Sample records for chronomics neuroendocrine feedsidewards

  1. Chronomics and ``Glocal'' (Combined Globaland Local) Assessment of Human Life (United States)

    Otsuka, K.; Cornélissen, G.; Norboo, T.; Takasugi, E.; Halberg, F.

    Most organisms, from cyanobacteria to mammals, are known to use circadian mechanisms to coordinate their activities with the natural 24-hour light/dark cycle and/or interacting socio-ecologic schedules. When the human clock gene was discovered in 1997, it was surprising to see that it was very similar in all earthly life. Recent findings suggest that organisms which evolved on Earth acquired many of the visible and invisible cycles of their habitat and/or of their cosmos. While circadian systems are well documented both time-macroscopically and time-microscopically, the temporal organization of physiological function is much more extensive. Long-term physiological quasi-ambulatory monitoring of blood pressure and heart rate, among other variables, such as those of the ECG and other tools of the neuroendocrinologic armamentarium, have already yielded information, among others, on circaseptan (about 7-day), transyears and cisyears (with periods slightly longer or shorter tha n one year, respectively), and circadecennian (about 10-year) cycles; the nervous system displays rhythms, chaos and trends, mapped as chronomes. Chronomes are time structures consisting of multifrequency rhythms covering frequencies over 18 orders of magnitude, elements of chaos, trends in chaotic and rhythmic endpoints, and other, as-yet unresolved variability. These resolvable time structures, chronomes, in us have counterparts around us, also consisting of rhythms, trends and chaos, as is increasingly being recognized. In 2000, we began a community-based study, relying on 7-day/24-hour monitoring of blood pressure as a public service. Our goal was the prevention of stroke and myocardial infarction and of the decline in cognitive function of the elderly in a community. Chronomic detection of elevated illness-risks aim at the prevention of diseases of individuals, such as myocardial infarctions and strokes, and, equally important, chronomics resolves illness of societies, such as crime and war

  2. Computer analysis of environmental temperature, light and noise in intensive care: chaos or chronome nurseries? (United States)

    Ardura, J; Andrés, J; Aldana, J; Revilla, M A; Cornélissen, G; Halberg, F


    Lighting, noise and temperature were monitored in two perinatal nurseries. Rhythms of several frequencies were found, including prominent 24-hour rhythms with acrophases around 13:00 (light intensity) and 16:00 (noise). For light and noise, the ratio formed by dividing the amplitude of a 1-week (circaseptan) or half-week (circasemiseptan) fitted cosine curve by the amplitude of a 24-hour fitted cosine curve is smaller than unity, since 24-hour rhythms are prominent for these variables. The amplitude ratios are larger than unity for temperature in the newborns' unit but not in the infants' unit. Earlier, the origin of the about-7-day rhythms of neonatal physiologic variables was demonstrated to have, in addition to a major endogenous, also a minor exogenous component. Hence, the possibility of optimizing maturation by manipulating environmental changes can be considered, using, as gauges of development, previously mapped chronomes (time structures of biologic multifrequency rhythms, trends and noise).

  3. [Neuroendocrine immunomodulation]. (United States)

    Uchakin, P N; Uchakina, O N; Tobin, B V; Ershov, F I


    Close interaction between the immune and nervous systems is well documented. The ability of immunocompetent cells to express receptors to neuroendocrine mediators as well as secrete many of them is proved. The current literature suggests that the hormones of the hypothalamic-pituitary-adrenal and the hypothalamic-pituitary-gonodal axes play the most significant role in the regulation of immune responsiveness. On the other hand, the immune system communicates with the CNS directly through the cytokines that are able to cross the blood-brain barrier, or directly via the nervus vagus, as well as via secondary messengers. Receptors to a number of cytokines have been found in the nervous tissue. Moreover, glial cells are able to secrete cytokines in the amount significant enough for at least autocrine action. In this article, the authors review the role of the "major" stress hormones such as cortisol, DHEA, growth hormone in the regulation of immune response, as well as neuro- and psychotropic properties of two major groups of cytokines that support cell-mediated (Type 1) and humoral (Type 2) immune reactions. This review emphasizes neuro-endocrine-immune interactions in response to infection both under laboratory and clinical conditions.

  4. 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 how many people survive this type of ...

  5. 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...

  6. 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

  7. Neuroendocrine mechanisms in athletes. (United States)

    Misra, Madhusmita


    Athletic activity may be associated with alterations in various neuroendocrine axes depending on the state of energy availability. In addition, genetic factors and an underlying predilection for polycystic ovarian syndrome (PCOS) may predispose some athletes to develop functional hypothalamic amenorrhea earlier than other athletes. In conditions of low energy availability associated with athletic activity, changes that occur in various neuroendocrine axes are primarily adaptive, and aim to either conserve energy for the most essential functions, or allow the body to draw on its reserves to meet energy needs. These hormonal changes, however, then lead to changes in body composition and bone metabolism. Impaired bone accrual in younger athletes and low bone density in older athletes constitutes the major pathologic consequence of neuroendocrine changes associated with low energy availability. The female athlete triad of low energy availability, menstrual dysfunction, and low bone density is prevalent in certain kinds of sports and activities, particularly endurance sports, gymnastics, and ballet. It is essential to screen for this condition in athletes at every preparticipation physical and during office visits, and to put in place an effective treatment team to manage the triad early, in order to optimize outcomes.

  8. Current concepts in neuroendocrine disruption. (United States)

    León-Olea, Martha; Martyniuk, Christopher J; Orlando, Edward F; Ottinger, Mary Ann; Rosenfeld, Cheryl S; Wolstenholme, Jennifer T; Trudeau, Vance L


    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

  9. Neuroendocrine responses to hypoglycemia. (United States)

    Tesfaye, Nolawit; Seaquist, Elizabeth R


    The counterregulatory response to hypoglycemia is a complex and well-coordinated process. As blood glucose concentration declines, peripheral and central glucose sensors relay this information to central integrative centers to coordinate neuroendocrine, autonomic, and behavioral responses and avert the progression of hypoglycemia. Diabetes, both type 1 and type 2, can perturb these counterregulatory responses. Moreover, defective counterregulation in the setting of diabetes can progress to hypoglycemia unawareness. While the mechanisms that underlie the development of hypoglycemia unawareness are not completely known, possible causes include altered sensing of hypoglycemia by the brain and/or impaired coordination of responses to hypoglycemia. Further study is needed to better understand the intricacies of the counterregulatory response and the mechanisms contributing to the development of hypoglycemia unawareness.

  10. Biochemistry of neuroendocrine tumours. (United States)

    de Herder, Wouter W


    Several circulating or urinary tumour markers can be used for the diagnosis and follow-up of functioning and clinically non-functioning neuroendocrine tumours of the pancreatic islet cells and intestinal tract. Among the specific tumour markers are serotonin and its metabolites--e.g. 5-hydroxyindoleacetic acid (5-HIAA)--in carcinoid tumours and the carcinoid syndrome, insulin and its precursors or breakdown products in insulinoma, and gastrin in gastrinoma. Plasma vasointestinal polypeptide (VIP) determinations have been used in the diagnosis of VIPoma, plasma glucagon for glucagonoma, and serum somatostatin for somatostatinoma. Among the tumour-non-specific markers are: chromogranins, neuron-specific enolase (NSE), alpha-subunits of the glycoprotein hormones, catecholamines, pancreatic polypeptide (PP), ghrelin and adrenomedullin.

  11. Neuroendocrine targets of endocrine disruptors. (United States)

    Gore, Andrea C


    The central neuroendocrine systems are responsible for the control of homeostatic processes in the body, including reproduction, growth, metabolism and energy balance, as well as stress responsiveness. These processes are initiated by signals in the central nervous system, specifically the hypothalamus, and are conveyed first by neural and then by endocrine effectors. The neuroendocrine systems, as the links between the brain and peripheral endocrine organs, play critical roles in the ability of an organism to respond to its environment under normal circumstances. When neuroendocrine homeostasis is disrupted by environmental endocrine-disrupting chemicals, a variety of perturbations can ensue, particularly when endocrine disruption occurs during critical developmental time periods. This article will discuss the evidence for environmental endocrine disruption of neuroendocrine systems and the effects on endocrine and reproductive functions.

  12. Neuroendocrine Immunoregulation in Multiple Sclerosis

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    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.

  13. Notch Signaling in Neuroendocrine Tumors

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    Judy Sue Crabtree


    Full Text Available Carcinoids and neuroendocrine tumors (NETs are a heterogeneous group of tumors that arise from the neuroendocrine cells of the GI tract, endocrine pancreas and the respiratory system. NETs remain significantly understudied with respect to molecular mechanisms of pathogenesis, particularly the role of cell fate signaling systems like Notch. The abundance of literature on the Notch pathway is a testament to its complexity in different cellular environments. Notch receptors can function as oncogenes in some contexts, and tumor suppressors in others. The genetic heterogeneity of NETs suggests that to fully understand the roles and the potential therapeutic implications of Notch signaling in NETs, a comprehensive analysis of Notch expression patterns and potential roles across all NET subtypes is required.

  14. Neuroendocrine abnormalities in Parkinson's disease. (United States)

    De Pablo-Fernández, Eduardo; Breen, David P; Bouloux, Pierre M; Barker, Roger A; Foltynie, Thomas; Warner, Thomas T


    Neuroendocrine abnormalities are common in Parkinson's disease (PD) and include disruption of melatonin secretion, disturbances of glucose, insulin resistance and bone metabolism, and body weight changes. They have been associated with multiple non-motor symptoms in PD and have important clinical consequences, including therapeutics. Some of the underlying mechanisms have been implicated in the pathogenesis of PD and represent promising targets for the development of disease biomarkers and neuroprotective therapies. In this systems-based review, we describe clinically relevant neuroendocrine abnormalities in Parkinson's disease to highlight their role in overall phenotype. We discuss pathophysiological mechanisms, clinical implications, and pharmacological and non-pharmacological interventions based on the current evidence. We also review recent advances in the field, focusing on the potential targets for development of neuroprotective drugs in Parkinson's disease and suggest future areas for research.

  15. 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.

  16. [Neuroendocrine neoplasms of the mediastinum]. (United States)

    Brcic, L; Heidinger, M; Popper, H


    Primary neuroendocrine tumors (NET) in the mediastinum are very rare and among them thymic NETs are the most common. They represent 5 % of all thymic and mediastinal tumors. The WHO classification from 2015 subdivides thymic NETs into three groups; low grade (typical carcinoid), intermediate grade (atypical carcinoid) and high grade (large cell neuroendocrine carcinoma and small cell carcinoma). Through this change of mediastinal/thymic NET classification into three groups of malignancy, the nomenclature was adapted to that of the lungs, while the histological criteria for each entity remained the same. Thymic NETs typically occur in middle-aged adults and predominantly in males. Approximately 30 % are asymptomatic and the rest present with symptoms caused by local tumor growth, distant metastases and/or endocrine manifestations. Carcinoids can also occur as a part of multiple endocrine neoplasia type 1 (MEN1) and at the time of diagnosis commonly present with regional lymph node or distant metastases, which most often affect the lungs and bones. For the correct diagnosis tumor cell morphology, mitotic count and/or necrosis are crucial. Patients with typical carcinoids have the best prognosis, whereas the prognosis is slightly worse for atypical carcinoids but very poor for large cell neuroendocrine carcinomas. Small cell carcinomas have the worst prognosis and the shortest median survival time of approximately 14 months.

  17. Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia and Neuroendocrine Hyperplasia of Infancy. (United States)

    Carr, Laurie L; Kern, Jeffrey A; Deutsch, Gail H


    Although incidental reactive pulmonary neuroendocrine cell hyperplasia (PNECH) is seen on biopsy specimens in adults with chronic lung disease, disorders characterized by marked PNECH are rare. Primary hyperplasia of neuroendocrine cells in the lung and obstructive lung disease related to remodeling or physiologic constriction of small airways define diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) in the adult and neuroendocrine cell hyperplasia of infancy (NEHI) in children. DIPENCH and NEHI share a similar physiology, typical imaging appearance, and increased neuroendocrine cells on biopsy. However, there are important differences related to the underlying disease mechanisms leading to disparate outcomes.

  18. Neuroendocrine Carcinomas of the Gastroenteropancreatic System

    DEFF Research Database (Denmark)

    Ilett, Emma Elizabeth; Langer, Seppo W; Olsen, Ingrid Holst;


    To date, empirical literature has generally been considered lacking in relation to neuroendocrine carcinomas (NECs), the highly malignant subgroup of neuroendocrine neoplasms. NECs are often found in the lungs or the gastroenteropancreatic (GEP) system and can be of small or large cell type...

  19. 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....

  20. Biomarkers in Pancreatic Neuroendocrine Tumors

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    Maria Serafeim Theochari


    Full Text Available The aim of biomarkers is to identify patients most likely to benefit from a therapeutic strategy. Pancreatic neuroendocrinetumors are rare neoplasms that arise in the endocrine tissues of the pancreas. Pancreatic neuroendocrine tumors represent3% of primary pancreatic neoplasms and their incidence has risen. The SMAD4 gene is located on chromosome 18q andsomeday the SMAD4 gene status may be useful for prognostic stratification and therapeutic decision. The cells respond toenvironmental signals by modulating the expressions of genes contained within the nucleus, when genes are activated aretranscribed to generate messenger RNA (mRNA. The examination of multiple expressed genes and proteins provides moreuseful information for prognostication of individual tumors. Here we summarize and discuss findings presented at the 2014ASCO Gastrointestinal Cancers Symposium. Anna Karpathakis et al. (Abstract #212 reported data about the role of DNAmethylation in gastrointestinal neuroendocrine tumors. Christina Lynn Roland et al. (Abstract #250 looked the impact OfSMAD4 on oncologic outcomes. Bong Kynn Kang et al. (Abstract #251 investigated prognostic biomarker using microRNAarray technology.

  1. Consensus on biomarkers for neuroendocrine tumour disease (United States)

    Oberg, Kjell; Modlin, Irvin M; De Herder, Wouter; Pavel, Marianne; Klimstra, David; Frilling, Andrea; Metz, David C; Heaney, Anthony; Kwekkeboom, Dik; Strosberg, Jonathan; Meyer, Timothy; Moss, Steven F; Washington, Kay; Wolin, Edward; Liu, Eric; Goldenring, James


    Management of neuroendocrine neoplasia represents a clinical challenge because of its late presentation, lack of treatment options, and limitations in present imaging modalities and biomarkers to guide management. Monoanalyte biomarkers have poor sensitivity, specificity, and predictive ability. A National Cancer Institute summit, held in 2007, on neuroendocrine tumours noted biomarker limitations to be a crucial unmet need in the management of neuroendocrine tumours. A multinational consensus meeting of multidisciplinary experts in neuroendocrine tumours assessed the use of current biomarkers and defined the perquisites for novel biomarkers via the Delphi method. Consensus (at >75%) was achieved for 88 (82%) of 107 assessment questions. The panel concluded that circulating multianalyte biomarkers provide the highest sensitivity and specificity necessary for minimum disease detection and that this type of biomarker had sufficient information to predict treatment effectiveness and prognosis. The panel also concluded that no monoanalyte biomarker of neuroendocrine tumours has yet fulfilled these criteria and there is insufficient information to support the clinical use of miRNA or circulating tumour cells as useful prognostic markers for this disease. The panel considered that trials measuring multianalytes (eg, neuroendocrine gene transcripts) should also identify how such information can optimise the management of patients with neuroendocrine tumours. PMID:26370353

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

    DEFF Research Database (Denmark)

    Christensen, Lene; 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....

  3. 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...... Syndrome that were diagnosed with pulmonary carcinoids....

  4. Neuroendocrine hormone amylin in diabetes

    Institute of Scientific and Technical Information of China (English)

    Xiao-Xi; Zhang; Yan-Hong; Pan; Yan-Mei; Huang; Hai-Lu; Zhao


    The neuroendocrine hormone amylin, also known as islet amyloid polypeptide, is co-localized, co-packaged and cosecreted with insulin from adult pancreatic islet β cells to maintain glucose homeostasis. Specifically, amylin reduces secretion of nutrient-stimulated glucagon, regulates blood pressure with an effect on renin-angiotensin system, and delays gastric emptying. The physiological actions of human amylin attribute to the conformational α-helix monomers whereas the misfolding instable oligomers may be detrimental to the islet β cells and further transform to β-sheet fibrils as amyloid deposits. No direct evidence proves that the amylin fibrils in amyloid deposits cause diabetes. Here we also have performed a systematic review of human amylin gene changes and reported the S20 G mutation is minor in the development of diabetes. In addition to the metabolic effects, human amylin may modulate autoimmunity and innate inflammation through regulatory T cells to impact on both human type 1 and type 2 diabetes.

  5. Gastric Large Cell Neuroendocrine Carcinoma (United States)

    Rustagi, Tarun; Alekshun, Todd J.


    Case: A 63-year-old male presented with unintentional weight loss of 20 pounds over a 4-month duration. He reported loss of appetite, intermittent post-prandial nausea, bloating and early satiety. He also complained of dyspepsia and had been treated for reflux during the previous 2 years. He denied vomiting, dysphagia, odynophagia, abdominal pain, melena, hematochezia, or alterations in bowel habits. Additionally, he denied fevers, night sweats, cough, or dyspnea. He quit smoking 25 years ago, and denied alcohol use. His past medical history was significant for basal cell carcinoma treated with local curative therapy and he was without recurrence on surveillance. Pertinent family history included a paternal uncle with lung cancer at the age of 74. Physical examination was unremarkable except for occult heme-positive stools. Laboratory evaluation revealed elevated liver enzymes (ALT-112, AST-81, AlkPhos-364). CT scan of the chest, abdomen and pelvis showed diffuse heterogeneous liver with extensive nodularity, raising the concern for metastases. Serum tumor-markers: PSA, CEA, CA 19-9, and AFP were all within normal limits. Screening colonoscopy was normal, but esophagogastroduodenoscopy revealed a malignant-appearing ulcerative lesion involving the gastro-esophageal junction and gastric cardia. Pathology confirmed an invasive gastric large cell neuroendocrine carcinoma. Ultrasound-guided fine needle aspiration of a hepatic lesion revealed malignant cells with cytologic features consistent with large-cell type carcinoma and positive immunostaining for synaptophysin favoring neuroendocrine differentiation. A PET-CT demonstrated intense diffuse FDG uptake of the liver, suggesting diffuse hepatic parenchymal infiltration by tumor. There were multiple foci of intense osseous FDG uptake with corresponding osteolytic lesions seen on CT scan. The remaining intra-abdominal and intra-thoracic structures were unremarkable. The patient will receive palliative systemic therapy

  6. Diagnosis and treatment of bronchopulmonary neuroendocrine tumours

    DEFF Research Database (Denmark)

    Tabaksblat, Elizaveta Mitkina; Langer, Seppo W; Knigge, Ulrich;


    Bronchopulmonary neuroendocrine tumours (BP-NET) are a heterogeneous population of neoplasms with different pathology, clinical behaviour and prognosis compared to the more common lung cancers. The management of BP-NET patients is largely based on studies with a low level of evidence and extrapol...... and extrapolation of data obtained from more common types of neuroendocrine tumours. This review reflects our view of the current state of the art of diagnosis and treatment of patients with BP-NET....

  7. Pathologic research update of colorectal neuroendocrine tumors

    Institute of Scientific and Technical Information of China (English)


    Colorectal neuroendocrine tumors (NETs) originate from neuroendocrine cells in the intestinal tract, and represent a small area within oncology, but one which has provided increasing new data during the past years. Although the World Health Organization has determined clinical and histological features to predict prognosis for such tumors, they may not be valid on an individual basis. We aim to give an overview of the recent findings with regard to pathology, molecular genetics and diagnosis of NETs.


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    Full Text Available INTRODUCTION: Traumatic brain injury (TBI is one of the main causes of death and disability in young adults, with consequences ranging from physical disabilities to long - term cognitive, behavioural, psychological and social defects. Recently, c linical evidence has demonstrated that TBI may frequently cause hypothalamic – pituitary dysfunction, probably contributing to a delayed or hampered recovery from TBI. CASE REPORT: 32 year s old female presented with a history of fall from two wheeler on back hitting the head on occipital region with no history of vomiting, loss of consciousness, ENT bleed. Her GCS was 15/15. Patient was asymptomatic and was discharged from hospital on fifth day. Seven days after discharge patient again presented with heavine ss in her both breasts associated with pain and whitish discharge from both the nipples and mild fever since last two days. CONCLUSION: TBI is a public health problem that requires more effective strategies to improve the outcome and minimize disability of the affected patients. Changes in pituitary hormone secretion may be observed during the acute phase post - TBI, representing part of the acute adaptive response to the injury. Neuroendocrine disturbances, caused by damage to the pituitary and/or hypothalam us, is a frequent complication of TBI and may occur at any time after the acute event. Pituitary dysfunction presents more frequently as an isolated, and more rarely as a complete, deficiency.

  9. Acute Pancreatitis Secondary to Pancreatic Neuroendocrine Tumours

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    Grinó P


    Full Text Available CONTEXT: Pancreatic neoplasms are an uncommon aetiology of acute pancreatitis. Pancreatic neuroendocrine tumours are a rare subgroup of pancreatic neoplasms. CASE REPORT: We report on three patients having acute pancreatitis secondary to pancreatic neuroendocrine tumours, one of them with severe pancreatitis, and review the published cases up to now. Only 22 patients with acute pancreatitis secondary to pancreatic neuroendocrine tumours have been reported (including the present cases. Most of these cases were of non-functioning neoplasms and the course of the pancreatitis tended to be mild. In the most recent reports and in the present cases, the initial diagnostic method was CT scan. Less than half had metastases when the tumour was diagnosed and mortality from these neoplasms reached approximately 50%. CONCLUSIONS: Pancreatic neuroendocrine tumours can cause acute pancreatitis even in patients under 50 years of age. On many occasions, the tumours are non-functioning; therefore, acute pancreatitis may be the first clinical symptom. Consequently, faced with acute pancreatitis of unknown origin, a non-functioning neuroendocrine tumour should be ruled out.

  10. Neuroendocrine aspects of Tourette syndrome. (United States)

    Martino, Davide; Macerollo, Antonella; Leckman, James F


    There is sparse evidence suggesting the participation of neuroendocrine mechanisms, mainly involving sex and stress steroid hormones, to the pathophysiology of neurodevelopmental disorders such as Tourette syndrome (TS) and obsessive-compulsive disorder (OCD). Patients with TS exhibit a sex-specific variability in gender distribution (male/female ratio=3-4/1) and in its natural history, with a severity peak in the period around puberty. The administration of exogenous androgens may worsen tics in males with TS, whereas drugs counteracting the action of testosterone might show some antitic efficacy. This suggests a higher susceptibility of patients with TS to androgen steroids. There are insufficient data on the regulation of the hypothalamic-pituitary-gonadal (HPG) axis in TS. However, preliminary evidence suggests that a subgroup of women with TS might be more sensitive to the premenstrual trough of estrogen levels. Patients with TS exhibit differences in a number of behavioral, cognitive, and anatomical traits that appear to be sex related. There is a body of evidence supporting, albeit indirectly, the hypothesis of an increased exposure to androgenic steroids during the very early phases of neural development. Animal models in rodents suggest a complex role of gonadal hormones upon the modulation of anxiety-related and stereotyped behaviors during adult life. Patients with TS exhibit an enhanced reactivity of the hypothalamic-pituitary-adrenal axis to external stressors, despite a preserved diurnal cortisol rhythm and a normal restoration of the baseline activity of the axis following the acute stress response. Preliminary evidence suggests the possible implication of oxytocin (OT) in disorders related to the TS spectrum, especially non-tic-related OCD. The injection of OT in the amygdala of rodents was shown to be able to induce hypergrooming, suggesting the possible involvement of this neuropeptide in the pathophysiology of complex, stereotyped behaviors. In

  11. Large Cell Neuroendocrine Carcinoma of the Lung

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    Yusuf Aydemir


    Full Text Available Large-cell neuroendocrine carcinomas of the lung are extremely rare. There are difficulties related to the diagnosis and treatment and there are no consensus because of the small number of studies. 65-year-old male patient presented with hemoptysis. Chest X-ray and thoracic computorized tomography scan showed a mass lesion and it could not be diagnosed by bronchoscopic biopsy and lavage. Lobectomy was performed due to the high value of standardized uptake value in positron emission tomography. Large cell neuroendocrine carcinoma was diagnosed with pathological evaluation and immunohistochemical study and after 20-month follow-up there was no recurrence. The diagnosis, treatment, and prognosis of large cell neuroendocrine carcinoma in the light of the literature is presented.

  12. [Pulmonary neuroendocrine tumors and preneoplasic lesions]. (United States)

    Rouquette Lassalle, Isabelle


    In the recently published 2015 World Health Organization (WHO) classification of tumors of the lungs, all neuroendocrine tumors of the lungs are presented for the first time in one single chapter. In this classification, high-grade small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are differentiated from intermediate grade atypical carcinoids (AC) and low-grade typical carcinoids as well as from preinvasive lesion diffuse neuroendocrine hyperplasia DIPNECH. In the 2004 WHO classification, SCLC and carcinoids each had a separate chapter and LCNEC was listed in the chapter on large cell carcinoma of the lungs. The new WHO classification also gives some recommendations for the diagnosis on small biopsies. This review describes morphological, immunohistochemical, and genomic characteristic of these tumors according to the new classification.

  13. Concepts of neuroendocrine cardiology and neuroendocrine immunology, chemistry and biology of signal molecules. (United States)

    Galoyan, Armen


    Discovery of neurosecretion of cardioactive neurohormones produced by hypothalamic nuclei (NSO and NPV), as well as the biosynthesis of several immunomodulators (signal molecules of the neuroendocrine immune system of brain), deciphering of their chemical structure and study of their biological properties led to the foundation of two important trends of neurobiology: neuroendocrine immunology and cardiology. Hormone formation by atrium ganglionary nerve cells and auriculum establishment of neurohumoral interactions between hypothalamic and atrium neurosecretion indicated the existence of the system neuroendocrine hypothalamus--endocrine heart. Study of their biological properties promoted creation of powerful neurohormonal preparations for the treatment of immune, cardio-vascular, neurodegenerative, infectious and tumor diseases. Concepts suggested by us on neuroendocrine cardiology and immunology, create large perspectives for development of the theory and its implementation in medicine.

  14. Peptide receptor therapies in neuroendocrine tumors

    NARCIS (Netherlands)

    Bodei, L.; Ferone, D.; Grana, C. M.; Cremonesi, M.; Signore, A.; Dierckx, R. A.; Paganelli, G.


    Neuroendocrine tumors (NETs) are relatively rare tumors, mainly originating from the digestive system, able to produce bioactive amines and hormones. NETs tend to be slow growing and are often diagnosed when metastatic. The localization of a NETs and the assessment of the extent of disease are cruci

  15. 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.

  16. 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.

  17. Neuroendocrine Disorders in Pediatric Craniopharyngioma Patients

    Directory of Open Access Journals (Sweden)

    Anna M. M. Daubenbüchel


    Full Text Available Childhood-onset craniopharyngiomas are partly cystic embryonic malformations of the sellar/parasellar region. The therapy of choice in patients with favorable tumor localization is complete resection with a specific focus on maintaining optical and hypothalamic neuroendocrine functions. In patients with unfavorable tumor localization (i.e., hypothalamic involvement, a limited hypothalamus-sparing surgical strategy followed by local irradiation is recommended. Involvement and/or surgical lesions of posterior hypothalamic areas cause major neuroendocrine sequelae. The overall survival rates are high (92% but neuroendocrine disorders such as obesity and metabolic syndrome due to involvement and/or treatment-related hypothalamic lesions have major negative impact on survival and quality of life. Recurrences and progressions are frequent post-surgical events. Because irradiation is efficient in preventing tumor progression, appropriate timing of post-surgical irradiation is currently under investigation in a randomized multinational trial (KRANIOPHARYNGEOM 2007. Childhood-onset craniopharyngioma should be recognized as a chronic disease requiring treatment and constant monitoring of the clinical and quality of life consequences, frequently impaired due to neuroendocrine disorders, by experienced multidisciplinary teams in order to provide optimal care of surviving patients.

  18. Clinical experience in appendiceal neuroendocrine neoplasms (United States)

    Ozcelik, Caglar K.; Bozdogan, Nazan; Dibekoglu, Cengiz


    Aim of the study To analyse the incidence of appendiceal neuroendocrine neoplasms in appendectomy specimens and establish the epidemiological and histopathological features, treatment, and clinical course. Material and methods Between 2004 and 2013, 975 patients who underwent appendectomy in Ankara Oncology Education and Research Hospital were retrospectively analysed. Results Neuroendocrine neoplasm was detected in the nine of 975 (0.9%) patients. Neuroendocrine neoplasms were diagnosed in eight patients by appendectomy, which was performed because of the prediagnosis of acute appendicitis, and in one patient by the suspicious mass detection during surgical procedures that were done in the appendix for a different reason. Eight of the patients’ tumours were in the tip of the appendix, and one of the patients’ tumours was at the base of appendix. Tumour size in 77.8% of patients was equal or less than 1 cm, in 22.2% patients it was 1–2 cm. There was tumour invasion in the muscularis propria layer in four patients, in the serosa layer in three patients, and in the deep mesoappendix in two patients. Patients were followed for a median of 78 months. In the follow-up of patients who were operated because of colon cancer, metachronous colon tumour evolved. This patient died due to progressive disease. Other patients are still disease-free. Conclusions The diagnosis of neuroendocrine neoplasm is often incidentally done after appendectomy. Tumour size is important in determining the extent of disease and in the selection of the surgical method during operation. PMID:26793027

  19. Skin manifestations of endocrine and neuroendocrine tumors. (United States)

    Leventhal, Jonathan S; Braverman, Irwin M


    The skin signs of benign and malignant endocrine and neuroendocrine tumors are manifold and early identification of these dermatologic features is crucial in initiating timely diagnosis and management. This article reviews the salient cutaneous features of these tumors that arise in the classic endocrine glands, lung and gastrointestinal tract either as individual neoplasms or as part of a syndrome.

  20. Programming of neuroendocrine self in the thymus and its defect in the development of neuroendocrine autoimmunity

    Directory of Open Access Journals (Sweden)

    Vincent eGeenen


    Full Text Available 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

  1. 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

  2. [Contemporary nuclear medicine diagnostics of neuroendocrine tumors]. (United States)


    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 (131/123I-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 spe- cificity (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

  3. Mixed Acinar-Neuroendocrine Carcinoma of the Pancreas with Neuroendocrine Predominance

    Directory of Open Access Journals (Sweden)

    Onyekachi Henry Ogbonna


    Full Text Available Background. Pancreatic tumors are rare and could arise from either the exocrine (ductal and acinar cells or the endocrine (neuroendocrine cells components of the pancreas. In some instances, the occurrence of pancreatic tumors comprising both acinar cells and neuroendocrine cells, with neuroendocrine cells making up more than 30% of the tumor, has been identified. This unique entity has been referred to as mixed acinar-neuroendocrine carcinoma (MANEC. Only about 20 such cases have been reported in the literature. Case Report. We report an interesting case of MANEC with neuroendocrine cell predominance in a woman presenting with epigastric pain secondary to a pancreatic mass with acinar and endocrine differentiation. She underwent surgical resection of the tumor and was offered adjuvant treatment chemotherapy with carboplatin, etoposide, and radiotherapy for positive tumor resection margins. Conclusions. Given the paucity of the cases of MANEC, continuous reporting of these cases when identified should be encouraged to aid oncologists in understanding the disease and help establish standardized management.

  4. 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.)

  5. Neuroendocrine gastric carcinoma expressing somatostatin: A highly malignant, rare tumor

    Institute of Scientific and Technical Information of China (English)

    Jaques Waisberg; Leandro Luongo de Matos; Ana Maria do Amaral Antonio Mader; Sérgio Pezzolo; Esmeralda Miristene Eher; Vera Luiza Capelozzi; Manlio Basilio Speranzini


    Poorly differentiated gastric neuroendocrine carcinomas,although rare, deserve particular attention, as they are aggressive and have an extremely poor prognosis. In this report we describe a gastric neuroendocrine carcinoma with rapidly fatal outcome. Immunohistological staining of the resected specimens revealed that the tumor was an endocrine carcinoma. The tumor disclosed intense immunoreactivity to pan-neuroendocrine markers and diffuse somatostatin immunoreactivity. There were no psammoma bodies and no demonstrable association with von Recklinghausen's neurofibromatosis. In the gastrointestinal tract, neuroendocrine tumors producing predominantly somatostatin have been described only in the duodenum. To the best of our knowledge, the present report is the second case report of a neuroendocrine gastric carcinoma expressing diffusely somatostatin as the only neuroendocrine regulatory peptide.

  6. 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.

  7. Treatment of lung large cell neuroendocrine carcinoma. (United States)

    Lo Russo, Giuseppe; Pusceddu, Sara; Proto, Claudia; Macerelli, Marianna; Signorelli, Diego; Vitali, Milena; Ganzinelli, Monica; Gallucci, Rosaria; Zilembo, Nicoletta; Platania, Marco; Buzzoni, Roberto; de Braud, Filippo; Garassino, Marina Chiara


    Lung large cell neuroendocrine carcinoma (L-LCNEC) is a rare, aggressive, and difficult-to-treat tumor. It is classified as a neuroendocrine subtype of large cell lung carcinoma (LCLC) belonging to the non-small cell lung cancer (NSCLC) group, but it is also included in the neuroendocrine tumor (NET) group. Most of the available data related to its treatment derive from retrospective analyses or small case series. For patients with L-LCNEC, prognosis is generally very poor. In early stages (I-II-III), surgery is recommended but does not seem to be sufficient. Platinum-based adjuvant chemotherapy may be useful while the role of neoadjuvant chemotherapy is still not well defined. In patients with advanced L-LCNEC, the chemotherapy regimens used in SCLC still remain the standard of treatment, but results are not satisfactory. Due to their peculiar clinical and biological features and the lack of literature data, there is an emerging need for a consensus on the best treatment strategy for L-LCNEC and for the identification of new therapeutic options. In this review, we will discuss the key aspects of L-LCNEC management with the aim to clarify the most controversial issues.

  8. 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

  9. 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 or

  10. 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...

  11. 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...... these PET tracers further....

  12. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases. (United States)

    Berber, Eren; Flesher, Nora; Siperstein, Allan E


    We previously reported on the safety and efficacy of laparoscopic radiofrequency thermal ablation (RFA) for treating hepatic neuroendocrine metastases. The aim of this study is to report our 5-year RFA experience in the treatment of these challenging group of patients. Of the 222 patients with 803 liver primary and secondary tumors undergoing laparoscopic RFA between January 1996 and August 2001, a total of 34 patients with 234 tumors had neuroendocrine liver metastases. There were 25 men and 9 women with a mean +/- SEM age of 52 +/- 2 years who underwent 42 ablations. Primary tumor types included carcinoid tumor in 18 patients, medullary thyroid cancer in 7, secreting islet cell tumor in 5, and nonsecreting islet cell tumor in 4. There was no mortality, and the morbidity was 5%. The mean hospital stay was 1.1 days. Symptoms were ameliorated in 95%, with significant or complete symptom control in 80% of the patients for a mean of 10+ months (range 6-24 months). All patients were followed for a mean +/- SEM of 1.6 +/- 0.2 years (range 1.0-5.4 years). During this period new liver lesions developed in 28% of patients, new extrahepatic disease in 25%, and local liver recurrence in 13%; existing liver lesions progressed in 13%. Overall 41% of patients showed no progression of their cancer. Nine patients (27%) died. Mean +/- SEM survivals after diagnosis of primary disease, detection of liver metastases, and performance of RFA were 5.5 +/- 0.8 years, 3.0 +/- 0.3 years, and 1.6 +/- 0.2 years, respectively. Sixty-five percent of the patients demonstrated a partial or significant decrease in their tumor markers during follow-up. In conclusion, RFA provides excellent local tumor control with overnight hospitalization and low morbidity in the treatment of liver metastases from neuroendocrine tumors. It is a useful modality in the management of these challenging group of patients.

  13. 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.

  14. Chronomics, human time estimation, and aging

    Directory of Open Access Journals (Sweden)

    Franz Halberg


    Full Text Available Franz Halberg, Robert B Sothern, Germaine Cornélissen, Jerzy Czaplicki1Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA; 1Institut de Pharmacologie et de Biologie Structurale CNRS, Université Paul Sabatier, Toulouse, FranceBackground: Circadian rhythm stage affects many outcomes, including those of mental aging.Methods: Estimations of 1 minute ∼5 times/day for a year, 25 years apart, by a healthy male biomedical scientist (RBS, are analyzed by the extended cosinor.Results: Cycles of a half-week, a week, ∼30 days, a half-year and a year, in self-assessed 1-minute estimation by RBS between 25 and 60 years of age in health, are mapped for the first time, compared and opposite effects are found. For RBS at 60 vs at 25 years of age, it takes less time in the morning around 10:30 (P < 0.001, but not in the evening around 19:30 (P = 0.956, to estimate 1 minute.Discussion: During the intervening decades, the time of estimating 1 minute differed greatly, dependent on circadian stage, being a linear decrease in the morning and increase in the evening, the latter modulated by a ∼33.6-year cycle.Conclusion: Circadian and infradian rhythm mapping is essential for a scrutiny of effects of aging. A ∼30-day and a circannual component apparent at 25 years of age are not found later; cycles longer than a year are detected. Rhythm stages await tests as markers for timing therapy in disease.Keywords: circadian rhythm, mental function, time estimation

  15. 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.

  16. 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...

  17. Molecular Pathogenesis of Pancreatic Neuroendocrine Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Ehehalt, Florian, E-mail:; Franke, Ellen; Pilarsky, Christian; Grützmann, Robert [Department for General, Thoracic and Vascular Surgery, University Hospital “Carl Gustav Carus”, University of Technology, Dresden (Germany)


    Pancreatic neuroendocrine tumors (PNETs) are rare primary neoplasms of the pancreas and arise sporadically or in the context of genetically determined syndromes. Depending on hormone production and sensing, PNETs clinically manifest due to a hormone-related syndrome (functional PNET) or by symptoms related to tumor bulk effects (non-functional PNET). So far, radical surgical excision is the only therapy to cure the disease. Development of tailored non-surgical approaches has been impeded by the lack of experimental laboratory models and there is, therefore, a limited understanding of the complex cellular and molecular biology of this heterogeneous group of neoplasm. This review aims to summarize current knowledge of tumorigenesis of familial and sporadic PNETs on a cellular and molecular level. Open questions in the field of PNET research are discussed with specific emphasis on the relevance of disease management.

  18. Peptide receptor radionuclide therapy of neuroendocrine tumours. (United States)

    Brabander, Tessa; Teunissen, Jaap J M; Van Eijck, Casper H J; Franssen, Gaston J H; Feelders, Richard A; de Herder, Wouter W; Kwekkeboom, Dik J


    In the past decades, the number of neuroendocrine tumours that are detected is increasing. A relative new and promising therapy for patients with metastasised or inoperable disease is peptide receptor radionuclide therapy (PRRT). This therapy involves an infusion of somatostatin analogues linked to radionuclides like Yttrium-90 or Lutetium-177. Objective response rates are reported in 15-35%. Response rates may vary between type of tumour and radionuclide. Besides the objective response rate, overall survival and progression free survival increase significantly. Also, the quality of life improves as well. Serious side-affects are rare. PRRT is usually well tolerated, also in patients with extensive metastasised disease. Recent studies combined PRRT with other types of therapies. Unfortunately no randomised trials comparing these strategies are available. In the future, more research is needed to evaluate the best therapy combinations or sequence of therapies.

  19. New drug development in digestive neuroendocrine tumors. (United States)

    Durán, I; Salazar, R; Casanovas, O; Arrazubi, V; Vilar, E; Siu, L L; Yao, J; Tabernero, J


    The traditional cytotoxic agents are of limited efficacy in the treatment of neuroendocrine tumors of the gastrointestinal tract (NETs). Recent investigations have brought up a number of biological features in this family of neoplasms that could represent targets for anticancer treatment. NETs seem to have an extraordinary tumor vascularization with high expression of proangiogenic molecules such as the vascular endothelial growth factor along with overexpression of certain tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR), the insulin growth factor receptor (IGFR) and their downstream signaling pathway components (PI3K-AKT-mTOR). The rationale of an antiangiogenic approach in the treatment of NETs and the use of other pharmacological strategies such as EGFR, IGFR and mammalian target of rapamycin inhibitors are discussed. Additionally, the emerging results of recent clinical trials with these targeted drugs are presented.

  20. Prenatal programming of neuroendocrine reproductive function. (United States)

    Evans, Neil P; Bellingham, Michelle; Robinson, Jane E


    It is now well recognized that the gestational environment can have long-lasting effects not only on the life span and health span of an individual but also, through potential epigenetic changes, on future generations. This article reviews the "prenatal programming" of the neuroendocrine systems that regulate reproduction, with a specific focus on the lessons learned using ovine models. The review examines the critical roles played by steroids in normal reproductive development before considering the effects of prenatal exposure to exogenous steroid hormones including androgens and estrogens, the effects of maternal nutrition and stress during gestation, and the effects of exogenous chemicals such as alcohol and environment chemicals. In so doing, it becomes evident that, to maximize fitness, the regulation of reproduction has evolved to be responsive to many different internal and external cues and that the GnRH neurosecretory system expresses a degree of plasticity throughout life. During fetal life, however, the system is particularly sensitive to change and at this time, the GnRH neurosecretory system can be "shaped" both to achieve normal sexually differentiated function but also in ways that may adversely affect or even prevent "normal function". The exact mechanisms through which these programmed changes are brought about remain largely uncharacterized but are likely to differ depending on the factor, the timing of exposure to that factor, and the species. It would appear, however, that some afferent systems to the GnRH neurons such as kisspeptin, may be critical in this regard as it would appear to be sensitive to a wide variety of factors that can program reproductive function. Finally, it has been noted that the prenatal programming of neuroendocrine reproductive function can be associated with epigenetic changes, which would suggest that in addition to direct effects on the exposed offspring, prenatal programming could have transgenerational effects on

  1. 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.

  2. Neuroendocrine cells in the urogenital tract of the buffalo

    Directory of Open Access Journals (Sweden)

    A. Vittoria


    Full Text Available Neuroendocrine cells or paraneurons are cytotypes producing biogenic amines and/or hormonal peptides, scattered in the glandular and lining epithelia of the body. In this study the presence of chromogranin A-, serotonin- and somatostatin-immunoreactive neuroendocrine cells has been described immunohistochemically in the urethro- prostatic complex and female urethra of subjects of the buffalo Bubalus bubalis. The chromogranin A- containing neuroendocrine cells resulted the most numerous cytotype, the serotonin- containing ones the most irregular in shape for the presence of dendritic-like cytoplasmic extensions and the somatostatin- containing the rarest. The role played by the amine serotonin in the genital tract has been related to the determinism of sexual climax and to the contraction of smooth muscle. The function played by the neuroendocrine genital somatostatin is unknown. Analogically to what described for the same gastrointestinal hormone, it could inhibit both exocrine and endocrine secretions.

  3. Orbital metastases from neuroendocrine carcinoma, masquerading as graves orbitopathy. (United States)

    Sira, Mano; Clauss, Ralf P; Maclean, Chris; Rose, Geoffrey E


    We describe a patient with metastases from neuroendocrine carcinoma masquerading as Graves ophthalmopathy. This rare tumour possibly has a propensity for orbital spread, and we postulate a mechanism evoking the 'seed and soil' hypothesis.

  4. A case of an intussuscepted neuroendocrine carcinoma of the appendix

    Institute of Scientific and Technical Information of China (English)

    Rachel E Thomas; Karen Maude; Olorunda Rotimi


    We have described a previously unreported entity of an intussuscepted neuroendocrine carcinoma of the appendix. Our patient was a 70-year-old man whose only complaint was insipient weight loss. Colonoscopy showed a malignant cecal "polyp", and an extended right hemicolectomy was performed. We have reviewed the literature on the causes of appendiceal intussusception and their appropriate treatment options, and clarified the classification of neuroendocrine tumors of the gastrointestinal tract.

  5. [Contemporary management of neuroendocrine neoplasms of the female genital organs]. (United States)

    Kuc-Rajca, Małgorzata; Dańska-Bidzińska, Anna


    Neuroendocrine neoplasms are a rare and heterogeneous group of diseases that account for only 2% of all gynecologic malignancies. The most common types are ovarian carcinoid tumor and small cell neuroendocrine carcinoma of the cervix. The tumors are staged according to FIGO clinical staging system. The diagnosis is usually made retrospectively after obtaining the results of histopathological evaluation of the primary tumor They rarely cause syndromes related to hormone overexpression. Neuroendocrine neoplasms are characterized by aggressive behaviour Even at an early stage there is high incidence of nodal and distant metastases. Survival is poor regardless of stage at diagnosis. The most important is to diagnose the neuroendocrine tumor accurately and treat it in multimodal, aggressive approach to control the disease better and reduce the incidence of reccurences. Apart from typical therapeutic approach, treatment may encompass isotope therapy using radiolabeled somatostatin analogs. This method should be reserved for patients with expression of somatostatin receptors detected by the somatostatin receptor scyntygraphy. Data concerning the management of neuroendocrin tumors are based mainly on retrospective studies and clinical case series. Lack of randomized trials makes it impossible to select the best treatment option. Better understanding of the biology of neuroendocrine tumors, especially the molecular genetics, will in the future help to determine the optimal treatment strategies for these tumors.

  6. Rectal neuroendocrine tumor with uncommon metastatic spread: A case report and review of literature. (United States)

    Tsoukalas, Nikolaos; Galanopoulos, Michail; Tolia, Maria; Kiakou, Maria; Nakos, Georgios; Papakostidi, Aristoula; Koumakis, Georgios


    Neuroendocrine tumors of the gastrointestinal tract are rare neoplasms. Rectal neuroendocrine tumors consist approximately the 5%-14% of all neuroendocrine neoplasms in Europe. These tumors are diagnosed in relatively young patients, with a mean age at diagnosis of 56 years. Distant metastases from rectal neuroendocrine tumors are not very common. Herein we describe a case of a rectal neuroendocrine tumor which metastasized to the lung, mediastinum and orbit. This case underscores the importance of early identification and optimal management to improve patient's prognosis. Therefore, the clinical significance of this case is the necessity of physicians' awareness and education regarding neuroendocrine tumors' diagnosis and management.

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

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


    Despite the fact that the first human was in space during 1961 and individuals have existed in a microgravity environment for more than a year, there are limited spaceflight data available on the responses of the neuroendocrine and immune systems. Because of mutual interactions between these respective integrative systems, it is inappropriate to assume that the responses of one have no impact on functions of the other. Blood and plasma volume consistently decrease with spaceflight; hence, blood endocrine and immune constituents will be modified by both gravitational and measurement influences. The majority of the in-flight data relates to endocrine responses that influence fluids and electrolytes during the first month in space. Adrenocorticotropin (ACTH), aldo-sterone. and anti-diuretic hormone (ADH) appear to be elevated with little change in the atrial natriuretic peptides (ANP). Flight results longer than 60 d show increased ADH variability with elevations in angiotensin and cortisol. Although post-flight results are influenced by reentry and recovery events, ACTH and ADH appear to be consistently elevated with variable results being reported for the other hormones. Limited in-flight data on insulin and growth hormone levels suggest they are not elevated to counteract the loss in muscle mass. Post-flight results from short- and long-term flights indicate that thyroxine and insulin are increased while growth hormone exhibits minimal change. In-flight parathyroid hormone (PTH) levels are variable for several weeks after which they remain elevated. Post-flight PTH was increased on missions that lasted either 7 or 237 d, whereas calcitonin concentrations were increased after 1 wk but decreased after longer flights. Leukocytes are elevated in flights of various durations because of an increase in neutrophils. The majority of post-flight data indicates immunoglobulin concentrations are not significantly changed from pre-flight measurements. However, the numbers of T

  8. Expression of Neuroendocrine Markers in Different Molecular Subtypes of Breast Carcinoma

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    David L. Wachter


    Full Text Available Background. Carcinomas of the breast with neuroendocrine features are incorporated in the World Health Organization classification since 2003 and include well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas/small cell carcinomas, and invasive breast carcinomas with neuroendocrine differentiation. Neuroendocrine differentiation is known to be more common in certain low-grade histologic special types and has been shown to mainly cluster to the molecular (intrinsic luminal A subtype. Methods. We analyzed the frequency of neuroendocrine differentiation in different molecular subtypes of breast carcinomas of no histologic special type using immunohistochemical stains with specific neuroendocrine markers (chromogranin A and synaptophysin. Results. We found neuroendocrine differentiation in 20% of luminal B-like carcinomas using current WHO criteria (at least 50% of tumor cells positive for synaptophysin or chromogranin A. In contrast, no neuroendocrine differentiation was seen in luminal A-like, HER2 amplified and triple-negative carcinomas. Breast carcinomas with neuroendocrine differentiation presented with advanced stage disease and showed aggressive behavior. Conclusions. We conclude that neuroendocrine differentiation is more common than assumed in poorly differentiated luminal B-like carcinomas. Use of specific neuroendocrine markers is thus encouraged in this subtype to enhance detection of neuroendocrine differentiation and hence characterize the biological and therapeutic relevance of this finding in future studies.

  9. Expression of Neuroendocrine Markers in Different Molecular Subtypes of Breast Carcinoma (United States)

    Wachter, David L.; Hartmann, Arndt; Beckmann, Matthias W.; Fasching, Peter A.; Hein, Alexander; Bayer, Christian M.; Agaimy, Abbas


    Background. Carcinomas of the breast with neuroendocrine features are incorporated in the World Health Organization classification since 2003 and include well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas/small cell carcinomas, and invasive breast carcinomas with neuroendocrine differentiation. Neuroendocrine differentiation is known to be more common in certain low-grade histologic special types and has been shown to mainly cluster to the molecular (intrinsic) luminal A subtype. Methods. We analyzed the frequency of neuroendocrine differentiation in different molecular subtypes of breast carcinomas of no histologic special type using immunohistochemical stains with specific neuroendocrine markers (chromogranin A and synaptophysin). Results. We found neuroendocrine differentiation in 20% of luminal B-like carcinomas using current WHO criteria (at least 50% of tumor cells positive for synaptophysin or chromogranin A). In contrast, no neuroendocrine differentiation was seen in luminal A-like, HER2 amplified and triple-negative carcinomas. Breast carcinomas with neuroendocrine differentiation presented with advanced stage disease and showed aggressive behavior. Conclusions. We conclude that neuroendocrine differentiation is more common than assumed in poorly differentiated luminal B-like carcinomas. Use of specific neuroendocrine markers is thus encouraged in this subtype to enhance detection of neuroendocrine differentiation and hence characterize the biological and therapeutic relevance of this finding in future studies. PMID:24701575

  10. Pancreatic Neuroendocrine Tumors: Role of Novel Agents

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    Alexios S Strimpakos


    Full Text Available Neuroendocrine tumors of pancreas (PNET are very rare, consisting of heterogeneous histological subtypes with a variable natural history and different clinical manifestations. Although the vast majority of these neoplasms are sporadic, it is possible to be part of a genetic syndrome such as multiple endocrine neoplasia 1 (MEN-1 or tuberous sclerosis (TSC. When systemic treatment is required the options are limited and management strategy is generally based on experts’ consensus or clinical experience. The prognosis is usually better than in pancreatic adenocarcinoma, though poorly differentiated PNET behave aggressively and survival is shortened. Since last year, there has been a significant advance in the management of PNET, after reported data confirmed the efficacy of everolimus, an mTOR inhibitor, in patients with advanced disease. At the 2011 American Society of Clinical Oncology (ASCO Gastrointestinal Symposium, updated results of the phase III trial (RADIANT-3 regarding the efficacy of everolimus in PNET (Abstract #158 were reported, along with the results of a subgroup analysis of the Japanese patients enrolled in this study (Abstract #289. Another agent with promising activity in PNET which will be discussed in this review is sunitinib, a biological agent with multikinase inhibitor properties (Abstract #244.

  11. An Overview of Neuroendocrine Tumour Markers

    Directory of Open Access Journals (Sweden)

    Ersin Özaslan


    Full Text Available As there are many different subtypes of neuroendocrine tumors (NETs, many kinds of markers are used for their diagnosis and follow-up. Most of these markers, such as calcitonin, catecholamines, 5-hydroxyindoleacetic acid (5-HIAA, insulin, gastrin, pancreatic polypeptide, and glucagon are specific to one subtype of NET. In addition, there are also general markers used in various NET subtypes; the most commonly used ones are chromogranin-A (CgA, neuron-specific enolase (NSE, and synaptophysin. The sensitivity and specificity levels of CgA are highest among all NET markers. However, specific markers, such as calcitonin in medullary thyroid carcinoma, insulin in insulinoma and cathecolamines in feocromocitoma are more useful than CgA. CgA is an auxiliary marker in cases with relapse or metastasis of such functional NETs. Carcinoid syndrome is characterized by serotonin hypersecretion with the other products and 5-HIAA level is used to determine the serotonin hypersecretion. Thus, 5-HIAA is the specific marker for carcinoid tumors which comprise two-thirds of all NETs.

  12. [Neuroendocrine changes in chronic cardiac insufficiency]. (United States)

    Jaeger, P; Cohen-Solal, A; Dahan, M; Juliard, J M; Charlier, P; Gourgon, R


    Throughout the course of chronic congestive heart failure cardiac and peripheral compensatory mechanisms are at play, most of them under the influence of the neuroendocrine system. The reserves of heart rate and contractility are regulated essentially by the noradrenergic system (NAS), but this mechanism is partial and transient owing to the gradual decrease in the density and sensitivity of myocardial beta-adrenergic receptors induced by overstimulation. Adaptation of the heart to exercise may be reduced. This escape phenomenon is also observed with almost all cardiotonic drugs which interfere with cyclic adenosine monophosphate (cAMP), in contrast with the paradoxically favourable effects of beta-blockers in small doses or of drugs that are both agonists and antagonists of beta-adrenergic receptors. The mechanisms which contribute to the induction of left ventricular hypertrophy are imperfectly known. The noradrenergic system and the renin-angiotensin-aldosterone system (RAAS) are probably not the only ones involved. The setting in action of Frank-Sterling heterometric regulation, at first during exercise then permanently, requires an increase in filling pressure obtained by venous constriction (predominantly controlled by the NAS) and, mostly, by an increase in circulating blood volume. NAS and RAAS intervene in the kidneys to produce water-and-salt retention.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. 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.

  14. Neuroendocrine Tumor of the Appendix in Children. (United States)

    Wu, Hao; Chintagumpala, Murali; Hicks, John; Nuchtern, Jed G; Okcu, M Fatih; Venkatramani, Rajkumar


    Neuroendocrine tumor (NET) of the appendix is the most common gastrointestinal epithelial tumor in children. The utility of serum markers or the indication for hemicolectomy has not been established in children. In 45 children diagnosed with appendiceal NET, 89% NETs were incidentally found following appendectomy performed for suspected acute appendicitis. The median age was 12 years, and 56% patients were female. Postoperative somatostatin scan (n=5), serum chromogranin A (n=4), and urine 5-HIAA (n=9) were all within normal limits. Pathology slides of 35 patients showed mesoappendiceal invasion in 29% patients, and vascular invasion in 6% patients. Seven patients (16%) underwent hemicolectomy for invasion of mesoappendix (n=5), tumor near the resection margin (n=1), and tumor size 1.5 cm with vascular invasion (n=1). Only 2 hemicolectomy specimens showed disease: one in the appendiceal stump and the other as a micrometastasis in a mesenteric lymph node. There were no recurrences and all patients were alive and without evidence of disease at last follow-up. Pediatric appendiceal NET tends to have a benign clinical course with excellent prognosis. In the absence of carcinoid syndrome, postoperative scans and serum biomarkers do not seem to be useful. With completely resected tumors, the indication for hemicolectomy is unclear.

  15. Primary hepatic neuroendocrine tumor: A case report (United States)



    We herein present a case of an 87-year-old patient with multiple liver tumors identified on abdominal ultrasound. The assessment performed on admission included physical examination, computed tomography (CT) during hepatic angiography and CT during arterial portography. The examination revealed contrast enhancement of a proportion of the liver tumors (20 mm maximum diameter) during the arterial phase and mild contrast washout of those tumors during the delayed phase. On contrast-enhanced magnetic resonance imaging using gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid, certain liver tumors exhibited contrast enhancement during the early phase and contrast washout during the hepatocyte phase in both lobes. By contrast, no lesions were identified during positron emission tomography imaging of the liver. A liver biopsy was performed and immunohistochemical staining revealed enhanced expression of cytokeratin AE1/AE3, synaptophysin, chromogranin A and CD56 and no expression of hepatocyte antigen or CΚ7. The mindbomb E3 ubiquitin protein ligase-1 index was ~2% in most of the tumor. The liver tumors were finally diagnosed as multiple intrahepatic metastases from a primary hepatic neuroendocrine tumor (PHNET). The patient underwent transarterial chemoembolisation with a combination of miriplatin (84 mg) mixed with gelatin sponge particles and lipiodol. To the best of our knowledge, this is the first report of PHNET in an patient aged >85 years. PMID:27284429

  16. Role of radiotherapy for pancreatobiliary neuroendocrine tumors

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    Lee, Jeong Shim; Choi, Jin Hyun; Choi, Chihwan; Seong, Jinsil [Dept. of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul (Korea, Republic of)


    We investigated the role of radiotherapy (RT) for pancreatobiliary neuroendocrine tumors (PB-NETs). We identified 9 patients with PB-NETs who received RT between January 2005 and March 2012. Of these 9 patients, 4 were diagnosed with NETs in the pancreas and 5 were diagnosed with NETs in the gallbladder. All patients received RT to the primary tumor or resection bed with a median total irradiation dose of 50.4 Gy, with or without chemotherapy. The tumor response rate and tumor control rate in the RT field were 60% and 100 %, respectively. All 4 patients who underwent surgery had no evidence of disease in the RT field. Of the 5 patients who received RT to the primary gross tumor, 1 had complete response, 2 had partial response, and 2 had stable disease in the RT field. The median time to progression was 11 months. Of the 9 patients, four patients had no progression, and 5 patients had progression of disease (locoregional, 2; distant, 2; locoregional/distant, 1). Of the 4 patients without progression, 3 were treated with RT in adjuvant or neoadjuvant setting, and one received RT to primary tumor. One patient experienced radiation-induced duodenitis at 3 months after concurrent chemoradiation without treatment-related mortality. RT can yield local control for advanced PB-NETs. RT should be considered an essential part of multimodality treatment in management of advanced PB-NETs.

  17. Pancreatic neuroendocrine neoplasms; Neuroendokrine Neoplasien des Pankreas

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    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.)

  18. Biological characteristics of breast carcinomas with neuroendocrine cell differentiation

    Institute of Scientific and Technical Information of China (English)

    姚根有; 周吉林; 赵仲生; 阮俊


    Background The aim of this study was to investigate DNA content and expression of c-erbB-2, PS2, and prostate-specific antigen (PSA) proteins in breast carcinomas with neuroendocrine (NE) cell differentiation.Methods Chromogranin, c-erbB-2, PS2, and PSA in 131 samples of breast cancer were detected immunohistochemically. Classic Feulgen staining image analysis techniques were used to quantify DNA content in 81 of the breast cancer samples.Results The c-erbB-2 positive rate in breast carcinoma samples containing neuroendocrine cells was 37.5% and the rate of high expression of c-erbB-2 (++ or +++) was 33.3%, both significantly lower than that in breast carcinomas without neuroendocrine cells (62.6% and 68.7%, respectively, P 5c aneuploidy cells, and rate of aneuploidy among cells were all lower than that in NE (-) breast carcinomas (P<0.01). In NE (+) grade I or II breast carcinomas, these indices were also all lower than that in the NE (-) breast carcinoma samples (P<0.01).Conclusion Breast carcinomas with neuroendocrine differentiation have a lower rate of malignancy. Neuroendocrine differentiation could serve as a prognostic marker in clinical practice.

