Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant endocrine disorders have been an enigma over the last few decades, from genetic, clinical, and imaging perspectives. The detection of the primary tumor and the identification of recurrent disease have been essentially based on various anatomic techniques, with localization procedures extensively developed for staging, follow-up, radio-guided surgery, and therapy. Frequently, the lesions are too small to cause anatomic alterations, or they are obscured by the changes in anatomic planes that occur after initial surgery. Small lesions, however, are the ones that can potentially be cured. Thus, every attempt should be made to localize these sites before further growth and dissemination occur beyond the scope of cure. Since the advent of iodine-131 for staging and follow-up of patients with differentiated thyroid carcinoma, the search has led to the use of radioiodinated metaiodobenzylguanidine (MIBG) for recurrent pheochromocytoma and neuroblastoma, to the development of antibodies to carcinoembryonic antigen for the staging and treatment of medullary thyroid carcinoma, and to the characterization of peptide receptors on neuroendocrine tumors. Additionally, there has been a breakthrough with the use of positron emitters in nuclear oncology, including F-18-fluorodeoxyglucose, for I-131-negative metastases of differentiated thyroid carcinoma, recurrent medullary thyroid carcinoma, malignant pheochromocytoma, and adrenocortical carcinoma. Undoubtedly, optimal care of the patient requires both the expertise of the treating endocrinologist and the use of various imaging techniques in the diagnosis, staging, and follow-up of these diseases.
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PMID:Nuclear endocrinology as a monitoring tool. 1143 May 30

With the development of new radiopharmaceuticals there is a tendency to apply nuclear medicine therapy for malignancies of higher incidence (lymphoma, prostate) than the ones which have been treated for many years (thyroid cancer, neuroendocrine tumours). One of the most important areas of current development in radionuclide cancer therapy is the monotherapeutic use of new or already available radiopharmaceuticals in preclinical or phase I studies and to a lesser degree in phase II trials. In this context, the radioimmunotherapy is showing important advances in the treatment of medullary thyroid carcinoma, malignant lymphomas en brain tumours with potential extension to neuroblastoma therapy. The development of DOTA as a chelating agent has lead to the use of Y-90-DOTATOC in the treatment of neuroendocrine tumours, particularly carcinoid tumours, and non-I131I-avid thyroid carcinomas. In an effort to improve tumour targeting together with simultaneous reduction of physiological organ uptake, 131I-MIBG is being used in combination with interferon a and pre-targeting with unlabelled MIBG in the treatment of carcinoid tumours. New routes of administration of radiopharmaceuticals (intratumoral, intra-arterial) have enhanced the treatment of malignancies of liver, pancreas and brain as well as the potential use of radioimmunotherapy by intravesical administration for bladder carcinoma. Another significant tendency in radionuclide therapy is its evolution from monotherapy towards a combined application with other anticancer modalities. Some recent examples of combined therapy with demonstrated anti-tumour effect are found in neuroblastoma (131I-MIBG and chemotherapy), bone metastases of prostatic carcinoma (addition of 89Sr to chemotherapy schedules), brain malignancies (adjuvant use of radioimmnunotherapy in relation to surgery and external radiotherapy) and lymphoma (radioimmunotherapy combined with chemotherapy or immunotherapy). Reinforcing this trend in phase II and III studies as well as the planning of multicenter trials following the guidelines and criteria of clinical oncology will determine the future advances in this field.
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PMID:[Therapeutic advances of nuclear medicine in oncology]. 1170 41

Germ-line point mutations of the RET gene are responsible for multiple endocrine neoplasia (MEN) type 2A and 2B that develop medullary thyroid carcinoma and pheochromocytoma. We performed a differential display analysis of gene expression using NIH 3T3 cells expressing the RET-MEN2A or RET-MEN2B mutant proteins. As a consequence, we identified 10 genes induced by both mutant proteins and eight genes repressed by them. The inducible genes include cyclin D1, cathepsins B and L, and cofilin genes that are known to be involved in cell growth, tumor progression, and invasion. In contrast, the repressed genes include type I collagen, lysyl oxidase, annexin I, and tissue inhibitor of matrix metalloproteinase 3 (TIMP3) genes that have been implicated in tumor suppression. In addition, six RET-MEN2A- and five RET-MEN2B-inducible genes were identified. Among 21 genes induced by RET-MEN2A and/or RET-MEN2B, six genes including cyclin D1, cathepsin B, cofilin, ring finger protein 11 (RNF11), integrin-alpha6, and stanniocalcin 1 (STC1) genes were also induced in TGW human neuroblastoma cells in response to glial cell line-derived neurotrophic factor stimulation. Because the STC1 gene was found to be highly induced by both RET-MEN2B and glial cell line-derived neurotrophic factor stimulation, and the expression of its product was detected in medullary thyroid carcinoma with the MEN2B mutation by immunohistochemistry, this may suggest a possible role for STC1 in the development of MEN 2B phenotype.
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PMID:Characterization of gene expression induced by RET with MEN2A or MEN2B mutation. 1210 9

