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3.
Z Gastroenterol ; 53(10): 1194-200, 2015 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-26480056

RESUMO

Neuroendocrine neoplasias are seldom, but increasing. This holds true for the incidence but even more for the prevalence, since patients are able to live with their disease for quite a long time. The European Neuroendocrine Tumor Society (ENETS) as well as other societies (NANETS: North American Neuroendocrine Tumor Society; NCCN: National Comprehensive Cancer Network; ESMO: European Society of Medical Oncology) have published diagnostic and therapeutic guidelines that we present in this review. We aim to summarize those actual guidelines in a practice-based diagnostic and therapeutic algorithm, but also wish to point to open questions that have to be discussed in a multidisciplinary approach.


Assuntos
Algoritmos , Gastroenterologia/normas , Neoplasias Gastrointestinais/terapia , Oncologia/normas , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/terapia , Tomada de Decisão Clínica , Europa (Continente) , Neoplasias Gastrointestinais/diagnóstico , Alemanha , Humanos , Internacionalidade , Tumores Neuroendócrinos/diagnóstico , América do Norte , Neoplasias Pancreáticas/diagnóstico , Guias de Prática Clínica como Assunto
4.
Pathologe ; 36(3): 261-70, 2015 May.
Artigo em Alemão | MEDLINE | ID: mdl-25986886

RESUMO

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


Assuntos
Neoplasias da Mama/patologia , Tumores Neuroendócrinos/patologia , Biomarcadores Tumorais/análise , Mama/patologia , Proliferação de Células , Cromogranina A/análise , Feminino , Humanos , Invasividade Neoplásica , Prognóstico , Sinaptofisina/análise
5.
Nuklearmedizin ; 54(1): 1-11; quiz N2, 2015.
Artigo em Alemão | MEDLINE | ID: mdl-25683107

RESUMO

This document describes the guideline for peptide receptor radionuclide therapy (PRRT) published by the German Society of Nuclear Medicine (DGN) and accepted by the Association of the Scientific Medical Societies in Germany (AWMF) to be included in the official AWMF Guideline Registry. These recommendations are a prerequisite for the quality management in the treatment of patients with somatostatin receptor expressing tumours using PRRT. They are aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRT and to deliver the treatment in a safe and effective manner. The recommendations are based on an interdisciplinary consensus. The document contains background information and definitions and covers the rationale, indications and contraindications for PRRT. Essential topics are the requirements for institutions performing the therapy, e. g. presence of an expert for medical physics, intense cooperation with all colleagues involved in the treatment of a patient, and a certificate of instruction in radiochemical labelling and quality control are required. Furthermore, it is specified which patient data have to be available prior to performance of therapy and how treatment has to be carried out technically. Here, quality control and documentation of labelling are of great importance. After treatment, clinical quality control is mandatory (work-up of therapy data and follow-up of patients). Essential elements of follow-up are specified in detail. The complete treatment inclusive after-care has to be realised in close cooperation with the involved medical disciplines. Generally, the decision for PRRT should be undertaken within the framework of a multi-disciplinary tumour board.


Assuntos
Neoplasias/metabolismo , Neoplasias/radioterapia , Peptídeos/farmacocinética , Radioterapia (Especialidade)/normas , Compostos Radiofarmacêuticos/uso terapêutico , Receptores de Somatostatina/metabolismo , Alemanha , Humanos , Guias de Prática Clínica como Assunto , Compostos Radiofarmacêuticos/farmacocinética
6.
Exp Clin Endocrinol Diabetes ; 123(2): 118-25, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25393342

RESUMO

Class 1A phosphoinositide 3-kinase (PI3K) is essential for beta-cell growth and survival. Although PI3K has been studied extensively in diabetes the effect of alternatively spliced isoforms of the catalytic subunit p85α on beta cell proliferation and survival remains to be defined.We examined expression and signaling of alternatively spliced PI3K regulatory subunits p85α, p55α and p50α in insulinoma cells (INS-1E), an insulin-producing beta cell line. PI3K regulatory isoforms were knocked down by siRNA transfection or overexpressed by adenoviral gene delivery.Knockdown of p85α elevated PI3K activation determined by Akt phosphorylation at baseline and after stimulation with growth factors. In contrast, Akt phosphorylation was inhibited by overexpression of all isoforms of p85α. Correspondingly, p55α and p85α overexpression decreased downstream kinase GSK-3 phosphorylation as well, whereas p50α overexpression resulted in an activation of GSK-3. Moreover, overexpression of p50α and p85α lead to retinoblastoma protein hyperphosphorylation and S-phase entry. Upon challenge of INS-1E cells with a cytotoxic cytokine cocktail, levels of p85α were reduced and p50α was upregulated. Selective overexpression of p50α prevented cytokine induced apoptosis in INS-1E cells.In conclusion, signalling of p50α, p55α and p85α is similar at the level of Akt, but differentially influence downstream GSK-3 activation and cell cycle entry. PI3K isoform p50α induction by cytokines provides a link between regeneration and cell survival under cytotoxic stress in insulin-producing pancreatic beta-cells.