  19. Middle ear adenoma. A tumor displaying mucinous and neuroendocrine differentiation. (United States)

    Wassef, M; Kanavaros, P; Polivka, M; Nemeth, J; Monteil, J P; Frachet, B; Tran Ba Huy, P


    Middle ear adenoma (MEA) is a distinctive, rare entity that appears to be derived from the lining epithelium of the middle ear mucosa. We report four cases of MEA displaying the typical histologic growth pattern. Two distinct tumor cell immunophenotypes were identified in all cases; the first type exhibited positivity with anti-epithelial membrane antigen and anti-keratin antibodies, and the second type showed immunoreactivity with anti-keratin, anti-vimentin, and anti-neuron-specific enolase antibodies. Ultrastructural studies revealed bidirectional mucinous and neuroendocrine differentiation, demonstrated by the presence of two distinct cell types containing apically located mucous granules and basally concentrated neuroendocrine granules, respectively. The presence of neuroendocrine differentiation was supported by the immunohistochemical detection of vasoactive intestinal polypeptide in the tumor cells in one case and neuron-specific enolase in three cases. These findings suggest that the potential for mixed mucinous/neuroendocrine differentiation described in other endodermally derived tumors also exists in middle ear mucosa. We also believe that the rare lesions diagnosed as primary carcinoid tumors of the middle ear might in fact be MEA with predominant or only neuroendocrine differentiation. The clinical course of our four cases and our review of the pertinent literature confirm the benign nature of MEA and indicate that these tumors should be treated by complete local excision without additional therapy.

  20. 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.

  1. [Neuroendocrine carcinoma of the ampullar region with oat-cell histological features and adenocarcinoma]. (United States)

    Fresno, M F; Floriano, P; Díaz Iglesias, J M; Ablanedo, P; Pérez del Río, M J; Barneo, L; Herrero, A


    We report a case of primary duodenal carcinoma showing neuroendocrine and glandular differentiation, in a 65-years-old male. Both components were closely related and transition between them was observed. The neuroendocrine component was composed of an undifferentiated "oat-cell" type, with positive immunostaining for neuroendocrine and epithelial markers. Ultrastructural findings confirmed this double differentiation, with dense cytoplasmatic granules of neurosecretory type. The neuroendocrine component showed greater aggressiveness with lymph node metastasis.

  2. 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.

  3. [Neuroendocrine pancreatic tumors and helpfulness of targeted therapies]. (United States)

    Vaysse, Thibaut; Coriat, Romain; Perkins, Géraldine; Dhooge, Marion; Brezault, Catherine; Chaussade, Stanislas


    The neuroendocrine pancreatic tumors are rare tumors, but their incidence is constantly rising. Even if the management of these tumors has to be surgical as soon as possible, the disease is most often metastatic at the stage of the diagnostic. The prognostic and the therapeutic options differ from pancreatic adenocarcinoma. Available treatments have evolved over the last years with recent publications of studies that bring to light the benefits of targeted therapies in this pathology. This has resulted in modifications of both practices and either French and international guidelines. Therefore, we focus on the management of the grade 1 and grade 2 well-differentiated neuroendocrine pancreatic tumors as classified in new WHO classification of neuroendocrine neoplasms published in 2010.

  4. Amantadine in the treatment of neuroendocrine side effects of neuroleptics. (United States)

    Correa, N; Opler, L A; Kay, S R; Birmaher, B


    An open-label reversal drug study was undertaken on 10 neuroleptic-treated schizophrenic inpatients to assess the impact of amantadine hydrochloride on presumed prolactin-mediated neuroendocrine side effects. Measures were conducted across 7 weeks, including a 2-week neuroleptic baseline, a 3-week neuroleptic-plus-amantadine phase, and a 2-week return to the baseline regimen. Significant reduction with amantadine was observed on all six indices of neuroendocrine side effects: serum prolactin levels, body weight, gynecomastia/galactorrhea, breast tenderness, decreased libido, and amenorrhea. Improvement on these parameters was noted for as many as nine or all 10 patients, while in no cases was there worsening. In terms of motor and clinical effects, significant diminution of extrapyramidal and psycho-pathological symptoms was also achieved during this phase. The results suggested that amantadine may be beneficial for the treatment of neuro-endocrine side effects of antipsychotic medication owing to its ability to reverse neuroleptic-induced hyperprolactinemia.

  5. Treatment of congestive heart failure a neuroendocrine disorder. (United States)

    Martin, M W S


    The understanding of heart failure is no longer based on a supply and demand model of pump failure. Rather, heart failure is seen as a complex pathophysiological process with activation of various neuroendocrine systems. The goals of treatment have changed towards modifying these counterproductive neuroendocrine systems and slowing myocardial maladaptation. Angiotensin converting enzyme inhibitors are the only licensed drugs in veterinary practice that have a direct effect on neurohormones in heart failure. The range of drug options in human medicine is greater and some of these drugs are also increasingly being used in veterinary cardiology practice. This review describes the neuroendocrine systems involved in heart failure and discusses the range of drugs available in human and veterinary medicine. In doing so, it concentrates on the evidence available from good quality randomised trials in both the veterinary field and, where relevant, the human medical field.

  6. A short history of neuroendocrine tumours and their peptide hormones. (United States)

    de Herder, Wouter W; Rehfeld, Jens F; Kidd, Mark; Modlin, Irvin M


    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 pancreatic islet cells were first described in 1869 by Paul Langerhans. In 1924, Seale Harris was the first to describe endogenous hyperinsulinism/insulinoma. In 1942 William Becker and colleagues were the first to describe the glucagonoma syndrome. The first description of gastrinoma by Robert Zollinger and Edwin Ellison dates from 1955. The first description of the VIPoma syndrome by John Verner and Ashton Morrison dates from 1958. In 1977, the groups of Lars-Inge Larsson and Jens Rehfeld, and of Om Ganda reported the first cases of somatostatinoma. But only in 2013, Jens Rehfeld and colleagues described the CCK-oma syndrome. The most recently updated WHO classification for gastrointestinal neuroendocrine tumours dates from 2010.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    DEFF Research Database (Denmark)

    Rasmussen, Jacob Ø; Von Holstein, Sara Linea; Prause, Jan U;


    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...... 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....

  9. Factors associated with survival of veterans with gastrointestinal neuroendocrine tumors.

    NARCIS (Netherlands)

    Balmadrid, B.L.; Thomas, C.M.G.; Coffman, C.J.; Liddle, R.A.; Fisher, D.A.


    Background. Gastrointestinal (GI) neuroendocrine tumor (NET) incidence has been increasing; however, GI NET within the national Veterans Affairs (VA) health system has not been described. Methods. We used the VA Central Cancer Registry to identify the cohort of patients diagnosed with GI NET in 1995

  10. A retroperitoneal neuroendocrine tumor in ectopic pancreatic tissue. (United States)

    Okasha, Hussein Hassan; Al-Bassiouni, Fahim; El-Ela, Monir Abo; Al-Gemeie, Emad Hamza; Ezzat, Reem


    Ectopic pancreas is the relatively uncommon presence of pancreatic tissue outside the normal location of the pancreas. We report a case of abdominal pain due to retroperitoneal neuroendocrine tumor arising from heterotopic pancreatic tissue between the duodenal wall and the head of the pancreas. Patient underwent surgical enucleation of the tumor.

  11. Composite neuroendocrine and adenomatous carcinoma of the papilla of Vater

    Institute of Scientific and Technical Information of China (English)

    Joanna A Musialik; Maciej J Kohut; Tomasz Marek; Anatol Wodo(I)a(z)ski; Marek Hartleb


    Malignant tumors of papilla are usually adenocarcinomas.We present a 67-year-old female who became icteric as result of a malignant tumor infiltrating the papilla of Vater. Histopathological assessment of surgically excised tumor showed both neuroendocrine and adenocarcinomatous features. To our knowledge, this is the seventh report of this rare neoplastic association in the duodenal periampullary region.

  12. Capnocytophaga Lung Abscess in a Patient with Metastatic Neuroendocrine Tumor


    Thirumala, Raghu; Rappo, Urania; Babady, N. Esther; Kamboj, Mini; Chawla, Mohit


    Capnocytophaga species are known commensals of the oral cavity of humans and animals (mainly dogs and cats) and are a rare cause of respiratory tract infections. We report a case of cavitary lung abscess caused by a Capnocytophaga species in a patient with a metastatic neuroendocrine tumor.

  13. Gastroenteropancreatic neuroendocrine tumors: role of imaging in diagnosis and management. (United States)

    Sahani, Dushyant V; Bonaffini, Pietro A; Fernández-Del Castillo, Carlos; Blake, Michael A


    Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of neoplasms that arise from cells of the diffuse neuroendocrine system and are characterized by a wide spectrum of clinical manifestations. All NETs are potentially malignant but differ in their biologic characteristics and the probability of metastatic disease. The pathologic classification of these tumors relies on their proliferation and differentiation. In the past decades, several nomenclatures have been proposed to stratify neuroendocrine tumors, but the World Health Organization classification is the one that is most widely accepted and used. The diagnosis of neuroendocrine tumor relies on clinical manifestation, laboratory parameters, imaging features, and tissue biomarkers in a biopsy specimen. With improved understanding of the natural history and lesion biology, management of GEP-NETs has also evolved. Although surgery remains the only potentially curative therapy for patients with primary GEP-NETs, other available treatments include chemotherapy, interferon, somatostatin analogs, and targeted therapies. Recent improvements in both morphologic and functional imaging methods have contributed immensely to patient care. Morphologic imaging with contrast agent-enhanced multidetector computed tomography and magnetic resonance imaging is most widely used for initial evaluation and staging of disease in these patients, whereas functional imaging techniques are useful both for detection and prognostic evaluation and can change treatment planning.

  14. [Neuroendocrine features of prostatic tumors: state of the art]. (United States)

    Turitto, Giacinto; Frattolillo, Adele; Iodice, Patrizia; Auriemma, Annunziata; Tortoriello, Annamaria; di Grazia, Maria; Iaffaioli, Rosario Vincenzo


    Neuroendocrine (NE) differentiation in prostate cancer has received much attention recently because it has been found to be associated with androgen independence and shortened patient survival in some studies. The present review focuses on morphogenics origins of NE cells, growth properties and the androgen receptor status and relationship between NE-secreted products and regulation of angiogenesis and apoptosis.

  15. 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.

  16. 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.)

  17. Neuroendocrine system response modulates oxidative cellular damage in burn patients. (United States)

    Xie, Xiao-Qi; Shinozawa, Yotaro; Sasaki, Junichi; Takuma, Kiyotsugu; Akaishi, Satoshi; Yamanouchi, Satoshi; Endo, Tomoyuki; Nomura, Ryosuke; Kobayashi, Michio; Kudo, Daisuke; Hojo, Nobuko


    Oxygen-derived free radicals play important roles in pathophysiological processes in critically ill patients, but the data characterizing relationships between radicals and neuroendocrine system response are sparse. To search the cue to reduce the oxidative cellular damage from the point of view of neuroendocrine system response, we studied the indicators of neuroendocrine and inflammatory responses excreted in urine in 14 burn patients (42.3 +/- 31.4 years old, and 32.3 +/- 27.6% burn of total body surface area [%TBSA]) during the first seven days post burn. The daily mean amounts of urinary excretion of 8-hydroxy-2'-deoxy-guanosine (8-OHdG), a marker of oxidative cellular damage, were above the upper limit of the standard value during the studied period. The total amount of urinary excretion of 8-OHdG in the first day post burn correlated with burn severity indices: %TBSA (r = 0.63, p = 0.021) and burn index (r = 0.70, p = 0.008). The daily urinary excretion of 8-OHdG correlated with the daily urinary excretion of norepinephrine and nitrite plus nitrate (NOx) during the studied period except day 2 post burn, and correlated with the daily urinary excretion of 17-hydroxycorticosteriod (17-OHCS) in days 2, 3, and 7 post burn. These data suggest that oxidative cellular damage correlates with burn severity and neuroendocrine system response modulates inflammation and oxidative cellular damage. Modulation of neuroendocrine system response and inflammation in the treatment in the early phase of burn may be useful to reduce the oxidative cellular damage and to prevent multiple organ failures in patients with extensive burn.

  18. Neuroendocrine tumors (carcinoids of the stomach and intestines - early diagnosis and minimally invasive endoscopic procedures

    Directory of Open Access Journals (Sweden)

    Kuryk O.G.


    Full Text Available Background. Neuroendocrine tumors of the stomach and intestines are rare diseases. Increasing incidence and complexity of diagnosis of these diseases cause acuteness of the problem. Objective. To evaluate the effectiveness of morphological examination of endoscopic biopsy material for diagnostics of neuroendocrine tumors and for evaluation of completeness of minimally invasive endoscopic surgical interventions (endoscopic mucosal resection and endoscopic submucosal dissection at neuroendocrine tumors. Methods. On the basis of Medical center "Oberig" in 2009 - 2013 in eight cases neuroendocrine tumors were diagnosed: 2 (25 % in the stomach, 2 (25% – in the duodenum, 2 (25% - in the small intestine, 1 (12.5 % - in the ascending colon, 1 (12.5% - in the rectum. Neuroendocrine tumors of stomach and ileum were removed by endoscopic mucosal resection, duodenal bulb and rectum neuroendocrine tumors – by endoscopic submucosal dissection, papillary duodenum, colon and jejunum neuroendocrine tumors – by surgical resection. Results. It was shown, that morphological evaluation of endoscopic mucosal biopsies is effective way to diagnose the neuroendocrine tumors. Conclusion. Endoscopic mucosal resection and endoscopic submucosal dissection allows to get advanced material for morphological diagnosis of neuroendocrine tumors and an adequate method of their removing Citation: Kuryk OG, Yakovenko VO, Bazdyrev VV, Bodnar LV. [Neuroendocrine tumors (carcinoids of the stomach and intestines - early diagnosis and minimally invasive endoscopic procedures]. Morphologia. 2014;8(1:58-64. Ukrainian.

  19. Neuroendocrine carcinoma of the skin: an immunohistochemical study of tumor markers and neuroendocrine products. (United States)

    Layfield, L; Ulich, T; Liao, S; Barr, R; Cheng, L; Lewin, K L


    Fifteen neuroendocrine carcinomas of the skin (Merkel cell tumors) were stained within the constraints of tissue availability by the Grimelius method and immunohistochemically for keratin, neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), S-100, common leukocyte antigen (CLA), met-enkephalin, bombesin, calcitonin, ACTH, gastrin, and somatostatin. Focal argyrophilia was present in 5 of 12 tumors. All tumors tested demonstrated immunoreactivity for NSE and 5 tumors were positive for keratin. One tumors appeared to demonstrate focal ACTH-like immunoreactivity, but otherwise no immunoreactivity for the above mentioned polypeptide hormones was noted in 11 completely studied tumors. One tumor contained histologically obvious areas of squamous differentiation in addition to areas of Merkel cell tumor. In various tumors, keratin immunoreactivity was present either in areas of histologically obvious squamous differentiation, in randomly scattered single cells not histologically identifiable as squamous, or in a paranuclear dot-like distribution. Immunoreactivity for CEA, S-100 and CLA was not present in any tumors. The lack of met-enkephalin and the presence of squamous differentiation in these tumors indicates multidirectional differentiation in a fashion not phenotypically typical of Merkel cells.

  20. A feline case of hepatic neuroendocrine carcinoma with gastrin immunoreactivity. (United States)

    Kita, Chiaki; Yamagami, Tetsushi; Kinouchi, Shigemi; Nakano, Masayuki; Nagata, Nao; Suzuki, Hitomi; Ohtake, Yuzo; Miyoshi, Takuma; Irie, Mitsuhiro; Uchida, Kazuyuki


    A 5-year-old castrated Japanese domestic cat was presented with persistent vomiting. Ultrasound examinations revealed many masses only in the liver, and the fine needle aspiration was performed. Cytologically, polygonal or oval shaped tumor cells forming rosette and cord-like patterns were demonstrated, and then, the hepatic lesions were diagnosed as neuroendocrine carcinoma tentatively. The cat died one month after admission and was necropsied. Histopathologically, the tumor cells of the hepatic mass were arranged in typical rosette and cord-like structures. They were considerably uniform in size with hyperchromatic round nuclei and eosinophilic cytoplasm. Most of tumor cells were immunopositive for chromogranin A, and some were positive for gastrin. The findings indicate the possibility that the present case was a gastrin-producing neuroendocrine carcinoma.

  1. Targeted Agents in Treatment of Neuroendocrine Tumors of Pancreas

    Directory of Open Access Journals (Sweden)

    Ilias N Karampelas


    Full Text Available Neuroendocrine tumors (NET of the pancreas are uncommon neoplasms that arise from the pancreatic islet cells. Surgical resections are being tested, as well as multiple chemotherapy agents. Current treatment options for nonresectable disease include somatostatin analogs and chemotherapy. New therapies focus on specific molecular targets such as sunitinib, angiogenesis inhibitor, that target vascular endothelial growth factor receptor (VEGFR and other growth factor receptors and everolimus, an inhibitor of the mammalian target of rapamycin. Functionally based medical therapies for NET include somatostatin analogs to control symptoms. The 2014 annual meeting of American Society of Clinical Oncology (ASCO brought us new insights into the management of pancreatic neuroendocrine tumors. The focus of this review will serve to highlight specific Abstracts (#e15160 and #e15161, that shed light on new therapeutic options that help target the unique pathways of this malignancies.

  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. Neuropsychology of Neuroendocrine Dysregulation after Traumatic Brain Injury

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    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.

  4. Neuroendocrine differentiation in a case of cervical cancer

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    Mona Mohamed Rashed


    Full Text Available Neuroendocrine neoplasms may occur in the uterine cervix, although rarely; it accounts for 0.5-1% of all malignant tumors of the uterine cervix. A case report of an Ethiopian female presented at the Gynecology Out-Patient Clinic at Jimma University Hospital, complaining from irregular vaginal bleeding over the previous three months. Clinically there was a cauliflower cervical mass; histopathologically it was formed of sheets of small cell 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 additional useful assistance

  5. [The behavioral-neuroendocrine mechanism of development of homosexuality]. (United States)

    Xue, Hui; Tai, Fa-Dao


    In this review, we primarily focus on the behavioral-neuroendocrine mechanism of development of homosexuality from genetic, neuroendocrine neuroanatomical and behavioral studies. Besides the influence of genetics and environment, sexual orientation was determined by the early perinatal hormone exposure. Gonadal steroidal hormone interacted with many neurotransmitters in individual development by hypothalamus pituitary adrenal axis and hypothalamus pituitary gonadal axis, which regulated the individual's sexual orientation. It was summarized here about the future directions on sexual orientation and demonstrated problems which would have to investigate next step. All these may be beneficial for our understanding of the homosexuality and paying attention to psychological and physiological health of homosexuality, which is useful to prevent the development of teenage homosexuality.

  6. [Biotherapy of neuroendocrine tumours of the gastrointestinal tract and pancreas

    DEFF Research Database (Denmark)

    Hansen, C.P.; Knigge, U.


    Biotherapy of hormonal symptoms and tumour growth is a mainstay in the therapy of metastatic neuroendocrine tumours of the gastrointestinal tract and pancreas. Symptomatic relief can be achieved by somatostatin analogues and interferon, either alone or in combination. The effect on tumour growth...... is less convincing although a stabilization of disease is recorded in almost 50% of patients. Interferon treatment should mainly be considered for tumours with a low proliferation index Udgivelsesdato: 2008/6/9...

  7. Neoadjuvant Chemotherapy in Neuroendocrine Bladder Cancer: A Case Report


    Prelaj, Arsela; Rebuzzi, Sara Elena; Magliocca, Fabio Massimo; Speranza, Iolanda; Corongiu, Emanuele; Borgoni, Giuseppe; Perugia, Giacomo; Liberti, Marcello; Bianco, Vincenzo


    Patient: Male, 71 Final Diagnosis: Neuroendocrine cancer bladder Symptoms: Dysuria • haematuria Medication: — Clinical Procedure: Transurethral resection of the bladder tumor Specialty: Oncology Objective: Rare disease Background: Small cell carcinoma of the urinary bladder is a rare and aggressive form of bladder cancer that mainly presents at an advanced stage. As a result of its rarity, it has been described in many case reports and reviews but few retrospective and prospective trials, sho...

  8. The Neuroendocrine Functions of the Parathyroid Hormone 2 Receptor

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    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

  9. 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.

  10. Assessment of intracranial metastases from neuroendocrine tumors/carcinoma

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    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.

  11. Neuroendocrine carcinomas arising in ulcerative colitis: coincidences or possible correlations? (United States)

    Grassia, Roberto; Bodini, Paolo; Dizioli, Paolo; Staiano, Teresa; Iiritano, Elena; Bianchi, Guglielmo; Buffoli, Federico


    Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal malignancies. Adenocarcinoma is the commonest type of colorectal neoplasm associated with ulcerative colitis (UC) and Crohn's disease, but other types of epithelial and non-epithelial tumors have also been described in inflamed bowel. With regards to non-epithelial malignancies, lymphomas and sarcomas represent the largest group of tumors reported in association with IBD, especially in immunosuppressed patients. Carcinoids and in particular neuroendocrine neoplasms other than carcinoids (NENs) are rare tumors and are infrequently described in the setting of IBD. Thus, this association requires further investigation. We report two cases of neoplasms arising in mild left-sided UC with immunohistochemical staining for neuroendocrine markers: a large cell and a small cell neuroendocrine carcinoma of the rectum. The two patients were different in age (35 years vs 77 years) and disease duration (11 years vs 27 years), and both had never received immunosuppressant drugs. Although the patients underwent regular endoscopic and histological follow-up, the two neoplasms were locally advanced at diagnosis. One of the two patients developed multiple liver metastases and died 15 mo after diagnosis. These findings confirm the aggressiveness and the poor prognosis of NENs compared to colorectal adenocarcinoma. While carcinoids seem to be coincidentally associated with IBD, NENs may also arise in this setting. In fact, long-standing inflammation could be directly responsible for the development of pancellular dysplasia involving epithelial, goblet, Paneth and neuroendocrine cells. It has yet to be established which IBD patients have a higher risk of developing NENs.

  12. Gene expression accurately distinguishes liver metastases of small bowel and pancreas neuroendocrine tumors


    Sherman, Scott K.; Maxwell, Jessica E.; Carr, Jennifer C.; Wang, Donghong; Bellizzi, Andrew M.; O’Dorisio, M. Sue; O’Dorisio, Thomas M.; Howe, James R.


    Small bowel (SBNETs) and pancreatic neuroendocrine tumors (PNETs) often present with liver metastases. Although liver biopsy establishes a neuroendocrine diagnosis, the primary tumor site is frequently unknown without exploratory surgery. Gene expression differences in metastases may distinguish primary SBNETs and PNETs. This study sought to determine expression differences of four genes in neuroendocrine metastases and to create a gene expression algorithm to distinguish the primary site. No...

  13. 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.

  14. 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.

  15. Unusual Paraneoplastic Syndrome Accompanies Neuroendocrine Tumours of the Pancreas

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    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.

  16. Low ambient temperature and neuroendocrine response to hypoglycemia in men. (United States)

    Jezová, D; Juránková, E; Kvetnanský, R; Kaciuba-Uscilko, H; Nazar, K; Vigas, M


    Nutritional factors, such as an excess or a deficiency of glucose, play an important role in neuroendocrine regulations. Hormonal and metabolic responses to hypoglycemia were examined in healthy non-obese volunteers under conditions of low ambient temperature. Hypoglycemia was induced by intravenous injection of insulin in two randomized trials performed at room temperature and at 4 degrees C. At room temperature, the typical neuroendocrine response to hypoglycemia was established. The increases of ACTH, beta-endorphin, growth hormone and cortisol in response to insulin hypoglycemia failed to be modified by low ambient temperature. Acute cold exposure significantly reduced epinephrine and totally inhibited prolactin response to insulin-induced hypoglycemia. In spite of significant changes in epinephrine response to hypoglycemia at low ambient temperature, no striking differences in plasma glucose levels compared to those measured at room temperature were observed. However, under conditions of low temperature the reestablishment of normoglycemia was delayed. No changes in free fatty acids were found under our experimental conditions. The presented data show that low ambient temperature exerts selective effects on some neuroendocrine and metabolic parameters.

  17. Rectal neuroendocrine tumor with uncommon metastaticspread: A case report and review of literature

    Institute of Scientific and Technical Information of China (English)


    Neuroendocrine tumors of the gastrointestinal tract arerare neoplasms. Rectal neuroendocrine tumors consistapproximately the 5%-14% of all neuroendocrine neoplasmsin Europe. These tumors are diagnosed in relativelyyoung patients, with a mean age at diagnosis of 56years. Distant metastases from rectal neuroendocrinetumors are not very common. Herein we describe a caseof a rectal neuroendocrine tumor which metastasized tothe lung, mediastinum and orbit. This case underscoresthe importance of early identification and optimalmanagement to improve patient's prognosis. Therefore,the clinical significance of this case is the necessityof physicians' awareness and education regardingneuroendocrine tumors' diagnosis and management.

  18. WHO Grade 2 Neuroendocrine Tumor in a 15-Year-Old Male: A Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Eric Johannesen


    Full Text Available Neuroendocrine tumors, distinguished from adenocarcinomas by their neuroendocrine differentiation, are the most common pediatric epithelial malignancy that most often occurs in the appendix. In 2010, the WHO classified neuroendocrine neoplasms into three grades based on morphology, mitotic count, and Ki67 proliferation index. A 15-year-old male with a history of anemia and failure to thrive was diagnosed with a well-differentiated neuroendocrine tumor in the jejunum that invaded into the subserosal soft tissue and metastasized to four lymph nodes. Pediatric neuroendocrine tumors frequently arise within hereditary tumor syndromes with pancreatic neuroendocrine tumors being the most common. Several studies also indicate an elevated risk of small intestinal neuroendocrine tumors in which children born to a parent with a history of neuroendocrine tumors in the small intestine have a significant increased risk of developing one.

  19. 6-L-(18)F-fluorodihydroxyphenylalanine PET in neuroendocrine tumors : Basic aspects and emerging clinical applications

    NARCIS (Netherlands)

    Jager, Pieter L.; Chirakal, Raman; Marriott, Christopher J.; Brouwers, Adrienne H.; Koopmans, Klaas Pieter; Gulenchyn, Karen Y.


    In recent years, 6-L-(18)F-fluorodihydroxyphenylalanine ((18)F-DOPA) PET has emerged as a new diagnostic tool for the imaging of neuroendocrine tumors. This application is based on the unique property of neuroendocrine tumors to produce and secrete various substances, a process that requires the upt

  20. 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.......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....

  1. 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 wer

  2. Aberrant Menin expression is an early event in pancreatic neuroendocrine tumorigenesis

    NARCIS (Netherlands)

    Hackeng, Wenzel M.; Brosens, Lodewijk A A; Poruk, Katherine E.; Noë, Michaël; Hosoda, Waki; Poling, Justin S.; Rizzo, Anthony; Campbell-Thompson, Martha; Atkinson, Mark A.; Konukiewitz, Björn; Klöppel, Günter; Heaphy, Christopher M.; Meeker, Alan K.; Wood, Laura D.


    Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic malignancy and cause significant morbidity and mortality. Neuroendocrine microadenomas have been proposed as a potential precursor lesion for sporadic PanNETs. In this study, we applied telomere-specific fluorescent in

  3. Neuroendocrine Inflammatory Responses in Overweight/Obese Infants (United States)

    de Andrade, Camila Alves; Oliveira, Katherine Simone Caires; Tossige-Gomes, Rosalina; Rocha-Vieira, Etel; Neves, Camila Danielle Cunha; Vieira, Érica Leandro Marciano; Leite, Hércules Ribeiro; Oliveira, Murilo Xavier; Júnior, Antônio Lúcio Teixeira; Coimbra, Cândido Celso


    Childhood obesity is related to a cascade of neuroendocrine inflammatory changes. However, there remains a gap in the current literature regarding the possible occurrence of these changes in overweight/obese infants. The objective of this study was to evaluate adipokines, cortisol, brain-derived neurotrophic factor (BDNF) and redox status in overweight/obese infants versus normal-weight peers. A cross-sectional study was conducted with 50 infants (25 in the overweight/obese group and 25 in the normal-weight group) between 6 and 24 months. Plasma levels of leptin, adiponectin, resistin, soluble tumor necrosis factor (TNF) receptors, chemokines, BDNF, serum cortisol and redox status were measured. Unpaired Student's t-test was used to analyze the results and a probability of p<0.05 was acceptable for rejection of the null hypothesis. The Pearson correlation was used to verify the association between the biomarkers analyzed in each group. Plasma levels of leptin (p = 0.0001), adiponectin (p = 0.0007) and BDNF (p = 0.003), and serum cortisol (p = 0.048) were significantly higher in overweight/obese infants than normal-weight infants. In contrast, the concentration of thiobarbituric acid reactive substances (TBARS) (p = 0.004), and catalase (p = 0.045) and superoxide dismutase activity (p = 0.02) were lower in overweight/obese infants than normal-weight peers. All the results together indicate neuroendocrine inflammatory response changes in overweight/obese infants between 6 and 24 months. Although there is already an environment that predisposes for a subsequent pro-inflammatory response, neuroendocrine secretion changes that permit the control of the inflammatory process in this age interval can be observed. PMID:27907172

  4. Mixed acinar-neuroendocrine carcinoma of the pancreas

    DEFF Research Database (Denmark)

    Jakobsen, Mark; Klöppel, Günter; Detlefsen, Sönke


    cells in the cystic areas were reminiscent of acinar cells, and the majority was arranged in a solid growth pattern. Immunohistochemistry revealed >30% positivity for chymotrypsin, chromogranin A, synaptophysin, and CD56. The diagnosis of a mixed acinar-neuroendocrine carcinoma (MAEC) was made. Review...... 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...

  5. 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.

  6. Neuroendocrine mechanisms of development of experimental hyperandrogen-induced anovulation. (United States)

    Reznikov, A G; Sinitsyn, P V; Tarasenko, L V; Polyakova, L I


    An experimental model of hyperandrogen-induced anovulatory infertility (s.c. implantation of Silastic capsules containing testosterone into adult female rats) was used to study morphological, hormonal, and biochemical measures characterizing the state of the hypothalamo-hypophyseal-ovarian system. Impairments in functional androgen metabolism in the hypothalamus were seen, with decreases in the Luliberin sensitivity of the hypophysis, changes in the structure of estral cycles, and morphological changes in the ovaries; these findings are evidence for neuroendocrine disturbances in the control of ovulation. Flutamide, an experimental antiandrogen, led to partial normalization of the hormonal, biochemical, and morphological characteristics, as well as to recovery of fertility in females with anovulatory infertility.

  7. Controversies in the treatment of digestive neuroendocrine tumors

    Institute of Scientific and Technical Information of China (English)

    Maria Rinzivillo; Francesco Panzuto; Gianfranco Delle Fave


    Gastroenteropancreatic neuroendocrine tumors (NETs) have an incidence of 2.39 per 100,000 inhabitants per year, and a prevalence of 35 cases per 100,000 inhabitants; the gap between these rates is due to the relatively long survival time of these tumors, which can be thus considered as chronic oncological diseases. Recently, more therapeutic options have become available, but criteria for deifning timing, priority and sequence of different therapeutic options are still debated. This review offers an overview of pancreatic and small bowel NETs, critically underlining the issues that still need to be clariifed and some controversial issues on the therapeutic approach for NET patients.

  8. Circulating neuroendocrine tumors biomarkers. Why? When? How? Suggestions for clinical practice from guidelines and consensus

    Institute of Scientific and Technical Information of China (English)

    Paola Razzore; Giorgio Arnaldi


    Neuroendocrine neoplasms (NETs) are rare tumors that are increasing in incidence. NETs are characterized by heterogeneous biological behaviour, clinical presentation and course. A sensitive and speciifc diagnostic and prognostic circulating biomarker useful for all sites, grading and staging of neuroendocrine tumors is still an unmet need. The aim of this article was to review current neuroendocrine and oncologic scientiifc society guidelines and position statements, and propose recommendations for the most frequent clinical practice queries on circulating neuroendocrine tumors biomarkers. The authors searched for NCCN, NANETS, ESMO, ENETS, UKINETS, AME management guidelines or position statements available from PubMed up to 7th January 2016. From these results we chose guidelines or position statements published by scientiifc societies or institutions in USA, Europe and Italy with recognized expertise in neuroendocrine tumor patient management. The authors present suggestions for clinical practice based on this analysis.

  9. Neuroendocrine carcinoma of the ampulla of Vater causing ectopic adrenocorticotropic hormone-dependent Cushing's syndrome (United States)



    Ectopic adrenocorticotropic hormone (ACTH) is rarely secreted by neuroendocrine tumors. Although neuroendocrine tumors may occur at any site in the gastrointestinal system, they very rarely occur in the ampulla of Vater and have a poor prognosis. The present study described the first Cushing's syndrome as a result of ectopic ACTH arising from the ampulla of Vater neuroendocrine carcinoma. A 69-year-old female was admitted with clinical features of Cushing's syndrome, confirmed biochemically by hypokalemia, and elevated levels of ACTH and cortisol. In further investigations, a tumor of the ampulla of Vater and liver metastases were detected. Pathological analysis of the biopsy confirmed a neuroendocrine carcinoma, which was immunohistochemically positive for chromogranin A, synaptophysin, cluster of differentiation 56 and ACTH. Therefore, the present study diagnosed a functional and metastatic neuroendocrine carcinoma of the ampulla of Vater with ectopic ACTH production causing Cushing's syndrome. The patient succumbed to mortality 4 months later, despite administration of combined chemotherapy with irinotecan and cisplatin. PMID:27330779

  10. Calcium dynamics in the secretory granules of neuroendocrine cells. (United States)

    Alvarez, Javier


    Cellular Ca(2+)signaling results from a complex interplay among a variety of Ca(2+) fluxes going across the plasma membrane and across the membranes of several organelles, together with the buffering effect of large numbers of Ca(2+)-binding sites distributed along the cell architecture. Endoplasmic and sarcoplasmic reticulum, mitochondria and even nucleus have all been involved in cellular Ca(2+) signaling, and the mechanisms for Ca(2+) uptake and release from these organelles are well known. In neuroendocrine cells, the secretory granules also constitute a very important Ca(2+)-storing organelle, and the possible role of the stored Ca(2+) as a trigger for secretion has attracted considerable attention. However, this possibility is frequently overlooked, and the main reason for that is that there is still considerable uncertainty on the main questions related with granular Ca(2+) dynamics, e.g., the free granular [Ca(2+)], the physical state of the stored Ca(2+) or the mechanisms for Ca(2+) accumulation and release from the granules. This review will give a critical overview of the present state of knowledge and the main conflicting points on secretory granule Ca(2+) homeostasis in neuroendocrine cells.

  11. Pancreatic neuroendocrine tumors: biology, diagnosis,and treatment

    Institute of Scientific and Technical Information of China (English)

    Cynthia Ro; Wanxing Chai; Victoria E.Yu; Run Yu


    Pancreatic neuroendocrine tumors (PNETs),a group of endocrine tumors arising in the pancreas,are among the most common neuroendocrine tumors.The genetic causes of familial and sporadic PNETs are somewhat understood,but their molecular pathogenesis remains unknown.Most PNETs are indolent but have malignant potential.The biological behavior of an individual PNET is unpredictable; higher tumor grade,lymph node and liver metastasis,and larger tumor size generally indicate a less favorable prognosis.Endocrine testing,imaging,and histological evidence are necessary to accurately diagnose PNETs.A 4-pronged aggressive treatment approach consisting of surgery,Iocoregional therapy,systemic therapy,and complication control has become popular in academic centers around the world.The optimal application of the multiple systemic therapeutic modalities is under development; efficacy,safety,availability,and cost should be considered when treating a specific patient.The clinical presentation,diagnosis,and treatment of specific types of PNETs and familial PNET syndromes,including the novel Mahvash disease,are summarized.

  12. 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.

  13. Morphological and functional investigations of neuroendocrine tumors of the pancreas. (United States)

    Pereira, Philippe L; Wiskirchen, Jakub


    Neuroendocrine tumors of the pancreas are rare neoplasms arising predominantly from the pancreatic islets of Langerhans and are thus known as islet cell tumors. More than the half of all neuroendocrine tumors are called functioning islet cell tumors because they secrete one or more biologically active peptides that may produce clinical symptoms. Clinical diagnosis of non-functioning, i.e., biologically inactive, tumors is often delayed and patients tend to present with advanced tumors (size greater than 5 cm) that are easily localized by using conventional imaging modalities. On the other hand, symptoms of functioning islet cell tumors usually appear early in the clinical course, rendering the preoperative localization of these small hormone-producing tumors (size less than 2 cm) difficult with non-invasive methods. Since functioning islet cell tumors can often be cured by surgical resection, invasive procedures are warranted when necessary for localization diagnosis. Failure to search for, detect, and resect these small tumors will invariably result in persistent symptoms. Regarding the unsatisfactory results of morphological imaging methods, functional studies, especially arterial stimulation with hepatic venous samplings, may provide a preoperative regionalization of the pancreatic adenoma, regardless of its size.

  14. A rare case report of a primary large-cell neuroendocrine carcinoma of the breast with coexisting Paget disease. (United States)

    Psoma, Elizabeth; Nikolaidou, Olga; Stavrogianni, Thomai; Mavromati, Areti; Lytras, Konstantinos; Xirou, Persefoni; Koumbanaki, Melanie; Panagiotopoulou, Dimitra


    Neuroendocrine carcinomas are malignancies deriving from neuroendocrine cells existing in various sites of the body, most commonly in the lungs and gastrointestinal tract. Primary neuroendocrine carcinomas of the breast are extremely rare, and their diagnosis is confirmed by positive neuroendocrine markers. We describe a case of a 46-year-old woman with a palpable mass in her left breast for the previous 3 months. The tumor was resected and a primary large-cell neuroendocrine tumor of the breast was confirmed by histopathologic examination. Paget disease of the nipple was noted as well.

  15. Well differentiated neuroendocrine tumor of the kidney: Report of a rare case with review of literature

    Directory of Open Access Journals (Sweden)

    Kavita Mardi


    Full Text Available Neuroendocrine tumors (NETs are uncommon tumors that exhibit a wide range of neuroendocrine differentiation and biological behavior. Primary NETs of the kidney, including carcinoid tumor, small cell carcinoma (SCC, and large cell neuroendocrine carcinoma (LCNEC are exceedingly rare. Renal carcinoids are typically slow-growing tumors and pursue a variable clinical course. In contrast, SCC and LCNEC often present with locally advanced or metastatic disease and carry a poor prognosis. We herein report a rare cases of well-differentiated NET (carcinoid in a 39-year-old male along with the immunohistochemical features. The rarity of these tumors poses a diagnostic and therapeutic challenge.

  16. Pancreatic neuroendocrine tumor accompanied with multiple liver metastases

    Institute of Scientific and Technical Information of China (English)

    Tomohide; Hori; Kyoichi; Takaori; Shinji; Uemoto


    Pancreatic neuroendocrine tumor(P-NET) is rare and slow-growing. Current classifications predict its progno-sis and postoperative recurrence. Curative resection is ideal, although often difficult, because over 80% of pa-tients have unresectable multiple liver metastases and extrahepatic metastasis. Aggressive surgery for liver metastases is important to improve survival. Aggressive or cytoreductive surgery for liver metastases is indi-cated to reduce hormone levels and improve symptoms and prognosis. Liver transplantation was originally con-ceived as an ideal therapy for unresectable liver metas-tases. Unfortunately, there is no clear consensus on the role and timing of surgery for primary tumor and liver metastases. Surgeons still face questions in deciding the best surgical scenario in patients with P-NET with unresectable liver metastases.

  17. An unusual presentation of "silent" disseminated pancreatic neuroendocrine tumor

    Institute of Scientific and Technical Information of China (English)

    Dragomir Marisavljevic; Natasa Petrovic; Nikola Milinic; Vesna Cemerikic; Miodrag Krstic; Olivera Markovic; Dragoljub Bilanovic


    To present a patient diagnosed with pancreatic carcinoid that was extremely rare and produced an atypical carcinoid syndrome.We reported a 58-year old male patient who presented with long standing,prominent cervical lymphadenopathy and occasional watery diarrhea.Pathohistological and immunohistochemical examination of lymph node biopsy showed a metastatic neuroendocrine tumor,which was histological type A of carcinoid (EMA+,cytokeratin+,CEA-,NSE+,chromogranin A+,synaptophysin+,insulin-).Bone marrow biopsy showed identical findings.Primary site of the tumor was pancreas and diagnosis was made according to cytological and immunocytochemical analysis of the tumor cells obtained with aspiration biopsy of pancreatic mass (12 mm in diameter) under endoscopic ultrasound guidance.However,serotonin levels in blood and urine samples were normal.It is difficulty to establish the precise diagnosis of a "functionally inactive" pancreatic carcinoid and aspiration biopsy of pancreatic tumor under endoscopic ultrasound guidance can be used as a new potent diagnostic tool.

  18. [Neuroendocrine dysfunction and brain damage. A consensus statement]. (United States)

    Leal-Cerro, Alfonso; Rincón, María Dolores; Domingo, Manel Puig


    This consensus statement aims to enhance awareness of the incidence and risks of hypopituitarism in patients with traumatic brain injury (TBI) and/or brain hemorrhages among physicians treating patients with brain damage. The importance of this problem is related not only to the frequency of TBI but also to its prevalence in younger populations. The consequences of TBI are characterized by a series of symptoms that depend on the type of sequels related to neuroendocrine dysfunction. The signs and symptoms of hypopituitarism are often confused with those of other sequels of TBI. Consequently, patients with posttraumatic hypopituitarism may receive suboptimal rehabilitation unless the underlying hormone deficiency is identified and treated. This consensus is based on the recommendation supported by expert opinion that patients with a TBI and/or brain hemorrhage should undergo endocrine evaluation in order to assess pituitary function and, if deficiency is detected, should receive hormone replacement therapy.

  19. 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. PMID:28190820

  20. 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.

  1. Role of neuropeptide FF in central cardiovascular and neuroendocrine regulation. (United States)

    Jhamandas, Jack H; Goncharuk, Valeri


    Neuropeptide FF (NPFF) is an octapeptide belonging to the RFamide family of peptides that have been implicated in a wide variety of physiological functions in the brain including central cardiovascular and neuroendocrine regulation. The effects of these peptides are mediated via NPFF1 and NPFF2 receptors that are abundantly expressed in the rat and human brain. Herein, we review evidence for the role of NPFF in central regulation of blood pressure particularly within the brainstem and the hypothalamic paraventricular nucleus (PVN). At a cellular level, NPFF demonstrates distinct responses in magnocellular and parvocellular neurons of the PVN, which regulate the secretion of neurohypophyseal hormones and sympathetic outflow, respectively. Finally, the presence of NPFF system in the human brain and its alterations within the hypertensive brain are discussed.

  2. Neuroendocrine mechanism of seasonal reproduction in birds and mammals. (United States)

    Yoshimura, Takashi


    In temperate zones, animals use changes in day length as a calendar to time their breeding season. However, the photoreceptive and neuroendocrine mechanisms of seasonal reproduction are considered to differ markedly between birds and mammals. This can be understood from the fact that the eye is the only photoreceptive organ, and melatonin mediates the photoperiodic information in mammals, whereas in birds, photoperiodic information is directly received by the deep brain photoreceptors and melatonin is not involved in seasonal reproduction. Recent molecular and functional genomics analysis uncovered the gene cascade regulating seasonal reproduction in birds and mammals. Long day-induced thyroid stimulating hormone in the pars tuberalis of the pituitary gland regulates thyroid hormone catabolism within the mediobasal hypothalamus. Further, this local thyroid hormone catabolism appears to regulate seasonal gonadotropin-releasing hormone secretion. These findings suggest that although the light input pathway is different between birds and mammals (i.e. light or melatonin), the core mechanisms are conserved in these vertebrates.

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

    Energy Technology Data Exchange (ETDEWEB)

    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)

  4. Intrahypothalamic neuroendocrine actions of corticotropin-releasing factor. (United States)

    Almeida, O F; Hassan, A H; Holsboer, F


    Most studies of the neuroendocrine effects of corticotropin-releasing factor (CRF) have focused on its role in the regulation of the pituitary-adrenal axis; activation of this axis follows release of the peptide from CRF-containing terminals in the median eminence. However, a sizeable proportion of CRF fibres terminate within the hypothalamus itself, where synaptic contacts with other hypothalamic neuropeptidergic neurons (e.g. gonadotropin-releasing hormone-containing and opioidergic neurons) have been identified. Here, we summarize physiological and pharmacological data which provide insights into the nature and significance of these intrahypothalamic connections. It is now clear that CRF is a potent secretagogue of the three major endogenous opioid peptides (beta-endorphin, Met-enkephalin and dynorphin) and that it stimulates opioidergic neurons tonically. In the case of beta-endorphin, another hypothalamic peptide, arginine vasopressin, appears to be an essential mediator of CRF's effect, suggesting the occurrence of CRF synapses on, or in the vicinity of, vasopressin neurons; morphological support for this assumption is still wanting. Evidence for direct and indirect inhibitory effects of CRF on sexual behaviour and secretion of reproductive hormones is also presented; the indirect pathways include opioidergic neurons. An important conclusion from all these studies is that, in addition to its better known functions in producing adaptive responses during stressful situations, CRF might also contribute to the coordinated functioning of various components of the neuroendocrine system under basal conditions. Although feedback regulation of hypothalamic neuronal activity by peripheral steroids is a well-established tenet of endocrinology, data on modulation of the intrahypothalamic actions of CRF by adrenal and sex steroids are just emerging. Some of these newer findings may be useful in framing questions related to the mechanisms underlying disease states (such as

  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. GLP1 and glucagon co-secreting pancreatic neuroendocrine tumor presenting as hypoglycemia after gastric bypass

    DEFF Research Database (Denmark)

    Guimarães, Marta; Rodrigues, Pedro; Pereira, Sofia S;


    Post-prandial hypoglycemia is frequently found after bariatric surgery. Although rare, pancreatic neuroendocrine tumors (pNET), which occasionally are mixed hormone secreting, can lead to atypical clinical manifestations, including reactive hypoglycemia. Two years after gastric bypass surgery for...

  7. SPECT/CT in neuroendocrine cancers; SPECT/CT bei neuroendokrinen Tumoren

    Energy Technology Data Exchange (ETDEWEB)

    Miederer, M. [Technische Univ. Muenchen (Germany). Nuklearmedizinische Klinik und Poliklinik; Mainz Univ. (Germany). Klinik und Poliklinik fuer Nuklearmedizin; Castrop, C.; Scheidhauer, K. [Technische Univ. Muenchen (Germany). Nuklearmedizinische Klinik und Poliklinik; Buck, A.K. [Universitaetsklinikum Wuerzburg (Germany). Nuklearmedizinische Klinik und Poliklinik


    The accuracy of functional SPECT imaging has been significantly improved by addition of CT. This is especially relevant for functional imaging of neuroendocrine tumors using highly specific radiopharmaceuticals. Parathyroid adenomas can be detected by {sup 99m}Tc-MIBI SPECT/CT with very high sensitivity and specificity, playing an important role especially when minimally invasive techniques are used for surgical resection. With SPECT/CT, extra-adrenal manifestations of pheochromocytomas and tumors of the adrenal cortex can be detected with high accuracy. Because of the availability of PET radiopharmaceuticals such as {sup 68}Ga-DOTATOC, the clinical relevance of {sup 111}In-Octreotide SPECT for detection of neuroendocrine cancers has been recently reduced. Because of the better availability, SPECT and SPECT/CT still represent standard tools for imaging neuroendocrine cancers. SPECT/CT represents the superior imaging modality for monitoring radiopeptide based therapies, which are now increasingly used for treatment of neuroendocrine cancers. (orig.)

  8. Small Cell Neuroendocrine Carcinoma of the Urinary Tract Successfully Managed with Neoadjuvant Chemotherapy


    Mustapha Ahsaini; Omar Riyach; Mohammed Fadl Tazi; Mohammed Jamal El Fassi; My Hassan Farih; Hind Elfatmi; Afaf Amarti


    Introduction. Small cell neuroendocrine carcinomas of the urinary tract is an extremely rare entity and very few cases have been reported in the literature. Small cell neuroendocrine carcinoma of the urinary tract (SCC-UT) is the association between bladder and urinary upper tract-small cell carcinoma (UUT-SCC). It characterized by an aggressive clinical course. The prognosis is poor due to local or distant metastases, and usually the muscle of the bladder is invaded. Case Presentation. We...

  9. Stress and the neuroendocrine system: the role of exercise as a stressor and modifier of stress


    Hackney, Anthony C


    In this article, the physiological impact of one form of stress – physical exercise – on the neuroendocrine system will be discussed. The specific intent of the review is to present an overview of stress endocrinology, the conceptual models associated with this area of study, and a discourse on the dual role of exercise as both a stressor and a modifier of stress within the neuroendocrine system. These points are addressed with respect to the current research literature dealing with exercise ...

  10. Basaloid squamous carcinoma of the supraglottic larynx with neuro-endocrine features

    Directory of Open Access Journals (Sweden)

    Rajjyoti Das


    Full Text Available Basaloid squamous carcinoma (BSC is a rare aggressive variant of squamous cell carcinoma and occurs mainly at the larynx, oropharynx and tongue of the head and neck region. Neuro-endocrine differentiation of BSC is further rare occurrence in laryngeal cancers. We report here a case of BSC of supraglottic larynx with neuro-endocrine differentiation, which was treated by radiotherapy and its response to treatment.

  11. Large-Cell Neuroendocrine Carcinoma of the Esophagus: A Case from Saudi Arabia

    Directory of Open Access Journals (Sweden)

    Hadi Kuriry


    Full Text Available Neuroendocrine carcinomas of the esophagus are very rare, and the majority are high grade (poorly differentiated. They occur most frequently in males in their sixth and seventh decades of life. There have been no concrete data published on clinical features or on prognosis. We report a case of large-cell neuroendocrine carcinoma of the esophagus in a 66-year-old Saudi female with progressive dysphagia and weight loss. Upper endoscopy revealed an esophageal ulcerated mass.

  12. Endoscopic resection of duodenal bulb neuroendocrine tumor larger than 10 mm in diameter

    Directory of Open Access Journals (Sweden)

    Naka Teiji


    Full Text Available Abstract Background Endoscopic treatment for duodenal bulb neuroendocrine tumor larger than 10 mm is still controversial. This report presents four cases successfully treated with endosonography (EUS-assisted endoscopic mucosal resection (EMR procedure for duodenal bulb neuroendocrine tumor larger than 10 mm in diameter. Methods The case series of four patients diagnosed with neuroendocrine tumor from 2003 to 2008 were reviewed. EUS demonstrated well-defined hypoechoic tumors confined to the submucosal hyperechoic layer and the underlying hypoechoic muscularis propria was intact in all four patients. EMR were planned and performed for the duodenal bulb neuroendocrine tumors larger than 10 mm. Results En bloc resections with tumor free lateral and basal margins were accomplished using an endoscopic diathermic snare with forward-viewing instruments without any complications. Neither residual duodenal neuroendocrine tumors nor metastatic lesions were detected during the observation period ranging 19 to 78 months Conclusion Duodenal bulb neuroendocrine, larger than 10 mm in diameter, can be treated by endoscopic procedure, after confirming that the tumor confined to the submucosal layer in EUS examination, and no lymph node involvement by abdominal CT and US.

  13. 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

  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. 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

  16. Intracerebroventricular leptin injection affects neuroendocrine reproductive axis in ovariectomized rats

    Institute of Scientific and Technical Information of China (English)

    Yuebing Qiao; Huixian Cui


    BACKGROUND: Leptin regulates neuroendocrine function of the hypothalamus-pituitary-ovary axis in humans.OBJECTIVE: To verify effects of intracerebroventricular leptin injection on neuroendocrine function of the hypothalamus-pituitary-ovary axis in nvariectomized rats.DESIGN, TIME AND SETTING: A randomized, controlled experiment was performed at the Basic Medical Institute, Chengde Medical College between June and October 2007.MATERIALS: Thirty healthy, female, Wistar rats were included in this study. The following compounds were used: leptin; gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) enzyme-linked immunosorbent assay kits.METHODS: Rats were randomly divided into 3 groups at 1, 2, and 4 hours after injection. Each group was subdivided into control and experimental groups (n = 5 animals per group and time point). All rats were subjected to bilateral ovariectomy and, beginning on day 7 after surgery, animals received daily subcutaneous injections of estradiol benzoate (2 μ g) for 7 consecutive days. The experimental groups were injected with 5 μ L leptin (1 g/L) into the lateral cerebral ventricle, and control groups received an equal volume of physiological saline.MAIN OUTCOME MEASURES: GnRH and LH secretion were examined 1, 2, and 4 hours after injection using GnRH and LH ELISA kits, respectively.RESULTS: In the experimental groups, GnRH secretion significantly increased (P < 0.01), followed by LH secretion (P < 0.01), compared with the control groups. GnRH secretion significantly increased l hour after leptin injection (P < 0.01). The LH increase was less pronounced, but still significant (P < 0.01); however,the most prominent LH increase occurred between 1 and 2 hours. Both GnRH and LH secretion reached peak levels at 2 hours after leptin injection. Thereafter, both GnRH and LH secretion decreased, but still maintained very high levels, compared with the control group (P < 0.01).CONCLUSION: lntracerebroventricular leptin injection

  17. Therapy of neuroendocrine tumors with radiolabeled somatostatin-analogues

    Energy Technology Data Exchange (ETDEWEB)

    De Jong, M.; Breeman, A.P.; Bernard, H.F.; Kooij, P.P.M.; Kwekkeboom, D.J.; Valkema, R. [Rotterdam University Hospital and Erasmus University, Rotterdam (Netherlands). Internal Medicine; Van Eijck, C.H.J.; Slooter, G.D. [Basel Surgery, Basel (Switzerland). Dept. of Nuclear Medicine; Maecke, H.R.; Krenning, E.P. [Basel Kantonspital, Basel (Switzerland). Dept. of Nuclear Medicine


    Peptide receptor scintigraphy with the radioactive somatostatin-analogue ({sup 111}In-DTPA{sup 0})octreotide (DTPA=diethylenetriaminepentaacetic acid) is a sensitive and specific technique to show in vivo the presence and abundance of somatostatin receptors on various tumors. With this technique primary tumors and metastases of neuroendocrine cancers as well as of many other cancer types can be localised. A new application is the use of peptide receptor radionuclide therapy, administrating high doses of {sup 111}In- or {sup 90}Y-labeled octreotide-analogues. In the preclinical situation it was investigated on the radiotherapeutic effect of {sup 90}Y- and {sup 111}In-labeled (DOTA{sup 0}, Tyr{sup 3})octreotide (DOTA=tetraazacyclododecanetetraacetic acid) or ({sup 111}In-DTPA{sup 0})octreotide in Lewis rats bearing the somatostatin receptor-positive rat pancreatic tumor CA20948 in (A) the flank of (B) in the liver. Thirty end-stage patients with mostly neuroendocrine progressing tumors were treated with ({sup 111}In-DTPA{sup 0})octreotide, up to a maximal cumulative patient dose of about 74 GBq, in a phase 1 trial. (A) Flank model: at least two 111MBq injections of ({sup 111}In-DOTA{sup 0}, Tyr{sup 3})octreotide were needed to reach tumor response, in 40% of the animals complete tumor remission was found after a follow-up period of 10 months. One or two injections of ({sup 90}Y-DOTA{sup 0}, Tyr{sup 3})octreotide yielded transient stable disease. (B) Liver model: it was found that peptide receptor radionuclide therapy is only effective if somatostatin receptors are present on the tumors, and is therefore receptor-mediated. High radioactive doses of 370 MBq ({sup 111}In-DTPA{sup 0})octreotide or 93 MBq ({sup 90}Y-DOTA{sup 0}, Tyr{sup 3})octreotide can inhibit the growth of somatostatin receptor-positive metastases. There were no major clinical side effects after up to 2 years treatment, except that a transient decline in platelet counts and lymphocyte subsets can occur

  18. Neuroendocrine carcinoma of the ovotestis: A case report and review of literatures (United States)

    Ashrafganjoei, Tahereh; Sourati, Ainaz; Mohamadianamiri, Mahdiss


    Background: Neuroendocine carcinoma of the gynecologic tract is rare and poses a significant clinical challenge because of tumor heterogeneity and lack of standardized guidelines for treatment. Ovotestis refers to the histology of a gonad that contains both ovarian follicles and testicular tubular elements. Ovotesticular disorder of sexual development occurs in fewer than 10% of all disorders of sexual development. Gonadal tumors with malignant potential occur in 2.6% of all cases of ovotesticular disorder of sexual development. Case: Here we represent a 77-year-old woman with primary amenorrhea, infertility and 10cm solid mass in left adnex with 46 XY in karyotype with ovotestis neuroendocrine neoplasm in pathology report which was treated with a multi-modality manner including surgery and chemotherapy but she came back with pulmonary metastasis after 2 cycles of chemotherapy. For women who present with a stage 1 primary ovarian neuroendocrine tumor the prognosis is excellent with greater than 90% survival. Neuroendocrine tumor of the ovary represents 3 % of all neuroendocrine tumors. The prevalence of ovotestis is 1/20000 births. For women with more advanced disease, the prognosis is poor. Neuroendocrine carcinoma of the ovary is a rare and aggressive tumor commonly associated with other surface epithelial and germ cell neoplasms. The prevalence of ovotestis is 1/20000 births and gonadal malignancies are the most reported neoplasm affected the ovotestis. Here we report a case of ovotestis which is presented with neuroendocrine carcinoma and poor prognosis. Conclusion: Neuroendocrine carcinoma of the ovary is a rare and aggressive tumor commonly associated with other surface epithelial and germ cell neoplasms. The prevalence of ovotestis is rare and gonadal malignancies are the most reported neoplasm affected the ovotestis. PMID:28066838


    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. Whole-genome landscape of pancreatic neuroendocrine tumours. (United States)

    Scarpa, Aldo; Chang, David K; Nones, Katia; Corbo, Vincenzo; Patch, Ann-Marie; Bailey, Peter; Lawlor, Rita T; Johns, Amber L; Miller, David K; Mafficini, Andrea; Rusev, Borislav; Scardoni, Maria; Antonello, Davide; Barbi, Stefano; Sikora, Katarzyna O; Cingarlini, Sara; Vicentini, Caterina; McKay, Skye; Quinn, Michael C J; Bruxner, Timothy J C; Christ, Angelika N; Harliwong, Ivon; Idrisoglu, Senel; McLean, Suzanne; Nourse, Craig; Nourbakhsh, Ehsan; Wilson, Peter J; Anderson, Matthew J; Fink, J Lynn; Newell, Felicity; Waddell, Nick; Holmes, Oliver; Kazakoff, Stephen H; Leonard, Conrad; Wood, Scott; Xu, Qinying; Nagaraj, Shivashankar Hiriyur; Amato, Eliana; Dalai, Irene; Bersani, Samantha; Cataldo, Ivana; Dei Tos, Angelo P; Capelli, Paola; Davì, Maria Vittoria; Landoni, Luca; Malpaga, Anna; Miotto, Marco; Whitehall, Vicki L J; Leggett, Barbara A; Harris, Janelle L; Harris, Jonathan; Jones, Marc D; Humphris, Jeremy; Chantrill, Lorraine A; Chin, Venessa; Nagrial, Adnan M; Pajic, Marina; Scarlett, Christopher J; Pinho, Andreia; Rooman, Ilse; Toon, Christopher; Wu, Jianmin; Pinese, Mark; Cowley, Mark; Barbour, Andrew; Mawson, Amanda; Humphrey, Emily S; Colvin, Emily K; Chou, Angela; Lovell, Jessica A; Jamieson, Nigel B; Duthie, Fraser; Gingras, Marie-Claude; Fisher, William E; Dagg, Rebecca A; Lau, Loretta M S; Lee, Michael; Pickett, Hilda A; Reddel, Roger R; Samra, Jaswinder S; Kench, James G; Merrett, Neil D; Epari, Krishna; Nguyen, Nam Q; Zeps, Nikolajs; Falconi, Massimo; Simbolo, Michele; Butturini, Giovanni; Van Buren, George; Partelli, Stefano; Fassan, Matteo; Khanna, Kum Kum; Gill, Anthony J; Wheeler, David A; Gibbs, Richard A; Musgrove, Elizabeth A; Bassi, Claudio; Tortora, Giampaolo; Pederzoli, Paolo; Pearson, John V; Waddell, Nicola; Biankin, Andrew V; Grimmond, Sean M


    The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

  1. Hepatic arterial embolization in patients with neuroendocrine tumors (United States)


    Liver metastases occur in 46-93% of patients with neuroendocrine neoplasms (NENs). Presence and extension of liver metastases are considered important prognostic factors, as they may significantly impair the patient’s quality of life, because of either tumor bulk or hormonal hypersecretion. Therapies for NEN liver metastases include surgical resection, liver transplantation, chemotherapy and biotherapy. Surgery is the gold standard for curative therapy, but in most of NEN patients with liver metastases, when surgery can not be applied, minimally invasive therapeutic approaches are adopted. They include trans-arterial embolization (TAE), trans-arterial chemoembolization (TACE), radiofrequency thermal ablation and new emerging techniques. TAE is based on selective infusion of particles in the branch of the hepatic artery supplying the tumor lesions. The goal of TAE is to occlude tumor blood vessels resulting in ischemia and necrosis. Many reports have shown that TAE can reduce tumor size and hormone output, resulting in palliation of symptoms without the use of cytotoxic drugs, resulting in better tolerability. This review will focus on TAE performance and safety in NEN patients with liver metastases. PMID:24887262

  2. Peptide receptor radionuclide therapy: focus on bronchial neuroendocrine tumors. (United States)

    Lo Russo, Giuseppe; Pusceddu, Sara; Prinzi, Natalie; Imbimbo, Martina; Proto, Claudia; Signorelli, Diego; Vitali, Milena; Ganzinelli, Monica; Maccauro, Marco; Buzzoni, Roberto; Seregni, Ettore; de Braud, Filippo; Garassino, Marina Chiara


    Well-differentiated bronchial neuroendocrine tumors (B-NETs) are rare. They represent 1-5 % of all lung cancers. The incidence of these neoplasms has risen over the past 30 years and, especially for advanced or metastatic disease, management is complex and requires a multidisciplinary approach. Treatment with somatostatin analogs (SSAs) is the most important first-line therapy, in particular in well-differentiated NETs with high somatostatin type receptor (SSTR) expression. In these tumors, the role of mammalian target of rapamycin (m-TOR) inhibitors and the potential utility of other target therapies remain unclear while chemotherapy represents the gold standard treatment only for aggressive forms with low SSTR expression. Peptide receptor radionuclide therapy (PRRT) is an emerging treatment modality for advanced NETs. There are many cumulative evidences about the effectiveness and tolerability of this therapeutic approach, especially in gastro-entero-pancreatic (GEP)-NETs. For B-NETs, scientific research is moving more slowly. Here, we performed a review in order to evaluate the efficacy and toxicity of PRRT with a focus on patients with inoperable or metastatic well-differentiated B-NETs.

