Showing papers in "Neuroendocrinology in 2016"

ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors.

Abstract: Only advances that occurred from 2011–2014 that either strengthen the previous 2011 guidelines [1;2] or lead to changes or additional guidelines are reviewed here. Advances and modifications in the treatment of advanced metastatic disease is only briefly dealt with here as it is covered in a separate chapter, similar to the 2011 guideline format [3]. The format used here is the same as used in the 2011 guidelines with page references to the appropriate section inserted [1;2] and this document is meant as a supplement to these guidelines and does not reiterate all of the points made in the previous guidelines, only changes, supporting findings or modifications of the 2011 guidelines are thus covered here. As in the previous F-p-NET guidelines [1], the F-p-NETs will be considered in three groups: the more frequent gastrinomas and insulinomas considered independently and all the rare functional p-NETs (RFTs) considered together and as a separate category (Annex 1 and Table 1). Table 1 Functional Pancreatic endocrine tumors [F-p-NET] syndromes

ENETS Consensus Guidelines Update for the Management of Distant Metastatic Disease of Intestinal, Pancreatic, Bronchial Neuroendocrine Neoplasms (NEN) and NEN of Unknown Primary Site

Abstract: The goal of this paper is to update a more extensive review and guidelines paper published in 2012 [1] . Gen-erally, any pertinent update pertaining to the diagnosis and staging of individual prima ...

ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas

Abstract: a Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid , Spain; b Department of Oncology, Haukeland University Hospital, Bergen , Norway; c Institut Gustave Roussy, Villejuif , and d Oncologie Médicale, Hôpitaux Universitaires Paris Nord Val de Seine, Paris , France; e Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin , Germany; f Department of Surgery, Medical University of Vienna, Vienna , Austria; g Department of Oncology, First Faculty of Medicine and General Teaching Hospital, Prague , Czech Republic; h Neuroendocrine Tumour Unit, Royal Free Hospital, London , UK; i Institut für Pathologie und Zytologie, St. Vincenz Krankenhaus, Limburg , Germany; j Department of Radiology, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn , Poland; k Neuroendocrine Tumour Unit, Royal Free Hospital, London , UK; l NET Centre, St. Vincent’s University and Department of Clinical Medicine, St. James Hospital and Trinity College, Dublin , Ireland; m Institute of Pathology, University of Bern, Bern , Switzerland

ENETS Consensus Guidelines Update for Neuroendocrine Neoplasms of the Jejunum and Ileum

Abstract: a Department of Surgery, Medical University of Vienna, Vienna , Austria; b Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin , Germany; c Centro de Oncologia, Hospital Sírio Libanês, São Paulo , Brazil; d Department of Endocrinology and Metabolism, Hadassah University Hospital, Mevasseret Tsion , Israel; e Department of Endocrinology, Erciyes University Medical School, Kayseri , Turkey; f Neuroendocrine Tumor Center of Excellence, Rigshospitalet, Copenhagen University Hospital, Copenhagen , Denmark; g Department of Medical Sciences, Endocrine Oncology Unit, University Hospital, Uppsala , Sweden; h Institute of Pathology, University of Bern, Bern , Switzerland; i Neuroendocrine Tumour Unit, Royal Free Hospital, London , UK; j Department of Clinical Oncology, Institute Alexander Fleming, Buenos Aires , Argentina; k National NET Centre, St. Vincent’s University and Department of Clinical Medicine, St. James Hospital and Trinity College, Dublin , Ireland; l Department of Internal Medicine, Division of Nuclear Medicine, Erasmus Medical Center, Rotterdam , The Netherlands; m Beatson Oncology Centre, Gartnavel General Hospital, Glasgow , UK; n Department of Surgery, CHU Robert Debré, Reims , France

ENETS Consensus Guidelines Update for Gastroduodenal Neuroendocrine Neoplasms.

