of treatment.

  16. Neuroendocrine coupling across adolescence and the longitudinal influence of early life stress. (United States)

    Ruttle, Paula L; Shirtcliff, Elizabeth A; Armstrong, Jeffrey M; Klein, Marjorie H; Essex, Marilyn J


    Drawing on conceptual models illustrating the advantages of a multisystemic, interactive, developmental approach to understanding development, the present study examines the covariation of stress and sex hormones across the adolescent transition and the effect of early life stress (ELS) on neuroendocrine coupling to gain insight into atypical development. Morning levels of cortisol, testosterone, and dehydroepiandrosterone (DHEA) were assessed at ages 11, 13, and 15; ELS was assessed during the infancy and preschool periods. Hierarchical linear modeling revealed that cortisol-DHEA coupling patterns progressed to tight, positive coupling across adolescence. Cortisol-testosterone coupling was positive at age 11 but became more negative at ages 13 and 15. Exposure to ELS resulted in more adultlike neuroendocrine coupling patterns earlier in life than non-exposed youth; however the effect of ELS on cortisol-testosterone coupling was unique to girls. Results illustrate trajectories of neuroendocrine coupling that may be unique to adolescence. Moderation by ELS suggests that early stress exposure may prompt earlier adultlike neuroendocrine coupling, particularly within girls, which may contribute to early pubertal development. © 2013 Wiley Periodicals, Inc.

  17. Neuroendocrine tumor of the appendix inside an incarcerated Amyand’s hernia

    Directory of Open Access Journals (Sweden)

    Khaled Y. Elbanna


    An incidental finding of neuroendocrine tumor of the appendix in a patient with s hernia is extremely rare. A high index of suspicion is the key to diagnose such a coincidence in order to safely and optimally treat such a condition.

  18. Niacin (Vitamin B-3) Supplementation in Patients with Serotonin-Producing Neuroendocrine Tumor

    NARCIS (Netherlands)

    Bouma, Grietje; van Faassen, Martijn; Kats-Ugurlu, Gursah; Vries, de Elisabeth G. E.; Kema, Ido P.; Walenkamp, Annemiek M. E.


    BACKGROUND/AIMS: Tryptophan is the precursor of serotonin and niacin (vitamin B3). The latter is critical for normal cellular metabolism. Tryptophan and niacin can be deficient in patients with serotonin producing neuroendocrine tumors (NETs). Niacin deficiency can lead to severe symptoms including

  19. Use of radioactive substances in diagnosis and treatment of neuroendocrine tumors

    DEFF Research Database (Denmark)

    Kjaer, Andreas; Knigge, Ulrich


    Radionuclides are needed both for nuclear medicine imaging as well as for peptide-receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NET). Imaging is important in the initial diagnostic work-up and for staging NETs. In therapy planning, somatostatin receptor imaging (SRI) is used when...

  20. The influence of postnatal handling on adult neuroendocrine and behavioural stress reactivity

    NARCIS (Netherlands)

    Meerlo, P; Horvath, KM; Nagy, GM; Bohus, B; Koolhaas, JM


    Environmental stimuli during early stages of life can influence the development of an organism and may result in permanent changes in adult behaviour and physiology. In the present study we investigated the influence of early postnatal handling on adult neuroendocrine and behavioural stress

  1. Neuroendocrine and Behavioral Effects of Vasopressin in Resting and Mild Stress Conditions

    NARCIS (Netherlands)

    Buwalda, B.; Nyakas, C.; Koolhaas, J.M.; Bohus, B.


    Neuroendocrine and behavioral effects of subcutaneously administered AVP (6 mug/kg b.wt.) were determined in resting conditions and after the mild stress of transportation to and placement in a novel environment. In resting conditions, systemic administration of AVP caused a rapid increase in blood

  2. Childhood neuroendocrine tumours : a descriptive study revealing clues for genetic predisposition

    NARCIS (Netherlands)

    Diets, I J; Nagtegaal, I D; Loeffen, J; de Blaauw, I; Waanders, E; Hoogerbrugge, N; Jongmans, M C J


    BACKGROUND: Neuroendocrine tumours (NETs) are rare in children and limited data are available. We aimed to specify tumour and patient characteristics and to investigate the role of genetic predisposition in the aetiology of paediatric NETs. METHODS: Using the Dutch Pathology Registry PALGA, we

  3. Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)—Health Professional Version (United States)

    Endocrine and neuroendocrine neoplasias may be inherited in syndromes such as multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2), familial pheochromocytoma and paraganglioma, and Carney-Stratakis syndrome. Learn about the genetics, clinical manifestations, and management of these hereditary cancer syndromes in this expert-reviewed summary.

  4. A case of giant prolactinoma, initially misdiagnosed as sinonasal neuroendocrine carcinoma

    Directory of Open Access Journals (Sweden)

    Yasaman Mohtasebi, M.D.


    Full Text Available Giant prolactinomas are defined as pituitary tumors greater than 4 cm, often associated with very high prolactin level (>1000 ng/mL. They are relatively rare tumors and can present differently from typical prolactinomas. They can be highly invasive, resulting in acute neurological complication at the time of presentation. We present a case of a young woman with giant prolactinoma initially misdiagnosed as sinonasal neuroendocrine carcinoma. The acute presentation of headache, ptosis and impending brain herniation, requiring emergent ventriculostomy and intubation, led to the clinical suspicion of a more sinister diagnosis. Transnasal biopsy of the mass was consistent with sinonasal neuroendocrine carcinoma, and chemotherapy was planned. Laboratory testing, however, revealed an elevated prolactin (27,400 ng/mL, after 1:100 dilution. Re-review of pathology with additional immunohistochemical staining was requested and confirmed the diagnosis of prolactinoma. After 5 months of cabergoline treatment, prolactin level has decreased to 118 ng/mL. There has been a marked reduction in tumor size and an almost complete resolution of neurological symptoms. Given their atypical presentation and potential for sharing common immunohistochemical stains with other neuroendocrine neoplasms, giant prolactinomas extending into the nasal cavity can be misdiagnosed as other neuroendocrine neoplasms which may develop at this site. Accurate diagnosis is imperative to prevent unnecessary surgery and/or radiation and to ensure implementation of dopamine agonist therapy.

  5. Nordic Guidelines 2010 for diagnosis and treatment of gastroenteropancreatic neuroendocrine tumours

    DEFF Research Database (Denmark)

    Janson, Eva Tiensuu; Sørbye, Halfdan; Welin, Staffan


    The diagnostic work-up and treatment of patients with neuroendocrine tumours has undergone a major change during the last decade. New diagnostic possibilities and treatment options have been developed. These Nordic guidelines, written by a group with a major interest in the subject, summarises ou...

  6. Neuroendocrine-immune interaction: regulation of inflammation via G-protein coupled receptors

    NARCIS (Netherlands)

    Verburg-van Kemenade, B.M.L.; Aa, van der L.M.; Chadzinska, M.K.


    Neuroendocrine- and immune systems interact in a bi-directional fashion to communicate the status of pathogen recognition to the brain and the immune response is influenced by physiological changes. The network of ligands and their receptors involved includes cytokines and chemokines,

  7. Carcinoid Syndrome and Carcinoid Heart Disease as Manifestations of Non-Metastatic Ovarian Neuroendocrine Tumour

    Directory of Open Access Journals (Sweden)

    Joana Simões-Pereira


    Full Text Available The carcinoid syndrome is rare but it is associated with carcinoid heart disease in more than a half of the cases. Carcinoid heart disease is typically characterised by morphological and functional modifications of right-sided valves. Its aetiology is probable multifactorial but serotonin appears to play a key role in the development of this valvular disease. Unlike gastrointestinal neuroendocrine tumours, ovarian neuroendocrine tumours can present with carcinoid syndrome and carcinoid heart disease in the absence of liver metastases; such ovarian neuroendocrine tumours are a unique clinical entity. The additional burden of cardiac impairment in these patients represents a significant reduction in survival. Early recognition and surgical valve replacement before advanced heart failure is established may improve the clinical outcome. We report the case of a woman with an ovarian neuroendocrine tumour and highly symptomatic carcinoid heart disease who was submitted to tumour resection followed by valvuloplasty. She demonstrated an outstanding clinical improvement and has remained free of tumour and symptomatology.

  8. Differentiation in neuroblastoma: diffusion-limited hypoxia induces neuro-endocrine secretory protein 55 and other markers of a chromaffin phenotype.

    Directory of Open Access Journals (Sweden)

    Fredrik Hedborg


    Full Text Available Neuroblastoma is a childhood malignancy of sympathetic embryonal origin. A high potential for differentiation is a hallmark of neuroblastoma cells. We have previously presented data to suggest that in situ differentiation in tumors frequently proceeds along the chromaffin lineage and that decreased oxygen (hypoxia plays a role in this. Here we explore the utility of Neuro-Endocrine Secretory Protein 55 (NESP55, a novel member of the chromogranin family, as a marker for this process.Immunohistochemical analyses and in situ hybridizations were performed on human fetal tissues, mouse xenografts of human neuroblastoma cell lines, and on specimens of human neuroblastoma/ganglioneuroma. Effects of anaerobic exposure on gene expression by cultured neuroblastoma cells was analyzed with quantitative real-time PCR. Fetal sympathetic nervous system expression of NESP55 was shown to be specific for chromaffin cell types. In experimental and clinical neuroblastoma NESP55 immunoreactivity was specific for regions of chronic hypoxia. NESP55 expression also correlated strikingly with morphological evidence of differentiation and with other chromaffin-specific patterns of gene expression, including IGF2 and HIF2α. Anaerobic culture of five neuroblastoma cell lines resulted in an 18.9-fold mean up-regulation of NESP55.The data confirms that chronic tumor hypoxia is a key microenvironmental factor for neuroblastoma cell differentiation, causing induction of chromaffin features and NESP55 provides a reliable marker for this neuronal to neuroendocrine transition. The hypoxia-induced phenotype is the predominant form of differentiation in stroma-poor tumors, while in stroma-rich tumors the chromaffin phenotype coexists with ganglion cell-like differentiation. The findings provide new insights into the biological diversity which is a striking feature of this group of tumors.

  9. Specificity and sensitivity of ⁹⁹mTc-EDDA/HYNIC-Tyr³-octreotide (⁹⁹mTc-TOC) for imaging neuroendocrine tumors. (United States)

    Sepúlveda-Méndez, Jesús; de Murphy, Consuelo Arteaga; Pedraza-López, Martha; Murphy-Stack, Eduardo; Rojas-Bautista, Juan Carlos; González-Treviño, Ofelia


    Gastroenteropancreatic neuroendocrine tumors (NETs) are cancers originating from neuroendocrine organs such as the pancreas, pituitary, thyroid, and adrenal glands and tumors arising from the diffuse neuroendocrine cells that are widely distributed throughout the body. NETs express somatostatin (SS) and contain a high density of SS receptors; therefore, they can be specifically targeted with SS-based radiopharmaceuticals. The aim of this research was to determine the validity in terms of specificity, sensitivity, and the agreement beyond chance with the biopsy (gold standard) of the ⁹⁹mTc-EDDA-HYNIC-Tyr³octreotide (⁹⁹mTc-TOC) to image and localize NETs and their metastases. Freeze-dried kits containing 0.0125 mg HYNIC-octreotide and co-ligands were easily labeled and quality controlled within the hospital radiopharmacy. Fifty-six consecutive Mexican patients with a previous presumptive diagnosis of NETs underwent several clinical and laboratory studies and were referred to the Nuclear Medicine Department for a routine scan with ⁹⁹mTc-TOC. The patients were injected with 500-600 MBq ⁹⁹mTc-TOC, and whole-body images were obtained 2 h later with a SPECT or a SPECT/CT camera. Two nuclear medicine physicians observed the images and classified them as 17 negative and 39 positive. After correlating the image of each patient with our 'gold standard' (biopsy, clinical history, morphological images, and tumor marker assays), the ⁹⁹mTc-TOC images were classified by the same two physicians as 12 true negatives, five false negatives, 38 true positives and one false positive. The validity of ⁹⁹mTc-TOC in terms of relative frequencies with corresponding 95% confidence intervals were as follows: 92.3% (64-100%) specificity; 88.4% (78-97%) sensitivity; and the agreement beyond chance was 73% (60-84%). The positive predictive value was 97.4% (87-100%); the negative predicted value was 70.6% (48-93%); the accuracy was 89.3% (89-97%); and the prevalence was 76

  10. Induction of Anti-Tumor Immune Responses by Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE in a Murine Model of a Human Neuroendocrine Tumor

    Directory of Open Access Journals (Sweden)

    Michael Bzorek


    Full Text Available Peptide receptor radionuclide therapy (PRRT is a relatively new mode of internally targeted radiotherapy currently in clinical trials. In PRRT, ionizing radioisotopes conjugated to somatostatin analogues are targeted to neuroendocrine tumors (NETs via somatostatin receptors. Despite promising clinical results, very little is known about the mechanism of tumor control. By using NCI-H727 cells in an in vivo murine xenograft model of human NETs, we showed that 177Lu-DOTATATE PRRT led to increased infiltration of CD86+ antigen presenting cells into tumor tissue. We also found that following treatment with PRRT, there was significantly increased tumor infiltration by CD49b+/FasL+ NK cells potentially capable of tumor killing. Further investigation into the immunomodulatory effects of PRRT will be essential in improving treatment efficacy.