  3. Neuroendocrine control of physiological color change in Chameleo gracilis. (United States)

    Okelo, O


    Color changes in Chameleo gracilis are under neuroendocrine control. Denervation of the limbs, by removal of the sciatic or brachial nerves, does not interfere with the normal color changes in the affected limbs. Denervated skins, placed back onto C. gracilis, show color changes in synchrony with the rest of the animal. Pieces of isolated skin turn very dark or black in alpha-melanophore stimulating hormone (alpha-MSH) and green in adrenaline, but do not show any color changes in physiological saline. Hypophysectomized animals turn green but never turn dark. Injections of alpha-MSH cause intact or hypophysectomized animals to turn dark or black, while injections of adrenaline cause them to turn light green. Injections of physiological saline have no effect. Crude pituitary extracts cause darkening of isolated skins or of intact animals injected with such extracts. Similar treatment with crude extracts of adrenal glands causes the skins to become light green. Electrical stimulation of transected spinal cord leads to localized lightening of the skin but never to darkening of the same. Light, temperature, darkness, and color of the surroundings influence color change. Color change to green at night and to darker colors in the daytime suggests a possible circadian rhythm in the phenomenon.

  4. Primary infertility associated with neuroendocrine tumor (Carcinoid) of the appendix

    Institute of Scientific and Technical Information of China (English)

    Brad B Swelstad; Paul R Brezina; Clark T Johnson; Nina Resetkova; Irene Woo; Lisa Kolp


    Neuroendocrine tumors of the appendix(NET-A), formerly called appendiceal carcinoids, are rare tumors of the gastrointestinal tract.Appendiceal tumors have also been associated with infertility. However, in many of these cases, significant abdominal pathology, specifically pseudomyxoma peritonei, was identified during definitive surgical intervention.A34-year-old nulligravid woman undergoing infertility evaluation presented to an academic tertiary care fertility center. An abnormal mass was identified on hysterosalpingogram andCT confirmed appendiceal mass. Surgical removal of the mass was performed and histopathology was consistent with anNET-A with negative margins extending to the serosa.Two months after surgical intervention, the patient spontaneously conceived pregnancy and subsequently delivered a normal infant.This case exemplifies the importance of careful inspection of radiologic films by the gynecologic physician. Of added interest, this case describes an asymptomaticNET-A associated with primary infertility. To our knowledge, this is the first report of an incidentally indentifiedNET-A that resulted in primary infertility.

  5. Neuroendocrine tumors of the gastro-entero-pancreatic system

    Institute of Scientific and Technical Information of China (English)

    Sara Massironi; Valentina Sciola; Maddalena Peracchi; Clorinda Ciafardini; Matilde Pia Spampatti; Dario Conte


    Gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs) are rare neoplasms,although their prevalence has increased substantially over the past three decades.Moreover,there has been an increased clinical recognition and characterization of these neoplasms.They show extremely variable biological behavior and clinical course.Most NETs have endocrine function and secrete peptides and neuroamines that cause distinct clinical syndromes,including carcinoid syndrome; however,many are clinically silent until late presentation with mass effects.Investigation and management should be individualized for each patient,taking into account the likely natural history of the tumor and general health of the patient.Management strategies include surgery for cure or palliation,and a variety of other cytoreductive techniques,and medical treatment including chemotherapy,and biotherapy to control symptoms due to hormone release and tumor growth,with somatostatin analogues (SSAs) and alphainterferon.New biological agents and somatostatintagged radionuclides are under investigation.Advances in the therapy and development of centers of excellence which coordinate multicenter studies,are needed to improve diagnosis,treatment and therefore survival of patients with GEP NETs.(C)2008 The WIG Press.All rights reserved.

  6. Endoscopic diagnosis and treatment of pancreatic neuroendocrine tumors. (United States)

    Rustagi, Tarun; Farrell, James J


    Pancreatic neuroendocrine tumors (PNETs) are rare pancreatic neoplasms comprising only 1% to 2% of all pancreatic tumors. In recent years, the number of incidentally discovered PNETs has greatly increased given the widespread use of axial imaging. However, a significant proportion of PNETs may not be visualized on conventional imaging such as computed tomography, magnetic resonance imaging, and somatostatin receptor scintigraphy. Endoscopic ultrasound (EUS) has become an integral part of the diagnosis of PNETs because of its high sensitivity for detecting, localizing, and diagnosing PNETs. EUS-guided tissue acquisition provides histologic and immunologic confirmation, and may also allow prognostication about tumor behavior. In addition to preoperative assessment of these tumors, EUS has also been shown to have an important role in nonoperative management of small nonfunctional PNETs. Finally, recent developments suggest that interventional EUS may be used to aid intraoperative localization of PNETs and to deliver therapeutic agents for the treatment of PNETs. This review will discuss the endoscopic diagnosis and treatment of PNETs, with focus on recent advances in the utility of EUS in the clinical management of these tumors.

  7. Advanced Gastric Neuroendocrine Carcinoma with an Adenocarcinoma Component

    Directory of Open Access Journals (Sweden)

    Masashi Miguchi


    Full Text Available In the present study, we observed that the adenocarcinoma component in the mucosa was continuous with neuroendocrine carcinoma (NEC in the deeper layers; this suggests the normal course of NEC carcinogenesis at the histological level. A 72-year-old man was admitted to our hospital with a chief complaint of tarry stools. Endoscopic examination of the upper gastrointestinal tract revealed a 2-cm tumor, with a deep central depression, surrounded by a smooth elevated area, in the middle of the stomach body. A biopsy showed that the tumor was a moderately differentiated gastric adenocarcinoma. The patient underwent total gastrectomy and standard lymph node dissection. The resected tumor was a 3.5 × 2.5 cm type 2 lesion. It comprised two elements at the histological level: (i a moderately differentiated adenocarcinoma in the superficial portion of the mucous membrane layer, and (ii NEC-like cells with dark, round nuclei and scant cytoplasm, presenting a solid and trabecular pattern, in the submucosal and muscularis propria layers. Immunohistochemical findings showed that the NEC-like cells were diffusely positive for chromogranin A, synaptophysin, neural cell adhesion molecule, and neuron-specific enolase, but were negative for carcinoembryonic antigen. The Ki-67 labeling index was 95%. The final pathological diagnosis was gastric NEC with an adenocarcinoma component and a high cellular proliferative potential.

  8. Pancreatic neuroendocrine tumours: correlation between MSCT features and pathological classification

    Energy Technology Data Exchange (ETDEWEB)

    Luo, Yanji; Dong, Zhi; Li, Zi-Ping; Feng, Shi-Ting [The First Affiliated Hospital, Sun Yat-Sen University, Department of Radiology, Guangzhou, Guangdong (China); Chen, Jie [The First Affiliated Hospital, Sun Yat-Sen University, Department of Gastroenterology, Guangzhou, Guangdong (China); Chan, Tao; Chen, Minhu [Union Hospital, Hong Kong, Medical Imaging Department, Shatin, N.T. (China); Lin, Yuan [The First Affiliated Hospital, Sun Yat-Sen University, Department of Pathology, Guangzhou, Guangdong (China)


    We aimed to evaluate the multi-slice computed tomography (MSCT) features of pancreatic neuroendocrine neoplasms (P-NENs) and analyse the correlation between the MSCT features and pathological classification of P-NENs. Forty-one patients, preoperatively investigated by MSCT and subsequently operated on with a histological diagnosis of P-NENs, were included. Various MSCT features of the primary tumour, lymph node, and distant metastasis were analysed. The relationship between MSCT features and pathologic classification of P-NENs was analysed with univariate and multivariate models. Contrast-enhanced images showed significant differences among the three grades of tumours in the absolute enhancement (P = 0.013) and relative enhancement (P = 0.025) at the arterial phase. Univariate analysis revealed statistically significant differences among the tumours of different grades (based on World Health Organization [WHO] 2010 classification) in tumour size (P = 0.001), tumour contour (P < 0.001), cystic necrosis (P = 0.001), tumour boundary (P = 0.003), dilatation of the main pancreatic duct (P = 0.001), peripancreatic tissue or vascular invasion (P < 0.001), lymphadenopathy (P = 0.011), and distant metastasis (P = 0.012). Multivariate analysis suggested that only peripancreatic tissue or vascular invasion (HR 3.934, 95 % CI, 0.426-7.442, P = 0.028) was significantly associated with WHO 2010 pathological classification. MSCT is helpful in evaluating the pathological classification of P-NENs. (orig.)

  9. Neuroendocrine carcinoma of the pancreas with soft tissue metastasis

    Institute of Scientific and Technical Information of China (English)

    Jie Chen; Qi Zheng; Zhe Yang; Xin-Yu Huang; Zhou Yuan; Juan Tang


    Neuroendocrine carcinoma (NEC) of the pancreas is rare.We report the case of a 34-year-old man with pancreatic NEC with soft tissue metastasis.The patient presented with right upper abdominal discomfort.Computed tomography revealed a low-density heterogeneous mass in the tail and body of the pancreas that encroached on the greater curvature of the stomach and spleen.We performed exploratory laparotomy and total pancreatectomy with splenectomy and total gastrectomy.Histopathological analysis showed spindleshaped cells with scanty cytoplasm and hyperchromatic nuclei,confirming a primary pancreatic NEC.One month after the surgery,the patient experienced leg swelling.Positron emission tomography-computed tomography revealed high uptake of fludeoxyglucose in the left leg,and the leg was amputated.Histopathological analysis confirmed metastasis of pancreatic NEC.The patient was followed up and received chemotherapy (etoposide and cisplatin).One month after amputation,the level of tumor marker neuron-specific enolase was 142.70 μg/L and computed tomography scan revealed an aggravated metastatic lesion.The patient suffered from unbearable pain and we treated him with odynolysis.Four months postoperatively,the patient died of respiratory failure.

  10. [Activation of the neuroendocrine system during changes in homeostasis during stress conditions]. (United States)

    Vigas, M; Jezová, D


    Neuroendocrine response to stress stimuli is aimed to maintain body homeostasis. The activation of the neuroendocrine system is accomplished mainly by two ways: by feedback regulation based on the recognition of altered metabolic homeostasis by appropriate receptors sending the signal into the CNS, and by forward regulation involving a direct stimulation of the neuroendocrine system by a central command coming from an activated brain regulatory center. With regard to mechanisms of neuroendocrine activation, the signal specificity and site of its origin are of particular importance. The significance of the signal in neuroendocrine responses has been evaluated in three different stress conditions: hypoglycemia, surgical trauma and dynamic physical exercise. The stimulus inducing neuroendocrine response during hypoglycemia is the glucopenia. The signal for the activation of the neuroendocrine response is generated in glucosensitive cells which are not located in a single brain structure (hypothetical glucostat). The signal for growth hormone, vasopressin and oxytocin release is produced in brain structures protected by the blood-brain barrier, that for ACTH release in regions both protected and unprotected by the barrier, while the signal for prolactin release is generated in tissues lacking the blood-brain barrier. The neuroendocrine response during surgical trauma is activated by a signal formed in the damaged tissue reaching the CNS by neural pathways. Moreover, cytokins may participate on endocrine stimulation in those surgical interventions in which a large amount of bacterial endotoxins is released. During a complicated surgery, e.g. during a bypass other signals and modifying factors, such as hypothermia, dilution of blood, hypoperfusion of organs, rewarming of the body and hormone degradation in the oxygenator are important. On the On the other hand, during a short-term dynamic exercise, a forward regulation by a central signal from the activated CNS motor

  11. 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 neuroendocr

  12. Primary Hepatic Neuroendocrine Tumor with Unusual Thyroid Follicular-Like Morphologic Characteristics (United States)

    Ibrahim, Mohd Elmugtaba; Abadeer, Kerolos; Zhai, Qihui (Jim)


    We describe a primary hepatic neuroendocrine tumor of a 57-year-old Thai woman who presented in 2004 with a suspicious mass in the left hepatic lobe. She underwent left hepatectomy for the 10.5-cm mass, called intermediate grade neuroendocrine carcinoma of unknown origin, likely metastatic. The tumor recurred in 2007, then called recurrent primary hepatic neuroendocrine tumor (PHNET), and the patient underwent liver transplant. Because of similarity between the neuroendocrine tumor and a thyroid tumor—specifically, follicular-like characteristics—immunohistochemical stains for thyroglobulin, TTF1, and calcitonin were performed. However, all were negative. All imaging studies revealed no evidence of a primary lesion other than the liver mass. In 2008, the patient's liver transplant failed because of ischemic cholangiopathy, and she underwent a second liver transplant. Seven years later, in 2015, she presented with metastatic neuroendocrine tumor of intermediate grade to the lung, consistent with metastatic PHNET. She underwent left upper-lobe wedge resection to remove the tumor. The patient is alive with no evidence of disease at 13 years after initial diagnosis. This rare variant of PHNET had thyroid-like morphologic characteristics but there is no evidence of primary thyroid tumor or thyroid markers in the primary and recurrent hepatic tumors and lung metastasis.

  13. 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.)

  14. Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the alpha-subunit of glycoprotein hormones



    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 neuroendocrine markers, have not clearly been defined, however. The objectives of this study were to evaluate the clinical usefulness of CgA as neuroendocrine serum marker. Serum levels of CgA, neuron-specific enolase (NSE), a...

  15. Unraveling tumor grading and genomic landscape in lung neuroendocrine tumors. (United States)

    Pelosi, Giuseppe; Papotti, Mauro; Rindi, Guido; Scarpa, Aldo


    Currently, grading in lung neuroendocrine tumors (NETs) is inherently defined by the histological classification based on cell features, mitosis count, and necrosis, for which typical carcinoids (TC) are low-grade malignant tumors with long life expectation, atypical carcinoids (AC) intermediate-grade malignant tumors with more aggressive clinical behavior, and large cell NE carcinomas (LCNEC) and small cell lung carcinomas (SCLC) high-grade malignant tumors with dismal prognosis. While Ki-67 antigen labeling index, highlighting the proportion of proliferating tumor cells, has largely been used in digestive NETs for assessing prognosis and assisting therapy decisions, the same marker does not play an established role in the diagnosis, grading, and prognosis of lung NETs. Next generation sequencing techniques (NGS), thanks to their astonishing ability to process in a shorter timeframe up to billions of DNA strands, are radically revolutionizing our approach to diagnosis and therapy of tumors, including lung cancer. When applied to single genes, panels of genes, exome, or the whole genome by using either frozen or paraffin tissues, NGS techniques increase our understanding of cancer, thus realizing the bases of precision medicine. Data are emerging that TC and AC are mainly altered in chromatin remodeling genes, whereas LCNEC and SCLC are also mutated in cell cycle checkpoint and cell differentiation regulators. A common denominator to all lung NETs is a deregulation of cell proliferation, which represents a biological rationale for morphologic (mitoses and necrosis) and molecular (Ki-67 antigen) parameters to successfully serve as predictors of tumor behavior (i.e., identification of pathological entities with clinical correlation). It is envisaged that a novel grading system in lung NETs based on the combined assessment of mitoses, necrosis, and Ki-67 LI may offer a better stratification of prognostic classes, realizing a bridge between molecular alterations

  16. Factors Associated with Survival of Veterans with Gastrointestinal Neuroendocrine Tumors

    Directory of Open Access Journals (Sweden)

    Bryan L. Balmadrid


    Full Text Available Background. Gastrointestinal (GI neuroendocrine tumor (NET incidence has been increasing; however, GI NET within the national Veterans Affairs (VA health system has not been described. Methods. We used the VA Central Cancer Registry to identify the cohort of patients diagnosed with GI NET in 1995–2009. Cox regression models were constructed to explore factors associated with survival. Results. We included 1793 patients with NET of the stomach (9%, duodenum (10%, small intestine (24%, colon (19% or rectum (38%. Twenty percent were diagnosed in 1995–1999, 35% in 2000–2004, and 45% in 2005–2009. Unadjusted 5-year survival rates were: stomach 56%, duodenum 66%, small intestine 52%, colon 67%, and rectum 84%. Factors associated with shorter survival were increasing age, hazard ratio (HR 1.05 (95% CI 1.04–1.06, NET location [compared to rectum: stomach HR 2.26 (95% CI 1.68–3.05, duodenum HR 1.70 (95% CI 1.26–2.28, small intestine HR 1.85 (95% CI 1.42–2.42, and colon 1.83 (95% CI 1.41–2.39], stage [compared to in situ/local: regional HR 1.15 (95% CI 0.90–1.47, distant HR 2.38 (95% CI 1.87–3.05], and earlier period of diagnosis [compared to 1995–1999: 2000–2004 HR 0.70 (95% CI 0.59–0.85, 2005–2009 HR 0.43 (95% CI 0.34–0.54]. Conclusions. The incidence of GI NET has also increased over time in the VA system with similar survival rates to those observed in non-VA settings. Worsened survival was associated with older age, tumor site, advanced stage, and earlier year of diagnosis.

  17. Genetics and epigenetics in small intestinal neuroendocrine tumours. (United States)

    Stålberg, P; Westin, G; Thirlwell, C


    Neuroendocrine tumour of the small intestine (SI-NET), formerly known as midgut carcinoid tumour, is the most common small intestinal malignancy. The incidence is rising, with recent reports of 0.67 per 100 000 in the USA and 1.12 per 100 000 in Sweden. SI-NETs often present a challenge in terms of diagnosis and treatment, as patients often have widespread disease and are beyond cure by surgery. Somatostatin analogues provide the mainstay of medical treatment to control hormonal excess and increase the time to progression. Despite overall favourable prognosis (5-year overall survival of 65%), there is a need to find markers to identify both patients with worse outcome and new targets for therapy. Loss on chromosome 18 has been reported in 60-90% of SI-NETs, but mutated genes on this chromosome have failed detection. Recently, a putative tumour suppressor role has been suggested for TCEB3C occurring at 18q21 (encoding elongin A3), which may undergo epigenetic repression. CDKN1B has recently been revealed as the only recurrently mutated gene in SI-NETs but, with a frequency as low as 8%, its role as a driver in SI-NET development may be questioned. Integrated genomewide analysis including exome and whole-genome sequencing, gene expression, DNA methylation and copy number analysis has identified three novel molecular subtypes of SI-NET with differing clinical outcome. DNA methylation analysis has demonstrated that SI-NETs have significant epigenetic dysregulation in 70-80% of tumours. In this review, we focus on understanding of the genetic, epigenetic and molecular events that lead to development and progression of SI-NETs.

  18. Neuroendocrine differentiation in endocrine and nonendocrine lung carcinomas. (United States)

    Linnoila, R I; Mulshine, J L; Steinberg, S M; Funa, K; Matthews, M J; Cotelingam, J D; Gazdar, A F


    Bronchial carcinoids and small cell lung cancer (SCLC) are currently recognized as neuroendocrine (NE) neoplasms. However, non-SCLC (NSCLC) may also express NE properties. Paraffin-embedded sections of a comprehensive panel of 113 lung carcinomas were analyzed for the expression of three general markers common to all NE cells, namely, chromogranin A, Leu-7 and neuron-specific enolase (NSE), five specific NE secretory products, and four other tumor markers by immunohistochemistry using the sensitive avidin-biotinylated peroxidase technique. The authors were able to demonstrate the following: (1) most, but not all carcinoids and SCLCs expressed multiple NE markers in a high percentage of tumor cells; (2) up to a half of NSCLC cases contained small subpopulations of cells expressing NE in a high percentage of tumor cells; (2) up to half of NSCLC cases contained small subpopulations of cells expressing NE markers; and (3) occasional NSCLCs showed staining patterns indistinguishable from SCLC. Specifically, 7 of 77 NSCLCs expressed four or more NE markers. NE markers in NSCLCs were more commonly expressed in adenocarcinomas and large cell carcinomas and rarely in squamous cell carcinomas. For comparison, the mean number of NE markers expressed by all cases of NSCLC was 1.5, carcinoids 6.0, and SCLCs 3.8. Individual "marker counts" were not useful in categorizing lung tumors as carcinoids and SCLC versus NSCLC. Instead, 95% of the tumors were correctly classified, applying a statistical model created from staining indices of the three general NE markers (chromogranin A, Leu-7, NSE) and three other tumor markers (carcinoembryonic antigen, keratin, vimentin). Because NSCLCs with NE features might have different clinical characteristics than other NSCLCs, immunohistochemistry provides an effective manner to identify this biologically interesting subset of NSCLCs in routine paraffin sections.

  19. The neuroendocrine system and stress, emotions, thoughts and feelings

    Directory of Open Access Journals (Sweden)

    Vaillant George


    Full Text Available 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.

  20. The neuroendocrine system and stress, emotions, thoughts and feelings

    Directory of Open Access Journals (Sweden)

    George E. Vaillant


    Full Text Available 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.

  1. Simultaneous large cell neuroendocrine carcinoma and adenocarcinoma of the stomach

    Institute of Scientific and Technical Information of China (English)

    Tadashi Terada; Hirotoshi Maruo


    A large cell neuroendocrine carcinoma (LCNEC) of the stomach is very rare. A 76-year-old Japanese man was admitted to our hospital because of epigastralgia and nausea. Endoscopy revealed 2 large tumors in the stomach. He did not have multiple endocrine neoplasia type Ⅰ or Zollinger-Ellison syndrome. Imaging modali-ties, including computed tomography and magnetic resonance imaging, revealed no other tumors. Gas-trectomy, cholecystectomy, and lymph node dissection were performed. The resected stomach had 2 tumors: one was an antral ulcerated type 3 tumor measuring 5 cm x 5 cm, and the other was a polypoid type 1 tumor measuring 6 cm x 6 cm x 3 cm in the fundus. Micro-scopically, the antral ulcerated tumor was a well differ-entiated adenocarcinoma with deep invasion. The fun-dus polypoid tumor was a LCNEC, being composed of malignant large cells arranged in trabecular and nested patterns. The tumor cells were large and the nuclei were vesicular. Nucleoli were frequently present, and there were many mitotic figures, apoptotic bodies, and necrotic areas. Much lymphovascular permeation was seen. Seven out of 29 dissected lymph nodes showed metastatic foci; 6 were from the LCNEC and 1 from the adenocarcinoma. Many intravascular tumor emboli of LCNEC were seen in the peritoneum around the lymph nodes. Mucins were present in the adenocarcinoma but not in the LCNEC. Immunohistochemically, the LCNEC tumor cells were positive for pancytokeratins, synaptophysin (50% positive), chromogranin A (10% positive), Ki-67 (90% labeled), and platelet-derived growth factor-α (80% positive). They were negative for KIT, p53, CD56, and neuron-specific enolase. The non-cancerous stomach showed a normal number of endocrine cells. The patient is now treated with adju-vant chemotherapy.

  2. 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.

  3. MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors. (United States)

    Cros, J; Hentic, O; Rebours, V; Zappa, M; Gille, N; Theou-Anton, N; Vernerey, D; Maire, F; Lévy, P; Bedossa, P; Paradis, V; Hammel, P; Ruszniewski, P; Couvelard, A


    Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O(6)-methylguanine-DNA methyltransferase (MGMT) expression and MGMT promoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression and MGMT promoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0-300) and MGMT promoter methylation by pyrosequencing. Forty-three patients (21 men, 58years (27-84)) with grade 1 WDPNET (n=6) or 2 (n=36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P=0.04) and better progression-free survival (PFS) (HR=0.35 (0.15-0.81), P=0.01). Disease control rate at 18months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. High MGMT promoter methylation was associated with a low MGMT expression and longer PFS (HR=0.37 (0.29-1.08), P=0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50-100) seems to be associated with prolonged stable disease.

  4. Neuroendocrine markers in adenocarcinomas: an investigation of 356 cases

    Institute of Scientific and Technical Information of China (English)

    Gen-You Yao; Ji-Lin Zhou; Mao-De Lai; Xiao-Qing Chen; Pei-Hui Chen


    AIM: To investigate the incidence of neuroendocrine (NE)cells and their hormone products in adenocarcinomas and evaluate their significance in clinical pathology and prognosis.METHODS: By using tissue sectioning and immunocytochemistry, 356 cases of adenocarcinomas were studied to examine the presence of chromorgranin and polypeptide hormones in adenocarcinoma samples from our hospital.RESULTS: The positive rate of NE cells and hormone products was 41.5 % (54/130) and 59.3 % (32/54), respectively in large intestinal adenocarcinoma cases; 39.6 % (38/96) and 36.8 % (14/38), respectively in gastric cancer cases; 38.1%(8/21) and 50.0 % (4/8), respectively in prostatic cancer cases; 21.0 % (17/81) and 17.6 % (3/17), respectively in breasr cancer cases; 17.9 % (5/28) and 60.0 % (3/5),respectively in pancreatic cancer cases. Among carcinomas of large intestine, pancreas and breast, the highly differentiated NE cell numbers were higher than the poorly differentiated NE cell numbers; while the gastric carcinoma cases had more poorly differentiated NE cells than highly differentiated NE cells. The higher detection rate of NE cells and their hormone products, the higher 5-year survival rate among the large intestine cancer cases.CONCLUSION: Close correlation was observed between NE cells and their hormone products with the cancer differentiations. For colorectal carcinomas, there is a close correlation of the presence of NE cells and their hormone products with the tumor staging and prognosis.

  5. [Neuroendocrine carcinoma with large cells of the breast: case report and review of the literature]. (United States)

    Bourhaleb, Z; Uri, N; Haddad, H; Azzouzi, S; Zamiati, S; Benchakroun, N; Tawfiq, N; Jouhadi, H; Sahraoui, S; Benider, A


    Neuroendocrine carcinoma with large cells is a slightly different tumor from the high rank of malignity. We report a case of breast localization in a 28-year-old patient. It is a locally advanced classified T4dN1M0 tumor that required neoadjuvant chemotherapy. The clinical answer was 75% of the level of the tumor. A standard surgery mastectomy with axillary lymph node dissection was realized, followed by external radiotherapy. The anatomopathologic and the immuno-histochemical study of the operational part confirmed the diagnosis of neuroendocrine carcinoma with large cells expressing the progesterone receptor. The patient is subjected to adjuvant hormonal treatment. After a 12 months retreat, a complete remission is maintained. Considering the scarcity of neuroendocrine carcinoma with large cells of the breast, the therapeutic standard is not yet available and the forecast remains difficult to determine.

  6. Profile of capecitabine/temozolomide combination in the treatment of well-differentiated neuroendocrine tumors (United States)

    Kotteas, Elias A; Syrigos, Konstantinos N; Saif, Muhammad Wasif


    Neuroendocrine tumors are a rare and heterogeneous group of tumors with a variety of primary origins and variable aggressiveness. Platinum-based chemotherapy has been the cornerstone of treatment for the poorly differentiated tumors. However, well-differentiated neuroendocrine tumors are quite chemoresistant and therapy options are limited. Octreotide analogs and tyrosine kinase inhibitors are widely acceptable treatments due to substantial efficacy and tolerable toxicity. On the contrary, monotherapy or combinations of the only approved cytotoxic agent streptozocin with other drugs have been almost abandoned because of excessive toxic events. In recent years, the combination of capecitabine and temozolomide has emerged as the most promising and efficacious treatment. The oral route of administration and the substantial improvement in the outcomes with manageable toxicity are the major advantages. We reviewed the current literature and presented the profile of the capecitabine/temozolomide combination in the management of well-differentiated neuroendocrine tumors. PMID:26929640

  7. Cytohistology of papillary carcinoid and emerging concept of pulmonary neuroendocrine neoplasms. (United States)

    Yang, Grace C H


    This timely review starts by reporting the clinical, cytologic and histologic features of a morphologic variant of pulmonary carcinoid tumor forming exclusively of papillae. This growth pattern is so rare that it was not included in 2014 WHO classification of pulmonary neuroendocrine neoplasms. The current concept is reviewed, and example of spindle cell carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma, and small cell carcinoma are illustrated with fine needle aspiration cytology, surgical and clinical follow-up. Finally, the new findings in cell biology and molecular biology that led to the emerging concept that carcinoids and high-grade neuroendocrine lung carcinomas are separate biological entities are reviewed and summarized in a tumorigenic module.

  8. Calcitonin-negative primary neuroendocrine tumor of the thyroid (nonmedullary) in a dog (United States)

    Arias, E.A. Soler; Castillo, V.A.; Aristarain, M.E. Caneda


    The Calcitonin-negative neuroendocrine tumor of the thyroid (CNNET) or “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 expression for calcitonin. An Argentine dogo bitch showed a solid, compact thyroid tumor, which was IHC negative for the expression of calcitonin, carcinoembryonic antigen, thyroglobulin and S100 protein, and positive for synaptophysin and cytokeratin AE1-AE3. The Ki-67 proliferation index was low. We cite this case not only because it is the first case report of calcitonin-negative primary neuroendocrine tumor of the thyroid in dogs but also because we want to highlight the diagnostic importance of IHC in this regard. PMID:27928520

  9. Topotecan Monotherapy in Heavily Pretreated Patients with Progressive Advanced Stage Neuroendocrine Carcinomas

    DEFF Research Database (Denmark)

    Olsen, Ingrid Marie Holst; Knigge, Ulrich; Federspiel, Birgitte;


    BACKGROUND: Neuroendocrine carcinomas (WHO grade 3) are highly aggressive tumors with an immense tendency to metastasize and with a poor prognosis. In advanced disease, there is no standard treatment beyond first-line platin/etoposide-based chemotherapy. Topotecan is widely used as second......-line treatment in small cell lung cancer, which also responds markedly on first-line platin/etoposide. Hence, we investigated the feasibility of topotecan in previously treated patients with neuroendocrine carcinomas. MATERIAL AND METHODS: Retrospective analysis of 22 patients with disseminated and progressive...... 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...

  10. Neuroendocrine-immune system interactions in amphibians: implications for understanding global amphibian declines. (United States)

    Rollins-Smith, L A


    Amphibians are ancient creatures valued by biologists and naturalists around the world. They share with all other vertebrates a complex neuroendocrine system that enables them to flourish in a variety of aquatic and semiaquatic environments. Studies from a number of laboratories have demonstrated that the immune system of amphibian species is nearly as complex as that of mammals. Yet for reasons that are not well understood, amphibian species are facing greater survival challenges than in the recent past. This article will review our current understanding of the neuroendocrine immune system interactions in amphibians and address the question of whether environmental stressors may contribute to immunosuppression and amphibian declines.

  11. Coexistence of small cell neuroendocrine carcinoma and villous adenoma in the ampulla of Vater

    Institute of Scientific and Technical Information of China (English)

    Ji-Hong Sun; Ming Chao; Shi-Zheng Zhang; Guang-Qiang Zhang; Bin Li; Jian-Jun Wu


    Small cell neuroendocrine carcinoma of the ampulla of Vater is extremely rare and different from the common ampullary adenocarcinoma. The ampullary adenoma is also a rare neoplasm and has the potential to develop an adenocarcinoma. Their coexistence has been rarely reported in the literature. We herein describe an unusual case of a small cell neuroendocrine carcinoma associated with a villous adenoma in the ampulla of Vater with emphasis on computed tomography (CT)and histopathological findings. We also discuss their clinical, histopathological and radiological features as well as possible histogenesis.

  12. Neoadjuvant peptide receptor radionuclide therapy for an inoperable neuroendocrine pancreatic tumor

    Institute of Scientific and Technical Information of China (English)

    Daniel Kaemmerer; Vikas Prasad; Wolfgang Daffner; Dieter H(o)rsch; Günter Kl(o)ppel; Merten Hommann; Richard P Baum


    Pancreatic endocrine tumors are rare but are among the most common neuroendocrine neoplasms of the abdomen. At diagnosis many of them are already advanced and difficult to treat. We report on an initially inoperable malignant pancreatic endocrine tumor in a 33-year-old woman, who received neoadjuvant peptide receptor radionuclide therapy (PRRT) as first-line treatment. This resulted in a significant downstaging of the tumor and allowed its subsequent complete surgical removal. Follow-up for eighteen months revealed a complete remission. This is the first report on neoadjuvant PRRT in a neuroendocrine neoplasm with subsequent successful complete resection.

  13. Neuroendocrine abnormalities in patients with traumatic brain injury (United States)

    Yuan, X. Q.; Wade, C. E.


    . Increased intracranial pressure, which releases vasopressin by altering normal hypothalamic anatomy, may represent a unique type of stress to neuroendocrine systems and may contribute to adrenal secretion by a mechanism that requires intact brainstem function. Endocrine function should be monitored in brain-injured patients with basilar skull fractures and protracted posttraumatic amnesia, and patients with SIADH or DI should be closely monitored for other endocrine abnormalities.

  14. Aspectos neuroendocrinos de la obesidad Neuroendocrine aspects of obesity

    Directory of Open Access Journals (Sweden)

    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

  15. Computation and brain processes, with special reference to neuroendocrine systems. (United States)

    Toni, Roberto; Spaletta, Giulia; Casa, Claudia Della; Ravera, Simone; Sandri, Giorgio


    The development of neural networks and brain automata has made neuroscientists aware that the performance limits of these brain-like devices lies, at least in part, in their computational power. The computational basis of a. standard cybernetic design, in fact, refers to that of a discrete and finite state machine or Turing Machine (TM). In contrast, it has been suggested that a number of human cerebral activites, from feedback controls up to mental processes, rely on a mixing of both finitary, digital-like and infinitary, continuous-like procedures. Therefore, the central nervous system (CNS) of man would exploit a form of computation going beyond that of a TM. This "non conventional" computation has been called hybrid computation. Some basic structures for hybrid brain computation are believed to be the brain computational maps, in which both Turing-like (digital) computation and continuous (analog) forms of calculus might occur. The cerebral cortex and brain stem appears primary candidate for this processing. However, also neuroendocrine structures like the hypothalamus are believed to exhibit hybrid computional processes, and might give rise to computational maps. Current theories on neural activity, including wiring and volume transmission, neuronal group selection and dynamic evolving models of brain automata, bring fuel to the existence of natural hybrid computation, stressing a cooperation between discrete and continuous forms of communication in the CNS. In addition, the recent advent of neuromorphic chips, like those to restore activity in damaged retina and visual cortex, suggests that assumption of a discrete-continuum polarity in designing biocompatible neural circuitries is crucial for their ensuing performance. In these bionic structures, in fact, a correspondence exists between the original anatomical architecture and synthetic wiring of the chip, resulting in a correspondence between natural and cybernetic neural activity. Thus, chip "form

  16. 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.

  17. Incidental intraoperative discovery of a pancreatic neuroendocrine tumor associated with chronic pancreatitis

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    Surlin Valeriu


    Full Text Available Abstract Pancreatic neuroendocrine tumors are a rare entity with an incidence between 2 per million to 5 per 100 000. Association with pancreatitis (acute or chronic is rare and is considered to be determined by the tumoral obstruction of pancreatic ducts, but sometimes occurs without any apparent relationship between them. Non-functional neuroendocrine pancreatic tumors are usually diagnosed when either very large or metastatic. Small ones are occasionally diagnosed when imagery is performed for other diagnostic reasons. Intraoperative discovery is even rarer and poses problems of differential diagnosis with other pancreatic tumors. Association with chronic pancreatitis is rare and usually due to pancreatic duct obstruction by the tumor. We describe the case of a patient with a small non-functioning neuroendocrine tumor in the pancreatic tail accidentally discovered during surgery for delayed traumatic splenic rupture associated with chronic alcoholic pancreatitis. The tumor of 1.5cm size was well differentiated and confined to the pancreas, and was resected by a distal splenopancreatectomy. Conclusions Surgeons should be well aware of the rare possibility of a non-functional neuroendocrine tumor in the pancreas, associated with chronic pancreatitis, surgical resection being the optimal treatment for cure. Histopathology is of utmost importance to establish the correct diagnosis, grade of differentiation, malignancy and prognosis. Virtual slides The virtual slide(s for this article can be found here:

  18. 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...

  19. Interrelation between Neuroendocrine Disturbances and Medical Complications Encountered during Rehabilitation after TBI

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    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.

  20. The importance of multimodality therapy in the treatment of sinonasal neuroendocrine carcinoma

    NARCIS (Netherlands)

    van der Laan, Tom P.; Bijl, Hendrik P.; van Hemel, Bettien M.; Plaat, Boudewijn E. C.; Wedman, Jan; van der Laan, Bernard F. A. M.; Halmos, Gyorgy


    Sinonasal carcinoma with neuroendocrine differentiation (SCND) is a rare group of tumors known for their aggressive behavior and poor response to treatment. The data in the literature are sparse and cover a wide range of therapeutic approaches over a protracted timeline. Therefore, it is important t

  1. Small Cell Neuroendocrine Carcinoma of the Urinary Tract Successfully Managed with Neoadjuvant Chemotherapy

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    Mustapha Ahsaini


    Full Text Available Introduction. Small cell neuroendocrine carcinomas of the urinary tract is an extremely rare entity and very few cases have been reported in the literature. Small cell neuroendocrine carcinoma of the urinary tract (SCC-UT is the association between bladder and urinary upper tract-small cell carcinoma (UUT-SCC. It characterized by an aggressive clinical course. The prognosis is poor due to local or distant metastases, and usually the muscle of the bladder is invaded. Case Presentation. We report a rare case of a 54-year-old Arab male native of moroccan; he is a smoker and was referred to our institution for intermittent hematuria. Following a diagnosis of small cell neuroendocrine carcinomas of the ureter and the bladder, thoracoabdominal-pelvic CT was done, and the staging of the tumor was done in the bladder (T2N0M0 and (T1N0M0 in the ureter. Neoadjuvant alternating doublet chemotherapy with ifosfamide/doxorubicin and etoposide/cisplatin was realized, and nephroureterectomy associated to a cystoprostatectomy was carried out. After 24 months of followup, no local or distant metastasis was detected. Conclusion. The purpose of this review is to present a rare case of pure small cell neuroendocrine carcinoma of the urinary tract and review the literature about the place of neoadjuvant chemotherapy in this rare tumors.

  2. 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...

  3. Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)—Health Professional Version (United States)

    Expert-reviewed information summary about the genetics of endocrine and neuroendocrine neoplasias. This summary contains information about the MEN1 gene, the RET gene, genetic testing, and clinical interventions. Psychosocial issues associated with genetic testing and counseling of individuals who may have a hereditary medullary thyroid cancer syndrome are also discussed.

  4. Body position and the neuroendocrine response to insulin-induced hypoglycemia in healthy subjects. (United States)

    Radikova, Z; Penesova, A; Jezova, D; Kvetnansky, R; Vigas, M; Macho, L; Koska, J


    Changes in body fluid distribution are known to influence neuroendocrine function. The aim of the present study was to test the hypothesis that changes in plasma volume affect the counterregulatory neuroendocrine response to hypoglycemia. The tests were performed in 12 subjects in two situations: 'head-up' (+60 degrees head-up tilt standing for 30 min and hypoglycemia in sitting position afterwards) and 'leg-up' (leg-up position for 30 min and hypoglycemia in leg-up position afterwards) in a random order. Insulin-induced hypoglycemia was adjusted to 2.7 mmol/l for 15 min by glucose infusion. Plasma volume was greater by 2.2% (p < 0.001) in leg-up and lower by 9.6% (p < 0.001) in head-up position compared to the basal value in sitting position. Head-up position was associated with increases in ACTH, aldosterone, norepinephrine levels and plasma renin activity (p < 0.01). Leg-up position resulted in decreases in plasma growth hormone and epinephrine concentrations (p < 0.05). Except epinephrine, the neuroendocrine response to hypoglycemia, if any, was mild. Hypoglycemia failed to activate ACTH release after head-up position. Body fluid redistribution did not modify hormonal changes during insulin hypoglycemia. In conclusion, we suggest that body position and accompanying plasma volume changes do not appear to affect neuroendocrine and counterregulatory responses to moderate, short duration hypoglycemia in healthy subjects.

  5. The Contributions of Maternal Sensitivity and Maternal Depressive Symptoms to Epigenetic Processes and Neuroendocrine Functioning (United States)

    Conradt, Elisabeth; Hawes, Katheleen; Guerin, Dylan; Armstrong, David A.; Marsit, Carmen J.; Tronick, Edward; Lester, Barry M.


    This study tested whether maternal responsiveness may buffer the child to the effects of maternal depressive symptoms on DNA methylation of "NR3C1," "11ß-HSD2," and neuroendocrine functioning. DNA was derived from buccal epithelial cells and prestress cortisol was obtained from the saliva of 128 infants. Mothers with depressive…

  6. Vulvar mucinous adenocarcinoma with neuroendocrine differentiation: A case report and review of the literature

    NARCIS (Netherlands)

    Rosmalen, M.H. Van; Reijnen, C.; Boll, D.; Pijnenborg, J.M.A.; Wurff, A.A. van der; Piek, J.M.


    BACKGROUND: There are limited cases in literature of patients with mucinous adenocarcinoma of the vulva with neuroendocrine differentiation have. With this new case, we aim to provide an overview of the existing literature and present a tool with relevant markers for the pathologist in the different

  7. Small cell carcinoma of the lung and large cell neuroendocrine carcinoma interobserver variability

    NARCIS (Netherlands)

    den Bakker, Michael A.; Willemsen, Sten; Gruenberg, Katrien; Noorduijn, L. Arnold; van Oosterhout, Matthijs F. M.; van Suylen, Robert J.; Timens, Wim; Vrugt, Bart; Wiersma-van Tilburg, Anne; Thunnissen, Frederik B. J. M.


    Aims: To test the hypothesis that the published morphological criteria permit reliable segregation of small cell carcinoma of the lung (SCLC) and large cell neuroendocrine carcinoma (LCNEC) cases by determining the interobserver variation. Methods and results: One hundred and seventy cases of SCLC,

  8. 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.

  9. GEP-NET : rare tumour connections. Pathophysiological aspects of gastroenteropancreatic neuroendocrine tumours

    NARCIS (Netherlands)

    Kuiper, Patricia


    Clinical behaviour of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) varies strikingly, both in terms of symptoms and outcome. An understanding of the basic biology unique to GEP-NETs is necessary for optimum management of patients with these complex tumors. Although markers for GEP-NETs ex

  10. [Neuroendocrine system of the pancreas and gastrointestinal tract: origin and development]. (United States)

    Díaz Pérez, José Angel


    Gastroenteropancreatic neuroendocrine tumours (GEP NETs) originate from the neuroendocrine cells through the gastrointestinal tract and endocrine pancreas. The embryologic development of the pancreas is a complex process that begins with the "stem cell" that come from the endodermus. These cells go through two phases: in the first transition the "stem cell" differentiates in exocrine and endocrine cells. This process is regulated by transcription factors such as Pdx1 ("insulin promoter factor 1"), Hlxb6 and SOX9. In the second transition the neuroendocrine cell differentiates in the 5 cell types (alpha, beta, delta, PP y epsilon.). This process is regulated through the balance between factors favoring differentiation (mainly neurogenin 3) and inhibitor factors which depend on Notch signals. The existence of a third transition in postnatal pancreas is hypothesized. The "stem cell" from pancreatic ducts would become adult beta cells, through autoduplication and neogenesis. In the small gut of the adult the stem cell are placed in the intestinal crypts and develop to villi in secretor lines (enterocytes, globet and Paneths cells) or neuroendocrine cells from which at least 10 cell types depend. This process is regulated by transcription factors: Math1, neurogenina 3 and NeuroD.

  11. 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 reactivi

  12. 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 re

  13. Aggressive Multi-Visceral Pancreatic Resections for Locally Advanced Neuroendocrine Tumours. Is It Worth It?

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    Mohammed Abu Hilal


    Full Text Available Context Traditional surgical principles state that pancreatic resection should not be contemplated when malignancies arise in the pancreas and involve other organs. While this is logic for ductal adenocarcinoma and other tumours with aggressive biological behavior; for even large neuroendocrine tumours, aggressive multivisceral resection may achieve useful palliation and excellent survival. Design Case records were retrospectively analyzed. Patients and interventions Twelve consecutive patients (7 males, 5 females; median age 57 years, range: 37-79 years underwent multi-visceral en bloc resections for neuroendocrine tumour arising in the pancreas between 1994 and 2008. Results Three patients underwent pancreaticoduodenectomy; 9 patients had left sided pancreatic resections for neuroendocrine tumour of median diameter 9.5 cm ( 5-25 cm. They had a median of 3 (range: 1-4 additional organs resected. There were no post-operative deaths or late mortality with median follow up of 24 months. Five patients experienced a complication (major in 3 patients. Median disease free survival was not attained and 3 patients experienced recurrent disease mostly in the liver and may be candidates for further resection. Conclusion Aggressive multi-visceral resection for locally advanced neuroendocrine tumour involving the pancreas is technically feasible and in selected patients can be achieved with low mortality and acceptable morbidity, offering good disease free and overall survival. However this complex surgery should be only performed in specialist centers.

  14. Hemodynamic and neuroendocrine responses to changes in sodium intake in compensated heart failure

    DEFF Research Database (Denmark)

    Damgaard, Morten; Norsk, Peter; Gustafsson, Finn


    inhibitors and beta-adrenoreceptor blockers. Therefore, we determined the hemodynamic and neuroendocrine responses to 1 wk of a low-sodium diet (70 mmol/day) and 1 wk of a high-sodium diet (250 mmol/day) in 12 HF patients and 12 age-matched controls in a randomized, balanced fashion. During steady...

  15. Diagnosis of prostatic neuroendocrine carcinoma: Two cases report and literature review

    Institute of Scientific and Technical Information of China (English)

    Hai-Qing; He; Shu-Feng; Fan; Qiong; Xu; Zhen-Jing; Chen; Zheng; Li


    Two cases of prostatic neuroendocrine carcinoma(PNEC) imaged by computed tomography(CT) and magnetic resonance imaging(MRI), and literature review are presented. Early enhanced CT, MRI, especially diffusionweighted image were emphasized, the complementary roles of ultrasound, CT, MRI, clinical and laboratory characteristic’s features in achieving accurate diagnosis were valued in the preoperative diagnosis of PNEC.

  16. Large cell neuroendocrine carcinoma of the parotid gland: case report and literature review. (United States)

    Casas, Pablo; Bernáldez, Ricardo; Patrón, Mercedes; López-Ferrer, Pilar; García-Cabezas, Miguel A


    A 74-year-old male presented with a large polinodular mass in the neck. Fine needle aspiration cytology (FNAC) showed an undifferentiated large cell carcinoma. Computed tomography (CT) showed a large parotid mass with multiple satelite nodules. The remaining radiological studies were normal. Radical parotidectomy was performed. The tumor was a large cell carcinoma with neuroendocrine features and positive immunostain for neuroendocrine markers. The patient received postoperative radiotherapy and was free of tumor eight months later. Only four cases of large cell neuroendocrine carcinoma (LCNEC) of the salivary gland have been communicated. All of them have involved the parotid gland. This tumor presents in elderly patients as a large infiltrating parotid mass. Fine needle aspiration cytology serves to recognize the carcinoma, but it fails in recognizing the neuroendocrine features of the tumor. The histopathological features of this tumor are the same as in other organs. Chromogranin and synaptophysin are useful immunohistochemical markers. A primary location of the tumor in another organ, specially the lung, should be ruled out. Surgery is the main treatment modality and can be complemented with postoperative radiotherapy. The prognosis seems to be poor. More studies are needed to better define the therapeutical alternatives and prognostic factors of these rare tumors.

  17. Occurrence of second primary malignancies in patients with neuroendocrine tumors of the digestive tract and pancreas

    NARCIS (Netherlands)

    K. Kamp; 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

  18. Nervous and Neuroendocrine regulation of the pathophysiology of cholestasis and of biliary carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Marco Marzioni; Giammarco Fava; Antonio Benedetti


    Cholangiocytes, the epithelial cells lining the biliary ducts, are the target cells in several liver diseases.Cholangiopathies and cholangiocarcinoma generate interest in many scientists since the genesis. The developing mechanisms, and the therapeutic tools of these diseases are still undefined. Several studies demonstrate that many hormones, neuropeptides and neurotransmitters regulate malignant and non-malignant cholangiocyte pathophysiology in the course of chronic biliary diseases. The aim of this review is to present the findings of several studies published in the recent years that contributed to clarifying the role of nervous and neuroendocrine regulation of the pathophysiologic events associated with cholestasis and cholangiocarcinoma development. This manuscript is organized into two parts. The first part offers an overview of the innervation of the liver and the origin of neuroendocrine hormones,neurotransmitters and neuropeptides affecting cholangiocyte function and metabolism. The first section also reviews the effects played by several neuroendocrine hormones and nervous system on cholangiocyte growth,survival and functional activity in the course of cholestasis. In the second section, we summarize the results of some studies describing the role of nervous system and neuroendocrine hormones in the regulation of malignant cholangiocyte growth.

  19. Immunohistochemical consistency between primary tumors and lymph node metastases of gastric neuroendocrine carcinoma

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    Uchiyama Chieko


    Full Text Available Abstract Background Gastric neuroendocrine carcinoma (G-NEC is a rare, highly malignant tumor that exhibits aggressive growth leading to vascular invasion, distant metastasis and extremely poor prognosis. We studied the clinicopathological findings of seven patients at our institute to better under this disease. Methods Seven cases of G-NEC were identified among 1,027 cases of gastric carcinoma that underwent gastrectomy at Kansai Rousai Hospital between 2002 and 2010. We studied the pathological and immunohistochemical features of gastric neuroendocrine carcinomas at both the primary site and metastatic lymph nodes. Results The mean patient age was 73 years (range 63 to 86 years. There were no females in this series. The final staging was Stage I in one case, Stage II in two, Stage III in two and Stage IV in two. A total of 31 metastatic lymph nodes were found in these patients. This study revealed that the ratio of neuroendocrine cells was similar between the primary and metastatic sites, which tended to show the same expression patterns of neuroendocrine markers. Conclusions Metastatic lymph nodes showed heterogeneous immunohistochemical expression patterns similar to the primary sites. G-NEC is far advanced at diagnosis and rapidly reaches the lymph nodes retaining its heterogeneity, carrying a worse prognosis than common gastric cancer. Mini abstract G-NEC grows rapidly and metastasizes to the lymph nodes, retaining its pathological and immunohistochemical heterogeneity even at the metastatic sites.

  20. Studies on the Relationship between Neuroendocrine Cellular Differentiation in Gastric Cancers and Post-operative Survival Time

    Institute of Scientific and Technical Information of China (English)


    OBJECTIVE To examine the ultrastructure of gastric cancer cells by the electron microscope, in order to assess the relationship between neuroendocrine differentiation and post-operative survival time.METHODS NSE, Syn and CgA immunohistochemical labeling was conducted in 168 cases with a common-type of gastric cancer. Electron microscopy was performed in 80 cases with positive immunohistochemical labeling.These cases were followed-up for over 5 years and the post-operative survival data analyzed.RESULTS Neuroendocrine granules were found by electron microscopy in 39 cases. The rate of neuroendocrine differentiation found was 23% (39/168), using routine diagnostic criteria and electron microscopy (REM).The post-operative survival time of gastric cancer patients with neuroendocrine differentiation was significantly shorter (P=0.0032) compared to those without neuroendocrine differentiation.CONCLUSION It is of significant clinical importance to determine if the neuroendocrine cells are differentiated in gastric cancers. The gastric cancer patients with neuroendocrine differentiation have a shorter post-operative survival time and a poorer prognosis. Electron microscopy is a reliable method of providing a diagnosis.

  1. Sinonasal malignancies with neuroendocrine differentiation: Case series and review of literature

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    Menon Santosh


    Full Text Available Primary sinonasal tumors with neuroendocrine differentiation (SCND are uncommon tumors with considerable overlap of histological features. Based on their neuroendocrine differentiation they can be sub categorized into sinonasal undifferentiated carcinoma (SNUC, sinonasal neuroendocrine carcinoma (SNEC, esthesioneuroblastoma (ENB and small cell carcinoma (SmCC. The natural history and biological behavior varies in this group of tumors. Hence the histo-morphological diagnosis coupled with grading/staging is important for the prognostication of these tumors. Aim : To study the clinicopathological characteristics of sinonasal neuroendocrine malignancies at our institute. Material and Methods : We searched our institute′s pathology database for the period from 2002 to 2007, for the four subcategories of sinonasal tumors with neuroendocrine differentiation. Morphological and immunohistochemical features were studied and, grading, staging was done in accordance with standard criteria. The clinical treatment and follow- up data were retrieved from the case files in available cases. Results : A total of 37 cases were retrieved from our database which include 14 cases of SNUC, 14 cases of ENB and nine cases of SNEC. The cases of SNUC were immunopositive for cytokeratin, epithelial membrane antigen and weakly for neuron-specific enolase. SNEC showed strong reactivity with epithelial and neuroendocrine markers whereas ENB demonstrated immunoreactivity to synaptophysisn and chromogranin strongly, with weak to negative expression of epithelial markers. All cases of SNUC and SNEC were of high grade and stage whereas 50% of ENB cases were of grade II but high stage tumors. Most of the SNUC and SNEC patients had been treated with multimodality treatment regimens including upfront chemotherapy followed by surgery and loco- regional radiation. In contrast, ENB patients had undergone surgical extirpation followed by radiation therapy in majority of cases. With

  2. [Is the immune system our sixth sense? Relation between the immune and neuroendocrine systems]. (United States)

    Ferencík, M; Stvrtinová, V


    There is an overwhelming evidence that cytokines, peptide hormones and neurotransmitters, as well as their receptors, are present in the brain, endocrine and immune systems. The structure and pattern of synthesis of these peptides by leukocytes appear similar to those synthesized in the neuroendocrine system, although some differences exist. Once secreted, these peptide hormones may function as endogenous regulators inside of the each system and also in bidirectional communication between the immune and neuroendocrine systems. Such communication suggest an immunoregulatory role for the brain and a sensory function for the immune system which may sense stimuli that are not recognized by the central and peripheral nervous systems (noncognitive stimuli). The plasma hormone concentrations contributed by lymphocytes usually do not reach the levels required when the pituitary gland is the source, but because immune cells are mobile, they have the potential to deposit the hormone locally at the target site. Several immunoregulatory cytokines, including IL-1, IL-2, IL-6, IFN-gama and TNF are produced not only in the immune system but in the neuroendocrine system as well. They have profound effects on neuroendocrine functions especially on hypothalamic pituitary axes. Neuroendocrine influences that modulate the immune function mainly include mental and physical stress. It can reduce the resistance of organism to infectious diseases and malignancies by compromising the immune system directly or indirectly. The brain is not an immunologically privileged site and therefore may become the target of immunologic attacks resulting in neuroimmunological diseases with an autoimmune component. The impact of psychological and psychosocial factors on the immune system is studied by psychoneuroimmunology whereas neuroendocrine immunology is generally interested in the interactions between the immune and neuroendocrine systems under physiological and pathological conditions. The

  3. Computed tomography characterization of neuroendocrine tumors of the thymus can aid identification and treatment

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    Li, Hui; Wang, De-ling; Liu, Xue-wen; Geng, Zhi-jun; Xie, Chuan-miao [State Key Lab. of Oncology in Southern China, Guangzhou (China); Medical Imaging and Minimally Invasive Interventional Center, Cancer Center, Sun Yat-sen Univ., Guangzhou (China)], e-mail:


    Background: Neuroendocrine tumors of the thymus are extremely rare anterior mediastinal tumors. The few studies reporting these tumors have focused on the clinical manifestations and do not provide a summary of characteristic computed tomography (CT) findings. Purpose: To investigate the CT appearances of neuroendocrine tumors of the thymus in order to improve the diagnostic and resection efficacy. Material and Methods: Nine cases of pathologically identified thymic neuroendocrine tumors were retrospectively analyzed by CT. All the patients underwent non-enhanced and contrast-enhanced CT. Multiple CT features were examined, including tumor location, shape, margins, CT attenuation, involvement of surrounding structures, and distant metastasis. Results: A total of nine masses were examined in this study. The maximum tumor diameter ranged from 5 to 14 cm (average, 9 cm). The shapes of six masses were lobulated and three were rounded or oval and the margins of seven masses were unclear while two masses were sharp. All the masses showed hypo density or isodensity compared to muscles in the anterior thoracic wall on non-enhanced CT images. Two masses showed homogeneous attenuation by non-enhanced CT imaging and moderate homogeneous enhancement after contrast administration, while seven masses showed heterogeneous attenuation with patchy low-attenuation foci and showed moderate to strong heterogeneous enhancement. Involvement of adjacent structures was observed in six cases. Five cases were observed to have lymph node metastases and four cases had distant metastases. Conclusion: Neuroendocrine tumors of the thymus are rare tumors of the anterior mediastinum with a number of distinct CT characteristics. Most importantly, the density of the tumors was heterogeneous with necrosis or cystic degeneration and moderately or strongly enhancement after bolus injection of contrast medium, which may allow for more efficient tumor identification. Thus, CT can improve of the diagnosis

  4. Chromophobe renal cell carcinoma of the kidney with neuroendocrine differentiation: A case report with review of literature

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    Ghadeer A Mokhtar


    Full Text Available Chromophobe renal cell carcinoma (chRCC is a distinctive type of malignant kidney tumor characterized by large cells with defined cell membrane. Primary renal neuroendocrine tumors (NET are rare with morphology similar to NET at other sites. There are few case reports describing the coexistence of these 2 neoplasms within the same tumor mass. We describe a case of chRCC with neuroendocrine features in a 70-year-old male patient who presented with hematuria and right flank pain. The histological and immunohistochemical features of both components were characteristic with no overlapping features. The neuroendocrine element was associated with nodal metastasis.

