Immunohistochemical, biochemical and immunoelectron microscopic analysis of antigenic proteins on neuroendocrine cell tumors using monoclonal antibody HISL-19.
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The monoclonal antibody HISL-19 was originally generated after immunizing BALB/c mice with human islet cells. We used this antibody to study a wide variety of neuroendocrine (NE) and non-NE tumors by immunohistochemical, immunoelectron microscopic, and biochemical (Western blotting) techniques. Of the thyroid tumors, HISL-19 specifically immunoreacted with medullary carcinoma of the thyroid (MCT); of the pancreatic tumors, it reacted with islet cell tumors such as insulinomas and a gastrinoma; of the adrenal tumors, it reacted with pheochromocytoma. HISL-19 showed particularly strong immunoreactivity to a gross granular material at the perinuclear area in the MCT and malignant pheochromocytoma but not in the benign pheochromocytoma, although the latter cells showed a faint and homogenous positive reactivity in the cytoplasm. The strongly HISL-19-positive material was found to consist of newly synthesized antigenic proteins with a molecular weight between 60 and 65 kilodaltons (kDa) by Western blotting. Immunoelectron microscopic analysis revealed that this antigenic protein was located in the secretory granules that appear markedly in malignant endocrine tumors, usually located close to the nucleus. Thus, HISL-19 is a useful and specific marker for the immunohistochemical diagnosis of NE cell tumors. The specific antigenic proteins of HISL-19 were defined in MCT and malignant pheochromocytoma. These proteins are speculated to be actively synthesized and more highly produced in the secretory granules of malignant endocrine tumors than benign ones. Thus, a preoperative immunohistochemical study using HISL-19 might be useful for predicting the grade of malignancy of endocrine malignant tumors and thus help determine an appropriate operative procedure, in addition to being a useful marker of neuroendocrine cell tumors. (+info)
Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo.
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The Eph family of receptor tyrosine kinases and their ligands, known as ephrins, play a crucial role in vascular development during embryogenesis. The function of these molecules in adult angiogenesis has not been well characterized. Here, we report that blocking Eph A class receptor activation inhibits angiogenesis in two independent tumor types, the RIP-Tag transgenic model of angiogenesis-dependent pancreatic islet cell carcinoma and the 4T1 model of metastatic mammary adenocarcinoma. Ephrin-A1 ligand was expressed in both tumor and endothelial cells, and EphA2 receptor was localized primarily in tumor-associated vascular endothelial cells. Soluble EphA2-Fc or EphA3-Fc receptors inhibited tumor angiogenesis in cutaneous window assays, and tumor growth in vivo. EphA2-Fc or EphA3-Fc treatment resulted in decreased tumor vascular density, tumor volume, and cell proliferation, but increased cell apoptosis. However, EphA2-Fc had no direct effect on tumor cell growth or apoptosis in culture, yet inhibited migration of endothelial cells in response to tumor cells, suggesting that the soluble receptor inhibited blood vessel recruitment by the tumor. These data provide the first functional evidence for Eph A class receptor regulation of pathogenic angiogenesis induced by tumors and support the function of A class Eph receptors in tumor progression. (+info)
Uncontrolled insulin secretion from a childhood pancreatic beta-cell adenoma is not due to the functional loss of ATP-sensitive potassium channels.
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We report the case of an 8-year-old child who presented with severe hyperinsulinaemic hypoglycaemia due to a pancreatic islet cell adenoma. In vivo, there was no beneficial response to the hyperglycaemia-inducing agent diazoxide and as a consequence the child underwent a subtotal pancreatectomy. In vitro studies of adenomatous beta-cells revealed no operational defects in ATP-sensitive potassium channel activity and appropriate responses to diazoxide. In comparison with patients with focal adenomatous hyperplasia, genetic analysis of the isolated adenoma showed no loss of heterozygosity for chromosome 11p15 and expression of the cyclin-dependent kinase inhibitor p57(kip2). This case illustrates that the excess insulin secretion from an infantile adenoma has an aetiology different from that observed in hyperinsulinism in infancy. (+info)
Evaluation of contrast enhancement patterns in pancreatic tumors by coded harmonic sonographic imaging with a microbubble contrast agent.
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OBJECTIVE: The purpose of the study was to assess patterns of primary pancreatic lesions by contrast-enhanced sonography for differentiating ductal carcinomas from other pancreatic tumors. METHODS: One hundred six consecutive patients with pancreatic masses, consisting of 83 ductal carcinomas, 7 endocrine carcinomas, 5 intraductal papillary mucinous tumors, 3 cases of autoimmune-related pancreatitis, 3 solid pseudopapillary tumors, 2 cases of chronic pancreatitis, 1 serous cystadenoma, 1 osteoclastoid giant cell tumor, and 1 follicular lymphoma, were examined by contrast-enhanced sonography with coded harmonic imaging in a phase inversion harmonic technique. The contrast enhancement patterns were assessed, and specimens removed during pancreatectomy were subjected to pathologic examination. RESULTS: Internal tumoral vascularity was detected in 47 (56.6%) of the 83 ductal carcinomas. Vascular image spreading and homogeneous staining throughout the tumors were observed in all endocrine carcinomas. Two of the 5 intraductal papillary mucinous tumors were positive for enhancement effects. Enhancement effects were observed in all 3 cases of autoimmune-related pancreatitis, but the degree varied. There was a significant correlation between the intensity of enhancement effects and the ratio of patent vessels in the tumors (P < .05). CONCLUSIONS: Vascularity was detected by contrast-enhanced sonography in only about half of the ductal carcinomas, confirming the difficulty in distinguishing those tumors from other pancreatic tumors. There was a correlation between the patency of the vessels in the tumors and their vascularity. (+info)
Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma.