Assuntos
Sobrevivência Celular/fisiologia , Insulinoma/metabolismo , Neoplasias Pancreáticas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/fisiologia , Animais , Linhagem Celular Tumoral , Quinase 3 da Glicogênio Sintase/metabolismo , Fosforilação , Ratos
7.
Clin Exp Metastasis ; 31(7): 817-27, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25098566

RESUMO

Gastroenteropancreatic neuroendocrine tumors (NETs) often present as liver metastasis from a carcinoma of unknown primary. We recently showed that primary NETs from the pancreas, small intestine and stomach as well as their respective liver metastases differ from each other by the expression profile of the three genes CD302, PPWD1 and ABHB14B. The gene and protein expression of CD302, PPWD1, and ABHB14B was studied in abdominal NET metastases to identify the site of the respective primary tumors. Cryopreserved tissue from NET metastases collected in different institutions (group A: 29, group B: 50, group C: 132 specimens) were examined by comparative genomic hybridization (Agilent 105 K), gene expression analysis (Agilent 44 K) (groups A and B) and immunohistochemistry (group C). The data were blindly evaluated, i.e. without knowing the site of the primary. Gene expression analysis correctly revealed the primary in the ileum in 94 % of the cases of group A and in 58 % of group B. A pancreatic primary was predicted in 83 % (group A) and 20 % (group B), respectively. The combined sensitivity of group A and B was 75 % for ileal NETs and 38 % for pancreatic NETs. Immunohistochemical analysis of group C revealed an overall sensitivity of 80 %. Gene and protein expression analysis of CD302 and PPWD1 in NET metastases correctly identifies the primary in the pancreas or the ileum in 80 % of the cases, provided that the tissue is well preserved. Immunohistochemical profiling revealed CD302 as the best marker for ileal and PPWD1 for pancreatic detection.


Assuntos
Glândulas Endócrinas/patologia , Metástase Neoplásica , Neoplasias/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Neoplasias/genética
8.
Pneumologie ; 68(7): 456-77, 2014 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-25006841

RESUMO

The pulmonary neuroendocrine neoplasms originate from the enterochromaffin cells which are diffusely distributed in the body. The incidence of these tumors has increased significantly in recent decades due to the available diagnostics. They make up about 1-2% of all lung tumors and 20-30% of all neuroendocrine neoplasms. The current WHO classification from 2004 divides them into typical carcinoids (TC), atypical carcinoids (AC), large cell neuroendocrine carcinomas (LCNEC) and small cell carcinomas (SCLC). The major neuroendocrine biomarkers are chromogranin A, synaptophysin and CD56. TC have a low mitotic rate of <2 mitoses/2mm(2) (10 HPF), whereas the mitotic rate of the AC is 2-10 mitoses/2 mm(2) (10 HPF). The Ki-67 staining is helpful to distinguish typical and atypical carcinoids from the highly malignant LCNEC and SCLC. Clinically, the patient presents usually with cough, hemoptysis or bronchial obstruction. The occurrence of a carcinoid or Cushing's syndrome and a tumor-associated acromegaly are rare. Surgical resection with radical lymph node dissection is the treatment of choice for achieving long-term survival. Endoscopic resection of the endobronchial tumor growth is a good alternative for inoperable endobronchially localized tumors. Peptide receptor radionuclide therapy (PRRT) is a promising treatment option for patients with metastatic or unresectable pulmonary neuroendocrine tumors. New targeted therapies using angiogenesis inhibitors, mTOR inhibitors, and tyrosine kinase inhibitors are being tested for their effectiveness in many previous studies. Typical carcinoid tumors metastasize less frequently than AC, the 5-year survival rate of patients with TC being over 90%. Patients with AC have a 5-year survival rate between 35% and 87%. The highly malignant LCNEC and SCLC, on the other hand, have a 5-year survival rate between 15% and 57%, and <5% respectively. The increasing number of therapeutic options and diagnostic procedures requires a multidisciplinary approach and decision-making in multidisciplinary tumor conferences to ensure a personalized treatment approach. Therefore patients with a neuroendocrine neoplasm of the lung should be treated in specialized centers.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Biomarcadores Tumorais/sangue , Endoscopia/métodos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/terapia , Endoscopia/estatística & dados numéricos , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/mortalidade , Tumores Neuroendócrinos/mortalidade , Prevalência , Taxa de Sobrevida , Resultado do Tratamento
9.
Chirurg ; 85(6): 500-4, 2014 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-24844432

