术前不同药物干预对人GH腺瘤增殖指标数的影响
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摘要
目的：分组研究术前不同给药对垂体瘤肿瘤增殖指标Mib-1和TopoⅡα的影响状况,探讨其对肢端肥大症最佳治疗手段的指导意义。
方法：收集Nurnberg-Erlangen大学附属神经外科医院2002-2010年确诊的肢端肥大症患者共362例,应用免疫组化染色法显示肿瘤细胞表达Mib-1和TopoⅡα并统计标记指数,收集其余临床资料并加以统计。
结果：Mib-1和TopoⅡα的标记指数与肿瘤Hardy分级和肿瘤侵袭性具有显著相关(P=0.000<0.05),肿瘤全切率只与Mib-1标记指数有显著相关性(P=0.000<0.05),两种标记指数并无性别差异(P=0.415和0.861)。不同的术前治疗手段对Mib-1和TopoⅡα的标记指数具有显著影响(P=0.000和0.001),其中生长抑素类似物治疗可以有效降低肿瘤增殖指标指数(P值均为0.000),生长激素受体拮抗剂与生长抑素类似物合用时对肿瘤增殖指标没有明显影响(P>0.05),多巴胺受体激动剂、多巴胺受体激动剂合用生长抑素类似物以及生长抑素类似物合用生长激素受体拮抗剂对肿瘤增殖指标无明显影响(P值均>0.05)。
结论：Mib-1和TopoⅡα标记指数在男女患者中没有显著差异,但高低可作为判断肿瘤侵袭程度和预后的指标。术前给予患者生长抑素类似物有助于降低术后肿瘤的复发和侵袭力,生长激素受体抑制剂有导致肿瘤增殖指标指数增高可能,不适合单独给药,最适合与生长抑素类似物合用。多巴胺受体激动剂对肿瘤增殖指标没有显著影响,适合于同时分泌GH和PRL阳性的垂体腺瘤。放疗可作为手术和药物治疗外的辅助手段。
Object:To study the influences of different preoperative treatments on proliferation index of pituitary adenoma tumor (Mib-1 and TopoⅡα) in groups, which would provide instructions for the best treatments of acromegaly.
Methods:To collect 362 cases of diagnosed acromegaly during 2002-2010 from Kopfklinik of Nurnberg-Erlangen University. Using immunohistochemical staining method to show the positive tumor cells that express Mib-1 and TopoⅡα, and comprehensive analysis the Labeling indexs with other clinical data statistically.
Results:The Labeling indexes of Mib-1 and TopoⅡαare significantly relative to pituitary tumors Hardy classification and invasiveness of tumor(all p=0.000<0.05), and only Mib-1 Labeling index correlated the total resection rate significantly(p=0.000<0.05), both Mib-1 and TopoⅡlabeling indexes have no gender difference (p=0.415,0.861. respectively). Different preoperative drug interventions have significant effects on the labeling indexes of Mib-1 and Topo-2a(p=0.000,0.001, respectively), one of which is Somatostatin analogue (SA), that can effectively reduce the tumor proliferation index(p=0.000). However, Somatostatin analogue contributed not significantly to the tumor proliferation labeling indexes when used along with growth hormone receptor antagonists (p>0.05). Administer of only dopamine agonists, or together with Sandostatin analogue, and administer of Sandostatin analogues together with growth hormone receptor antagonist showed no significant influences on tumor proliferation index(p>0.05).
Conclusion:The Labeling indexes of Mib-1 and Topo-2a showed no remarkable differences between male and female patients, but which could be the indicator to estimate tumor invade degree and prognosis. Preoperative administration of Somatostatin analogues helps reducing postoperative recurrence and aggressiveness of tumor. Growth hormone receptor inhibitors may increase the tumor proliferation marks index, which are not suitable for single use but recommended to apply together with STT analogue. Dopamine agonists has no significant influence on tumor proliferation index, but it's suitable for pituitary adenomas which release GH and also PRL. Radiation therapy can be used as auxiliary method besides surgery and pharmacotherapy.
方法：收集Nurnberg-Erlangen大学附属神经外科医院2002-2010年确诊的肢端肥大症患者共362例,应用免疫组化染色法显示肿瘤细胞表达Mib-1和TopoⅡα并统计标记指数,收集其余临床资料并加以统计。
结果：Mib-1和TopoⅡα的标记指数与肿瘤Hardy分级和肿瘤侵袭性具有显著相关(P=0.000<0.05),肿瘤全切率只与Mib-1标记指数有显著相关性(P=0.000<0.05),两种标记指数并无性别差异(P=0.415和0.861)。不同的术前治疗手段对Mib-1和TopoⅡα的标记指数具有显著影响(P=0.000和0.001),其中生长抑素类似物治疗可以有效降低肿瘤增殖指标指数(P值均为0.000),生长激素受体拮抗剂与生长抑素类似物合用时对肿瘤增殖指标没有明显影响(P>0.05),多巴胺受体激动剂、多巴胺受体激动剂合用生长抑素类似物以及生长抑素类似物合用生长激素受体拮抗剂对肿瘤增殖指标无明显影响(P值均>0.05)。
结论：Mib-1和TopoⅡα标记指数在男女患者中没有显著差异,但高低可作为判断肿瘤侵袭程度和预后的指标。术前给予患者生长抑素类似物有助于降低术后肿瘤的复发和侵袭力,生长激素受体抑制剂有导致肿瘤增殖指标指数增高可能,不适合单独给药,最适合与生长抑素类似物合用。多巴胺受体激动剂对肿瘤增殖指标没有显著影响,适合于同时分泌GH和PRL阳性的垂体腺瘤。放疗可作为手术和药物治疗外的辅助手段。
Object:To study the influences of different preoperative treatments on proliferation index of pituitary adenoma tumor (Mib-1 and TopoⅡα) in groups, which would provide instructions for the best treatments of acromegaly.