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BACKGROUND: The combination of streptozocin and fluorouracil has become the standard therapy for advanced islet-cell carcinoma. However, doxorubicin has also been shown to be active against this type of tumor, as has chlorozotocin, a drug that is structurally similar to streptozocin but less frequently causes vomiting. METHODS: In this multicenter trial, we randomly assigned 105 patients with advanced islet-cell carcinoma to receive one of three treatment regimens: streptozocin plus fluorouracil, streptozocin plus doxorubicin, or chlorozotocin alone. The 31 patients in whom the disease did not respond to treatment were crossed over to chlorozotocin alone or to one of the combination regimens. RESULTS: Streptozocin plus doxorubicin was superior to streptozocin plus fluorouracil in terms of the rate of tumor regression, measured objectively (69 percent vs. 45 percent, P = 0.05), and the length of time to tumor progression (median, 20 vs. 6.9 months; P = 0.001). Streptozocin plus doxorubicin also had a significant advantage in terms of survival (median, 2.2 vs. 1.4 years; P = 0.004) that was accentuated when we considered long-term survival (greater than 2 years). Chlorozotocin alone produced a 30 percent regression rate, with the length of time to tumor progression and the survival time equivalent to those observed with streptozocin plus fluorouracil. Crossover therapy after the failure of either chlorozotocin alone or one of the combination regimens produced an overall response rate of only 17 percent, and the responses were transient. Toxic reactions to all regimens included vomiting, which was least severe with chlorozotocin; hematologic depression; and, with long-term therapy, renal insufficiency. CONCLUSIONS: The combination of streptozocin and doxorubicin is superior to the current standard regimen of streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. Chlorozotocin alone is similar in efficacy to streptozocin plus fluorouracil, but it produces fewer gastrointestinal side effects than the regimens containing streptozocin. It therefore merits study as a constituent of combination drug regimens. (+info)
Endoscopic ultrasound for localisation of islet cell tumours.
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In a prospective study endoscopic ultrasound localisation of pancreatic endocrine tumours was attempted in 21 patients with clinically suspected islet cell tumours. Most patients were referred after the failure of conventional imaging methods. Endoscopic ultrasound correctly identified the site of 12 of 15 insulinomas, one glucagonoma, and a diffuse pancreatic abnormality in a patient with multiple endocrine adenopathy. There were two true negative examinations and one technical failure. The sensitivity of endoscopic ultrasound was much greater than that of computed tomography or conventional transabdominal ultrasonography. (+info)
Characterization of the ELSV transgenic mouse model of pancreatic carcinoma. Histologic type of large and small tumors.
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Carcinomas of the pancreas that developed in Tg(Ela-1, SV40E)Bri18 and Tg(Ela-1, SV40E+Ela-1, neo)Bri19 strains of transgenic mice were classified into eight histologic patterns. Most were variants of acinar cell carcinoma, but cystic and undifferentiated carcinomas were found. The spectrum of phenotypes was similar in small and large carcinomas, but the small group included a higher fraction of well-differentiated tumors and fewer poorly differentiated and anaplastic tumors. The incidence of islet cell tumors was far higher in the Bri18 strain (77%) than in the Bri19 strain (1.6%). Islet cell hyperplasia was much more prevalent in Bri18 than Bri19 mice. In both strains, the nontumorous pancreas showed acinar cell dysplasia with a more abnormal and distinctive pattern in the Bri19 strain. While the spectrum of exocrine tumor phenotypes is similar, significant differences occurred between these two transgenic mouse strains as models for pancreatic carcinogenesis. (+info)
Localization of pancreatic endocrine tumors by endoscopic ultrasonography.
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BACKGROUND: After a pancreatic endocrine tumor has been diagnosed on the basis of clinical signs and the results of laboratory tests, localization of the tumor by the usual imaging procedures fails in as many as 40 to 60 percent of patients. Endoscopic ultrasonography, a sensitive test for small carcinomas of the pancreas, might also be useful in patients with endocrine tumors of the pancreas that cannot be localized by conventional methods. METHODS: We studied 37 patients later shown to have 39 endocrine tumors of the pancreas who had negative results on transabdominal ultrasonography and CT. All the patients underwent endoscopic ultrasonography, and 22 also underwent selective angiography. All the tumors were confirmed by surgical excision and immunohistologic examination; they consisted of 31 insulinomas, 7 gastrinomas, and 1 glucagonoma, 0.5 to 2.5 cm (mean, 1.4 cm) in diameter. All but one of the patients were cured of their disease, as ascertained by at least six months of clinical and laboratory follow-up. RESULTS: Using endoscopic ultrasonography, we were able to localize 32 of the 39 tumors (sensitivity, 82 percent); no tumor was incorrectly localized. The size of the tumors was very similar (within 2 mm) to that predicted by endoscopic ultrasonography. Among the 22 patients who underwent both angiography and endoscopic ultrasonography, ultrasonography was significantly more sensitive than angiography for tumor localization (sensitivity, 82 percent vs. 27 percent). Among 19 control patients without pancreatic endocrine tumors, endoscopic ultrasonography was negative in 18 (specificity, 95 percent). CONCLUSIONS: Endoscopic ultrasonography is a highly sensitive and specific procedure for the localization of pancreatic endocrine tumors. It should be considered for the preoperative localization of such tumors once the clinical and laboratory diagnosis has been established. (+info)