Abstract: a Department of Digestive and Liver Disease, Ospedale Sant’Andrea, Rome , Italy; b NET Centre, St. Vincent’s University and Department of Clinical Medicine, St. James Hospital and Trinity College, Dublin , Ireland; c Department of Radiology, Section for Molecular Imaging, University Hospital, Uppsala , Sweden; d Netherlands Cancer Centre, Lijnden , The Netherlands; e NET Centre, Umbria Regional Cancer Network, Università degli Studi di Perugia, Perugia , Italy; f Gastroenterology Department, Hampshire Hospitals NHS Trust, Hampshire , UK; g Department of Endocrine and Metabolic Sciences, University of Genoa, Genoa , Italy; h Pancreatic Diseases Branch, Kyushu University Hospital, Fukuoka , Japan; i Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, N.Y. , USA; j Department of Endocrinology, Peking Union Medical College Hospital, Beijing , China; k Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, Rotterdam , The Netherlands; l Department of Visceral and Transplant Surgery, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin , Germany; m Department of Gastroenterology, Beaujon Hospital, Clichy , France

ENETS Consensus Guidelines Update for Colorectal Neuroendocrine Neoplasms

Abstract: a Gastroenterology Department, Hampshire Hospitals NHS Trust, Hampshire , UK; b Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, Rotterdam , The Netherlands; c Department of Digestive and Liver Disease, Ospedale Sant’Andrea, Rome , d NET Centre, Umbria Regional Cancer Network, Università degli Studi di Perugia, Perugia , and e Department of Endocrine and Metabolic Sciences (DIMI), University of Genoa, Genoa , Italy; f Pancreatic Diseases Branch, Kyushu University Hospital, Fukuoka , Japan; g Department of Gastroenterology, Beaujon Hospital, Clichy , France; h Department of Radiology, Section for Molecular Imaging, University Hospital, Uppsala , Sweden; i Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, N.Y. , USA; j Department of Endocrinology, Peking Union Medical College Hospital, Beijing , China; k Netherlands Cancer Centre, Lijnden , The Netherlands; l Department of Visceral and Transplant Surgery, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin , Germany

ENETS Consensus Guidelines for Neuroendocrine Neoplasms of the Appendix (Excluding Goblet Cell Carcinomas)

Abstract: ENETS Consensus Guidelines for Neuroendocrine Neoplasms of the Appendix (Excluding Goblet Cell Carcinomas)

Poststroke Inflammasome Expression and Regulation in the Peri-Infarct Area by Gonadal Steroids after Transient Focal Ischemia in the Rat Brain

Abstract: CNS ischemia results in locally confined and rapid tissue damage accompanied by a loss of neurons and their circuits. Early and time-delayed inflammatory responses are critical variables determining the extent of neural disintegration and regeneration. Inflammasomes are vital effectors in innate immunity. Their activation in brain-intrinsic immune cells contributes to ischemia-related brain damage. The steroids 17β-estradiol (E2) and progesterone (P) are neuroprotective and anti-inflammatory. Using a transient focal rat ischemic model, we evaluated the time response of different inflammasomes in the peri-infarct zone from the early to late phases after poststroke ischemia. We show that the different inflammasome complexes reveal a specific time-oriented sequential expression pattern with a maximum at approximately 24 h after the infarct. Within the limits of antibody availability, immunofluorescence labeling demonstrated that microglia and neurons are major sources of the locally activated inflammasomes NOD-like receptor protein-3 (NLRP3) and associated speck-like protein (ASC), respectively. E2 and P given for 24 h immediately after ischemia onset reduced hypoxia-induced mRNA expression of the inflammasomes NLRC4, AIM2 and ASC, and decreased the protein levels of ASC and NLRP3. In addition, mRNA protein levels of the cytokines interleukin-1β (IL1β), IL18 and TNFα were reduced by the steroids. The findings provide for the first time a detailed flow chart of hypoxia-driven inflammasome regulation in the peri-infarct cerebral cortex. Further, we demonstrate that E2 and P alleviate the expression of certain inflammasome components, sometimes in a hormone-specific way. Besides directly regulating other cellular neuroprotective pathways, the control of inflammasomes by these steroids might contribute to its neuroprotective potency.

ENETS 2016 Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Tumors: An Update.