RESUMO

Neuroendocrine neoplasms (NEN) are rare malignancies with a wide spectrum of metastatic potential which originate from the endocrine cells of the body and express somatostatin receptors. The (68)gallium somatostatin receptor positron emission tomography-computed tomography (PET/CT) technique is the most sensitive method of assessment of well-differentiated NENs and for the detection of cancer of unknown primary (CUP syndrome) NENs. Imaging with 18F-fluorodeoxyglucose (18F-FDG PET/CT) is indicated in poorly differentiated neuroendocrine carcinomas. The receptor-dependent imaging of NENs has a decisive impact on further management.


Assuntos
Imagem Molecular/métodos , Imagem Multimodal/métodos , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/cirurgia , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X/métodos , Fluordesoxiglucose F18 , Radioisótopos de Gálio , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Primárias Desconhecidas/diagnóstico , Neoplasias Primárias Desconhecidas/genética , Neoplasias Primárias Desconhecidas/patologia , Neoplasias Primárias Desconhecidas/cirurgia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Receptores de Somatostatina , Sensibilidade e Especificidade , Somatostatina
10.
Pathologe ; 35(3): 283-93; quiz 294, 2014 May.
Artigo em Alemão | MEDLINE | ID: mdl-24671468

RESUMO

Neuroendocrine neoplasms (NEN) of the distal jejunum and ileum derive from serotonin-producing enterochromaffin (EC) cells. Due to their low proliferation rate and their infiltrative growth, they are often discovered at an advanced disease stage when metastasis has already occurred. The biology of these tumours is different from other NEN of the digestive tract. In order to standardise and improve diagnosis and therapy, the guidelines for the diagnosis and clinical management of jejuno-ileal NEN as well as for the management of patients with liver and other distant metastases from NEN were revised by the European Neuroendocrine Tumour Society (ENETS) in 2012. This review focuses on aspects relevant for surgical pathology.


Assuntos
Neoplasias do Íleo/patologia , Neoplasias do Jejuno/patologia , Tumores Neuroendócrinos/patologia , Proliferação de Células , Diagnóstico Diferencial , Progressão da Doença , Células Enterocromafins/patologia , Humanos , Neoplasias do Íleo/cirurgia , Íleo/patologia , Íleo/cirurgia , Neoplasias do Jejuno/cirurgia , Jejuno/patologia , Jejuno/cirurgia , Tumores Neuroendócrinos/cirurgia , Guias de Prática Clínica como Assunto , Receptores de Somatostatina/análise
11.
Zentralbl Chir ; 139(4): 415-27, 2014 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-24327486

RESUMO

Diffuse localised neuroendocrinal cells represent the largest population of endocrinally active cells and can degenerate to malignant neuroendocrine tumours (NET). In this review the most important hereditary syndromes that predispose for endocrine and neuroendocrine tumours are presented and discussed. NET occur mainly as sporadic tumours. Current investigations on the pathogenesis of sporadic neuroendocrine tumours have revealed a close relationship between hereditary and sporadic neuroendocrine tumours. In the course of hereditary syndromes, such as multiple endocrine neoplasia, endocrine and neuroendocrine tumours as well as non-endocrine neoplasias can occur. In order to recognise these syndromes in good time a knowledge of the predisposing syndromes and their cardinal symptoms is essential. In this way not only individualised diagnosis and therapy can be planned but also an appropriate early management of first degree relatives can be initiated.