  11. Induction of Anti-Tumor Immune Responses by Peptide Receptor Radionuclide Therapy with (177)Lu-DOTATATE in a Murine Model of a Human Neuroendocrine Tumor

    DEFF Research Database (Denmark)

    Wu, Yin; Pfeifer, Andreas Klaus; Myschetzky, Rebecca


    Peptide receptor radionuclide therapy (PRRT) is a relatively new mode of internally targeted radiotherapy currently in clinical trials. In PRRT, ionizing radioisotopes conjugated to somatostatin analogues are targeted to neuroendocrine tumors (NETs) via somatostatin receptors. Despite promising...... clinical results, very little is known about the mechanism of tumor control. By using NCI-H727 cells in an in vivo murine xenograft model of human NETs, we showed that 177Lu-DOTATATE PRRT led to increased infiltration of CD86+ antigen presenting cells into tumor tissue. We also found that following...... treatment with PRRT, there was significantly increased tumor infiltration by CD49b+/FasL+ NK cells potentially capable of tumor killing. Further investigation into the immunomodulatory effects of PRRT will be essential in improving treatment efficacy....

  12. Genome-wide features of neuroendocrine regulation in Drosophila by the basic helix-loop-helix transcription factor DIMMED. (United States)

    Hadžić, Tarik; Park, Dongkook; Abruzzi, Katharine C; Yang, Lin; Trigg, Jennifer S; Rohs, Remo; Rosbash, Michael; Taghert, Paul H


    Neuroendocrine (NE) cells use large dense core vesicles (LDCVs) to traffic, process, store and secrete neuropeptide hormones through the regulated secretory pathway. The dimmed (DIMM) basic helix-loop-helix transcription factor of Drosophila controls the level of regulated secretory activity in NE cells. To pursue its mechanisms, we have performed two independent genome-wide analyses of DIMM's activities: (i) in vivo chromatin immunoprecipitation (ChIP) to define genomic sites of DIMM occupancy and (ii) deep sequencing of purified DIMM neurons to characterize their transcriptional profile. By this combined approach, we showed that DIMM binds to conserved E-boxes in enhancers of 212 genes whose expression is enriched in DIMM-expressing NE cells. DIMM binds preferentially to certain E-boxes within first introns of specific gene isoforms. Statistical machine learning revealed that flanking regions of putative DIMM binding sites contribute to its DNA binding specificity. DIMM's transcriptional repertoire features at least 20 LDCV constituents. In addition, DIMM notably targets the pro-secretory transcription factor, creb-A, but significantly, DIMM does not target any neuropeptide genes. DIMM therefore prescribes the scale of secretory activity in NE neurons, by a systematic control of both proximal and distal points in the regulated secretory pathway. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  13. The value of the Ki-67 proliferation marker as a prognostic factor in gastroenteropancreatic neuroendocrine tumours. (United States)

    Foltyn, Wanda; Zajęcki, Wojciech; Marek, Bogdan; Kajdaniuk, Dariusz; Siemińska, Lucyna; Zemczak, Anna; Kos-Kudła, Beata


    Gastroenteropancreatic neuroendocrine tumours (GEP NETs) are a heterogenous group of tumours of various clinical presentations. Proliferative activity of tumour cells is an essential parameter determining the course of the disease and affecting the prognosis. The Ki-67 antigen is an important marker of cell proliferation, which shows activity in all the phases of the cell cycle, excluding the G0 phase. To assess the expression of Ki-67 in GEP NETs and to examine the association of Ki-67 with the stage of the tumour (tumour size, presence of metastases) and the hormonal function of the tumour. We included 61 patients with GEP NETs (25 males and 36 females aged between 20 and 82 years [mean age: 56 years]). The proliferative activity was examined in paraffin blocks containing surgically removed tumour samples and in core-needle biopsies of primary and metastatic tumours. The presence of the Ki-67 antigen was assessed by immunohistochemistry using MIB‑1 monoclonal antibodies. Based on the Ki-67 proliferative index we determined the tumour grade. In addition, we determined the tumour stage according to the TNM classification. In all the subjects we determined the levels of the non-specific NET marker (chromogranin A) and of specific NET markers (serotonin, insulin and gastrin in the blood and 5‑hydroxyindoleacetic acid [5‑HIAA] in 24-hour urine). The diagnoses of low-grade (Ki‑67 ≤ 2%), intermediate-grade (Ki-67 3-20%) and high-grade (Ki‑67 > 20%) NET were established in 38, 12 and 11 patients, respectively. Metastatic disease was diagnosed in 36/61 patients. A significantly higher expression of K-67 was observed in patients with metastatic disease (p = 0.01). A positive correlation was demonstrated between Ki-67 and the stage of the disease (p = 0.01) and between the histologic grade of the tumour and the stage of the disease (p = 0.01). No association between Ki-67 and the levels of chromogranin A, serotonin, insulin, gastrin and 5-HIAA was shown. There

  14. [Radioisotopic imaging of neuroendocrine tumours. Which radiopharmaceutical and which diagnostic procedure?]. (United States)

    Bombardieri, E; Maccauro, M; Castellani, M R; Chiti, A; Procopio, G; Bajetta, E; Seregni, E


    Neuroendocrine tumours can be visualized by several nuclear medicine modalities based on different mechanisms of cellular uptake. The most widely used radiopharmaceutical are the metaiodobenzylguanidine (123I/131I MIBG) and pentetreotide (111In pentetreotide). The first tracer follows the metabolic pathway of norephinephrine while the second one binds to somatostatin receptors which are expressed with high intensity on the neuroendocrine tissue. Some radiopharmaceuticals (Anti-CEA, Anti-CgA, Anti-GD2 monoclonal antibodies) have today only an experimental value, others such as 99mTc(V)DMSA had in the past very limited indications (medullary thyroid cancer) but at present their production is going to be stopped. An interesting series of new peptides showing a great affinity for the receptors/structures expressed by the neuroendocrine tissue is under evaluation in order to obtain a better tumour specificity. Among the positron-emitting radiopharmaceuticals, the 18F-fluorodeoxyglucose (FDG), in spite it is considered the most widely used tracer for clinical PET in oncology, did not show a satisfactory uptake in the well differentiated neuroendocrine tissues. On the contrary 18F-FDG is the best radiopharmaceutical to visualize those rare poorly differentiated neurondocrine tumours with a high proliferative index. For this reason also in this area, new radiopharmaceuticals have been studies and developed. A serotonin precursor 5-hydroxytryptophan (5-HTP) labelled with 11C has shown an increased uptake in carcinoids. Another radiopharmaceutical in development for PET is 11C L-DOPA which seems to be useful in visualizing endocrine pancreatic tumours. 18F-DOPA whole body PET may be a more promising imaging approach. Aim of this review is to summarize the potential of nuclear medicine techniques in the diagnosis of neuroendocrine tumours and to stresses the renewed role of nuclear medicine in the management of this disease.

  15. Partial cystectomy in a 76 year old patient suffering from small cell carcinoma of the urinary bladder


    Starownik, Radosław; Korolczuk, Agnieszka; Bar, Krzysztof; Płaza, Paweł; Kiś, Jacek; Muc, Kamil; Bar, Marek


    Small cell carcinomas of the urinary bladder originating from the neuroendocrine cells are extremely rare. We present a case of a 76–year–old patient with small cell carcinoma of the urinary bladder. The patient had hematuria and cystoscopy revealed a tumor located in a urinary bladder diverticulum. Partial resection of the bladder wall with diverticulectomy was performed. Microscopic examination established the diagnosis of neuroendocrine carcinoma, which was confirmed by immunohistochemistr...

  16. Study of Efficacy and Safety of PDR001 in Patients With Advanced or Metastatic, Well-differentiated, Non-functional Neuroendocrine Tumors of Pancreatic, Gastrointestinal (GI), or Thoracic Origin or Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC) (United States)


    Well-differentiated Non-functional NET of Thoracic Origin; Well-differentiated Non-functional NET of Gastrointestinal Origin; Well-differentiated Non-functional NET of Pancreatic Origin; Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma

  17. A massive hepatic tumor demonstrating hepatocellular, cholangiocarcinoma and neuroendocrine lineages: A case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Rachel E. Beard


    Conclusion: This is one of the only reports of a hepatic tumor arising from hepatocellular carcinoma, cholangiocarcinoma and neuroendocrine lineages. Increased awareness of this tumor type may optimize improve future management.

  18. Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival

    National Research Council Canada - National Science Library

    Gupta, Sanjay; Johnson, Marcella M; Murthy, Ravi; Ahrar, Kamran; Wallace, Michael J; Madoff, David C; McRae, Stephen E; Hicks, Marshall E; Rao, Sujaya; Vauthey, Jean-Nicolas; Ajani, Jaffer A; Yao, James C


    The objective of this study was to determine the prognostic variables that influence response and survival in patients with metastatic neuroendocrine tumors who are treated with hepatic arterial embolization (HAE...

  19. Diagnosis and Treatment of Gastroenteropancreatic Neuroendocrine Tumors: Current Data on a Prospectively Collected, Retrospectively Analyzed Clinical Multicenter Investigation


    Niederle, Martin B.; Niederle, Bruno


    Clinical information concerning diagnosis, symptoms, and treatment of 277 patients with gastrointestinal neuroendocrine tumors (including pancreatic tumors) diagnosed prospectively within 1 year were analyzed. Endoscopic and surgical techniques are the key to both correct diagnosis and effective treatment.

  20. 99mTc-HYNIC-TOC imaging in the evaluation of pancreatic masses which are potential neuroendocrine tumors. (United States)

    Qiao, Zhen; Zhang, Jingjing; Jin, Xiaona; Huo, Li; Zhu, Zhaohui; Xing, Haiqun; Li, Fang


    The aim of this investigation was to determine the accuracy of the findings and the diagnoses of Tc-hydrazinonicotinyl-Tyr3-octreotide scan (Tc-HYNIC-TOC imaging) in patients with pancreatic masses which were potential neuroendocrine tumors. Records of total 20 patients with pancreatic masses were retrospectively reviewed. All of the patients had been revealed by abdominal contrast CT and possibility of neuroendocrine tumors could not be excluded by CT imaging before Tc-HYNIC-TOC imaging. Tc-HYNIC-TOC imaging was performed at 1 and 4 hours post-tracer injection, and SPECT/CT images of the abdomen were also acquired. The image findings were compared to final diagnoses which were made from pathological examination. Among all 20 pancreatic masses evaluated, there were 16 malignant lesions which included 1 ductal adenocarcinoma and 15 neuroendocrine tumors. Tc-HYNIC-TOC imaging identified 14 of 15 pancreatic neuroendocrine tumors and excluded 4 of 5 lesions which were not neuroendocrine tumors. The overall sensitivity, specificity, and accuracy was therefore 93.3% (14 of 15), 80% (4 of 5), and 90.0% (18 of 20), respectively, in our patient population. Tc-HYNIC-TOC imaging provides reasonable accuracy in the evaluation pancreatic mass suspected to be neuroendocrine tumors.

  1. Functional live cell imaging of the pulmonary neuroepithelial body microenvironment

    NARCIS (Netherlands)

    De Proost, Ian; Pintelon, Isabel; Brouns, Inge; Kroese, A; Riccardi, Daniela; Kemp, Paul J.; Timmermans, Jean-Pierre; Adriaensen, Dirk

    Pulmonary neuroepithelial bodies (NEBs) are densely innervated groups of neuroendocrine cells invariably accompanied by Clara-like cells. Together with NEBs, Clara-like cells form the so-called "NEB microenvironment," which recently has been assigned a potential pulmonary stem cell niche. Conclusive

  2. Evaluation of neuroendocrine tumors with 99mTc-EDDA/HYNIC TOC. (United States)

    Artiko, Vera; Afgan, Aida; Petrović, Jelena; Radović, Branislava; Petrović, Nebojša; Vlajković, Marina; Šobić-Šaranović, Dragana; Obradović, Vladimir


    This paper is the short review of our preliminary results obtained with 99mTc-EDDA/HYNIC-TOC. The total of 495 patients with different neuroendocrine tumors were investigated during last few years. There have been 334 true positive (TP), 73 true negative (TN), 6 false positive (FP) and 82 false negative findings (FN). Diagnosis was made according to SPECT findings in 122 patients (25%). The mean T/NT ratio for TP cases was significantly higher (p Tektrotyd is a useful method for diagnosis, staging and follow up of the patients suspected to have neuroendocrine tumors. SPECT had important role in diagnosis. It is also helpful in the appropriate choice of the therapy, including the peptide receptor radionuclide therapy. In the absence of 68Ga-labeled peptides and PET/CT, the special emphasize should be given to application of SPECT/CT as well as to the radioguided surgery.