Abstract: The participants at the conference were asked to focus on the relevant literature published between 2011 and 2015. They met over two and a half days, in which data and new evidence were presented. The participants then retreated to break-out sessions according to their disciplines and were required to answer questions listed in a workbook created by the session chairs and the organizing committee. The workbook questions were tailored on the text of the initial guidelines framework [2, 4] , focusing on the new available evidence. All relevant areas were updated via a thorough literature review and the questions that the chairpersons considered appropriate to discuss the new evidence. All participants were encouraged to challenge the document. Recent data on new evidence and insights were intensely discussed in working-group sessions as well as during the plenary session. Notes were taken continuously, so that the final agreement on each question was noted and returned to each session chair for preparation of the consensus statements. The magnitude of the consensus for each answer was estimated to achieve unanimity. In addition to providing textual guidelines, delegates were requested to elaborate accurate but simple Several guidelines and standards of care on the management of neuroendocrine tumors (NETs) have been published by expert national and international groups in recent years [1–9] ; additional changes in how these patients are managed are evolving rapidly, and since the last European Neuroendocrine Tumor Society (ENETS) Guidelines in 2011/12 [8] , new important data have become available pertaining to novel diagnostic tools and therapies. On October 30th and 31st, 2014, the ENETS held an Advisory Board meeting in Vienna aiming at critically discussing and updating the ENETS Guidelines on the Diagnosis and Treatment of Neuroendocrine Tumors generated initially in 2005–2006 [2, 4] and revised in 2011 [8] . The consensus sessions covered the following neuroendocrine neoplasm-related topics by sites of origin or stage: gastroduodenal, midgut (including appendix), hindgut, functional pancreatic, non-functional pancreatic, and two final sessions that covered liver and other distant metastases from neuroendocrine neoplasms of any origin and a separate session devoted to neuroendocrine high-grade tumors and carcinomas. Published online: January 6, 2016

Pancreatic Neuroendocrine Tumor Control: Durable Objective Response to Combination 177Lu-Octreotate-Capecitabine-Temozolomide Radiopeptide Chemotherapy

Abstract: Background/Methods: Thirty patients with advanced progressive grade 1 or 2 pancreatic neuroendocrine tumors (pNETs), treated on a prospective phase II single-cent

Streptozocin and 5-Fluorouracil for the Treatment of Pancreatic Neuroendocrine Tumors: Efficacy, Prognostic Factors and Toxicity.

Abstract: BACKGROUND: In our center, the combination of streptozocin (STZ) and 5-fluorouracil (5-FU) has been used as the first-line treatment in the majority of patients with pancreatic neuroendocrine tumor ...

MEN1, MEN4, and Carney Complex: Pathology and Molecular Genetics

Abstract: Pituitary adenomas are a common feature of a subset of endocrine neoplasia syndromes, which have otherwise highly variable disease manifestations. We provide here a review of the clinical features and human molecular genetics of multiple endocrine neoplasia (MEN) type 1 and 4 (MEN1 and MEN4, respectively) and Carney complex (CNC). MEN1, MEN4, and CNC are hereditary autosomal dominant syndromes that can present with pituitary adenomas. MEN1 is caused by inactivating mutations in the MEN1 gene, whose product menin is involved in multiple intracellular pathways contributing to transcriptional control and cell proliferation. MEN1 clinical features include primary hyperparathyroidism, pancreatic neuroendocrine tumours and prolactinomas as well as other pituitary adenomas. A subset of patients with pituitary adenomas and other MEN1 features have mutations in the CDKN1B gene; their disease has been called MEN4. Inactivating mutations in the type 1α regulatory subunit of protein kinase A (PKA; the PRKAR1A gene), that lead to dysregulation and activation of the PKA pathway, are the main genetic cause of CNC, which is clinically characterised by primary pigmented nodular adrenocortical disease, spotty skin pigmentation (lentigines), cardiac and other myxomas and acromegaly due to somatotropinomas or somatotrope hyperplasia.

Bone and Joint Disorders in Acromegaly

Abstract: Acromegaly is a chronic, progressive disease caused by a growth hormone (GH)-producing pituitary adenoma, resulting in elevated GH and insulin-like growth factor 1 concentrations. Following appropriate therapy (surgery, radiotherapy and/or medical treatment), many systemic GH-induced comorbid conditions improve considerably. Unfortunately, despite biochemical control, acromegaly patients suffer from a high prevalence of late manifestations of transient GH excess, significantly impairing their quality of life. In this overview article, we summarize the pathophysiology, diagnosis, clinical picture, disease course and management of skeletal complications of acromegaly, focusing on vertebral fractures and arthropathy.

Oxaliplatin-Based Chemotherapy in Advanced Neuroendocrine Tumors: Clinical Outcomes and Preliminary Correlation with Biological Factors

