Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/13407
標題: 以大鼠模式應用磁振造影於肝臟纖維化之研究
MRI Study of Liver Fibrosis in Rat Model
作者: 洪義文
Hung, Yi-Wen
關鍵字: 肝纖維化;Liver fibrosis;磁振造影;MRI
出版社: 獸醫學系暨研究所
引用: 1. 行政院衛生署國健局。94年台灣地區十大死因統計摘要。2006。 2. Global estimates for health situation assessment and projections. World Health Stat Q Spec No: 1-51, 1990. 3. Agren MS, Taplin CJ, Woessner JF, Jr., Eaglstein WH, and Mertz PM. Collagenase in wound healing: effect of wound age and type. J Invest Dermatol 99: 709-714, 1992. 4. Aisen AM, Doi K, and Swanson SD. Detection of liver fibrosis with magnetic cross-relaxation. Magn Reson Med 31: 551-556, 1994. 5. Arroyo V. Pathophysiology, diagnosis and treatment of ascites in cirrhosis. Ann Hepatol 1: 72-79, 2002. 6. Arthur MJ. Degradation of matrix proteins in liver fibrosis. Pathol Res Pract 190: 825-833, 1994. 7. Arthur MJ, Mann DA, and Iredale JP. Tissue inhibitors of metalloproteinases, hepatic stellate cells and liver fibrosis. J Gastroenterol Hepatol 13 Suppl: S33-38, 1998. 8. Balaban RS, Chesnick S, Hedges K, Samaha F, and Heineman FW. Magnetization transfer contrast in MR imaging of the heart. Radiology 180: 671-675, 1991. 9. Bataller R and Brenner DA. Liver fibrosis. J Clin Invest 115: 209-218, 2005. 10. Benyon RC and Arthur MJ. Extracellular matrix degradation and the role of hepatic stellate cells. Semin Liver Dis 21: 373-384, 2001. 11. Benyon RC, Iredale JP, Goddard S, Winwood PJ, and Arthur MJ. Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver. Gastroenterology 110: 821-831, 1996. 12. Bergman JR. Nodular hyperplasia in the liver of the dog: an association with changes in the Ito cell population. Vet Pathol 22: 427-438, 1985. 13. Blumgart LH. Resection of the liver. Journal of the American College of Surgeons 201: 492-494, 2005. 14. Bottomley PA, Foster TH, Argersinger RE, and Pfeifer LM. A review of normal tissue hydrogen NMR relaxation times and relaxation mechanisms from 1-100 MHz: dependence on tissue type, NMR frequency, temperature, species, excision, and age. Med Phys 11: 425-448, 1984. 15. Brenner DA, Waterboer T, Choi SK, Lindquist JN, Stefanovic B, Burchardt E, Yamauchi M, Gillan A, and Rippe RA. New aspects of hepatic fibrosis. J Hepatol 32: 32-38, 2000. 16. Brown JJ, Naylor MJ, and Yagan N. Imaging of hepatic cirrhosis. Radiology 202: 1-16, 1997. 17. Cabre M, Camps J, Paternain JL, Ferre N, and Joven J. Time-course of changes in hepatic lipid peroxidation and glutathione metabolism in rats with carbon tetrachloride-induced cirrhosis. Clin Exp Pharmacol Physiol 27: 694-699, 2000. 18. Chai JW, Chen C, Chen JH, Lee SK, and Yeung HN. Estimation of in vivo proton intrinsic and cross-relaxation rate in human brain. Magn Reson Med 36: 147-152, 1996. 19. Chai JW, Lin YC, Chen JH, Wu CC, Lee CP, Chu WC, and Lee SK. In vivo magnetic resonance [MR] study of fatty liver: importance of intracellular ultrastructural alteration for MR tissue parameters change. J Magn Reson Imaging 14: 35-41, 2001. 20. Chen JH, Chai JW, and Shen WC. Magnetization transfer contrast imaging of liver cirrhosis. Hepatogastroenterology 46: 2872-2877, 1999. 21. Chen JH, Chai JW, and Yeung HN. In vivo characterization of liver cirrhosis by assessment using magnetization transfer via crossrelaxation. San Francisco, 1994. 22. Chen JH, Yeung HN, Lee SK, and Chai JW. Evaluation of liver diseases via MTC and contrast agent. J Magn Reson Imaging 9: 257-265, 1999. 23. Cobbold J, Lim A, Wylezinska M, Cunningham C, Crossey M, Thomas H, Patel N, Cox J, and Taylor-Robinson S. Magnetic resonance and ultrasound techniques for the evaluation of hepatic fibrosis. Hepatology 43: 1401-1402; author reply 1402, 2006. 24. David DS and Willamg B. Magnetic Resonance Imaging, 1992. 