Assuntos
Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/cirurgia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/cirurgia , Diagnóstico Diferencial , Neoplasias Gastrointestinais/diagnóstico , Humanos , Tumores Neuroendócrinos/diagnóstico , Síndrome
12.
Eur J Nucl Med Mol Imaging ; 40(5): 800-16, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23389427

RESUMO

Peptide receptor radionuclide therapy (PRRNT) is a molecularly targeted radiation therapy involving the systemic administration of a radiolabelled peptide designed to target with high affinity and specificity receptors overexpressed on tumours. PRRNT employing the radiotagged somatostatin receptor agonists (90)Y-DOTATOC ([(90)Y-DOTA(0),Tyr(3)]-octreotide) or (177)Lu-DOTATATE ([(177)Lu-DOTA(0),Tyr(3),Thr(8)]-octreotide or [(177)Lu-DOTA(0),Tyr(3)]-octreotate) have been successfully used for the past 15 years to target metastatic or inoperable neuroendocrine tumours expressing the somatostatin receptor subtype 2. Accumulated evidence from clinical experience indicates that these tumours can be subjected to a high absorbed dose which leads to partial or complete objective responses in up to 30 % of treated patients. Survival analyses indicate that patients presenting with high tumour receptor expression at study entry and receiving (177)Lu-DOTATATE or (90)Y-DOTATOC treatment show significantly higher objective responses, leading to longer survival and improved quality of life. Side effects of PRRNT are typically seen in the kidneys and bone marrow. These, however, are usually mild provided adequate protective measures are undertaken. Despite the large body of evidence regarding efficacy and clinical safety, PRRNT is still considered an investigational treatment and its implementation must comply with national legislation, and ethical guidelines concerning human therapeutic investigations. This guidance was formulated based on recent literature and leading experts' opinions. It covers the rationale, indications and contraindications for PRRNT, assessment of treatment response and patient follow-up. This document is aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRNT and to deliver the treatment in a safe and effective manner. This document is largely based on the book published through a joint international effort under the auspices of the Nuclear Medicine Section of the International Atomic Energy Agency.


Assuntos
Agências Internacionais , Terapia de Alvo Molecular/métodos , Tumores Neuroendócrinos/radioterapia , Energia Nuclear , Radioterapia/métodos , Receptores de Peptídeos/metabolismo , Sociedades Científicas , Europa (Continente) , Seguimentos , Humanos , Rim/fisiologia , Rim/efeitos da radiação , Terapia de Alvo Molecular/efeitos adversos , Tumores Neuroendócrinos/metabolismo , Controle de Qualidade , Radiometria , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/uso terapêutico , Radioterapia/efeitos adversos
13.
Minerva Gastroenterol Dietol ; 58(4): 401-26, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23207615

RESUMO

Pancreatic neuroendocrine tumors originate from the diffuse neuroendocrine system in the pancreatic region. These tumors exhibit a rising incidence despite their rareness and due to their benign behavior a considerable prevalence. Pathogenesis of pancreatic neuroendocrine tumors is characterized by common pathways of hereditary and sporadic tumors. Pancreatic neuroendocrine tumors may secrete peptide hormones or biogenic amines in an autonomous fashion as functional active tumors. Pathological grading and staging by TNM systems has been established in recent years classifying well and moderately differentiated pancreatice neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Chromogranin A and less so pancreatic polypeptide are suitable tumor markers for pancreatic neuroendocrine tumors. Expression of receptors for somatostatin is the basis of treatment of pancreatic neuroendocrine tumors with somatostatin analogues as antisecretive and antiproliferative agents. In addition, somatostatin scintigraphy or PET/CT allows comprehensive diagnosis of pancreatic neuroendocrine tumors, which should be supported by (endoscopic and contrast enhanced) ultrasound, CT and MRI. Therapy of pancreatic neuroendocrine tumors consists of somatostatin analogues, chemotherapy, targeted therapy and peptide receptor radionuclide therapy. Two molecular substances hav been registered for pancreatic neuroendocrine tumors recently, sunitinib (Sutent®) and everolimus (Afinitor®). Predominant tumor load in the liver may be treated by local ablative therapy or liver transplantation. These treatment options have been included in guidelines of several professional societies and weighted for sequential therapy of patients with pancreatic neuroendocrine tumors according to effects and side effects.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/tratamento farmacológico , Biomarcadores/sangue , Cromogranina A/sangue , Endossonografia , Everolimo , Alemanha/epidemiologia , Hepatectomia , Humanos , Incidência , Indóis/administração & dosagem , Transplante de Fígado , Imageamento por Ressonância Magnética , Imagem Multimodal , Gradação de Tumores , Estadiamento de Neoplasias , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/epidemiologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/epidemiologia , Tomografia por Emissão de Pósitrons , Prevalência , Prognóstico , Pirróis/administração & dosagem , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Somatostatina/análogos & derivados , Sunitinibe , Tomografia Computadorizada por Raios X , Resultado do Tratamento
14.
Drugs Today (Barc) ; 48(11): 723-33, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23170308

