Cushing syndrome is caused by an excess of adrenocorticotropic hormone (ACTH) production by neuroendocrine tumors, which subsequently results in chronic glucocorticoid excess. We found that retinoic acid inhibits the transcriptional activity of AP-1 and the orphan receptors Nur77 and Nurr1 in ACTH-secreting tumor cells. Retinoic acid treatment resulted in reduced pro-opiomelanocortin transcription and ACTH production. ACTH inhibition was also observed in human pituitary ACTH-secreting tumor cells and a small-cell lung cancer cell line, but not in normal cells. This correlated with the expression of the orphan receptor COUP-TFI, which was found in normal corticotrophs but not in pituitary Cushing tumors. COUP-TFI expression in ACTH-secreting tumor cells blocked retinoic acid action. Retinoic acid also inhibited cell proliferation and, after prolonged treatment, increased caspase-3 activity and induced cell death in ACTH-secreting cells. In adrenal cortex cells, retinoic acid inhibited corticosterone production and cell proliferation. The antiproliferative action and the inhibition of ACTH and corticosterone produced by retinoic acid were confirmed in vivo in experimental ACTH-secreting tumors in nude mice. Thus, we conclude that the effects of retinoic acid combine in vivo to reverse the endocrine alterations and symptoms observed in experimental Cushing syndrome. (+info)
The humoral immune response to macrocyclic chelating agent DOTA depends on the carrier molecule.
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The chelating agent 1,4,7,10-tetraazacyclododecane-N,N', N",N"'-tetraacetic acid (DOTA) is used to label monoclonal antibodies (mAbs) and peptides with (90)Y. DOTA allows the generation of clinically useful stable metallic radioconjugates for the treatment of a variety of tumors, but its immunogenicity has remained controversial. In this study, we evaluated the immune response to DOTA in a preclinical mouse model and in patients entered in a clinical trial. METHODS: Sera were obtained from BALB/c mice injected intraperitoneally or subcutaneously with different doses and formulations of syngeneic and xenogeneic mAbs or peptide (murine mAb Mov19 [mM19]; its chimeric version; murine V/human C ChiMov19 [cM19]; or Tyr(3)-octreotide)-DOTA conjugates. Sera from patients with neuroendocrine tumors, enrolled in a protocol for somatostatin receptor-mediated radionuclide therapy with (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide (DOTATOC), were also collected before and after each treatment. Levels and specificity of antibody response to relevant (Mov19, ChiMov19, or Tyr(3)-octreotide) and nonrelevant (human serum albumin) DOTA targets were tested by enzyme-linked immunosorbent assay and competition assays. An anti-DOTA mAb (IgG1) derived from a ChiMov19-DOTA immunized mouse was used, in a competitive radioimmunoassay, to determine the efficiency of DOTA presentation on the different carriers. RESULTS: Depending on the immunogenicity and dosage of the mAb, a specific anti-DOTA response was revealed in the preclinical system. However, DOTA-peptide conjugate induced no immune-detectable response against either chelator or carrier. DOTA was poorly presented on small peptides, as determined using the anti-DOTA mAb. CONCLUSION: A humoral response against DOTA is possible, but only as a consequence of the response elicited against the carrier. Octreotide was not immunogenic. Thus, (90)Y-DOTATOC can be considered a safe and useful tool for receptor-mediated radionuclide therapy of somatostatin receptor-overexpressing tumors. (+info)
Role of p53 as a prognostic factor for survival in lung cancer: a systematic review of the literature with a meta-analysis.
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The role of p53, as a prognostic factor for survival in lung cancer, is controversial and the purpose of the present systematic review of the literature is to determine this effect. Published studies were identified with the objective to aggregate the available survival results after a methodological assessment using a scale specifically designed by the European Lung Cancer Working Party (ELCWP). To be eligible, a study had to deal with p53 assessment in lung cancer (primary site) only, and to provide a survival comparison according to the p53 status. Among the 74 eligible papers, 30 identified p53 abnormalities as a univariate statistically significant poor prognostic factor and 56 provided sufficient data to allow survival results aggregation. There was no significant difference between the trials that either showed or did not show a prognostic effect of p53 according to the methodological score or to the laboratory technique used. The studies were categorized by histology, disease stage, treatment and laboratory technique. Combined hazard ratios suggested that an abnormal p53 status had an unfavourable impact on survival: in any stage nonsmall cell lung cancer (NSCLC) the mean (95% confidence interval) was 1.44 (1.20-1.72) (number of studies included in the subgroup was 11), 1.50 (1.32-1.70) in stages I-II NSCLC (n=19), 1.68 (1.23-2.29) in stages I-IIIB NSCLC (n=5), 1.68 (1.30-2.18) in stages III-IV NSCLC (n=9), 1.48 (1.29-1.70) in surgically resected NSCLC (n=20), 1.37 (1.02-1.85) in squamous cell carcinoma (n=9), 2.24 (1.70-2.95) in adenocarcinoma (n=9), 1.57 (1.28-1.91) for a positive immunohistochemistry with antibody 1801 (n=8), 1.25 (1.09-1.43) for a positive immunohistochemistry with antibody DO-7 (n=16), and 1.65 (1.35-2.00) for an abnormal molecular biology test (n=13). Data were insufficient to determine the prognostic value of p53 in small cell lung cancer. In each subgroup of nonsmall cell lung cancer, p53 abnormal status was shown to be associated with a poorer survival prognosis. (+info)
Identification of somatostatin receptor subtypes 1, 2A, 3, and 5 in neuroendocrine tumours with subtype specific antibodies.