25. Earls JP, Theise ND, Weinreb JC, DeCorato DR, Krinsky GA, Rofsky NM, Mizrachi H, and Teperman LW. Dysplastic nodules and hepatocellular carcinoma: thin-section MR imaging of explanted cirrhotic livers with pathologic correlation. Radiology 201: 207-214, 1996. 26. Elizondo G, Weissleder R, Stark DD, Guerra J, Garza J, Fretz CJ, Todd LE, and Ferrucci JT. Hepatic cirrhosis and hepatitis: MR imaging enhanced with superparamagnetic iron oxide. Radiology 174: 797-801, 1990. 27. Friedman SL. Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies. N Engl J Med 328: 1828-1835, 1993. 28. Friedman SL, Roll FJ, Boyles J, and Bissell DM. Hepatic lipocytes: the principal collagen-producing cells of normal rat liver. Proc Natl Acad Sci U S A 82: 8681-8685, 1985. 29. Fujita M, Yamamoto R, Fritz-Zieroth B, Yamanaka T, Takahashi M, Miyazawa T, Tatsuta M, Terada N, Hosomi N, Inoue E, and Kuroda C. Contrast enhancement with Gd-EOB-DTPA in MR imaging of hepatocellular carcinoma in mice: a comparison with superparamagnetic iron oxide. J Magn Reson Imaging 6: 472-477, 1996. 30. Geerts A. History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis 21: 311-335, 2001. 31. Goldberg HI, Moss AA, Stark DD, McKerrow J, Engelstad B, and Brito A. Hepatic cirrhosis: magnetic resonance imaging. Radiology 153: 737-739, 1984. 32. Gressner AM. Mediators of hepatic fibrogenesis. Hepatogastroenterology 43: 92-103, 1996. 33. Guan S, Zhou KR, Zhao WD, Peng WJ, Tang F, and Mao J. Magnetic resonance diffusion-weighted imaging in the diagnosis of diffuse liver diseases in rats. Chin Med J [Engl] 118: 639-644, 2005. 34. Hahn PF, Stark DD, Weissleder R, Elizondo G, Saini S, and Ferrucci JT. Clinical application of superparamagnetic iron oxide to MR imaging of tissue perfusion in vascular liver tumors. Radiology 174: 361-366, 1990. 35. Hashem RH, Bradley WG, and Lisanti CJ. MRI the basics. Philadelphia, 2004. 36. Henkelman RM, Stanisz GJ, and Graham SJ. Magnetization transfer in MRI: a review. NMR Biomed 14: 57-64, 2001. 37. Hollett MD, Aisen AM, Yeung HN, Francis IR, and Bree RL. Magnetization transfer contrast imaging of hepatic neoplasms. Magn Reson Imaging 12: 1-8, 1994. 38. Iredale JP. Hepatic stellate cell behavior during resolution of liver injury. Semin Liver Dis 21: 427-436, 2001. 39. Ishida T, Murakami T, Kato N, Takahashi M, Miyazawa T, Tsuda K, Tomoda K, Narumi Y, and Nakamura H. Superparamagnetic iron oxide enhanced magnetic resonance imaging of rat liver with hepatocellular carcinoma and benign hyperplastic nodule. Invest Radiol 32: 282-287, 1997. 40. Itai Y, Ohnishi S, Ohtomo K, Kokubo T, Yoshida H, Yoshikawa K, and Imawari M. Regenerating nodules of liver cirrhosis: MR imaging. Radiology 165: 419-423, 1987. 41. Jonker AM, Dijkhuis FW, Boes A, Hardonk MJ, and Grond J. Immunohistochemical study of extracellular matrix in acute galactosamine hepatitis in rats. Hepatology 15: 423-431, 1992. 42. Kahn CE, Jr., Perera SD, Sepponen RE, Tanttu JI, Tierala EK, and Lipton MJ. Magnetization transfer imaging of the abdomen at 0.1 T: detection of hepatic neoplasms. Magn Reson Imaging 11: 67-71, 1993. 43. Kato N, Ihara S, Tsujimoto T, and Miyazawa T. Effect of resovist on rats with different severities of liver cirrhosis. Invest Radiol 37: 292-298, 2002. 44. Kawamura Y, Endo K, Watanabe Y, Saga T, Nakai T, Hikita H, Kagawa K, and Konishi J. Use of magnetite particles as a contrast agent for MR imaging of the liver. Radiology 174: 357-360, 1990. 45. Kopp AF, Laniado M, Dammann F, Stern W, Gronewaller E, Balzer T, Schimpfky C, and Claussen CD. MR imaging of the liver with Resovist: safety, efficacy, and pharmacodynamic properties. Radiology 204: 749-756, 1997. 46. Kreft B, Dombrowski F, Block W, Bachmann R, Pfeifer U, and Schild H. Evaluation of different models of experimentally induced liver cirrhosis for MRI research with correlation to histopathologic findings. Invest Radiol 34: 360-366, 1999. 