Methods:To collect 362 cases of diagnosed acromegaly during 2002-2010 from Kopfklinik of Nurnberg-Erlangen University. Using immunohistochemical staining method to show the positive tumor cells that express Mib-1 and TopoⅡα, and comprehensive analysis the Labeling indexs with other clinical data statistically.
Results:The Labeling indexes of Mib-1 and TopoⅡαare significantly relative to pituitary tumors Hardy classification and invasiveness of tumor(all p=0.000<0.05), and only Mib-1 Labeling index correlated the total resection rate significantly(p=0.000<0.05), both Mib-1 and TopoⅡlabeling indexes have no gender difference (p=0.415,0.861. respectively). Different preoperative drug interventions have significant effects on the labeling indexes of Mib-1 and Topo-2a(p=0.000,0.001, respectively), one of which is Somatostatin analogue (SA), that can effectively reduce the tumor proliferation index(p=0.000). However, Somatostatin analogue contributed not significantly to the tumor proliferation labeling indexes when used along with growth hormone receptor antagonists (p>0.05). Administer of only dopamine agonists, or together with Sandostatin analogue, and administer of Sandostatin analogues together with growth hormone receptor antagonist showed no significant influences on tumor proliferation index(p>0.05).
Conclusion:The Labeling indexes of Mib-1 and Topo-2a showed no remarkable differences between male and female patients, but which could be the indicator to estimate tumor invade degree and prognosis. Preoperative administration of Somatostatin analogues helps reducing postoperative recurrence and aggressiveness of tumor. Growth hormone receptor inhibitors may increase the tumor proliferation marks index, which are not suitable for single use but recommended to apply together with STT analogue. Dopamine agonists has no significant influence on tumor proliferation index, but it's suitable for pituitary adenomas which release GH and also PRL. Radiation therapy can be used as auxiliary method besides surgery and pharmacotherapy.
引文
[1]. Orme, S.M., et al., Mortality and cancer incidence in acromegaly:a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab,1998. 83(8):p.2730-4.
[2]. van der Lely, A.J., et al., Control of tumor size and disease activity during cotreatment with octreotide and the growth hormone receptor antagonist pegvisomant in an acromegalic patient. J Clin Endocrinol Metab,2001.86(2):p.478-81.
[3]. Scholzen, T. and J. Gerdes, The Ki-67 protein:from the known and the unknown. J Cell Physiol,2000.182(3):p.311-22.
[4]. Duchrow, M., J. Gerdes and C. Schluter, The proliferation-associated Ki-67 protein:definition in molecular terms. Cell Prolif,1994.27(5):p.235-42.
[5]. Nakano, T. and K. Oka, Differential values of Ki-67 index and mitotic index of proliferating cell population. An assessment of cell cycle and prognosis in radiation therapy for cervical cancer. Cancer,1993.72(8):p.2401-8.
[6]. Kawasaki, H., et al., Expression of survivin correlates with apoptosis, proliferation, and angiogenesis during human colorectal tumorigenesis. Cancer,2001. 91(11):p.2026-32.
[7]. MacGrogan, G., et al., DNA topoisomerase Ⅱalpha expression and the response toprimary chemotherapy in breast cancer. Br J Cancer,2003.89(4):p.666-71.
[8]. Rudolph, P., et al., Prognostic significance of Ki-67 and topoisomerase Ⅱalpha expression in infiltrating ductal carcinoma of the breast. A multivariate analysis of 863 cases. Breast Cancer Res Treat,1999.55(1):p.61-71.
[9]. Wang, J.C., DNA topoisomerases. Annu Rev Biochem,1996.65:p.635-92.
[10]. Berger, J.M., et al., Structure and mechanism of DNA topoisomerase Ⅱ. Nature, 1996.379(6562):p.225-32.
[11]. Turley, H., et al., The distribution and expression of the two isoforms of DNA topoisomerase Ⅱ in normal and neoplastic human tissues. Br J Cancer,1997.75(9):p. 1340-6.
[12]. Champoux, J.J., DNA topoisomerases:structure, function, and mechanism. Annu Rev Biochem,2001.70:p.369-413.
[13]. Bakshi, R.P., S. Galande and K. Muniyappa, Functional and regulatory characteristics of eukaryotic type II DNA topoisomerase. Crit Rev Biochem Mol Biol, 2001.36(1):p.1-37.
[14]. Kellner, U., et al., Culprit and victim--DNA topoisomerase II. Lancet Oncol, 2002.3(4):p.235-43.
[15]. Yabuki, N., et al., Immunohistochemical study of DNA topoisomerase Ⅱ in human gastric disorders. Am J Pathol,1996.149(3):p.997-1007.
