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      From basic to clinical research in gastroenteropancreatic neuroendocrine tumor disease -- the clinician-scientist perspective.

      1 ,
      Neuroendocrinology
      S. Karger AG

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          Abstract

          Patients with rare tumors represent a diagnostic and therapeutic challenge for non-specialized physicians, surgeons and other medical doctors. Whereas several specialized centers have gathered data for an improved diagnosis and therapy of neuroendocrine tumor disease, numerous clinical issues have not been resolved on an evidence-based medicine level. Furthermore, the evaluation of new treatment options has been overshadowed by the low incidence of the disease. In this article, a major medical challenge for the diagnosis and therapy of neuroendocrine tumor disease is addressed. As well, new therapeutic treatment options translated from current findings in the fields of molecular and tumor biology are discussed.

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          Most cited references28

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          Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms.

          Forty-five patients with metastatic neuroendocrine tumors were treated with a regimen of etoposide 130 mg/m2/d for 3 days plus cisplatin 45 mg/m2/d on days 2 and 3. Both drugs were given by continuous intravenous infusion. Among 27 patients with well-differentiated carcinoid tumors or islet cell carcinomas, only two partial objective tumor regressions were observed (7%). Among 18 patients prospectively classified as having anaplastic neuroendocrine carcinomas, however, there were nine partial regressions and three complete regressions, an overall regression rate of 67%. For anaplastic disease, the median duration of regression was 8 months (range to 21 months). Tumor response was unrelated to primary site, endocrine hyperfunction, or prior therapy experience. The median survival of all patients with anaplastic tumors was 19 months; this seemed favorable when considering the small experiences with these rare tumors reported in the literature. Toxicity, which was severe for most patients, consisted primarily of vomiting, leukopenia, thrombocytopenia, anemia, alopecia, and neuropathy. The anaplastic neuroendocrine tumor is strongly responsive to therapy with combined etoposide and cisplatin. Patients with undifferentiated carcinomas, originating in typical neuroendocrine tumor sites (small and large bowel, pancreas, and stomach) or of unknown origin, who have consistent histologic findings by light microscopy should be evaluated for this possibility with appropriate immune staining or electron microscopy.
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            Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma.

            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. 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. 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. 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.
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              Fundamental concepts of the angiogenic process.

              The process of angiogenesis encompasses the growth and regression of capillary blood vessels. Angiogenesis is finely regulated at the molecular and genetic levels, not unlike other physiologic processes such as coagulation, glucose metabolism, and blood pressure. During the development of the field of angiogenesis research over the past three decades, fundamental concepts have been introduced along the way in an attempt where possible, to unify new data from a variety of different laboratories. I have assembled here the major concepts which underlie the angiogenic process as we currently understand it. Many of these are now taken for granted, but this was not always the case, and I have tried to show how they were developed. My goal is to provide a conceptual framework for those basic scientists or clinicians who may enter this rapidly expanding field. Each concept discussed here is accompanied by a few key references as a guide to the pertinent literature.
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                Author and article information

                Journal
                Neuroendocrinology
                Neuroendocrinology
                S. Karger AG
                0028-3835
                0028-3835
                2004
                : 80 Suppl 1
                Affiliations
                [1 ] Department of Internal Medicine, Division of Hepatology and Gastroenterology, Interdisciplinary Center of Metabolism and Endocrinology, Charité, Campus Virchow Hospital, University Medicine Berlin, Berlin, Germany. betram.wiedenmann@charite.de
                Article
                80749
                10.1159/000080749
                15477725
                4b5dbb8b-b274-4ec2-85fe-847579da8347
                History

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