  5. Neuroendocrine carcinoma of the breast - a pilot study of a Danish population of 240 breast cancer patients

    DEFF Research Database (Denmark)

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


    Neuroendocrine carcinoma of the breast - a very recent diagnosis, which was not recognized by WHO until 2003 - has lately been the subject of increasing attention. It is defined as a primary breast cancer with morphologic features similar to other types of neuroendocrine tumors of the lung...... and gastrointestinal tract combined with positive neuroendocrine immunohistochemical markers. While much information has been gathered during the last decade, most studies suffer from poor statistics due to a low incidence, and there are still fundamental open questions regarding etiology and prognosis. Furthermore...

  6. 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.

  7. Neuroendocrine differentiation in prostate cancer%前列腺癌的神经内分泌分化

    Institute of Scientific and Technical Information of China (English)

    Jingwen Wang; Yang Yao


    Hormonal therapy is an important treatment for advanced/metastatic prostate cancer. But it can induce neuroen-docrine (NE) differentiation in prostate cancer cells. These NE cells will secrete manifold neural peptide or hormones which can lead to androgen-independent growth of non-NE tumor cells. When this happens, hormonal therapy becomes useless and indicates bad prognosis. In this paper, the mechanism of neuroendocrine differentiation and its relationship with androgen-independent were reviewed.

  8. Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and thymic neoplasms). Part I-general overview

    DEFF Research Database (Denmark)

    Oberg, Kjell; Astrup, Lone; Eriksson, Barbro;


    The incidence of neuroendocrine tumours of the gastroenteropancreatic system seems to have increased during the past decade. New diagnostic and therapeutic procedures have aroused the interest of physicians, though most see very few cases of such diseases. A group of members of the Nordic Neuroen...... Neuroendocrine Tumour Group decided to compile some guidelines to facilitate the diagnosis and treatment of patients with these tumours. Part I of these guidelines discusses the principles of histopathology, biochemical and radiological diagnosis as well as therapeutic options....

  9. Influence of Exposure to Extremely Low Frequency Magnetic Field on Neuroendocrine Cells and Hormones in Stomach of Rats


    Hong, Min Eui; Yoon, Kyu Hyun; Jung, Yoon Yang; Lee, Tae Jin; Park, Eon Sub; Sohn, Uy Dong; Jeong, Ji Hoon


    Extremely low frequency magnetic fields (ELF-MF) have the ability to produce a variety of behavioral and physiological changes in animals. The stomach, as the most sensitive part of the neuroendocrine organ of the gastrointestinal tract, is crucial for the initiation of a full stress response against all harmful stress. Thus, the purpose of this study was to examine whether ELF-MF stimuli induce changes in the activity of neuroendocrine cells, considering their involvement in endocrine or par...

  10. Neuroendocrine diffuse system of the respiratory tract of Rana temporaria: an immunocytochemical study. (United States)

    Bodegas, M E; Montuenga, L M; Sesma, P


    The neuroendocrine cell population of the respiratory system of Rana temporaria has been studied by means of immunocytochemical methods at the light-microscopic level. Isolated or clustered endocrine cells have been found in the epithelium of the buccal cavity, glottis, larynx, and lung. Nine different types of endocrine isolated cell types can be distinguished according to their immunoreactivity to several regulatory peptides [calcitonin, substance P, bombesin, peptide histidine isoleucine (PHI), cholecystokinin (CCK), and endothelin 1] and neuroendocrine markers (7B2, chromogranin, and serotonin). Neuroepithelial bodies are innervated clusters of cells simultaneously immunoreactive for serotonin and 7B2. Nerves and/or neurons have been detected in different regions of the respiratory system using antibodies against protein gene product 9.5, serotonin, calcitonin gene-related peptide (CGRP), substance P, PHI, helodermin, and CCK.

  11. 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.

  12. 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...

  13. Neuroendocrine-immune systems response to environmental stressors in the cephalopod Octopus vulgaris

    Directory of Open Access Journals (Sweden)

    Anna Di Cosmo


    Full Text Available Under a continuous changing environment, animals are challenged with stresses and stimuli which demanding adaptation at behavioral and physiological levels. The adaptation strategies are finely regulated by animal nervous, endocrine and immune systems. Although it’s been established by now the usage of integrative approach to the study the endocrine and nervous systems (neuroendocrine, yet our understanding of how they cooperate with the immune system remains far from complete. The possible role that immune system plays as a component of the network has only been recognized recently. Octopus vulgaris is an important member of cephalopods and is considered as a model species, with considerable information about the neuroendocrine and immune systems. In the current review, we anticipate to shed light on the complexity and cross talk among the three systems and how they cooperate in setting physiological response to stresses-stimuli in Octopus vulgaris as a target species and primary example.

  14. Neuroendocrine tumors of the gastrointestinal tract: Case reports and literature review

    Institute of Scientific and Technical Information of China (English)

    William; J; Salyers; Kenneth; J; Vega; Juan; Carlos; Munoz; Bruce; W; Trotman; Silvio; S; Tanev


    Neuroendocrine tumors(NET)previously called carcinoid tumors are neoplasms of enterochromaffin/neuroendocrine cell origin which display neurosecretory capacity that may result in the carcinoid syndrome.The annual incidence of patients with NET is 8.4 per 100000;yet many NET remain asymptomatic and clinically undetected.A majority of NET follows a benign course;however,some will display malignant characteristics.NET most commonly occur in the gastrointestinal tract(67%)and bronchopulmonary system(25%).Gastrointestinal NET occur within the stomach,small intestine,liver,and rectum.We report a retrospective study of 11 subjects:Eight with benign carcinoid tumors:duodenal bulb(n=2),terminal ileum(n=1),sigmoid colon(n=2),and rectum(n=3);three with malignant carcinoid:liver(n=1)and intra-abdominal site(n=2).The diagnosis,endoscopic images,outcome,treatment and review of the literature are presented.

  15. Neuroendocrine regulation of prolactin secretion during late pregnancy: easing the transition into lactation. (United States)

    Andrews, Z B


    Prolactin is an anterior pituitary hormone critical for maintaining pregnancy and lactation. Under normal conditions, prolactin secretion is tightly regulated by inhibitory dopaminergic neuronal systems within the mediobasal hypothalamus in a process known as short-loop negative feedback. This review focuses on neuroendocrine adaptations to prolactin negative feedback during late pregnancy. It is suggested that, in terms of prolactin regulation, late pregnancy is a transition period into lactation because many of the neuroendocrine adaptations promoting hyperprolactinemia in lactation develop during late pregnancy. As a consequence, the maternal brain is geared to provide unrestrained prolactin release critical for milk production, maternal care and thus survival of the offspring before parturition. The mechanisms responsible for these changes are discussed.

  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...... syndrome in man has remained unknown until now. MATERIAL AND METHODS: Using a panel of immunoassays for CCK peptides and proCCK as well as for chromogranin A, we have examined plasma samples from 284 fasting patients with gastroenteropancreatic neuroendocrine tumors. In hyperCCKemic samples, plasma CCK...... was further characterized by chromatography. RESULTS: One of the patients displayed gross hyperCCKemia. She was a 58-year old woman with a pancreatic endocrine tumor, liver metastases, 500-1000-fold elevated basal CCK concentration in plasma, diarrhea, severe weight loss, recurrent peptic ulcer and bilestone...

  17. 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.

  18. Changes in blood-brain barrier function modify the neuroendocrine response to circulating substances. (United States)

    Jezová, D; Johansson, B B; Oprsalová, Z; Vigas, M


    It is known that various experimental, pathological and even physiological situations may be accompanied by transient increases in blood-brain barrier (BBB) permeability. The hypothesis that under such conditions the blood-borne substances can reach the active sites in the brain in concentrations high enough to influence central control of hormone release was verified in these studies. A suitable experimental model of BBB opening by protamine sulfate administration in conscious rats was introduced. Using this model it was shown that the dopaminergic blocker domperidone inhibited apomorphine-induced ACTH release if permeability of the BBB was increased, but not under normal conditions. It is suggested that the changes in BBB function can modify the neuroendocrine response also to other circulating substances and this may be an important, until now unconsidered phenomenon in neuroendocrine research.

  19. GLUT1: A novel tool reflecting proliferative activity of lung neuroendocrine tumors? (United States)

    Benzerdjeb, Nazim; Berna, Pascal; Sevestre, Henri


    Lung neuroendocrine tumors (LNT) represents approximately 20% of all lung cancers. The classification of LNT relies upon morphology. Recently, in the World Health Organization (WHO) classification, Ki-67 rate has been proposed for classification. It is, however, known that Ki-67 count has a poor interlaboratory reproducibly. For that reason, our team has looked for a new biomarker. GLUT1 protein a facilitative glucose transporter protein which has ubiquitous expression in mammalian. GLUT1 is overexpressed in many human cancers. But, no study has evaluated the GLUT1 staining as an aid diagnosis in LNT. Our team have assessed the GLUT1 immunohistochemical staining in 36 LNT and to assess its diagnostic value. GLUT1 staining was higher in neuroendocrine carcinoma than in carcinoid tumor. A positive predictive value in a priori and posteriori testing for diagnosis of LNT is demonstrated. GLUT1 staining could aid in the diagnosis and should be validated in a large prospective cohort.

  20. 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.

  1. Mathematical modeling of the circadian dynamics of the neuroendocrine-immune network in experimentally induced arthritis. (United States)

    Rao, R; DuBois, D; Almon, R; Jusko, W J; Androulakis, I P


    The circadian dynamics of important neuroendocrine-immune mediators have been implicated in progression of rheumatoid arthritis pathophysiology, both clinically as well as in animal models. We present a mathematical model that describes the circadian interactions between mediators of the hypothalamic-pituitary-adrenal (HPA) axis and the proinflammatory cytokines. Model predictions demonstrate that chronically elevated cytokine expression results in the development of adrenal insufficiency and circadian variability in paw edema. Notably, our model also predicts that an increase in mean secretion of corticosterone (CST) after the induction of the disease is accompanied by a decrease in the amplitude of the CST oscillation. Furthermore, alterations in the phase of circadian oscillation of both cytokines and HPA axis mediators are observed. Therefore, by incorporating the circadian interactions between the neuroendocrine-immune mediators, our model is able to simulate important features of rheumatoid arthritis pathophysiology.

  2. Review of recent advances in medical treatment for neuroendocrine neoplasms:somatostatin analogs and chemotherapy

    Institute of Scientific and Technical Information of China (English)

    Francesca Spada; Monica Valente


    Neuroendocrine neoplasms (NENs) are a heterogeneous group of rare tumours often producing high levels of hormones and causing symptoms. There are a number of different types of NENs. They usually arise as advanced and low/intermediate grade only in a minority of cases, as high grade. Treatment depends on which type and may include surgery, interventional radiology, and systemic treatment, including chemotherapy, somatostatin analogs, interferon α2b, peptide receptor radionuclide therapy, and only for pancreatic neuroendocrine tumors, molecular targeted agents, including everolimus and sunitinib. The aim of the article is to review the medical approaches with somatostatin analogs and chemotherapy. The treatment of NENs is mainly based on their biological characteristics of aggressiveness and functional features, such as symptoms and endocrine markers.

  3. 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...

  4. Effects of ghrelin on food intake and neuroendocrine function in sheep. (United States)

    Sugino, T; Hasegawa, Y; Kurose, Y; Kojima, M; Kangawa, K; Terashima, Y


    Ghrelin, a novel acylated peptide, is the endogenous ligand for growth hormone secretagogue (GHS) receptor. Ghrelin is produced mainly in the oxyntic glands of the stomach, but also produced in the intestines, kidneys, hypothalamus and pituitary gland. Circulating ghrelin levels have been shown to rise before a meal and fall afterwards, suggesting that anticipation of a meal may stimulate secretion. In some species, ghrelin administration has been shown to stimulate growth hormone (GH) secretion, and to cause weight gain by increasing food intake and reducing metabolic utilization of fat. Furthermore, intracerebroventricular and intravascular administration of ghrelin increases gastric acid output in a dose-dependent manner. Thus, ghrelin may play an important role in controlling feeding behavior and energy homeostasis. We have investigated the role of ghrelin in the control of feeding and neuroendocrine function in ruminants using sheep as an experimental model. This mini review describes mechanisms regulating ghrelin secretion at feeding time, and also focuses on the neuroendocrine functions of ghrelin.

  5. The Thyro-Gastric syndrome: from thyroid autoimmunity to neuroendocrine gastric tumors



    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...

  6. Posttraumatic stress disorder under ongoing threat: a review of neurobiological and neuroendocrine findings

    Directory of Open Access Journals (Sweden)

    Iro Fragkaki


    Full Text Available Background: Although numerous studies have investigated the neurobiology and neuroendocrinology of posttraumatic stress disorder (PTSD after single finished trauma, studies on PTSD under ongoing threat are scarce and it is still unclear whether these individuals present similar abnormalities. Objective: The purpose of this review is to present the neurobiological and neuroendocrine findings on PTSD under ongoing threat. Ongoing threat considerably affects PTSD severity and treatment response and thus disentangling its neurobiological and neuroendocrine differences from PTSD after finished trauma could provide useful information for treatment. Method: Eighteen studies that examined brain functioning and cortisol levels in relation to PTSD in individuals exposed to intimate partner violence, police officers, and fire fighters were included. Results: Hippocampal volume was decreased in PTSD under ongoing threat, although not consistently associated with symptom severity. The neuroimaging studies revealed that PTSD under ongoing threat was not characterized by reduced volume of amygdala or parahippocampal gyrus. The neurocircuitry model of PTSD after finished trauma with hyperactivation of amygdala and hypoactivation of prefrontal cortex and hippocampus was also confirmed in PTSD under ongoing threat. The neuroendocrine findings were inconsistent, revealing increased, decreased, or no association between cortisol levels and PTSD under ongoing threat. Conclusions: Although PTSD under ongoing threat is characterized by abnormal neurocircuitry patterns similar to those previously found in PTSD after finished trauma, this is less so for other neurobiological and in particular neuroendocrine findings. Direct comparisons between samples with ongoing versus finished trauma are needed in future research to draw more solid conclusions before administering cortisol to patients with PTSD under ongoing threat who may already exhibit increased endogenous

  7. Therapy evaluation and diagnostic accuracy in neuroendocrine tumours: assessment of radiological methods

    Energy Technology Data Exchange (ETDEWEB)

    Elvin, A.


    The diagnostic accuracy of ultrasonically guided biopsy-gun biopsies was assessed in a group of 47 patients with suspected pancreatic carcinoma. A correct diagnosis was obtained in 44 of the 47 patients (94%). Twenty-five patients with known neuroendocrine tumour disease were biopsied with 1.2 mm and 0.9 mm biopsy-gun needles. The influence of treatment-related fibrosis was also evaluated. The overall diagnostic accuracy with the 0.9 mm needle was 69% as compared to 92% with the 1.2 mm needle. In order to assess the diagnostic accuracy rate for radiologists with different experience of biopsy procedures 175 cases of renal biopsy-gun biopsies were evaluated. No statistical significant difference was found between the different operators. The role of duplex Doppler ultrasound in monitoring interferon treatment-related changes in carcinoid metastases was evaluated. It present duplex Doppler ultrasound does not seem to play a role in the evaluation of tumour therapy in carcinoid patients. Therapy response evaluation was performed with MR imaging in a group of 17 patients with neuroendocrine liver metastases. A significant difference was found between patients responding to and patients with failure of treatment in terms of tumour T1, contrast enhancement and signal intensity ratio. This indicates that MR investigation may be used in therapy monitoring of patients with neuroendocrine metastases. The neuroendocrine-differentiated colonic carcinoma cell line (LCC-18) was transplanted to 29 mice to establish a tumour/animal model that would allow the monitoring of changes with MR imaging induced by interferon therapy and to evaluate whether the therapeutic response could be modulated by different interferon dosages. Interferon does not seem to have any prolonged anti-proliferative effect on the LCC-18 tumour cell line when transplanted to nude mice.

  8. Advances in the Treatment of Pancreatic Neuroendocrine Tumors (pNETs)


    Strosberg, Jonathan


    Recent clinical trials have led to significant advancements in treatment options for metastatic neuroendocrine tumors of the pancreas. Sunitinib and everolimus have been approved by the Food and Drug Administration for treatment of progressive pancreatic NETs based on phase III trial data demonstrating improvements in progression-free survival. Cytotoxic drugs such as temozolomide and capecitabine have been associated with high radiographic response rates; however data derives primarily from ...

  9. 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.

  10. Chromogranin A as serum marker for gastroenteropancreatic neuroendocrine tumors: a single center experience and literature review.


    Christoph J Auernhammer; Christine Spitzweg; Burkhard Göke; Hoffmann, Johannes N.; Herrmann, Karin A.; Alexander Haug; Michael Vogeser; Axel Kuttner; Michael Lauseker; Svenja Nölting


    The aim of this study was to assess the clinical sensitivities of the tumor markers chromogranin A (CgA), urinary 5-hydroxyindoleacetic acid (5-HIAA) and alkaline phosphatase (AP) in neuroendocrine tumors (NETs) of the GastroEnteroPancreatic-(GEP-) system depending on tumor primary location and metastatic spread. In a retrospective single-center series, sensitivities were evaluated in serum samples from 110 patients with midgut (n = 62) and pancreatic (n = 48) NETs. CgA levels were analyzed b...

  11. Developmental programming: postnatal estradiol modulation of prenatally organized reproductive neuroendocrine function in sheep. (United States)

    Puttabyatappa, Muraly; Cardoso, Rodolfo C; Herkimer, Carol; Veiga-Lopez, Almudena; Padmanabhan, Vasantha


    Gestational testosterone (TS) excess, acting via both the androgenic and estrogenic pathways, advances puberty and disrupts the neuroendocrine estradiol (E2) feedback and periovulatory hormonal dynamics in female sheep. These prenatally programmed defects may be subject to postnatal modifications by continued organizational and/or activational effects of steroids. This study investigated (1) the organizational contribution of prenatal estrogen excess and (2) the impact of postnatal exposure to E2 in modulating the effects of prenatal androgen excess (TS and dihydrotestosterone (DHT)) on puberty, neuroendocrine feedback mechanisms, and periovulatory hormonal dynamics in sheep. Pregnant Suffolk sheep were treated with TS, DHT, E2, or E2 plus DHT (ED) from days 30 to 90 of gestation. A subset of the control (C), TS, and DHT female offspring received a constant-release E2 implant postnatally. Findings revealed that (1) prenatal E2-treatment failed to reproduce the neuroendocrine disruptions predicted to be programmed by the estrogenic pathway and (2) prenatal E2D-treatment did not adequately replicate the reproductive neuroendocrine defects induced by prenatal TS excess. More importantly, continuous postnatal E2-treatment, while delaying the onset of puberty and reducing the inhibitory effects of E2 on tonic luteinizing hormone (LH) release, failed to amplify the E2-positive feedback and periovulatory defects induced by prenatal TS-treatment. Our results indicate that disruptions in E2-positive feedback mechanisms and periovulatory gonadotropin secretion induced by prenatal TS-treatment are programmed predominantly during the prenatal life with postnatal exposure to E2 excess not contributing further to these disruptions.

  12. Association between time to disease progression end points and overall survival in patients with neuroendocrine tumors

    Directory of Open Access Journals (Sweden)

    Singh S


    Full Text Available Simron Singh,1 Xufang Wang,2 Calvin HL Law1 1Sunnybrook Odette Cancer Center, University of Toronto, Toronto, ON, Canada; 2Novartis Oncology, Florham Park, NJ, USA Abstract: Overall survival can be difficult to determine for slowly progressing malignancies, such as neuroendocrine tumors. We investigated whether time to disease progression is positively associated with overall survival in patients with such tumors. A literature review identified 22 clinical trials in patients with neuroendocrine tumors that reported survival probabilities for both time to disease progression (progression-free survival and time to progression and overall survival. Associations between median time to disease progression and median overall survival and between treatment effects on time to disease progression and treatment effects on overall survival were analyzed using weighted least-squares regression. Median time to disease progression was significantly associated with median overall survival (coefficient 0.595; P=0.022. In the seven randomized studies identified, the risk reduction for time to disease progression was positively associated with the risk reduction for overall survival (coefficient on −ln[HR] 0.151; 95% confidence interval −0.843, 1.145; P=0.713. The significant association between median time to disease progression and median overall survival supports the assertion that time to disease progression is an alternative end point to overall survival in patients with neuroendocrine tumors. An apparent albeit not significant trend correlates treatment effects on time to disease progression and treatment effects on overall survival. Informal surveys of physicians’ perceptions are consistent with these concepts, although additional randomized trials are needed. Keywords: neuroendocrine tumors, progression-free survival, disease progression, mortality

  13. Metformin with everolimus and octreotide in pancreatic neuroendocrine tumor patients with diabetes. (United States)

    Pusceddu, Sara; Buzzoni, Roberto; Vernieri, Claudio; Concas, Laura; Marceglia, Sara; Giacomelli, Luca; Milione, Massimo; Leuzzi, Livia; Femia, Daniela; Formisano, Barbara; Mazzaferro, Vincenzo; de Braud, Filippo


    A bidirectional relationship seems to exist between diabetes mellitus and development of pancreatic tumors. Metformin, the most widely used drug in the treatment of Type 2 diabetes mellitus, has recently emerged as a potentially active agent in cancer chemoprevention and treatment. In this article, we discuss the potential correlation between glycemic status, administration of antiglycemic treatments, such as metformin or insulin, and prognosis of pancreatic neuroendocrine tumors patients treated with everolimus and octreotide, on the basis of existing evidence and our experience.

  14. Diagnosis, treatment and prognosis of neuroendocrine tumor in stomach and duodenum

    Directory of Open Access Journals (Sweden)

    Xiang-yao WANG


    Full Text Available Objective  To investigate the clinicopathological characteristics and prognosis of patients with neuroendocrine tumor in stomach and duodenum for early diagnosis. Methods  The clinical, endoscopic and pathological data of 20 patients admitted to the PLA General Hospital from Jan. 2012 to Jan. 2015 and diagnosed as gastric and duodenal neuroendocrine tumor were collected for retrospective analysis. The histopathological classification of the disease was made according to the WHO 2010 Classification of the Neuroendocrine Neoplasms. Result  Ten male and 10 female patients aged between 35 and 77 (mean 55.5±10.6 years old were recruited in the present study. Tumor located in the stomach in 13 cases, and in duodenum in 7 cases. The maximum diameter of the tumor was 0.2-2.5cm. Endoscopic features included polypoid protrusion, hemispheric submucosal protrusion, and mucosal erosion. All the patients were treated endoscopically, among them, four patients were treated with electrocoagulation and electrosection, 10 by endoscopic resection (EMR, and 6 by endoscopic submucosal dissection (ESD. In one patient, surgical excision was done after ESD. Biopsy under gastroscopy and endoscopic ultrasonography were conducive to the diagnosis and treatment. According to the histopathological classification, 19 cases were classified as NET grade 1, and another one as NET grade 2. The follow-up study showed no metastasis and recurrence. Conclusions  The early diagnosis and treatment for gastric and duodenal neuroendocrine tumor can lead to satisfactory results. DOI: 10.11855/j.issn.0577-7402.2016.03.12

  15. Neuroendocrine Differentiation in Prostate Cancer: Role of Bone Morphogenetic Protein-6 and Macrophages (United States)


    7-10-2010 11 Fig 6. When RAW 264.7 cells were treated with SB203580 and BMP-6, ChIP assay using GATA4 antibody no longer amplified...neuroendocrine differentiation was no longer observed. Mechanistically, series of studies including shRNA knockdowns and immunoprecipitation assays al., 2005). These mice express the human diphtheria toxin receptor (DTR) under the control of cd11b, a macrophage-specific promoter. Because the

  16. Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1 – molecular pathways


    Cakir, Mehtap; Dworakowska, Dorota; Grossman, Ashley


    Abstract Neuroendocrine tumours (NETs) may occur at many sites in the body although the majority occur within the gastroenteropancreatic axis. Non-gastroenteropancreatic NETs encompass phaeochromocytomas and paragangliomas, medullary thyroid carcinoma, anterior pituitary tumour, broncho-pulmonary NETs and parathyroid tumours. Like most endocrine tumours, NETs also express somatostatin (SST) receptors (subtypes 1–5) whose ligand SST is known to inhibit endocrine and exocrine secretions and hav...

  17. 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. PMID:28194228

  18. [Neoplasms of the disseminated neuroendocrine cell system of the gastrointestinal tract]. (United States)

    Klöppel, G


    The classification of neuroendocrine neoplasms (NEN) of the gastrointestinal tract and also the pancreas is based on the World Health Organization (WHO) classification from 2010, the site-related TNM stage classification and the clinicopathological characterization. This allows a classification of NEN that is adapted to the individual patient, is of high prognostic relevance and serves the needs of an adequate treatment. This article summarizes the current knowledge on the clinical pathology of gastrointestinal NEN, in order to enable a rapid diagnostic orientation.

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

    Directory of Open Access Journals (Sweden)

    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.

  20. Neuroendocrine carcinomas arising in ulcerative colitis:Coincidences or possible correlations?

    Institute of Scientific and Technical Information of China (English)

    Roberto Grassia; Paolo Bodini; Paolo Dizioli; Teresa Staiano; Elena Iiritano; Guglielmo Bianchi; Federico Buffoli


    Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal malignancies. Adenocarcinoma is the commonest type of colorectal neoplasm associated with ulcerative colitis (UC) and Crohn's disease,but other types of epithelial and non-epithelial tumors have also been described in inflamed bowel.With regards to non-epithelial malignancies, lymphomas and sarcomas represent the largest group oftumors reported in association with IBD, especially in immunosuppressed patients. Carcinoids and in particular neuroendocrine neoplasms other than carcinoids (NENs) are rare tumors and are infrequently described in the setting of IBD. Thus, this association requires further investigation. We report two cases of neoplasms arising in mild left-sided UC with immunohistochemical staining for neuroendocrine markers: a large cell and a small cell neuroendocrine carcinoma of the rectum. The two patients were different in age (35 years vs 77 years) and disease duration (11 years vs 27 years), and both had never received immunosuppressant drugs. Although the patients underwent regular endoscopic and histological follow-up, the two neoplasms were locally advanced at diagnosis. One of the two patients developed multiple liver metastases and died 15 mo after diagnosis. These findings confirm the aggressiveness and the poor prognosis of NENs compared to colorectal adenocarcinoma. While carcinoids seem to be coincidentally associated with IBD,NENs may also arise in this setting. In fact, long-standing inflammation could be directly responsible for the development of pancellular dysplasia involving epithelial,goblet, Paneth and neuroendocrine cells. It has yetto be established which IBD patients have a higher risk of developing NENs.

  1. Liver metastases of neuroendocrine tumours; early reduction of tumour load to improve life expectancy

    Directory of Open Access Journals (Sweden)

    Lips Cornelis JM


    Full Text Available Abstract Background Neuroendocrine tumours frequently metastasize to the liver. Although generally slowly progressing, hepatic metastases are the major cause of carcinoid syndrome and ultimately lead to liver dysfunction, cardiac insufficiency and finally death. Methods A literature review was performed to define the optimal treatment strategy and work-up in patients with neuroendocrine hepatic metastases. Based on this, an algorithm for the management of these patients was established. Results Platelet serotonin and chromogranin A are useful biomarkers for detection and follow-up of neuroendocrine tumour. Helical computed tomography and somatostatin receptor scintigraphy are the most sensitive diagnostic modalities. Surgical debulking is an accepted approach for reducing hormonal symptoms and to establish better conditions for medical treatment, but is frequently impossible due to the extent of disease. A novel approach is the local ablation of tumour by thermal coagulation using therapies such as radiofrequency ablation (RFA or laser induced thermotherapy (LITT. These techniques preserve normal liver tissue. There is a tendency to destroy metastases early in the course of disease, thereby postponing or eliminating the surgically untreatable stage. This can be combined with postoperative radioactive octreotide to eliminate small multiple metastases. In patients with extensive metastases who are not suitable for local destruction, systemic therapy by octreotide, 131I-MIBG treatment or targeted chemo- and radiotherapy should be attempted. A final option for selective patients is orthotopic liver transplantation. Conclusion Treatment for patients with neuroendocrine hepatic metastases must be tailored for each individual patient. When local ablative therapies are used early in the course of the disease, the occurrence of carcinoid syndrome with end stage hepatic disease can be postponed or prevented.

  2. 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.

  3. CT and magnetic resonance imaging features of middle ear adenoma of neuroendocrine differentiation: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Sang Kwon; Choe, Mi Sun [Keimyung University School of Medicine, Daegu (Korea, Republic of)


    Middle ear adenoma is a rare benign epithelial tumor. We report the CT and magnetic resonance imaging findings of a case of middle ear adenoma of neuroendocrine differentiation in a 36-year-old man. On high-resolution CT, the mass was found to fill the middle ear, in which the ossicles were embedded, but not destroyed, with outward bulging of the intact tympanic membrane. On MRI, the mass, which was intensely enhanced on 3-dimensional (3D) gadolinium (Gd)-enhanced spoiled gradient-recalled (SPGR) sequence, involved the middle ear, aditus ad antrum and a portion of mastoid antrum. Histological and immunohistochemical findings of the specimen obtained by surgical excisions were consistent with middle ear adenoma of neuroendocrine differentiation. Middle ear adenoma of neuroendocrine differentiation should be included in the differential diagnosis of an intensely enhancing mass filling the middle ear/mastoid antrum without ossicular destructions. The extent of the mass can be excellently assessed with 3D Gd-enhanced SPGR sequence.

  4. 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.)

  5. 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)

  6. Neuroendocrine tumors:current therapies, notch signaling, and cancer stem cells

    Institute of Scientific and Technical Information of China (English)

    Judy S. Crabtree; Lucio Miele


    Neuroendocrine tumors (NETs) encompass a broad spectrum of malignancies all derived from neuroendocrine cell lineage, affecting many different organs including the gastrointestinal (GI) tract, the endocrine pancreas, the thyroid, the skin and the respiratory tract. These tumors as a group are very heterogeneous, with varying characteristics attributed to each tissue of origin and tumor subtype. The pathogenesis of the different subtypes of NETs is not fully understood, but recent studies suggest the Notch signaling pathway may be dysregulated in these tumors either by under or overexpression of Notch receptors and/or ligands, or by disruption of pathway functionality through other means. Notch receptors can function as tumor suppressors in some cellular contexts and oncogenes in others which may, in part, account for the wide range of phenotypes present in NETs. Cancer stem cells are present in these tumors and may be responsible for the high rate of chemotherapy resistance, recurrence and metastasis. The heterogeneity of NETs suggests that to fully understand the role of Notch signaling and the therapeutic implications thereof, a comprehensive and systematic analysis of Notch expression and function across all NET subtypes is required. Here we outline the current knowledge base with respect to current therapies and Notch signaling in neuroendocrine tumors of the lung, skin, thyroid, GI tract and endocrine pancreas.

  7. IGF-1 drives chromogranin A secretion via activation of Arf1 in human neuroendocrine tumour cells. (United States)

    Münzberg, Christin; Höhn, Katharina; Krndija, Denis; Maaß, Ulrike; Bartsch, Detlef K; Slater, Emily P; Oswald, Franz; Walther, Paul; Seufferlein, Thomas; von Wichert, Götz


    Hypersecretion is the major symptom of functional neuroendocrine tumours. The mechanisms that contribute to this excessive secretion of hormones are still elusive. A key event in secretion is the exit of secretory products from the Golgi apparatus. ADP-ribosylation factor (Arf) GTPases are known to control vesicle budding and trafficking, and have a leading function in the regulation of formation of secretory granula at the Golgi. Here, we show that Arf1 is the predominant Arf protein family member expressed in the neuroendocrine pancreatic tumour cell lines BON and QGP-1. In BON cells Arf1 colocalizes with Golgi markers as well as chromogranin A, and shows significant basal activity. The inhibition of Arf1 activity or expression significantly impaired secretion of chromogranin A. Furthermore, we show that the insulin-like growth factor 1 (IGF-1), a major regulator of growth and secretion in BON cells, induces Arf1 activity. We found that activation of Arf1 upon IGF-1 receptor stimulation is mediated by MEK/ERK signalling pathway in BON and QGP-1 cells. Moreover, the activity of Arf1 in BON cells is mediated by autocrinely secreted IGF-1, and concomitantly, autocrine IGF1 secretion is maintained by Arf1 activity. In summary, our data indicate an important regulatory role for Arf1 at the Golgi in hypersecretion in neuroendocrine cancer cells.

  8. 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.

  9. Ethylenediaminetetraacetic acid-dependent pseudothrombocytopenia associated with neuroendocrine carcinoma: A case report. (United States)

    Kim, Hee Jun; Moh, In Ho; Yoo, Hana; Son, Seungyeon; Jung, DA Hye; Lee, Hun Gu; Han, Dong Hee; Park, Jae Hyun; Kim, Hyeong Su; Kim, Jung Han


    Ethylenediaminetetraacetic acid-dependent pseudothrombocytopenia (EDTA-PTCP) is an in vitro phenomenon of EDTA-induced platelet aggregation at room temperature. This phenomenon consists of platelet clumping due to anti-platelet antibodies in blood anticoagulated with EDTA. It has been reported in patients with various diseases, including sepsis, multiple myeloma, acute myocardial infarction and breast cancer. Since unrecognized EDTA-PTCP may lead to inappropriate treatment, it should always be considered as a possible cause in patients with low platelet counts. This study identified a case of transient EDTA-PTCP in a patient with neuroendocrine carcinoma of the stomach. In the present study, a 50-year-old male presented with epigastric pain and a weight loss of 15 kg. The patient presented with EDTA-PTCP and was diagnosed with neuroendocrine carcinoma of the stomach. Following systemic chemotherapy, the tumor showed a marked regression and the EDTA-PTCP disappeared. The mechanism by which this occurred is not clear but an association of EDTA-PTCP with neuroendocrine carcinoma is strongly suggested.

  10. Values of Seven Tumor Markers in Identiifcation and Diagnosis of Esophageal Carcinoma Accompanied by Neuroendocrine Differentiation

    Institute of Scientific and Technical Information of China (English)

    LIU Lian-ke; SHAO Ming-wen; MA Lan; SUN Jing; GUAN Dan; SHU Yongqian


    Objective:To explore the values of seven tumor markers in the identiifcation and diagnosis of esophageal carcinoma accompanied by neuroendocrine differentiation (E-NED). Methods:A total of 378 patients diagnosed as low differentiation of esophageal carcinoma in The First Affiliated Hospital with Nanjing Medical University from Jan., 2008 to Dec., 2013 were selected, in which there were 349 with esophageal carcinoma with no neuroendocrine differentiation (E-NNED, E-NNED group) and 29 with E-NED (E-NED group). The levels of seven tumor markers including synaptophysin (Syn), Chromogranin A (CgA), neuron-specific enolase (NSE), neural cell adhesion molecule (CD56), protein gene product 9.5 (PGP9.5), secretagogue (SCGN) and thyroid transcription factor-1 (TTF-1) of both groups were detected with histoimmunochemical method and the influences of the single and combined detection of above indexes on E-NED patients were analyzed. Results:Except TTF-1, expressions of Syn, CgA, NSE, CD56, PGP9.5 and SCGN in E-NED group were evidently higher than those in E-NNED group and the differences were significant (P Conclusion:PGP9.5 and SCGN can be used as neuroendocrine markers for the pathological diagnosis of E-NED and Syn + CD56, Syn + PGP9.5 and Syn + SCGN can all be used as combined detection.

  11. Esthesioneuroblastoma, Neuroendocrine Carcinoma, and Sinonasal Undifferentiated Carcinoma: Differentiation in Diagnosis and Treatment (United States)

    Su, Shirley Y.; Bell, Diana; Hanna, Ehab Y.


    Introduction Malignant sinonasal tumors comprise less than 1% of all neoplasms. A wide variety of tumors occurring primarily in this site can present with an undifferentiated or poorly differentiated morphology. Among them are esthesioneuroblastomas, sinonasal undifferentiated carcinomas, and neuroendocrine carcinomas. Objectives We will discuss diagnostic strategies, recent advances in immunohistochemistry and molecular diagnosis, and treatment strategies. Data Synthesis These lesions are diagnostically challenging, and up to 30% of sinonasal malignancies referred to the University of Texas MD Anderson Cancer Center are given a different diagnosis on review of pathology. Correct classification is vital, as these tumors are significantly different in biological behavior and response to treatment. The past decade has witnessed advances in diagnosis and therapeutic modalities leading to improvements in survival. However, the optimal treatment for esthesioneuroblastoma, sinonasal undifferentiated carcinoma, and neuroendocrine carcinoma remain debated. We discuss advances in immunohistochemistry and molecular diagnosis, diagnostic strategies, and treatment selection. Conclusions There are significant differences in prognosis and treatment for esthesioneuroblastoma, neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma. Recent advances have the potential to improve oncologic outcomes but further investigation in needed. PMID:25992139

  12. Advance in the Studies on Small Cell Neuroendocrine Carcinoma of the Paranasal Sinuses

    Institute of Scientific and Technical Information of China (English)

    Changsheng Cong; Yonghua Yu; Shuanghu Yuan; Dongwei Gao


    Small cell neuroendocrine carcinoma (SCNEC) of the paranasal sinuses is extremely rare, with an unclear pathogenesis. The presence of neuroendocrine granules is suggestive of neuroendocrine differentiation. It was reported that this disease relates to the presence of accessory salivary glands, and some basic research has shown that it might originate from the multi-potent stem cells.There are no specific clinical symptoms but rhinal and ophthalmological symptoms are found in most cases.Diagnosis mainly depends on histopathological manifestations.Immunohistochemical results and features of the electron microscopic ultra.Structure.Pathologfcal differentiation from poorly differentiated squamous carcinom,melanoma,esthesioneuroblastoma and neuroglioma needed.No unified regimen has been employed in treating the disease.At present,combined theraPY has a manifest therapeutic effect.such as success with the 2003 French regimen.Tumor relapse iS common and prognosis is poor.A complete combined treatment plan will be helpful to improve the prognosis.

  13. Temozolomide as Second or Third Line Treatment of Patients with Neuroendocrine Carcinomas

    Directory of Open Access Journals (Sweden)

    Ingrid H. Olsen


    Full Text Available Background. 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. Patients and Methods. Analysis of consecutive patients with neuroendocrine carcinomas (Ki-67 proliferation index >20% and performance status 0–2 treated with temozolomide 200 mg/sqm orally days 1–5 every 28 days after at least one previous platin-containing chemotherapy regimen. Results. Twenty-eight eligible patients received a median of 3 courses. Sixteen patients were evaluable for response: Six achieved stable disease and ten progressed. The median survival for the 28 patients was 3.5 months. Survival in patients with tumors of pancreatic origin (n=7 was 7.0 months versus 2.9 months in non-pancreatic origin (n=21. Patients in PS 0-1 (n=22 had a median survival of 4.5 months versus 1.1 months in patients in PS 2 (n=6. Ki-67 index ≥50% was associated with a significantly shorter median survival than Ki-67 index <50% (2.7 months versus 10.9 months. The treatment was well tolerated. Conclusion. Temozolomide monotherapy has limited effect in treatment of recurrent neuroendocrine carcinomas. Second line treatment with temozolomide in combination with other compounds should be further investigated in patients in good performance with Ki-67 index <50%.

  14. Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1--molecular pathways. (United States)

    Cakir, Mehtap; Dworakowska, Dorota; Grossman, Ashley


    Neuroendocrine tumours (NETs) may occur at many sites in the body although the majority occur within the gastroenteropancreatic axis. Non-gastroenteropancreatic NETs encompass phaeochromocytomas and paragangliomas, medullary thyroid carcinoma, anterior pituitary tumour, broncho-pulmonary NETs and parathyroid tumours. Like most endocrine tumours, NETs also express somatostatin (SST) receptors (subtypes 1-5) whose ligand SST is known to inhibit endocrine and exocrine secretions and have anti-tumour effects. In the light of this knowledge, the idea of using SST analogues in the treatment of NETs has become increasingly popular and new studies have centred upon the development of new SST analogues. We attempt to review SST receptor (SSTR) biology primarily in neuroendocrine tissues, focusing on pituitary tumours. A full data search was performed through PubMed over the years 2000-2009 with keywords 'somatostatin, molecular biology, somatostatin receptors, somatostatin signalling, NET, pituitary' and all relevant publications have been included, together with selected publications prior to that date. SSTR signalling in non-neuroendocrine solid tumours is beyond the scope of this review. SST is a potent anti-proliferative and anti-secretory agent for some NETs. The successful therapeutic use of SST analogues in the treatment of these tumours depends on a thorough understanding of the diverse effects of SSTR subtypes in different tissues and cell types. Further studies will focus on critical points of SSTR biology such as homo- and heterodimerization of SSTRs and the differences between post-receptor signalling pathways of SSTR subtypes.

  15. 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.)

  16. An overview of computer algorithms for deconvolution-based assessment of in vivo neuroendocrine secretory events. (United States)

    Veldhuis, J D; Johnson, M L


    The availability of increasingly efficient computational systems has made feasible the otherwise burdensome analysis of complex neurobiological data, such as in vivo neuroendocrine glandular secretory activity. Neuroendocrine data sets are typically sparse, noisy and generated by combined processes (such as secretion and metabolic clearance) operating simultaneously over both short and long time spans. The concept of a convolution integral to describe the impact of two or more processes acting jointly has offered an informative mathematical construct with which to dissect (deconvolve) specific quantitative features of in vivo neuroendocrine phenomena. Appropriate computer-based deconvolution algorithms are capable of solving families of 100-300 simultaneous integral equations for a large number of secretion and/or clearance parameters of interest. For example, one application of computer technology allows investigators to deconvolve the number, amplitude and duration of statistically significant underlying secretory episodes of algebraically specifiable waveform and simultaneously estimate subject- and condition-specific neurohormone metabolic clearance rates using all observed data and their experimental variances considered simultaneously. Here, we will provide a definition of selected deconvolution techniques, review their conceptual basis, illustrate their applicability to biological data and discuss new perspectives in the arena of computer-based deconvolution methodologies for evaluating complex biological events.

  17. Succinate Dehydrogenase B Subunit Immunohistochemical Expression Predicts Aggressiveness in Well Differentiated Neuroendocrine Tumors of the Ileum

    Energy Technology Data Exchange (ETDEWEB)

    Milione, Massimo [Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan I-20133 (Italy); Pusceddu, Sara [Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan I-20133 (Italy); Gasparini, Patrizia [Molecular Cytogenetics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan I-20133 (Italy); Melotti, Flavia [Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan I-20133 (Italy); Maisonneuve, Patrick [Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan 20141 (Italy); Mazzaferro, Vincenzo [Division of Gastrointestinal Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan I-20133 (Italy); Braud, Filippo G. de [Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan I-20133 (Italy); Pelosi, Giuseppe, E-mail: [Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan I-20133 (Italy); Department of Medicine, Surgery and Dentistry, Università degli Studi, Facoltà di Medicina, Milan 20122 (Italy)


    Immunohistochemical loss of the succinate dehydrogenase subunit B (SDHB) has recently been reported as a surrogate biomarker of malignancy in sporadic and familial pheocromocytomas and paragangliomas through the activation of hypoxia pathways. However, data on the prevalence and the clinical implications of SDHB immunoreactivity in ileal neuroendocrine tumors are still lacking. Thirty-one consecutive, advanced primary midgut neuroendocrine tumors and related lymph node or liver metastases from 24 males and seven females were immunohistochemically assessed for SDHB. All patients were G1 tumors (Ki-67 labeling index ≤2%). SDHB immunohistochemistry results were expressed as immunostaining intensity and scored as low or strong according to the internal control represented by normal intestinal cells. Strong positivity for SDHB, with granular cytoplasmatic reactivity, was found in 77% of primary tumors (T), whilst low SDHB expression was detected in 90% of metastases (M). The combined analysis (T+M) confirmed the loss of SDHB expression in 82% of metastases compared to 18% of primary tumors. SDHB expression was inversely correlated with Ki-67 labeling index, which accounted for 1.54% in metastastic sites and 0.7% in primary tumors. A correlation between SDHB expression loss, increased Ki-67 labeling index and biological aggressiveness was shown in advanced midgut neuroendocrine tumors, suggesting a role of tumor suppressor gene.

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

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    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.

  19. Somatostatin receptor subtypes in neuroendocrine tumor cell lines and tumor tissues. (United States)

    Jonas, S; John, M; Boese-Landgraf, J; Häring, R; Prevost, G; Thomas, F; Rosewicz, S; Riecken, E O; Wiedenmann, B; Neuhaus, P


    Somatostatin receptor scintigraphy (SRS) is positive in approximately 80% of all patients who have been found to have neuroendocrine (NE) gastroenteropancreatic (GEP) tumors. The reasons for negative results are unclear. The aim of the present study was identification of the specific somatostatin receptor (SSTR) subtypes that are responsible for the in vivo binding of the widely used somatostatin (SST) analogues octreotide and lanreotide in human neuroendocrine gastroenteropancreatic tumors. Ten patients were subjected to SRS with radiolabeled octreotide. Following surgical resection, tumor tissues were analyzed for SSTR subtype mRNA expression by the reverse transcription-polymerase chain reaction (RT-PCR). In addition, SSTR subtype transcripts were investigated by Northern blot analysis and RT-PCR in neuroendocrine tumor cell lines. Expression of SSTR at the protein level was studied by chemical cross-linking experiments. Three patients were negative by SRS. However, RT-PCR revealed most prominently SSTR 2 expression in all tumor specimens. In addition, all tumor tissues analyzed by chemical crosslinking exhibited SST-14 binding sites, indicating that at least some NE tumors were false-negative on SRS.

  20. Neuroendocrine and squamous colonic composite carcinoma: Case report with molecular analysis

    Institute of Scientific and Technical Information of China (English)

    Sabrina C Wentz; Cindy Vnencak-Jones; William V Chopp


    Composite colorectal carcinomas are rare. There are a modest number of cases in the medical literature, with even fewer cases describing composite carcinoma with neuroendocrine and squamous components. There are to our knowledge no reports of composite carcinoma molecular alterations. We present a case of composite carcinoma of the splenic flexure in a 33 year-old Cau casian male to investigate the presence and prognos tic significance of molecular alterations in rare colonic carcinoma subtypes. Formalin-fixed paraffin-embedded (FFPE) tissue was hematoxylin and eosin- and mucicar-mine-stained according to protocol, and immuno-stained with cytokeratin (CK)7, CK20, CDX2, AE1/AE3, chromo-granin-A and synaptophysin. DNA was extracted from FFPE tissues and molecular analyses were performedaccording to lab-developed methods, followed by capil lary electrophoresis. Hematoxylin and eosin staining showed admixed neuroendocrine and keratinized squa mous cells. Positive nuclear CDX2 expression confirmed intestinal derivation. CK7 and CK20 were negative. Neuroendocrine cells stained positively for synaptophy sin and AE1/AE3 and negatively for chromogranin and mucicarmine. Hepatic metastases showed a similar im munohistochemical profile. Molecular analysis revealed a G13D KRAS mutation. BRAF mutational testing was negative and microsatellite instability was not detected. The patient had rapid disease progression on chemo therapy and died 60 d after presentation. Although the G13D KRAS mutation normally predicts an intermediate outcome, the aggressive tumor behavior suggests other modifying factors in rare types of colonic carcinomas.

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

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    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.

  2. Relaxin-3/RXFP3 Signaling and Neuroendocrine Function - A Perspective on Extrinsic Hypothalamic Control. (United States)

    Ganella, Despina E; Ma, Sherie; Gundlach, Andrew L


    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.

  3. Pancreatic Neuroendocrine Neoplasms: Basic Biology, Current Treatment Strategies and Prospects for the Future (United States)

    Ohmoto, Akihiro; Rokutan, Hirofumi; Yachida, Shinichi


    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. PMID:28098761

  4. Neuroendocrine differentiation as a survival prognostic factor in advanced non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Petrović Marina


    Full Text Available Beckground/Aim. Neuroendrocine lung tumors are histologically heterogenous group of cancers with different clinical progression. In non-small cell lung cancer (NSCLC neuroendocrine differentiation exists in 10-30% of patients. The aim of this study was to determine the frequency and influence of neuroendocrine differentiation on survival of treated patients with advanced non-small cell lung cancer (NSCLC. Methods. A clinical trial included 158 patients (74% males and 26% females, with the diagnosis of NSCLC, determined by histological verification. The patients were treated by combined chemo - and X-ray therapy in stage III (without pleural effusion or chemotherapy only in stage III (with pleural effusion and stage IV. Chemotherapy was conducted until progression of the disease, but no more than six cycles. When the progression had been noted in stage III (without pleural effusion, the treatment was continued with X-ray therapy. Neuron specific enolase, chromogranin A, as well as synapthophysin expression in tissue examples were determined by immunohistochemical analysis with monoclonal mouse anti-human-bodies. Survival was assessed within a year and two years follow-up examination. Results. A total of 53 patients (34% had NSCLC with neuroendocrine differentiation, confirmed rather in large cell lung cancer and lung adenocarcinoma (66.7% and 40%, respectively. Neuron specific enolase, chromogranin A and synapthophysin expression was noted in 45 (28.5%, 34 (21.5% and 33 (20.1% patients, respectively. The one year and two years follow-up survival periods were confirmed in 39% and 17% of patients respectively. The median survival time in the patients with the neuroendocrine expression as compared to those without the expression was 15.6 vs 10.8 months; one year survival time with the expression compared to those without the expression achieved in 62% vs 27% of the patients, (p < 0.001; a two - year survival time noted in 30% of the patients (p = 0

  5. Influence of chemiotherapeutic protocol and neuroendocrine differentiation on metastatic non-small cell lung cancer treatment results

    Directory of Open Access Journals (Sweden)

    Tomić Ilija


    Full Text Available Background/Aim. In 40-50% of patients with non-small cell lung cancer (NSCLC at the time of making a diagnosis, the disease is yet at IIIb and IV stage. Standard in the treatment of these patient is the application of systemic chemiotherapy based on CIS/Carboplatin preparations. The aim of this study was to determine the influence of two different chemiotherapeutic protocols and neuroendocrine differentiation on treatment response and survival in patients with metastatic NSCLC. Methods. We examined 85 patients with metastatic NSCLC, of which 51 with stage IIIb, and 34 with stage IV of the disease. The histologic diagnosis of NSCLC was determined by tissue assays using hematoxylin eosin method. Neuroendocrine differentiation was determined by immunohistochemical analysis of neuron- specific enolase (NSE, chromogranin A, and synapthophysin expression using monoclonal mouse anti- human bodies (DAKO, Denmark. According to chemiotherapeutic protocol, the patients were randomly assigned into combined Taxol + Cisplatin group (Tax + Cis, n = 35, and Cyclophosphamide + Etoposide + Carboplatin group (CEP, n = 50. The treatment was conducted within 4-6 chemiotherapeutic cycles. The efficacy was assessed after the therapy regimen and median survival time was assessed after the randomization. Results. A total of 31 (36.47% patients had a favourable therapeutic response, both partial and complete response (54.2% in the Tax + Cis group and 24% in CEP group of patients, respectively, p < 0.001. The median survival time in both groups was 13.1 months (15.3 months in the Tax + Cis group and 10.6 months in the CEP group, respectively, p < 0.001. A one-year follow-up survival period was confirmed in 40% of patients (60% only in the Tax + Cis group. A total of 23 (27.05% patients with metastatic NSCLC had neuroendocrine differentiation. The disease progression or stable disease was noted only in patient with NSCLC without neuroendocrine differentiation (n = 42, 67

  6. C-cell-derived calcitonin-free neuroendocrine carcinoma of the thyroid: the diagnostic importance of CGRP immunoreactivity. (United States)

    Nakazawa, Tadao; Cameselle-Teijeiro, José; Vinagre, João; Soares, Paula; Rousseau, Emmanuel; Eloy, Catarina; Sobrinho-Simões, Manuel


    In the thyroid, primary neuroendocrine tumors encompass medullary thyroid carcinoma (MTC) and, rarely, other tumors such as paragangliomas. MTCs are derived from C-cells and express calcitonin and neuroendocrine markers. Besides classic MTC, some reports have documented thyroid neuroendocrine tumors, which show no calcitonin expression and raise difficult diagnostic problems. A 76-year-old man presented with a mass in the left thyroid with neither serological calcitonin elevation nor familial history. A thorough clinico-laboratorial study did not disclose any other mass elsewhere. A left hemithyroidectomy was performed, and the histological examination revealed a neuroendocrine carcinoma resembling a paraganglioma-like MTC displaying unequivocal signs of vascular invasion. Immunohistochemically, the tumor cells showed reactivity for chromogranin A, synaptophysin, thyroid transcription factor-1 (TTF-1), paired box gene 8 (PAX8), cytokeratins (AE1/AE3 and CK8/18), and calcitonin gene-related peptide (CGRP) and negativity for calcitonin, carcinoembryonic antigen, TTF-2, thyroperoxidase, and thyroglobulin. In situ hybridization showed that the tumor cells lacked expression for calcitonin and thyroglobulin mRNA. Genetic analysis did not disclose any RET mutation. A diagnosis of C-cell-derived primary neuroendocrine carcinoma of the thyroid without calcitonin expression was made, and the patient remains free of metastasis or recurrence 18 months after surgery.

  7. Neuroendocrine tumor of the pancreas in a patient with tuberous sclerosis: a case report and review of the literature. (United States)

    Díaz Díaz, Delissa; Ibarrola, Carolina; Goméz Sanz, Ramón; Pérez Hurtado, Bladimir; Salazar Tabares, Johny; Colina Ruizdelgado, Francisco


    A rare case of pancreatic neuroendocrine neoplasm in a patient with tuberous sclerosis complex is described. The patient was a 31-year-old man who had multiple congenital subependymal nodules, bilateral cortical tubers, and seizures of difficult control. A 2.3 cm × 2 cm well-delimitated solid tumor in the tail of the pancreas was discovered during a monitoring abdominal computed tomography. A distal pancreatectomy was performed. Histologically, the tumor was formed by uniform cells with moderated cytoplasm arranged in a combined trabecular and nested pattern. The nuclear features were bland, and mitosis was infrequent. There was no vascular invasion. Immunoreactivity for cytokeratine AE1/AE3, chromogranin A, and synaptophysin confirmed the neuroendocrine nature of this neoplasia. Pancreatic hormones were negatives. One of the 5 lymph nodes isolated from the peripancreatic adipose tissue was positive for metastases. Small series and case reports have documented that in tuberous sclerosis many endocrine system alterations might occur, affecting the function of the pituitary, parathyroid, and other neuroendocrine tissue, including islet cells of the pancreas. However, the true association of these pathological conditions remains uncertain. As far as we know, there are 10 cases reported of pancreatic neuroendocrine tumors in a setting of tuberous sclerosis complex, in which 2 cases resulted in malignant, nonfunctioning pancreatic neuroendocrine tumors.


    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 tissu

  9. 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

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    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.)

  10. Filial caregiving is associated with greater neuroendocrine dysfunction: Evidence from the 2005 National Survey of Midlife in the United States

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    SunWoo Kang


    Full Text Available Objectives: This study examined associations between providing caregiving for a biological or adoptive parent and clinically assessed biological risk factors (allostatic load and its three subscales—inflammatory dysfunction, metabolic dysfunction, and neuroendocrine dysfunction, as well as moderation of these associations by gender. Methods: Regression models were estimated using telephone and self-report data from 962 men and women who participated in the National Survey of Midlife in the United States in 2005. Results: Filial caregivers demonstrated higher levels of neuroendocrine dysfunction. No gender difference in biological risks was found. Discussion: Filial caregiving is the most prevalent form of family caregiving, and results indicating the presence of greater neuroendocrine dysfunction among filial caregivers in contrast to noncaregivers suggest an important public health concern. Future research needs to continue to examine different relationship types of caregivers and include a range of biological risk measurement to further the understanding of how family caregiving is linked to biological health risks.

  11. 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


    Directory of Open Access Journals (Sweden)

    Rosario Rodríguez


    Full Text Available Serotonin immunoreactive neuroendocrine cells and peptidergic nerves (NPY and VIP could have a role in prostate growth and function. In the present study, rats grouped by stages of postnatal development (prepubertal, pubertal, young and aged adults were employed in order to ascertain whether age causes changes in the number of serotoninergic neuroendocrine cells and the length of NPY and VIP fibres. Discriminant analysis was performed in order to ascertain the classificatory power of stereologic variables (absolute and relative measurements of cell number and fibre length on age groups. The following conclusions were drawn: a discriminant analysis confirms the androgen-dependence of both neuroendocrine cells and NPYVIP innervation during the postnatal development of the rat prostate; b periglandular innervation has more relevance than interglandular innervation in classifying the rats in age groups; and c peptidergic nerves from ventral, ampullar and periductal regions were more age-dependent than nerves from the dorso-lateral region.

  13. Prenatal caffeine ingestion induces transgenerational neuroendocrine metabolic programming alteration in second generation rats

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    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

  14. Gene expression accurately distinguishes liver metastases of small bowel and pancreas neuroendocrine tumors. (United States)

    Sherman, Scott K; Maxwell, Jessica E; Carr, Jennifer C; Wang, Donghong; Bellizzi, Andrew M; Sue O'Dorisio, M; O'Dorisio, Thomas M; Howe, James R


    Small bowel (SBNETs) and pancreatic neuroendocrine tumors (PNETs) often present with liver metastases. Although liver biopsy establishes a neuroendocrine diagnosis, the primary tumor site is frequently unknown without exploratory surgery. Gene expression differences in metastases may distinguish primary SBNETs and PNETs. This study sought to determine expression differences of four genes in neuroendocrine metastases and to create a gene expression algorithm to distinguish the primary site. Nodal and liver metastases from SBNETs and PNETs (n = 136) were collected at surgery under an Institutional Review Board-approved protocol. Quantitative PCR measured expression of bombesin-like receptor-3, opioid receptor kappa-1, oxytocin receptor, and secretin receptor in metastases. Logistic regression models defined an algorithm predicting the primary tumor site. Models were developed on a training set of 21 nodal metastases and performance was validated on an independent set of nodal and liver metastases. Expression of all four genes was significantly different in SBNET compared to PNET metastases. The optimal model employed expression of bombesin-like receptor-3 and opioid receptor kappa-1. When these genes did not amplify, the algorithm used oxytocin receptor and secretin receptor expression, which allowed classification of all 136 metastases with 94.1 % accuracy. In the independent liver metastasis validation set, 52/56 (92.9 %) were correctly classified. Positive predictive values were 92.5 % for SBNETs and 93.8 % for PNETs. This validated algorithm accurately distinguishes SBNET and PNET metastases based on their expression of four genes. High accuracy in liver metastases demonstrates applicability to the clinical setting. Studies assessing this algorithm's utility in prospective clinical decision-making are warranted.

  15. Does orthostatic stress influence the neuroendocrine response to subsequent hypoglycemia in humans? (United States)

    Radikova, Z; Penesova, A; Koska, J; Kvetnansky, R; Jezova, D; Huckova, M; Vigas, M; Macho, L


    Neuroendocrine response to stress stimuli is influenced by previous stimuli of different nature. The aim of the study was to test whether antecedent orthostatic stress may affect the neuroendocrine response to subsequent hypoglycemia. A group of 12 (6 men, 6 women) nonobese, healthy volunteers aged 19 to 27 y (mean 24 +/- 0.8) participated in the study in two sessions: controlled insulin-induced hypoglycemia to 2.7 mmol/L for 15 min either with or without antecedent orthostatic stress (30 min of 60 degrees head-up tilt before insulin administration). Orthostatic stress caused a significant decrease in plasma volume (-9.6%; P < 0.001) and a significant increase in plasma renin activity, aldosterone, norepinephrine (P < 0.01), and adrenocorticotropic hormone (ACTH) concentrations (P < 0.05) in all subjects. Growth hormone response to hypoglycemia was diminished in women (P < 0.01). The epinephrine response to hypoglycemia was diminished in women in comparison to men (P < 0.001), but was unaffected by antecedent orthostatic stress. Hypoglycemia failed to induce the ACTH release after its elevation during orthostatic stress. ACTH response to moderate hypoglycemia without previous orthostatic stress was evident only in men in comparison to women (P < 0.05). We conclude that the epinephrine, growth hormone, and ACTH responses to hypoglycemia were diminished in women. Except ACTH, the neuroendocrine response to mild hypoglycemia was not affected by previous orthostatic stress in healthy subjects. In the case of ACTH, the first stress stimulus is consequential for the subsequent response of this hormone, probably due to short-loop negative feedback effects.