[16]. Golusinski, W., et al., A comprehensive analysis of selected diagnostic methods with respect to their usefulness in evaluating the biology of neoplastic cells in patients with laryngeal cancer. Eur Arch Otorhinolaryngol,1999.256(6):p.306-11.
[17]. Korshunov, A., L. Shishkina and A. Golanov, DNA topoisomerase Ⅱ-alpha and cyclin A immunoexpression in meningiomas and its prognostic significance:an analysis of 263 cases. Arch Pathol Lab Med,2002.126(9):p.1079-86.
[18]. McKeever, P.E., et al., A comparison of the predictive power for survival in gliomas provided by MIB-1, bromodeoxyuridine and proliferating cell nuclear antigen with histopathologic and clinical parameters. J Neuropathol Exp Neurol,1997.56(7):p. 798-805.
[19]. Onda, K., et al., Correlation between the bromodeoxyuridine labeling index and the MIB-1 and Ki-67 proliferating cell indices in cerebral gliomas. Cancer,1994.74(7):p. 1921-6.
[20]. Plonowski, A., et al., Inhibition of proliferation of PC-3 human prostate cancer by antagonists of growth hormone-releasing hormone:lack of correlation with the levels of serum IGF-I and expression of tumoral IGF-Ⅱ and vascular endothelial growth factor. Prostate,2002.52(3):p.173-82.
[21].雷霆等,生长激素第三调节途径在人垂体生长激素腺瘤生长激素释放中的作用.中华实验外科杂志,1999.16：第429-431页.
[22]. 雷霆等,gsp癌基因在人垂体GH腺瘤的表达与GHRH对GH分泌效应比较.同济医科大学学报,1997.16(增刊)：第10-14页.
[23]. 白祥军等,gsp癌基因在国人肢端肥大症患者垂体肿瘤中的表达.中华实验外科杂志,2000.17(1)：第53-54页.
[24]. 张雅轩与杨雷霆,基因异常表达在判断垂体腺瘤侵袭性中的作用.中国神经肿瘤杂志,2010.8(1)：第51-55页.
[25]. 顾锋,中国肢端肥大症诊治规范(草案).中国实用内科杂志,2006.26(22)：第1772-1777页.
[26]. Ludecke, D.K. and T. Abe, Transsphenoidal microsurgery for newly diagnosed acromegaly:a personal view after more than 1,000 operations. Neuroendocrinology,2006. 83(3-4):p.230-9.
[27]. De P, et al., Transsphenoidal surgery for acromegaly in wales:results based on stringent criteria of remission. J Clin Endocrinol Metab,2003.88(8):p.3567-72.
[28]. Biermasz, N.R., et al., Determinants of survival in treated acromegaly in a single center:predictive value of serial insulin-like growth factor I measurements. J Clin Endocrinol Metab,2004.89(6):p.2789-96.
[29]. Beauregard, C., et al., Long-term outcome and mortality after transsphenoidal adenomectomy for acromegaly. Clin Endocrinol (Oxf),2003.58(1):p.86-91.
[30]. Arita, K., et al., Mortality in 154 surgically treated patients with acromegaly--a 10-year follow-up survey. Endocr J,2003.50(2):p.163-72.
[31]. Zada, G., et al., Recognition and management of delayed hyponatremia following transsphenoidal pituitary surgery. J Neurosurg,2007.106(1):p.66-71.
[32]. Biermasz. N.R., et al., Determinants of survival in treated acromegaly in a single center:predictive value of serial insulin-like growth factor I measurements. J Clin Endocrinol Metab,2004.89(6):p.2789-96.
[33]. De P, et al., Transsphenoidal surgery for acromegaly in wales:results based on stringent criteria of remission. J Clin Endocrinol Metab,2003.88(8):p.3567-72.
[34]. Beauregard, C., et al., Long-term outcome and mortality after transsphenoidal adenomectomy for acromegaly. Clin Endocrinol (Oxf),2003.58(1):p.86-91.
[35]. Lindholm, J., et al., Investigation of the criteria for assessing the outcome of treatment in acromegaly. Clin Endocrinol (Oxf),1987.27(5):p.553-62.
[36]. Colao, A., et al., Effect of different dopaminergic agents in the treatment of acromegaly. J Clin Endocrinol Metab,1997.82(2):p.518-23.
[37]. Abs, R., et al., Cabergoline in the treatment of acromegaly:a study in 64 patients. J Clin Endocrinol Metab,1998.83(2):p.374-8.
[38].冯文忠与尹维珍,溴隐亭治疗肢端肥大症继发糖尿病与糖耐量异常报告.云南医药,1994.15(3)：第170-173页.
[39]. Ikeda, U., et al., Endothelin-1 inhibits nitric oxide synthesis in vascular smooth muscle cells. Hypertension,1997.29(1 Pt 1):p.65-9.
[40]. Kvols, L.K. and E.A. Woltering, Role of somatostatin analogs in the clinical management of non-neuroendocrine solid tumors. Anticancer Drugs,2006.17(6):p. 601-8.
[41]. Lamberts, S.W., et al., Octreotide. N Engl J Med,1996.334(4):p.246-54.