  3. An Eustachian Tube Neuroendocrine Carcinoma: A Previously Undescribed Entity and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Gavin J. le Nobel


    Full Text Available Primary sinonasal and middle ear neuroendocrine carcinomas are rare malignancies of the head and neck. Owing to the rarity of these tumors, the clinical behavior and optimal management of these tumors are not well defined. We present a case of an incidentally discovered sinonasal neuroendocrine carcinoma that was found to originate from the Eustachian tube, which has not previously been described in the literature. This patient was treated with primary surgical resection using a combination of transnasal and transaural approaches and achieved an incomplete resection. Follow-up imaging demonstrated continued tumor growth in the Eustachian tube as well as a new growth in the ipsilateral cerebellopontine angle and findings suspicious of perineural invasion. However, the tumor exhibited a benign growth pattern and despite continued growth the patient did not receive additional treatment and he remains asymptomatic 35 months following his original surgery.

  4. Neuroendocrine regulation of feminine sexual behavior: lessons from rodent models and thoughts about humans. (United States)

    Blaustein, Jeffrey D


    Much has been learned concerning the neuroendocrine processes and cellular mechanisms by which steroid hormones influence reproductive behaviors in rodents and other animals. In this review, a short discussion of hormones and feminine sexual behavior in some rodent species is followed by an outline of the main principles that have been learned from these studies. Examples are given of the importance of considering the timing of hormone treatments, dosage of hormone, use of a specific hormone, particular class of hormones, or form of hormone, interactions between hormones, route of administration, peripheral factors that influence hormonal response, and the possible mechanisms of action by which hormones and other factors influence sexual behaviors. Although cellular studies in humans are presently impossible to perform, mechanistic studies in rodents may provide clues about the neuroendocrine mechanisms by which hormones act and interact in the brain to influence behavior in all species, including humans.

  5. Neuroendocrine and renal effects of intravascular volume expansion in compensated heart failure

    DEFF Research Database (Denmark)

    Gabrielsen, A; Bie, P; Holstein-Rathlou, N H


    To examine if the neuroendocrine link between volume sensing and renal function is preserved in compensated chronic heart failure [HF, ejection fraction 0.29 +/- 0.03 (mean +/- SE)] we tested the hypothesis that intravascular and central blood volume expansion by 3 h of water immersion (WI) elicits...... sustained angiotensin-converting enzyme inhibitor therapy, n = 9) absolute and fractional sodium excretion increased (P Renal free water clearance increased during WI in control subjects but not in HF......, albeit plasma vasopressin concentrations were similar in the two groups. In conclusion, the neuroendocrine link between volume sensing and renal sodium excretion is preserved in compensated HF. The natriuresis of WI is, however, modulated by the prevailing ANG II and Aldo concentrations. In contrast...

  6. Imaging findings of neuroendocrine neoplasm in biliary duct with liver metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Oh, Jung Hwa; Chung, Dong Jin; Hahn, Sung Tae; Lee, Jae Moon [Dept. of Radiology, Yeouido St. Mary' s Hospital, College of Medicine, The Catholic University of Korea, Seoul (Korea, Republic of)


    A 64-year-old man was transferred to our hospital because of indigestion and jaundice. The initial abdominal CT and MRI revealed a 2.0 cm enhancing mass in the proximal common bile duct (CBD) with several enlarged lymph nodes. The mass was presumed to be a cholangiocarcinoma, and a CBD segmental resection and choledochojejunostomy was performed. However, the final diagnosis was that of a mixed endocrine-exocrine carcinoma, a high-grade neuroendocrine neoplasm. Seven months after the operation, a follow-up abdominal CT study revealed multiple small arterial enhancing nodules in both hepatic lobes. A sono-guided liver biopsy confirmed these as metastastic mixed endocrine-exocrine carcinoma. This case is unique in that the imaging study regarding the neuroendocrine neoplasm of biliary duct has not been previously reported.

  7. Melatonin acutely improves the neuroendocrine architecture of sleep in blind individuals. (United States)

    Fischer, Stefan; Smolnik, Rüdiger; Herms, Markus; Born, Jan; Fehm, Horst L


    In blind individuals, the absence of light cues results in disturbances of sleep and sleep-related neuroendocrine patterns. The Zeitgeber influence of light on the timing of sleep is assumed to be mediated by melatonin, a hormone of the pineal gland, whose secretion is inhibited by light and enhanced during darkness. Here, we investigated whether a single administration of melatonin improves sleep and associated neuroendocrine patterns in blind individuals. In a double-blind crossover study, 12 totally blind subjects received 5 mg melatonin and placebo orally 1 h before bedtime starting at 2300 h. The dose used enhanced blood melatonin concentrations to clearly supraphysiological levels. Melatonin increased total sleep time and sleep efficiency (P blind individuals the single administration of a clearly pharmacological dose of melatonin can improve sleep function by synchronizing in time the inhibition of pituitary-adrenal activity with central nervous sleep processes.

  8. Salmonella Typhi sense host neuroendocrine stress hormones and release the toxin haemolysin E (United States)

    Karavolos, Michail H; Bulmer, David M; Spencer, Hannah; Rampioni, Giordano; Schmalen, Ira; Baker, Stephen; Pickard, Derek; Gray, Joe; Fookes, Maria; Winzer, Klaus; Ivens, Alasdair; Dougan, Gordon; Williams, Paul; Khan, C M Anjam


    Salmonella enterica serovar Typhi (S. typhi) causes typhoid fever. We show that exposure of S. typhi to neuroendocrine stress hormones results in haemolysis, which is associated with the release of haemolysin E in membrane vesicles. This effect is attributed to increased expression of the small RNA micA and RNA chaperone Hfq, with concomitant downregulation of outer membrane protein A. Deletion of micA or the two-component signal-transduction system, CpxAR, abolishes the phenotype. The hormone response is inhibited by the β-blocker propranolol. We provide mechanistic insights into the basis of neuroendocrine hormone-mediated haemolysis by S. typhi, increasing our understanding of inter-kingdom signalling. PMID:21331094

  9. {sup 18}F-Fluorodihydroxyphenylalanine vs other radiopharmaceuticals for imaging neuroendocrine tumours according to their type

    Energy Technology Data Exchange (ETDEWEB)

    Balogova, Sona [Comenius University and St. Elisabeth Institute, Department of Nuclear Medicine, Bratislava (Slovakia); Hopital Tenon, AP-HP and Universite Pierre et Marie Curie, Department of Nuclear Medicine, Paris (France); Talbot, Jean-Noel; Michaud, Laure; Huchet, Virginie; Kerrou, Khaldoun; Montravers, Francoise [Hopital Tenon, AP-HP and Universite Pierre et Marie Curie, Department of Nuclear Medicine, Paris (France); Nataf, Valerie [Hopital Tenon, AP-HP, Department of Radiopharmacy, Paris (France)


    6-Fluoro-({sup 18}F)-L-3,4-dihydroxyphenylalanine (FDOPA) is an amino acid analogue for positron emission tomography (PET) imaging which has been registered since 2006 in several European Union (EU) countries and by several pharmaceutical firms. Neuroendocrine tumour (NET) imaging is part of its registered indications. NET functional imaging is a very competitive niche, competitors of FDOPA being two well-established radiopharmaceuticals for scintigraphy, {sup 123}I-metaiodobenzylguanidine (MIBG) and {sup 111}In-pentetreotide, and even more radiopharmaceuticals for PET, including fluorodeoxyglucose (FDG) and somatostatin analogues. Nevertheless, there is no universal single photon emission computed tomography (SPECT) or PET tracer for NET imaging, at least for the moment. FDOPA, as the other PET tracers, is superior in diagnostic performance in a limited number of precise NET types which are currently medullary thyroid cancer, catecholamine-producing tumours with a low aggressiveness and well-differentiated carcinoid tumours of the midgut, and in cases of congenital hyperinsulinism. This article reports on diagnostic performance and impact on management of FDOPA according to the NET type, emphasising the results of comparative studies with other radiopharmaceuticals. By pooling the results of the published studies with a defined standard of truth, patient-based sensitivity to detect recurrent medullary thyroid cancer was 70 % [95 % confidence interval (CI) 62.1-77.6] for FDOPA vs 44 % (95 % CI 35-53.4) for FDG; patient-based sensitivity to detect phaeochromocytoma/paraganglioma was 94 % (95 % CI 91.4-97.1) for FDOPA vs 69 % (95 % CI 60.2-77.1) for {sup 123}I-MIBG; and patient-based sensitivity to detect midgut NET was 89 % (95 % CI 80.3-95.3) for FDOPA vs 80 % (95 % CI 69.2-88.4) for somatostatin receptor scintigraphy with a larger gap in lesion-based sensitivity (97 vs 49 %). Previously unpublished FDOPA results from our team are reported in some rare NET, such as

  10. Castration Induced Neuroendocrine Mediated Progression of Prostate Cancer (United States)


    lineage. In other organs, the origin of NE cells has been shown to be endodermal stem cells,9,10 and a similar model was Received 14 September 2006...Leonhardt M, Janssen M, Konrad L, Bjartell A, Abrahamsson PA. Neurogenic origin of human prostate endocrine cells. Urology 1999; 53: 1041–1048. 13 Luttrell...xenograft LuCaP 23 following castration. Int J Cancer 1996; 65: 85–89. 73 Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin

  11. Neuroendocrine regulation of long-term pair maintenance in the monogamous zebra finch. (United States)

    Prior, Nora H; Soma, Kiran K


    This article is part of a Special Issue "SBN 2014". Understanding affiliative behavior is critical to understanding social organisms. While affiliative behaviors are present across a wide range of taxa and contexts, much of what is known about the neuroendocrine regulation of affiliation comes from studies of pair-bond formation in prairie voles. This leaves at least three gaps in our current knowledge. First, little is known about long-term pair-bond maintenance. Second, few studies have examined non-mammalian systems, even though monogamy is much more common in birds than in mammals. Third, the influence of breeding condition on affiliation is largely unknown. The zebra finch (Taeniopygia guttata) is an excellent model system for examining the neuroendocrine regulation of affiliative behaviors, including the formation and maintenance of a long-term pair bond. Zebra finches form genetically monogamous pair bonds, which they actively maintain throughout the year. The genomic and neuroanatomical resources, combined with the wealth of knowledge on the ecology and ethology of wild zebra finches, give this model system unique advantages to study the neuroendocrine regulation of pair bonding. Here, we review the endocrinology of opportunistic breeding in zebra finches, the sex steroid profiles of breeding and non-breeding zebra finches (domesticated and wild), and the roles of sex steroids and other signaling molecules in pair-maintenance behaviors in the zebra finch and other monogamous species. Studies of zebra finches and other songbirds will be useful for broadly understanding the neuroendocrine regulation of affiliative behaviors, including pair bonding and monogamy. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Results after surgical treatment of liver metastases in patients with high-grade gastroenteropancreatic neuroendocrine carcinomas

    DEFF Research Database (Denmark)

    Galleberg, R. B.; Knigge, U; Tiensuu Janson, E.


    Background: Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are generally characterized by synchronous metastases, high aggressiveness and a dismal prognosis. Current international guidelines do not recommend surgical treatment of liver metastases, however the existing data are scarce......, particularly for the group with a Ki-67 in the relatively lower G3 range. Our findings indicate a possible role for surgical treatment of liver metastases in the management of this patient population....