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BACKGROUND AND AIMS: Recently, novel somatostatin receptor (sstr) subtype specific ligand analogues have been developed for medical treatment of neuroendocrine tumours expressing different sstrs (sstr1-5). At present, individual expression patterns of sstr subtypes are based on methods such as in situ hybridisation and polymerase chain reaction at the transcriptional level. Therefore, we generated subtype specific antibodies against sstr1, 2A, 3, and 5 and analysed their presence, cellular localisation, distribution, and expression pattern in 33 gastrinomas, 36 insulinomas, and 35 tumours associated with a carcinoid syndrome by immunohistochemistry at the translational level. METHODS: Western blotting experiments were performed in the normal human pancreas used as a reference organ and in tumour tissues; at the cellular level, sstrs were localised by immunohistochemistry in tissue paraffin sections. RESULTS: In western blot analyses, the antibodies identified the respective receptors in their correct molecular range in extracts of the pancreas and neuroendocrine tumours. Using immunohistochemistry and immunofluorescence, the antibodies specifically detected the receptors in islet cells of the normal pancreas. Immunohistochemistry in the tumours revealed that all investigated sstr subtypes were highly expressed in the different tumour types. The frequency and expression pattern of the individual sstr subtypes varied considerably not only between the different tumour types but also in each patient. CONCLUSIONS: We conclude that immunohistochemistry with subtype specific antibodies can be used in clinical routine work to analyse sstr expression patterns for each patient before treatment and to facilitate well directed individual medical therapy by administering subtype specific somatostatin analogues. (+info)
Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq (90)Y-DOTATOC.
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The aim of this prospective phase II study was to evaluate the tumor response of neuroendocrine tumors to high-dose targeted irradiation with 7.4 GBq/m(2) of the radiolabeled somatostatin analog (90)Y-1,4,7,10-tetra-azacyclododecan-4,7,10-tricarboxy-methyl-1-yl-acetyl-D-Phe-T yr(3)-octreotide (DOTATOC). In addition, we investigated the clinical benefit of (90)Y-DOTATOC regarding the malignant carcinoid syndrome and tumor-associated pain. METHODS: Thirty-nine patients (mean age, 55 y) with progressive neuroendocrine gastroenteropancreatic and bronchial tumors were included. The treatment consisted of 4 equal intravenous injections of a total of 7.4 GBq/m(2) (90)Y-DOTATOC, administered at intervals of 6 wk. After each treatment cycle, a standardized clinical benefit assessment using the National Cancer Institute grading criteria (NCI-CTC) was performed. RESULTS: The objective response rate according to World Health Organization (WHO) criteria was 23%. For endocrine pancreatic tumors (13 patients), the objective response rate was 38%. Complete remissions were found in 5% (2/39), partial remissions in 18% (7/39), stable disease in 69% (27/39), and progressive disease in 8% (3/39). A significant reduction of clinical symptoms could be found in 83% of patients with diarrhea, in 46% of patients with flush, in 63% of patients with wheezing, and in 75% of patients with pellagra. The overall clinical benefit was 63%. All responses (both clinical benefit and WHO response) were ongoing for the duration of follow-up (median, 6 mo; range, 2-12 mo). Side effects were grade 3 or 4 (NCI-CTC) lymphocytopenia in 23%, grade 3 anemia in 3%, and grade 2 renal insufficiency in 3%. CONCLUSION: High-dose targeted radiotherapy with 7.4 GBq/m(2) (90)Y-DOTATOC is a well-tolerated treatment for neuroendocrine tumors, with remarkable clinical benefit and objective response. (+info)
Recessive transmission of a multiple endocrine neoplasia syndrome in the rat.