[42]. Shimon, I., et al., Somatostatin receptor subtype specificity in human fetal pituitary cultures. Differential role of SSTR2 and SSTR5 for growth hormone, thyroid-stimulating hormone, and prolactin regulation. J Clin Invest,1997.99(4):p. 789-98.
[43]. Ritz, M.A., et al., The effects of vapreotide, a somatostatin analogue, on gastric acidity, gallbladder emptying and hormone release after 1 week of continuous subcutaneous infusion in normal subjects. Br J Clin Pharmacol,1999.47(2):p.195-201.
[44]. Giusti, M., et al., Effectiveness and tolerability of slow release lanreotide treatment in active acromegaly:six-month report on an Italian multicenter study. Italian Multicenter Slow Release Lanreotide Study Group. J Clin Endocrinol Metab,1996.81(6): p.2089-97.
[45]. Amato, G., et al., Long-term effects of lanreotide SR and octreotide LAR on tumour shrinkage and GH hypersecretion in patients with previously untreated acromegaly. Clin Endocrinol (Oxf),2002.56(1):p.65-71.
[46]. Jaquet, P., et al., Human somatostatin receptor subtypes in acromegaly:distinct patterns of messenger ribonucleic acid expression and hormone suppression identify different tumoral phenotypes. J Clin Endocrinol Metab,2000.85(2):p.781-92.
[47]. Caron, P., et al., Three year follow-up of acromegalic patients treated with intramuscular slow-release lanreotide. J Clin Endocrinol Metab,1997.82(1):p.18-22.
[48]. Cozzi, R., et al., Primary treatment of acromegaly with octreotide LAR:a long-term (up to nine years) prospective study of its efficacy in the control of disease activity and tumor shrinkage. J Clin Endocrinol Metab,2006.91(4):p.1397403.
[49]. Amato, G., et al., Long-term effects of lanreotide SR and octreotide LAR on tumour shrinkage and GH hypersecretion in patients with previously untreated acromegaly. Clin Endocrinol (Oxf),2002.56(1):p.65-71.
[50]. Tsukamoto, N., et al., Octreotide treatment results in the inhibition of GH gene expression in the adenoma of the patients with acromegaly. Endocr J,1994.41(4):p. 437-44.
[51]. Fredstorp, L., Y. Pernow and S. Werner, The short and long-term effects of octreotide on calcium homeostasis in patients with acromegaly. Clin Endocrinol (Oxf), 1993.39(3):p.331-6.
[52]. Chanson, P., et al., Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly. Clin Endocrinol (Oxf),2000.53(5):p.577-86.
[53]. Stewart, P.M., et al., Depot long-acting somatostatin analog (Sandostatin-LAR) is an effective treatment for acromegaly. J Clin Endocrinol Metab,1995.80(11):p. 3267-72.
[54]. Lucas, T., R. Astorga and M. Catala, Preoperative lanreotide treatment for GH-secreting pituitary adenomas:effect on tumour volume and predictive factors of significant tumour shrinkage. Clin Endocrinol (Oxf),2003.58(4):p.471-81.
[55]. Baldelli, R., et al., Two-year follow-up of acromegalic patients treated with slow release lanreotide (30 mg). J Clin Endocrinol Metab,2000.85(11):p.4099-103.
[56]. McKnight, J.A., et al., Changes in glucose tolerance and development of gall stones during high dose treatment with octreotide for acromegaly. BMJ,1989.299(6699): p.604-5.
[57]. Vance, M.L. and A.G. Harris, Long-term treatment of 189 acromegalic patients with the somatostatin analog octreotide. Results of the International Multicenter Acromegaly Study Group. Arch Intern Med,1991.151(8):p.1573-8.
[58]. Ezzat, S., et al., A prospective multicenter octreotide dose response study in the treatment of acromegaly. J Endocrinol Invest,1995.18(5):p.364-9.
[59]. Newman, C.B., et al., Safety and efficacy of long-term octreotide therapy of acromegaly:results of a multicenter trial in 103 patients--a clinical research center study. J Clin Endocrinol Metab,1995.80(9):p.2768-75.
[60]. Flogstad, A.K., et al., Sandostatin LAR in acromegalic patients:long-term treatment. J Clin Endocrinol Metab,1997.82(1):p.23-8.
[61]. Lancranjan, I. and A.B. Atkinson, Results of a European multicentre study with Sandostatin LAR in acromegalic patients. Sandostatin LAR Group. Pituitary,1999.1(2): p.105-14.
[62]. Higham, C.E., et al., Long-term experience of pegvisomant therapy as a treatment for acromegaly. Clin Endocrinol (Oxf),2009.71(1):p.86-91.
[63]. Stolk, M.F., et al., Effect of octreotide on fasting gall bladder emptying, antroduodenal motility, and motilin release in acromegaly. Gut,1995.36(5):p.755-60.
[64]. Catnach, S.M., et al., Effect of octreotide on gall stone prevalence and gall bladder motility in acromegaly. Gut,1993.34(2):p.270-3.
[65]. Nakauchi, Y., et al., Scalp hair loss caused by octreotide in a patient with acromegaly:a case report. Endocr J,1995.42(3):p.385-9.
[66]. Ishii, K., et al., MR imaging of pituitary adenomas with sphenoid sinus invasion: characteristic MR findings indicating fibrosis. Radiat Med,1996.14(4):p.173-8.