  16. Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1 – molecular pathways (United States)

    Cakir, Mehtap; Dworakowska, Dorota; Grossman, Ashley


    Abstract Neuroendocrine tumours (NETs) may occur at many sites in the body although the majority occur within the gastroenteropancreatic axis. Non-gastroenteropancreatic NETs encompass phaeochromocytomas and paragangliomas, medullary thyroid carcinoma, anterior pituitary tumour, broncho-pulmonary NETs and parathyroid tumours. Like most endocrine tumours, NETs also express somatostatin (SST) receptors (subtypes 1–5) whose ligand SST is known to inhibit endocrine and exocrine secretions and have anti-tumour effects. In the light of this knowledge, the idea of using SST analogues in the treatment of NETs has become increasingly popular and new studies have centred upon the development of new SST analogues. We attempt to review SST receptor (SSTR) biology primarily in neuroendocrine tissues, focusing on pituitary tumours. A full data search was performed through PubMed over the years 2000–2009 with keywords ‘somatostatin, molecular biology, somatostatin receptors, somatostatin signalling, NET, pituitary’ and all relevant publications have been included, together with selected publications prior to that date. SSTR signalling in non-neuroendocrine solid tumours is beyond the scope of this review. SST is a potent anti-proliferative and anti-secretory agent for some NETs. The successful therapeutic use of SST analogues in the treatment of these tumours depends on a thorough understanding of the diverse effects of SSTR subtypes in different tissues and cell types. Further studies will focus on critical points of SSTR biology such as homo- and heterodimerization of SSTRs and the differences between post-receptor signalling pathways of SSTR subtypes. PMID:20629989

  17. [Modern technologies and diagnostics in treatment of neuroendocrine tumors of the pancreas]. (United States)

    Maistrenko, N A; Romashchenko, P N; Lysanyuk, M V


    The article presents the results of investigation and treat- ment of 124 patients with neuroendocrine tumors of the pancreas (NET P): insulinima (68 cases), gastrinoma (43 cases), rare forms of tumor (13 patients). It was stated that clinical manifestations of NET P resembled the signs of neurological and gastroentero- logical diseases. Thus, the terms of detection would be prolonged during pre-admission stage and this validated the reasonabil- ity of well-timed application of current laboratory methods of diagnostics. An appropriate clinic neuroendocrine syndrome could be confirmed in 93-96% of patients. The authors showed that available diagnostic technique of NET P were the helical computer tomography and endoscopic ultrasound study with sen- sitivity 75% and 91%, respectively. It was rational to complete study with the data of intraoperative sonography for final tumor localization and its assessment in relation to the connection with pancreas duct and vessels. At the same time, it could be used in case of suspicion to multiple neoplasia. Angiography in combi- nation with arterial-stimulated blood sampling from the hepatic vein and positron emission tomography with 18-fluorodeoxyglu- cose were the additional methods of diagnostics concerning the main forms of limited hyperinsulinism and generalized forms of NET P. Immunohistochemical study of removed pancreas tumor was the main method of morphological verification of the diagnosis and it's used to develop the further strategy of postop- erative treatment for patients. The surgical method of treatment of patients with NET P allowed elimination of clinical laboratory manifestations of neuroendocrine syndrome and getting general cumulative 5-year survival (69.3 ± 4.7%) of radically operated patients.

  18. L-tyrosine improves neuroendocrine function in a mouse model of chronic stress

    Institute of Scientific and Technical Information of China (English)

    Zhihua Wang; Jinghua Li; Zhiming Wang; Lingyan Xue; Yi Zhang; Yingjie Chen; Jun Su; Zhongming Li


    Adult BALB/c mice, individually housed, were stimulated with nine different stressors, arranged randomly, for 4 continuous weeks to generate an animal model of chronic stress. In chronically stressed mice, spontaneous locomotor activity was significantly decreased, escape latency in the Morris water maze test was prolonged, serum levels of total thyrotropin and total triiodothyronine were significantly decreased, and dopamine and norepinephrine content in the pallium, hippocampus and hypothalamus were significantly reduced. All of these changes were suppressed, to varying degrees, by L-tyrosine supplementation. These findings indicate that the neuroendocrine network plays an important role in chronic stress, and that L-tyrosine supplementation has therapeutic effects.

  19. Radioembolization for Neuroendocrine Liver Metastases: Safety, Imaging, and Long-Term Outcomes

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    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

  20. Neuroendocrine responses to hypoglycaemia decrease within the first year after diagnosis of type 1 diabetes

    DEFF Research Database (Denmark)

    Damholt, M B; Christensen, N J; Hilsted, Jannik


    in neuroendocrine responses occur early in the course of diabetes, we investigated the responses to insulin-induced hxypoglycaemia during the first year of type 1 diabetes. Autonomic and somatic nerve function tests were performed concomitantly. Six type 1 diabetes patients were studied 3 and 12 months after.......025) and noradrenaline (p 12 months compared with 3 months after diagnosis of type 1 diabetes. Rate of glucose recovery did not differ at month 12 compared with month 3. Cardiovascular autonomic nerve function tests did not change and remained...

  1. [Microbial endocrinology: impact of interactions between microbes and neuroendocrine hormones on infection--a review]. (United States)

    Xu, Fuzhou; Wu, Cun; Lin, Jun


    Microbial endocrinology is a crossdisciplinary field representing the intersection of microbiology with mammalian endocrinology and neurophysiology. In this review, effects of catecholamine on bacteria were used as an example to demonstrate the interactions between microbes and neuroendocrine hormones. Catecholamine modulates bacterial infectivity by stimulation of bacteria growth and augmentation of host tissue attachment and invasion. Moreover, the bacterial adrenergic receptors recognized by catecholamine and its relationship with quorum sensing signals were also addressed. This review will be helpful for understanding the interactions between microorganism and host as well as health breeding and food safety in animal industries.

  2. 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

  3. Atypical carcinoid and large cell neuroendocrine carcinoma of the lung: a proteomic dataset from formalin-fixed archival samples (United States)

    Tanca, Alessandro; Addis, Maria Filippa; Pisanu, Salvatore; Abbondio, Marcello; Pagnozzi, Daniela; Eccher, Albino; Rindi, Guido; Cossu-Rocca, Paolo; Uzzau, Sergio; Fanciulli, Giuseppe


    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 PMID:27054153

  4. Atypical carcinoid and large cell neuroendocrine carcinoma of the lung: a proteomic dataset from formalin-fixed archival samples. (United States)

    Tanca, Alessandro; Addis, Maria Filippa; Pisanu, Salvatore; Abbondio, Marcello; Pagnozzi, Daniela; Eccher, Albino; Rindi, Guido; Cossu-Rocca, Paolo; Uzzau, Sergio; Fanciulli, Giuseppe


    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

  5. High-grade neuroendocrine carcinomas of the lung highly express enhancer of zeste homolog 2, but carcinoids do not. (United States)

    Findeis-Hosey, Jennifer J; Huang, Jiaoti; Li, Faqian; Yang, Qi; McMahon, Loralee A; Xu, Haodong


    Enhancer of zeste homolog 2, the catalytic subunit of polycomb repressive complex 2, is a histone methyltransferase and plays an important role in cell proliferation and cell cycle regulation. It has been shown to be overexpressed in a number of malignant neoplasms. This study aimed to determine the expression pattern of enhancer of zeste homolog 2 in neuroendocrine tumors of the lung and the potential of enhancer of zeste homolog 2 to serve as a biomarker to segregate carcinoids from high-grade neuroendocrine carcinomas. Fifty-four cases, including 25 typical carcinoids, 7 atypical carcinoids, 9 large-cell neuroendocrine carcinomas, and 13 small-cell lung carcinomas, were immunohistochemically studied using a monoclonal antibody against enhancer of zeste homolog 2. All 13 small-cell lung carcinomas demonstrated moderate to strong nuclear staining with 12 exhibiting more than 90% of tumor cells staining. All 9 large-cell neuroendocrine carcinomas were moderately to strongly positive for enhancer of zeste homolog 2, with 6 cases having staining in more than 80% of tumor cells. In contrast, all 25 typical carcinoids and 6 atypical carcinoids showed only rare scattered enhancer of zeste homolog 2-positive tumor cells, with 1 case of atypical carcinoid exhibiting moderate staining in 40% of tumor cells. A subsequent validation study of the 14 specimens of lung or mediastinal lymph node biopsy and fine-needle aspiration, including 6 small-cell lung carcinomas, 2 large-cell neuroendocrine carcinomas, 5 typical carcinoids, and 1 atypical carcinoid, was performed. Enhancer of zeste homolog 2 was diffusely and strongly positive in all small-cell lung carcinomas and large-cell neuroendocrine carcinomas, even with severe crush artifact, whereas it was only positive in rare tumor cells in carcinoids. These findings support the formulation that enhancer of zeste homolog 2 may play an important role in the regulation of biologic behavior of high-grade neuroendocrine carcinomas

  6. Well-differentiated pancreatic neuroendocrine tumor with solitary hepatic metastasis presenting as a benign cystic mass: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Su Joa; Choi, Seung Joon; Kim, Hyung Sik; Kim, Jeong Ho; Choi, Hye Young [Dept. of Radiology, Gachon University Gil Hospital, Incheon (Korea, Republic of)


    Pancreatic neuroendocrine tumors and their hepatic metastases have an inconsistent appearance with only a small percentage of lesions appearing as cystic masses in computed tomography (CT) and magnetic resonance imaging (MRI). Therefore, they can be mistaken as benign or infectious lesions, which can lead to a false diagnosis with delayed or inadequate treatment. We reported a patient with upper abdominal pain that lasted for several months, caused by a huge cystic neuroendocrine carcinoma of the liver. This was mistakenly interpreted as a complicated or hydatid cyst, and the findings in the CT and MRI was presented.

  7. Surgical Treatment as a Principle for Patients with High-Grade Pancreatic Neuroendocrine Carcinoma

    DEFF Research Database (Denmark)

    Haugvik, Sven-Petter; Janson, Eva Tiensuu; Österlund, Pia;


    BACKGROUND: This study aimed to evaluate the role of surgery for patients with high-grade pancreatic neuroendocrine carcinoma (hgPNEC) in a large Nordic multicenter cohort study. Prior studies evaluating the role of surgery for patients with hgPNEC are limited, and the benefit of the surgery is u....... Patients selected for resection of the primary tumor and synchronous liver metastases had a high 3-year survival rate. Selected patients with both localized hgPNEC and metastatic hgPNEC should be considered for radical surgical treatment.......BACKGROUND: This study aimed to evaluate the role of surgery for patients with high-grade pancreatic neuroendocrine carcinoma (hgPNEC) in a large Nordic multicenter cohort study. Prior studies evaluating the role of surgery for patients with hgPNEC are limited, and the benefit of the surgery...... is uncertain. METHODS: Data from patients with a diagnosis of hgPNEC determined between 1998 and 2012 were retrospectively registered at 10 Nordic university hospitals. Kaplan-Meier curves were used to compare the overall survival of different treatment groups, and Cox-regression analysis was used to evaluate...

  8. Management of hepatic metastases of well/moderately differentiated neuroendocrine tumors of the digestive tract

    Institute of Scientific and Technical Information of China (English)

    Anna La Salvia; Stefano Partelli; Marco Tampellini; Domenico Tamburrino; Massimo Falconi; Giorgio V Scagliotti; Maria Pia Brizzi


    In neuroendocrine tumors (NETs), liver metastases (LM) represent the most crucial prognostic factor, irrespective of the primary tumor site. At diagnosis, about 65-95% of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) show hepatic metastasis. Management strategies of LM are heterogeneous and range from systemic therapy to liver-directed procedures. The type of systemic therapy used is dependent on the grade and proliferation of the tumor and includes somatostatin analogues, interferon, m-Tor and tyrosine kinase inhibitors, and chemotherapy. Angiographic liver-directed techniques, such as transarterial embolization/chemoembolization and selective internal radiation therapy, offer excellent palliation for patients with liver-predominant disease. In highly selected cases, liver transplantation and peptide receptor radionuclide therapy are considered. The relatively low disease incidence and the diversity of presentation have led to a lack of well-conducted randomized controlled trials comparing the efifcacy of different treatment options. Experience indicates that surgery is the only treatment that offers potential for cure. For unresectable lesions, the absence of data from rigorous trials limits the validity of many publications that detail management. In this review we will discuss the existing approaches for hepatic metastases from GEP-NETs.

  9. F-18 FDG PET/CT imaging of primary hepatic neuroendocrine tumor

    Directory of Open Access Journals (Sweden)

    Katsuya Mitamura


    Full Text Available Primary hepatic neuroendocrine tumors (PHNETs are extremely rare neoplasms. Herein, we report a case of a 70-year-old man with a hepatic mass. The non-contrast computed tomography (CT image showed a low-density mass, and dynamic CT images indicated the enhancement of the mass in the arterial phase and early washout in the late phase. F18- fluorodeoxyglucose (18F-FDG positron emission tomography (PET and fused PET/CT images showed increased uptake in the hepatic mass. Whole-body 18F-FDG PET images showed no abnormal activity except for the liver lesion. Presence of an extrahepatic tumor was also ruled out by performing upper gastrointestinal endoscopy, total colonoscopy, and chest and abdominal CT. A posterior segmentectomy was performed, and histologic examination confirmed a neuroendocrine tumor (grade 1. The patient was followed up for about 2 years after the resection, and no extrahepatic lesions were radiologically found. Therefore, the patient was diagnosed with PHNET. To the best of our knowledge, no previous case of PHNET have been detected by 18F-FDG PET imaging.

  10. Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism.

    Directory of Open Access Journals (Sweden)

    Laurent Kappeler


    Full Text Available Mutations that decrease insulin-like growth factor (IGF and growth hormone signaling limit body size and prolong lifespan in mice. In vertebrates, these somatotropic hormones are controlled by the neuroendocrine brain. Hormone-like regulations discovered in nematodes and flies suggest that IGF signals in the nervous system can determine lifespan, but it is unknown whether this applies to higher organisms. Using conditional mutagenesis in the mouse, we show that brain IGF receptors (IGF-1R efficiently regulate somatotropic development. Partial inactivation of IGF-1R in the embryonic brain selectively inhibited GH and IGF-I pathways after birth. This caused growth retardation, smaller adult size, and metabolic alterations, and led to delayed mortality and longer mean lifespan. Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals. The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments. Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.

  11. Neuroendocrine Disturbances after Brain Damage: An Important and Often Undiagnosed Disorder. (United States)

    Tanriverdi, Fatih; Kelestimur, Fahrettin


    Traumatic brain injury (TBI) is a common and significant public health problem all over the world. Until recently, TBI has been recognized as an uncommon cause of hypopituitarism. The studies conducted during the last 15 years revealed that TBI is a serious cause of hypopituitarism. Although the underlying pathophysiology has not yet been fully clarified, new data indicate that genetic predisposition, autoimmunity and neuroinflammatory changes may play a role in the development of hypopituitarism. Combative sports, including boxing and kickboxing, both of which are characterized by chronic repetitive head trauma, have been shown as new causes of neuroendocrine abnormalities, mainly hypopituitarism, for the first time during the last 10 years. Most patients with TBI-induced pituitary dysfunction remain undiagnosed and untreated because of the non-specific and subtle clinical manifestations of hypopituitarism. Replacement of the deficient hormones, of which GH is the commonest hormone lost, may not only reverse the clinical manifestations and neurocognitive dysfunction, but may also help posttraumatic disabled patients resistant to classical treatment who have undiagnosed hypopituitarism and GH deficiency in particular. Therefore, early diagnosis, which depends on the awareness of TBI as a cause of neuroendocrine abnormalities among the medical community, is crucially important.

  12. 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)

  13. Psychosocial stress evoked by a virtual audience: relation to neuroendocrine activity. (United States)

    Kelly, Owen; Matheson, Kimberly; Martinez, Alejandra; Merali, Zul; Anisman, Hymie


    A modified version of the Trier Social Stress Test (TSST) was employed to determine whether exposure to a virtual audience using virtual reality (VR) technology would prompt an increase of neuroendocrine activity comparable to that prompted by a real audience. Following an anticipatory period, participants completed a speech or a speech-plus-math challenge in front of either a virtual audience, a panel of judges they were led to believe was behind a one-way mirror, or an audience comprised of confederates. An additional group that had prepared a speech was simply directed to observe the virtual audience but did not deliver the speech. Finally, a control group completed questionnaires for the duration of the experiment. Cortisol samples were obtained upon arrival to the laboratory, just before the challenge, and 15 and 30 minutes after the task. Participants also completed a measure assessing stressor appraisals of the task before and after the challenge. Anticipation of the task was associated with a modest increase of cortisol levels, and a further rise of cortisol was evident in response to the challenge. The neuroendocrine changes evoked by the virtual audience were comparable to those elicited by the imagined audience (behind the one-way mirror) but less than changes evoked by the panel of confederates. Stressor appraisals were higher post-challenge compared to those reported prior to the task; however, appraisals were similar across each group. These data suggest that VR technology may be amenable to evaluating the impact of psychosocial stressors such as the TSST.

  14. Neuroendocrine carcinoma arising in soft tissue: three case reports and literature review

    Directory of Open Access Journals (Sweden)

    McAleese Jonathan


    Full Text Available Abstract Background Neuroendocrine tumours (NET are tumours arising from neuroendocrine cells of neural crest origin. They are characterised by the presence of neurosecretory granules which react positively to silver stains and to specific markers including neuron specific enolase, synaptophysin and chromogranin. Metastasis to the skin occurs infrequently but primary soft tissue NET is excessively rare. Case presentation We report our experience with 3 such cases. In the first case, the NET originated in muscle and was treated with wide surgical excision and adjuvant radiotherapy. The second case presented as a subcutaneous mass in the foot and the tumour was positive on 123I mIBG scan. She has had prolonged recurrence-free survival following primary hypo-fractionated radiotherapy. In the third case, a cutaneous nodule proved to be a NET and at surgery, lymph node disease was present. He has remained disease-free after surgical excision without the need for external beam radiotherapy. Conclusion These tumours appear to have a good prognosis. Complete excision offers potentially curative treatment. Adjuvant radiotherapy may be helpful when the tumour margin is narrow. For patients with unresectable disease or where surgery would not be appropriate, radiotherapy appears to be an effective therapeutic option.

  15. Multiple-scale neuroendocrine signals connect brain and pituitary hormone rhythms (United States)

    Romanò, Nicola; Guillou, Anne; Martin, Agnès O; Mollard, Patrice


    Small assemblies of hypothalamic “parvocellular” neurons release their neuroendocrine signals at the median eminence (ME) to control long-lasting pituitary hormone rhythms essential for homeostasis. How such rapid hypothalamic neurotransmission leads to slowly evolving hormonal signals remains unknown. Here, we show that the temporal organization of dopamine (DA) release events in freely behaving animals relies on a set of characteristic features that are adapted to the dynamic dopaminergic control of pituitary prolactin secretion, a key reproductive hormone. First, locally generated DA release signals are organized over more than four orders of magnitude (0.001 Hz–10 Hz). Second, these DA events are finely tuned within and between frequency domains as building blocks that recur over days to weeks. Third, an integration time window is detected across the ME and consists of high-frequency DA discharges that are coordinated within the minutes range. Thus, a hierarchical combination of time-scaled neuroendocrine signals displays local–global integration to connect brain–pituitary rhythms and pace hormone secretion. PMID:28193889

  16. Combined choriocarcinoma,neuroendocrine cell carcinoma and tubular adenocarcinoma in the stomach

    Institute of Scientific and Technical Information of China (English)

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


    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 fiborscopy 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 loci contained cells positive for synaptophysin,neuron-specific enolase (NSF),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.

  17. Diagnosis and management of gastrointestinal neuroendocrine tumors: An evidence-based Canadian consensus. (United States)

    Singh, Simron; Asa, Sylvia L; Dey, Chris; Kennecke, Hagen; Laidley, David; Law, Calvin; Asmis, Timothy; Chan, David; Ezzat, Shereen; Goodwin, Rachel; Mete, Ozgur; Pasieka, Janice; Rivera, Juan; Wong, Ralph; Segelov, Eva; Rayson, Daniel


    The majority of neuroendocrine tumors originate in the digestive system and incidence is increasing within Canada and globally. Due to rapidly evolving evidence related to diagnosis and clinical management, updated guidance on the diagnosis and treatment of gastrointestinal neuroendocrine tumors (GI-NETs) are of clinical importance. Well-differentiated GI-NETs may exhibit indolent clinical behavior and are often metastatic at diagnosis. Some NET patients will develop secretory disease requiring symptom control to optimize quality of life and clinical outcomes. Optimal management of GI-NETs is in a multidisciplinary environment and is multimodal, requiring collaboration between medical, surgical, imaging and pathology specialties. Clinical application of advances in pathological classification and diagnostic technologies, along with evolving surgical, radiotherapeutic and medical therapies are critical to the advancement of patient care. We performed a systematic literature search to update our last set of published guidelines (2010) and identified new level 1 evidence for novel therapies, including telotristat etiprate (TELESTAR), lanreotide (CLARINET), everolimus (RADIANT-2; RADIANT-4) and peptide receptor radionuclide therapy (PRRT; NETTER-1). Integrating these data with the clinical knowledge of 16 multi-disciplinary experts, we devised consensus recommendations to guide state of the art clinical management of GI-NETs.

  18. Testing of neuroendocrine function in astronauts as related to fluid shifts. (United States)

    Sauseng-Fellegger, G; Konig, E M; Hinghofer-Szalkay, H; Jezova, D; Vigas, M


    We addressed the question of optimal conditions for neuroendocrine and cardiovascular testing in astronauts. We tested stress reactions during LBNP of < or = -50 mmHg. There was a mild transient elevation of plasma GH concentration and a nonsignificant rise of plasma ACTH, while PRL, insulin and glucose remained unchanged. Aldosterone was decreased 5 and 10 min after beginning of LBNP, thereafter rose significantly, and displayed further significant concentration increase 5 min post-LBNP. The endocrine and cardiovascular responses to submaximal exercise were tested at 8.00 am and 8.00 pm. Exercise-induced changes of heart rate and blood pressure remained unchanged with daytime whereas plasma concentrations of epinephrine, GH and PRL in response to work load were significantly higher in the evening than in the morning. As expected, basal resting values of plasma cortisol were significantly lower in the evening than in the morning but were similar one hour after cessation of exercise. Our findings demonstrate the importance of frequent sampling in case of transient physiological phenomena, and contribute to existing knowledge on circadian influences upon neuroendocrine stress responses.

  19. Enhanced neuroendocrine response to insulin tolerance test performed under increased ambient temperature. (United States)

    Jezová, D; Kvetnanský, R; Nazar, K; Vigas, M


    The hypothesis that an increase in ambient temperature modulates neuroendocrine response in clinically used provocative pituitary function tests was verified. Healthy male volunteers were subjected to insulin tolerance tests in two randomized trials. In the first trial hypoglycemia was induced by a bolus injection of insulin (0.1 U per kg of BW, i.v.) at room temperature. In the second trial, the subjects were exposed to increased ambient temperature for 45 min before insulin injection and for 45 min thereafter. The environmental temperature was selected to increase body temperature less than 1C. Under conditions of increased temperature basal hormone levels as measured in antecubital venous blood samples failed to be modified and the hypoglycemia was less severe. Nevertheless, the responses of most (beta-endorphin, ACTH, prolactin, catecholamines), but not all (growth hormone, cortisol), hormones to hypoglycemia were exaggerated. The remarkable increase in ACTH and beta-endorphin release was not accompanied by concomitant increase of plasma cortisol response. The sympathetic-adrenomedullary system was significantly activated, which was manifested particularly by enhanced norepinephrine release. Growth hormone response to hypoglycemia was not modified, while that of prolactin was enhanced. Thus during evaluation of neuroendocrine function under clinical conditions, changes in ambient and body temperature should not be underestimated.

  20. Neuroendocrine differentiated breast carcinoma: imaging features correlated with clinical and histopathological findings

    Energy Technology Data Exchange (ETDEWEB)

    Guenhan-Bilgen, Isil; Ustuen, Esin Emin; Memis, Aysenur [Department of Radiology, Ege University Hospital, Bornova, 35100 Izmir (Turkey); Zekioglu, Osman; Erhan, Yildiz [Department of Pathology, Ege University Hospital, Bornova, 35100 Izmir (Turkey)


    The aim of this study was to describe the imaging features of neuroendocrine differentiated breast carcinoma (NEDBC) and to correlate the radiological findings with the clinical and histopathological findings. A retrospective review of the mammograms of 1845 histopathologically proven breast cancer cases revealed five NEDBC. The clinical, imaging, and histopathological findings were analyzed. On mammography, a high-density mass was seen in all patients. The shape of the mass was round in 4 and irregular in 1 patient. The margins were spiculated in 2, indistinct in 1, microlobulated in 1, and partially obscured in 1 patient. On sonography, 4 patients had homogeneously hypoechoic masses with normal sound transmission. In 1 patient the mass was heterogeneously hypoechoic with mild posterior acoustic enhancement. The margins were microlobulated in 2, irregular in 2, and well-circumscribed in 1 patient. Neuroendocrine differentiated breast carcinoma should be included in the differential diagnosis of mammographically dense, round masses with predominantly spiculated or lobulated margins. Sonographically, they mostly present as irregular or microlobulated, homogeneously hypoechoic masses with normal sound transmission. (orig.)

  1. Small-cell neuroendocrine carcinoma of the esophagus: an autopsy case report

    Directory of Open Access Journals (Sweden)

    Mariana Bellaguarda de Castro Sepulvida


    Full Text Available Small-cell neuroendocrine carcinoma is a well-known aggressive neoplasia, which is usually associated with a poor prognosis. The lung is the most common primary site, but other organs may be involved, especially those of the digestive tract. The authors report the case of a 71-year-old Caucasian, male patient who was admitted because of congestive heart failure and loss of vision accompanied by right proptosis. Skull and sinuses computed tomography showed a tumoral mass involving the posterior region of the right eye, local bones, and paranasal sinuses. Because of severe hemodynamic instability, the patient died and no diagnostic investigation could be performed. Autopsy findings revealed small-cell neuroendocrine carcinoma of the esophagus and metastases to the posterior region of the right ocular globe, which affected the sinuses, the muscles of the ocular region, the orbit bones, the skull, the meninges and the brain, plus the liver, adrenal glands, and the pericardium. This case called the author’s attention to the extent of the metastatic disease in a patient who was firstly interpreted as presenting solely with congestive heart failure. The autopsy findings substantially aid the understanding of the immediate cause of death.

  2. Well-differentiated neuroendocrine tumor of tailgut cyst. A rare entity with controversial medical opportunities. (United States)

    Damato, Angela; Pusceddu, Sara; Milione, Massimo; Mazzaferro, Vincenzo; Magli, Michelle; Seregni, Ettore; De Braud, Filippo; Buzzoni, Roberto


    The incidence of neuroendocrine tumors is rising, and this rise is explained by more than just better diagnostic procedures. About 85% of these neoplasms arise in gastrointestinal or pulmonary sites, but cases where the location is more unusual also occur in clinical practice. The tailgut cyst is a rare entity well described in the medical literature, but a neuroendocrine tumor within such a cyst is a very rare event, with about 30 cases described in the literature to date. In this report we present the case of a young woman with this unusual diagnosis. The characteristics of the case differ from most previous case reports in a few respects: the patient was a young rather than middle-aged female; she had a presacral mass with a significant solid component; at diagnosis, there was evidence of a lytic lesion in the coccyx. Despite this particular medical presentation, radical surgery was accomplished. In this disease the greatest risk is local relapse, but adjuvant radiotherapy may compromise the patient's fertility. We therefore opted for strict control only, but this decision might be debatable.

  3. Salvage treatment after r-interferon [alpha]-2a in advanced neuroendocrine tumors

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    Zilembo, N. (Italian Trials in Medical Oncology (I.T.M.O.) Group, Ist. Nazionale per lo Studio et la Cura dei Tumori, Milano (Italy)); Buzzoni, R. (Italian Trials in Medical Oncology (I.T.M.O.) Group, Ist. Nazionale per lo Studio et la Cura dei Tumori, Milano (Italy)); Bajetta, E. (Italian Trials in Medical Oncology (I.T.M.O.) Group, Ist. Nazionale per lo Studio et la Cura dei Tumori, Milano (Italy)); Di Bartolomeo, M. (Italian Trials in Medical Oncology (I.T.M.O.) Group, Ist. Nazionale per lo Studio et la Cura dei Tumori, Milano (Italy)); De Braud, F. (Italian Trials in Medical Oncology (I.T.M.O.) Group, Ist. Nazionale per lo Studio et la Cura dei Tumori, Milano (Italy)); Castellani, R. (Italian Trials in Medical Oncology (I.T.M.O.) Group, Ist. Nazionale per lo Studio et la Cura dei Tumori, Milano (Italy)); Maffioli, L. (Italian Trials in Medical Oncology (I.T.M.O.) Group, Ist. Nazionale per lo Studio et la Cura dei Tumori, Milano (Italy)); Celio, L. (Italian Trials in Medical


    The use of interferon (IFN) in neuroendocrine advanced tumors has achieved control of hormonal symptoms but low objective tumor response rate. In patients resistant to, or failing on, IFN a second line treatment may be required. Seventeen patients having received recombinant IFN [alpha]-2a as last treatment entered the study. There were 12 carcinoids, 3 medullary thyroid carcinomas, one Merkel cell carcinoma, and one neuroendocrine pancreatic tumor. Two different treatments were used: one radiometabolic therapy with metaiodobenzylguanidine (MIBG) in 3 patients with high MIBG uptake and one polychemotherapy regimen, including streptozotocin 500 mg/m[sup 2] intravenously days 1, 2, 3 and epirubicin 75 mg/m[sup 2] intravenously day 1, in the remaining 14 patients. Stable disease with relief of symptoms and tumor marker reduction was obtained in two patients receiving MIGB therapy, whereas the third patient had progressive disease. In the chemotherapy group only one partial response was obtained and neither tumor marker reduction nor subjective improvement were seen. Our second-line treatment was not especially effective but may be considered for rapidly progressive and/or symptomatic disease. The radiometabolic therapy appears promising in symptomatic patients with small tumor burden whereas our chemotherapy regimen appears ineffective. (orig.).

  4. Physiologically Based Pharmacokinetic (PBPK model for biodistribution of radiolabeled peptides in patients with neuroendocrine tumours

    Directory of Open Access Journals (Sweden)

    Viktor Popov


    Full Text Available Objective(s: The objectives of this work was to assess the benefits of the application of Physiologically Based Pharmacokinetic (PBPK models in patients with different neuroendocrine tumours (NET who were treatedwith Lu-177 DOTATATE. The model utilises clinical data on biodistribution of radiolabeled peptides (RLPs obtained by whole body scintigraphy (WBS of the patients.Methods: The blood flow restricted (perfusion rate limited type of the PBPK model for biodistribution of radiolabeled peptides (RLPs in individual human organs is based on the multi-compartment approach, which takes into account the main physiological processes in the organism: absorption, distribution, metabolism and excretion (ADME. The approachcalibrates the PBPK model for each patient in order to increase the accuracy of the dose estimation. Datasets obtained using WBS in four patients have been used to obtain the unknown model parameters. The scintigraphic data were acquired using a double head gamma camera in patients with different neuroendocrine tumours who were treated with Lu-177 DOTATATE. The activity administered to each patient was 7400MBq.Results: Satisfactory agreement of the model predictions with the data obtained from the WBS for each patient has been achieved. Conclusion: The study indicates that the PBPK model can be used for more accurate calculation of biodistribution and absorbed doses in patients. This approach is the first attempt of utilizing scintigraphic data in PBPK models, which was obtained during Lu-177 peptide therapy of patients with NET.

  5. Pancreatic Neuroendocrine Tumors in Mice Deficient in Proglucagon-Derived Peptides.

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    Yuko Takano

    Full Text Available Animal models with defective glucagon action show hyperplasia of islet α-cells, however, the regulatory mechanisms underlying the proliferation of islet endocrine cells remain largely to be elucidated. The Gcggfp/gfp mice, which are homozygous for glucagon/green fluorescent protein knock-in allele (GCGKO, lack all proglucagon-derived peptides including glucagon and GLP-1. The present study was aimed to characterize pancreatic neuroendocrine tumors (panNETs, which develop in the GCGKO mice. At 15 months of age, macroscopic GFP-positive tumors were identified in the pancreas of all the GCGKO mice, but not in that of the control heterozygous mice. The tumor manifested several features that were consistent with pancreatic neuroendocrine tumors (panNETs, such as organoid structures with trabecular and cribriform patterns, and the expression of chromogranin A and synaptophysin. Dissemination of GFP-positive cells was observed in the liver and lungs in 100% and 95%, respectively, of 15-month-old GCGKO mice. To elucidate the regulatory mechanism for tumor growth, PanNET grafts were transplanted into subrenal capsules in GCGKO and control mice. Ki-67 positive cells were identified in panNET grafts transplanted to GCGKO mice 1 month after transplantation, but not in those to control mice. These results suggest that humoral factors or conditions specific to GCGKO mice, are involved in the proliferation of panNETs. Taken together, GCGKO mice are novel animal model for studying the development, pathogenesis, and metastasis panNETs.

  6. Effect of salinity on regulation mechanism of neuroendocrine-immunoregulatory network in Litopenaeus vannamei. (United States)

    Zhao, Qun; Pan, Luqing; Ren, Qin; Wang, Lin; Miao, Jingjing


    The effects of low salinity (transferred from 31‰ to 26‰, 21‰, and 16‰) on the regulation pathways of neuroendocrine-immunoregulatory network were investigated in Litopenaeus vannamei. The results showed that the hormones (corticotrophin-releasing hormone, adrenocorticotropic hormone) and biogenic amines (dopamine, noradrenaline, 5-hydroxytryptamine) concentrations in lower salinity groups increased significantly within 12 h. The gene expression of biogenic amine receptors showed that dopamine receptor D4 and α2 adrenergic receptor in lower salinity groups decreased significantly within 12 h, whereas the 5-HT7 receptor significantly increased within 1d. The second messenger synthetases (adenylyl cyclase, phospholipase C) and the second messengers (cyclic adenosine monophosphate, cyclic guanosine monophosphate) of lower salinity groups shared a similar trend in which adenylyl cyclase and cyclic adenosine monophosphate reached the maximum at 12 h, whereas phospholipase C and cyclic guanosine monophosphate reached the minimum. The immune parameters (total hemocyte count, phenoloxidase activity, phagocytic activity, crustin expression, antibacterial activity, C-type lectin expression, hemagglutinating activity) in lower salinity groups decreased significantly within 12 h. Except for the total hemocyte count, all the parameters recovered to the control levels afterwards. Therefore, it may be concluded that the neuroendocrine-immunoregulatory network plays a principal role in adapting to salinity changes as the main center for sensing the stress and causes immune response in L. vannamei.

  7. Two capa-genes are expressed in the neuroendocrine system of Rhodnius prolixus. (United States)

    Neupert, Susanne; Russell, William K; Russell, David H; Predel, Reinhard


    CAPA-peptides have been isolated from a broad range of insect species and are typical of the neurosecretory system of the abdominal ventral nerve cord. In Rhodnius prolixus, which is known to transmit Chagas' disease, CAPA-peptides have potent antidiuretic effects. Recently, two capa-genes were isolated from this hemipteran insect; it was the first description of the occurrence of multiple capa-genes from a single insect species. The expression of peptides from one of these capa-genes was confirmed by mass spectrometry Paluzzi (2008) [10]. In this study, the abdominal neuroendocrine system of R. prolixus was screened for the occurrence of products of the second annotated capa-gene. Single nerve preparations of abdominal segmental nerves 1-3 of R. prolixus were analyzed by MALDI-TOF mass spectrometry and the products of both capa-genes were identified by tandem mass spectrometry. The co-occurrence of the different CAPA-peptides, including CAPA-precursor peptides, in all spectra from abdominal segmental nerves 1 to 3 suggests a common expression of both capa-genes in the same neuroendocrine cells. A comparison of mass spectra obtained from abdominal segmental nerves with those of the subesophageal ganglion (SEG) revealed an obvious differential processing of the CAPA-precursors within the CNS.

  8. The simple neuroendocrine-immune regulatory network in oyster Crassostrea gigas mediates complex functions (United States)

    Liu, Zhaoqun; Wang, Lingling; Zhou, Zhi; Sun, Ying; Wang, Mengqiang; Wang, Hao; Hou, Zhanhui; Gao, Dahai; Gao, Qiang; Song, Linsheng


    The neuroendocrine-immune (NEI) regulatory network is a complex system, which plays an indispensable role in the immunity of the host. In the present study, the bioinformatical analysis of the transcriptomic data from oyster Crassostrea gigas and further biological validation revealed that oyster TNF (CgTNF-1 CGI_10018786) could activate the transcription factors NF-κB and HSF (heat shock transcription factor) through MAPK signaling pathway, and then regulate apoptosis, redox reaction, neuro-regulation and protein folding in oyster haemocytes. The activated immune cells then released neurotransmitters including acetylcholine, norepinephrine and [Met5]-enkephalin to regulate the immune response by arising the expression of three TNF (CGI_10005109, CGI_10005110 and CGI_10006440) and translocating two NF-κB (Cgp65, CGI_10018142 and CgRel, CGI_10021567) between the cytoplasm and nuclei of haemocytes. Neurotransmitters exhibited the immunomodulation effects by influencing apoptosis and phagocytosis of oyster haemocytes. Acetylcholine and norepinephrine could down-regulate the immune response, while [Met5]-enkephalin up-regulate the immune response. These results suggested that the simple neuroendocrine-immune regulatory network in oyster might be activated by oyster TNF and then regulate the immune response by virtue of neurotransmitters, cytokines and transcription factors.

  9. Neuroendocrine Disturbances after Brain Damage: An Important and Often Undiagnosed Disorder

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    Fatih Tanriverdi


    Full Text Available Traumatic brain injury (TBI is a common and significant public health problem all over the world. Until recently, TBI has been recognized as an uncommon cause of hypopituitarism. The studies conducted during the last 15 years revealed that TBI is a serious cause of hypopituitarism. Although the underlying pathophysiology has not yet been fully clarified, new data indicate that genetic predisposition, autoimmunity and neuroinflammatory changes may play a role in the development of hypopituitarism. Combative sports, including boxing and kickboxing, both of which are characterized by chronic repetitive head trauma, have been shown as new causes of neuroendocrine abnormalities, mainly hypopituitarism, for the first time during the last 10 years. Most patients with TBI-induced pituitary dysfunction remain undiagnosed and untreated because of the non-specific and subtle clinical manifestations of hypopituitarism. Replacement of the deficient hormones, of which GH is the commonest hormone lost, may not only reverse the clinical manifestations and neurocognitive dysfunction, but may also help posttraumatic disabled patients resistant to classical treatment who have undiagnosed hypopituitarism and GH deficiency in particular. Therefore, early diagnosis, which depends on the awareness of TBI as a cause of neuroendocrine abnormalities among the medical community, is crucially important.

  10. Ascending mechanisms of stress integration: Implications for brainstem regulation of neuroendocrine and behavioral stress responses. (United States)

    Myers, Brent; Scheimann, Jessie R; Franco-Villanueva, Ana; Herman, James P


    In response to stress, defined as a real or perceived threat to homeostasis or well-being, brain systems initiate divergent physiological and behavioral processes that mobilize energy and promote adaptation. The brainstem contains multiple nuclei that engage in autonomic control and reflexive responses to systemic stressors. However, brainstem nuclei also play an important role in neuroendocrine responses to psychogenic stressors mediated by the hypothalamic-pituitary-adrenocortical axis. Further, these nuclei integrate neuroendocrine responses with stress-related behaviors, significantly impacting mood and anxiety. The current review focuses on the prominent brainstem monosynaptic inputs to the endocrine paraventricular hypothalamic nucleus (PVN), including the periaqueductal gray, raphe nuclei, parabrachial nuclei, locus coeruleus, and nucleus of the solitary tract (NTS). The NTS is a particularly intriguing area, as the region contains multiple cell groups that provide neurochemically-distinct inputs to the PVN. Furthermore, the NTS, under regulatory control by glucocorticoid-mediated feedback, integrates affective processes with physiological status to regulate stress responding. Collectively, these brainstem circuits represent an important avenue for delineating interactions between stress and health.

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

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    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.

  12. Prognosis and Long-Term Survival after Operation in Patients with Pancreatic and Peripancreatic Neuroendocrine Tumors of a Single Center

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    Monika S Janot


    Full Text Available Background Pancreatic neuroendocrine tumors are very rare. The aim of this study was to assess the survival rate in patients with functioning or non-functional pancreatic neuroendocrine tumors. Methods The data for 49 patients with pancreatic neuroendocrine tumors who were treated at a single institution from January 2004 to December 2010 were analyzed retrospectively with regard to short-term and long-term outcomes, as well as predictive factors for survival and prognosis. Overall survival was evaluated using the Kaplan–Meier method. Cox regression analysis was used to identify factors associated with the prognosis in a multivariate analysis. Results Patients’ median age at diagnosis was 59 years (range 17–83 years. Nine lesions (19% were functioning tumors and 40 (81% were non-functional. The 5-year survival rate was 85.5%. Among patients who underwent potentially curative resection, tumor stage (P=0.001, pathological classification (P=0.03 and presence of liver metastases (P=0.003, as well as the resection margin, were significant prognostic factors. Conclusions Surgical resection should be attempted and should play a central role in the therapeutic approach to patients with neuroendocrine tumors. The important aspect is early diagnosis, which makes it possible to carry out radical surgery before the tumor has metastasized.

  13. Psychomotor slowing, neuroendocrine responses, and behavioral changes after oral administration of meta-chlorophenylpiperazine in normal volunteers.

    NARCIS (Netherlands)

    Sabbe, B.G.C.; Hulstijn, W.; Maes, M.; Pier, M.P.B.I.; Scharpé, S.; Zitman, F.G.


    The mixed 5-HT receptor agonist/antagonist meta-chlorophenylpiperazine (mCPP) is known to suppress locomotor activity in mice and rats. This study aimed: (1) to determine whether mCPP induces cognitive and motor changes in normal human volunteers and how these changes relate to the neuroendocrine ef

  14. Psychomotor slowing, neuroendocrine responses, and behavioral changes after oral administration of meta-chlorophenylpiperazine in normal volunteers

    NARCIS (Netherlands)

    Sabbe, B.G.C.; Hulstijn, W.; Maes, M.; Pier, M.P.B.I.; Scharpé, S.; Zitman, F.G.


    The mixed 5-HT receptor agonist/antagonist meta-chlorophenylpiperazine (mCPP) is known to suppress locomotor activity in mice and rats. This study aimed: (1) to determine whether mCPP induces cognitive and motor changes in normal human volunteers and how these changes relate to the neuroendocrine ef

  15. Sister Mary Joseph Nodules on 99mTc HYNIC-TOC scintigraphy in patients with neuroendocrine tumors. (United States)

    Jing, Hongli; Zhang, Yingqiang; Li, Fang


    A Sister Mary Joseph nodule represents an umbilical metastasis, which is more commonly caused by a primary malignancy in gastrointestinal tract or from reproductive system. We report Sister Mary Joseph nodules caused by neuroendocrine tumor and revealed on Tc HYNIC-TOC scintigraphy.

  16. Is there a role for radioguided surgery with iodine-labeled metaiodobenzylguanidine in resection of neuroendocrine tumors?

    NARCIS (Netherlands)

    Hulsteijn, L.T. van; Corssmit, E.P.; Hiel, B. van der; Smit, J.W.A.; Stokkel, M.P.


    PURPOSE: The aim of this study was to systematically review literature, exploring the role of radioguided surgery with iodine-labeled metaiodobenzylguanidine (MIBG) in resection of neuroendocrine tumors. METHODS: PubMed, EMBASE, Web of Science, COCHRANE, CINAHL, Academic Search Premier, ScienceDirec

  17. Effects of neuroprotector cortexin on the dynamics of neuroendocrine system parameters in patients with organic emotionally labile (asthenic) disorders. (United States)

    Levchuk, L A; Ivanova, S A; Semke, V Ya


    Addition of neuroprotector Cortexin to standard drug therapy of patients with organic emotionally labile (asthenic) disorders had a great influence on the neuroendocrine system and neurosteroid content: normalization of blood concentration of cortisol, dehydroepiandrosterone sulphate, and thyroid hormones was observed. Clinical improvement was associated with the recovery of organism homeostatic systems.

  18. m-Chlorophenylpiperazine challenge in borderline personality disorder: relationship of neuroendocrine response, behavioral response, and clinical measures. (United States)

    Stein, D J; Hollander, E; DeCaria, C M; Simeon, D; Cohen, L; Aronowitz, B


    We have previously found that a subgroup of patients with impulsive personality disorders respond to m-chlorophenylpiperazine (m-CPP) administration with a distinctive spacy/high behavioral reaction and with increased cortisol responses. In this report we analyzed the relationship between behavioral and neuroendocrine responses to m-CPP in an enlarged sample of patients with borderline personality disorder (BPD). We also assessed the association of behavioral and neuroendocrine responses with clinical symptoms and with m-CPP blood levels. We found that in BPD patients the presence of a spacy/high behavioral response was significantly associated with increased prolactin and cortisol responses to m-CPP. In BPD patients increased m-CPP levels were significantly associated with neuroendocrine hypersensitivity and with a spacy/high behavioral response, while in controls increased m-CPP levels were not significantly associated with neuroendocrine hypersensitivity but were significantly associated with dysphoric behavioral responses. Taken together with previous work on m-CPP in obsessive-compulsive disorder, these results are partially consistent with the hypothesis that compulsive and impulsive symptoms fall at opposite ends of a phenomenologic and neurobiologic spectrum.

  19. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3)

    DEFF Research Database (Denmark)

    Sorbye, H; Welin, S; Langer, S W;


    Background As studies on gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) are limited, we reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients. Patients and methods Data from advanced GI-NEC patients diagnosed 2000-2009 were retrospectively...

  20. Meta-analysis of 701 published cases of sinonasal neuroendocrine carcinoma : The importance of differentiation grade in determining treatment strategy

    NARCIS (Netherlands)

    van der Laan, Tom P; Iepsma, René; Witjes, Max J H; van der Laan, Bernard F A M; Plaat, Boudewijn E C; Halmos, Gyorgy B


    The aim of this meta-analysis was to provide treatment guidelines for sinonasal neuroendocrine carcinoma (SNC) by combining all available data in the literature. A literature search for all studies concerning SNC was performed against the MEDLINE and EMBASE databases. Available clinical data was nor

  1. Characterization and regulation of voltage-operated Ca2+ channels in neuroendocrine melanotrope cells of Xenopus laevis

    NARCIS (Netherlands)

    Zhang, H.Y.


    To investigate the way by which multiple incoming neurochemical messengers control second messenger systems to evoke an unambiguous neuronal output, melanotrope neuroendocrine cells in the pars intermedia of the pituitary gland of the South African clawed toad Xenopus laevis were studied. Researches

  2. Mixed exocrine-neuroendocrine carcinoma of the nasal cavity: clinico-pathologic and molecular study of a case and review of the literature. (United States)

    La Rosa, Stefano; Furlan, Daniela; Franzi, Francesca; Battaglia, Paolo; Frattini, Milo; Zanellato, Elena; Marando, Alessandro; Sahnane, Nora; Turri-Zanoni, Mario; Castelnuovo, Paolo; Capella, Carlo


    Sinonasal intestinal-type adenocarcinomas (ITACs) are rare neoplasms histologically resembling intestinal adenocarcinomas. Although a neuroendocrine differentiation in ITACs has been described, true mixed exocrine-neuroendocrine carcinomas, neoplasms in which each component represents at least 30 % of the lesion, are extremely rare and their molecular alterations are largely unknown. We describe herein the clinico-pathologic features, the methylation profile, chromosomal gains and losses, and mutation analysis of KRAS, BRAF and p53 in a nasal mixed exocrine-neuroendocrine carcinoma resected in a 79-year-old man. The tumor was composed of an ITAC and a poorly differentiated neuroendocrine carcinoma. Both exocrine and neuroendocrine components were CK8, CK20, CDX2 and p53 positive, and CK7 and TTF1 negative. The neuroendocrine component also showed immunoreactivity for chromogranin A, synaptophysin, serotonin and glicentin. Gains and losses were found at following chromosome regions: 17p13 (TP53), 14q24 (MLH3), 19q13 (KLK3), 5q21 (APC), 7q21 (CDK6), 9q34 (DAPK1), 12p13 (TNFRSF 1A, CDKN1B), 13q12 (BRCA2), 17p13.3 (HIC1), 18q21 (BCL2), and 22q12 (TIMP3). Aberrant methylation was detected only in the neuroendocrine component and involved APC and DAPK1 genes. No mutation of KRAS (exons 2-4), BRAF (exon 15), and p53 (exons 4-10) was found in both components. The results suggest a monoclonal origin of the tumor from a pluripotent cell undergoing a biphenotypic differentiation and that the neuroendocrine differentiation may be from an exocrine to an endocrine pathway. We have also reviewed the literature on sinonasal mixed exocrine-neuroendocrine carcinomas to give to the reader a comprehensive overview of these very rare tumor types.

  3. Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the alpha-subunit of glycoprotein hormones. (United States)

    Nobels, F R; Kwekkeboom, D J; Coopmans, W; Schoenmakers, C H; Lindemans, J; De Herder, W W; Krenning, E P; Bouillon, R; Lamberts, S W


    Chromogranin 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 neuroendocrine markers, have not clearly been defined, however. The objectives of this study were to evaluate the clinical usefulness of CgA as neuroendocrine serum marker. Serum levels of CgA, neuron-specific enolase (NSE), and the alpha-subunit of glycoprotein hormones (alpha-SU) were determined in 211 patients with neuroendocrine tumors and 180 control subjects with nonendocrine tumors. The concentrations of CgA, NSE, and alpha-SU were elevated in 50%, 43%, and 24% of patients with neuroendocrine tumors, respectively. Serum CgA was most frequently increased in subjects with gastrinomas (100%), pheochromocytomas (89%), carcinoid tumors (80%), nonfunctioning tumors of the endocrine pancreas (69%), and medullary thyroid carcinomas (50%). The highest levels were observed in subjects with carcinoid tumors. NSE was most frequently elevated in patients with small cell lung carcinoma (74%), and alpha-SU was most frequently elevated in patients with carcinoid tumors (39%). Most subjects with elevated alpha-SU levels also had elevated CgA concentrations. A significant positive relationship was demonstrated between the tumor load and serum CgA levels (P NSE, and alpha-SU were present in, respectively, 7%, 35%, and 15% of control subjects. Markedly elevated serum levels of CgA, exceeding 300 micrograms/L, were observed in only 2% of control patients (n = 3) compared to 40% of patients with neuroendocrine tumors (n = 76). We conclude that CgA is the best general neuroendocrine serum marker available. It has the highest specificity for the detection of neuroendocrine tumors compared to the other neuroendocrine markers, NSE and alpha-SU. Elevated levels are strongly correlated with tumor volume; therefore, small tumors may

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

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    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

  5. Adolescent caffeine consumption increases adulthood anxiety-related behavior and modifies neuroendocrine signaling. (United States)

    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 (0.3g/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 (P62) 7 days after removal of caffeine. Adolescent caffeine consumption enhanced anxiety-related behavior in an open field, social interaction test, and elevated plus maze. Similar caffeine consumption in adult rats did not alter anxiety-related behavior after caffeine removal. Characterization of neuroendocrine measures was next assessed to determine whether the changes in anxiety were associated with modifications in the HPA axis. Blood plasma levels of corticosterone (CORT) were assessed throughout the caffeine consumption procedure in adolescent rats. Adolescent caffeine consumption elevated plasma CORT 24h after initiation of caffeine consumption that normalized over the course of the 28-day consumption procedure. CORT levels were also elevated 24h after caffeine removal and remained elevated for 7 days. Despite elevated basal CORT in adult rats that consumed caffeine during adolescence, the adrenocorticotropic hormone (ACTH) and CORT response to placement on an elevated pedestal (a mild stressor) was significantly blunted. Lastly, we assessed changes in basal and stress-induced c-fos and corticotropin-releasing factor (Crf) mRNA expression in brain tissue collected at 7 days withdrawal from adolescent caffeine. Adolescent caffeine consumption increased basal c-fos mRNA in the paraventricular nucleus of the hypothalamus. Adolescent caffeine consumption had no other effects on the basal or stress-induced c-fos mRNA changes. Caffeine consumption during adolescence increased

  6. Validation of somatostatin receptor scintigraphy in the localization of neuroendocrine tumors

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    Lamberts, S.W.J. (Depts. of Medicine and Nuclear Medicine, Erasmus Univ., Rotterdam (Netherlands) Div. of Cell Biology and Experimental Cancer Research, Institution of Pathology, Bern Univ. (Switzerland)); Reubi, J.C. (Depts. of Medicine and Nuclear Medicine, Erasmus Univ., Rotterdam (Netherlands) Div. of Cell Biology and Experimental Cancer Research, Institution of Pathology, Bern Univ. (Switzerland)); Krenning, E.P. (Depts. of Medicine and Nuclear Medicine, Erasmus Univ., Rotterdam (Netherlands) Div. of Cell Biology and Experimental Cancer Research, Institution of Pathology, Bern Univ. (Switzerland))


    Somatostatin analogs are used in the control of hormonal hypersecretion and tumor growth of patients with acromegaly, islet cell carcinomas and carcinoids. Recently we showed that somatostatin receptor positive tumors can be visualized in vivo after the administration of radionuclide-labeled somatostatin analogs. Receptor imaging was positive in 18/21 islet cell tumors, 32/37 carcinoids, 26/28 paragangliomas, 9/14 medullary thyroid carcinomas, and 5/7 small cell lung cancers. Somatostatin receptor imaging is an easy, harmless and painless diagnostic method. It localizes multiple and/or metastatic tumors, predicts the successful control of hormonal hypersecretion by octreotide and seems to be of prognostic value in certain types of cancer. This scintigraphic method might help in patient selection for clinical trials with somatostatin analogs in the treatment of neuroendocrine cancers. (orig.).

  7. The p53 network as therapeutic target in gastroenteropancreatic neuroendocrine neoplasms. (United States)

    Briest, Franziska; Grabowski, Patricia


    Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous and especially the midgut tumors currently lack effective therapy options. Actionable driver mutations as therapeutic targets are rare. Subtype specific data concerning regulatory mechanisms or epigenetic aberrations are necessary for novel clinical trials. Although the p53 protein itself is rarely mutated in GEP-NENs, epigenetic and regulatory aberrations interfere with the p53 network activity and might function as s target for novel therapeutic approaches. In this review we analyze the current knowledge about the p53 network in GEP-NENs and discuss three possible strategies that include recovering p53 function, enforcing apoptosis by genotoxic stress induction and restoring silenced gene function, based on in vitro, in vivo and clinical data.

  8. Neuroendocrine carcinoma of the seminal vesicles presenting with Lambert Eaton syndrome: a case report

    Directory of Open Access Journals (Sweden)

    Burger Maximilian


    Full Text Available Abstract Introduction Primary tumors of seminal vesicles are rare and only a few cases have been reported. Diagnosis is difficult due to the absence of early clinical signs. Prognosis is generally poor. Case presentation We present the case of a 70-year-old Caucasian man with a seminal vesicle mass and concomitant lymph node metastasis detected by computed tomography and body positron emission tomography/low-dose computed tomography scan carried out for evaluation of Lambert Eaton syndrome. Transrectal ultrasound-guided biopsy showed a poorly differented neuroendocrine carcinoma with an immunhistochemical profile similar to small cell lung cancer. Following chemotherapy the disease was stable and active surveillance was initiated. Conclusions Lambert Eaton syndrome may be the initial symptom of a seminal vesicle mass. Diagnosis needs to be obtained by transrectal biopsy and chemotherapy may delay progression of the tumor.

  9. Oral application of citalopram (20 mg) and its usefulness for neuroendocrine challenge tests. (United States)

    Henning, J; Netter, P


    The present study was conducted to investigate whether a single oral dosage of 20 mg of the selective serotonin reuptake inhibitor citalopram could be used as a tool to stimulate hormone secretion in neuroendocrine challenge paradigms. A total number of 48 healthy male subjects received either 20 mg citalopram or placebo in a randomized, double-blind cross-over design at an interval of 1 wk between both sessions. Citalopram was well tolerated without side-effects. Growth hormone (GH), prolactin (Prl) and cortisol (Cort) were determined in blood samples obtained at different time-points across the experiment according to drug kinetics. While GH and Prl were not changed after citalopram Cort levels increased as compared to the placebo condition, significantly about 2 h after drug intake. Results will be discussed in respect of the question of whether or not Prl and GH responses after treatment with i.v. applications of SSRIs reflect sertonergic involvement.

  10. Amenorrhea as a rare drug-related adverse event associated with everolimus for pancreatic neuroendocrine tumors. (United States)

    Kawaguchi, Yoshiaki; Maruno, Atsuko; Kawashima, Yohei; Ito, Hiroyuki; Ogawa, Masami; Mine, Tetsuya


    The patient was an asymptomatic 43-year-old woman. Abdominal ultrasonography and enhanced computed tomography showed a tumor lesion accompanied by multiple cystic changes in the liver and the pancreatic tail. Endoscopic ultrasound-fine needle aspiration was performed on the pancreatic tumor lesion and revealed pancreatic neuroendocrine tumor (PNET). As it was unresectable due to multiple liver metastases, the decision was made to initiate treatment with everolimus and transcatheter arterial chemoembolization. The patient ceased menstruating after the start of everolimus administration. When the administration was discontinued due to interstitial lung disease, menstruation resumed, but then again stopped with everolimus resumption. An association between everolimus and amenorrhea was highly suspected. Amenorrhea occurred as a rare adverse event of everolimus. As the younger women might be included in PNETs patients, we should put this adverse event into consideration.

  11. Treatment of neuroendocrine tumours with radioactive labelled somatostatin analogues; Therapie neuroendokriner Tumoren mit radioaktiv markierten Somatostatinanaloga

    Energy Technology Data Exchange (ETDEWEB)

    Geisler, J.; Bartenstein, P.; Haug, Alexander R. [Ludwig-Maximilians-Univ., Muenchen (Germany). Klinik fuer Nuklearmedizin


    Therapy of neuroendocrine tumors (NET) using radiolabelled somatostatin receptors such as {sup 177}-Lu-DOTATATE or {sup 90}Y-DOTATOC is gaining more and more importance. Due to the over expression of somatostatin receptors in NET the tumor-to-background ratio is very favourable. A significant therapy response is achievable between 20% and up to 46% of treated patients with a median time to progression of up to 40 months. Furthermore, this kind of therapy is very beneficial in the case of hormonal active, functional NET in terms of symptom control. Also quality of life is significantly improved after therapy, even in non-responding patients. The most common side effects of this therapy are nausea, vomiting and transient hematologic toxicity. However, late serious side effects such as renal impairment or myelodysplastic syndrome are rare if renal protection is used during the course of therapy. (orig.)

  12. 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.

  13. Directed Migration of Pulmonary Neuroendocrine Cells toward Airway Branches Organizes the Stereotypic Location of Neuroepithelial Bodies

    Directory of Open Access Journals (Sweden)

    Masafumi Noguchi


    Full Text Available The airway epithelium consists of diverse cell types, including neuroendocrine (NE cells. These cells are thought to function as chemoreceptors and as a component of the stem cell niche as well as the cells of origin in small-cell lung cancer. NE cells often localize at bifurcation points of airway tubes, forming small clusters called neuroepithelial bodies (NEBs. To investigate NEB development, we established methods for 3D mapping and ex vivo 4D imaging of developing lungs. We found that NEBs localize at stereotypic positions in the bifurcation area irrespective of variations in size. Notch-Hes1 signaling contributes to the differentiation of solitary NE cells, regulating their number but not localization. Live imaging revealed that individual NE cells migrate distally to and cluster at bifurcation points, driving NEB formation. We propose that NEB development is a multistep process involving differentiation of individual NE cells and their directional migration to organize NEBs.