  13. Guidelines for the management of neuroendocrine tumours by the Brazilian gastrointestinal tumour group. (United States)

    Riechelmann, Rachel P; Weschenfelder, Rui F; Costa, Frederico P; Andrade, Aline Chaves; Osvaldt, Alessandro Bersch; Quidute, Ana Rosa P; Dos Santos, Allan; Hoff, Ana Amélia O; Gumz, Brenda; Buchpiguel, Carlos; Vilhena Pereira, Bruno S; Lourenço Junior, Delmar Muniz; da Rocha Filho, Duilio Reis; Fonseca, Eduardo Antunes; Riello Mello, Eduardo Linhares; Makdissi, Fabio Ferrari; Waechter, Fabio Luiz; Carnevale, Francisco Cesar; Coura-Filho, George B; de Paulo, Gustavo Andrade; Girotto, Gustavo Colagiovanni; Neto, João Evangelista Bezerra; Glasberg, João; Casali-da-Rocha, Jose Claudio; Rego, Juliana Florinda M; de Meirelles, Luciana Rodrigues; Hajjar, Ludhmila; Menezes, Marcos; Bronstein, Marcello D; Sapienza, Marcelo Tatit; Fragoso, Maria Candida Barisson Villares; Pereira, Maria Adelaide Albergaria; Barros, Milton; Forones, Nora Manoukian; do Amaral, Paulo Cezar Galvão; de Medeiros, Raphael Salles Scortegagna; Araujo, Raphael L C; Bezerra, Regis Otaviano França; Peixoto, Renata D'Alpino; Aguiar, Samuel; Ribeiro, Ulysses; Pfiffer, Tulio; Hoff, Paulo M; Coutinho, Anelisa K


    Neuroendocrine tumours are a heterogeneous group of diseases with a significant variety of diagnostic tests and treatment modalities. Guidelines were developed by North American and European groups to recommend their best management. However, local particularities and relativisms found worldwide led us to create Brazilian guidelines. Our consensus considered the best feasible strategies in an environment involving more limited resources. We believe that our recommendations may be extended to other countries with similar economic standards.

  14. Carcinome neuroendocrine du sein: à propos d'un cas et revue de ...

    African Journals Online (AJOL)

    Les carcinomes neuroendocrines primitifs (CNEP) du sein sont des tumeurs rares. Ils sont actuellement inclus dans la dernière classification de l'OMS des tumeurs du sein. Nous rapportons un cas de localisation mammaire chez une patiente de 39 ans. Il s'agissait d'une tumeur localement avancée ayant nécessité une ...

  15. Adolescent caffeine consumption increases adulthood anxiety-related behavior and modifies neuroendocrine signaling


    O’Neill, Casey E.; Newsom, Ryan J.; Stafford, Jacob; Scott, Talia; Archuleta, Solana; Levis, Sophia C.; Spencer, Robert L.; Campeau, Serge; Bachtell, Ryan K.


    Caffeine is a commonly used psychoactive substance and consumption by children and adolescents continues to rise. Here, we examine the lasting effects of adolescent caffeine consumption on anxiety-related behaviors and several neuroendocrine measures in adulthood. Adolescent male Sprague-Dawley rats consumed caffeine (0.3 g/L) for 28 consecutive days from postnatal day 28 (P28) to P55. Age-matched control rats consumed water. Behavioral testing for anxiety-related behavior began in adulthood ...

  16. Medullary thyroid carcinoma and duodenal calcitonin-secreting neuroendocrine tumour: more than coincidence?


    Huguet, I; Lamas, C; Vera, R; Lomas, A; Quilez, R P; Grossman, A.; Botella, F.


    Summary Neuroendocrine tumours (NETs) are a heterogeneous group of neoplasms whose management can be problematic. In many cases, multiple tumours may occur in the same patient or his or her family, and some of these have now been defined genetically, although in other cases the underlying gene or genes involved remain unclear. We describe a patient, a 63-year-old female, who was diagnosed with a medullary thyroid carcinoma (MTC), which was confirmed pathologically after thyroidectomy, but who...

  17. The Thyro-Gastric syndrome: from thyroid autoimmunity to neuroendocrine gastric tumors


    VALDES SOCIN, Hernan Gonzalo; Beckers, Albert


    THE THYRO-GASTRIC SYNDROME: FROM THYROID AUTOIMMUNITY TO NEUROENDOCRINE GASTRIC TUMORS. In 1849, Prof Addison described a fatal case of anemia, or anemia perniciosa. Dr Biermer expanded this original description in 1872. Nowadays, this pathological condition associating a megaloglastic anemia associated with a metabolic polyneuropathy is recognized as Biermer disease. Biermer anemia or anemia perniciosa and its associated polyneuropathy are the consequence of vitamine B12 malabsorpti...

  18. Brachytherapy should not be omitted when treating locally advanced neuroendocrine cervical cancer with definitive chemoradiation therapy. (United States)

    Robin, Tyler P; Amini, Arya; Schefter, Tracey E; Behbakht, Kian; Fisher, Christine M

    Neuroendocrine cervical cancer is a rare malignancy with a poor prognosis, yet there is a paucity of data to guide treatment decisions when managing patients with this diagnosis. Specifically, there are little data to aid practitioners in deciding if there is added value to brachytherapy given the additional time, cost, discomfort, and toxicity to patients. We used the National Cancer Data Base to identify women with locally advanced neuroendocrine cervical cancer treated with definitive chemoradiotherapy to determine if the addition of brachytherapy improves outcomes in this disease. We also assessed outcomes based on chemotherapy timing in this cohort. We identified 100 patients with locally advanced nonmetastatic neuroendocrine cervical cancer that were treated with definitive chemoradiotherapy between 2004 and 2012. There was a substantial improvement in overall survival when brachytherapy was administered in addition to external beam radiotherapy. In multivariate analysis, the addition of brachytherapy, compared with external beam radiotherapy alone, was associated with an improved median survival of 48.6 vs. 21.6 months (hazard ratio (HR), 0.475; 95% CI, 0.255-0.883; p = 0.019). We observed no difference in overall survival for patients treated with neoadjuvant chemotherapy compared with the group who received chemotherapy started concurrently with radiation (HR, 0.851; 95% CI, 0.483-1.500; p = 0.578). Brachytherapy should be considered an essential component of definitive chemoradiotherapy for the treatment of neuroendocrine cervical cancer. Chemotherapy timing, however, does not impact outcome. Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

  19. Primary neuroendocrine carcinoma of breast: a rare case report ...

    African Journals Online (AJOL)

    Immunohistochemistry showed estrogen, progesterone positivity and NE markers positivity in more than 50% of tumor cells for chromogranin, synaptophysin, neuron specific enolase. On further investigation by whole body computed tomography and magnetic resonance imaging revealed no extra mammary primary tumor.

  20. Late neuro endocrinological sequelae of radiation therapy; Effets tardifs de la radiotherapie sur la sphere neuroendocrine

    Energy Technology Data Exchange (ETDEWEB)

    Bieri, S.; Bernier, J. [Ospedale San Giovanni (Switzerland); Sklar, C. [Memorial Sloan-Kettering Cancer Center, New York, NY (United States); Constine, L. [Rochester Univ., NY (United States)


    When the hypothalamic-pituitary axis (HPA) is included in the treatment field in children and adults, a variety of neuroendocrine disturbances are more common than has been appreciated in the past. Clinical damage to the pituitary and thyroid glands usually occurs months to years after treatment, and is preceded by a long subclinical phase. Primary brain tumors represent the largest group of malignant solid tumors in children. The survival rates of 50 reported in the literature are achieved at the expense of late occurring effects. Radiation-induced abnormalities are generally dose-dependent. Growth hormone deficiency and premature sexual development can occur at doses as low as 18 Gy in conventional fractionation, and is the most common neuroendocrine problem in children. In patients treated with > 40 Gy on the HPA, deficiency of gonadotropins, thyroid stimulation hormone, and adrenocorticotropin (> 50 Gy), hyperprolactinemia can be seen, especially among young women. Most neuroendocrine disturbances that develop as a result of HPA can be treated efficiently, provided that an early detection of these endocrine dysfunctions abnormalities is done. (authors)

  1. The clinical value of scintigraphy of neuroendocrine tumors using (99m)Tc-HYNIC-TOC. (United States)

    Artiko, V; Sobic-Saranovic, D; Pavlovic, S; Petrovic, M; Zuvela, M; Antic, A; Matic, S; Odalovic, S; Petrovic, N; Milovanovic, A; Obradovic, V


    To assess the value of whole body scintigraphy using (99m)Tc-HYNIC-TOC (Tektrotyd) and with single photon emission computerized tomography (SPECT) in the detection of primary and metastatic neuroendocrine tumors (NETs). Thirty patients with different neuroendocrine tumors, mainly gastroenteropancreatic (GEP), were investigated. Whole body scintigraphy was performed 2 h (if necessary 10 min and 24h) after i.v. administration of 740 Mbq (99m)Tc-Tektrotyd, Polatom. In cases of unclear findings obtained by whole body scintigraphy, investigation was followed by SPECT. From 12 patients with NETs of unknown origin, there were 10 true positive (TP), and 2 false negative (FN) findings. Diagnosis was made with SPECT in 6 patients. From 8 patients with gut carcinoids, there were 4 TP, 2 true negative (TN), one FN, and one false positive (FP) finding. Diagnosis was made with SPECT in 2 patients. From 7 patients with neuroendocrine pancreatic carcinomas there were 4 TP and 3 TN findings. Diagnosis was made with SPECT in 2 patients. From 3 patients with gastrinomas there were 2 TP findings and one TN findings. Diagnosis was made with SPECT findings in 2 patients. Sensitivity of (99m)Tc-HYNIC-TOC was 87%, specificity 86%, positive predictive value 95%, negative predictive value 67% and accuracy 87%. We concluded that scintigraphy with (99m)Tc-Tektrotyd is an useful method for diagnosis, staging and follow up of the patients with NETs.

  2. Primary neuroendocrine tumor of the sacrum: case report and review of the literature

    Energy Technology Data Exchange (ETDEWEB)

    Dujardin, Fanny; Muret, Anne de [Hopital Trousseau, CHRU de Tours, Department of Pathology, Tours (France); Beaussart, Pauline; Waynberger, Eric [Hopital Trousseau, CHRU de Tours, Department of Radiology, Tours (France); Rosset, Philippe [Hopital Trousseau, CHRU de Tours, Department of Orthopaedic Surgery, Tours (France); Mulleman, Denis [Hopital Trousseau, CHRU de Tours, Department of Rheumatology, Tours (France); Pinieux, Gonzague de [Hopital Trousseau, CHRU de Tours, Department of Pathology, Tours (France); Hopital Trousseau, CHRU de Tours, Service d' Anatomie et Cytologie Pathologiques, Tours Cedex 09 (France)


    Primary carcinoid tumor (well-differentiated neuroendocrine tumor) of the bone involving the sacrum is extremely rare. We report the case of a 72-year-old man who presented with a 20-year history of intermittent low back pain and was found to have an intraosseous sacral mass on imaging. A needle biopsy revealed that this lesion was a well-differentiated neuroendocrine tumor. Workup did not show any primary tumor or other metastatic disease. There was no associated tailgut cyst or sacrococcygeal teratoma. The lesion was treated with radiation therapy because a surgical approach was rejected. The patient is free of metastatic disease after 28 years evolution of the lesion, retrospectively seen to be present on a conventional radiography performed in 1980. A review of the literature revealed 20 case reports of neuroendocrine tumors arising from the presacral region (with or without associated tailgut cyst or sacrococcygeal teratoma) and sometimes extending to the sacrum. One additional case was located within the neural canal and involved the sacrum, the presacral region, and the rectal wall. Our case is the only tumor arising primarily from the sacrum. The long evolution of this lesion without any other location makes metastatic disease very improbable and this case appears to be a unique example of primary intraosseous sacral carcinoid tumor. (orig.)

  3. Multiple neuroendocrine responses to chronic social stress: interaction between individual characteristics and situational factors. (United States)

    Mormède, P; Lemaire, V; Castanon, N; Dulluc, J; Laval, M; Le Moal, M


    After four weeks of individual housing, male Wistar rats (selected for high or low spontaneous aggressiveness by multiple round-robin encounters) were housed three per cage and submitted to four weeks of chronic social stress consisting of changing membership in the social groups by daily rotation of the animals among cages every day according to a random permutation procedure. In addition, half the males in each condition were housed with three females. Each environmental condition triggered different neuroendocrine changes. Cohabitation with females increased the hypothalamo-pituitary-adrenocortical axis activity, including enlargement of adrenals and increased circulating corticosterone levels. On the other hand, daily rotation of the rats between different social groups activated part of the sympathetic nervous system, such as increased phenylethanolamine N-methyl transferase (PNMT) activity in the adrenals. The level of aggressiveness, however, had no direct influence but interacted with environmental factors on such neuroendocrine measures as circulating testosterone or plasma renin activity. These results indicate that during chronic stress, there is no single, unique response by the animal, but a highly complex set of neuroendocrine changes, dependent on the interaction between individual characteristics (the level of aggressiveness is an example) and situational factors.