[67]. Schuppan, D., et al., Fibrosis of liver, pancreas and intestine:common mechanisms and clear targets? Acta Gastroenterol Belg,2000.63(4):p.366-70.
[68]. Wang, J., H. Zheng and M. Hauer-Jensen, Influence of Short-Term Octreotide Administration on Chronic Tissue Injury, Transforming Growth Factor beta (TGF-beta) Overexpression, and Collagen Accumulation in Irradiated Rat Intestine. J Pharmacol Exp Ther,2001.297(1):p.35-42.
[69]. Heijckmann, C.A., et al., Clinical experience with Sandostatin LAR in patients with acromegaly. Neth J Med,2001.59(6):p.286-91.
[70]. Bevan, J.S., et al., Primary medical therapy for acromegaly:an open, prospective, multicenter study of the effects of subcutaneous and intramuscular slow-release octreotide on growth hormone, insulin-like growth factor-I, and tumor size. J Clin Endocrinol Metab, 2002.87(10):p.4554-63.
[71]. Cunningham, B.C., et al., Receptor and antibody epitopes in human growth hormone identified by homolog-scanning mutagenesis. Science,1989.243(4896):p. 1330-6.
[72]. Cunningham, B.C. and J.A. Wells, High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis. Science,1989.244(4908):p. 1081-5.
[73]. Cunningham, B.C., et al., Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule. Science,1991.254(5033):p. 821-5.
[74]. de Vos, A.M., M. Ultsch and A.A. Kossiakoff, Human growth hormone and extracellular domain of its receptor:crystal structure of the complex. Science,1992. 255(5042):p.306-12.
[75]. Chen, N.Y., et al., Effects of streptozotocin treatment in growth hormone (GH) and GH antagonist transgenic mice. Endocrinology,1995.136(2):p.660-7.
[76]. Chen, W.Y., et al., Expression of a mutated bovine growth hormone gene suppresses growth of transgenic mice. Proc Natl Acad Sci U S A,1990.87(13):p. 5061-5.
[77]. Fuh, G., et al., Rational design of potent antagonists to the human growth hormone receptor. Science,1992.256(5064):p.1677-80.
[78]. Clark, R., et al., Long-acting growth hormones produced by conjugation with polyethylene glycol. J Biol Chem,1996.271(36):p.21969-77.
[79]. Herman-Bonert, V.S., et al., Growth hormone receptor antagonist therapy in acromegalic patients resistant to somatostatin analogs. J Clin Endocrinol Metab,2000. 85(8):p.2958-61.
[80]. Trainer, P.J., et al., Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med,2000.342(16):p.1171-7.
[81]. Newman, C.B., et al., Octreotide as primary therapy for acromegaly. J Clin Endocrinol Metab,1998.83(9):p.3034-40.
[82]. Barkan, A.L., et al., Pituitary irradiation is ineffective in normalizing plasma insulin-like growth factor I in patients with acromegaly. J Clin Endocrinol Metab,1997. 82(10):p.3187-91.
[83]. van der Lely, A.J., W.W. de Herder and S.W. Lamberts, The role of radiotherapy in acromegaly. J Clin Endocrinol Metab,1997.82(10):p.3185-6.
[84]. Voges, J., et al., Linear accelerator radiosurgery for pituitary macroadenomas:a 7-year follow-up study. Cancer,2006.107(6):p.1355-64.
[85]. Minniti, G., et al., The long-term efficacy of conventional radiotherapy in patients with GH-secreting pituitary adenomas. Clin Endocrinol (Oxf),2005.62(2):p. 210-6.
[86]. Pollock, B.E., et al., Radiosurgery of growth hormone-producing pituitary adenomas:factors associated with biochemical remission. J Neurosurg,2007.106(5):p. 833-8.
[87]. Paisley, A.N., et al., Small vessel remodeling and impaired endothelial-dependent dilatation in subcutaneous resistance arteries from patients with acromegaly. J Clin Endocrinol Metab,2009.94(4):p.1111-7.
[2]. van der Lely, A.J., et al., Control of tumor size and disease activity during cotreatment with octreotide and the growth hormone receptor antagonist pegvisomant in an acromegalic patient. J Clin Endocrinol Metab,2001.86(2):p.478-81.
[3]. Scholzen, T. and J. Gerdes, The Ki-67 protein:from the known and the unknown. J Cell Physiol,2000.182(3):p.311-22.
[4]. Duchrow, M., J. Gerdes and C. Schluter, The proliferation-associated Ki-67 protein:definition in molecular terms. Cell Prolif,1994.27(5):p.235-42.
[5]. Nakano, T. and K. Oka, Differential values of Ki-67 index and mitotic index of proliferating cell population. An assessment of cell cycle and prognosis in radiation therapy for cervical cancer. Cancer,1993.72(8):p.2401-8.
[6]. Kawasaki, H., et al., Expression of survivin correlates with apoptosis, proliferation, and angiogenesis during human colorectal tumorigenesis. Cancer,2001. 91(11):p.2026-32.
[7]. MacGrogan, G., et al., DNA topoisomerase Ⅱalpha expression and the response toprimary chemotherapy in breast cancer. Br J Cancer,2003.89(4):p.666-71.