RESUMO

The U.S. Food and Drug Administration (FDA) approved vandetanib in April 2011 for the treatment of unresectable, locally advanced or metastatic medullary thyroid cancer (MTC). In Europe it was approved in March 2012, but only for the treatment of aggressive and symptomatic MTC. This small molecule is a tyrosine kinase inhibitor of several growth factors involved in cellular proliferation and angiogenesis, including the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptors 2 and 3 (VEGFR-2, VEGFR-3). In addition, vandetanib is an inhibitor of the RET (rearranged during transfection) gene, a proto-oncogene often mutated in familial MTC. Since MTC is a rare disease, for which no previous medical therapies are approved, vandetanib is the first drug shown to be effective in a large phase III trial treating patients with metastatic or locally advanced MTC. Common adverse events are diarrhea, nausea, hypertension, headache and QT prolongation that are manageable and are commonly outweighed by the benefits of vandetanib in terms of delaying disease progression and inducing tumor response.


Assuntos
Antineoplásicos/uso terapêutico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Carcinoma Neuroendócrino , Interações Medicamentosas , Receptores ErbB/metabolismo , Humanos , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-ret/metabolismo , Quinazolinas/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Neoplasias da Glândula Tireoide/metabolismo
16.
Pneumologie ; 66(1): 44-8, 2012 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-22250054

RESUMO

BACKGROUND: Neuroendocrine tumours of the lung exhibit an increasing incidence and prevalence. However, data on the diagnosis of and therapy for these tumours are sparse compared to neuroendocrine tumours of the gastroenteropancreatic system. METHODS: The present article reflects a dialogue between experts on neuroendocrine tumors of the lung and the gastroenteropancreatic system held on February 25th and 26th in Weimar, Germany. RESULTS: Many similarities exist between neuroendocrine tumours of the lung and the gastroenteropancreatic system but there are also significant differences. Similarities exist mainly concerning pathology, diagnosis and therapy. Differences exist regarding the systemic therapy and the significantly lower incidence of paraneoplastic syndromes. Somatostatin receptor PET/CT with gallium-68 labelled somatostatin analogues and peptide receptor radiotherapy are innovative methods for the diagnosis of and therapy for neuroendocrine tumours of the lung. The first treatment option remains complete resection of the tumour. Small molecules like everolimus (Afinitor®) have been tested in clinical trials and have been shown to prolong progression-free survival. CONCLUSIONS: Additional studies are necessary and efforts should be undertaken to establish a registry to increase data on methods suitable for he diagnosis of and therapy for neuroendocrine tumours of the lung.


Assuntos
Prova Pericial , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/terapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/terapia , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia
17.
Drugs Today (Barc) ; 47(10): 773-86, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22076492

RESUMO

Neuroendocrine tumors are heterogeneous in their clinical behavior and require therapies specially tailored according to staging and grading, origin and expression of peptide receptors. Somatostatin analogues act as antisecretory and antiproliferative agents. Chemotherapy is mandatory for poorly differentiated neuroendocrine carcinomas and is also effective in neuroendocrine tumors of the pancreas and of the bronchial system. For localized neuroendocrine tumors, surgery should be performed with curative intent and is also an option in advanced or metastasized neuroendocrine tumors with the goal to debulk tumor masses. Local ablative therapies may be applied to decrease tumor load in the liver; however, results are often of short duration. Peptide receptor radiotherapy is a new treatment method applying radionuclide-targeted somatostatin receptor agonists for internal cytotoxic radiotherapy in somatostatin receptor-expressing neuroendocrine tumors. Retrospective and prospective clinical studies indicate prolonged progression-free survival and overall survival of patients responding by stable disease or any kind of remission with this innovative treatment, which is, however, available only in a few specialized centers. Finally, small-molecule inhibitors of vascular endothelial growth factor and serine/threonine-protein kinase mTOR pathways have been shown to delay progression in patients with neuroendocrine tumors. In summary, treatment options for neuroendocrine tumors have expanded considerably in the last years leading to prolonged overall survival.