Pre-therapeutic metaiodobenzylguanidine (MIBG) scans can be performed using labelling with either iodine-123 or iodine-131. (123)I-MIBG scans provide better image quality and count statistics, while (131)I-MIBG allows registration of tracer kinetics over a longer period. The aim of this study was to determine how much information about the (131)I-MIBG therapy total body dose according to the MIRD formalism can be gathered from (123)I-MIBG pre-therapy scans. Thirty-eight (131)I-MIBG therapies administered to a total of 15 patients suffering from neuroblastoma ( n=6), carcinoid tumours ( n=5), phaeochromocytoma ( n=3) and medullary thyroid carcinoma ( n=1) were included. The mean administered activity was 5.3 GBq (SD 2.4 GBq). Three biplanar (123)I-MIBG total body scans were taken only once before a series of therapies while three biplanar (131)I-MIBG scans were taken after each therapy. Attenuation correction was performed taking into account the difference in attenuation between (123)I and (131)I. Using the MIRD formalism, the total body dose to the patient was calculated on the basis of: (1) a single exponential fit drawn through the data from the (123)I-MIBG pre-therapy scans, (2) a bi-exponential fit through the combined data of (123)I-MIBG pre-therapy and (131)I-MIBG post-therapy scans. The mean total body dose calculated in our study was significantly higher for patients suffering from neuroblastoma (mean+/-SD 0.37+/-0.21 mGy/MBq) than for patients suffering from phaeochromocytoma (0.08+/-0.02 mGy/MBq), carcinoid tumours (0.07+/-0.01 mGy/MBq) and medullary thyroid carcinoma (0.09 mGy/MBq). The correlation coefficient between the dose calculated on the basis of the (123)I-MIBG pre-therapy scans and the subsequent (131)I-MIBG therapy was 0.93 when a correction factor of 1.26 was taken into account. When considering all following therapies, the correlation was 0.85 and the correction factor, 1.20. Our results show that it is feasible to use data from pre-therapy (123)I-MIBG scans to calculate the total body dose of the subsequent (131)I-MIBG therapy.
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PMID:Patient dosimetry for 131I-MIBG therapy for neuroendocrine tumours based on 123I-MIBG scans. 1245 91

In the beginning, Trk was an oncogene. Yet Neurotrophin-Trk signaling came to preeminence in the field of neurobiology. Now it is appreciated that Trks regulate important processes in nonneuronal cells and, in addition to their impact on tumors of neural origin, may contribute to the pathogenesis of carcinomas, myelomas, and prostate and lymphoid tumors. Although mutations and rearrangements of Trk are seen only sporadically in human cancers, such as medullary thyroid carcinoma, a number of recent studies indicate that expression of TrkB contributes to tumor pathology. In neuroblastoma, TrkA expression marks good prognosis which TrkB and Brain-derived neurotrophic factor (BDNF) expression marks poor prognosis. Activation of the BDNF/TrkB signal transduction pathway also stimulates tumor cell survival and angiogenesis and contributes to resistance to cytotoxic drugs and anoikis, enabling cells to acquire many of the characteristic features required for tumorigenesis. Small molecule inhibitors, such as Cephalon's CEP-701, are in phase 1 and 2 clinical trials, and a series of AstraZeneca Trk inhibitors are poised to enter the clinic. As monotherapy, inhibitors may be effective only in tumors with activating Trk mutations. Important clinical follow-up will be the assessment of Trk inhibitors in combination with standard chemo- or radiotherapy or other signal transduction pathway inhibitors.
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PMID:On Trk--the TrkB signal transduction pathway is an increasingly important target in cancer biology. 1975 85

Fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) is utilized in more than 90% of cancers in staging, re-staging, assessing therapy response and during the follow-up. However, not all tumors show significant increase of metabolic activity on FDG-PET imaging. This is particularly true for prostate cancer, neuroendocrine tumors and hepatic tumors. In this review we have considered those already used for clinical applications such as 11C- and 18F-Choline, 11C-Methionine and 18F-FET, 18F-DOPA, 68Ga-DOTA-somatostatine analogues, 11C-Acetate and 18F-FLT. Choline presents a high affinity for malignant prostate tissue, even if low grade. Choline can be labeled with either 11C or 18F, the former being the preference due to lower urinary excretion and patients exposure. The latter is more useful for possible distribution to centers lacking in on-site cyclotron. Methionine is needed for protein synthesis and tumor cells require an external supply of methionine. These tracers have primarily been used for imaging of CNS neoplasms. The most appropriate indication is when conventional imaging procedures do not distinguish between edema, fibrosis or necrosis and disease relapse. In addition, the uptake of 11C-Methionine is proportional to the tumor grade and, therefore, the maximum small unilamellar vesicles (SUV) inside the brain mass before therapy is somehow considered a prognostic value. Neuroendocrine tumors (carcinoids, pheocromocytoma, neuroblastoma, medullary thyroid cancer, microcytoma, carotid glomus tumors, and melanoma) demonstrate an increased activity of L-DOPA decarboxylase, and hence they show a high uptake of 18FDOPA. For the study of NETs, 68Ga-DOTA-TOC/DOTA-NOC has been introduced as PET tracer. This compound for PET imaging has a high affinity for sst2 and sst5 and has been used in the detection of NETs in preliminary studies; 68Ga-DOTA-NOC PET is useful before metabolic radiotherapy in order to evaluate the biodistribution of the therapeutic compound; 18F-FLT is a specific marker of cell proliferation and the most important field of application of FLT is lung cancer. Other tracers are used in PET utilized as markers of hypoxia inside big neoplastic masses include 18F-MISO, 64Cu-ATSM, 18F-EF5, which highlight the presence of hypoxic areas are useful for patients that must be treated with radiotherapy.
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PMID:Non-FDG PET in the practice of oncology. 2044 72

Multiple Endocrine Neoplasia type 2B (MEN 2B) is an autosomal dominant complex oncologic neurocristopathy including medullary thyroid carcinoma, pheochromocytoma, gastrointestinal disorders, marphanoid face, and mucosal multiple ganglioneuromas. Medullary thyroid carcinoma is the major cause of mortality in MEN 2B syndrome, and it often appears during the first years of life. RET proto-oncogene germline activating mutations are causative for MEN 2B. The 95% of MEN 2B patients are associated with a point mutation in exon 16 (M918/T). A second point mutation at codon 883 has been found in 2%-3% of MEN 2B cases. RET proto-oncogene is also involved in different neoplastic and not neoplastic neurocristopathies. Other RET mutations cause MEN 2A syndrome, familial medullary thyroid carcinoma, or Hirschsprung's disease. RET gene expression is also involved in Neuroblastoma. The main diagnosis standards are the acetylcholinesterase study of rectal mucosa and the molecular analysis of RET. In our protocol the rectal biopsy is, therefore, the first approach. RET mutation detection offers the possibility to diagnose MEN 2B predisposition at a pre-clinical stage in familial cases, and to perform an early total prophylactic thyroidectomy. The surgical treatment of MEN 2B is total thyroidectomy with cervical limphadenectomy of the central compartment of the neck. When possible, this intervention should be performed with prophylactic aim before 1 year of age in patients with molecular genetic diagnosis. Recent advances into the mechanisms of RET proto-oncogene signaling and pathways of RET signal transduction in the development of MEN 2 and MTC will allow new treatment possibilities.
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PMID:Multiple endocrine neoplasias type 2B and RET proto-oncogene. 2242 13