[8]. Rudolph, P., et al., Prognostic significance of Ki-67 and topoisomerase Ⅱalpha expression in infiltrating ductal carcinoma of the breast. A multivariate analysis of 863 cases. Breast Cancer Res Treat,1999.55(1):p.61-71.
[9]. Wang, J.C., DNA topoisomerases. Annu Rev Biochem,1996.65:p.635-92.
[10]. Berger, J.M., et al., Structure and mechanism of DNA topoisomerase Ⅱ. Nature, 1996.379(6562):p.225-32.
[11]. Turley, H., et al., The distribution and expression of the two isoforms of DNA topoisomerase Ⅱ in normal and neoplastic human tissues. Br J Cancer,1997.75(9):p. 1340-6.
[12]. Champoux, J.J., DNA topoisomerases:structure, function, and mechanism. Annu Rev Biochem,2001.70:p.369-413.
[13]. Bakshi, R.P., S. Galande and K. Muniyappa, Functional and regulatory characteristics of eukaryotic type II DNA topoisomerase. Crit Rev Biochem Mol Biol, 2001.36(1):p.1-37.
[14]. Kellner, U., et al., Culprit and victim--DNA topoisomerase II. Lancet Oncol, 2002.3(4):p.235-43.
[15]. Yabuki, N., et al., Immunohistochemical study of DNA topoisomerase Ⅱ in human gastric disorders. Am J Pathol,1996.149(3):p.997-1007.
[16]. Golusinski, W., et al., A comprehensive analysis of selected diagnostic methods with respect to their usefulness in evaluating the biology of neoplastic cells in patients with laryngeal cancer. Eur Arch Otorhinolaryngol,1999.256(6):p.306-11.
[17]. Korshunov, A., L. Shishkina and A. Golanov, DNA topoisomerase Ⅱ-alpha and cyclin A immunoexpression in meningiomas and its prognostic significance:an analysis of 263 cases. Arch Pathol Lab Med,2002.126(9):p.1079-86.
[18]. McKeever, P.E., et al., A comparison of the predictive power for survival in gliomas provided by MIB-1, bromodeoxyuridine and proliferating cell nuclear antigen with histopathologic and clinical parameters. J Neuropathol Exp Neurol,1997.56(7):p. 798-805.
[19]. Onda, K., et al., Correlation between the bromodeoxyuridine labeling index and the MIB-1 and Ki-67 proliferating cell indices in cerebral gliomas. Cancer,1994.74(7):p. 1921-6.
[20]. Plonowski, A., et al., Inhibition of proliferation of PC-3 human prostate cancer by antagonists of growth hormone-releasing hormone:lack of correlation with the levels of serum IGF-I and expression of tumoral IGF-Ⅱ and vascular endothelial growth factor. Prostate,2002.52(3):p.173-82.
[21].雷霆等,生长激素第三调节途径在人垂体生长激素腺瘤生长激素释放中的作用.中华实验外科杂志,1999.16：第429-431页.
[22]. 雷霆等,gsp癌基因在人垂体GH腺瘤的表达与GHRH对GH分泌效应比较.同济医科大学学报,1997.16(增刊)：第10-14页.
[23]. 白祥军等,gsp癌基因在国人肢端肥大症患者垂体肿瘤中的表达.中华实验外科杂志,2000.17(1)：第53-54页.
[24]. 张雅轩与杨雷霆,基因异常表达在判断垂体腺瘤侵袭性中的作用.中国神经肿瘤杂志,2010.8(1)：第51-55页.
[25]. 顾锋,中国肢端肥大症诊治规范(草案).中国实用内科杂志,2006.26(22)：第1772-1777页.
[26]. Ludecke, D.K. and T. Abe, Transsphenoidal microsurgery for newly diagnosed acromegaly:a personal view after more than 1,000 operations. Neuroendocrinology,2006. 83(3-4):p.230-9.
[27]. De P, et al., Transsphenoidal surgery for acromegaly in wales:results based on stringent criteria of remission. J Clin Endocrinol Metab,2003.88(8):p.3567-72.
[28]. Biermasz, N.R., et al., Determinants of survival in treated acromegaly in a single center:predictive value of serial insulin-like growth factor I measurements. J Clin Endocrinol Metab,2004.89(6):p.2789-96.
[29]. Beauregard, C., et al., Long-term outcome and mortality after transsphenoidal adenomectomy for acromegaly. Clin Endocrinol (Oxf),2003.58(1):p.86-91.
[30]. Arita, K., et al., Mortality in 154 surgically treated patients with acromegaly--a 10-year follow-up survey. Endocr J,2003.50(2):p.163-72.
[31]. Zada, G., et al., Recognition and management of delayed hyponatremia following transsphenoidal pituitary surgery. J Neurosurg,2007.106(1):p.66-71.
[32]. Biermasz. N.R., et al., Determinants of survival in treated acromegaly in a single center:predictive value of serial insulin-like growth factor I measurements. J Clin Endocrinol Metab,2004.89(6):p.2789-96.
[33]. De P, et al., Transsphenoidal surgery for acromegaly in wales:results based on stringent criteria of remission. J Clin Endocrinol Metab,2003.88(8):p.3567-72.
[34]. Beauregard, C., et al., Long-term outcome and mortality after transsphenoidal adenomectomy for acromegaly. Clin Endocrinol (Oxf),2003.58(1):p.86-91.