Abstract: Purpose: The role of chemotherapy in low-/intermediate-grade neuroendocrine tumors (NETs) is still debated. We present the results of an Italian multicenter retrospective study evaluating activity and toxicity of oxaliplatin-based chemotherapy in patients with advanced NETs. Methods: Clinical records from 5 referral centers were reviewed. Disease control rate (DCR) corresponding to PR + SD (partial response + stable disease) at 6 months, progression-free survival (PFS), overall survival (OS) and toxicity were calculated. Ki67 labeling index, grade of differentiation and excision- repair-cross-complementing group 1 (ERCC-1) were analyzed in tissue tumor samples. Results: Seventy-eight patients entered the study. Primary sites were: pancreas in 46, gastrointestinal in 24, lung in 19 and unknown in 10% of patients. The vast majority were G2 (2010 WHO classification). Eighty-six percent of the patients were metastatic, and 87% were pretreated and progressive to previous therapies. Sixty-five percent of the patients received capecitabine/oxaliplatin (CAPOX), 6% gemcitabine/oxaliplatin (GEMOX), and 29% leucovorin/fluorouracil/oxaliplatin (FOLFOX-6). PR occurred in 26% of the patients, half of them with pancreatic NETs, and SD in 54%. With a median follow-up of 21 months, the median PFS and OS were 8 and 32 months with 70 and 45 events, respectively. The most frequent G3 toxicities were neurological and gastrointestinal. ERCC-1 immunohistochemical overexpression was positive in 4/28 evaluated samples, with no significant correlation with clinical outcome. Conclusion: This analysis suggests that oxaliplatin-based chemotherapy can be active with a manageable safety profile in advanced NETs irrespective of the primary sites and tumor grade. The 80% DCR and 8-month PFS could justify a prospective study in NETs with intermediate biological characteristics, especially with pancreatic primary tumors.

Grade Increases in Gastroenteropancreatic Neuroendocrine Tumor Metastases Compared to the Primary Tumor.

Abstract: Background/Aim: The neuroendocrine tumor (NET) proliferation-based grading system (ENETS/WHO) for gastroenteropancreatic (GEP) tumors has proved reliable for prognostic stratification. To date, concerns exist regarding Ki-67 heterogeneity within the tumor and little is known on whether grade varies between primary and secondary sites. As tumor heterogeneity may have a significant impact on clinical management, our aim was to retrospectively evaluate Ki-67 on a series of GEP NETs in order to establish whether there is variability in different samples of the same lesion or between primary and metastatic disease (local/distant, synchronous/metachronous). Methods: Sixty patients with multiple samples of tumor were accrued from a total of 338 GEP NETs; 44 of them also had tissue from local/distant metastases and a further 5 had multiple metastatic foci from unknown primary tumors. Immunohistochemistry for Ki-67 was performed on all paraffin blocks from both primary and metastatic tumors. Results: Intratumor Ki-67 heterogeneity sufficient to change grade at first diagnosis was seen in 3/60 cases (5%). Out of 49 patients with primary NETs and/or multiple metastases, discrepancy in grade between sites was identified in 19 (39%) cases and in particular in 11/47 (23%) and in 10/12 (83%) patients with synchronous and metachronous metastases, respectively (p = 0.0002). Change in grade was more frequent in distant compared to locoregional metastases (p = 0.024) and in particular in distant sites other than the liver (p = 0.006). Conclusions: NETs show frequent differences in grade between primary sites and their synchronous/metachronous metastases; assessment of Ki-67 at all sites may prove to be significant for patient management.

Cardiovascular Disease and Sleep-Disordered Breathing in Acromegaly

Abstract: Treatment goals in acromegaly include symptom relief, tumour control and reversal of the excess morbidity and mortality associated with the disorder. Cardiovascular complications include concentric bi

Subclinical Thyroid Dysfunction and Depressive Symptoms among the Elderly: A Prospective Cohort Study.

Abstract: Background: Subclinical hypothyroidism has been associated with depressive symptoms in cross-sectional studies, but prospective data and data on subclinical hyperthyroidism are scarce. Methods: In the Leiden substudy of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), thyroid-stimulating hormone and free T4 levels were measured at baseline and repeated after 6 months in adults aged 70-82 years with preexisting cardiovascular disease or known cardiovascular risk factors to define persistent thyroid functional status. Main outcome measures were depressive symptoms, assessed with the Geriatric Depression Scale 15 (GDS-15) at baseline and after 3 years. All analyses were adjusted for age, gender and education. Results: In 606 participants (41% women; mean age 75 years) without antidepressant medication, GDS-15 scores at baseline did not differ for participants with subclinical hypothyroidism (n = 47; GDS-15 score 1.75, 95% CI 1.29-2.20, p = 0.53) or subclinical hyperthyroidism (n = 13; GDS-15 score 1.64, 95% CI 0.78-2.51, p = 0.96) compared to euthyroid participants (n = 546; mean GDS-15 score 1.60, 95% CI 1.46-1.73). After 3 years, compared to the euthyroid participants, changes in GDS-15 scores did not differ for participants with subclinical hypothyroidism (ΔGDS-15 score -0.03, 95% CI -0.50 to 0.44, p = 0.83), while subclinical hyperthyroidism was associated with an increase in GDS scores (ΔGDS-15 score 1.13, 95% CI 0.32-1.93, p = 0.04). All results were similar for persistent subclinical thyroid dysfunction. Conclusions: In this largest prospective study on the association of persistent subclinical thyroid dysfunction and depression, subclinical hypothyroidism was not associated with increased depressive symptoms among older adults at high cardiovascular risk. Persistent subclinical hyperthyroidism might be associated with increased depressive symptoms, which requires confirmation in a larger prospective study.