  14. Is There a Role for Liver Transplantation in Metastatic Pancreatic Neuroendocrine Tumors (PNET?

    Directory of Open Access Journals (Sweden)

    Anthony Paul Gulati


    Full Text Available Dear Sir, recently, we published an important report on the role of radiotherapy in pancreatic neuroendocrine tumors (PNET consisting of our experience and the data presented at the 2012 ASCO Gastrointestinal Cancers Symposium by the University of Maryland School of Medicine, Baltimore, MD, USA and Johns Hopkins University School of Medicine, Baltimore, MD, USA [1, 2]. We received multiple calls, emails as well as questions by the patients about the role of liver transplant in this population of patients with PNET. This question probably received a lot of attention in the media with the unfortunate passing of Steve Jobs in 2011. In 2009, Mr. Jobs was the recipient of a liver transplant, an unusual treatment for this disease.

  15. Von Hippel Lindau disease with metastatic pancreatic neuroendocrine tumor causing ectopic Cushing's syndrome. (United States)

    Hatipoglu, Esra; Kepicoglu, Hasan; Rusen, Elif; Kabasakal, Levent; Gundogdu, Sadi; Kadioglu, Pinar


    We present a 39-year-old woman who was previously diagnosed with Von Hippel Lindau Disease (VHLD). She had surgery and radiotherapy for cranial hemangioblastoma (HA) 11 years ago and had unilateral adrenalectomy for pheochromocytoma in another hospital 6 month prior to her admission to our center. Moon face, buffalo hump, central obesity, progressive weight gain and menstrual irregularities persisted after adrenalectomy. Her laboratory results were consistent with ectopic Cushing's syndrome (ECS). A pancreatic solid mass with a nodule on the left lung were revealed upon computed tomography. In addition, Gallium-68 Somatostatin Receptor PET confirmed the pancreatic involvement and demonstrated additional lesions on the left lung and in the aortocaval lymphatic system on the right side, suggesting metastatic pancreatic neuroendocrine tumor (PNET). Peptide receptor radionuclide therapy (PRRT) with [177Lutetium-DOTA0,Tyr3] octreotate was performed on the patient, with no side effects observed. She was discharged from the hospital 10 days after the first cycle.

  16. 18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors

    DEFF Research Database (Denmark)

    Binderup, Tina; Knigge, Ulrich; Jakobsen, Annika Loft;


    -eight prospectively enrolled patients with NE tumors underwent FDG-PET imaging. FDG uptake was quantified by maximal standardized uptake value (SUVmax). The prognostic value of FDG uptake, proliferation index, chromogranin A, and liver metastases were assessed. RESULTS: During the 1-year follow-up, 14 patients died......PURPOSE: (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) is currently not used on a routine basis for imaging of neuroendocrine (NE) tumors. The aim of this study was to investigate the prognostic value of FDG-PET in patients with NE tumors. EXPERIMENTAL DESIGN: Ninety...... was the only predictor of progression-free survival (HR, 8.4; P value of FDG-PET for NE tumors, which exceeds the prognostic value of traditional markers such as Ki67, chromogranin A, and liver metastases. FDG-PET may obtain an important role for NE...

  17. Red wine is less stress reducing than vodka; no differences in neuroendocrine challenge test. (United States)

    Jarrett, N; Peatfield, R; Glover, V


    Red wine, like the drugs reserpine and fenfluramine, causes the release of 5-hydroxytryptamine (5-HT) from storage sites in vitro. This study used a neuroendocrine challenge test design to determine whether the parallel between red wine and these drugs can be extended to central actions in healthy volunteers. Vodka diluted to an equal alcohol content was used as a control. No significant differences were observed between the groups in plasma cortisol, plasma prolactin or in temperature levels. Thus no evidence was obtained for a central 5-HT releasing action by red wine. Self-rating stress and arousal questionnaires were also given. No differences were found in arousal. However whereas vodka had a clear effect in reducing stress, red wine did not. This suggests that red wine does have psychoactive properties independent of its alcohol effects.

  18. Neoadjuvant Chemotherapy with Capecitabine and Temozolomide for Unresectable Pancreatic Neuroendocrine Tumor

    Directory of Open Access Journals (Sweden)

    Sumana Devata


    Full Text Available Pancreatic neuroendocrine tumors (PNETs are relatively rare tumors that arise in the endocrine cells of the pancreas. Historically, somatostatin analogues have been used in this disease primarily for symptom control and, to a limited extent, disease stability. More recently, sunitinib and everolimus have been approved for advanced stage PNETs based on a survival benefit. However, both agents have a <10% actual response rate and cause nontrivial side effect profiles that limit duration of therapy. In locally advanced disease, there is a paucity of data to support an optimal neoadjuvant approach with the expectation of down-staging to allow for curative resection. We describe in this case a young woman who was successfully down-staged using a chemotherapy regimen of capecitabine and temozolomide with minimal toxicity.

  19. Endoscopic ultrasound-guided ethanol ablation ofpancreatic neuroendocrine tumours: A case study andliterature review

    Institute of Scientific and Technical Information of China (English)


    Here we offer a review of the literature regardingendoscopic ultrasound-guided ethanol ablation forpancreatic neuroendocrine tumours and describe thecase of a cystic tumour completely ablated after amultisession procedure. A total of 35 PubMed indexedcases of treated functioning and non-functioningpancreatic neuroendocrinetumours resulted fromour search, 29 of which are well-documented andsummarised. Endoscopic ultrasound-guided ethanolablation appears as a local, minimallyinvasive treatmentof pancreatic neuroendocrinetumours, suitable forselected patients. This techniqueappears feasible,relatively safe and efficient, especiallywhen applied tosymptom relief in functioning tumours, aiming at loss ofendocrine secretion. For non-functioning tumours, wherethe goal is complete tissue ablation, eus guided ethanolablation can provide good results for patients whoare unfit for surgery or for those who refuse surgicalresection. Its role in "fit for surgery" patients requiresassessment through further studies.

  20. [Neuropeptides, Cytokines and Thymus Peptides as Effectors of Interactions Between Thymus and Neuroendocrine System]. (United States)

    Torkhovskaya, T I; Belova, O V; Zimina, I V; Kryuchkova, A V; Moskvina, S N; Bystrova, O V; Arion, V Ya; Sergienko, V I


    The review presents data on mutual influence of nervous system and thymus, realized through the neuroendocrine-immune interactions. The pres- ence of adrenergic and peptidergic nerves in thymus creates conditions for implementation of the effect of neuropeptides secreted by them. These neuropeptides induce activation of thymus cells receptors and influence on the main processes in thymus, including T-lymphocyte maturation, cytokine and hormones production. In turn, thymuspeptides and/or cytokines, controlled by them, enter the brain and exert influence on neuro- nalfunction, which creates the basis for changes of behavior and homeostasis maintenance in response to infection. Ageing and some infectious, autoimmune, neurodegenerative and cancer diseases are accompanied by distortion of interactions between thymus and central nervous system. Mechanisms of signaling pathways, which determine these interactions, are not revealed yet, and their understanding will promote the development of effective therapeutic strategies.

  1. Neuroendocrine tumors: fascination and infrequency Tumores neuroendocrinos: fascinación e infrecuencia

    Directory of Open Access Journals (Sweden)

    M. J. Varas Lorenzo


    Full Text Available In this article, I review and update of gastro-entero-pancreatic neuroendocrine tumors, which so much fascination have risen among healthcare providers on grounds of their infrequency, hormonal syndromes, and high survival rate, is performed based on references from the past fifteen years.Se efectúa una revisión y puesta al día, basándose en citas bibliográficas de los últimos quince años, de los tumores neuroendocrinos gastroenteropancreáticos, que tanta fascinación han provocado en el estamento médico por su infrecuencia, síndromes hormonales y supervivencia elevada.

  2. 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...

  3. Neuroendocrine recovery after 2-week 12-h day and night shifts

    DEFF Research Database (Denmark)

    Merkus, Suzanne L; Holte, Kari Anne; Huysmans, Maaike A


    PURPOSE: The study aimed to investigate the course and duration of neuroendocrine recovery after 2-week 12-h day and night shift working periods and to study whether there were differences in recovery between the shift groups. METHODS: Twenty-nine male offshore employees working 2-week 12-h shift....... Differences were tested using generalised estimating equations analysis. RESULTS: Compared to the reference day, night shift workers had a significantly flatter cortisol profile on the 1st day off, significantly lower cortisol concentrations at 30 min after awakening on day 4 and at awakening on day 7......, and a significantly smaller decline to evening concentration on days 4 and 11. Compared to the reference day, day shift workers only showed a significantly lower cortisol concentration at awakening on the 1st day off. Compared to day workers, night shift workers had a flatter profile on the 1st day off and a lower...

  4. Stress-induced glucocorticoids as a neuroendocrine alarm signal of danger. (United States)

    Frank, Matthew G; Watkins, Linda R; Maier, Steven F


    A considerable number of studies demonstrate that acute and chronic stressors prime CNS innate immune responses to subsequent pro-inflammatory challenges and that glucocorticoids mediate, in part, stress-induced sensitization of pro-inflammatory immune responses. Here, we explore the notion that GCs produce a persisting sensitization of CNS innate immune effectors (e.g. microglia) so that they will generate a potentiated pro-inflammatory response after the GC rise has dissipated, thereby enhancing the sickness response to infection or injury and maximizing the animal's ability to neutralize danger. The stress-induced GC response is conceptualized here as an neuroendocrine warning signal or alarmin to the innate immune system, which prepares or sensitizes the innate immune response to potential danger. Thus, a new understanding of the stress response and its function (priming CNS innate immune responses to infection or injury during a fight/flight emergency) would be suggested.

  5. Argyrophilic carcinoma of the male breast. A neuroendocrine tumor containing predominantly chromogranin B (secretogranin I). (United States)

    Scopsi, L; Andreola, S; Saccozzi, R; Pilotti, S; Boracchi, P; Rosa, P; Conti, A R; Manzari, A; Huttner, W B; Rilke, F


    Argyrophilic tumors were diagnosed in 28 of 134 (20.8%) consecutive male patients who had a carcinoma of the breast removed between 1961 and 1990. Histologically, most argyrophilic tumors showed uniform cellularity and prevalent expansive growth. Ultrastructural observation disclosed the presence of electron-dense cored granules in the cytoplasm of the tumor cells. By immunocytochemistry, 17 of 28 argyrophilic tumors (60.7%) contained chromogranin B (secretogranin I)-immunoreactive cells, whereas chromogranin A was present in four of these 17 tumors only (14.2%). Immunoblotting studies showed chromogranin B immunoreactivity similar to that found in normal neuroendocrine cells. Despite these findings, which would argue for a distinct morphologic and immunochemical entity, no statistically significant differences between argyrophilic and common male breast carcinomas were found when a number of clinicopathologic features and relapse-free survival were considered.

  6. Complete Remission of Metastatic Neuroendocrine Paragastric Carcinoma After "Neoadjuvant" Peptide Receptor Radionuclide Therapy and Surgery. (United States)

    Schmidt, Matthias C; Uhrhan, Klara; Fischer, Thomas; Schmitz, Stephan; Markiefka, Birgid; Drzezga, Alexander; Stippel, Dirk


    A 48-year-old man presenting with upper abdominal pain was diagnosed with neuroendocrine tumor after biopsy of a paragastric mass with multiple liver metastases. (68)Ga-DOTATATE PET/CT showed intense uptake in the paragastric tumor and in multiple liver metastases not allowing primary surgery. Two cycles with cumulative 14.6 GBq (177)Lu-DOTATATE were given resulting in a considerable improvement. Subsequent surgery resulted in a complete remission as demonstrated by (68)Ga-DOTATATE PET/CT. Usually, peptide receptor radionuclide (PRRT) therapy is considered a palliative treatment. Few patients demonstrate a very favorable response allowing resection of the primary tumor after downstaging metastatic disease burden.

  7. Neuroendocrine tumors of the gastrointestinal tract; Multimodale Bildgebung neuroendokriner Tumoren des Gastrointestinaltrakts

    Energy Technology Data Exchange (ETDEWEB)

    Holzapfel, Konstantin; Eiber, Matthias; Rummeny, Ernst J. [Klinikum rechts der Isar der Technischen Univ. Muenchen (Germany). Inst. fuer Radiologie; Gaertner, Florian C. [Bonn Univ. (Germany). Klinik und Poliklinik fuer Nuklearmedizin


    Neuroendocrine tumors (neuroendokrine Tumoren) are rare entities. They can be found in all organs and show substantial biologic heterogeneity depending on involved organ, clinical symptoms and histopathologic morphology. Involvement of organs like larynx, cervix uteri, ovary, gallbladder, liver or kidney is extensively rare. The majority of neuroendokrine Tumoren are found in gastrointestinal tract and lung and are classified as neuroendokrine Tumoren of foregut (stomach, duodenum, pancreas, lung), midgut (jejunum, ileum, appendix, right side of the colon) and hindgut (left side of the colon, rectum). The role of imaging is to localize and delineate the primary tumor and to detect metastases. In the diagnosis of neuroendokrine Tumoren radiologic techniques like computed tomography (CT) and magnetic resonance imaging (MRI) are applied. In certain cases nuclear medicine techniques like somatostatin receptor scintigraphy (SRS) and positron emission tomography (PET) using radioactively labelled somatostatin analogues are used. The present article reviews characteristic imaging findings of neuroendokrine Tumoren of the gastrointestinal tract. (orig.)

  8. Housing in Pyramid Counteracts Neuroendocrine and Oxidative Stress Caused by Chronic Restraint in Rats

    Directory of Open Access Journals (Sweden)

    M. Surekha Bhat


    Full Text Available The space within the great pyramid and its smaller replicas is believed to have an antistress effect. Research has shown that the energy field within the pyramid can protect the hippocampal neurons of mice from stress-induced atrophy and also reduce neuroendocrine stress, oxidative stress and increase antioxidant defence in rats. In this study, we have, for the first time, attempted to study the antistress effects of pyramid exposure on the status of cortisol level, oxidative damage and antioxidant status in rats during chronic restraint stress. Adult female Wistar rats were divided into four groups as follows: normal controls (NC housed in home cage and left in the laboratory; restrained rats (with three subgroups subject to chronic restraint stress by placing in a wire mesh restrainer for 6 h per day for 14 days, the restrained controls (RC having their restrainers kept in the laboratory; restrained pyramid rats (RP being kept in the pyramid; and restrained square box rats (RS in the square box during the period of restraint stress everyday. Erythrocyte malondialdehyde (MDA and plasma cortisol levels were significantly increased and erythrocyte-reduced glutathione (GSH levels, erythrocyte glutathione peroxidase (GSH-Px and superoxide dismutase (SOD activities were significantly decreased in RC and RS rats as compared to NC. However, these parameters were maintained to near normal levels in RP rats which showed significantly decreased erythrocyte MDA and plasma cortisol and significantly increased erythrocyte GSH levels, erythrocyte GSH-Px and SOD activities when compared with RS rats. The results showed that housing in pyramid counteracts neuroendocrine and oxidative stress caused by chronic restraint in rats.

  9. Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor. (United States)

    Di Florio, Alessia; Sancho, Veronica; Moreno, Paola; Delle Fave, Gianfranco; Jensen, Robert T


    Foregut neuroendocrine tumors [NETs] usually pursuit a benign course, but some show aggressive behavior. The treatment of patients with advanced NETs is marginally effective and new approaches are needed. In other tumors, transactivation of the EGF receptor (EGFR) by growth factors, gastrointestinal (GI) hormones and lipids can stimulate growth, which has led to new treatments. Recent studies show a direct correlation between NET malignancy and EGFR expression, EGFR inhibition decreases basal NET growth and an autocrine growth effect exerted by GI hormones, for some NETs. To determine if GI hormones can stimulate NET growth by inducing transactivation of EGFR, we examined the ability of EGF, TGFα and various GI hormones to stimulate growth of the human foregut carcinoid,BON, the somatostatinoma QGP-1 and the rat islet tumor,Rin-14B-cell lines. The EGFR tyrosine-kinase inhibitor, AG1478 strongly inhibited EGF and the GI hormones stimulated cell growth, both in BON and QGP-1 cells. In all the three neuroendocrine cell lines studied, we found EGF, TGFα and the other growth-stimulating GI hormones increased Tyr(1068) EGFR phosphorylation. In BON cells, both the GI hormones neurotensin and a bombesin analogue caused a time- and dose-dependent increase in EGFR phosphorylation, which was strongly inhibited by AG1478. Moreover, we found this stimulated phosphorylation was dependent on Src kinases, PKCs, matrix metalloproteinase activation and the generation of reactive oxygen species. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists may be a novel therapeutic approach for treatment of foregut NETs/PETs.

  10. Housing in pyramid counteracts neuroendocrine and oxidative stress caused by chronic restraint in rats. (United States)

    Bhat, M Surekha; Rao, Guruprasad; Murthy, K Dilip; Bhat, P Gopalakrishna


    The space within the great pyramid and its smaller replicas is believed to have an antistress effect. Research has shown that the energy field within the pyramid can protect the hippocampal neurons of mice from stress-induced atrophy and also reduce neuroendocrine stress, oxidative stress and increase antioxidant defence in rats. In this study, we have, for the first time, attempted to study the antistress effects of pyramid exposure on the status of cortisol level, oxidative damage and antioxidant status in rats during chronic restraint stress. Adult female Wistar rats were divided into four groups as follows: normal controls (NC) housed in home cage and left in the laboratory; restrained rats (with three subgroups) subject to chronic restraint stress by placing in a wire mesh restrainer for 6 h per day for 14 days, the restrained controls (RC) having their restrainers kept in the laboratory; restrained pyramid rats (RP) being kept in the pyramid; and restrained square box rats (RS) in the square box during the period of restraint stress everyday. Erythrocyte malondialdehyde (MDA) and plasma cortisol levels were significantly increased and erythrocyte-reduced glutathione (GSH) levels, erythrocyte glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities were significantly decreased in RC and RS rats as compared to NC. However, these parameters were maintained to near normal levels in RP rats which showed significantly decreased erythrocyte MDA and plasma cortisol and significantly increased erythrocyte GSH levels, erythrocyte GSH-Px and SOD activities when compared with RS rats. The results showed that housing in pyramid counteracts neuroendocrine and oxidative stress caused by chronic restraint in rats.

  11. GLP1 and glucagon co-secreting pancreatic neuroendocrine tumor presenting as hypoglycemia after gastric bypass (United States)

    Guimarães, Marta; Rodrigues, Pedro; Pereira, Sofia S; Nora, Mário; Gonçalves, Gil; Albrechtsen, Nicolai Wewer; Hartmann, Bolette; Holst, Jens Juul


    Summary Post-prandial hypoglycemia is frequently found after bariatric surgery. Although rare, pancreatic neuroendocrine tumors (pNET), which occasionally are mixed hormone secreting, can lead to atypical clinical manifestations, including reactive hypoglycemia. Two years after gastric bypass surgery for the treatment of severe obesity, a 54-year-old female with previous type 2 diabetes, developed post-prandial sweating, fainting and hypoglycemic episodes, which eventually led to the finding by ultrasound of a 1.8-cm solid mass in the pancreatic head. The 72-h fast test and the plasma chromogranin A levels were normal but octreotide scintigraphy showed a single focus of abnormal radiotracer uptake at the site of the nodule. There were no other clinical signs of hormone secreting pNET and gastrointestinal hormone measurements were not performed. The patient underwent surgical enucleation with complete remission of the hypoglycemic episodes. Histopathology revealed a well-differentiated neuroendocrine carcinoma with low-grade malignancy with positive chromogranin A and glucagon immunostaining. An extract of the resected tumor contained a high concentration of glucagon (26.707 pmol/g tissue), in addition to traces of GLP1 (471 pmol/g), insulin (139 pmol/g) and somatostatin (23 pmol/g). This is the first report of a GLP1 and glucagon co-secreting pNET presenting as hypoglycemia after gastric bypass surgery. Although pNET are rare, they should be considered in the differential diagnosis of the clinical approach to the post-bariatric surgery hypoglycemia patient. Learning points pNETs can be multihormonal-secreting, leading to atypical clinical manifestations.Reactive hypoglycemic episodes are frequent after gastric bypass.pNETs should be considered in the differential diagnosis of hypoglycemia after bariatric surgery. PMID:26266036

  12. Medical therapy for advanced gastro-entero-pancreatic and bronchopulmonary neuroendocrine tumors

    Institute of Scientific and Technical Information of China (English)

    Mariangela Torniai; Silvia Rinaldi; Francesca Morgese; Giulia Ricci; Azzurra Onofri; Christian Groh; Rossana Berardi


    Neuroendocrine tumors (NETs) represent a spectrum of rare neoplasms arising in different organism sites. Depending on the site of onset, they also can be distinguished using lab exams (secretingvs. nonsecreting), clinical symptoms (functioningvs. nonfunctioning), behavioral, morphological characteristics (tumor cells’ architectural growth patterns, mitotic and Ki-67 index, presence of necrosis), and grade of cellular differentiation. The aim of this review is to focus on the main signaling pathways targeted by medical treatments of advanced sporadic gastro-entero-pancreatic (GEP) and bronchopulmonary (BP) neuroendocrine neoplasms. The scientiifc literature regarding treatment of advanced GEP and BP-NETs has been extensively reviewed using MEDLINE and PubMed databases, selecting principal and more recent research articles, clinical trials, and updated guidelines. Somatostatin analogues represent a valid approach to control symptoms in functioning tumors and to inhibit tumor progression in certain categories on the basis of the typical somatostatin receptor expression observed in NETs. The pathogenesis of NETs has been the subject of increased interest in recent years. Many driver mutations pathway genes have been identiifed as important factors in the carcinogenesis process and, therefore, as potential targets for new anticancer therapies. Activating mutations have been shown in epidermal growth factor receptor, stem cell factor receptor, platelet-derived growth factor receptor, vascular endothelial growth factor, basic-ifbroblastic growth factor, transforming growth factor, insulin-like growth factor-1, and their receptors. Effective M-Tor inhibition pathway modulation has led to the approval of drugs in this ifeld such as everolimus. New drugs and several combination regimens with targeted and newer biological agents are being developed and tested in recently conducted and ongoing trials.

  13. Defining global neuroendocrine gene expression patterns associated with reproductive seasonality in fish.

    Directory of Open Access Journals (Sweden)

    Dapeng Zhang

    Full Text Available BACKGROUND: Many vertebrates, including the goldfish, exhibit seasonal reproductive rhythms, which are a result of interactions between external environmental stimuli and internal endocrine systems in the hypothalamo-pituitary-gonadal axis. While it is long believed that differential expression of neuroendocrine genes contributes to establishing seasonal reproductive rhythms, no systems-level investigation has yet been conducted. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, by analyzing multiple female goldfish brain microarray datasets, we have characterized global gene expression patterns for a seasonal cycle. A core set of genes (873 genes in the hypothalamus were identified to be differentially expressed between May, August and December, which correspond to physiologically distinct stages that are sexually mature (prespawning, sexual regression, and early gonadal redevelopment, respectively. Expression changes of these genes are also shared by another brain region, the telencephalon, as revealed by multivariate analysis. More importantly, by examining one dataset obtained from fish in October who were kept under long-daylength photoperiod (16 h typical of the springtime breeding season (May, we observed that the expression of identified genes appears regulated by photoperiod, a major factor controlling vertebrate reproductive cyclicity. Gene ontology analysis revealed that hormone genes and genes functionally involved in G-protein coupled receptor signaling pathway and transmission of nerve impulses are significantly enriched in an expression pattern, whose transition is located between prespawning and sexually regressed stages. The existence of seasonal expression patterns was verified for several genes including isotocin, ependymin II, GABA(A gamma2 receptor, calmodulin, and aromatase b by independent samplings of goldfish brains from six seasonal time points and real-time PCR assays. CONCLUSIONS/SIGNIFICANCE: Using both

  14. Initial Australian experience with high dose indium-111 pentreotide therapy in progressive, symptomatic neuroendocrine tumours

    Energy Technology Data Exchange (ETDEWEB)

    Hicks, R.J.; Keady, M.A.; Johnson, V. [The Peter McCallum Cancer Institute, Melbourne, VIC (Australia). Department of Nuclear Medicine and PET


    Full text: Neuroendocrine tumours variably express somatostatin receptors enabling imaging using somatostatin analogues, including In-111 pentreotide. Due to the emission of Auger electrons in the decay of In-1 11, there is the potential to use this agent for therapy. Based on favourable experience with high dose In-111 pentreotide therapy a the University of Rotterdam, a prospective trial of this treatment was performed in 6 patients with progressive, symptomatic neuroendocrine tumours (carcinoid in 4 patients and glucagonoma in 2 patients). Patients were selected based on the presence of uptake at multiple sites on In-1 11 pentreotide scanning with intensity equal to or greater than splenic activity. Follow-up of haematology, endocrine and renal function was performed and serial imaging correlation of index lesions was performed. Three treatments of approximately 6.5 GBq of In-111 pentreotide were administered to each patient over 3-5 months. One pt with bone metastases from carcinoid had an initial flare in symptoms 1 week following treatment but subsequent palliation which lasted 6 months before requiring local radiotherapy. The three remaining carcinoid patients had symptomatic improvement and reduced 5-HIAA levels when abnormal at baseline. Both patients with glucagonoma had symptomatic improvement and reduction in glucagon levels. No patients had evidence of disease progression up to 6 months post-treatment in index lesions with high In-1 11 pentreotide uptake. One lesion with low uptake progressed despite regression in other lesions with high uptake in the same patient Minor transient lymphopaenia was seen following treatment but no clinically significant toxicity was noted. These preliminary results complement European data suggesting good palliation from high dose In-111 pentreotide therapy in patients with high somatostatin receptor expression

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. Clinical characteristics and prognostic factors of patients with gastric neuroendocrine carcinoma treated with radical surgery

    Institute of Scientific and Technical Information of China (English)

    Xu Xuefeng; Li Jian'ang; Han Xu; Shi Chenye; Jin Dayong; Lou Wenhui


    Background Gastric neuroendocrine carcinomas (g-NECs) are rare tumors that have aggressive biological behaviors and poor prognosis,but the prognostic factors of postoperative patients with g-NEC are still unclear.Our aim was to study and explore the clinical characteristics and prognostic factors of patients with g-NEC treated with radical surgery.Methods The clinical data of 43 g-NEC patients who underwent surgery from January 2002 to January 2011 at the Zhongshan Hospital of Fudan University were analyzed.Follow-up was conducted by telephone,mail,or returning visit survey.Results The sizes of the 43 neuroendocrine carcinomas (G3) were 1.5 cm × 1.5 cm × 0.5 cm to 7 cm × 8 cm × 1.5 cm.Eight NECs were localized,and 35 had lymph node involvement,of which 1 also had hepatic metastasis.At the end of the follow-up,the follow-up rate was 97.7% (42/43),and the median follow-up time was 22.2 months.The median overall survival of g-NEC patients was 36.5 months,and the 1-,3-,and 5-year overall survival rates were 86.0%,51.6%,and 36.7%,respectively.Sex (P <0.05) and lymph node involvement (P <0.05) were prognostic factors of postoperative g-NEC patients,among which sex was an independent prognostic factor (P <0.05),as a survival advantage of female patients over male was observed.Conclusions Most of the g-NECs were diagnosed at an advanced stage.The prognosis of g-NECs was related with sex and lymph node involvement,of which sex was an independent prognostic factor,with female patients having a survival advantage.

  20. Calcitonin gene-related peptide expression is altered in pulmonary neuroendocrine cells in developing lungs of rats with congenital diaphragmatic hernia

    NARCIS (Netherlands)

    H. IJsselstijn (Hanneke); N. Hung; J.C. de Jongste (Johan); D. Tibboel (Dick); E. Cutz


    textabstractCongenital diaphragmatic hernia (CDH) is associated with high neonatal mortality from lung hypoplasia and persistent pulmonary hypertension. Pulmonary neuroendocrine cells (PNEC) produce calcitonin gene-related peptide (CGRP), a potent vasodilator. We previo

  1. Quantitative gene-expression of the tumor angiogenesis markers vascular endothelial growth factor, integrin alphaV and integrin beta3 in human neuroendocrine tumors

    DEFF Research Database (Denmark)

    Oxboel, Jytte; Binderup, Tina; Knigge, Ulrich;


    Anti-angiogenesis treatment is a promising new therapy for cancer that recently has also been suggested for patients with neuroendocrine tumors. The aim of the present study was therefore to investigate the level of tumor angiogenesis, and thereby the molecular basis for anti-angiogenesis treatment......, in neuroendocrine tumors. We used quantitative real-time PCR for measuring mRNA gene-expression of vascular endothelial growth factor (VEGF), integrin alphaV, and integrin beta3, and CD34 for a group of patients with neuroendocrine tumors (n=13). Tissue from patients with colorectal cancer liver metastases (n=14......) and normal liver tissues (n=16) was used as control. We found a lower mRNA level of VEGF in neuroendocrine tumors compared to both colorectal liver metastases (ptumors...

  2. Peptide receptor radionuclide therapy with Y-DOTATOC and (177)Lu-DOTATOC in advanced neuroendocrine tumors: results from a Danish cohort treated in Switzerland

    DEFF Research Database (Denmark)

    Pfeifer, Andreas Klaus; Gregersen, Tine; Grønbæk, Henning


    Limited therapeutic options have highlighted the demand for new treatment modalities for patients with advanced neuroendocrine tumors (NET). Promising results of initial studies have warranted the implementation of peptide receptor radionuclide therapy (PRRT) in clinical practice. However, this t...

  3. Peptide Receptor Radionuclide Therapy with (90)Y-DOTATOC and (177)Lu-DOTATOC in Advanced Neuroendocrine Tumors: Results from a Danish Cohort Treated in Switzerland

    DEFF Research Database (Denmark)

    Pfeifer, Andreas Klaus; Gregersen, Tine; Grønbæk, Henning


    Limited therapeutic options have highlighted the demand for new treatment modalities for patients with advanced neuroendocrine tumors (NET). Promising results of initial studies have warranted the implementation of peptide receptor radionuclide therapy (PRRT) in clinical practice. However, this t...

  4. Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. (United States)

    Kulke, Matthew H; Siu, Lillian L; Tepper, Joel E; Fisher, George; Jaffe, Deborah; Haller, Daniel G; Ellis, Lee M; Benedetti, Jacqueline K; Bergsland, Emily K; Hobday, Timothy J; Van Cutsem, Eric; Pingpank, James; Oberg, Kjell; Cohen, Steven J; Posner, Mitchell C; Yao, James C


    Neuroendocrine tumors (NETs) arise from a variety of anatomic sites and share the capacity for production of hormones and vasoactive peptides. Because of their perceived rarity, NETs have not historically been a focus of rigorous clinical research. However, the diagnosed incidence of NETs has been increasing, and the estimated prevalence in the United States exceeds 100,000 individuals. The recent completion of several phase III studies, including those evaluating octreotide, sunitinib, and everolimus, has demonstrated that rigorous evaluation of novel agents in this disease is both feasible and can lead to practice-changing outcomes. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trials planning meeting to identify key unmet needs, develop appropriate study end points, standardize clinical trial inclusion criteria, and formulate priorities for future NET studies for the US cooperative group program. Emphasis was placed on the development of well-designed clinical trials with clearly defined efficacy criteria. Key recommendations include the evaluation of pancreatic NET separately from NETs of other sites and the exclusion of patients with poorly differentiated histologies from trials focused on low-grade histologies. Studies evaluating novel agents for the control of hormonal syndromes should avoid somatostatin analog washout periods when possible and should include quality-of-life end points. Because of the observed long survival after progression of many patients, progression-free survival is recommended as a feasible and relevant primary end point for both phase III studies and phase II studies where a delay in progression is expected in the absence of radiologic responses.

  5. Periampullary mass--a rare presentation of poorly differentiated neuroendocrine cancer of duodenum in a young adult: a case report and review of literature. (United States)

    Singh, Neha; Nayak, Hemanta K; Bagchi, Avishek; Kar, Premashis


    Poorly differentiated neuroendocrine tumour in the periampullary region of the duodenum is a rare entity. This entity usually present in old men. Here we report a periampullary poorly differentiated neuroendocrine cancer (PDEC) of duodenum presenting in a young man with subacute history of jaundice, abdominal pain, pancreatitis and constitutional symptoms. MRI localised the tumour and endoscopy-guided biopsy of the lesion proved the diagnosis. Although palliative surgery and chemotherapy were planned, the patient opted to leave against medical advice.

  6. Design and Validation of the GI-NEC Score to Prognosticate Overall Survival in Patients With High-Grade Gastrointestinal Neuroendocrine Carcinomas


    Valle, Juan; Lamarca, Angela; McNamara, Mairead; Hubner, Richard; Barriuso, Jorge


    BACKGROUND: Prognostic markers for risk stratification of patients with gastrointestinal high-grade neuroendocrine carcinomas (GI-NECs) are lacking; we designed and validated a prognostic score for overall survival (OS). METHODS: Consecutive patients diagnosed in five neuroendocrine specialist European centers were included. Patients were divided into three cohorts: a training cohort (TC), an external validation cohort (EVC), and a prospective validation cohort (PVC). Prognostic factors were ...

  7. Metastatic Neuroendocrine Carcinoma of the Breast Identified by Tc-99m-HYNIC-TOC SPECT/CT: A Rare Case Report. (United States)

    Claimon, Apichaya; Chuthapisith, Suebwong; Samarnthai, Norasate; Pusuwan, Pawana


    The authors reported an uncommon presentation of metastatic neuroendocrine carcinoma to the breast detected by Tc-99m-HYNIC-TOC SPECT/CT in a 49 years old woman who, previously, had carcinoid tumor of left main bronchus and invasive ductal carcinoma of the right breast. Later, the patient developed left breast mass. Core needle biopsy of the mass revealed poorly differentiated invasive ductal carcinoma. The disease remained stable for 12 years without any treatment on that left breast (due to patient's rejection). On the later investigation using Tc-99m-HYNIC-TOC scintigraphy examination, rather than invasive ductal carcinoma, metastatic neuroendocrine cancer was suggested. The final diagnosis was confirmed by pathological examination after surgical excision. Multiple metastatic lesions of neuroendocrine carcinoma at lung, liver, ovaries, and bones were also depicted. Due to the good behavior of the disease, patient had been doing well for eight months, without specific treatment. This report confirmed the advantage and the accuracy of Tc-99m-HYNIC-TOC scintigraphy in detection of neuroendocrine carcinoma. Furthermore, metastatic neuroendocrine tumor should be in differential diagnosis for patient with breast mass together with history of neuroendocrine tumor

  8. Treatment of gastrointestinal neuroendocrine tumors with inhibitors of growth factor receptors and their signaling pathways: Recent advances and future perspectives

    Institute of Scientific and Technical Information of China (English)

    Michael H(o)pfner; Detlef Schuppan; Hans Scherübl


    The limited efficacy of conventional cytotoxic treatment regimes for advanced gastrointestinal neuroendocrine cancers emphasizes the need for novel and more effective medical treatment options.Recent findings on the specific biological features of this family of neoplasms has led to the development of new targeted therapies,which take into account the high vascularization and abundant expression of specific growth factors and cognate tyrosine kinase receptors.This review will briefly summarize the status and future perspectives of antiangiogenic, mTOR- or growth factor receptor-based pharmacological approaches for the innovative treatment of gastrointestinal neuroendocrine tumors.In view of the multitude of novel targeted approaches, the rationale for innovative combination therapies, i.e.combining growth factor (receptor)-targeting agents with chemoor biotherapeutics or with other novel anticancer drugs such as HDAC or proteasome inhibitors will be taken into account.

  9. A systematic review of management of neuroendocrine tumors: An experience from a tertiary care centre from India

    Directory of Open Access Journals (Sweden)

    Rakesh Kapoor


    Full Text Available Neuroendocrine tumors (NETs encompass a heterogeneous group of tumors demonstrating varied clinical behavior. The field has recently witnessed several important developments stemming from improvements in the histopathological classification schemes, advanced imaging techniques, and a deeper understanding of the molecular mechanisms underlying tumor progression. These tumors have indolent clinical courses, with long survival rates even for the patients with metastatic disease. The mainstay of treatment is surgery. Somatostatin analogs play a key role in controlling the symptoms; however, they are seldom associated with tumor regression. Traditional cytotoxic chemotherapies have a very limited role in well differentiated NETs, but platinum based chemotherapy is highly effective in neuroendocrine carcinomas. Recently, the biological targeted agents have shown promise in patients with metastatic disease. Evolving modalities like peptide receptor targeted therapies and radioembolization have opened up new avenues in refractory and advanced disease.

  10. Uterus neuroendocrine tumor - a severe prognostic factor in a female patient with alcoholic cirrhosis undergoing chronic hemodialysis. (United States)

    Sinescu, Ruxandra Diana; Niculae, Andrei; Peride, Ileana; Vasilescu, Florina; Bratu, Ovidiu Gabriel; Mischianu, Dan Liviu Dorel; Jinga, Mariana; Checheriţă, Ionel Alexandru


    There is increased evidence that end-stage renal disease patients, especially the hemodialyzed population, may present various unexpected forms of complications, contributing to a poor prognosis. Furthermore, neuroendocrine tumors, rarely encountered in daily practice, present in dialyzed individuals can significantly exacerbate the inflammatory condition with negative impact on patients' quality of life. We present an unusual case of uterus neuroendocrine tumor with multiple metastases in a 49-year-old female hemodialyzed patient with a history of alcoholic liver cirrhosis and uterus fibromatous. Multiple endoscopic techniques (e.g., upper endoscopy, colonoscopy, upper and lower echoendoscopy), histological evaluation of biopsy samples from involved areas (the operatory piece) were performed in order to complete and refine the diagnosis.

  11. Extracellular pH Modulates Neuroendocrine Prostate Cancer Cell Metabolism and Susceptibility to the Mitochondrial Inhibitor Niclosamide.

    Directory of Open Access Journals (Sweden)

    Joseph E Ippolito

    Full Text Available Neuroendocrine prostate cancer is a lethal variant of prostate cancer that is associated with castrate-resistant growth, metastasis, and mortality. The tumor environment of neuroendocrine prostate cancer is heterogeneous and characterized by hypoxia, necrosis, and numerous mitoses. Although acidic extracellular pH has been implicated in aggressive cancer features including metastasis and therapeutic resistance, its role in neuroendocrine prostate cancer physiology and metabolism has not yet been explored. We used the well-characterized PNEC cell line as a model to establish the effects of extracellular pH (pH 6.5, 7.4, and 8.5 on neuroendocrine prostate cancer cell metabolism. We discovered that alkalinization of extracellular pH converted cellular metabolism to a nutrient consumption-dependent state that was susceptible to glucose deprivation, glutamine deprivation, and 2-deoxyglucose (2-DG mediated inhibition of glycolysis. Conversely, acidic pH shifted cellular metabolism toward an oxidative phosphorylation (OXPHOS-dependent state that was susceptible to OXPHOS inhibition. Based upon this mechanistic knowledge of pH-dependent metabolism, we identified that the FDA-approved anti-helminthic niclosamide depolarized mitochondrial potential and depleted ATP levels in PNEC cells whose effects were enhanced in acidic pH. To further establish relevance of these findings, we tested the effects of extracellular pH on susceptibility to nutrient deprivation and OXPHOS inhibition in a cohort of castrate-resistant prostate cancer cell lines C4-2B, PC-3, and PC-3M. We discovered similar pH-dependent toxicity profiles among all cell lines with these treatments. These findings underscore a potential importance to acidic extracellular pH in the modulation of cell metabolism in tumors and development of an emerging paradigm that exploits the synergy of environment and therapeutic efficacy in cancer.

  12. The selective glucocorticoid receptor antagonist CORT 108297 decreases neuroendocrine stress responses and immobility in the forced swim test. (United States)

    Solomon, Matia B; Wulsin, Aynara C; Rice, Taylor; Wick, Dayna; Myers, Brent; McKlveen, Jessica; Flak, Jonathan N; Ulrich-Lai, Yvonne; Herman, James P


    Pre-clinical and clinical studies have employed treatment with glucocorticoid receptor (GR) antagonists in an attempt to limit the deleterious behavioral and physiological effects of excess glucocorticoids. Here, we examined the effects of GR antagonists on neuroendocrine and behavioral stress responses, using two compounds: mifepristone, a GR antagonist that is also a progesterone receptor antagonist, and CORT 108297, a specific GR antagonist lacking anti-progestin activity. Given its well-documented impact on neuroendocrine and behavioral stress responses, imipramine (tricyclic antidepressant) served as a positive control. Male rats were treated for five days with mifepristone (10mg/kg), CORT 108297 (30mg/kg and 60mg/kg), imipramine (10mg/kg) or vehicle and exposed to forced swim test (FST) or restraint stress. Relative to vehicle, imipramine potently suppressed adrenocorticotropin hormone (ACTH) responses to FST and restraint exposure. Imipramine also decreased immobility in the FST, consistent with antidepressant actions. Both doses of CORT 108297 potently suppressed peak corticosterone responses to FST and restraint stress. However, only the higher dose of CORT 108297 (60mg/kg) significantly decreased immobility in the FST. In contrast, mifepristone induced protracted secretion of corticosterone in response to both stressors, and modestly decreased immobility in the FST. Taken together, the data indicate distinct effects of each compound on neuroendocrine stress responses and also highlight dissociation between corticosterone responses and immobility in the FST. Within the context of the present study, our data suggest that CORT 108297 may be an attractive alternative for mitigating neuroendocrine and behavioral states associated with excess glucocorticoid secretion.

  13. Improved Benefit of SPECT/CT Compared to SPECT Alone for the Accurate Localization of Endocrine and Neuroendocrine Tumors

    Directory of Open Access Journals (Sweden)

    Gonca G. Bural


    Full Text Available Objective: To assess the clinical utility of SPECT/ CT in subjects with endocrine and neuroendocrine tumors compared to SPECT alone. Material and Methods: 48 subjects (31 women;17 men; mean age 54±11 with clinical suspicion or diagnosis of endocrine and neuroendocrine tumor had 50 SPECT/CT scans (32 Tc-99m MIBI, 5 post treatment I-131, 8 In-111 Pentetreotide, and 5 I-123 MIBG. SPECT alone findings were compared to SPECT/CT and to pathology or radiological follow up. Results: From the 32 Tc-99m MIBI scans, SPECT accurately localized the lesion in 22 positive subjects while SPECT/CT did in 31 subjects. Parathyroid lesions not seen on SPECT alone were smaller than 10 mm. In five post treatment I-131 scans, SPECT alone neither characterized, nor localized any lesions accurately. SPECT/CT revealed 3 benign etiologies, a metastatic lymph node, and one equivocal lesion. In 8 In-111 Pentetreotide scans, SPECT alone could not localize primary or metastatic lesions in 6 subjects all of which were localized with SPECT/CT. In five I-123 MIBG scans, SPECT alone could not detect a 1.1 cm adrenal lesion or correctly characterize normal physiologic adrenal uptake in consecutive scans of the same patient with prior history of adrenelectomy, all of which were correctly localized and characterized with SPECT/CT. Conclusion: SPECT/CT is superior to SPECT alone in the assessment of endocrine and neuroendocrine tumors. It is better in lesion localization and lesion characterization leading to a decrease in the number of equivocal findings. SPECT/CT should be included in the clinical work up of all patients with diagnosis or suspicion of endocrine and neuroendocrine tumors. (MIRT 2012;21:91-96

  14. Transfusion free radical antegrade modular pancreaticosplenectomy of metastatic neuroendocrine tumor of the pancreas in Jehovah's Witness patient


    Jeon, Young Bae; Yun, Sangchul; Choi, Dongho


    In a popular sense, Jehovah's Witnesses (JW) have their creeds, one of which is refusal of blood transfusion. Such refusal may impinge on their proper management, especially in critical situations. We present a case of successful bloodless multimodality therapy, which was performed for a JW. The patient was a 49-year-old woman and JW who had general weakness 7 days before admission. She was diagnosed with a pancreatic neuroendocrine tumor (PNET) with hepatic metastases. Transcatheter arterial...

  15. Combination therapy of gemcitabine or oral S-1 with the anti-VEGF monoclonal antibody bevacizumab for pancreatic neuroendocrine carcinoma. (United States)

    Kasuya, Kazuhiko; Nagakawa, Yuichi; Suzuki, Minako; Suzuki, Yoshiaki; Kyo, Bunso; Suzuki, Satoru; Matsudo, Takaaki; Itoi, Takao; Tsuchida, Akihiko; Aoki, Tatsuya


    We previously reported that the administration of bevacizumab for pancreatic neuroendocrine tumors inhibited angiogenesis in the host, resulting in tumor growth inhibition. In light of these results, we compared the effect of bevacizumab/gemcitabine/S-1 combination therapy vs. bevacizumab monotherapy. The QGP-1 pancreatic neuroendocrine carcinoma cell line and the BxPC-3 ductal cell carcinoma cell line were transplanted into the subcutaneous tissue of mice, and the mice were treated for 3 weeks with bevacizumab [50 mg/kg intraperitoneally (i.p.) twice weekly], gemcitabine (240 mg/kg i.p. once weekly) and S-1 (10 mg/kg orally five times weekly). The antitumor effect and side effects were evaluated by measuring the tumor volume and weight and by changes in body weight, respectively. The tumor volume became smaller (from the maximum volume) in the group treated with bevacizumab, gemcitabine and S-1 (BGS) and the group treated with bevacizumab and gemcitabine (BG). A significant difference was noted in the tumor weight between the BG group and the group treated with bevacizumab alone. A relatively significant decrease in the body weight was observed in the BGS and BG groups. We conclude that gemcitabine is appropriate as a drug used in combination with bevacizumab for pancreatic neuroendocrine tumors.

  16. Estrogenic environmental endocrine-disrupting chemical effects on reproductive neuroendocrine function and dysfunction across the life cycle. (United States)

    Dickerson, Sarah M; Gore, Andrea C


    Endocrine disrupting chemicals (EDCs) are natural or synthetic compounds that interfere with the normal function of an organism's endocrine system. Many EDCs are resistant to biodegradation, due to their structural stability, and persist in the environment. The focus of this review is on natural and artificial EDCs that act through estrogenic mechanisms to affect reproductive neuroendocrine systems. This endocrine axis comprises the hypothalamic gonadotropin-releasing hormone (GnRH), pituitary gonadotropins, and gonadal steroid hormones, including estrogens. Although it is not surprising that EDCs that mimic or antagonize estrogen receptors may exert actions upon reproductive targets, the mechanisms for these effects are complex and involve all three levels of the hypothalamic-pituitary-gonadal (HPG) system. Nevertheless, considerable evidence links exposure to estrogenic environmental EDCs with neuroendocrine reproductive deficits in wildlife and in humans. The effects of an EDC are variable across the life cycle of an animal, and are particularly potent when exposure occurs during fetal and early postnatal development. As a consequence, abnormal sexual differentiation, disrupted reproductive function, or inappropriate sexual behavior may be detected later in life. This review will cover the effects of two representative classes of estrogenic EDCs, phytoestrogens and polychlorinated biphenyls (PCBs), on neuroendocrine reproductive function, from molecules to behavior, across the vertebrate life cycle. Finally, we identify the gaps of knowledge in this field and suggest future directions for study.

  17. The prognostic influence of the proliferative discordance in metastatic pancreatic neuroendocrine carcinoma revealed by peptide receptor radionuclide therapy (United States)

    Montanier, Nathanaëlle; Joubert-Zakeyh, Juliette; Pétorin, Caroline; Montoriol, Pierre François; Maqdasy, Salwan; Kelly, Antony


    Abstract Rationale: Pancreatic neuroendocrine tumors (pNET) are rare slowly growing tumors with a high metastatic potential. Peptide receptor radionuclide therapy (PRRT) with radiolabeled analogues has been developed as a new tool for the management of metastatic well-differentiated (grade 1 and 2) neuroendocrine tumors expressing somatostatin receptor (SSTR2). Chemotherapy is the mainstay in the management of grade 3 (G3) unresectable pancreatic neuroendocrine carcinoma (pNEC). To date, no study has evaluated the efficacy of PRRT in such tumors. Diagnoses and interventions: We describe a case of a progressive G3 pNEC with huge liver metastases successfully treated with PRRT (177Lu DOTATATE). Outcomes: Complete remission was obtained for 3 years. Indeed, the mitotic index was low (as G2 tumors) but with a very high Ki-67 index (45%–70%). Such discordance between the proliferative markers should consider the use of PRRT before chemotherapy in unresectable metastatic G3 tumors expressing SSTR2. Lessons: This case supports the hypotheses highlighting the heterogeneity of G3 pNEC. The latter should be subdivided into 2 distinct categories: proliferation-discordant (well differentiated) and concordant (poorly differentiated) NEC. PRRT could be suggested for the former group before the conventional chemotherapy. PMID:28178157

  18. The genetics of neuroendocrine prostate cancers: a review of current and emerging candidates

    Directory of Open Access Journals (Sweden)

    Ather MH


    Full Text Available M Hammad Ather,1 Tahmeena Siddiqui21Dept of Surgery, Aga Khan University, 2Karachi Medical and Dental College, Karachi, PakistanAbstract: Prostate cancer (PC displays a strong familial link and genetic factors; genes regulating inflammation may have a pivotal role in the disease. Epigenetic changes control chromosomal integrity, gene functions, and, ultimately, carcinogenesis. The most widely studied epigenetic event in PC is aberrant DNA methylation (hypo- and hypermethylation; besides this, chromatin remodeling and micro RNA (miRNA are other studied alterations in PC. These all lead to genomic instability and inappropriate gene expression. Causative dysfunction of histone modifying enzymes results in generic and locus-specific changes in chromatin remodeling. miRNA deregulation also contributes to prostate carcinogenesis, including interference with androgen-receptor signaling and apoptosis. These epigenetic alterations have the potential to act as biomarkers for PC for screening and diagnosis as well as prognosis and follow-up. The variable biological potential for a newly diagnosed PC is one of the biggest challenges. The other major clinical problem is in the management of castration-resistant PC. Neuroendocrine (NE differentiation is one of the putative explanations for the development of castration-resistant disease. Most advanced and poorly differentiated cancer does not produce prostate-specific antigen (PSA in response to disease progression. Circulating and tissue biomarkers like chromogranin A (CgA thus become important tools. There is the potential to use various genetic and epigenetic alterations and NE differentiation as therapeutic targets in the management of PC. However, we are still some distance from developing clinically effective tools. Valuable insights into the nature of NE differentiation in PC have been gained in the last decades, but additional understanding of its pathogenetic mechanisms is needed. This will help in

  19. Riding a roller coaster: narrative typologies of patients with neuroendocrine tumors

    Directory of Open Access Journals (Sweden)

    Miconi A


    Full Text Available Alessia Miconi,1 Daniele De Nuzzo,1 Solfrid Vatne,2 Paola Pierantognetti11Faculty of Medicine and Psychology, Sapienza Università di Roma, Rome, Italy; 2Molde University College, Molde, NorwayBackground and objective: Illness stories have attracted growing attention in health care research in the context of learning from looking at the world through the patients' eyes. No narrative studies were found about the patients with neuroendocrine tumors (NETs; a rare illness including tumors usually starting in hormone-producing cells. The aim of this article was to develop an extended understanding of these patients' experiences and struggles, as well as their solutions to a common problem.Methods: The data source was 21 letters written by the patients with NETs treated at an ambulatory treatment center at a large urban hospital in Italy. The letters were analyzed using the Arthur Frank's narrative method. We paid particular attention to statements of self-experience, which is crucial to get the character of the story.Results: We identified four different typologies: “Not illness stories”, “Living in imbalance”, “Living a new life in balance”, and “Living a normal life”. The main characteristics of these four groups could be linked to Frank's typologies. However, the patients with this periodically changing disease were continuously in the process of attaining balance in life, and they might move between these various typologies.Conclusion: The NETs are incurable illnesses that challenged the peoples to attaining a new balance in life. We will highlight stories focusing on the patients' imbalance and chaos because they illuminated the patients' concrete suffering, which might provide clinicians with specific information about the patients' emotional, physical, and spiritual state. Through learning from the stories of the patients attaining new balance, it seems possible to move forward to acceptance and to develop a model for a new way

  20. The Clinicopathologic Features and Treatment of 607 Hindgut Neuroendocrine Tumor (NET) Patients at a Single Institution. (United States)

    Kim, Seung Tae; Ha, Sang Yun; Lee, Jeeyun; Hong, Sung No; Chang, Dong Kyung; Kim, Young Ho; Park, Yoon Ah; Huh, Jung Wook; Cho, Yong Beom; Yun, Seong Hyeon; Lee, Woo Yong; Kim, Hee Cheol; Park, Young Suk


    The clinicopathologic features of hindgut neuroendocrine tumor (NET) as well as the treatment outcomes are not well known. There are currently no published data on treatment outcomes for patients with metastatic hindgut NET. The aim of this study was to conduct a comprehensive analysis of clinicopathologic features, treatments and survival in hindgut NET patients. Among patients who were pathologically diagnosed with hindgut NET at Samsung Medical Center between March 2001 and February 2015, 607 were analyzed in this study. Hindgut NETs were defined as NETs that originated from the transverse and distal colon, rectum, and anus. Primary sites included 81 colon (13.3%) and 526 rectum (86.7%). According to the WHO classification, 578 patients (95.2%) had grade 1 NETs, 17 (2.8%) grade 2 NETs, and 12 (2.0%) had neuroendocrine carcinoma (NEC). Forty-two patients (6.9%) had extensive disease, while the majority (93.1%, 565 patients) only exhibited localized disease. The 5- and 10-year survival rates of 565 localized NET patients were 98.1% and 95.3%, respectively. The median OS in 42 patients with extensive disease was 24.8 months (95% CI, 10.7-38.8). Among 565 patients with localized disease, the majority (484 patients, 85.7%) were treated with endoscopic procedure by gastroenterologists. For 42 patients with extensive disease, 17 patients were managed by supportive care, 3 by concurrent chemoradiotherapy (CCRT), and 22 by systemic therapy. Among these 22 patients, 12 patients received only first-line therapy, 8 had second-line, and only 2 patients had third-line therapy. As first-line chemotherapy, the most commonly used regimens were etoposide plus cisplatin (N = 7) and long acting octreotide (N = 7). During treatment courses, the most commonly used regimen was long-acting octreotide. The median OS in 22 metastatic NET patients receiving systemic therapy was 19.3 months (95% CI, 3.2-35.3). Multivariate analysis in all 607 hindgut NETs patients suggested that

  1. Dietary isoflavones alter regulatory behaviors, metabolic hormones and neuroendocrine function in Long-Evans male rats

    Directory of Open Access Journals (Sweden)

    Bu Lihong


    Full Text Available Abstract Background Phytoestrogens derived from soy foods (or isoflavones have received prevalent usage due to their 'health benefits' of decreasing: a age-related diseases, b hormone-dependent cancers and c postmenopausal symptoms. However, little is known about the influence of dietary phytoestrogens on regulatory behaviors, such as food and water intake, metabolic hormones and neuroendocrine parameters. This study examined important hormonal and metabolic health issues by testing the hypotheses that dietary soy-derived isoflavones influence: 1 body weight and adipose deposition, 2 food and water intake, 3 metabolic hormones (i.e., leptin, insulin, T3 and glucose levels, 4 brain neuropeptide Y (NPY levels, 5 heat production [in brown adipose tissue (BAT quantifying uncoupling protein (UCP-1 mRNA levels] and 6 core body temperature. Methods This was accomplished by conducting longitudinal studies where male Long-Evans rats were exposed (from conception to time of testing or tissue collection to a diet rich in isoflavones (at 600 micrograms/gram of diet or 600 ppm vs. a diet low in isoflavones (at approximately 10–15 micrograms/gram of diet or 10–15 ppm. Body, white adipose tissue and food intake were measured in grams and water intake in milliliters. The hormones (leptin, insulin, T3, glucose and NPY were quantified by radioimmunoassays (RIA. BAT UCP-1 mRNA levels were quantified by PCR and polyacrylamide gel electrophoresis while core body temperatures were recorded by radio telemetry. The data were tested by analysis of variance (ANOVA (or where appropriate by repeated measures. Results Body and adipose tissue weights were decreased in Phyto-600 vs. Phyto-free fed rats. Food and water intake was greater in Phyto-600 animals, that displayed higher hypothalamic (NPY concentrations, but lower plasma leptin and insulin levels, vs. Phyto-free fed males. Higher thyroid levels (and a tendency for higher glucose levels and increased uncoupling


    Institute of Scientific and Technical Information of China (English)

    Lin Lin; Min Ji; Hong-jie Zhang; Zheng Lin; Zhi-quan Zhao


    (P< 0.05). (3) The blood glucose was lower in erythromycin group than DM group (P < 0.01).Conclusions Erythromycin has direct effects on contractive activity of gastric smooth muscle in diabetic rats, but there are few effects on neuroendocrine peptides. Gastric-motility disorders in diabetic rats have a correlation with the changes of neuroendocrine peptide levels in plasma and gastric antrum tissue.

  3. Neuroendocrine transcriptional programs adapt dynamically to the supply and demand for neuropeptides as revealed in NSF mutant zebrafish

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    Baier Herwig


    Full Text Available Abstract Background Regulated secretion of specialized neuropeptides in the vertebrate neuroendocrine system is critical for ensuring physiological homeostasis. Expression of these cell-specific peptide markers in the differentiating hypothalamus commences prior to birth, often predating the physiological demand for secreted neuropeptides. The conserved function and spatial expression of hypothalamic peptides in vertebrates prompted us to search for critical neuroendocrine genes in newly hatched zebrafish larvae. Results We screened mutant 5 days post-fertilization zebrafish larvae that fail to undergo visually mediated background adaptation for disruption in hypothalamic pomc expression. To our surprise, the ATPase N-ethylmaleimide sensitive factor (nsf was identified as an essential gene for maintenance of neuroendocrine transcriptional programs during the embryo-to-larva transition. Despite normal hypothalamic development in nsfst53 mutants, neuropeptidergic cells exhibited a dramatic loss of cell-specific markers by 5 days post-fertilization that is accompanied by elevated intracellular neuropeptide protein. Consistent with the role of NSF in vesicle-membrane fusion events and intracellular trafficking, cytoplasmic endoplasmic reticulum-like membranes accumulate in nsf-/- hypothalamic neurons similar to that observed for SEC18 (nsf ortholog yeast mutants. Our data support a model in which unspent neuropeptide cargo feedbacks to extinguish transcription in neuropeptidergic cells just as they become functionally required. In support of this model we found that gnrh3 transcripts remained unchanged in pre-migratory, non-functional gonadotropin-releasing hormone (GnRH neurons in nsf-/- zebrafish. Furthermore, oxytocin-like (oxtl, intp transcripts, which are found in osmoreceptive neurons and persist in mutant zebrafish, drop precipitously after mutant zebrafish are acutely challenged with high salt. Conclusion Our analyses of nsf mutant zebrafish

  4. Primar y hepatic neuroendocrine carcinoma:clinical analysis of 11 cases

    Institute of Scientific and Technical Information of China (English)

    Yang-Qing Huang; Feng Xu; Jia-Mei Yang; Bin Huang


    BACKGROUND: Primary hepatic neuroendocrine carcinoma (PHNEC) is extremely rare, and fewer than 300 cases have been reported in the English/Chinese-language literature, therefore it is dififcult to make a proper diagnosis and determine a therapeutic approach. METHODS: Eleven PHNEC patients were admitted to our hospital between January 1996 and May 2008. Laboratory examination, digestive endoscopy, B-ultrasonography, CT, MRI, or PET-CT were performed on the patients for preoperative diagnosis. All patients received liver resection. Some patients received transcatheter arterial chemoembolization (TACE), percutaneous ethanol injection treatment (PEIT), or octreotide injection when a recurrence was found. The patients' clinical data were recorded and all patients were followed up. RESULTS: The patients were conifrmed pathologically as having PHNEC . Their median follow-up time was 33 months (12-107 months). All patients survived, and the longest post-operative survival time was 107 months, the longest disease-free survival time was 98 months, the 1-year survival rate was 100%, and the 1-year recurrence rate was 45.5%(5/11). CONCLUSIONS: Since PHNEC is easy to confuse with hepato-cellular carcinoma, careful screening of symptoms is needed to avoid misdiagnosis. Resection is the ifrst choice of treatment for PHNEC and provides the most favorable outcomes including long-term survival. Other treatment such as TACE and PEIT can be considered as well, especially when a tumor recurs.