[35]. Lindholm, J., et al., Investigation of the criteria for assessing the outcome of treatment in acromegaly. Clin Endocrinol (Oxf),1987.27(5):p.553-62.
[36]. Colao, A., et al., Effect of different dopaminergic agents in the treatment of acromegaly. J Clin Endocrinol Metab,1997.82(2):p.518-23.
[37]. Abs, R., et al., Cabergoline in the treatment of acromegaly:a study in 64 patients. J Clin Endocrinol Metab,1998.83(2):p.374-8.
[38].冯文忠与尹维珍,溴隐亭治疗肢端肥大症继发糖尿病与糖耐量异常报告.云南医药,1994.15(3)：第170-173页.
[39]. Ikeda, U., et al., Endothelin-1 inhibits nitric oxide synthesis in vascular smooth muscle cells. Hypertension,1997.29(1 Pt 1):p.65-9.
[40]. Kvols, L.K. and E.A. Woltering, Role of somatostatin analogs in the clinical management of non-neuroendocrine solid tumors. Anticancer Drugs,2006.17(6):p. 601-8.
[41]. Lamberts, S.W., et al., Octreotide. N Engl J Med,1996.334(4):p.246-54.
[42]. Shimon, I., et al., Somatostatin receptor subtype specificity in human fetal pituitary cultures. Differential role of SSTR2 and SSTR5 for growth hormone, thyroid-stimulating hormone, and prolactin regulation. J Clin Invest,1997.99(4):p. 789-98.
[43]. Ritz, M.A., et al., The effects of vapreotide, a somatostatin analogue, on gastric acidity, gallbladder emptying and hormone release after 1 week of continuous subcutaneous infusion in normal subjects. Br J Clin Pharmacol,1999.47(2):p.195-201.
[44]. Giusti, M., et al., Effectiveness and tolerability of slow release lanreotide treatment in active acromegaly:six-month report on an Italian multicenter study. Italian Multicenter Slow Release Lanreotide Study Group. J Clin Endocrinol Metab,1996.81(6): p.2089-97.
[45]. Amato, G., et al., Long-term effects of lanreotide SR and octreotide LAR on tumour shrinkage and GH hypersecretion in patients with previously untreated acromegaly. Clin Endocrinol (Oxf),2002.56(1):p.65-71.
[46]. Jaquet, P., et al., Human somatostatin receptor subtypes in acromegaly:distinct patterns of messenger ribonucleic acid expression and hormone suppression identify different tumoral phenotypes. J Clin Endocrinol Metab,2000.85(2):p.781-92.
[47]. Caron, P., et al., Three year follow-up of acromegalic patients treated with intramuscular slow-release lanreotide. J Clin Endocrinol Metab,1997.82(1):p.18-22.
[48]. Cozzi, R., et al., Primary treatment of acromegaly with octreotide LAR:a long-term (up to nine years) prospective study of its efficacy in the control of disease activity and tumor shrinkage. J Clin Endocrinol Metab,2006.91(4):p.1397403.
[49]. Amato, G., et al., Long-term effects of lanreotide SR and octreotide LAR on tumour shrinkage and GH hypersecretion in patients with previously untreated acromegaly. Clin Endocrinol (Oxf),2002.56(1):p.65-71.
[50]. Tsukamoto, N., et al., Octreotide treatment results in the inhibition of GH gene expression in the adenoma of the patients with acromegaly. Endocr J,1994.41(4):p. 437-44.
[51]. Fredstorp, L., Y. Pernow and S. Werner, The short and long-term effects of octreotide on calcium homeostasis in patients with acromegaly. Clin Endocrinol (Oxf), 1993.39(3):p.331-6.
[52]. Chanson, P., et al., Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly. Clin Endocrinol (Oxf),2000.53(5):p.577-86.
[53]. Stewart, P.M., et al., Depot long-acting somatostatin analog (Sandostatin-LAR) is an effective treatment for acromegaly. J Clin Endocrinol Metab,1995.80(11):p. 3267-72.
[54]. Lucas, T., R. Astorga and M. Catala, Preoperative lanreotide treatment for GH-secreting pituitary adenomas:effect on tumour volume and predictive factors of significant tumour shrinkage. Clin Endocrinol (Oxf),2003.58(4):p.471-81.
[55]. Baldelli, R., et al., Two-year follow-up of acromegalic patients treated with slow release lanreotide (30 mg). J Clin Endocrinol Metab,2000.85(11):p.4099-103.
[56]. McKnight, J.A., et al., Changes in glucose tolerance and development of gall stones during high dose treatment with octreotide for acromegaly. BMJ,1989.299(6699): p.604-5.
[57]. Vance, M.L. and A.G. Harris, Long-term treatment of 189 acromegalic patients with the somatostatin analog octreotide. Results of the International Multicenter Acromegaly Study Group. Arch Intern Med,1991.151(8):p.1573-8.
[58]. Ezzat, S., et al., A prospective multicenter octreotide dose response study in the treatment of acromegaly. J Endocrinol Invest,1995.18(5):p.364-9.
[59]. Newman, C.B., et al., Safety and efficacy of long-term octreotide therapy of acromegaly:results of a multicenter trial in 103 patients--a clinical research center study. J Clin Endocrinol Metab,1995.80(9):p.2768-75.