Toward a Preoperative Classification of Lymph Node Metastases in Patients with Small Intestinal Neuroendocrine Tumors in the Era of Intestinal-Sparing Surgery.

Abstract: Introduction: In patients with small intestinal neuroendocrine tumors (siNETs), surgical resection of the primary tumor and associated mesenteric lymph nodes (LNs) is recommended, but is not well standardized and can be risky in patients with superior mesenteric vessel involvement. Objective: We aimed to evaluate the correlation between the length of resected small bowel and the number of removed LNs, and to propose a preoperative morphological classification of siNET-associated LNs. Methods: The records of patients operated on for siNETs at two expert centers between August 2005 and November 2013 were analyzed. Two specialist radiologists reviewed the preoperative imaging and classified mesenteric LNs into five stages according to their proximity to the trunk and/or branches of the superior mesenteric artery. Results: 72 patients were included. The mean number of removed LNs was 12 ± 15 and the length of removed small intestine was 53 ± 43 cm. No correlation existed between the length of small bowel resection and the number of removed LNs. Overall, 9 (12%), 13 (18%), 36 (50%), 14 (19%) and 0 patients were classified into LN stages 0, I, II, III and IV. The correlation rate between the two observers was 0.98. Patients with LN stage III (hardly resectable) had more removed LNs than those with LN stages 0, I or II (easily removable). Conclusion: Optimal lymphadenectomy is not always associated with extended small bowel resection. In the era of small bowel-sparing surgery, the preoperative classification of mesenteric LNs could help to standardize the surgical management of patients with siNETs.

Active Surveillance versus Surgery of Nonfunctioning Pancreatic Neuroendocrine Neoplasms ≤2 cm in MEN1 Patients.

Abstract: Background: The aim of this study was to evaluate the efficacy of conservative treatment for nonfunctioning pancreatic neuroendocrine neoplasms (NF-PNEN) ≤2 cm in

Growth Hormone Dynamics in Healthy Adults Are Related to Age and Sex and Strongly Dependent on Body Mass Index.

Abstract: Background: Studies on 24-hour growth hormone (GH) secretion are rare. The influences of sex, age, and adiposity are well recognized but generally derived from specific, selected subject groups, not spanning sexes, many age decades, and a range of body weights. Objective: Our goal was to investigate GH dynamics in a group of 130 healthy adult subjects, both men and women, across 5 age decades as well as a 2.5-fold range of body mass index (BMI) values. Methods: GH was measured by a sensitive immunofluorometric assay. Secretion parameters were quantified by automated deconvolution and relative pattern randomness by approximate entropy (ApEn). Results: The median age was 40 years (range 20-77). The median BMI was 26 (range 18.3-49.8). Pulsatile 24-hour GH secretion was negatively correlated with age (p = 0.002) and BMI (p Conclusions: BMI dominates the negative regulation of 24-hour GH secretion across 5 decades of age in this up till now largest cohort of healthy adults who underwent 24-hour blood sampling. Sex also impacts GH secretion before the age of 50 years as well as its regularity at all ages. Differences in serum IGF-1 partly depend on the pre- or postmenopausal state. Finally, a single GH measurement is not informative of 24-hour GH secretion.