47. Lauterbur PC. Image formation by induced local interactions. Examples employing nuclear magnetic resonance. 1973. Clin Orthop Relat Res: 3-6, 1989. 48. Lawaczeck R, Bauer H, Frenzel T, Hasegawa M, Ito Y, Kito K, Miwa N, Tsutsui H, Vogler H, and Weinmann HJ. Magnetic iron oxide particles coated with carboxydextran for parenteral administration and liver contrasting. Pre-clinical profile of SH U555A. Acta Radiol 38: 584-597, 1997. 49. Lee HS, Huang GT, Miau LH, Chiou LL, Chen CH, and Sheu JC. Expression of matrix metalloproteinases in spontaneous regression of liver fibrosis. Hepatogastroenterology 48: 1114-1117, 2001. 50. Lee VS. Science to Practice: Can MR imaging replace liver biopsy for the diagnosis of early fibrosis? Radiology 239: 309-310, 2006. 51. Li KC, Jeffrey RB, Jr., Ning SC, Kandil A, Hahn GM, Pike B, Glover G, and Kosek J. Experimental hepatic tumor necrosis. Comparison of spin-echo and pulsed magnetization transfer contrast magnetic resonance imaging. Invest Radiol 28: 896-902, 1993. 52. Li YL, Sato M, Kojima N, Miura M, and Senoo H. Regulatory role of extracellular matrix components in expression of matrix metalloproteinases in cultured hepatic stellate cells. Cell Struct Funct 24: 255-261, 1999. 53. Loesberg AC, Kormano M, and Lipton MJ. Magnetization transfer imaging of normal and abnormal liver at 0.1 T. Invest Radiol 28: 726-731, 1993. 54. Look DC and Locker DR. Time saving in measurement of NMR and EPR relaxation time. Rev Sci Instrum 41: 250-251, 1970. 55. Lopez-De Leon A and Rojkind M. A simple micromethod for collagen and total protein determination in formalin-fixed paraffin-embedded sections. J Histochem Cytochem 33: 737-743, 1985. 56. Luckey SW and Petersen DR. Activation of Kupffer cells during the course of carbon tetrachloride-induced liver injury and fibrosis in rats. Exp Mol Pathol 71: 226-240, 2001. 57. Lundbom N. Determination of magnetization transfer contrast in tissue: an MR imaging study of brain tumors. AJR Am J Roentgenol 159: 1279-1285, 1992. 58. Maclachlan NJ and Cullen JM. Liver, Biliary System, and Exocrine Pancrease. Mosboy Chiacgo, 1995. 59. MacSween RN, Desmet VJ, Roskams T, and Scothorne RJ. Developmental anatomy and normal structure, 2000. 60. Maher JJ. Hepatic fibrosis caused by alcohol. Semin Liver Dis 10: 66-74, 1990. 61. Mann DA and Smart DE. Transcriptional regulation of hepatic stellate cell activation. Gut 50: 891-896, 2002. 62. Marti-Bonmati L, Talens A, del Olmo J, de Val A, Serra MA, Rodrigo JM, Ferrandez A, Torres V, Rayon M, and Vilar JS. Chronic hepatitis and cirrhosis: evaluation by means of MR imaging with histologic correlation. Radiology 188: 37-43, 1993. 63. Martin DR and Semelka RC. Magnetic resonance imaging of the liver: review of techniques and approach to common diseases. Semin Ultrasound CT MR 26: 116-131, 2005. 64. Mathie RT and Wheatley AM. Liver blood flow: physiology, measurement and clinical relevance. London: Harcourt, 2000. 65. Mehta RC, Pike GB, and Enzmann DR. Magnetization transfer magnetic resonance imaging: a clinical review. Top Magn Reson Imaging 8: 214-230, 1996. 66. Mergo PJ, Ros PR, Buetow PC, and Buck JL. Diffuse disease of the liver: radiologic-pathologic correlation. Radiographics 14: 1291-1307, 1994. 67. Milani S, Herbst H, Schuppan D, Grappone C, and Heinrichs OE. Cellular sources of extracellular matrix proteins in normal and fibrotic liver. Studies of gene expression by in situ hybridization. J Hepatol 22: 71-76, 1995. 68. Millward-Sadler GH. Alpha-1-antitrypsin deficiency and liver disease. Acta medica portuguesa: 91-102, 1981. 69. Mortele KJ and Ros PR. MR imaging in chronic hepatitis and cirrhosis. Semin Ultrasound CT MR 23: 79-100, 2002. 70. Numminen K, Halavaara J, Tervahartiala P, Isoniemi H, Kivisaari L, Palomaki M, and Hockerstedt K. Liver tumour MRI: what do we need for lesion characterization? Scand J Gastroenterol 39: 67-73, 2004. 