Since 1981, meta-iodobenzylguanidine (MIBG), labeled with (131)I and later (123)I, has become a valuable agent in the diagnosis and therapy of a number of endocrine tumors. Initially, the agent located pheochromocytomas and paragangliomas (PGLs), both sporadic and familial, in multiple anatomic sites; surgeons were thereby guided to excisional therapies, which were previously difficult and sometimes impossible. The specificity in diagnosis has remained above 95%, but sensitivity has varied with the nature of the tumor: close to 90% for intra-adrenal pheochromocytomas but 70% or less for PGLs. For patients with neuroblastoma, carcinoid tumors, and medullary thyroid carcinoma, imaging with radiolabeled MIBG portrays important diagnostic evidence, but for these neoplasms, use has been primarily as an adjunct to therapy. Although diagnosis by radiolabeled MIBG has been supplemented and sometimes surpassed by newer scintigraphic agents, searches by this radiopharmaceutical remain indispensable for optimal care of some patients. The radiation imparted by concentrations of (131)I-MIBG in malignant pheochromocytomas, PGLs, carcinoid tumors, and medullary thyroid carcinoma has reduced tumor volumes and lessened excretions of symptom-inflicting hormones, but its value as a therapeutic agent is being fulfilled primarily in attacks on neuroblastomas, which are scourges of children. Much promise has been found in tumor disappearance and prolonged survival of treated patients. The experiences with therapeutic (131)I-MIBG have led to development of new tactics and strategies and to well-founded hopes for elimination of cancers. Radiolabeled MIBG is an exemplar of theranostics and remains a worthy agent for both diagnosis and therapy of endocrine tumors.
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PMID:Theranostics: evolution of the radiopharmaceutical meta-iodobenzylguanidine in endocrine tumors. 2247 26

This article gives an overview of the established radionuclide therapies for endocrine-related cancer that already have market authorization or are currently under evaluation in clinical trials. Radioiodine therapy is still the gold standard for differentiated iodine-avid thyroid cancer. In patients with bone and lung metastases (near) total remission is seen in approximately 50% and the 15-year survival rate for these patients is approximately 90%. In contrast to the USA, meta-iodobenzylguanidine (MIBG) therapy has market approval in Europe. According to the current literature, in the setting of advanced stage neuroblastoma and malignant pheochromocytoma or paraganglioma, radiological remission can be achieved in >30% and symptom control in almost 80% of the treated patients. Somatostatin receptor targeted radionuclide therapies (e.g. with DOTATATE or DOTATOC) demonstrated promising results in phase 2 trials, reporting progression-free survival in the range of 24-36 months. A first phase 3 pivotal trial for intestinal carcinoids is currently recruiting and another trial for pancreatic neuroendocrine tumors is planned. Radiopharmaceuticals based on glucagon-like peptide 1 (GLP1) or minigastrins are in the early evaluation stage for application in the treatment of insulinomas and medullary thyroid cancer. In general, radiopharmaceutical therapy belongs to the group of so-called theranostics which means that therapy is tailored for individual patients based on molecular imaging diagnostics to stratify target positive or target negative tumor phenotypes.
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PMID:[Radionuclide therapy of endocrine-related cancer]. 2526 25

Neuroendocrine neoplasms (NEN) functional imaging is an evolving field that witnessed major advances in the past two decades. The routine use of PET/CT with an array of new radiotracers to specifically study NEN resulted in an increase in lesions detection. Currently, PET radiopharmaceuticals for NEN imaging include both metabolic ([18F]DOPA, [18F]FDG, [11C]/[18F]-HTP) and receptor-mediated compounds ([68Ga]DOTA-peptides). Discussion is still on-going regarding the clinical setting that may benefit the most from the use of one tracer over the other. [68Ga]DOTA-peptides are accurate for the detection of well differentiated NEN and are increasingly employed. Moreover, providing data on somatostatin receptors expression on NEN cells, they represent a fundamental procedure to be performed before starting therapy, as well as to guide treatment, with either hot or cold somatostatin analogues. The easy and economic synthesis process also favours their clinical employment even in centres without an on-site cyclotron. [18F]DOPA is accurate for studying well differentiated tumours however the difficult and expensive synthesis have limited its clinical employment. It currently can be successfully used for imaging tumours with variable to low expression of SSR (medullary thyroid carcinoma, neuroblastoma, pheocromocytoma), that cannot be accurately studied with [68Ga]DOTA-peptides. [11C]/[18F]-HTP has also been proposed to image well differentiated NEN, on the basis of serotonin pathway activity, for which [11C]/[18F]-HTP can be used as precursor. However, although preliminary data are encouraging, the feasibility of its widespread clinical use is still under discussion, mainly limited by a complex synthesis process and more proven advantages over other currently employed compounds. This review aims to provide an overview of the current status and clinical application of PET tracers to image well differentiated NEN and to focus on the still open-issues of debate.
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PMID:Current status of PET imaging of neuroendocrine tumours ([18F]FDOPA, [68Ga]tracers, [11C]/[18F]-HTP). 2567 89


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