[60]. Flogstad, A.K., et al., Sandostatin LAR in acromegalic patients:long-term treatment. J Clin Endocrinol Metab,1997.82(1):p.23-8.
[61]. Lancranjan, I. and A.B. Atkinson, Results of a European multicentre study with Sandostatin LAR in acromegalic patients. Sandostatin LAR Group. Pituitary,1999.1(2): p.105-14.
[62]. Higham, C.E., et al., Long-term experience of pegvisomant therapy as a treatment for acromegaly. Clin Endocrinol (Oxf),2009.71(1):p.86-91.
[63]. Stolk, M.F., et al., Effect of octreotide on fasting gall bladder emptying, antroduodenal motility, and motilin release in acromegaly. Gut,1995.36(5):p.755-60.
[64]. Catnach, S.M., et al., Effect of octreotide on gall stone prevalence and gall bladder motility in acromegaly. Gut,1993.34(2):p.270-3.
[65]. Nakauchi, Y., et al., Scalp hair loss caused by octreotide in a patient with acromegaly:a case report. Endocr J,1995.42(3):p.385-9.
[66]. Ishii, K., et al., MR imaging of pituitary adenomas with sphenoid sinus invasion: characteristic MR findings indicating fibrosis. Radiat Med,1996.14(4):p.173-8.
[67]. Schuppan, D., et al., Fibrosis of liver, pancreas and intestine:common mechanisms and clear targets? Acta Gastroenterol Belg,2000.63(4):p.366-70.
[68]. Wang, J., H. Zheng and M. Hauer-Jensen, Influence of Short-Term Octreotide Administration on Chronic Tissue Injury, Transforming Growth Factor beta (TGF-beta) Overexpression, and Collagen Accumulation in Irradiated Rat Intestine. J Pharmacol Exp Ther,2001.297(1):p.35-42.
[69]. Heijckmann, C.A., et al., Clinical experience with Sandostatin LAR in patients with acromegaly. Neth J Med,2001.59(6):p.286-91.
[70]. Bevan, J.S., et al., Primary medical therapy for acromegaly:an open, prospective, multicenter study of the effects of subcutaneous and intramuscular slow-release octreotide on growth hormone, insulin-like growth factor-I, and tumor size. J Clin Endocrinol Metab, 2002.87(10):p.4554-63.
[71]. Cunningham, B.C., et al., Receptor and antibody epitopes in human growth hormone identified by homolog-scanning mutagenesis. Science,1989.243(4896):p. 1330-6.
[72]. Cunningham, B.C. and J.A. Wells, High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis. Science,1989.244(4908):p. 1081-5.
[73]. Cunningham, B.C., et al., Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule. Science,1991.254(5033):p. 821-5.
[74]. de Vos, A.M., M. Ultsch and A.A. Kossiakoff, Human growth hormone and extracellular domain of its receptor:crystal structure of the complex. Science,1992. 255(5042):p.306-12.
[75]. Chen, N.Y., et al., Effects of streptozotocin treatment in growth hormone (GH) and GH antagonist transgenic mice. Endocrinology,1995.136(2):p.660-7.
[76]. Chen, W.Y., et al., Expression of a mutated bovine growth hormone gene suppresses growth of transgenic mice. Proc Natl Acad Sci U S A,1990.87(13):p. 5061-5.
[77]. Fuh, G., et al., Rational design of potent antagonists to the human growth hormone receptor. Science,1992.256(5064):p.1677-80.
[78]. Clark, R., et al., Long-acting growth hormones produced by conjugation with polyethylene glycol. J Biol Chem,1996.271(36):p.21969-77.
[79]. Herman-Bonert, V.S., et al., Growth hormone receptor antagonist therapy in acromegalic patients resistant to somatostatin analogs. J Clin Endocrinol Metab,2000. 85(8):p.2958-61.
[80]. Trainer, P.J., et al., Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med,2000.342(16):p.1171-7.
[81]. Newman, C.B., et al., Octreotide as primary therapy for acromegaly. J Clin Endocrinol Metab,1998.83(9):p.3034-40.
[82]. Barkan, A.L., et al., Pituitary irradiation is ineffective in normalizing plasma insulin-like growth factor I in patients with acromegaly. J Clin Endocrinol Metab,1997. 82(10):p.3187-91.
[83]. van der Lely, A.J., W.W. de Herder and S.W. Lamberts, The role of radiotherapy in acromegaly. J Clin Endocrinol Metab,1997.82(10):p.3185-6.
[84]. Voges, J., et al., Linear accelerator radiosurgery for pituitary macroadenomas:a 7-year follow-up study. Cancer,2006.107(6):p.1355-64.
[85]. Minniti, G., et al., The long-term efficacy of conventional radiotherapy in patients with GH-secreting pituitary adenomas. Clin Endocrinol (Oxf),2005.62(2):p. 210-6.
[86]. Pollock, B.E., et al., Radiosurgery of growth hormone-producing pituitary adenomas:factors associated with biochemical remission. J Neurosurg,2007.106(5):p. 833-8.
[87]. Paisley, A.N., et al., Small vessel remodeling and impaired endothelial-dependent dilatation in subcutaneous resistance arteries from patients with acromegaly. J Clin Endocrinol Metab,2009.94(4):p.1111-7.