  4. Relaxin-3/RXFP3 signaling and neuroendocrine function – A perspective on extrinsic hypothalamic control

    Directory of Open Access Journals (Sweden)

    Despina E Ganella


    Full Text Available Complex neural circuits within the hypothalamus that govern essential autonomic processes and associated behaviors signal using amino acid and monoamine transmitters and a variety of neuropeptide (hormone modulators, often via G-protein coupled receptors (GPCRs and associated cellular pathways. Relaxin-3 is a recently identified neuropeptide that is highly conserved throughout evolution. Neurons expressing relaxin-3 are located in the brainstem, but broadly innervate the entire limbic system including the hypothalamus. Extensive anatomical data in rodents and non-human primate, and recent regulatory and functional data, suggest relaxin-3 signaling via its cognate GPCR, RXFP3, has a broad range of effects on neuroendocrine function associated with stress responses, feeding and metabolism, motivation and reward, and possibly sexual behavior and reproduction. Therefore, this article aims to highlight the growing appreciation of the relaxin-3/RXFP3 system as an important ‘extrinsic’ regulator of the neuroendocrine axis by reviewing its neuroanatomy and its putative roles in arousal-, stress- and feeding-related behaviors and links to associated neural substrates and signaling networks. Current evidence identifies RXFP3 as a potential therapeutic target for treatment of neuroendocrine disorders and related behavioral dysfunction.

  5. Convergent evolution of neuroendocrine control of phenotypic plasticity in pupal colour in butterflies (United States)

    Starnecker, G.; Hazel, W.


    Phenotypic plasticity in pupal colour occurs in three families of butterflies (the Nymphalidae, Papilionidae and Pieridae), typically in species whose pupation sites vary unpredictably in colour. In all species studied to date, larvae ready for pupation respond to environmental cues associated with the colour of their pupation sites and moult into cryptic light (yellow–green) or dark (brown–black) pupae. In nymphalids and pierids, pupal colour is controlled by a neuroendocrine factor, pupal melanization-reducing factor (PMRF), the release of which inhibits the melanization of the pupal cuticle resulting in light pupae. In contrast, the neuroendocrine factor controlling pupal colour in papilionid butterflies results in the production of brown pupae. PMRF was extracted from the ventral nerve chains of the peacock butterfly Inachis io (Nymphalidae) and black swallowtail butterfly Papilio polyxenes (Papilionidae). When injected into pre-pupae, the extracts resulted in yellow pupae in I. io but brown pupae in P. polyxenes. These results suggest that the same neuroendocrine factor controls the plasticity in pupal colour, but that plasticity in pupal colour in these species has evolved independently (convergently).

  6. Expanded criteria for debulking of liver metastasis also apply to pancreatic neuroendocrine tumors. (United States)

    Morgan, Rosemary E; Pommier, SuEllen J; Pommier, Rodney F


    Recently, there has been a move toward decreasing the threshold for liver debulking for metastatic carcinoid tumors from 90% to 70%. The debulking threshold and factors that predict outcomes of liver debulking operations specifically among pancreatic neuroendocrine tumors are not well defined. Records of patients with pancreatic neuroendocrine tumors undergoing liver debulking with a threshold of 70% from 2006 to 2016 were reviewed. Extrahepatic metastases and positive margins by enucleation were allowed. Liver progression-free survival and overall survival were calculated by the Kaplan-Meier method for various factors and compared by log-rank. Factors also were correlated with liver progression-free survival and overall survival by multivariate regression analyses. Forty-two patients underwent 44 operations, of which 24 resulted in 100% debulking, 12 resulted in ≥90% debulking, and 8 resulted in ≥70% debulking. Median liver progression-free survival was 11 months. The 5-year overall survival rate was 81%. There were no significant differences in outcome based on percent debulked. Only liver metastasis ≥5 cm correlated with liver progression-free survival and overall survival. Consideration should be given to expanding the criteria for liver debulking in pancreatic neuroendocrine tumors to include a new threshold of >70% debulking, intermediate grade tumors, positive margins, and extrahepatic metastases; these criteria yield results indistinguishable from complete resection. Using these expanded criteria will increase the number of patients eligible for an operation and maintain high survival rates. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Circadian variation in neuroendocrine response to L-dopa in patients with restless legs syndrome. (United States)

    Garcia-Borreguero, Diego; Larrosa, Oscar; Granizo, Juan José; de la Llave, Yolanda; Hening, Wayne A


    To investigate circadian changes in dopaminergic function by means of a neuroendocrine challenge (growth hormone and prolactin responses to an acute oral administration of L-dopa) in patients with idiopathic restless legs syndrome (RLS) and controls. Randomized administration of the L-dopa neuroendocrine challenge. Sleep disorders laboratory at a 500-bed academic hospital. Twelve patients diagnosed with idiopathic RLS and 12 age- and sex-matched healthy controls. Following a comprehensive evaluation that included nocturnal polysomnographic study, all participants underwent the L-dopa neuroendocrine challenge on 2 occasions (11 am and 11 pm). Subjects were previously randomly assigned to the time of first challenge (11 am or 11 pm). On each occasion, subjects took 200 mg of L-dopa (plus 50 mg carbidopa) by mouth. Blood was drawn 20 minutes and 5 minutes before administration of the drug, as well as 15, 30, 45, 60, 75, 90, 102, and 120 minutes after administration. Prechallenge levels of plasma values of growth hormone or prolactin did not differ in the 2 subject groups. Following only the nighttime administration of L-dopa, RLS patients manifested a more pronounced inhibition of prolactin release and an increase in growth hormone secretion. Prolactin plasma levels were significantly correlated to the periodic limb movement index on the polysomnogram. These findings may reflect enhanced circadian variations in dopaminergic function and support an increased sensitivity at night of dopamine receptors in patients with RLS.

  8. Dimethyl-Benz(aanthracene: A mammary carcinogen and a neuroendocrine disruptor

    Directory of Open Access Journals (Sweden)

    Bernard Kerdelhué


    Full Text Available Polycyclic Aromatic Hydrocarbons (PAHs are potent carcinogens. Among these, dimethylbenz(aanthracene (DMBA is well known for its capacity to induce mammary carcinomas in female Sprague-Dawley (SD rats. Ovariectomy suppresses the susceptibility of this model to DMBA, thus suggesting that the inducible action of the carcinogen depends on ovarian hormones. The promotion of DMBA-induced adenocarcinoma is accompanied by a series of neuroendocrine disruptions of both Hypothalamo-Pituitary-Gonadal (HPG and Hypothalamo-Pituitary-Adrenal (HPA axes and of the secretion of melatonin during the latency period of 2 months that precedes the occurrence of the first mammary tumor. The present review analyses the various neuroendocrine disruptions that occur along the HPG and the HPA axes, and the marked inhibitory effect of the carcinogen on melatonin secretion. The possible relationships between the neuroendocrine disruptions, which essentially consist in an increased pre-ovulatory secretion of 17β-estradiol and prolactin, associated with a marked reduction of melatonin secretion, and the decrease in gene expression of the receptors for aryl-hydrocarbons receptor (AhR and 17β-estradiol (ERα; ERβ are also discussed.

  9. Neuroendocrine stress responses predict catecholamine-dependent working memory-related dorsolateral prefrontal cortex activity. (United States)

    Hernaus, Dennis; Quaedflieg, Conny W E M; Offermann, Jan Stefan; Casales Santa, Marta M; van Amelsvoort, Thérèse


    It is generally thought that the effect of acute stress on higher-order functions such as working memory is, for an important part, mediated by central catecholamine activity. However, little is known about the association between neuroendocrine stress responses and catecholamine-dependent working memory-related brain function in the absence of stress. Here, we investigate for the first time in healthy humans (n = 18) how neuroendocrine responses to stress (cortisol and alpha-amylase) relate to fronto-parietal working memory activity changes in response to atomoxetine, a noradrenaline transporter inhibitor that selectively increases extracellular cortical dopamine and noradrenaline. We observed positive correlations between stress-induced cortisol (Pearson's r = 0.75, P working memory-related activity in dorsolateral prefrontal cortex. Stress-induced cortisol increases furthermore correlated with supramarginal gyrus working memory-related activity (r = 0.79, P working memory activity on placebo and greater working memory activity increases following atomoxetine in high stress responders. These results further corroborate the notion that neuroendocrine responses to stress are an informative proxy of catecholamine function relevant to higher order functions and provide novel hints on the complex relationship between acute stress, catecholamine function and working memory. © The Author (2017). Published by Oxford University Press.

  10. Classification of gastro-entero-pancreatic neuroendocrine tumors; Klassifikation gastroenteropankreatischer neuroendokriner Tumoren

    Energy Technology Data Exchange (ETDEWEB)

    Perren, A. [Klinikum Rechts der Isar, Technische UniversitaetMuenchen, Institut fuer Pathologie und pathologische Anatomie, Muenchen (Germany); Schmitt, A. [Universitaetsspital Zuerich, Institut fuer Klinische Pathologie, Departement Pathologie, Zuerich (Switzerland); Komminoth, P. [Stadtspital Triemli, Zuerich (Switzerland). Institut fuer Pathologie; Pavel, M. [Charite, Universitaetsmedizin Berlin (Germany). Medizinische Klinik mit Schwerpunkt Hepatologie and Gastroenterologie


    Tumors of the disseminated/diffuse neuroendocrine system (NET) are characterized by a common phenotype. However, the biology varies according to histomorphology, endocrine symptoms and organ of origin. The WHO classification takes these differences into account and uses a common framework, where the parameters size and extent of invasion vary according to the organ of origin. In order to achieve a further standardization of reporting the European Neuroendocrine Tumor Society (ENETS) recently proposed a tumor-node-metastasis (TNM) staging and grading system for gastro-entero-pancreatic NET. (orig.) [German] Tumoren des disseminierten/diffusen neuroendokrinen Systems sind durch einen gemeinsamen Phaenotyp gekennzeichnet. In ihrer Biologie unterscheiden sich neuroendokrine Tumoren (NET) jedoch bzgl. Morphologie, endokrinologischer Symptomatik und Ursprungsorgan. Die WHO-Klassifikation traegt diesen Unterschieden Rechnung und klassifiziert NET nach einem einheitlichen Vorgehen, wobei die Parameter Groesse und Invasionstiefe je nach Ursprungsorgan variieren. Um die Nomenklatur weiter zu vereinheitlichen, wurde vor kurzem von der ''European Neuroendocrine Tumor Society'' (ENETS) der Vorschlag einer TNM-Stadien-Einteilung und Graduierung gastroenteropankreatischer NET vorgelegt. (orig.)

  11. Two childhood pheochromocytoma cases due to von Hippel -Lindau disease, one associated with pancreatic neuroendocrine tumor; a rare manifestation. (United States)

    Dağdeviren Çakır, Aydilek; Turan, Hande; Aykut, Ayça; Durmaz, Asude; Ercan, Oya; Evliyaoğlu, Olcay


    (VHL) disease is an autosomal dominantly inherited disorder characterized by hemangioblastomas of retina and central nervous system (CNS); renal cysts, clear cell carcinoma; PCC; endolymphatic sac tumors; cystadenomas of the epididymis in males, broad ligament of uterus in females; pancreatic cysts, cystadenomas and neuroendocrine tumors. We here report two cases of VHL disease presented with PCC as the first manifestation. Hemangioblastoma of CNS in the first case and PNET in the second case developed during follow- up and led to the diagnosis of VHL disease. Genetic analyses of cases revealed p.Arg161Gln (c.482G>A) and p.Leu129Pro(c.386T>G) heterozygous missense mutation in VHL gene, respectively. In children, PCC may be the only and/or initial manifestation of the disease with delayed manifestations of the syndrome in other organs. PNET is a very rare manifestation of VHL disease. To best of our knowledge, this is the second case in literature, presenting with combination of PNET and bilateral PCC as components of childhood VHL disease. Pediatric patients diagnosed with PCC should be investigated for the genetic causes especially for VHL.