Appendiceal Goblet Cell Carcinoids: Management Considerations from a Reference Peritoneal Tumour Service Centre and ENETS Centre of Excellence

Abstract: Background: Appendix goblet cell carcinoids are known to share histological features of adenocarcinoma and neuroendocrine tumours. Due to their low incidence, quality evidence is lacking for the management of these patients. Methods: We performed a single-centre retrospective study of patients with a confirmed diagnosis of appendiceal goblet cell carcinoid (GCC; 1996-2014). Patients were divided into curative intent (CI) and palliative intent (PI) cohorts. Our primary end point was overall survival (OS). Results: Seventy-four patients were eligible; 76% were treated with CI [surgery only (36%), cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC; 36%), adjuvant chemotherapy (20%) and a combination of CRS and HIPEC followed by adjuvant chemotherapy (9%)], and 23% had advanced-stage disease amenable to palliative treatment (chemotherapy or supportive care) only. Completion right hemicolectomy, performed in 64% of the CI cohort, did not impact on the relapse rate or disease-free survival. FOLFOX chemotherapy was used in both the adjuvant and palliative settings; safety was as expected, and we observed a high rate (60%) of disease control in the palliative cohort. The estimated median OS (all patients), disease-free survival (CI patients) and progression-free survival (PI patients) were 52.1 (95% CI 29.4-90.3), 75.9 (26.6-not reached) and 5.3 (0.6-5.7) months, respectively. Age and stage were independent factors associated with OS in the multivariable analysis. Tang classification showed a trend for impact on OS. No benefit from specific adjuvant approach was identified; however, selection bias for treatment approach was observed. Conclusion: Prospective trials are needed to define optimal approaches in GCC. All GCC patients should be managed by specialized centres due to their esoteric behaviour; we provide management considerations based on our experience and conclusions.

Niacin (Vitamin B3) Supplementation in Patients with Serotonin-Producing Neuroendocrine Tumor.

Abstract: Background/Aims: Tryptophan is the precursor of serotonin and niacin (vitamin B3) The latter is critical for normal cellular metabolism Tryptophan and niacin can be deficient in patients with serotonin-producing neuroendocrine tumors (NETs) Niacin deficiency may lead to severe symptoms including pellagra In patients with serotonin-producing NET, data on niacin status are scarce and niacin supplementation hardly receives attention We aimed to assess the niacin status before and after supplementation in these patients Methods: We identified serotonin-producing NET patients who had received oral niacin supplementation (mean dose 144 mg daily) for tryptophan deficiency and/or pellagra-associated symptoms Presupplementation plasma tryptophan levels and niacin status based on the urinary niacin metabolite N1-methylnicotinamide (N1-MN) before (n = 42) and after the start of the supplementation (in 34 paired samples) were assessed Reference values for urinary N1-MN levels were established in 133 healthy individuals Results: The mean presupplementation plasma tryptophan level was 318 ± 97 µmol/l (reference value 400-700) Presupplementation urinary N1-MN levels were lower in patients (median 179 µmol/24 h, range 26-703) compared to healthy controls (median 437 µmol/24 h, range 95-1693, p 1-MN levels to high normal levels (median 555 µmol/24 h, range 74-4890) in 86% of the niacin-deficient patients Conclusion: In serotonin-producing NET patients, niacin deficiency is prevalent Therefore, urinary N1-MN deserves to be included in their standard biochemical evaluation Niacin supplementation normalizes the niacin status in most niacin-deficient serotonin-producing NET patients A prospective study is warranted

Effects of Subchronic Finasteride Treatment and Withdrawal on Neuroactive Steroid Levels and Their Receptors in the Male Rat Brain

Abstract: The enzymatic conversion of progesterone and testosterone by the enzyme 5alpha-reductase exerts a crucial role in the control of nervous function. The effects of finasteride in the brain, an inhibitor of this enzyme used for the treatment of human benign prostatic hyperplasia and androgenic alopecia, have been poorly explored. Therefore, the effects of a subchronic treatment with finasteride at low doses (3 mg/kg/day) and the consequences of its withdrawal on neuroactive steroid levels in plasma, cerebrospinal fluid and some brain regions as well as on the expression of classical and non-classical steroid receptors have been evaluated in male rats. After subchronic treatment (i.e., for 20 days) the following effects were detected: (i) depending on the compartment considered, alteration in the levels of neuroactive steroids, not only in 5alpha-reduced metabolites but also in its precursors and in neuroactive steroids from other steroidogenic pathways and (ii) an upregulation of the androgen receptor in the cerebral cortex and beta3 subunit of the GABA-A receptor in the cerebellum. One month after the last treatment (i.e., withdrawal period), some of these effects persisted (i.e., the upregulation of the androgen receptor in the cerebral cortex, an increase of dihydroprogesterone in the cerebellum, a decrease of dihydrotestosterone in plasma). Moreover, other changes in neuroactive steroid levels, steroid receptors (i.e., an upregulation of the estrogen receptor alpha and a downregulation of the estrogen receptor beta in the cerebral cortex) and GABA-A receptor subunits (i.e., a decrease of alpha 4 and beta 3 mRNA levels in the cerebral cortex) were detected. These findings suggest that finasteride treatment may have broad consequences for brain function.

Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells

Abstract: Background/Aims: Histone deacetylases (HDACs) modulate lysine acetylation on histones and are frequently deregulated in cancer. HDAC inhibitors with potent anti-tumour effects have been developed and are now being tested in clinical trials. The aim of this study was to investigate the effects of valproic acid (VPA), an inhibitor of class I and class IIa HDACs, on neuroendocrine tumour (NET) cell growth. Methods: Three NET cell lines, GOT1 (small intestinal), KRJ-I (small intestinal), and BON (pancreatic), were treated with VPA and examined with respect to cell viability, cell cycle arrest, apoptosis, and global transcriptional response. Results: We found that VPA induced a dose-dependent growth inhibition of NET cells in vitro, which was mainly due to activation of extrinsic and intrinsic apoptotic pathways. VPA induced a major transcriptional response by altering the expression of 16-19% of the protein-coding genes in NET cell lines. Pathway analysis allowed the prediction of alterations in key regulatory pathways, e.g. activation of TGF-β1, FOXO3, p53 signalling, and inhibition of MYC signalling. Analysis of GOT1 xenografts showed reduced growth and reduced Ki-67 index, as well as an increase in apoptosis and necrosis after VPA treatment. Conclusions: We found that VPA treatment has a cytotoxic effect on NET cells of intestinal and pancreatic origin. There are several mechanisms by which VPA kills NET cells, which suggests the possibility of combination therapy. We propose that epigenetic therapy with HDAC inhibitors should be evaluated further in patients with NET disease.

Pegvisomant Treatment in Acromegaly.

Abstract: Historically, medical treatment of acromegaly has mainly been used as an adjuvant therapy after surgery. In the last decades, an increased range of medical therapy options has been available. Somatostatin analogues have become the cornerstones of medical treatment in acromegaly and are even seen as a primary treatment in a selected group of acromegaly patients. The most recent medical treatment available for acromegaly patients is pegvisomant, a growth hormone receptor antagonist. To date, it is the most effective medical treatment, but it is costly. Pegvisomant is used as monotherapy and combined with somatostatin analogues. In this article, we review clinical studies and cohorts that have documented the efficacy of pegvisomant monotherapy and combined therapy and give a concise overview of associated side effects.

Effects of Long-Term Treatment with Estradiol and Estrogen Receptor Subtype Agonists on Serotonergic Function in Ovariectomized Rats.

Abstract: Acute estradiol treatment was reported to slow the clearance of serotonin via activation of estrogen receptors (ER)β and/or GPR30 and to block the ability of a selective serotonin reuptake inhibitor (SSRI) to slow serotonin clearance via activation of ERα. In this study, the behavioral consequences of longer-term treatments with estradiol or ER subtype-selective agonists and/or an SSRI were examined in the forced swim test (FST). Ovariectomized rats were administered the following for 2 weeks: estradiol, ERβ agonist (diarylpropionitrile, DPN), GPR30 agonist (G1), ERα agonist (PPT), and/or the SSRI sertraline. Similar to sertraline, longer-term treatment with estradiol, DPN or G1 induced an antidepressant-like effect. By contrast, PPT did not, even though it blocked the antidepressant-like effect of sertraline. Uterus weights, used as a peripheral measure of estrogenic activity, were increased by estradiol and PPT but not DPN or G1 treatment. A second part of this study investigated, using Western blot analyses in homogenates from hippocampus, whether these behavioral effects are accompanied by changes in the activation of specific signaling pathways and/or TrkB. Estradiol and G1 increased phosphorylation of Akt, ERK and TrkB. These effects were similar to those obtained after treatment with sertraline. Treatment with DPN increased phosphorylation of ERK and TrkB, but it did not alter that of Akt. Treatment with PPT increased phosphorylation of Akt and ERK without altering that of TrkB. In conclusion, activation of at least TrkB and possibly ERK may be involved in the antidepressant-like effect of estradiol, ERβ and GPR30 agonists whereas Akt activation may not be necessary.