  5. Comprehensive treatment of a functional pancreatic neuroendocrine tumor with multifocal liver metastases. (United States)

    Wang, Wei; Seeruttun, Sharvesh Raj; Fang, Cheng; Zhou, Zhiwei


    A 64-year-old man was admitted to the Sun Yat-Sen University Cancer Center with chief complaints of recurrent abdominal pain and diarrhea for about 3 years and with a history of surgical repair for intestinal perforation owing to stress ulcer. Positron emission tomography (PET)/computed tomography (CT) demonstrated a primary tumor on the pancreatic tail with multifocal liver metastases. Pathological and immunohistochemistry staining revealed the lesion to be a pancreatic neuroendocrine tumor (pNET). According to the latest World Health Organization (WHO, 2013) classification, the tumor was classified as stage IV functional G1 pNET. After referral to the multidisciplinary treatment board (MDT), the patient was started on periodic dose of omeprazole, somatostatin analogues and Interferon α (IFNα) and had scanning follow-ups. Based upon the imaging results, CT-guided radioactive iodine-125 ((125)I) seeds implantation therapy, radiofrequency ablation therapy (RFA) or microwave ablation technique were chosen for the treatment of the primary tumor. Transarterial chemoembolization (TACE), RFA and microwave ablation techniques were decided upon for liver metastases. The patient showed beneficial response to the treatment with clinically manageable low-grade side effects and attained partial remission (RECIST criteria) with a good quality of life.

  6. [Analysis of interdependence of temperament, neuroendocrine control and psychophysiological status during dry immersion]. (United States)

    Nichiporuk, I A


    Interdependence of temperament, hormonal and psychophysiological status was investigated in 8 young volunteers for 7-d dry immersion (DI). Blood levels of insulin, sex, steroid, thyroid hormones and psychomotor parameters were determined on DI days 3 and 7, and on day 7 of recovery. Before DI, the volunteers filled in the Kettelle personality questionnaire. During DI, anxious subjects spent less time to compare visual patterns demonstrating high and stable speed of reactions but made a bit more errors. Extraverts showed high speed of reactions and stability of psychomotor parameters and did not increase the number of errors. Easy-tempered and introvert subjects preserved inherently high insulin concentrations in DI. Support deprivation was attended by drop of the levels of triiodothyronine and cortisol and rise of prolactin and thyroxin. Results of multiple correlation analysis led to the conclusion that DI accentuates the role of original extra-introversion and dampens origin anxiety. Successfulness can be attained by adequate alteration of the levels of steroid and thyroid hormones with effectively balanced vagoinsulin-sympathoadrenal neuroendocrine control and monoaminergic CNV activity.

  7. Disruption of insulin signalling affects the neuroendocrine stress reaction in Drosophila females. (United States)

    Rauschenbach, Inga Y; Karpova, Evgenia K; Adonyeva, Natalya V; Andreenkova, Olga V; Faddeeva, Natalya V; Burdina, Elena V; Alekseev, Alexander A; Menshanov, Petr N; Gruntenko, Nataly E


    Juvenile hormone (JH) and dopamine are involved in the stress response in insects. The insulin/insulin-like growth factor signalling pathway has also recently been found to be involved in the regulation of various processes, including stress tolerance. However, the relationships between the JH, dopamine and insulin signalling pathways remain unclear. Here, we study the role of insulin signalling in the regulation of JH and dopamine metabolism under normal and heat stress conditions in Drosophila melanogaster females. We show that suppression of the insulin-like receptor (InR) in the corpus allatum, a specialised endocrine gland that synthesises JH, causes an increase in dopamine level and JH-hydrolysing activity and alters the activities of enzymes that produce as well as those that degrade dopamine [alkaline phosphatase (ALP), tyrosine hydroxylase (TH) and dopamine-dependent arylalkylamine N-acetyltransferase (DAT)]. We also found that InR suppression in the corpus allatum modulates dopamine, ALP, TH and JH-hydrolysing activity in response to heat stress and that it decreases the fecundity of the flies. JH application restores dopamine metabolism and fecundity in females with decreased InR expression in the corpus allatum. Our data provide evidence that the insulin/insulin-like growth factor signalling pathway regulates dopamine metabolism in females of D. melanogaster via the system of JH metabolism and that it affects the development of the neuroendocrine stress reaction and interacts with JH in the control of reproduction in this species.

  8. Initial impact of a systematic multidisciplinary approach on the management of patients with gastroenteropancreatic neuroendocrine tumor.

    LENUS (Irish Health Repository)

    Tamagno, Gianluca


    According to the international guidelines, a multidisciplinary approach is currently advised for the optimal care of patients with a gastroenteropancreatic neuroendocrine tumor (GEP NET). In our institution (tertiary care center), a systematic multidisciplinary approach was established in May 2007. In this study, we have aimed to assess the initial impact of establishing a systematic multidisciplinary approach to the management of GEP NET patients. We have collected and compared the biochemical, imaging, and pathological data and the therapeutic strategies in GEP NET patients diagnosed, treated, or followed-up from January 1993 to April 2007 versus GEP NET patients attending our institution after the multidisciplinary approach starting, from May 2007 to October 2008. Data of 91 patients before and 42 patients after the establishment of the multidisciplinary approach (total: 133 consecutive GEP NET patients) have been finally collected and analyzed. Before the establishment of the multidisciplinary approach, a lack of consistency in the biochemical, imaging, and pathological findings before treatment initiation as well as during follow-up of GEP NET patients was identified. These inconsistencies have been reduced by the systematic multidisciplinary approach. In addition, the therapeutic management of GEP NET patients has been altered by the multidisciplinary approach and became more consistent with recommended guidelines. We think that a systematic multidisciplinary approach significantly impacts on GEP NET patient care and should be established in all centers dealing with these tumors.

  9. Peptidomic identification and biological validation of neuroendocrine regulatory peptide-1 and -2. (United States)

    Yamaguchi, Hideki; Sasaki, Kazuki; Satomi, Yoshinori; Shimbara, Takuya; Kageyama, Haruaki; Mondal, Muhtashan S; Toshinai, Koji; Date, Yukari; González, Luis J; Shioda, Seiji; Takao, Toshifumi; Nakazato, Masamitsu; Minamino, Naoto


    Recent advances in peptidomics have enabled the identification of previously uncharacterized peptides. However, sequence information alone does not allow us to identify candidates for bioactive peptides. To increase an opportunity to discover bioactive peptides, we have focused on C-terminal amidation, a post-translational modification shared by many bioactive peptides. We analyzed peptides secreted from human medullary thyroid carcinoma TT cells that produce amidated peptides, and we identified two novel amidated peptides, designated neuroendocrine regulatory peptide (NERP)-1 and NERP-2. NERPs are derived from distinct regions of the neurosecretory protein that was originally identified as a product of a nerve growth factor-responsive gene in PC12 cells. Mass spectrometric analysis of the immunoprecipitate using specific antibodies as well as reversed phase-high performance liquid chromatography coupled with radioimmunoassay analysis of brain extract demonstrated the endogenous presence of NERP-1 and NERP-2 in the rat. NERPs are abundant in the paraventricular and supraoptic nuclei of the rat hypothalamus and colocalized frequently with vasopressin but rarely with oxytocin. NERPs dose-dependently suppressed vasopressin release induced by intracerebroventricular injection of hypertonic NaCl or angiotensin II in vivo. NERPs also suppressed basal and angiotensin II-induced vasopressin secretion from hypothalamic explants in vitro. Bioactivity of NERPs required C-terminal amidation. Anti-NERP IgGs canceled plasma vasopressin reduction in response to water loading, indicating that NERPs could be potent endogenous suppressors of vasopressin release. These findings suggest that NERPs are novel modulators in body fluid homeostasis.

  10. Anxiety Sensitivity, the Menstrual Cycle, and Panic Disorder: A Putative Neuroendocrine and Psychological Interaction (United States)

    Nillni, Yael I.; Toufexis, Donna J.; Rohan, Kelly J.


    The 2:1 female-to-male sex difference in the prevalence of Panic Disorder (PD) suggests that there is a sex-specific vulnerability involved in the etiology and/or maintenance of this disorder. The purpose of this paper is to present a new conceptual model, which emphasizes the interaction between a cognitive vulnerability for PD, anxiety sensitivity, and the effects of progesterone and its metabolite, allopregnanolone, on behavioral and physiological responses to stress during the premenstrual phase. This interaction is proposed to be a potential sex-specific pathway that may initiate and/or maintain panic and anxiety symptoms in women. This review paper presents preliminary evidence from both the human and animal literatures to support this new model. Specific topics reviewed include: psychopathology related to the menstrual cycle, anxiety sensitivity and its relationship to the menstrual cycle, PMS, and PMDD, anxiety-modulating effects of progesterone and its neuroactive metabolite, allopregnanolone, and how results from the neuroendocrine literature relate to psychopathology or symptoms associated with the menstrual cycle. PMID:21855828

  11. Loneliness and stress-related inflammatory and neuroendocrine responses in older men and women. (United States)

    Hackett, Ruth A; Hamer, Mark; Endrighi, Romano; Brydon, Lena; Steptoe, Andrew


    Loneliness is a predictor of mortality and increased cardiovascular morbidity. Inflammation is a potential pathway through which loneliness might impact health. The aim of the study was to investigate the relationship between loneliness and inflammatory interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra) and monocyte chemotactic protein-1 (MCP-1) responses to standardized mental stress. A secondary purpose was to evaluate whether individual variations in cortisol responses influenced the hypothesised relationship between loneliness and inflammation. Saliva samples and blood were taken from 524 healthy middle-aged men and women from the Whitehall II cohort at baseline, immediately after the stress tasks and 45min later. Loneliness was measured using the revised UCLA loneliness scale. Greater loneliness was associated with larger IL-6 (p=0.044) and IL-1Ra (p=0.006) responses to psychological stress and higher MCP-1 (ploneliness in women, with the odds of being a cortisol responder decreasing with increased loneliness independently of covariates (p=0.008). The impact of loneliness on health in women may be mediated in part through dysregulation of inflammatory and neuroendocrine systems.

  12. Cellular prion protein is expressed in a subset of neuroendocrine cells of the rat gastrointestinal tract. (United States)

    Marcos, Zuberoa; Pffeifer, Kristine; Bodegas, María E; Sesma, María P; Guembe, Laura


    Prion diseases are believed to develop from the conformational change of normal cellular prion protein (PrPc) to a pathogenic isoform (PrPsc). PrPc is present in both the central nervous system and many peripheral tissues, although protein concentration is significantly lower in non-neuronal tissues. PrPc expression is essential for internalization and replication of the infectious agent. Several works have pointed to the gastrointestinal (GI) tract as the principal site of entry of PrPsc, but how passage through the GI mucosa occurs is not yet known. Here we studied PrPc expression using Western blot, RT-PCR, and immunohistochemistry in rat GI tract. PrPc mRNA and protein were detected in corpus, antrum, duodenum, and colon. Immunoreactivity was found in scattered cells of the GI epithelium. With double immunofluorescence, these cells have been identified as neuroendocrine cells. PrPc immunostaining was found in subsets of histamine, somatostatin (Som), ghrelin, gastrin (G), and serotonin (5HT) cells in stomach. In small and large bowel, PrPc cells co-localized with subpopulations of 5HT-, Som-, G-, and peptide YY-immunolabeled cells. Our results provide evidence for a possible and important role of endocrine cells in the internalization of PrPsc from gut lumen.

  13. Resected Pancreatic Neuroendocrine Tumors: Patterns of Failure and Disease-Related Outcomes With or Without Radiotherapy

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    Zagar, Timothy M. [Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC (United States); White, Rebekah R. [Department of Surgery, Duke University Medical Center, Durham, NC (United States); Willett, Christopher G. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Tyler, Douglas S. [Department of Surgery, Duke University Medical Center, Durham, NC (United States); Papavassiliou, Paulie [Department of Pathology, Duke University Medical Center, Durham, NC (United States); Papalezova, Katia T. [Department of Surgery, Duke University Medical Center, Durham, NC (United States); Guy, Cynthia D. [Department of Pathology, Duke University Medical Center, Durham, NC (United States); Broadwater, Gloria [Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC (United States); Clough, Robert W. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Czito, Brian G., E-mail: [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States)


    Purpose: Pancreatic neuroendocrine tumors (NET) are rare and have better disease-related outcomes compared with pancreatic adenocarcinoma. Surgical resection remains the standard of care, although many patients present with locally advanced or metastatic disease. Little is known regarding the use of radiotherapy in the prevention of local recurrence after resection. To better define the role of radiotherapy, we performed an analysis of resected patients at our institution. Methods: Between 1994 and 2009, 33 patients with NET of the pancreatic head and neck underwent treatment with curative intent at Duke University Medical Center. Sixteen patients were treated with surgical resection alone while an additional 17 underwent resection with adjuvant or neoadjuvant radiation therapy, usually with concurrent fluoropyrimidine-based chemotherapy (CMT). Median radiation dose was 50.4 Gy and median follow-up 28 months. Results: Thirteen patients (39%) experienced treatment failure. Eleven of the initial failures were distant, one was local only and one was local and distant. Two-year overall survival was 77% for all patients. Two-year local control for all patients was 87%: 85% for the CMT group and 90% for the surgery alone group (p = 0.38). Two-year distant metastasis-free survival was 56% for all patients: 46% and 69% for the CMT and surgery patients, respectively (p = 0.10). Conclusions: The primary mode of failure is distant which often results in mortality, with local failure occurring much less commonly. The role of radiotherapy in the adjuvant management of NET remains unclear.

  14. 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.

  15. Struma ovarii with follicular thyroid-type carcinoma and neuroendocrine component: case report

    Directory of Open Access Journals (Sweden)

    Selvaggi Federico


    Full Text Available Abstract Struma ovarii (SO is a slow-growing ovarian neoplasm with thyroid tissue as its predominant component. It is an uncommon neoplasm, usually asymptomatic with an unknown risk of malignant transformation. Due to difficulties in assessing the rare biological nature and the discrepancies in the reported cases, a consensus on the appropriate treatment has not been definitively reached. A 50-year-old female was subjected to upper gut endoscopy which showed a 30-mm mass located in the gastric antrum, suggestive of mesenchimal tumor. Incidentally, a pelvic CT scan also documented a solid mass in the right adnexa, with morphological characteristics of ovarian neoplasm. The patient underwent gastrectomy, total hysterectomy, bilateral salpingo-oophorectomy with lymph node dissection, and omentectomy. Histology documented the presence of gastric cavernous angioma, and, in the right adnexa, foci of follicular thyroid-type carcinoma arising in SO with a well-differentiated neuroendocrine component. Here we report and discuss the clinical and morphological presentation of follicular thyroid-type carcinoma arising in SO. The neoplasm was discovered incidentally and had a favorable clinical outcome at 1-year follow-up.

  16. Capsaicin induces cytotoxicity in pancreatic neuroendocrine tumor cells via mitochondrial action. (United States)

    Skrzypski, M; Sassek, M; Abdelmessih, S; Mergler, S; Grötzinger, C; Metzke, D; Wojciechowicz, T; Nowak, K W; Strowski, M Z


    Capsaicin (CAP), the pungent ingredient of chili peppers, inhibits growth of various solid cancers via TRPV1 as well as TRPV1-independent mechanisms. Recently, we showed that TRPV1 regulates intracellular calcium level and chromogranin A secretion in pancreatic neuroendocrine tumor (NET) cells. In the present study, we characterize the role of the TRPV1 agonist - CAP - in controlling proliferation and apoptosis of pancreatic BON and QGP-1 NET cells. We demonstrate that CAP reduces viability and proliferation, and stimulates apoptotic death of NET cells. CAP causes mitochondrial membrane potential loss, inhibits ATP synthesis and reduces mitochondrial Bcl-2 protein production. In addition, CAP increases cytochrome c and cleaved caspase 3 levels in cytoplasm. CAP reduces reactive oxygen species (ROS) generation. The antioxidant N-acetyl-l-cysteine (NAC) acts synergistically with CAP to reduce ROS generation, without affecting CAP-induced toxicity. TRPV1 protein reduction by 75% reduction fails to attenuate CAP-induced cytotoxicity. In summary, these results suggest that CAP induces cytotoxicity by disturbing mitochondrial potential, and inhibits ATP synthesis in NET cells. Stimulation of ROS generation by CAP appears to be a secondary effect, not related to CAP-induced cytotoxicity. These results justify further evaluation of CAP in modulating pancreatic NETs in vivo.

  17. Neurotensin, a novel target of Wnt/β-catenin pathway, promotes growth of neuroendocrine tumor cells. (United States)

    Kim, Ji Tae; Liu, Chunming; Zaytseva, Yekaterina Y; Weiss, Heidi L; Townsend, Courtney M; Evers, B Mark


    Wnt/β-catenin signaling plays a pivotal role in regulating cell growth and differentiation by activation of the β-catenin/T-cell factor (TCF) complex and subsequent regulation of a set of target genes that have one or more TCF-binding elements (TBEs). Hyperactivation of this pathway has been implicated in numerous malignancies including human neuroendocrine tumors (NETs). Neurotensin (NT), an intestinal hormone, induces proliferation of several gastrointestinal (GI) cancers including cancers of the pancreas and colon. Here, we analyzed the human NT promoter in silico and found at least four consensus TBEs within the proximal promoter region. Using a combination of ChIP and luciferase reporter assays, we identified one TBE (located ∼900 bp proximal from the transcription start site) that was immunoprecipitated efficiently by TCF4-targeting antibody; mutation of this site attenuated the responsiveness to β-catenin. We also confirmed that the promoter activity and the mRNA and protein expression levels of NT were increased by various Wnt pathway activators and decreased by Wnt inhibitors in NET cell lines BON and QGP-1, which express and secrete NT. Similarly, the intracellular content and secretion of NT were induced by Wnt3a in these cells. Finally, inhibition of NT signaling suppressed cell proliferation and anchorage-independent growth and decreased expression levels of growth-related proteins in NET cells. Our results indicate that NT is a direct target of the Wnt/β-catenin pathway and may be a mediator for NET cell growth.

  18. TRPV6 modulates proliferation of human pancreatic neuroendocrine BON-1 tumour cells. (United States)

    Skrzypski, Marek; Kołodziejski, Paweł A; Mergler, Stefan; Khajavi, Noushafarin; Nowak, Krzysztof W; Strowski, Mathias Z


    Highly Ca(2+) permeable receptor potential channel vanilloid type 6 (TRPV6) modulates a variety of biological functions including calcium-dependent cell growth and apoptosis. So far, the role of TRPV6 in controlling growth of pancreatic neuroendocrine tumour (NET) cells is unknown. In the present study, we characterize the expression of TRPV6 in pancreatic BON-1 and QGP-1 NET cells. Furthermore, we evaluate the impact of TRPV6 on intracellular calcium, the activity of nuclear factor of activated T-cells (NFAT) and proliferation of BON-1 cells. TRPV6 expression was assessed by real-time PCR and Western blot. TRPV6 mRNA expression and protein production were down-regulated by siRNA. Changes in intracellular calcium levels were detected by fluorescence calcium imaging (fura-2/AM). NFAT activity was studied by NFAT reporter assay; cell proliferation by bromodeoxyuridine (BrdU), MTT and propidium iodine staining. TRPV6 mRNA and protein are present in BON-1 and QGP-1 NET-cells. Down-regulation of TRPV6 attenuates BON-1 cell proliferation. TRPV6 down-regulation is associated with decreased Ca(2+) response pattern and reduced NFAT activity. In conclusion, TRPV6 is expressed in pancreatic NETs and modulates cell proliferation via Ca(2+)-dependent mechanism, which is accompanied by NFAT activation.

  19. Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells. (United States)

    Veenstra, Marije J; van Koetsveld, Peter M; Dogan, Fadime; Farrell, William E; Feelders, Richard A; Lamberts, Steven W J; de Herder, Wouter W; Vitale, Giovanni; Hofland, Leo J


    Somatostatin receptors are a pivotal target for treatment of pancreatic neuroendocrine tumors (pNET), either with somatostatin analogues (SSA) or radiolabeled SSA. The highest affinity target for the most commonly used SSA is the somatostatin receptor type 2 (sst2). An important factor that may complicate treatment efficacy, is the variable number of receptors expressed on pNETs. Gene expression is subject to complex regulation, in which epigenetics has a central role. In this study we explored the possible role of epigenetic modifications in the variations in sst2 expression levels in two human pNET cell lines, BON-1 and QGP-1. We found upregulation of sst2 mRNA after treatment with the epidrugs 5-aza-2'-deoxycytidine (5-aza-dC) and valproic acid (VPA), an increased uptake of radiolabeled octreotide, as well as increased sensitivity to the SSA octreotide in functional cAMP inhibition. At epigenetic level we observed low methylation levels of the sst2 gene promoter region irrespective of expression. Activating histone mark H3K9Ac can be regulated with epidrug treatment, with an angle of effect corresponding to the effect on mRNA expression. Repressive histone mark H3K27me3 is not regulated by either 5-aza-dC or VPA. We conclude that epidrug treatment, in particular with combined 5-aza-dC and VPA treatment, might hold promise for improving and adding to current SSA treatment strategies of patients with pNETs.

  20. Rab Proteins and the Secretory Pathway: The Case of Rab18 in Neuroendocrine Cells

    Directory of Open Access Journals (Sweden)



    Full Text Available The secretory pathway is a process characteristic of cells specialized in secretion such as endocrine cells and neurons. It consists of different stages that are dependent on specific transport of proteins in vesicular-tubular carriers. Biochemical analyses have unveiled a number of protein families that confer identity to carrier vesicles and specificity to their transport. Among them is the family of Rab proteins, Ras-like small GTPases that anchor to the surface of transport vesicles and participate in vesicle formation from the donor compartment, transport along cytoskeletal tracks, and docking and fusion with the acceptor compartment. All of these functions are accomplished through the recruitment of effector proteins, such as sorting adaptors, tethering factors, kinases, phosphatases and motors. The numerous Rab proteins have distinct subcellular distributions throughout the endomembrane system, which ensures efficient cargo transfer. Rab proteins act as molecular switches that alternate between a cytosolic GDP-bound, inactive form and a membrane-associated GTP-bound, active conformation. Cycling between inactive and active states is a highly regulated process that enables Rabs to confer spatio-temporal precision to the different stages through which a vesicle passes during its lifespan. This review focuses on our current knowledge on Rab functioning, from their structural features to the multiple regulatory proteins and effectors that control Rab activity and translate Rab function. Furthermore, we also summarize the information available on a particular Rab protein, Rab18, which has been linked to the control of secretory granule traffic in neuroendocrine cells.

  1. ⁶⁸Ga-DOTA-TOC-PET/CT detects heart metastases from ileal neuroendocrine tumors. (United States)

    Calissendorff, Jan; Sundin, Anders; Falhammar, Henrik


    Metastases from ileal neuroendocrine tumors (NETs) to the myocardium are rare and generally seen in patients with widespread metastatic NET disease. The objectives of this investigation were to describe the frequency of intracardiac metastases in ileal NET patients examined by (68)Ga-DOTA-TOC-PET/CT and to describe the cases in detail. All (68)Ga-DOTA-TOC-PET/CT examinations performed at the Karolinska University Hospital since 2010 until April 2012 were reviewed. In all, 128 out of 337 examinations were in patients with ileal NETs. Four patients had seven myocardiac metastases, yielding a frequency of 4.3 % in patients with ileal NETs. One patient had cardiac surgery while three were treated with somatostatin analogs. The cardiac metastases did not affect the patients' activity of daily life. (68)Ga-DOTA-TOC-PET/CT is an established imaging modality in identifying cardiac metastases in ileal NETs. Prospective studies are needed to confirm the true clinical value of (68)Ga-DOTA-TOC-PET/CT in detecting cardiac metastases in both ileal and non-ileal NETs.

  2. Carcinoid syndrome, acromegaly, and hypoglycemia due to an insulin-secreting neuroendocrine tumor of the liver. (United States)

    Furrer, J; Hättenschwiler, A; Komminoth, P; Pfammatter, T; Wiesli, P


    We report a patient with a hepatic neuroendocrine tumor showing an extraordinary change of the tumor's humoral manifestations from a clinically documented extrapituitary acromegaly and a typical carcinoid syndrome toward a hyperinsulinemic hypoglycemia syndrome. At the primary manifestation of the tumor, an increased serum level of insulin-like growth factor I due to overproduction of GHRH and an increased urinary excretion of 5-hydroxyindoleacetic acid were found. The clinical manifestation of the GHRH excess was an arthralgia, which resolved completely after operative tumor debulking and normalization of insulin-like growth factor I and GHRH serum levels. The secretion of serotonin from the tumor resulted in a typical carcinoid syndrome including right-sided valvular heart disease. On the later course of the disease, the humoral manifestations of the tumor were supplemented by the secretion of insulin, leading to recurrent severe hyperinsulinemic hypoglycemia. The hepatic origin of hyperinsulinism was demonstrated by selective arterial calcium stimulation. Moreover, tumor cells revealed insulin and C-peptide immunoreactivity in the immunohistochemical analysis. The patient died 8 yr after the initial diagnosis of the tumor, and a carefully performed autopsy procedure confirmed the absence of any extrahepatic tumor manifestation.

  3. A case of neuroendocrine tumor G1 with unique histopathological growth progress

    Institute of Scientific and Technical Information of China (English)

    Misuzu; Hirai; Kenshi; Matsumoto; Hiroya; Ueyama; Hirohumi; Fukushima; Takashi; Murakami; Hitoshi; Sasaki; Akihito; Nagahara; Takashi; Yao; Sumio; Watanabe


    A gastric neuroendocrine tumor(NET)is generated from deep within the tissue mucosal layers.In many cases,NETs are discovered as submucosal tumor(SMT)-like structures by forming a tumor mass.This case has a clear mucosal demarcation line and developed like a polyp.A dilated blood vessel was found on the surface.The mass lacked the yellow color characteristic of NETs,and a SMT-like form was evident.Therefore,a nonspecific epithelial lesion was suspected and we performed endoscopy with magnifying narrowband imaging(M-NBI).However,this approach did not lead to the diagnosis,as we diagnosed the lesion as a NET by biopsy examination.The lesion was excised by endoscopic submucosal dissection.The histopathological examination proved that the lesion was a polypoid lesion although it was also a NET because the tumorcells extended upward through the normal gland ducts scatteredly.To our knowledge,there is no previous report of NET G1 with such unique histopathological growth progress and macroscopic appearance shown by detailed examination using endoscopy with M-NBI.

  4. Pancreatic neuroendocrine tumor and solid-pseudopapillary neoplasm: Key immunohistochemical profiles for differential diagnosis (United States)

    Ohara, Yusuke; Oda, Tatsuya; Hashimoto, Shinji; Akashi, Yoshimasa; Miyamoto, Ryoichi; Enomoto, Tsuyoshi; Satomi, Kaishi; Morishita, Yukio; Ohkohchi, Nobuhiro


    AIM To reveal better diagnostic markers for differentiating neuroendocrine tumor (NET) from solid-pseudopapillary neoplasm (SPN), focusing primarily on immunohistochemical analysis. METHODS We reviewed 30 pancreatic surgical specimens of NET (24 cases) and SPN (6 cases). We carried out comprehensive immunohistochemical profiling using 9 markers: Synaptophysin, chromogranin A, pan-cytokeratin, E-cadherin, progesterone receptor, vimentin, α-1-antitrypsin, CD10, and β-catenin. RESULTS E-cadherin staining in NETs, and nuclear labeling of β-catenin in SPNs were the most sensitive and specific markers. Dot-like staining of chromogranin A might indicate the possibility of SPNs rather than NETs. The other six markers were not useful because their expression overlapped widely between NETs and SPNs. Moreover, two cases that had been initially diagnosed as NETs on the basis of their morphological features, demonstrated SPN-like immunohistochemical profiles. Careful diagnosis is crucial as we actually found two confusing cases showing disagreement between the tumor morphology and immunohistochemical profiles. CONCLUSION E-cadherin, chromogranin A, and β-catenin were the most useful markers which should be employed for differentiating between NET and SPN.

  5. Synchronous Peripancreatic Lymph Node Gastrinoma and Gastric Neuroendocrine Tumor Type 2 (United States)

    Lee, Hee Woo; Chung, Jun-Won; Kim, Yoon Jae; Kwon, Kwang Ahn; Kim, Eui Joo; Kim, Keon Kuk; Lee, Woon Ki; Sym, Sun Jin


    A 34-year-old man was referred to our hospital with gastric polypoid lesions and biopsy-confirmed neuroendocrine tumor (NET). Computed tomography (CT) revealed a 3×3.5×8-cm retroperitoneal mass behind the pancreas, with multiple hepatic metastases. His serum gastrin level was elevated to 1,396 pg/mL. We performed a wedge resection of the stomach, a right hemi-hepatectomy, and a retroperitoneal mass excision. After careful review of the clinical, radiological, histopathological, and immunohistochemical findings, peripancreatic gastrinoma, and synchronous gastric NET were ultimately diagnosed. We reviewed a CT scan that had been performed 6 years previously after surgery for a duodenal perforation. There was no evidence of gastric or hepatic lesions, but the retroperitoneal mass was present at the same site. Had gastrinoma been detected earlier, our patient could have been cured using less invasive treatment. This case demonstrates how important it is to consider Zollinger-Ellison syndrome in patients with a recurrent or aggressive ulcer. PMID:27209642

  6. Prognostic Impact of DNA-Image-Cytometry in Neuroendocrine (Carcinoid Tumours

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    H. Raatz


    Full Text Available Establishing prognosis proves particularly difficult with neuroendocrine tumours (NETs as a benign looking histology can be associated with a malignant behaviour. In order to identify prognostic factors we examined 44 gastrointestinal and pulmonary, paraffin‐embedded NETs histologically and immunohistochemically. DNA‐image‐cytometry was used to examine 40 of these. We found that poor differentiation (corresponding to a Soga and Tazawa type D and infiltrative growth correlated with a poorer prognosis. Moreover, parameters determined by diagnostic DNA cytometry like the 5c‐exceeding rate, the 2c‐deviation index, DNA‐grade of malignancy, DNA‐entropy and the type of DNA histogram were found to be of prognostic relevance. Morphometric parameters like the form factor and the mean nuclear area were relevant for survival, tumour recurrence and metastasis. However, in the multivariate analysis the only independent risk factor was the histological differentiation. The 5c‐exceeding rate is a good objective risk factor, which can be used particularly in cases in which only a fine needle biopsie is available. Direct comparison of the histology and the 5c‐exceeding rate in the multivariate analysis suggests that the 5c‐exceeding rate taken as sole prognostic factor might be of higher prognostic relevance than the histology but larger studies are needed to confirm this.

  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. Stathmin in pancreatic neuroendocrine neoplasms: a marker of proliferation and PI3K signaling. (United States)

    Schimmack, Simon; Taylor, Andrew; Lawrence, Ben; Schmitz-Winnenthal, Hubertus; Fischer, Lars; Büchler, Markus W; Modlin, Irvin M; Kidd, Mark; Tang, Laura H


    Chromosome 1p35-36, which encodes tumor suppressors and mitotic checkpoint control genes, is commonly altered in human malignancies. One gene at this locus, stathmin 1 (STMN1), is involved in cell cycle progression and metastasis. We hypothesized that increased STMN1 expression may play a role in pancreatic neuroendocrine neoplasm (pNEN) malignancy. We investigated stathmin copy number variation, mRNA, and protein expression using PCR-Taqman Copy Number Assays, Q-PCR, Western blot, and immunohistochemistry. A mechanistic role for stathmin in proliferation was assessed in the BON cell line under growth-restrictive conditions and siRNA silencing. Furthermore, its role in PI3K signaling pathway activation was evaluated using pharmacological inhibitors. mRNA (p = 0.0001) and protein (p stathmin inactivation (dephosphorylation p stathmin was overexpressed and associated with pathological parameters in pancreatic NENs. We postulate that STMN1 overexpression and phosphorylation result in a loss of cell cycle mitotic checkpoint control and may render tumors amenable to PI3K inhibitory therapy.

  9. MR imaging features and staging of neuroendocrine carcinomas of the uterine cervix with pathological correlations

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    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.)

  10. Modeling neuroendocrine stress reactivity in salivary cortisol: adjusting for peak latency variability. (United States)

    Lopez-Duran, Nestor L; Mayer, Stefanie E; Abelson, James L


    In this report, we present growth curve modeling (GCM) with landmark registration as an alternative statistical approach for the analysis of time series cortisol data. This approach addresses an often-ignored but critical source of variability in salivary cortisol analyses: individual and group differences in the time latency of post-stress peak concentrations. It allows for the simultaneous examination of cortisol changes before and after the peak while controlling for timing differences, and thus provides additional information that can help elucidate group differences in the underlying biological processes (e.g., intensity of response, regulatory capacity). We tested whether GCM with landmark registration is more sensitive than traditional statistical approaches (e.g., repeated measures ANOVA--rANOVA) in identifying sex differences in salivary cortisol responses to a psychosocial stressor (Trier Social Stress Test--TSST) in healthy adults (mean age 23). We used plasma ACTH measures as our "standard" and show that the new approach confirms in salivary cortisol the ACTH finding that males had longer peak latencies, higher post-stress peaks but a more intense post-peak decline. This finding would have been missed if only saliva cortisol was available and only more traditional analytic methods were used. This new approach may provide neuroendocrine researchers with a highly sensitive complementary tool to examine the dynamics of the cortisol response in a way that reduces risk of false negative findings when blood samples are not feasible.

  11. Dynamics of neuroendocrine stress response: bistability, timing, and control of hypocortisolism (United States)

    D'Orsogna, Maria; Chou, Tom; Kim, Lae

    The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system that regulates numerous physiological processes. Disruptions in its activity are correlated with stress-related diseases such as post-traumatic stress disorder (PTSD) and major depressive disorder. We characterize ``normal'' and ``diseased'' states of the HPA axis as basins of attraction of a dynamical system describing the inhibition of peptide hormones, corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH), by circulating glucocorticoids such as cortisol (CORT). Our model includes ultradian oscillations, CRH self-upregulation of CRH release, and distinguishes two components of negative feedback by cortisol on circulating CRH levels: a slow direct suppression of CRH synthesis and a fast indirect effect on CRH release. The slow regulation mechanism mediates external stress-driven transitions between the stable states in novel, intensity, duration, and timing-dependent ways. We find that the timing of traumatic events may be an important factor in determining if and how the hallmarks of depressive disorders will manifest. Our model also suggests a mechanism whereby exposure therapy of stress disorders may act to normalize downstream dysregulation of the HPA axis.

  12. Ectopic adrenocorticotropic hormone syndrome caused by neuroendocrine carcinoma of the colon. (United States)

    Fujimoto, Kazuyo; Nakashima, Takatoshi; Sasaki, Kazunari; Hayashi, Kenichi; Hanafusa, Masao; Yoshida, Shiei; Myojo, Satoshi; Yoshida, Shun-Ichi; Sawai, Shigeaki; Sano, Nobuya

    A 48-year-old woman with a history of autoimmune hemolytic anemia and taking long-term corticosteroid therapy presented with a 3-month history of general fatigue, abdominal distension, and pigmentation. A computed tomography scan of the abdomen showed a tumor in the sigmoid colon and multiple metastatic nodules in the liver. A colonoscopy revealed an obstructing mass with the presence of an irregular ulcer in the sigmoid colon. Following biopsy and histopathological analysis, the patient was diagnosed with neuroendocrine carcinoma (NEC) of the colon. She received her first cycle of chemotherapy, with carboplatin and etoposide. During hospitalization, her pigmentation and hypertension worsened and hypokalemia was observed, all of which suggsted Cushing's syndrome. Her plasma adrenocorticotropic hormone (ACTH) and cortisol levels were high, and an ectopic ACTH-producing tumor was suspected. After a second chemotherapy cycle, she developed neutropenic fever and subsequently died. At autopsy, two histological types were found in the tumor: small cell carcinoma and large cell NEC. Immunohistochemical analysis revealed ACTH in the large cell NEC. This is the first reported case of an ectopic ACTH syndrome caused by NEC of the colon.

  13. Prolonged clinical benefit of everolimus therapy in the management of high-grade pancreatic neuroendocrine carcinoma. (United States)

    Fonseca, Paula J; Uriol, Esther; Galván, José A; Alvarez, Carlos; Pérez, Quionia; Villanueva, Noemi; Berros, José P; Izquierdo, Marta; Viéitez, José M


    Treatment options for patients with high-grade pancreatic neuroendocrine tumors (pNET) are limited, especially for those with progressive disease and for those who experience treatment failure. Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has been approved for the treatment of patients with low- or intermediate-grade advanced pNET. In the randomized phase III RADIANT-3 study in patients with low- or intermediate-grade advanced pNET, everolimus significantly increased progression-free survival (PFS) and decreased the relative risk for disease progression by 65% over placebo. This case report describes a heavily pretreated patient with high-grade pNET and liver and peritoneal metastases who achieved prolonged PFS, clinically relevant partial radiologic tumor response, and resolution of constitutional symptoms with improvement in Karnofsky performance status while receiving a combination of everolimus and octreotide long-acting repeatable (LAR). Radiologic and clinical responses were maintained for 19 months, with minimal toxicity over the course of treatment. This case supports the findings that the combination of everolimus plus octreotide LAR may be considered for use in patients with high-grade pNET and progressive disease. Although behavior and aggressiveness are different between low- or intermediate-grade and high-grade pNET, some high-grade pNET may express mTOR; hence, everolimus should be considered in a clinical trial.

  14. Prolonged Clinical Benefit of Everolimus Therapy in the Management of High-Grade Pancreatic Neuroendocrine Carcinoma

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    Paula J. Fonseca


    Full Text Available Treatment options for patients with high-grade pancreatic neuroendocrine tumors (pNET are limited, especially for those with progressive disease and for those who experience treatment failure. Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR, has been approved for the treatment of patients with low- or intermediate-grade advanced pNET. In the randomized phase III RADIANT-3 study in patients with low- or intermediate-grade advanced pNET, everolimus significantly increased progression-free survival (PFS and decreased the relative risk for disease progression by 65% over placebo. This case report describes a heavily pretreated patient with high-grade pNET and liver and peritoneal metastases who achieved prolonged PFS, clinically relevant partial radiologic tumor response, and resolution of constitutional symptoms with improvement in Karnofsky performance status while receiving a combination of everolimus and octreotide long-acting repeatable (LAR. Radiologic and clinical responses were maintained for 19 months, with minimal toxicity over the course of treatment. This case supports the findings that the combination of everolimus plus octreotide LAR may be considered for use in patients with high-grade pNET and progressive disease. Although behavior and aggressiveness are different between low- or intermediate-grade and high-grade pNET, some high-grade pNET may express mTOR; hence, everolimus should be considered in a clinical trial.

  15. Are neuroendocrine tumours a feature of tuberous sclerosis? A systematic review. (United States)

    Dworakowska, Dorota; Grossman, Ashley B


    Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterised by the development of multiple hamartomas in numerous organs. It is caused by mutations of two tumour suppressor genes, TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13.3, which encode for hamartin and tuberin respectively. The interaction between these two proteins, the tuberin-hamartin complex, has been shown to be critical to multiple intracellular signalling pathways, especially those controlling cell growth and proliferation. TSC may affect skin, central nervous system, kidneys, heart, eyes, blood vessels, lung, bone and gastrointestinal tract. Small series and case reports have documented that in tuberous sclerosis patients many endocrine system alterations might occur, affecting the function of the pituitary, parathyroid and other neuroendocrine tissue. There have been scattered reports of the involvement of such tissue in the pathological process of TSC, but no systematic review as to whether this is a true association. We have therefore systematically assessed all available published literature in this area. We conclude that there may be an association with pituitary and parathyroid tumours, and two recent descriptions of Cushing's disease are especially intriguing. However, the evidence seems more firm in the case of islet cell tumours, particularly insulinomas. As these latter may cause changes in mental state that may be confused with the cerebral manifestations of TSC per se, it is particularly important for physicians working with these patients to be aware of the putative and indeed likely association.

  16. Expression of O(6)-methylguanine DNA methyltransferase (MGMT) and its clinical significance in gastroenteropancreatic neuroendocrine neoplasm. (United States)

    Yang, Qiu-Chen; Wang, Yu-Hong; Lin, Yuan; Xue, Ling; Chen, Yuan-Jia; Chen, Min-Hu; Chen, Jie


    O(6)-methylguanine-DNA methyltransferase (MGMT) is a widespread DNA repair enzyme defending against mutation caused by guanine O(6)-alkylating agents. Until now, we know only little about the expression of MGMT in gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN). To study the expression of MGMT and its clinical significance in GEP-NEN, 174 specimens of GEP-NEN were examined, of which 152 specimens came from The First Affiliated Hospital, Sun Yat-sen University during October 1995 to November 2013, 22 specimens came from Peking Union Medical College Hospital during September 2004 to April 2010. MGMT protein was detected with EnVision immunohistochemical staining method. Clinicopathological factors were also collected and analyzed. We observed that the overall expression rate of MGMT was 83.9%. Over expression of MGMT protein was not associated with sex, age, functional status, primary tumor location, grading, classification, TNM stage and metastasis (P > 0.05). Kaplan-Meier analysis revealed that there was no significant difference in survival between MGMT-positive and MGMT-negative tumors of GEP-NEN patients (χ(2) = 0.887, P = 0.346). In multivariate analyses carried out by Cox proportional hazards regression model, MGMT expression was also not an independent predictors of survival. These results demonstrated that MGMT protein was highly expressed in GEP-NEN. MGMT deficiency rate was similar in pancreatic NEN and in gastrointestinal NEN. MGMT expression was not correlated with prognosis of GEP-NEN.

  17. Neuroendocrine and behavioral effects of embryonic exposure to endocrine disrupting chemicals in birds. (United States)

    Ottinger, Mary Ann; Lavoie, Emma; Thompson, Nichola; Barton, Ashley; Whitehouse, Kasen; Barton, Meredith; Abdelnabi, Mahmoud; Quinn, Michael; Panzica, GianCarlo; Viglietti-Panzica, Carla


    Endocrine disrupting chemicals (EDCs) exert hormone-like activity in vertebrates and exposure to these compounds may induce both short- and long-term deleterious effects including functional alterations that contribute to decreased reproduction and fitness. An overview of the effects of a number of EDCs, including androgenic and estrogenic compounds, will be considered. Many studies have been conducted in the precocial Japanese quail, which provides an excellent avian model for testing these compounds. Long-term impacts have also been studied by raising a subset of animals through maturation. The EDCs examined included estradiol, androgen active compounds, soy phytoestrogens, and atrazine. Effects on behavior and hypothalamic neuroendocrine systems were examined. All EDCs impaired reproduction, regardless of potential mechanism of action. Male sexual behavior proved to be a sensitive index of EDC exposure and embryonic exposure to a variety of EDCs consistently resulted in impaired male sexual behavior. Several hypothalamic neural systems proved to be EDC responsive, including arginine vasotocin (VT), catecholamines, and gonadotropin releasing hormone system (GnRH-I). Finally, EDCs are known to impact both the immune and thyroid systems; these effects are significant for assessing the overall impact of EDCs on the fitness of avian populations. Therefore, exposure to EDCs during embryonic development has consequences beyond impaired function of the reproductive axis. In conclusion, behavioral alterations have the advantage of revealing both direct and indirect effects of exposure to an EDC and in some cases can provide a valuable clue into functional deficits at different physiological levels.

  18. Trends of Incidence and Survival of Gastrointestinal Neuroendocrine Tumors in the United States: A Seer Analysis

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    Vassiliki L. Tsikitis, Betsy C. Wertheim, Marlon A. Guerrero


    Full Text Available OBJECTIVES: To examine trends in detection and survival of hollow viscus gastrointestinal neuroendocrine tumors (NETs across time and geographic regions of the U.S.METHODS: We used the Surveillance, Epidemiology and End Results (SEER database to investigate 19,669 individuals with newly diagnosed gastrointestinal NETs. Trends in incidence were tested using Poisson regression. Cox proportional hazards regression was used to examine survival.RESULTS: Incidence increased over time for NETs of all gastrointestinal sites (all P < 0.001, except appendix. Rates have risen faster for NETs of the small intestine and rectum than stomach and colon. Rectal NETs were detected at a faster pace among blacks than whites (P < 0.001 and slower in the East than other regions (P < 0.001. We observed that appendiceal and rectal NETs carry the best prognosis and survival of small intestinal and colon NETs has improved for both men and women. Colon NETs showed different temporal trends in survival according to geographic region (Pinteraction = 0.028. Improved prognosis was more consistent across the country for small intestinal NETs.CONCLUSIONS: Incidence of gastrointestinal NETs has increased, accompanied by inconsistently improved survival for different anatomic sites among certain groups defined by race and geographic region.

  19. Two patients with a neuroendocrine tumour of the small intestine and paraneoplastic myasthenia gravis (United States)

    Hermans, M A W; Stelten, B M L; Haak, H R; de Herder, W W; Dercksen, M W


    Summary This paper reports on two patients with a long-standing diagnosis of an ENETS stage IV neuroendocrine tumour (NET) of the small intestine who developed neurological symptoms. The first patient only had bulbar symptoms and tested positive for acetylcholine receptor antibodies. The second patient had more classical symptoms of fatigable diplopia and muscle weakness of the legs, but no detectable antibodies. The diagnosis of paraneoplastical myasthenia gravis (MG) was postulated. Both patients were treated with pyridostigmine for MG and octreotide for the NETs. Interestingly, treatment of the NETs resulted in improvement of myasthenic symptoms. Paraneoplastic MG has been described to occur with certain malignancies, mainly thymoma. Herein, we prove that the association with gastrointestinal NETs, however, rare, is also one to be considered by clinicians dealing with either of these diseases. The pathogenesis has yet to be elucidated. Learning points NETs are rare malignancies with a wide variety of symptoms.Paraneoplastic MG can occur with various types of malignancies.Herein, we provide evidence of paraneoplastic MG in association with a grade IV NET of the small intestine.Treatment of the NETs resulted in remission of myasthenic symptoms in one patient. PMID:24839548

  20. Solid neuroendocrine breast carcinoma: mammographic and sonographic features in thirteen cases

    Institute of Scientific and Technical Information of China (English)

    Jing Wu; Rong Zhang; Qiu-Xia Yang; Yao-Pan Wu; De-Ling Wang; Xue-Wen Liu; Chun-Yan Cui; Ling Wang; Yao Chen; Chuan-Miao Xie


    This study aimed to determine and quantitate the mammographic and sonographic characteristics in 13 cases of solid neuroendocrine breast carcinoma (NEBC) and to analyze the association of radiological findings with the clinical and histopathologic findings.The clinical data and imaging findings of 13 female patients with histologically confirmed solid NEBC were reviewed.Imaging data were evaluated by two radiologists for a consensual diagnosis.All patients presented with one palpable mass; only 1 experienced occasional breast pain,and 5 complained of fluid discharge.In 7 patients,the masses were firm and mobile.Regional lymph node metastasis was noted in only 1 patient.For the 10 patients who underwent mammography,6 had a mass,1 had clustered small nodules with clustered punctuate microcalcifications,2 had asymmetric focal density,and 1 had solitary punctuate calcification.Most of the masses had irregular shape with indistinct or microlobulated margins.For the 9 patients who underwent ultrasonography (US),9 masses were depicted,all of which were hypoechoic,mostly with irregular shape and without acoustic phenomena.Different types of acoustic phenomena were also identified.One patient had developed distant metastases during follow-up.NEBC has a variety of presentations,but it is mostly observed on mammograms as a dense,irregular mass with indistinct or microlobulated margins.Sonographically,it typically presents as an irregular,heterogeneously hypoechoic mass with normal sound transmission.Histories of nipple discharge and calcification observed using imaging are not rare.

  1. Trait Mindfulness Modulates Neuroendocrine and Affective Responses to Social Evaluative Threat (United States)

    Brown, Kirk Warren; Weinstein, Netta; Creswell, J. David


    Background Individual differences in mindfulness have been associated with numerous self-report indicators of stress, but research has not examined how mindfulness may buffer neuroendocrine and psychological stress responses under controlled laboratory conditions. The present study investigated the role of trait mindfulness in buffering cortisol and affective responses to a social evaluative stress challenge versus a control task. Methods Participants completed measures of trait mindfulness, perceived stress, anxiety, and fear of negative evaluation before being randomized to complete the Trier Social Stress Test (TSST; Kirschbaum et al., 1993) or a control task. At points throughout the session, participants provided five saliva samples to assess cortisol response patterns, and completed four self-report measures of anxiety and negative affect to assess psychological responses. Results In accord with hypotheses, higher trait mindfulness predicted lower cortisol responses to the TSST, relative to the control task, as well as lower anxiety and negative affect. These relations remained significant when controlling for the role of other variables that predicted cortisol and affective responses. Conclusions The findings suggest that trait mindfulness modulates cortisol and affective responses to an acute social stressor. Further research is needed to understand the neural pathways through which mindfulness impacts these responses. PMID:22626868

  2. Comparison of methods for proliferative index analysis for grading pancreatic well-differentiated neuroendocrine tumors. (United States)

    Goodell, Pamela P; Krasinskas, Alyssa M; Davison, Jon M; Hartman, Douglas J


    Assessment of proliferative activity is required for grading well-differentiated pancreatic neuroendocrine tumors. However, a standardized method for obtaining the Ki-67 proliferative index is lacking. This study compared proliferative activity obtained by 3 methods: single-field hot spot (Ki-67 HS) and 10 consecutive field average (Ki-67 CFA) using the Ventana image analysis system (Ventana Medical Systems, Tucson, AZ) and mitotic index (MI). These methods resulted in discrepant grades in 30 (67%) of our 45 cases. With the current Ki-67 cutoff of more than 2% for intermediate-grade tumors, MI, CFA, and HS resulted in specificities of 91%, 94%, and 31%, respectively, for detecting metastasis, with positive predictive values (PPVs) of 25%, 67%, and 31%, respectively. At a higher Ki-67 cutoff of 7.5%, HS analysis resulted in a specificity of 94% and PPV of 71% for predicting metastasis. While single-field HS analysis may be practical and reliable at a higher cutoff, this study emphasizes the variability that can exist when different methods of assessment are used.

  3. 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.

  4. Metabolic syndrome: psychosocial, neuroendocrine, and classical risk factors in type 2 diabetes. (United States)

    Abraham, N G; Brunner, E J; Eriksson, J W; Robertson, R P


    This article summarizes some aspects of stress in the metabolic syndrome at the psychosocial, tissue, and cellular levels. The metabolic syndrome is a valuable research concept for studying population health and social-biological translation. The cluster of cardiovascular risk factors labeled the metabolic syndrome is linked with low socioeconomic status. Systematic differences in diet and physical activity contribute to social patterning of the syndrome. In addition, psychosocial factors including chronic work stress are linked with its development. Psychosocial factors could lead to metabolic perturbations and increase cardiovascular risk via activation of neuroendocrine responses, for example, in the autonomic nervous system and in several hormonal pathways. High glucocorticoid levels will promote lipid storage in visceral rather than subcutaneous adipose tissue. Adipocytes secrete several proinflammatory cytokines, which considered major contributors to increase in oxidants and cell injury. Upregulation of heme oxygenase 1 (HO-1) and peroxidase in the early development of diabetes produces a decrease in oxidative-mediated injury. Increased HO activity is associated with a significant decrease in superoxide, endothelial cell shedding and blood pressure. Finally, it is proposed that overexpression of glutathione peroxidase in beta cells may protect beta cell deterioration from oxidative stress during development of diabetes and hyperglycemia and this may result in attenuation of beta cell failure. If this proves to be the case, then the scene will be set to develop glutathione peroxidase mimetics for use in preclinical and clinical trials.

  5. Expression of squamous cell carcinoma markers and adenocarcinoma markers in primary pulmonary neuroendocrine carcinomas. (United States)

    Masai, Kyohei; Tsuta, Koji; Kawago, Mitsumasa; Tatsumori, Takahiro; Kinno, Tomoaki; Taniyama, Tomoko; Yoshida, Akihiko; Asamura, Hisao; Tsuda, Hitoshi


    Recent clinical trials have revealed that accurate histologic typing of non-small cell lung cancer is essential. Until now, squamous cell carcinoma (SQC) and adenocarcinoma (ADC) markers have not been thoroughly analyzed for pulmonary neuroendocrine carcinomas (NECs). We analyzed the expression of 8 markers [p63, cytokeratin (CK) 5/6, SOX2, CK7, desmocollin 3, thyroid transcription factor-1 (8G7G3/1 and SPT24), and napsin A] in 224 NECs. SOX2 (76.2%) had the greatest expression for NECs. CK5/6 (1.4%), desmocollin 3 (0.5%), and napsin A (0%) were expressed less or not at all in NECs. Although our investigated markers have been reported useful for differentiating between SQC and ADC, some of them were also present in a portion of pulmonary NECs. In our study, CK5/6 and desmocollin 3 were highly specific markers for SQC, and napsin A was highly specific for ADC. These markers are recommended for diagnosis of poorly differentiated non-small cell lung cancer.

  6. Hypervascular solid-appearing serous cystic neoplasms of the pancreas: Differential diagnosis with neuroendocrine tumours

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    Park, Hye Sun; Kim, So Yeon; Park, Seong Ho; Lee, Seung Soo; Byun, Jae Ho; Kim, Jin Hee; Kim, Hyoung Jung; Lee, Moon-Gyu [University of Ulsan College of Medicine, Asan Medical Center, Department of Radiology and Research Institute of Radiology, Seoul (Korea, Republic of); Hong, Seung-Mo [University of Ulsan College of Medicine, Asan Medical Center, Department of Pathology, Seoul (Korea, Republic of)


    To describe imaging findings of arterial hypervascular solid-appearing serous cystic neoplasms (SCNs) of the pancreas on CT and MR and determine imaging features differentiating them from neuroendocrine tumours (NETs). We retrospectively identified 15 arterial hypervascular solid-appearing SCNs and randomly chose 30 size-matched pancreatic NETs. On CT, two radiologists in consensus assessed the size, morphology, and CT attenuation. On MR, predominant signal intensity and the amount of the cystic component on T2-weighted images and ADC maps were evaluated and compared using Fisher's exact and Student's t-test. The mean SCN size was 2.6 cm (range, 0.8-8.3). The CT findings were similar between the two tumours: location, shape, margin, and enhancement pattern. SCNs were significantly more hypodense on non-enhanced CT images than NETs (P =.03). They differed significantly on MR: bright signal intensity (P =.01) and more than a 10 % cystic component on T2-weighted images (P =.01) were more common in SCNs than in NETs. All SCNs showed a non-restrictive pattern on the ADC map, while NETs showed diffusion restriction (P <.01). Arterial hypervascular solid-appearing SCNs and NETs share similar imaging features. Non-enhanced CT and MR images with T2-weighted images and ADC maps can facilitate the differentiation. (orig.)

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

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    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.

  8. Use of PET in neuroendocrine tumors. In vivo applications and in vitro studies. (United States)

    Eriksson, B; Bergström, M; Orlefors, H; Sundin, A; Oberg, K; Långström, B


    Positron emission tomography (PET) performed with various radiolabelled compounds facilitates the study of tumor biochemistry. If the tumor uptake of an administered tracer is greater than that of surrounding normal tissue, it is also possible to localize the tumor. In initial studies, 18F-labeled deoxyglucose (FDG) was attempted to visualize the tumors, since this tracer had been successfully used in oncology, reflecting increased glucose metabolism in cancerous tissue. However, this tracer was not to any significant degree taken up by the neuroendocrine tumors. Instead, the serotonin precursor 5-hydroxytryptophan (5-HTP) labeled with 11C was used and showed an increased uptake and irreversible trapping of this tracer in carcinoid tumors. The uptake was selective and the resolution so high that we could detect more liver and lymph node metastases with PET than with CT or octreotide scintigraphy. One problem was, however, the high renal excretion of the tracer producing streaky artifacts in the area of interest. Using the decarboxylase inhibitor carbidopa, given as peroral premedication, the renal excretion decreased 6-fold and at the same time the tumor uptake increased 3-fold, hence improving the visualization of the tumors. When patients were followed during treatment with PET using 5-HTP as a tracer, a > 95% correlation between changes in urinary 5-hydroxyindoleacetic acid (U-5-HIAA) and changes in the transport rate constant for 5-HTP was observed. Thus, PET can be used to monitor treatment effects. Elevation of U-5-HIAA is considered to be uncommon in endocrine pancreatic tumors (EPTs). Initially, 11C-labeled L-DOPA was attempted as another amine important in the APUD system. With L-DOPA about half of the EPTs, mainly functioning tumors, could be detected. Recently, 5-HTP was explored as a universal tracer also for EPT and foregut carcinoids, extending the PET-examination to both thorax and abdomen (whole-body PET-examination). With this method we were able

  9. Chronobiology of reproduction in garter snakes: neuroendocrine mechanisms and geographic variation. (United States)

    Lutterschmidt, Deborah I


    The majority of studies on reproductive neuroendocrinology in snakes have focused on one particular snake population in Manitoba, Canada, the red-sided garter snake (Thamnophis sirtalis parietalis). Although traditionally these studies have emphasized its unusual temporal dissociation between mating behavior and peak gonadal activity, current evidence suggests that reproductive regulation in this population may be more similar to the norm than previously thought. Like other ectotherms, temperature plays a critical role in activating reproductive behavior in red-sided garter snakes. Diel melatonin and corticosterone rhythms appear to be important in transducing temperature cues, and it is clear that both hormones regulate courtship behavior during spring. Current evidence also suggests that sex steroid hormones are in fact central to reproductive regulation in males, although the timing of their action occurs during winter dormancy. Whether this is also true for female T. sirtalis parietalis requires further study, but it should be noted that patterns of sex steroid hormones are sexually dimorphic during winter dormancy, as are melatonin rhythms during spring emergence. While continuing to advance our understanding of reproductive regulation in this extremely well-studied population is prudent, future comparative studies are critical for understanding if and how reproductive regulatory mechanisms differ across environments, populations, and phylogenies. For example, melatonin and corticosterone responses to environmental cues vary significantly among populations of T. sirtalis in a common garden, as do male courtship behavior and androgen concentrations. These data support the hypothesis that neuroendocrine-mediated responses to environmental cues underlie phenotypic plasticity in reproductive life history traits.

  10. 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.

  11. 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.

  12. Predisposing Factors of Liver Necrosis after Transcatheter Arterial Chemoembolization in Liver Metastases from Neuroendocrine Tumor

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    Joskin, Julien, E-mail:; Baere, Thierry de, E-mail: [Institut Gustave Roussy, Department of Interventional Radiology (France); Auperin, Anne, E-mail: [Institut Gustave Roussy, Department of Epidemiology (France); Tselikas, Lambros, E-mail:; Guiu, Boris, E-mail:; Farouil, Geoffroy, E-mail: [Institut Gustave Roussy, Department of Interventional Radiology (France); Boige, Valérie, E-mail:; Malka, David, E-mail: [Institut Gustave Roussy, Department of Digestive Oncology (France); Leboulleux, Sophie, E-mail: [Institut Gustave Roussy, Department of Nuclear Medicine and Endocrine Oncology (France); Ducreux, Michel, E-mail: [Institut Gustave Roussy, Department of Digestive Oncology (France); Baudin, Eric, E-mail: [Institut Gustave Roussy, Department of Nuclear Medicine and Endocrine Oncology (France); Deschamps, Frédéric, E-mail: [Institut Gustave Roussy, Department of Interventional Radiology (France)


    PurposeTo investigate predictive factors for liver necrosis after transcatheter arterial chemoembolization (TACE) of neuroendocrine liver metastases.MethodsA total of 164 patients receiving 374 TACE were reviewed retrospectively to analyze predictive factors of liver necrosis. We analyzed patient age and sex; metastasis number and location; percentage of liver involvement; baseline liver function test; and pretreatment imaging abnormalities such as bile duct dilatation (BDD), portal vein narrowing (PVN), and portal vein thrombosis (PVT). We analyzed TACE technique such as Lipiodol or drug-eluting beads (DEB) as the drug’s vector; dose of chemotherapy; diameter of DEB; and number, frequency, and selectivity of TACE.ResultsLiver necrosis developed after 23 (6.1 %) of 374 TACE. In multivariate analysis, DEB > 300 μm in size induced more liver necrosis compared to Lipiodol (odds ratio [OR] 35.20; p < 0.0001) or with DEB < 300 μm in size (OR 19.95; p < 0.010). Pretreatment BDD (OR 119.64; p < 0.0001) and PVT (OR 9.83; p = 0.030) were predictive of liver necrosis. BDD or PVT responsible for liver necrosis were present before TACE in 59 % (13 of 22) and were induced by a previous TACE in 41 % (9 of 22) of cases.ConclusionDEB > 300 μm in size, BDD, and PVT are responsible for increased rate of liver necrosis after TACE. Careful analysis of BDD or PVT on pretreatment images as well as images taken between two courses can help avoid TACE complications.