  12. Disentangling puberty: novel neuroendocrine pathways and mechanisms for the control of mammalian puberty. (United States)

    Avendaño, M S; Vazquez, M J; Tena-Sempere, M


    Puberty is a complex developmental event, controlled by sophisticated regulatory networks that integrate peripheral and internal cues and impinge at the brain centers driving the reproductive axis. The tempo of puberty is genetically determined but is also sensitive to numerous modifiers, from metabolic and sex steroid signals to environmental factors. Recent epidemiological evidence suggests that the onset of puberty is advancing in humans, through as yet unknown mechanisms. In fact, while much knowledge has been gleaned recently on the mechanisms responsible for the control of mammalian puberty, fundamental questions regarding the intimate molecular and neuroendocrine pathways responsible for the precise timing of puberty and its deviations remain unsolved. By combining data from suitable model species and humans, we aim to provide a comprehensive summary of our current understanding of the neuroendocrine mechanisms governing puberty, with particular focus on its central regulatory pathways, underlying molecular basis and mechanisms for metabolic control. A comprehensive MEDLINE search of articles published mostly from 2003 to 2017 has been carried out. Data from cellular and animal models (including our own results) as well as clinical studies focusing on the pathophysiology of puberty in mammals were considered and cross-referenced with terms related with central neuroendocrine mechanisms, metabolic control and epigenetic/miRNA regulation. Studies conducted during the last decade have revealed the essential role of novel central neuroendocrine pathways in the control of puberty, with a prominent role of kisspeptins in the precise regulation of the pubertal activation of GnRH neurosecretory activity. In addition, different transmitters, including neurokinin-B (NKB) and, possibly, melanocortins, have been shown to interplay with kisspeptins in tuning puberty onset. Alike, recent studies have documented the role of epigenetic mechanisms, involving mainly

  13. Mixed Neuroendocrine-Nonneuroendocrine Neoplasms (MiNENs): Unifying the Concept of a Heterogeneous Group of Neoplasms. (United States)

    La Rosa, Stefano; Sessa, Fausto; Uccella, Silvia


    The wide application of immunohistochemistry to the study of tumors has led to the recognition that epithelial neoplasms composed of both a neuroendocrine and nonneuroendocrine component are not as rare as traditionally believed. It has been recommended that mixed neuroendocrine-nonneuroendocrine epithelial neoplasms are classified as only those in which either component represents at least 30 % of the lesion but this cutoff has not been universally accepted. Moreover, since their pathogenetic and clinical features are still unclear, mixed neuroendocrine-nonneuroendocrine epithelial neoplasms are not included as a separate clinicopathological entity in most WHO classifications, although they have been observed in virtually all organs. In the WHO classification of digestive tumors, mixed neuroendocrine-nonneuroendocrine neoplasm is considered a specific type and is defined as mixed adenoneuroendocrine carcinoma, a definition that has not been accepted for other organs. In fact, this term does not adequately convey the morphological and biological heterogeneity of digestive mixed neoplasms and has created some misunderstanding among both pathologists and clinicians. In the present study, we have reviewed the literature on mixed neuroendocrine-nonneuroendocrine epithelial neoplasms reported in the pituitary, thyroid, nasal cavity, larynx, lung, digestive system, urinary system, male and female genital organs, and skin to give the reader an overview of the most important clinicopathological features and morphological criteria for diagnosing each entity. We also propose to use the term "mixed neuroendocrine-nonneuroendocrine neoplasm (MiNEN)" to define and to unify the concept of this heterogeneous group of neoplasms, which show different characteristics mainly depending on the type of neuroendocrine and nonneuroendocrine components.

  14. Risk factors of type 1 gastric neuroendocrine neoplasia in patients with chronic atrophic gastritis. A retrospective, multicentre study. (United States)

    Campana, Davide; Ravizza, Davide; Ferolla, Piero; Faggiano, Antongiulio; Grimaldi, Franco; Albertelli, Manuela; Ricci, Claudio; Santini, Donatella; Brighi, Nicole; Fazio, Nicola; Colao, Annamaria; Ferone, Diego; Tomassetti, Paola


    The aim of this retrospective study was to evaluate the presence of risk factors for a type 1 gastric neuroendocrine neoplasia in a large cohort of patients with chronic atrophic gastritis. The study design consisted of an Italian multicentre, retrospective analysis. The study included all consecutive patients with chronic atrophic gastritis with or without type 1 gastric neuroendocrine neoplasias followed at the participating centres. Two hundred and twenty-nine patients with chronic atrophic gastritis were enroled at the participating centres. A total of 207 patients (154 female, 53 males, median age: 56.0 years) were included in the final analysis. One hundred and twenty-six patients had chronic atrophic gastritis without a gastric neuroendocrine neoplasia and 81 had a chronic atrophic gastritis with type 1 gastric neuroendocrine neoplasia. The median Chromogranin A level, evaluated in 141 patients, was 52.0 U/L. At upper gastrointestinal endoscopy, atrophy of the gastric mucosa was mild/moderate in 137 patients and severe in 68. Intestinal metaplasia of the corpus was present in 168 patients. At histological examination, 81 patients had a gastric neuroendocrine neoplasia (42 patients had a NET G1 and 33 a NET G2). The median Ki67 index was 2.0 %. At univariate and multivariate analysis, the risk factors for a gastric neuroendocrine neoplasia were: male gender, chromogranin A greater than 61 U/L, presence of intestinal metaplasia and age equal to or greater than 59 years. Chromogranin A greater than 61 U/L, the presence of intestinal metaplasia and male gender were independent risk factors for a type 1 gastric neuroendocrine neoplasia in patients with chronic atrophic gastritis.

  15. Plasticity in the melanotrope neuroendocrine interface of Xenopus laevis

    NARCIS (Netherlands)

    Jenks, B.G.; Kidane, A.H.; Scheenen, W.J.; Roubos, E.W.


    Melanotrope cells of the amphibian pituitary pars intermedia produce alpha-melanophore-stimulating hormone (alpha-MSH), a peptide which causes skin darkening during adaptation to a dark background. The secretory activity of the melanotrope of the South African clawed toad Xenopus laevis is regulated

  16. Mixed acinar-neuroendocrine carcinoma of the pancreas

    DEFF Research Database (Denmark)

    Jakobsen, Mark; Klöppel, Günter; Detlefsen, Sönke


    of the English-language literature revealed 44 previously published cases of resected MAECs. We found that, compared to pure acinar cell carcinoma, patients with MAEC have a slightly higher age and are less frequently males, as the male / female ratio was almost equal. The histogenesis of MAEC is still...

  17. The utility of (68)Ga-DOTATATE positron-emission tomography/computed tomography in the diagnosis, management, follow-up and prognosis of neuroendocrine tumors. (United States)

    Tirosh, Amit; Kebebew, Electron


    Neuroendocrine tumors (NETs) are rare neoplasms that emerge mainly from the GI tract, pancreas and respiratory tract. The incidence of NETs has increased more than sixfold in the last decades. NETs typically express somatostatin receptors on their cell surface, which can be targeted by 'cold' somatostatin analogs for therapy or by 'hot' radiolabeled somatostatin analogs for tumor localization and treatment. 68-Gallium-DOTA peptides (DOTATATE, DOTATOC, DOTANOC) positron emission tomography/computed tomography is a highly accurate imaging modality for NETs that has been found to be more sensitive for NET detection than other imaging modalities. In the current review, we will discuss the clinical utility of 68-Gallium-DOTATATE positron emission tomography/computed tomography for the diagnosis and management of patients with NETs.

  18. Use of social media to conduct a cross-sectional epidemiologic and quality of life survey of patients with neuroendocrine carcinoma of the cervix: a feasibility study. (United States)

    Zaid, Tarrik; Burzawa, Jennifer; Basen-Engquist, Karen; Bodurka, Diane C; Ramondetta, Lois M; Brown, Jubilee; Frumovitz, Michael


    To determine the feasibility of using social media to perform cross-sectional epidemiologic and quality-of-life research on patients with rare gynecologic tumors, we performed a survey of patients with neuroendocrine tumors of the cervix using Facebook. After approval from our Institutional Review Board, a support group of patients with neuroendocrine tumors of the cervix was identified on Facebook. Group members were asked to complete a survey comprising 84 questions evaluating clinical presentation; treatment; recurrence; quality of life; and sexual function. The survey was posted for 30 days, during which 57 women responded from 8 countries across 4 continents treated at 51 centers. All respondents provided a detailed clinical and tumor history. The mean age was 38.5 years. The stage distribution was stage I, 36 patients (63%); II, 13 (23%); III, 2 (4%); and IV, 6 (11%). Forty-nine patients (86%) had small cell and 8 (14%) had large cell tumors. Forty-five of the respondents (79%) had completed primary therapy and were without evidence of disease. Five (9%) had recurrence, 3 (5%) had persistent disease after therapy, and 4 (7%) were still under treatment. Forty-one patients (72%) reported symptoms at time of presentation. Thirty-seven patients (65%) received multimodality primary therapy. Quality of life instruments demonstrated high scores for anxiety and a negative impact of anxiety and cancer on functional and emotional well-being. Sexual function scores did not differ significantly between respondents and the PROMIS reference population. Use of a social media network to perform epidemiologic and quality of life research on patients with rare gynecologic tumors is feasible and permits such research to be conducted efficiently and rapidly. © 2013.

  19. Comparative evaluation of three proliferation markers, Ki-67, TOP2A, and RacGAP1, in bronchopulmonary neuroendocrine neoplasms: Issues and prospects. (United States)

    Neubauer, Elisa; Wirtz, Ralph M; Kaemmerer, Daniel; Athelogou, Maria; Schmidt, Lydia; Sänger, Jörg; Lupp, Amelie


    The classification of bronchopulmonary neuroendocrine neoplasms (BP-NEN) into four tumor entities (typical carcinoids (TC), atypical carcinoids (AC), small cell lung cancers (SCLC), large cell neuroendocrine lung carcinomas (LCNEC)) is difficult to perform accurately, but important for prognostic statements and therapeutic management decisions. In this regard, we compared the expression of three proliferation markers, Ki-67, Topoisomerase II alpha (TOP2A), and RacGAP1, in a series of tumor samples from 104 BP-NEN patients (24 TC, 21 AC, 52 SCLC, 7 LCNEC) using different evaluation methods (immunohistochemistry (IHC): Average evaluation, Hotspot evaluation, digital image analysis; RT-qPCR).The results indicated that all three markers had increased protein and mRNA expression with poorer differentiation and correlated well with each other, as well as with grading, staging, and poor survival. Compared with Ki-67 and TOP2A, RacGAP1 allowed for a clearer prognostic statement. The cut-off limits obtained for Ki-67-Average (IHC) were TC-AC 1.5, AC-SCLC 19, and AC-LCNEC 23.5. The Hotspot evaluation generated equal to higher, the digital image analysis generally lower between-entity cut-off limits.All three markers enabled a clear-cut differentiation between the BP-NEN entities, and all methods evaluated were suitable for marker assessment. However, to define optimal cut-off limits, the Ki-67 evaluation methods should be standardized. RacGAP1 appeared to be a new marker with great potential.

  20. Circadian, neuroendocrine and neurobehavioral effects of polychromatic light in humans.


    Hanifin, John P


    Abstract In the last eighteen years there has been the identification of a novel photopigment, melanopsin, and its subsequent localization to human intrinsically photosensitive retinal ganglion cells (ipRGCs). Since melanopsin’s peak sensitivity is in the short wavelength portion of the visible spectrum (from 447 nm to 484 nm), there has been a steady increase in studies investigating the physiological effects of blue light. This thesis examines polychromatic light mixtures of blue light f...

  1. Solitary pulmonary metastasis from prostate cancer with neuroendocrine differentiation: a case report and review of relevant cases from the literature. (United States)

    Maebayashi, Toshiya; Abe, Katsumi; Aizawa, Takuya; Sakaguchi, Masakuni; Ishibash, Naoya; Fukushima, Shoko; Honma, Taku; Kusumi, Yoshiaki; Matsui, Tsuyoshi; Kawata, Nozomu


    Solitary lung metastasis from prostate cancer is rare. There are few reports of such cases with neuroendocrine differentiation. A 50-year-old man presented to our hospital with a chief complaint of dysuria. Histological examination revealed prostate cancer, which was classified as cT4 N0 M0, stage IV adenocarcinoma. Since the patient was at high risk, endocrine and radiation therapies were started. One year after starting radiation therapy, the patient developed bloody sputum. Chest radiography revealed a nodular shadow in his left lung (S5). Although 18-fluoro-2-deoxyglucose positron emission tomography revealed abnormal accumulation in the lesion, the cytological diagnosis was class IIIa, which did not yield a definitive diagnosis. Given that prostate specific antigen (PSA) was not elevated, a primary lung tumor was suspected, and thoracoscopic segmental resection of the lung was performed with lymph node dissection. The final pathological diagnosis was solitary lung metastasis from prostate cancer with neuroendocrine differentiation and mediastinal lymph node metastasis. The specimen showed a mixed pattern of conventional prostatic and neuroendocrine carcinomas. We herein report a case with neuroendocrine differentiation (NED), along with a review of the relevant literature, including histopathological findings. According to previous case reports, some patients with solitary lung metastasis from prostate cancer achieved relatively good long-term survival. We consider establishing the correct diagnosis and implementing an appropriate treatment plan to be essential in prostate cancer patients with oligometastases that have the potential to be neuroendocrine (NE) tumors.