Medical Treatment of Acromegaly with Dopamine Agonists or Somatostatin Analogs

Abstract: Treatment of acromegaly aims to correct (or prevent) tumor compression of surrounding tissues by excising the disease-causing lesion and reduce growth hormone (GH) and IGF-1 levels to normal values. When surgery (the usual first-line treatment) fails to correct GH/IGF-1 hypersecretion, medical treatment with dopamine agonists (DAs; particularly cabergoline) or somatostatin analogs (SAs) can be used. The GH receptor antagonist pegvisomant is helpful in patients who are totally or partially resistant to SAs and can be given in association with both SAs and/or DAs. Thanks to this multistep therapeutic strategy, adequate hormonal disease control is achieved in most patients, giving them normal life expectancy. Comorbidities associated with acromegaly generally improve after treatment, but persistent sequelae may nonetheless impair quality of life.

The History of Acromegaly.

Abstract: Pierre Marie coined the term 'acromegaly' in 1886 and linked it to a distinct clinical disease with a characteristic clinical picture. However, Pierre Marie was not the first physician to give a full record of the clinical picture of acromegaly; others had preceded him, like the Dutch physician Johannes Wier. After Marie, pituitary enlargement was noted in almost all patients with acromegaly. Subsequently it was discovered that pituitary hyperfunction caused by a pituitary tumour was indeed the cause of acromegaly. The cause of acromegaly could be further determined after the discovery of growth hormone (GH) and insulin-like growth factor I (IGF-I) and after demonstrating an association with GH hypersecretion and elevated circulating IGF-I. From the beginning of the 20th century, acromegaly could be treated by pituitary surgery and/or radiotherapy. After 1970, medical therapies were introduced that could control acromegaly. First, dopamine agonists were introduced, followed by somatostatin analogues and GH receptor blockers.

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

Abstract: Background: Numerous studies have reported on the neuroprotective activity of estradiol, whereas the effect of the other ovarian steroid, progesterone, is much less documented. Methods: This study sought to investigate neuroprotection with a low dose of progesterone (1 µg) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated male mice to model Parkinson's disease and compare it to the effect of this steroid in intact mice (experiment 1). We also investigated if high doses of progesterone could protect dopaminergic neurons already exposed to MPTP (experiment 2). We measured progesterone effects on various dopaminergic markers [dopamine and its metabolites, dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2)] and on neuroactive steroids in both plasma and the brain. Results: For experiment 1, our results showed that progesterone completely prevented the effect of MPTP toxicity on dopamine concentrations, on the increase in the 3-methoxytyramine/dopamine ratio, as well as on VMAT2-specific binding in the striatum and the substantia nigra. Progesterone decreased MPTP effects on 3,4-dihydroxyphenylacetic acid concentrations and DAT-specific binding in the lateral part of the anterior striatum and in the middle striatum (medial and lateral parts). Progesterone treatment of intact mice had no effect on the markers investigated. For experiment 2, measures of dopaminergic markers in the striatum showed that 8 mg/kg of progesterone was the most effective dose to reduce MPTP effects, and more limited effects were observed with 16 mg/kg. We found that progesterone treatment increases the levels of brain progesterone itself as well as of its metabolites. Conclusion: Our result showed that progesterone has neuroprotective effects on dopaminergic neurons in MPTP-treated male mice.

The Metabolic Risk in Patients Newly Diagnosed with Acromegaly Is Related to Fat Distribution and Circulating Adipokines and Improves after Treatment

Abstract: Background/Aims: Adipose tissue (AT) distribution is closely related to metabolic disease risk. Growth hormone (GH) reduces visceral and total body fat mass and induces whole-body insulin resistance. Our aim was to assess the effects of total and visceral AT (VAT) distribution and derived adipokines on systemic insulin resistance and lipid metabolism in acromegaly. Methods: Seventy adult patients with active acromegaly (43 males, age 49 ± 14 years) were evaluated before treatment, and a subset (n = 30, 20 males) was evaluated after treatment for acromegaly. Body composition and VAT, glucose metabolism parameters, lipids, C-reactive protein, and selected adipokines (vaspin, omentin, adiponectin, and leptin) were measured. Results: At baseline, VAT was positively associated with glucose metabolism parameters and with lipids. GH, but not IGF-I, was negatively associated with all AT depots (visceral, trunk, limbs, and total; 0.41 ≤ r ≤ 0.61, p 2 = 0.59, p = 0.001). Conclusions: (1) VAT is a metabolic risk factor for patients with active acromegaly; (2) vaspin and omentin levels are influenced by the disease activity but are not associated with VAT mass; (3) fat deposition after treatment occurs predominantly on the trunk and in visceral depots, and (4) insulin resistance decreases and the lipid profile partially improves with treatment.