Assuntos
Tumores Neuroendócrinos/terapia , Humanos , Estadiamento de Neoplasias , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
19.
Diabetologia ; 50(6): 1243-7, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17443309

RESUMO

AIMS/HYPOTHESIS: Pro-inflammatory cytokines play a crucial role in immune-mediated beta cell destruction, an essential mechanism in the pathogenesis of type 1 diabetes mellitus. Microarray analysis recently identified osteoprotegerin (OPG; now known as tumour necrosis factor receptor superfamily, member 11b [TNFRSF11B]) as a cytokine-induced gene in beta cells. The aim of the present study was to characterise the functional role and signalling pathways of OPG that are involved in cytokine-induced beta cell death. MATERIALS AND METHODS: As cellular models, the rat beta cell line INS-1E and human primary pancreatic islets were employed. The effects of IL-1beta and TNF-alpha on OPG expression were characterised by northern blot and immunoassay. The effect of OPG on beta cell survival was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Signalling pathways were evaluated by western blot analysis using antibodies against p38 mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2. RESULTS: The INS-1E cell line and primary pancreatic islets expressed OPG mRNA and secreted OPG protein, both of which were enhanced by IL-1beta and TNF-alpha. Exposure to IL-1beta resulted in sustained phosphorylation of p38 MAPK in INS-1E cells and subsequent cell death. Administration of exogenous OPG prevented both IL-1beta-induced beta cell death and sustained p38 MAPK phosphorylation. CONCLUSIONS/INTERPRETATION: Our data indicate that cytokine-induced production of OPG may protect beta cells from further damage. This protective effect is, at least in part, mediated through inhibition of p38 MAPK phosphorylation. Thus OPG is an autocrine or paracrine survival factor for beta cells.


Assuntos
Citocinas/farmacologia , Regulação da Expressão Gênica/fisiologia , Células Secretoras de Insulina/fisiologia , Osteoprotegerina/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Ativação Enzimática , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células Secretoras de Insulina/enzimologia , Interleucina-1beta/farmacologia , Cinética , Osteoprotegerina/fisiologia , Fosforilação , Ratos , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/farmacologia
20.
Diabetologia ; 48(8): 1534-40, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15995848

RESUMO

AIMS/HYPOTHESIS: Glucose and glucagon-like peptide-1 have been shown to activate extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase in beta cells. We examined the contributions of the small GTPases Rap and Ras and the serine-threonine kinases B-Raf and Raf-1 to the activation of these kinases in human islet cells. METHODS: The expression of Rap, Ras, B-Raf and Raf-1 in human islets was examined by immunohistochemistry and immunoblotting. Human islets were incubated in glucose at concentrations of 2.5 and 15 mmol/l and were stimulated with 10 nmol/l glucagon-like peptide-1. The activation of ERK and Raf kinases was examined by phosphorylation-specific antibodies and immuno-complexed kinase assays. The activation of Rap and Ras was determined by pull-down assays. Stimulation of phosphoinositide 3-kinase was detected by immuno-complexed lipid kinase assays. RESULTS: Extracellular-regulated kinase and protein kinase B (a downstream target of phosphoinositide 3-kinase) were activated in islets stimulated with glucose and glucagon-like peptide-1. In these islets, the Rap-B-Raf signalling pathway was activated preferentially compared with Ras and Raf-1, and activated Rap and B-Raf mediated ERK stimulation in kinase assays in vitro. In addition, Rap rather than Ras mediated activation of phosphoinositide 3-kinase in islets stimulated with glucose and glucagon-like peptide-1. CONCLUSIONS/INTERPRETATION: In human islet cells, glucose and glucagon-like peptide-1 activate the Rap and B-Raf signalling module, which mediates ERK activation in assays in vitro. Rap also activates phosphoinositide 3-kinase, delineating central roles for Rap and B-Raf as therapeutic targets for beta cell growth in diabetes mellitus.


Assuntos
Produtos do Gene vpr/fisiologia , Glucagon/farmacologia , Glucose/farmacologia , Ilhotas Pancreáticas/metabolismo , Fragmentos de Peptídeos/farmacologia , Precursores de Proteínas/farmacologia , Proteínas Proto-Oncogênicas B-raf/fisiologia , Transdução de Sinais/efeitos dos fármacos , Células Cultivadas , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , GTP Fosfo-Hidrolases/metabolismo , Peptídeo 1 Semelhante ao Glucagon , Humanos , Imuno-Histoquímica , Ilhotas Pancreáticas/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Quinases raf/antagonistas & inibidores , Quinases raf/metabolismo
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