  2. C2-domain containing calcium sensors in neuroendocrine secretion

    DEFF Research Database (Denmark)

    Pinheiro, Paulo S; Houy, Sébastien; Sørensen, Jakob B


    to calcium, trigger the merger of cargo-filled vesicles with the plasma membrane. Low-affinity, fast-kinetics calcium sensors of the synaptotagmin family - especially synaptotagmin-1 and synaptotagmin-2 - are the main calcium sensors for fast exocytosis triggering in many cell types. Their functions extend...... the properties and possible interplay of (some of) the major C2-domain containing calcium sensors in calcium-triggered exocytosis. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases"....

  3. The Functional Significance of Synaptotagmin Diversity in Neuroendocrine Secretion

    Directory of Open Access Journals (Sweden)

    Paanteha K Moghadam


    Full Text Available Synaptotagmins (syts are abundant, evolutionarily-conserved integral membrane proteins that play essential roles in regulated exocytosis in nervous and endocrine systems. There are at least 17 syt isoforms in mammals, all with tandem C-terminal C2 domains with highly variable capacities for Ca2+ binding. Many syts play roles in neurotransmitter release or hormone secretion or both, and a growing body of work supports a role for some syts as Ca2+ sensors of exocytosis. Work in many types of endocrine cells has documented the presence of a number of syt isoforms on dense-core vesicles containing various hormones. Syts can influence the kinetics of exocytotic fusion pores and the choice of release mode between kiss-and-run and full-fusion. Vesicles harboring different syt isoforms can preferentially undergo distinct modes of exocytosis with different forms of stimulation. The diverse properties of syt isoforms enable these proteins to shape Ca2+ sensing in endocrine cells, thus contributing to the regulation of hormone release and the organization of complex endocrine functions.

  4. Profiling of metastatic small intestine neuroendocrine tumors reveals characteristic miRNAs detectable in plasma. (United States)

    Bowden, Michaela; Zhou, Chensheng W; Zhang, Sui; Brais, Lauren; Rossi, Ashley; Naudin, Laurent; Thiagalingam, Arunthi; Sicinska, Ewa; Kulke, Matthew H


    Current diagnostic and prognostic blood-based biomarkers for neuroendocrine tumors are limited. MiRNAs have tumor-specific expression patterns, are relatively stable, and can be measured in patient blood specimens. We performed a multi-stage study to identify and validate characteristic circulating miRNAs in patients with metastatic small intestine neuroendocrine tumors, and to assess associations between miRNA levels and survival. Using a 742-miRNA panel, we identified candidate miRNAs similarly expressed in 19 small intestine neuroendocrine tumors and matched plasma samples. We refined our panel in an independent cohort of plasma samples from 40 patients with metastatic small intestine NET and 40 controls, and then validated this panel in a second, large cohort of 120 patients with metastatic small intestine NET and 120 independent controls. miRNA profiling of 19 matched small intestine neuroendocrine tumors and matched plasma samples revealed 31 candidate miRNAs similarly expressed in both tissue and plasma. We evaluated expression of these 31 candidate miRNAs in 40 independent cases and 40 normal controls, and identified 4 miRNAs (miR-21-5p, miR-22-3p, miR-29b-3p, and miR-150-5p) that were differently expressed in cases and controls (p<0.05). We validated these 4 miRNAs in a separate, larger panel of 120 cases and 120 controls. We confirmed that high circulating levels of miR-22-3p (p<0.0001), high levels of miR 21-5p, and low levels of miR-150-5p (p=0.027) were associated with the presence of metastatic small intestine NET. While levels of 29b-3p were lower in cases than in controls in both the initial cohort and the validation cohort, the difference in the validation cohort did not reach statistical significance. We further found that high levels of circulating miR-21-5p, high levels of circulating miR-22-3p and low levels of circulating miR-150-5p were each independently associated with shorter overall survival. A combined analysis using all three markers

  5. Effects of TNF antagonists on immune and neuroendocrine system

    Directory of Open Access Journals (Sweden)

    M. Cutolo


    Full Text Available In the article, the literature on the effects of TNFa-antagonists (etanercept, infliximab and adalimumab on the immune system is reviewed. These biologic agents are employed in chronic inflammatory diseases such as rheumatoid arthritis, seronegative spondyloarthritides, as well as psoriasis and Crohn’s disease. The differences of these drugs, testified by the different effects on the immune response, are discussed. These molecules exert their effect through cytokine inhibition, but they present striking differences since they can modulate macrophage activity, T cells apoptosis, leukocyte migration, and angiogenesis to a different degree. Some studies showed that these agents also affect the hypothalamo- pituitary-adrenal axis. The potential immunogenicity of these biologic agents is also discussed.

  6. Concordance in the neuroendocrine tumors between scintigraphy with pentetreotide labelled with indium 111 and morphological imaging; Concordance dans les tumeurs neuroendocrines entre la scintigraphie au pentetreotide marque a l'indium 111 et l'imagerie morphologique

    Energy Technology Data Exchange (ETDEWEB)

    Elkadri, N.; Sellem, A.; El Ajmi, W.; Meddeb, I.; Hammami, H. [Hopital militaire de Tunis, Service de medecine nucleaire (Tunisia); Rejeb, O.; Slimene, H. [Hopital La Rabta, service d' endocrinologie, Tunis (Tunisia)


    Assess the consistency in the exploration of neuroendocrine tumors between pentetreotide scintigraphy labeled with {sup 111}In (octreoscan) and morphological imaging by CT and / or magnetic resonance imaging (CT and / or MRI). Conclusions: The association between Octreoscan and morphologic imaging (CT and / or MRI) allows a more complete assessment of the lesions of neuroendocrine tumors. Octreoscan is probably not indicated in cases of carcinoid syndrome with a positive urine assay for 5-hydroxy-indole-acetic acid (5-H.I.A.A.) and without hepatic localization in morphological imaging.Scintigraphy with depreotide labelled with {sup 99m}Tc would be probably more appropriate. (N.C.)

  7. Clinical utility of chromogranin A and octerotide in large cell neuro endocrine carcinoma of the uterine corpus

    Directory of Open Access Journals (Sweden)

    Shohreh Shahabi


    Full Text Available Primary neuroendocrine tumors of the female genital tract have been described in the cervix, ovaries and uterus. Large cell neuroendocrine carcinoma (LCNC of the uterine corpus is the least common and appears to behave the most aggressively. We report a rare case of a large cell neuroendocrine tumor of the endometrium. These tumors are not well characterized, unlike neuroendocrine tumors of the uterine cervix, consequently, the optimal management remains still unclear. The treatment of our case consisted of surgery, radiotherapy, chemotherapy, and octreotide. Despite the aggressive treatment, the patient died of disease progression 12 months after the initial diagnosis. We discuss the diagnosis, prognosis, and treatment options for LCNC of the genital tract, and potential future therapeutics.

  8. Prenatal caffeine ingestion induces transgenerational neuroendocrine metabolic programming alteration in second generation rats

    Energy Technology Data Exchange (ETDEWEB)

    Luo, Hanwen [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Deng, Zixin; Liu, Lian; Shen, Lang; Kou, Hao; He, Zheng [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Ping, Jie; Xu, Dan [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China); Ma, Lu [Department of Epidemiology and Health Statistics, Public Health School of Wuhan University, Wuhan 430071 (China); Chen, Liaobin, E-mail: [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Wang, Hui, E-mail: [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China)


    Our previous studies have demonstrated that prenatal caffeine ingestion induces an increased susceptibility to metabolic syndrome with alterations of glucose and lipid metabolic phenotypes in adult first generation (F1) of intrauterine growth retardation (IUGR) rats, and the underlying mechanism is originated from a hypothalamic–pituitary–adrenal (HPA) axis-associated neuroendocrine metabolic programming alteration in utero. This study aims to investigate the transgenerational effects of this programming alteration in adult second generation (F2). Pregnant Wistar rats were administered with caffeine (120 mg/kg·d) from gestational day 11 until delivery. Four groups in F2 were set according to the cross-mating between control and caffeine-induced IUGR rats. F2 were subjected to a fortnight ice water swimming stimulus on postnatal month 4, and blood samples were collected before and after stress. Results showed that the majority of the activities of HPA axis and phenotypes of glucose and lipid metabolism were altered in F2. Particularly, comparing with the control group, caffeine groups had an enhanced corticosterone levels after chronic stress. Compared with before stress, the serum glucose levels were increased in some groups whereas the triglyceride levels were decreased. Furthermore, total cholesterol gain rates were enhanced but the high-density lipoprotein-cholesterol gain rates were decreased in most caffeine groups after stress. These transgenerational effects were characterized partially with gender and parental differences. Taken together, these results indicate that the reproductive and developmental toxicities and the neuroendocrine metabolic programming mechanism by prenatal caffeine ingestion have transgenerational effects in rats, which may help to explain the susceptibility to metabolic syndrome and associated diseases in F2. - Highlights: • Caffeine-induced neuroendocrine metabolic programming of HPA has hereditary effect. • Caffeine

  9. Child Maltreatment and Gender Interactions as Predictors of Differential Neuroendocrine Profiles (United States)

    Doom, Jenalee R.; Cicchetti, Dante; Rogosch, Fred A.; Dackis, Melissa N.


    Summary Child maltreatment is a potent stressor associated with neuroendocrine dysregulation and increased risk for mental and physical disorders throughout the lifespan. Gender differences in stress reactivity and adult psychopathology prevalence may be related to sex-specific responsivity to stress. The purpose of this study is to examine whether gender interacts with the stress of maltreatment to produce differential neuroendocrine profiles in children. Participants included 137 maltreated and 110 nonmaltreated low-income, racially and ethnically diverse children (range: 7.9–10.9 years; M= 9.42 years; 52% male) who attended a summer research day camp. Saliva was collected 3 times across the day for 5 days for cortisol and dehydroepiandosterone (DHEA) analysis. Department of Human Services records were examined to determine the type, severity, chronicity, onset, and recency of maltreatment for children in the maltreated group. Significant interactions between gender and maltreatment pervasiveness predicted diurnal cortisol, DHEA, and cortisol/DHEA ratio levels. Elevated daily cortisol levels were reported for boys compared to girls in the group with more pervasive maltreatment. Boys with less pervasive maltreatment had lower DHEA and higher cortisol/DHEA ratio levels than girls with similar experiences, nonmaltreated boys, and boys with more pervasive maltreatment. Further results are consistent with down-regulation of cortisol production in girls with more pervasive maltreatment and girls who experienced maltreatment that was early onset and not recent. The effectiveness of interventions for maltreated children may be improved with greater knowledge of how maltreatment differentially affects neuroendocrine regulation by gender. PMID:23333253

  10. Neuroendocrine disruption of organizational and activational hormone programming in poikilothermic vertebrates. (United States)

    Rosenfeld, Cheryl S; Denslow, Nancy D; Orlando, Edward F; Gutierrez-Villagomez, Juan Manuel; Trudeau, Vance L


    In vertebrates, sexual differentiation of the reproductive system and brain is tightly orchestrated by organizational and activational effects of endogenous hormones. In mammals and birds, the organizational period is typified by a surge of sex hormones during differentiation of specific neural circuits; whereas activational effects are dependent upon later increases in these same hormones at sexual maturation. Depending on the reproductive organ or brain region, initial programming events may be modulated by androgens or require conversion of androgens to estrogens. The prevailing notion based upon findings in mammalian models is that male brain is sculpted to undergo masculinization and defeminization. In absence of these responses, the female brain develops. While timing of organizational and activational events vary across taxa, there are shared features. Further, exposure of different animal models to environmental chemicals such as xenoestrogens such as bisphenol A-BPA and ethinylestradiol-EE2, gestagens, and thyroid hormone disruptors, broadly classified as neuroendocrine disrupting chemicals (NED), during these critical periods may result in similar alterations in brain structure, function, and consequently, behaviors. Organizational effects of neuroendocrine systems in mammals and birds appear to be permanent, whereas teleost fish neuroendocrine systems exhibit plasticity. While there are fewer NED studies in amphibians and reptiles, data suggest that NED disrupt normal organizational-activational effects of endogenous hormones, although it remains to be determined if these disturbances are reversible. The aim of this review is to examine how various environmental chemicals may interrupt normal organizational and activational events in poikilothermic vertebrates. By altering such processes, these chemicals may affect reproductive health of an animal and result in compromised populations and ecosystem-level effects.