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We describe a novel hereditary cancer syndrome in the rat that is transmitted by a recessive gene mutation. Animals exhibiting the mutant phenotype develop multiple neuroendocrine malignancies within the first year of life. The endocrine neoplasia is characterized by bilateral adrenal pheochromocytoma, multiple extra-adrenal pheochromocytoma, bilateral medullary thyroid cell neoplasia, bilateral parathyroid hyperplasia, and pituitary adenoma. The appearance of neoplastic disease is preceded by the development of bilateral juvenile cataracts. Although the spectrum of affected tissues is reminiscent of human forms of multiple endocrine neoplasia (MEN), no germ-line mutations were detected in the Ret or Menin genes that are responsible for the dominantly inherited MEN syndromes in humans. Segregation studies in F1 and F2 crosses yielded frequencies of affected animals entirely consistent with a recessive autosomal mode of inheritance. The lack of the phenotype in F1 animals effectively excludes a germ-line tumor suppressor gene mutation as the causal event. The absence of mutation of known MEN genes and the unique constellation of affected tissues, plus the recessive mode of inheritance, lead us to conclude that the mutation of an as yet unknown gene is responsible for this syndrome of inherited neuroendocrine cancer. (+info)
Efficacy of a chemotherapy combination for the treatment of metastatic neuroendocrine tumours.
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OBJECTIVES: Neuroendocrine tumours (NETs) are heterogeneous neoplasms for which there is no standard treatment. We have previously proposed an effective polychemotherapy (5-fluorouracil, dacarbazine and epirubicin), which only produced objective responses of brief duration. The present study aimed to assess in a multidisciplinary manner the efficacy of the same regimen at intensified doses in patients with advanced NETs. PATIENTS AND METHODS: Eighty-two consecutive patients entered the study, of whom 21 had inoperable, locally advanced disease and 61 had metastatic disease. Seventy-two patients were evaluated for objective, biochemical and subjective responses. Response rate, time to progression (TTP) and overall survival (OS) were evaluated based on histotype. RESULTS: An objective response was observed in 20 patients (intention-to-treat and standard analysis 24.4% and 27.8%, respectively). Complete biochemical and subjective responses were obtained in 25.1% and 38.9% of the cases. The median duration of treatment was 4 months and the objective responses had a median duration of 38 months. After a 60-month follow-up the median TTP and OS were 21 and 38 months, respectively. CONCLUSIONS: Our polychemotherapy regimen is effective, with long duration, and is well tolerated both for gastroenteropancreatic and lung NETs, as well as for tumours with a more aggressive clinical behaviour. The new WHO endocrine tumour histotyping, examining also the tumour biology, may give additional information for selecting patients to chemotherapy. (+info)
Detection of neuroendocrine tumors: 99mTc-P829 scintigraphy compared with 111In-pentetreotide scintigraphy.
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The aim of this study was to evaluate the diagnostic value of a new somatostatin analog, 99mTc-P829, compared with that of 111In-pentetreotide. METHODS: Forty-three patients (32 men, 11 women; age range, 24-78 y; mean age, 56 y) with biologically or histologically proven neuroendocrine tumors were prospectively included: 11 patients with Zollinger-Ellison syndrome, 16 patients with carcinoid tumors, and 16 patients with other types of functioning (n = 6) or nonfunctioning (n = 10) endocrine tumors. 111In-Pentetreotide planar images (head, chest, abdomen, and pelvis) were obtained 4 and 24 h after injection of 10 microg somatostatin analog labeled with 148 +/- 17 MBq 111In, and SPECT was performed 24 h after injection. Similar (99m)Tc-P829 planar images were obtained at 1, 4-6, and 24 h after injection of 50 microg peptide labeled with 991.6 +/- 187.59 MBq 99mTc. Abdominal SPECT was performed 4-6 h after injection. RESULTS: 111In-Pentetreotide detected 203 tumoral sites in 39 (91%) of 43 patients, whereas 99mTc-P829 detected 77 sites in 28 (65%) of 43 patients (P < 0.005). In the liver, 129 sites (in 24 patients) were detected by 111In-pentetreotide scintigraphy and 34 sites (in 10 patients) were detected by 99mTc-P829 scintigraphy. CONCLUSION: In patients with endocrine tumors, the detection rate of 99mTc-P829 scintigraphy was lower than that of 111In-pentetreotide scintigraphy, which appeared to be more sensitive, especially for liver metastases. (+info)