  13. Neurochemical and neuroendocrine effects of ibogaine in rats: comparison to MK-801. (United States)

    Baumann, M H; Rothman, R B; Ali, S F


    Ibogaine (IBO) is a naturally-occurring indole compound that is being evaluated as a potential medication for substance use disorders. Although the precise mechanism of IBO action is unclear, recent in vitro data show this drug displays properties similar to the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801. The purpose of the present work was to compare in vivo neurobiological effects of IBO and MK-801 in rats. Groups of male rats (n = 6-8/group) were decapitated 30 and 60 min after receiving intraperitoneal (i.p.) IBO (10 & 100 mg/kg), MK-801 (0.1 & 1.0 mg/kg) or vehicle. Trunk blood was collected for the analysis of plasma prolactin and corticosterone; brains were harvested and dissected for determination of dopamine (DA), serotonin (5-HT) and their metabolites. Both IBO and MK-801 increased corticosterone secretion, but only IBO elevated plasma prolactin. IBO produced dramatic reductions in tissue DA levels with concurrent increases in the metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This profile of IBO-induced changes in DA transmission was observed in the striatum, olfactory tubercle, and hypothalamus. The effects of MK-801 on DA metabolism did not mimic IBO, as MK-801 tended to increase DA and its metabolites. Neither drug appreciably affected 5-HT systems. Our results suggest that the effects of IBO on neuroendocrine function and DA transmission are not due to MK-801-like properties of IBO. Thus, the in vivo mechanism of IBO action cannot be explained simply on the basis of antagonism at NMDA receptors.

  14. Thiocoraline alters neuroendocrine phenotype and activates the Notch pathway in MTC-TT cell line. (United States)

    Tesfazghi, Sara; Eide, Jacob; Dammalapati, Ajitha; Korlesky, Colin; Wyche, Thomas P; Bugni, Tim S; Chen, Herbert; Jaskula-Sztul, Renata


    Medullary thyroid cancer (MTC) is an aggressive neuroendocrine tumor (NET). Previous research has shown that activation of Notch signaling has a tumor suppressor role in NETs. The potential therapeutic effect of thiocoraline on the activation of the Notch pathway in an MTC cell line (TT) was investigated. Thiocoraline was isolated from a marine bacterium Verrucosispora sp. MTT assay (3-[4, 5-dimethylthiazole-2-yl]-2, 5-diphenyltetrazolium bromide) was used to determine the IC50 value and to measure cell proliferation. Western blot revealed the expression of Notch isoforms, NET, and cell cycle markers. Cell cycle progression was validated by flow cytometry. The mRNA expression of Notch isoforms and downstream targets were measured using real-time PCR. The IC50 value for thiocoraline treatment in TT cells was determined to be 7.6 nmol/L. Thiocoraline treatment decreased cell proliferation in a dose- and time-dependent manner. The mechanism of growth inhibition was found to be cell cycle arrest in G1 phase. Thiocoraline activated the Notch pathway as demonstrated by the dose-dependent increase in mRNA and protein expression of Notch isoforms. Furthermore, treatment with thiocoraline resulted in changes in the expression of downstream targets of the Notch pathway (HES1, HES2, HES6, HEY1, and HEY2) and reduced expression of NET markers, CgA, and ASCL1. Thiocoraline is a potent Notch pathway activator and an inhibitor of MTC-TT cell proliferation at low nanomolar concentrations. These results provide exciting evidence for the use of thiocoraline as a potential treatment for intractable MTC.

  15. Impact and Clinical Predictors of Lymph Node Metastases in Nonfunctional Pancreatic Neuroendocrine Tumors

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    Yu Jiang


    Full Text Available Background: The optimal surgical management of nonfunctional pancreatic neuroendocrine tumors (NF-PNETs is still controversial. Here, we evaluated the impact of lymph node status on postoperative recurrence in patients with NF-PNET and the potential of preoperative variables for predicting lymph node metastasis (LNM. Methods: In this mono-institutional retrospective cohort study conducted in 100 consecutive patients who underwent NF-PNET resection between January 2004 and December 2014, we evaluated risk factors for survival using the Kaplan-Meier method and the Cox regression model. Predictors of LNM were evaluated using the logistic regression model, and the power of predictive models was evaluated using receiver operating characteristic curve analysis. Results: Five-year disease-free survival of resected NF-PNET was 64.1%. LNM was independently associated with postoperative recurrence (hazard ratio = 3.995, P = 0.003. Multivariate analysis revealed tumor grade as an independent factor associated with LNM (G2 vs. G1: odds ratio [OR] =6.287, P = 0.008; G3 vs. G1: OR = 12.407, P = 0.001. When tumor grade was excluded, radiological tumor diameter >2.5 cm (OR = 5.430, P = 0.013 and presence of symptoms (OR = 3.366, P = 0.039 were significantly associated with LNM. Compared to neoplasms with radiological diameter >2.5 cm (32.1%, tumors ≤2.5 cm had an obviously lower risk of LNM (7.7%, indicating the reliability of this parameter in predicting LNM (area under the curve, 0.693. Incidentally discovered NF-PNETs ≤2.5 cm were associated with a low-risk of LNM and excellent survival. Conclusions: LNM is significantly associated with postoperative recurrence. Radiological tumor diameter is a reliable predictor of LNM in NF-PNETs. Our results indicate that lymphadenectomy in small (≤2.5 cm NF-PNETs is not routinely necessary.

  16. 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.

  17. Whole-exome characterization of pancreatic neuroendocrine tumor cell lines BON-1 and QGP-1. (United States)

    Vandamme, Timon; Peeters, Marc; Dogan, Fadime; Pauwels, Patrick; Van Assche, Elvire; Beyens, Matthias; Mortier, Geert; Vandeweyer, Geert; de Herder, Wouter; Van Camp, Guy; Hofland, Leo J; Op de Beeck, Ken


    The human BON-1 and QGP-1 cell lines are two frequently used models in pancreatic neuroendocrine tumor (PNET) research. Data on the whole-exome genetic constitution of these cell lines is largely lacking. This study presents, to our knowledge, the first whole-exome profile of the BON-1 and QGP-1 cell lines. Cell line identity was confirmed by short tandem repeat profiling. Using GTG-banding and a CytoSNP-12v2 Beadchip array, cell line ploidy and chromosomal alterations were determined in BON-1 and QGP-1. The exomes of both cell lines were sequenced on Ilumina's HiSeq next-generation sequencing (NGS) platform. Single-nucleotide variants (SNVs) and insertions and deletions (indels) were detected using the Genome Analysis ToolKit. SNVs were validated by Sanger sequencing. Ploidy of BON-1 and QGP-1 was 3 and 4 respectively, with long stretches of loss of heterozygosity across multiple chromosomes, which is associated with aggressive tumor behavior. In BON-1, 57 frameshift indels and 1725 possible protein-altering SNVs were identified in the NGS data. In the QGP-1 cell line, 56 frameshift indels and 1095 SNVs were identified. ATRX, a PNET-associated gene, was mutated in both cell lines, while mutation of TSC2 was detected in BON-1. A mutation in NRAS was detected in BON-1, while KRAS was mutated in QGP-1, implicating aberrations in the RAS pathway in both cell lines. Homozygous mutations in TP53 with possible loss of function were identified in both cell lines. Various MUC genes, implicated in cell signaling, lubrication and chemical barriers, which are frequently expressed in PNET tissue samples, showed homozygous protein-altering SNVs in the BON-1 and QGP-1 cell lines.

  18. Co-Targeting the PI3K and RAS Pathways for the Treatment of Neuroendocrine Tumors (United States)

    Valentino, Joseph D.; Li, Jing; Zaytseva, Yekaterina Y.; Mustain, W. Conan; Elliott, Victoria A.; Kim, Ji Tae; Harris, Jennifer W.; Campbell, Katherine; Weiss, Heidi; Wang, Chi; Song, Jun; Anthony, Lowell; Townsend, Courtney M.; Evers, B. Mark


    Background The precise involvement of the PI3K/mTOR and RAS/MEK pathways in carcinoid tumors is not well defined. Therefore, the purpose of our study was to evaluate the role these pathways play in carcinoid cell proliferation, apoptosis, and secretion and to determine the effects of combined treatment on carcinoid tumor inhibition. Methods The human neuroendocrine cell lines BON (pancreatic carcinoid), NCI-H727 (lung carcinoid), and QGP-1 (somatostatinoma) were treated with either the pan-PI3K inhibitor, BKM120, or the dual PI3K-mTOR inhibitor, BEZ235, alone or in combination with the MEK inhibitor, PD0325901; proliferation, apoptosis, and protein expression were assessed. Peptide secretion was evaluated in BON and QGP-1 cells. The anti-proliferative effect of BEZ235, alone or combined with PD0325901, was then tested in vivo. Results Both BKM120 and BEZ235 decreased proliferation and increased apoptosis; combination with PD0325901 significantly enhanced the antineoplastic effects of either treatment alone. In contrast, neurotensin (NT) peptide secretion was markedly stimulated with BKM120 treatment, but not BEZ235. The combination of BEZ235 + PD0325901 significantly inhibited the growth of BON xenografts without systemic toxicity. Conclusions Both BKM120 and BEZ235 effectively inhibited NET cell proliferation and stimulated apoptosis. However, inhibition of the PI3K pathway alone with BKM120 significantly stimulated NT peptide secretion; this did not occur with the dual inhibition of both PI3K and mTOR using BEZ235 suggesting that this would be a more effective treatment regimen for NETs. Moreover, the combination of BEZ235 and the MEK inhibitor PD0325901 was a safe and more effective therapy in vivo compared with single agents alone. PMID:24443523

  19. Concurrent AURKA and MYCN Gene Amplifications Are Harbingers of Lethal TreatmentRelated Neuroendocrine Prostate Cancer

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    Juan Miguel Mosquera


    Full Text Available Neuroendocrine prostate cancer (NEPC, also referred to as anaplastic prostate cancer, is a lethal tumor that most commonly arises in late stages of prostate adenocarcinoma (PCA with predilection to metastasize to visceral organs. In the current study, we explore for evidence that Aurora kinase A (AURKA and N-myc (MYCN gene abnormalities are harbingers of treatment-related NEPC (t-NEPC. We studied primary prostate tissue from 15 hormone naïve PCAs, 51 castration-resistant prostate cancers, and 15 metastatic tumors from 72 patients at different stages of disease progression to t-NEPC, some with multiple specimens. Histologic evaluation, immunohistochemistry, and fluorescence in situ hybridization were performed and correlated with clinical variables. AURKA amplification was identified in overall 65% of PCAs (hormone naïve and treated from patients that developed t-NEPC and in 86% of metastases. Concurrent amplification of MYCN was present in 70% of primary PCAs, 69% of treated PCAs, and 83% of metastases. In contrast, in an unselected PCA cohort, AURKA and MYCN amplifications were identified in only 5% of 169 cases. When metastatic t-NEPC was compared to primary PCA from the same patients, there was 100% concordance of ERG rearrangement, 100% concordance of AURKA amplification, and 60% concordance of MYCN amplification. In tumors with mixed features, there was also 100% concordance of ERG rearrangement and 94% concordance of AURKA and MYCN co-amplification between areas of NEPC and adenocarcinoma. AURKA and MYCN amplifications may be prognostic and predictive biomarkers, as they are harbingers of tumors at risk of progressing to t-NEPC after hormonal therapy.

  20. The epidemiology of neuroendocrine tumors in Taiwan: a nation-wide cancer registry-based study.

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    Hui-Jen Tsai

    Full Text Available BACKGROUND: The epidemiology of neuroendocrine tumors (NETs is not well illustrated, particularly for Asian countries. METHODS: The age-standardized incidence rates and observed survival rates of NETs diagnosed in Taiwan from January 1, 1996 to December 31, 2008 were calculated using data of the Taiwan Cancer Registry (TCR and compared to those of the Norwegian Registry of Cancer (NRC and the US Surveillance, Epidemiology, and End Results (SEER program. RESULTS: During the study period, a total of 2,187 NET cases were diagnosed in Taiwan, with 62% males and a mean age of 57.9 years-old. The age-standardized incidence rate of NETs increased from 0.30 per 100,000 in 1996 to 1.51 per 100,000 in 2008. The most common primary sites were rectum (25.4%, lung and bronchus (20% and stomach (7.4%. The 5-year observed survival was 50.4% for all NETs (43.4% for men and 61.8% for women, P<0.0001. The best 5-year observed survivals for NETs by sites were rectum (80.9%, appendix (75.7%, and breast (64.8%. CONCLUSIONS: Compared to the data of Norway and the US, the age-standardized incidence rate of NETs in Taiwan is lower and the major primary sites are different, whereas the long-term outcome is similar. More studies on the pathogenesis of NETs are warranted to devise preventive strategies and improve treatment outcomes for NETs.

  1. High-Dose Lanreotide in the Treatment of Poorly Differentiated Pancreatic Neuroendocrine Carcinoma: A Case Report

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    Frank Van Fraeyenhove


    Full Text Available Pancreatic neuroendocrine tumors (NETs, including poorly differentiated carcinomas (NECs, are rarely encountered. The majority of these tumors do not secrete excess hormones, but functioning NETs produce large amounts of vasoactive peptides and may cause carcinoid syndrome. Synthetic somatostatin analogs (SSAs have been widely used in NETs for control of hormonal syndromes. Here, we present a case of poorly differentiated, grade 3 pancreatic NEC associated with carcinoid syndrome, for which adequate symptom control was achieved for 2 years and 4 months using the long-acting SSA lanreotide Autogel®. In February 2009, a 55-year-old woman presented with episodes of flushing, diarrhea and epigastric pain. Imaging techniques revealed the presence of a metabolically active mass expressing somatostatin receptors in the hilar area of the liver. Histopathological examination confirmed the malignant nature of the mass, which was identified as a poorly differentiated grade 3 pancreatic NEC (TNM staging: T4NxM0. Therapeutic options were limited for the patient because of the extent of the primary mass involving the celiac axis, severe gastrointestinal toxicity experienced as a side effect of chemotherapy with cisplatin-etoposide and, later in the course of the disease, extensive liver metastases and carcinoid heart syndrome. Along with a palliative debulking surgery and right portal vein embolization, biotherapy with a high dose of lanreotide Autogel (120 mg/14 days contributed to alleviation of symptoms caused by hormone overproduction, even after the development of liver metastases. These results suggest that patients with poorly differentiated NECs who exhibit signs of carcinoid syndrome can benefit from treatment with somatostatin analogs.

  2. A Delphic consensus assessment: imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management

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    Kjell Oberg


    Full Text Available 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, resolution inadequacies and inter-/intra-facility device variability and that RECIST (Response Evaluation Criteria in Solid Tumors criteria are not optimal for NEN. Limitations of currently used biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase and pancreastatin; monoanalyte measurements; and lack sensitivity, specificity and predictive capacity. None of them meet the NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n = 33 assessed current imaging strategies and biomarkers in NEN management. Consensus (>75% was achieved for 78% of the 142 questions. The panel concluded that morphological imaging has a diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring the disease status and predicting the therapeutic efficacy. RECIST remains suboptimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group considered that circulating RNA was better than current general NEN biomarkers and preliminary clinical data were considered promising. It was resolved that circulating multianalyte mRNA (NETest had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumor spatial and functional imaging with circulating transcripts (mRNA would represent the future strategy for real-time monitoring of disease progress and therapeutic efficacy.

  3. Chemometric Evaluation of Urinary Steroid Hormone Levels as Potential Biomarkers of Neuroendocrine Tumors

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    Barbara Seroczyńska


    Full Text Available Neuroendocrine tumors (NETs are uncommon tumors which can secrete specific hormone products such as peptides, biogenic amines and hormones. So far, the diagnosis of NETs has been difficult because most NET markers are not specific for a given tumor and none of the NET markers can be used to fulfil the criteria of high specificity and high sensitivity for the screening procedure. However, by combining the measurements of different NET markers, they become highly sensitive and specific diagnostic tests. The aim of the work was to identify whether urinary steroid hormones can be identified as potential new biomarkers of NETs, which could be used as prognostic and clinical course monitoring factors. Thus, a rapid and sensitive reversed-phase high-performance liquid chromatographic method (RP-HPLC with UV detection has been developed for the determination of cortisol, cortisone, corticosterone, testosterone, epitestosterone and progesterone in human urine. The method has been validated for accuracy, precision, selectivity, linearity, recovery and stability. The limits of detection and quantification were 0.5 and 1 ng mL−1 for each steroid hormone, respectively. Linearity was confirmed within a range of 1–300 ng mL−1 with a correlation coefficient greater than 0.9995 for all analytes. The described method was successfully applied for the quantification of six endogenous steroid levels in human urine. Studies were performed on 20 healthy volunteers and 19 patients with NETs. Next, for better understanding of tumor biology in NETs and for checking whether steroid hormones can be used as potential biomarkers of NETs, a chemometric analysis of urinary steroid hormone levels in both data sets was performed.

  4. Human achaete-scute homolog-1 expression in neuroendocrine breast carcinoma. (United States)

    Righi, Luisella; Rapa, Ida; Votta, Arianna; Papotti, Mauro; Sapino, Anna


    Neuroendocrine (NE) breast carcinoma is defined by morphological features similar to those of NE tumors of other organs and NE marker expression in at least 50 % of neoplastic cells. However, a NE morphology may be observed even in breast carcinomas lacking NE markers. Human achaete-scute homolog-1 (hASH-1) is a transcription factor that plays a key role in the regulation of mammalian neural and NE cell development and has been identified in several human NE tumors. The aim of this study was to investigate hASH-1 expression in human breast cancers. hASH-1 expression was evaluated in 482 consecutive non-NE invasive breast carcinomas, in a series of 84 breast cancers with >50 % NE marker expression (high NE differentiation) and 21 carcinomas with NE histology but negative or focally (<50 %) positive for NE markers (low NE differentiation). hASH-1 protein was evaluated by a specific monoclonal antibody using immunohistochemistry and gene expression by real-time polymerase chain reaction. None of the non-NE invasive breast carcinomas expressed hASH-1 at any levels. hASH-1 was expressed in tumor cell nuclei of 63 and 38 % of cases with high and low NE differentiation, respectively. Strong correlation with protein and gene expression levels was observed (p < 0.0001). hASH-1 expression was correlated to a low mitotic count (p = 0.02) and a low Ki67 proliferative index (p = 0.0062). hASH-1 expression occurs in breast cancers with NE differentiation regardless of the extent of the NE cell population, and it is restricted to a subset of tumor cells having a low proliferative potential.

  5. The Long-term Benefit of Liver Transplantation for Hepatic Metastases from Neuroendocrine Tumors. (United States)

    Mazzaferro, V; Sposito, C; Coppa, J; Miceli, R; Bhoori, S; Bongini, M; Camerini, T; Milione, M; Regalia, E; Spreafico, C; Gangeri, L; Buzzoni, R; de Braud, F G; De Feo, T; Mariani, L


    Selection criteria and benefit of liver transplantation for hepatic metastases from neuroendocrine tumors (NETs) remains uncertain. Eighty-eight consecutive patients with metastatic NETs eligible for liver transplantation according to Milan-NET criteria were offered transplant (n.42) vs. non-transplant options (n.46) depending on list dynamics, patient disposition and age. Tumor burden between groups did not differ. Transplant patients were younger (40.5 vs. 55.5 years; p<0.001). Long-term outcomes were compared after matching between groups made on multiple Cox models adjusted for propensity score built on logistic models. Survival-benefit was the difference in mean survival between transplant vs. non-transplant options. No patients were lost or died without recurrence. Median follow-up was 122 months. Transplant group showed significant advantage over non-transplant strategies at 5 and 10-yrs in survival (97.2% and 88.8% vs. 50.9% and 22.4% respectively; p<0.001) and time-to-progression (13.1% and 13.1% vs. 83.5% and 89%; p<0.001). After adjustment for propensity score, survival advantage of transplant group was significant (HR=7.4; 95%CI: 2.4-23.0; p=0.001). Adjusted transplant-related survival-benefit was 6.82 months (95%CI: 1.10-12.54; p=0.019) and 38.43 months (95%CI: 21.41-55.45; p<0.001) at 5 and 10-yrs respectively. Liver transplantation for metastatic NETs under restrictive criteria provides excellent long-term outcome. Transplant-related survival-benefit increases over time and maximizes after 10 yrs. This article is protected by copyright. All rights reserved.

  6. Thymomas: a cytological and immunohistochemical study, with emphasis on lymphoid and neuroendocrine markers

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    Burke Allen P


    Full Text Available Abstract Background The current study correlates cytologic morphology with histologic type and describes immunophenotypes with a focus on epithelial, neuroendocrine, and lymphoid characteristics in an institutional series of surgically excised thymomas. Methods Fine needle aspirates (FNAs and surgical specimens were retrospectively analyzed, and immunohistochemical stains were performed for EMA, cytokeratin 7, cytokeratin 20, CD57 CD5, bcl-2, calretinin, vimentin, CD3, CD20, CD1a, CD99 and Ki67. Tumors were classified by WHO criteria. Results There were eleven male and six female patients with an age range of 41 to 84 years (mean, 61 years and a male to female ratio of 1.8:1. Four thymomas (4/17, 23.5% were associated with neuromuscular disease: myasthenia gravis (n = 3 and limbic encephalitis (n = 1. FNA, under CT guidance, was performed in 7 cases. The positive predictive value for thymoma by FNA cytology was 100% and the sensitivity was 71%. Thymomas associated with neuromuscular disorders were WHO types B2 (n = 1 and B3 (n = 3, and showed a strong expression of CD57 in the majority of neoplastic epithelial cells accompanied by large numbers of CD20+ intratumoral B lymphocytes. Two of seventeen (11.7% thymomas (all sporadic B3 type contained numerous neoplastic epithelial cells positive for CD5 and bcl-2. Conclusion Our results suggest that thymomas associated with autoimmune disorders contain a significant population of CD20+ intratumoral B lymphocytes. Strong CD57 positivity in thymomas may suggest a concomitant neuromuscular disorder, notably myasthenia gravis. CD5 expression is of limited value in the differential diagnosis of primary thymic epithelial neoplasms since both thymic carcinomas and thymomas may express CD5.

  7. Impact of Helicobacter pylori infection on ghrelin and various neuroendocrine hormones in plasma

    Institute of Scientific and Technical Information of China (English)

    Hajime Isomoto; Hiroaki Ueno; Yoshito Nishi; Chun-Yang Wen; Masamitsu Nakazato; Shigeru Kohno


    AIM: Ghrelin, an endogenous ligand for growth hormone secretagogue receptor, influences appetite, energy balance, gastric motility and acid secretion. The stomach is the main source of circulating ghrelin. There are inconsistent reports on the influence of Helicobacter pylori (H pylori) infection on circulating ghrelin levels. We sought to elucidate the relationship between ghrelin and various peptides in plasma, with special reference to H pylori.METHODS: Plasma ghrelin levels were measured by radioimmunoassay in 89 subjects who were referred for upper gastrointestinal endoscopy, consisting of 42 H pylori infected and 47 uninfected ones. Plasma gastrin,somatostatin, leptin, insulin-like growth hormone 1 (IGF-1)and chromogranin A concentrations were also measured.Twelve patients were treated with anti- H pylori regimen.RESULTS: Ghrelin circulating levels were greatly decreased in H pylori-positive than negative individuals (194.2±90.2fmol/mL and 250.4±84.1 respectively, P<0.05), but did not significantly alter following the cure of infection (176.5±79.5 vs 191.3±120.4). There was a significant negative correlation between circulating ghrelin and leptin levels, as well as body mass index, for the whole and uninfected population, but not in H pylori-infected patients. Plasma ghrelin concentrations correlated positively with IGF-1 in H pylori-negative group and negatively with chromogranin A in the infected group.There were no significant correlations among circulating levels of ghrelin, gastrin and somatostatin irrespective of H pylori status.CONCLUSION: H pylori infection influences plasma ghrelin dynamics and its interaction with diverse bioactive peptides involved in energy balance, growth and neuroendocrine function.

  8. 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.

  9. Maternal separation modifies behavioural and neuroendocrine responses to stress in CCR7 deficient mice. (United States)

    Harrison, Emma L; Jaehne, Emily J; Jawahar, M Catharine; Corrigan, Frances; Baune, Bernhard T


    Alterations in immune function of various humoral and cellular factors, including chemokines, secondary to early stress may play a role in the enhanced vulnerability to psychiatric conditions in those with a history of childhood adversity. C57BL/6 (WT) mice and mice deficient for the chemokine receptor type 7 (CCR7(-/-)) were used to determine the effects of maternal separation on a range of behaviours and the biological stress response. Unpredictable maternal separation (MS) was conducted for 3h daily from postnatal day 1 to 14, with subsequent behavioural testing at 10 weeks of age. Corticosterone was quantified in 11-week-old mice. Maternally separated (MS) CCR7(-/-), but not WT mice, displayed reduced interest in social novelty compared to CCR7(-/-) naïve mice. Separated CCR7(-/-) mice also exhibited significantly lower serum corticosterone concentrations compared to non-separated mice. CCR7(-/-) mice spent less time in the centre during an open field test and more time in the closed arm of the elevated zero maze compared to their wild-type (WT) controls suggesting they were more anxious, however, no difference was observed between MS and control mice in either strain or test. Together these findings suggest that CCR7 is involved in mediating social behaviour and stress response following maternal separation, whereas other behaviours such as anxiety appear to be modified by CCR7 independent of maternal separation. The observed altered cell-mediated immune function possibly underlying the behavioural and neuroendocrine differences in CCR7(-/-) mice following maternal separation requires further investigation.

  10. Chromogranin A as Serum Marker for Gastroenteropancreatic Neuroendocrine Tumors: A Single Center Experience and Literature Review

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    Christoph J. Auernhammer


    Full Text Available The aim of this study was to assess the clinical sensitivities of the tumor markers chromogranin A (CgA, urinary 5-hydroxyindoleacetic acid (5-HIAA and alkaline phosphatase (AP in neuroendocrine tumors (NETs of the GastroEnteroPancreatic-(GEP- system depending on tumor primary location and metastatic spread. In a retrospective single-center series, sensitivities were evaluated in serum samples from 110 patients with midgut (n = 62 and pancreatic (n = 48 NETs. CgA levels were analyzed by a commercially-available immunoradiometric assay (CIS-bio during routine follow-up in the years 2000–2009. CgA showed a higher sensitivity for midgut (68% than pancreatic (54% NETs. A higher CgA sensitivity and significantly higher median CgA values were found in patients with liver metastases than in those without, and in patients with hepatic and additionally extra-hepatic metastases than in those with hepatic and nodal metastases alone, respectively. We found an overall sensitivity for elevated 5HIAA excretion of 69% for midgut NETs and a significant correlation between median CgA and 5-HIAA values. The sensitivity of AP and the correlations of AP/CgA-data-pairs were low in both midgut and pancreatic NETs, although highest for metastatic pancreatic NETs. The sensitivity of CgA measurement depends on the NET primary location and spread of disease. 5-HIAA and CgA showed comparable sensitivity in midgut NETs, while AP does not seem to be useful as a tumor marker in GEP-NETs.

  11. Pasireotide and octreotide antiproliferative effects and sst2 trafficking in human pancreatic neuroendocrine tumor cultures. (United States)

    Mohamed, Amira; Blanchard, Marie-Pierre; Albertelli, Manuela; Barbieri, Federica; Brue, Thierry; Niccoli, Patricia; Delpero, Jean-Robert; Monges, Genevieve; Garcia, Stephane; Ferone, Diego; Florio, Tullio; Enjalbert, Alain; Moutardier, Vincent; Schonbrunn, Agnes; Gerard, Corinne; Barlier, Anne; Saveanu, Alexandru


    Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) raise difficult therapeutic problems despite the emergence of targeted therapies. Somatostatin analogs (SSA) remain pivotal therapeutic drugs. However, the tachyphylaxis and the limited antitumoral effects observed with the classical somatostatin 2 (sst2) agonists (octreotide and lanreotide) led to the development of new SSA, such as the pan sst receptor agonist pasireotide. Our aim was to compare the effects of pasireotide and octreotide on cell survival, chromogranin A (CgA) secretion, and sst2 phosphorylation/trafficking in pancreatic NET (pNET) primary cells from 15 tumors. We established and characterized the primary cultures of human pancreatic tumors (pNETs) as powerful preclinical models for understanding the biological effects of SSA. At clinically relevant concentrations (1-10 nM), pasireotide was at least as efficient as octreotide in inhibiting CgA secretion and cell viability through caspase-dependent apoptosis during short treatments, irrespective of the expression levels of the different sst receptors or the WHO grade of the parental tumor. Interestingly, unlike octreotide, which induces a rapid and persistent partial internalization of sst2 associated with its phosphorylation on Ser341/343, pasireotide did not phosphorylate sst2 and induced a rapid and transient internalization of the receptor followed by a persistent recycling at the cell surface. These results provide the first evidence, to our knowledge, of striking differences in the dynamics of sst2 trafficking in pNET cells treated with the two SSAs, but with similar efficiency in the control of CgA secretion and cell viability.

  12. Diagnostic criteria and follow-up in neuroendocrine cell hyperplasia of infancy: a case series

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    Vivianne Calheiros Chaves Gomes


    Full Text Available OBJECTIVE: Neuroendocrine cell hyperplasia of infancy (NEHI is a form of childhood interstitial lung disease characterized by tachypnea, retractions, crackles, and hypoxia. The aim of this study was to report and discuss the clinical, imaging, and histopathological findings in a series of NEHI cases at a tertiary pediatric hospital, with an emphasis on diagnostic criteria and clinical outcomes. METHODS: Between 2003 and 2011, 12 full-term infants were diagnosed with NEHI, based on clinical and tomographic findings. Those infants were followed for 1-91 months. Four infants were biopsied, and the histopathological specimens were stained with bombesin antibody. RESULTS: In this case series, symptoms appeared at birth in 6 infants and by 3 months of age in the remaining 6. In all of the cases, NEHI was associated with acute respiratory infection. The most common initial chest HRCT findings were ground-glass opacities that were in the middle lobe/lingula in 12 patients and in other medullary areas in 10. Air trapping was the second most common finding, being observed in 7 patients. Follow-up HRCT scans (performed in 10 patients revealed normal results in 1 patient and improvement in 9. The biopsy findings were nonspecific, and the staining was positive for bombesin in all samples. Confirmation of NEHI was primarily based on clinical and tomographic findings. Symptoms improved during the follow-up period (mean, 41 months. A clinical cure was achieved in 4 patients. CONCLUSIONS: In this sample of patients, the diagnosis of NEHI was made on the basis of the clinical and tomographic findings, independent of the lung biopsy results. Most of the patients showed clinical improvement and persistent tomographic changes during the follow-up period, regardless of the initial severity of the disease or type of treatment.


    Stefanov, R; Miteva-Katrandjieva, Ts; Iskrov, G; Damyanov, D; Korukov, B; Kermedchiev, M; Terziev, I; Madjov, R; Ivanov, K; Kolev, N; Chenopolski, P; Tsaneva, M; Dimitrova, V; Todorov, G; Hristova, S; Tosheva, E; Grozdev, K; Vladov, N; Mihova, A; Stoyanova, R; Cholakov, O; Haralanov, S; Draganov, K; Marinov, V; Radionov, M; Dimitrov, O; Kurtev, P; Angelova, E; Hadjiev, B; Murdjev, K; Dermendjieva, T; Deliisky, T; Valcheva-Petrova, G; Popovska, S; Julianov, A; Georgiev, I


    The National registry of patients with neuroendocrine tumors (NET) in Bulgaria was established in 2013 as a joint initiative of the Bulgarian Surgical Society and the Institute for Rare Diseases. The register aims to explore the epidemiology of NET in Bulgaria, as well as the different diagnostic and treatment approaches for the disease throughout the country. This the first of its kind retrospective study of NET in the country is covering the period January 2012 - January 2013. A total of 127 patients with NET were identified. At the time of the survey the average age of patients with NET was 58.61 ± 15.59 years. The data show almost equal distribution between the genders with a slight predominance of women. The largest relative part of NET is those of NET located in the gastrointestinal tract (54.10 ± 4.51%), followed by those located in the pancreas (12.30 ± 2.97%) and in the lungs (10.66 ± 2.79%). In 72.44 ± 3.96% of the patients a immunohistochemical diagnosis was performed. The study confirmed the leading role of the surgery method of the NET management. In 65.83 ± 4.33% of the patients a radical removal of the tumor was conducted, while the relative part of the undertaken partial resection was 7.50 ± 2.40%. A statistically significant association between the type of surgical treatment and during the follow-up of patients was found. An update of the information in the register will allow a more precise determining of the distribution and management of NET in Bulgaria.

  14. Plasma acylated and plasma unacylated ghrelin: useful new biomarkers in patients with neuroendocrine tumors? (United States)

    van Adrichem, Roxanne C S; van der Lely, Aart Jan; Huisman, Martin; Kramer, Piet; Feelders, Richard A; Delhanty, Patric J D; de Herder, Wouter W


    To date, the value of fasting plasma acylated ghrelin (AG) and unacylated ghrelin (UAG) as potential novel biomarkers in patients with neuroendocrine tumors (NETs) is unknown. The aims of this study are to (i) compare fasting AG and UAG levels between nonobese, nondiabetic NET patients (N=28) and age- (±3 years) and sex-matched nonobese, nondiabetic controls (N=28); and (ii) study the relationship between AG, UAG, and AG/UAG ratios and biochemical (chromogranin-A (CgA) and neuron-specific enolase (NSE) levels) and clinical parameters (age at diagnosis, sex, primary tumor location, carcinoid syndrome, ENETS TNM classification, Ki-67 proliferation index, grading, prior incomplete surgery) in NET patients. Fasting venous blood samples (N=56) were collected and directly stabilized with 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride after withdrawal. Plasma AG and UAG levels were determined by ELISA. Expression of ghrelin was examined in tumor tissue by immunohistochemistry. There were no significant differences between NET patients and controls in AG (median: 62.5 pg/mL, IQR: 33.1-112.8 vs median: 57.2pg/mL, IQR: 26.7-128.3, P=0.66) and UAG in levels (median: 76.6pg/mL, IQR: 35.23-121.7 vs median: 64.9, IQR: 27.5-93.1, P=0.44). No significant correlations were found between AG, UAG, and AG/UAG ratios versus biochemical and clinical parameters in NET patients with the exception of age at diagnosis (AG: ρ= -0.47, P=0.012; AG/UAG ratio: ρ= -0.50, P=0.007) and baseline chromogranin-A levels (AG/UAG ratio: ρ= -0.44, P=0.019). In our view, fasting plasma acylated and unacylated ghrelin appear to have no value as diagnostic biomarkers in the clinical follow-up of patients with NETs.

  15. Chromogranin A, Ki-67 index and IGF-related genes in patients with neuroendocrine tumors (United States)

    van Adrichem, R C S; Hofland, L J; Feelders, R A; De Martino, M C; van Koetsveld, P M; van Eijck, C H J; de Krijger, R R; Sprij-Mooij, D M; Janssen, J A M J L; de Herder, W W


    Chromogranin A (CgA) and the Ki-67 proliferation index are considered as important biochemical and pathological markers for clinical behaviour of gastroenteropancreatic neuroendocrine tumors (GEP NETs), respectively. The IGF system has been suggested as an important regulator of GEP NET proliferation and differentiation. A possible relationship between serum CgA (sCgA), Ki-67 proliferation index, and expression of IGF-related genes in patients with GEP NETs has not been demonstrated yet. This study investigates the relationship between sCgA, the Ki-67 proliferation index, and the expression of IGF-related genes in GEP NET tissues and their relation with 5-year survival. Tumor and blood samples from 22 GEP NET patients were studied. Tumoral mRNA expression of IGF-related genes (IGFs: IGF1, IGF2; IGF receptors: IGF1R, IGF2R; insulin receptors: subtype A (IR-A) and B (IR-B); IGF-binding proteins (IGFBPs): IGFBP1, IGFBP2, IGFBP3, and IGFBP6) was measured using quantitative RT-PCR. Ki-67 proliferation index was determined using immunohistochemistry. sCgA was measured with ELISA. Five-year survival in patients with nonelevated sCgA (n=11) was 91 vs 46% in patients with elevated sCgA (n=11) (P=0.006). IR-A mRNA expression was significantly higher in tumors obtained from patients with elevated sCgA than in those from patients with nonelevated sCgA (6.42±2.08 vs 2.60±0.40; P=0.04). This data suggests that sCgA correlates well with 5-year survival of GEP NET patients, and that IR-A mRNA expression correlates well with tumor mass in GEP NET patients. PMID:24042314

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

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    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.

  17. Patient-reported outcomes in subjects with neuroendocrine tumors of the pancreas

    Institute of Scientific and Technical Information of China (English)

    Raffaele Pezzilli; Davide Campana; Antonio M Morselli-Labate; Maria C Fabbri; Emilio Brocchi; Paola Tomassetti


    AIM: To assess the patient-reported outcomes (PROs) of pancreatic neuroendocrine tumor (PNET) patients. METHODS: Fifty-one consecutive patients (21 male,30 female, 61.0 ± 10.3 years) with proven PNETs were studied. An SF-12 questionnaire capable of exploring the physical (PCS) and mental (MCS) aspects of daily life was used. Four questionnaires were also used [12 items General Health Questionnaire (GHQ-12) for nonpsychotic psychiatric disorders, State Trait Anxiety Inventory (STAI) Y-1 and Y-2 for anxiety and BDI-Ⅱ for depressive symptoms] to explore the psychological aspects of the disease. Forty-four sex- and age-matched Italian normative subjects were included and evaluated using the SF-12, STAI Y-1 and Y-2 questionnaires.RESULTS: Seven patients refused to participate to the study; they were clinically similar to the 44 participants who agreed to complete the questionnaires. PNET patients had a PCS score (44.7 ± 11.0) were not significantly different from the norms (46.1 ± 9.9, P = 0.610), whereas the MCS score was significantly lower in patients (42.4 ± 13.0) as compared to the norms (48.2 ± 9.8, P = 0.036). GHQ-12 identified 11 patients (25.0%) as having non-psychotic psychiatric disorders. The STAI scores were similar in the patients and in the normative population. Finally, BDI-Ⅱ identified eight patients (18.2%) with moderate depression and 9 (20.5%) with mild depression whereas 27 patients (61.4%) had no depression. CONCLUSION: The PNET patients had a good physical but an impaired mental component of their quality of life; in addition, mild or moderate depressive symptoms are present in about 40% of PNET patients.

  18. Evidence for a heritable contribution to neuroendocrine tumors of the small intestine. (United States)

    Neklason, Deborah W; VanDerslice, James; Curtin, Karen; Cannon-Albright, Lisa A


    Small intestinal neuroendocrine tumors (SI-NETs) are rare tumors arising from the enterochromaffin cells of the gut. Having a first-degree relative with a SI-NET has been shown to confer a substantial risk arising from shared environment and genetics. Heritable risk was examined using a computerized genealogy linked to historical statewide cancer data. A population-based analysis of the observed familial clustering of SI-NETs was performed to assess the genetic risk in distant relatives. A test for significant excess relatedness of 384 individuals with genealogy data and histologically confirmed SI-NETs was performed by comparing pairwise relatedness of cases to 1000 sets of matched controls. Overall significant excess pairwise relatedness was found for the 384 cases (P<0.001) and was still observed when closer than first cousin relationships were ignored (P=0.041). Relative risks (RRs) for SI-NETs were estimated as a ratio of observed to expected number of SI-NET cases among each relationship class. Siblings have a 13.4-fold (P<0.0001) and parents have a 6.5-fold (P=0.143) RR, suggesting both genetic and environmental influences. The risk extends out to third-degree relatives with a 2.3-fold RR (P=0.008). Metachronous cancers were also reported in 26% of the SI-NET cases demonstrating an increased RR of colon, bladder, non-Hodgkin lymphoma, melanoma, and prostate cancers. Although SI-NETs are rare, relatives of these cases are at a significantly elevated risk of developing a SI-NET due to heritable genetic factors. Definition of the genetic risk factors will be an important tool for earlier diagnosis and better outcomes for SI-NETs.

  19. Splenosis Mimicking Relapse of a Neuroendocrine Tumor at Gallium-68-DOTATOC PET/CT

    Energy Technology Data Exchange (ETDEWEB)

    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.

  20. Plasma CCN2/connective tissue growth factor is associated with right ventricular dysfunction in patients with neuroendocrine tumors

    Directory of Open Access Journals (Sweden)

    Aakhus Svend


    Full Text Available Abstract Background Carcinoid heart disease, a known complication of neuroendocrine tumors, is characterized by right heart fibrotic lesions. Carcinoid heart disease has traditionally been defined by the degree of valvular involvement. Right ventricular (RV dysfunction due to mural involvement may also be a manifestation. Connective tissue growth factor (CCN2 is elevated in many fibrotic disorders. Its role in carcinoid heart disease is unknown. We sought to investigate the relationship between plasma CCN2 and valvular and mural involvement in carcinoid heart disease. Methods Echocardiography was performed in 69 patients with neuroendocrine tumors. RV function was assessed using tissue Doppler analysis of myocardial systolic strain. Plasma CCN2 was analyzed using an enzyme-linked immunosorbent assay. Mann-Whitney U, Kruskal-Wallis, Chi-squared and Fisher's exact tests were used to compare groups where appropriate. Linear regression was used to evaluate correlation. Results Mean strain was -21% ± 5. Thirty-three patients had reduced RV function (strain > -20%, mean -16% ± 3. Of these, 8 had no or minimal tricuspid and/or pulmonary regurgitation (TR/PR. Thirty-six patients had normal or mildly reduced RV function (strain ≤ -20%, mean -25% ± 3. There was a significant inverse correlation between RV function and plasma CCN2 levels (r = 0.47, p Conclusions Elevated plasma CCN2 levels are associated with RV dysfunction and valvular regurgitation in NET patients. CCN2 may play a role in neuroendocrine tumor-related cardiac fibrosis and may serve as a marker of its earliest stages.

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

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    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

  2. Serotonin and the 5-HT7 receptor: the link between hepatocytes, IGF-1 and small intestinal neuroendocrine tumors. (United States)

    Svejda, Bernhard; Kidd, Mark; Timberlake, Andrew; Harry, Kathy; Kazberouk, Alexander; Schimmack, Simon; Lawrence, Ben; Pfragner, Roswitha; Modlin, Irvin M


    Platelet-derived serotonin (5-HT) is involved in liver regeneration. The liver is also the metastatic site for malignant enterochromaffin (EC) cell "carcinoid" (neuroendocrine) neoplasms, the principal cellular source of 5-HT. We hypothesized that 5-HT produced by metastatic EC cells played a role in the hepatic tumor-microenvironment principally via 5-HT₇ receptor-mediated activation of hepatocyte IGF-1 synthesis and secretion. Using isolated rat hepatocytes, we evaluated 5-HT₇ receptor expression (using PCR, sequencing and western blot). ELISA, cell transfection and western blots delineated 5-HT-mediated signaling pathways (pCREB, AKT and ERK). IGF-1 synthesis/secretion was evaluated using QPCR and ELISA. IGF-1 was tested on small intestinal neuroendocrine neoplasm proliferation, while IGF-1 production and 5-HT₇ expression were examined in an in vivo SCID metastasis model. Our results demonstrated evidence for a functional 5-HT₇ receptor. 5-HT activated cAMP/PKA activity, pCREB (130-205%, P < 0.05) and pERK/pAKT (1.2-1.75, P < 0.05). Signaling was reversed by the 5-HT₇ receptor antagonist SB269970. IGF-1 significantly stimulated proliferation of two small intestinal neuroendocrine neoplasm cell lines (EC₅₀: 7-70 pg/mL) and could be reversed by the small molecule inhibitor BMS-754807. IGF-1 and 5-HT were elevated (40-300×) in peri-tumoral hepatic tissue in nude mice, while 5-HT₇ was increased fourfold compared to sham-operated animals. We conclude that hepatocytes express a cAMP-coupled 5-HT₇ receptor, which, at elevated 5-HT concentrations that occur in liver metastases, signals via CREB/AKT and is linked to IGF-1 synthesis and secretion. Because IGF-1 regulates NEN proliferation, identification of a role for 5-HT₇ in the hepatic metastatic tumor microenvironment suggests the potential for novel therapeutic strategies for amine-producing mid-gut tumors.

  3. Peptide receptor radionuclide therapy in the management of gastrointestinal neuroendocrine tumors: efficacy profile, safety, and quality of life (United States)

    Severi, Stefano; Grassi, Ilaria; Nicolini, Silvia; Sansovini, Maddalena; Bongiovanni, Alberto; Paganelli, Giovanni


    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. Our results on the retreatment of patients previously administered 90Y-DOTA-Tyr3-octreotide with a low dosage of 177Lu-Dotatate are also included. A comment on potential future developments of PRRT in GEP-NETs is provided. PMID:28203088

  4. Child maltreatment, inflammation, and internalizing symptoms: Investigating the roles of C-reactive protein, gene variation, and neuroendocrine regulation. (United States)

    Cicchetti, Dante; Handley, Elizabeth D; Rogosch, Fred A


    Prior research has found inconsistent evidence regarding the association among childhood adversity, inflammation, and internalizing symptoms, perhaps because previous studies have yet to adequately integrate important factors such as the timing of the adversity, genetic variation, and other relevant processes such as neuroendocrine regulation. The aims of the present study were threefold: (a) to determine whether the effect of the timing of child maltreatment on C-reactive protein (CRP), an inflammatory marker, varies by CRP gene variation; (b) to explore whether links between salivary CRP and childhood internalizing symptoms depend on the presence and timing of maltreatment experiences; and (c) to investigate the role of CRP in the relations between child neuroendocrine regulation and internalizing symptoms and examine whether these associations are moderated by the presence and timing of child maltreatment. Participants included a sample of 267 maltreated and 222 nonmaltreated children (M age = 9.72, SD = 0.99; 52.4% male; 66% African American) who attended a summer day camp research program designed for school-aged low-income children. Department of Human Services records were examined to determine the onset and recency of maltreatment for children in the maltreated group. The results indicated that among children with recent onset maltreatment, those with at least one A allele from CRP single nucleotide polymorphism rs1417938 evidenced significantly higher CRP levels compared to recently maltreated children carrying the TT genotype. Moreover, higher levels of CRP were associated with higher levels of internalizing symptoms only for recently maltreated children. Finally, we did not find support for salivary CRP as a mechanism in the relation between neuroendocrine regulation and childhood internalizing symptoms. Our findings highlight the importance of the timing of child maltreatment and have important implications for characterizing variability in inflammation

  5. Current Status of Interventional Radiology in the Management of Gastro-Entero-Pancreatic Neuroendocrine Tumours (GEP-NETs)

    Energy Technology Data Exchange (ETDEWEB)

    Orgera, Gianluigi [S. Andrea University Hospital “Sapienza”, Unit of Interventional Radiology (Italy); Krokidis, Miltiadis, E-mail: [Cambridge University Hospitals NHS Trust, Department of Radiology (United Kingdom); Cappucci, Matteo [S. Andrea University Hospital “Sapienza”, Unit of Interventional Radiology (Italy); Gourtsoyianni, Sofia [Guy’s and St Thomas’ NHS Foundation Trust, Department of Radiology (United Kingdom); Tipaldi, Marcello Andrea [S. Andrea University Hospital “Sapienza”, Unit of Interventional Radiology (Italy); Hatzidakis, Adam [University Hospital of Heraklion, Department of Radiology, Medical School of Crete (Greece); Rebonato, Alberto [Santa Maria della Misericordia University Hospital, University of Perugia, Department of Surgical and Biomedical Sciences (Italy); Rossi, Michele [S. Andrea University Hospital “Sapienza”, Unit of Interventional Radiology (Italy)


    Within the group of Gastro-Entero-Pancreatic Neuroendocrine tumours (GEP-NETs), several heterogeneous malignancies are included with a variety of clinical manifestations and imaging characteristics. Often these cases are inoperable and minimal invasive treatment offered by image-guided procedures appears to be the only option. Interventional radiology offers a valid solution in the management of primary and metastatic GEP-NETs. The purpose of this review article is to describe the current status of the role of Interventional Radiology in the management of GEP-NETs.

  6. 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


    ., Rouille, Y., Holst, J., Carroll, R., Ravazzola, M., Orci, L., Furuta, H. & Steiner, D. (1997) Proc. Natl. Acad. Sci. USA 94, 6646-6651). The PC1/3-null mice differ from a human subject reported with compound heterozygosity for defects in this gene, who was of normal stature but markedly obese from early...... life. The PC1/3-null mice are not obese. The basis for these phenotypic differences is an interesting topic for further study. These findings prove the importance of PC1/3 as a key neuroendocrine convertase....

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

    Directory of Open Access Journals (Sweden)

    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.

  8. Class III/IV POU transcription factors expressed in small cell lung cancer cells are involved in proneural/neuroendocrine differentiation. (United States)

    Ishii, Jun; Sato, Hanako; Yazawa, Takuya; Shishido-Hara, Yukiko; Hiramatsu, Chie; Nakatani, Yukio; Kamma, Hiroshi


    One-third of lung malignancies demonstrate a proneural/neuroendocrine phenotype or type of differentiation. However, it has not been clearly elucidated how proneural/neuroendocrine differentiation is controlled in lung cancers. We recently demonstrated that the POU3F2 gene plays a significant role in proneural/neuroendocrine differentiation of lung cancers. Because class III POU genes (POU3F1, POU3F2, POU3F3, and POU3F4) and class IV POU genes (POU4F1, POU4F2, and POU4F3) share similar properties in neural development, we analyzed the association between class III/IV POU genes and a proneural/neuroendocrine phenotype in lung cancers using seven small cell lung cancer (SCLC) cell lines and twelve non-SCLC (NSCLC) cell lines. Class III/IV POU gene expression was generally restricted to SCLC cells. However, the forced expression of class III/IV POU genes in the NSCLC cell lines induced the expression of neuroendocrine-specific markers (neural call adhesion molecule 1, synaptophysin, and chromogranin A) and proneural transcription factors (achaete-scute homolog-like 1, NeuroD1, and thyroid transcription factor 1) in various degrees. Furthermore, each class III/IV POU gene induced other class III/IV POU genes, suggesting the mutual induction of class III/IV POU genes. These findings suggest that the expression of class III/IV POU genes is important for the proneural/neuroendocrine differentiation of lung cancer cells.

  9. The Ace of Spades: Reverse Takotsubo Cardiomyopathy in the Context of Angiographic Embolization of Recurrent Metastatic Serotonin-Positive Neuroendocrine Tumour of the Pancreas

    Directory of Open Access Journals (Sweden)

    Ian A. Mazzetti


    Full Text Available A 62-year-old woman undergoing embolization of recurrent neuroendocrine tumor, positive for serotonin, developed chest pain and bradycardia with lateral ST-segment depression. Cardiac biomarkers were elevated, and echocardiography revealed akinesis of all basal segments with a normally contracting apex. The absence of flow-limiting coronary disease on angiography confirmed the presence of reverse Takotsubo cardiomyopathy. After optimal medical therapy for six weeks, left ventricular function returned to normal. Takotsubo cardiomyopathy has been described across a wide variety of hyperadrenergic states; the description of the reverse-type Takotsubo cardiomyopathy in the setting of embolization of recurrent neuroendocrine with serotonergic positivity tumour is novel.

  10. Combined Undifferentiated and Neuroendocrine Carcinomas of the Gallbladder Appearing as Two Separate Lesions: A Case Report with Radiological-Pathological Correlation. (United States)

    Lee, So Won; Baek, Seung Yon; Sung, Sun Hee


    We report herein a rare case of incidentally detected combined undifferentiated and neuroendocrine carcinomas of the gallbladder. An incidental gallbladder malignancy was revealed on abdominal ultrasound and multi-detector computed tomography in a 54-year-old man. A short distance from the main polypoid hypoechoic mass at the fundus of the gallbladder, focal wall thickening was noted with prominently increased power Doppler flow. Extended cholecystectomy was performed, and histology confirmed the main polypoid mass as undifferentiated carcinoma and the separate nodule as neuroendocrine carcinoma. To our knowledge, this is the first report presenting two separate lesions of combined gallbladder carcinomas by radiological features.

  11. Activity of the neuroendocrine axes in patients with polymyalgia rheumatica before and after TNF-α blocking etanercept treatment

    DEFF Research Database (Denmark)

    Kreiner, Frederik Flindt; Galbo, Henrik


    ABSTRACT: INTRODUCTION: In this study, we evaluated the activity of the neuroendocrine axes in patients with polymyalgia rheumatica (PMR) before and after tumor necrosis factor (TNF)-α-blocking etanercept treatment, which previously has been shown to reduce interleukin 6 (IL-6) and C-reactive pro......ABSTRACT: INTRODUCTION: In this study, we evaluated the activity of the neuroendocrine axes in patients with polymyalgia rheumatica (PMR) before and after tumor necrosis factor (TNF)-α-blocking etanercept treatment, which previously has been shown to reduce interleukin 6 (IL-6) and C......-reactive protein (CRP) markedly in PMR. METHODS: Plasma samples were collected from 10 glucocorticoid-naïve patients with PMR and 10 matched controls before and after etanercept treatment (25 mg biweekly for 2 weeks). The primary end points were pre- and posttreatment levels of adrenocorticotropic hormone (ACTH...... treatment in patients, levels had decreased (P 0.05). CONCLUSIONS: In PMR, TNF-α may increase the activities of the hypothalamic-pituitary-adrenal and the hypothalamic...

  12. The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells (United States)

    Labrecque, Mark P.; Takhar, Mandeep K.; Nason, Rebecca; Santacruz, Stephanie; Tam, Kevin J.; Massah, Shabnam; Haegert, Anne; Bell, Robert H.; Altamirano-Dimas, Manuel; Collins, Colin C.; Lee, Frank J.S.; Prefontaine, Gratien G.; Cox, Michael E.; Beischlag, Timothy V.


    Loss of tumor suppressor proteins, such as the retinoblastoma protein (Rb), results in tumor progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumor that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1α and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role Rb plays in mediating hypoxia-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22Rv1 human prostate cancer cells. DNA microarray analysis revealed that loss of Rb in conjunction with hypoxia leads to aberrant expression of hypoxia-regulated genetic programs that increase cell invasion and promote neuroendocrine differentiation. For the first time, we have established a direct link between hypoxic tumor environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumors to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies. PMID:27015368

  13. The neuroendocrine-derived peptide parathyroid hormone-related protein promotes prostate cancer cell growth by stabilizing the androgen receptor. (United States)

    DaSilva, John; Gioeli, Daniel; Weber, Michael J; Parsons, Sarah J


    During progression to an androgen-independent state following androgen ablation therapy, prostate cancer cells continue to express the androgen receptor (AR) and androgen-regulated genes, indicating that AR is critical for the proliferation of hormone-refractory prostate cancer cells. Multiple mechanisms have been proposed for the development of AR-dependent hormone-refractory disease, including changes in expression of AR coregulatory proteins, AR mutation, growth factor-mediated activation of AR, and AR protein up-regulation. The most prominent of these progressive changes is the up-regulation of AR that occurs in >90% of prostate cancers. A common feature of the most aggressive hormone-refractory prostate cancers is the accumulation of cells with neuroendocrine characteristics that produce paracrine factors and may provide a novel mechanism for the regulation of AR during advanced stages of the disease. In this study, we show that neuroendocrine-derived parathyroid hormone-related protein (PTHrP)-mediated signaling through the epidermal growth factor receptor (EGFR) and Src pathways contributes to the phenotype of advanced prostate cancer by reducing AR protein turnover. PTHrP-induced accumulation of AR depended on the activity of Src and EGFR and consequent phosphorylation of the AR on Tyr(534). PTHrP-induced tyrosine phosphorylation of AR resulted in reduced AR ubiquitination and interaction with the ubiquitin ligase COOH terminus of Hsp70-interacting protein. These events result in increased accumulation of AR and thus enhanced growth of prostate cancer cells at low levels of androgen.

  14. Relationship Between Job Burnout and Neuroendocrine Indicators in Soldiers in the Xinjiang Arid Desert: A Cross-Sectional Study. (United States)

    Tao, Ning; Zhang, Jianjiang; Song, Zhixin; Tang, Jinhua; Liu, Jiwen


    The purpose of this study was to explore the relationship between job burnout and neuroendocrine indicators in soldiers living in a harsh environment. Three hundred soldiers stationed in the arid desert and 600 in an urban area were recruited. They filled in the Chinese Maslach Burnout Inventory questionnaire. One hundred soldiers were randomly selected from each group to measure their levels of noradrenaline, serotonin, heat shock protein (HSP)-70, adrenocorticotropic hormone, and serum cortisol. Job burnout was more common in soldiers from urban areas than those from rural areas. Job burnout was significantly higher among soldiers stationed in the arid desert than those in urban areas. For soldiers in the arid desert, the levels of HSP-70, serum cortisol, and adrenocorticotropic hormone were significantly higher than in soldiers in urban areas. Correlation analyses showed that the degree of job burnout was weakly negatively correlated with the level of HSP-70. Being an only child, HSP-70 levels, cortisol levels, and ACTH levels were independently associated with job burnout in soldiers stationed in the arid desert. A higher level of job burnout in soldiers stationed in arid desert and a corresponding change in neuroendocrine indicators indicated a correlation between occupational stress and neurotransmitters.

  15. Overcrowding-mediated stress alters cell proliferation in key neuroendocrine areas during larval development in Rhinella arenarum. (United States)

    Distler, Mijal J; Jungblut, Lucas D; Ceballos, Nora R; Paz, Dante A; Pozzi, Andrea G


    Exposure to adverse environmental conditions can elicit a stress response, which results in an increase in endogenous corticosterone levels. In early life stages, it has been thoroughly demonstrated that amphibian larval growth and development is altered as a consequence of chronic stress by interfering with the metamorphic process, however, the underlying mechanisms involved have only been partially disentangled. We examined the effect of intraspecific competition on corticosterone levels during larval development of the toad Rhinella arenarum and its ultimate effects on cell proliferation in particular brain areas as well as the pituitary gland. While overcrowding altered the number of proliferating cells in the pituitary gland, hypothalamus, and third ventricle of the brain, no differences were observed in areas which are less associated with neuroendocrine processes, such as the first ventricle of the brain. Apoptosis was increased in hypothalamic regions but not in the pituitary. With regards to pituitary cell populations, thyrotrophs but not somatoatrophs and corticotrophs showed a decrease in the cell number in overcrowded larvae. Our study shows that alterations in growth and development, produced by stress, results from an imbalance in the neuroendocrine systems implicated in orchestrating the timing of metamorphosis.

  16. Hegemony and cost-effectiveness of endoscopic ultrasound (EUS) in the field of gastroenteropancreatic-neuroendocrine tumors (GEP-NETs). (United States)

    De Angelis, C; Manfrè, S F; Bruno, M; Pellicano, R


    Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a group of neoplasms arising from the diffuse neuroendocrine system of the gastrointestinal (GI) tract. They often represent a diagnostic challenge because of their little dimensions, the deep localization into the retroperitoneum or in extramucosal sites, the possibility to be multilocated and the heterogeneous patterns of presentation. Endoscopic ultrasound (EUS) is a cost-effective technique that enables to look very definitely at a suspicious mass and at the surrounding area both withi