  11. Neuroendocrine and behavioral response to social confrontation: residents versus intruders, active versus passive coping styles. (United States)

    Ebner, Karl; Wotjak, Carsten T; Landgraf, Rainer; Engelmann, Mario


    We investigated in the present study the neuroendocrine correlates in intruder and resident rats of a social confrontation. Adult male Wistar rats (intruders) were introduced into the home cage of a well-trained resident to induce characteristic agonistic interactions including physical attacks prior to separation by a wire mesh. The hypothalamic-pituitary-adrenal (HPA) axis activity and the intrahypothalamic release of arginine vasopressin (AVP) were monitored via chronically implanted jugular venous catheters and microdialysis probes aimed at the hypothalamic paraventricular nucleus (PVN), respectively. Based on the behavioral data collected during the 30-min confrontation, intruders and residents were additionally classified into two different subgroups: intruders which showed almost no freezing behavior (active copers) versus those showing pronounced freezing behavior (passive copers) and residents which were either predominantly aggressive or non-aggressive. The neuroendocrine data show that social confrontation caused a significantly increased secretion of the adrenocorticotropic hormone (ACTH) into plasma in both intruder subgroups, independently of their coping strategy. In contrast, plasma ACTH in residents was increased in response to social confrontation in non-aggressive animals only, whereas aggressive residents failed to mount an ACTH response. Interestingly, plasma AVP decreased in response to social confrontation in active intruders. As measured in microdialysates, the two groups of residents and passive intruders failed to show significant changes of intra-PVN release of AVP. In contrast, an increased release of this neuropeptide within the PVN could be monitored for active intruders. The data of the present study suggest that the different interpretation of an aversive encounter results in differences in the neuroendocrine response and intrahypothalamic vasopressinergic signaling in intruders versus residents.

  12. The regulation of reproductive neuroendocrine function by insulin and insulin-like growth factor-1 (IGF-1) (United States)

    Wolfe, Andrew; Divall, Sara; Wu, Sheng


    The mammalian reproductive hormone axis regulates gonadal steroid hormone levels and gonadal function essential for reproduction. The neuroendocrine control of the axis integrates signals from a wide array of inputs. The regulatory pathways important for mediating these inputs have been the subject of numerous studies. One class of proteins that have been shown to mediate metabolic and growth signals to the CNS includes Insulin and IGF-1. These proteins are structurally related and can exert endocrine and growth factor like action via related receptor tyrosine kinases. The role that insulin and IGF-1 play in controlling the hypothalamus and pituitary and their role in regulating puberty and nutritional control of reproduction has been studied extensively. This review summarizes the in vitro and in vivo models that have been used to study these neuroendocrine structures and the influence of these growth factors on neuroendocrine control of reproduction. PMID:24929098

  13. A tachykinin-like neuroendocrine signalling axis couples central serotonin action and nutrient sensing with peripheral lipid metabolism (United States)

    Palamiuc, Lavinia; Noble, Tallie; Witham, Emily; Ratanpal, Harkaranveer; Vaughan, Megan; Srinivasan, Supriya


    Serotonin, a central neuromodulator with ancient ties to feeding and metabolism, is a major driver of body fat loss. However, mechanisms by which central serotonin action leads to fat loss remain unknown. Here, we report that the FLP-7 neuropeptide and its cognate receptor, NPR-22, function as the ligand-receptor pair that defines the neuroendocrine axis of serotonergic body fat loss in Caenorhabditis elegans. FLP-7 is secreted as a neuroendocrine peptide in proportion to fluctuations in neural serotonin circuit functions, and its release is regulated from secretory neurons via the nutrient sensor AMPK. FLP-7 acts via the NPR-22/Tachykinin2 receptor in the intestine and drives fat loss via the adipocyte triglyceride lipase ATGL-1. Importantly, this ligand-receptor pair does not alter other serotonin-dependent behaviours including food intake. For global modulators such as serotonin, the use of distinct neuroendocrine peptides for each output may be one means to achieve phenotypic selectivity. PMID:28128367

  14. Cutaneous Neuroendocrine Carcinoma of the External Auditory Canal: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Yi-Ke Li


    Full Text Available Cutaneous neuroendocrine carcinoma (cNEC is rarely seen in the external ear. In this paper, we newly describe a patient with cNEC in his right external auditory canal, followed by a further discussion on the clinical features, diagnosis, and treatments of cNEC of the external ear. A review of the literature showed that cNEC of the external auditory canal generally presents as asymptomatic and that pathology yields the most confirmative diagnosis. A wide resection with adjuvant radiotherapy and chemotherapy is recommended. The overall prognosis of this condition is poor.

  15. [The relationship between neuroendocrine dysfunction and free-radical oxidation in old age alcoholism]. (United States)

    Vinogradov, D B; Mingazov, A Kh; Izarovskaya, I V; Babin, K A; Sinitsky, A I


    to study the relationship between dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and free-radical oxidation in old age alcoholism. Authors examined 46 men and women, aged 60-80 years, with alcoholism. Contents of cortisol, lipid peroxidation products and the level of an oxidatively modified protein were measured. A decrease in blood cortisol content and correlations between its level and activity of free-radical oxidation were identified. The severity of neuroendocrine dysfunction in old patients was sex-related. It has been suggested that the impairment of HPA system activity may be a cause of oxidative stress and development of alcoholism.

  16. The uncovering and characterization of a CCKoma syndrome in enteropancreatic neuroendocrine tumor patients

    DEFF Research Database (Denmark)

    Rehfeld, Jens F; Federspiel, Birgitte; Agersnap, Mikkel


    OBJECTIVE: Neuroendocrine tumors in the pancreas and the gastrointestinal tract may secrete hormones which cause specific syndromes. Well-known examples are gastrinomas, glucagonomas, and insulinomas. Cholecystokinin-producing tumors (CCKomas) have been induced experimentally in rats, but a CCKoma...... attacks from a contracted gallbladder. The CCK concentrations in plasma were not affected by resection of the pancreatic tumor, but decreased to normal after hemihepatectomy with removal of the metastases. CONCLUSION: A CCKoma syndrome with severe hypersecretion of CCK exists in man. The duodenal ulcer...

  17. Neuroendocrine circuits governing energy balance and stress regulation: functional overlap and therapeutic implications. (United States)

    Ulrich-Lai, Yvonne M; Ryan, Karen K


    Significant comorbidities between obesity-related metabolic disease and stress-related psychological disorders suggest important functional interactions between energy balance and brain stress integration. Largely overlapping neural circuits control these systems, and this anatomical arrangement optimizes opportunities for mutual influence. Here we first review the current literature identifying effects of metabolic neuroendocrine signals on stress regulation, and vice versa. Next, the contributions of reward-driven food intake to these metabolic and stress interactions are discussed. Lastly, we consider the interrelationships between metabolism, stress, and reward in light of their important implications in the development of therapies for metabolism- or stress-related disease. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. End-Stage Renal Disease From Cast Nephropathy in a Teenager With Neuroendocrine Carcinoma. (United States)

    Butani, Lavjay; Ducore, Jonathan


    Cast nephropathy is the most common manifestation of renal injury in patients with multiple myeloma but is rarely reported in other conditions. We are reporting our experience in caring for a teenager with a metastatic neuroendocrine carcinoma who developed rapidly progressive kidney injury that advanced to end-stage renal disease. On renal biopsy extensive tubular necrosis and intratubular eosinophilic casts were noted. This previously unreported finding should prompt oncologists to closely monitor for such a complication in patients with secretory tumors. Whether early plasmapheresis could be of benefit, as has been tried in multiple myeloma, remains to be determined.

  19. Radioembolization for neuroendocrine liver metastases: safety, imaging, and long-term outcomes. (United States)

    Memon, Khairuddin; Lewandowski, Robert J; Mulcahy, Mary F; Riaz, Ahsun; Ryu, Robert K; Sato, Kent T; Gupta, Ramona; Nikolaidis, Paul; Miller, Frank H; Yaghmai, Vahid; Gates, Vanessa L; Atassi, Bassel; Newman, Steven; Omary, Reed A; Benson, Al B; Salem, Riad


    To present long-term outcomes on the safety and efficacy of Yttrium-90 radioembolization in the treatment of unresectable hepatic neuroendocrine metastases refractory to standard-of-care therapy. This study was approved by our institutional review board and was compliant with the Health Insurance Portability and Accountability Act. Forty patients with hepatic neuroendocrine metastases were treated with (90)Y radioembolization at a single center. Toxicity was assessed using National Cancer Institute Common Terminology Criteria v3.0. Response to therapy was assessed by World Health Organization (WHO) guidelines for size and European Association for the Study of the Liver disease (EASL) guidelines for necrosis. Time to response and overall survival were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed. The median dose was 113 Gy (29-299 Gy). Clinical toxicities included fatigue (63%), nausea/vomiting (40%), abdominal pain (18%), fever (8%), diarrhea and weight loss (5%); Grade 3 and 4 bilirubin toxicities were experienced by 2 patients and 1 patient, respectively. Different responses were noted by WHO (complete response, 1.2%; partial response, 62.7%) and EASL (complete response, 20.5%; partial response, 43.4%). Median time to response was 4 and 4.9 months by lesion and patient, respectively. The 1-, 2-, and 3-year overall survival rates were 72.5%, 62.5%, and 45%, respectively. Eastern Cooperative Oncology Group (ECOG) performance score 0 (p < 0.0001), tumor burden ≤25% (p = 0.0019), albumin ≥3.5 g/dL (p = 0.017), and bilirubin ≤1.2 mg/dL (p = 0.002) prognosticated survival on univariate analysis; only ECOG performance score 0 and bilirubin ≤1.2 mg/dL prognosticated better survival outcome on multivariate analysis (p = 0.0001 and p = 0.02). Yttrium-90 therapy for hepatic neuroendocrine metastases leads to satisfactory tumor response and patient survival with low toxicity, in line with published national guidelines

  20. Radioembolization for Neuroendocrine Liver Metastases: Safety, Imaging, and Long-Term Outcomes

    Energy Technology Data Exchange (ETDEWEB)

    Memon, Khairuddin; Lewandowski, Robert J. [Department of Radiology, Section of Interventional Radiology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL (United States); Mulcahy, Mary F. [Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL (United States); Riaz, Ahsun; Ryu, Robert K.; Sato, Kent T.; Gupta, Ramona; Nikolaidis, Paul; Miller, Frank H.; Yaghmai, Vahid; Gates, Vanessa L.; Atassi, Bassel [Department of Radiology, Section of Interventional Radiology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL (United States); Newman, Steven [Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL (United States); Omary, Reed A. [Department of Radiology, Section of Interventional Radiology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL (United States); Benson, Al B. [Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL (United States); Salem, Riad, E-mail: [Department of Radiology, Section of Interventional Radiology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL (United States); Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL (United States)


    Purpose: To present long-term outcomes on the safety and efficacy of Yttrium-90 radioembolization in the treatment of unresectable hepatic neuroendocrine metastases refractory to standard-of-care therapy. Methods and Materials: This study was approved by our institutional review board and was compliant with the Health Insurance Portability and Accountability Act. Forty patients with hepatic neuroendocrine metastases were treated with {sup 90}Y radioembolization at a single center. Toxicity was assessed using National Cancer Institute Common Terminology Criteria v3.0. Response to therapy was assessed by World Health Organization (WHO) guidelines for size and European Association for the Study of the Liver disease (EASL) guidelines for necrosis. Time to response and overall survival were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed. Results: The median dose was 113 Gy (29-299 Gy). Clinical toxicities included fatigue (63%), nausea/vomiting (40%), abdominal pain (18%), fever (8%), diarrhea and weight loss (5%); Grade 3 and 4 bilirubin toxicities were experienced by 2 patients and 1 patient, respectively. Different responses were noted by WHO (complete response, 1.2%; partial response, 62.7%) and EASL (complete response, 20.5%; partial response, 43.4%). Median time to response was 4 and 4.9 months by lesion and patient, respectively. The 1-, 2-, and 3-year overall survival rates were 72.5%, 62.5%, and 45%, respectively. Eastern Cooperative Oncology Group (ECOG) performance score 0 (p < 0.0001), tumor burden {<=}25% (p = 0.0019), albumin {>=}3.5 g/dL (p = 0.017), and bilirubin {<=}1.2 mg/dL (p = 0.002) prognosticated survival on univariate analysis; only ECOG performance score 0 and bilirubin {<=}1.2 mg/dL prognosticated better survival outcome on multivariate analysis (p = 0.0001 and p = 0.02). Conclusion: Yttrium-90 therapy for hepatic neuroendocrine metastases leads to satisfactory tumor response and patient survival