71. Numminen K, Tervahartiala P, Halavaara J, Isoniemi H, and Hockerstedt K. Non-invasive diagnosis of liver cirrhosis: magnetic resonance imaging presents special features. Scand J Gastroenterol 40: 76-82, 2005. 72. Okazaki M, Furuya E, Kasahara T, and Sakamoto K. Function of reticuloendothelial system on CCl4 induced liver injury in mice. Jpn J Pharmacol 39: 503-514, 1985. 73. Outwater E, Schnall MD, Braitman LE, Dinsmore BJ, and Kressel HY. Magnetization transfer of hepatic lesions: evaluation of a novel contrast technique in the abdomen. Radiology 182: 535-540, 1992. 74. Perez Tamayo R. Is cirrhosis of the liver experimentally produced by CCl4 and adequate model of human cirrhosis? Hepatology 3: 112-120, 1983. 75. Pinzani M, Rombouts K, and Colagrande S. Fibrosis in chronic liver diseases: diagnosis and management. J Hepatol 42 Suppl: S22-36, 2005. 76. Poyer JL, McCay PB, Lai EK, Janzen EG, and Davis ER. Confirmation of assignment of the trichloromethyl radical spin adduct detected by spin trapping during 13C-carbon tetrachloride metabolism in vitro and in vivo. Biochem Biophys Res Commun 94: 1154-1160, 1980. 77. Recknagel RO and Ghoshal AK. Quantitative estimation of peroxidative degeneration of rat liver microsomal and mitochondrial lipids after carbon tetrachloride poisoning. Exp Mol Pathol 5: 413-426, 1966. 78. Reimer P, Rummeny EJ, Daldrup HE, Balzer T, Tombach B, Berns T, and Peters PE. Clinical results with Resovist: a phase 2 clinical trial. Radiology 195: 489-496, 1995. 79. Repa JJ and Mangelsdorf DJ. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu Rev Cell Dev Biol 16: 459-481, 2000. 80. Rockey DC and Bissell DM. Noninvasive measures of liver fibrosis. Hepatology 43: S113-120, 2006. 81. Ruwart MJ, Wilkinson KF, Rush BD, Vidmar TJ, Peters KM, Henley KS, Appelman HD, Kim KY, Schuppan D, and Hahn EG. The integrated value of serum procollagen III peptide over time predicts hepatic hydroxyproline content and stainable collagen in a model of dietary cirrhosis in the rat. Hepatology 10: 801-806, 1989. 82. Sato M, Suzuki S, and Senoo H. Hepatic stellate cells: unique characteristics in cell biology and phenotype. Cell Struct Funct 28: 105-112, 2003. 83. Saxena R, Theise ND, and Crawford JM. Microanatomy of the human liver-exploring the hidden interfaces. Hepatology 30: 1339-1346, 1999. 84. Scheuer PJ and Lefkowitch JH. The normal liver. London: Harcourt, 2000. 85. Schuppan D. Structure of the extracellular matrix in normal and fibrotic liver: collagens and glycoproteins. Semin Liver Dis 10: 1-10, 1990. 86. Schwartz LH, Seltzer SE, Tempany CM, Silverman SG, Piwnica-Worms DR, Adams DF, Herman L, Herman LA, and Hooshmand R. Superparamagnetic iron oxide hepatic MR imaging: efficacy and safety using conventional and fast spin-echo pulse sequences. J Magn Reson Imaging 5: 566-570, 1995. 87. Senoo H, Imai K, Matano Y, and Sato M. Molecular mechanisms in the reversible regulation of morphology, proliferation and collagen metabolism in hepatic stellate cells by the three-dimensional structure of the extracellular matrix. J Gastroenterol Hepatol 13 Suppl: S19-32, 1998. 88. Stark DD, Weissleder R, Elizondo G, Hahn PF, Saini S, Todd LE, Wittenberg J, and Ferrucci JT. Superparamagnetic iron oxide: clinical application as a contrast agent for MR imaging of the liver. Radiology 168: 297-301, 1988. 89. Stickel F, Brinkhaus B, Krahmer N, Seitz HK, Hahn EG, and Schuppan D. Antifibrotic properties of botanicals in chronic liver disease. Hepatogastroenterology 49: 1102-1108, 2002. 90. Tanimoto A, Satoh Y, Yuasa Y, Jinzaki M, and Hiramatsu K. Performance of Gd-EOB-DTPA and superparamagnetic iron oxide particles in the detection of primary liver cancer: a comparative study by alternative free-response receiver operating characteristic analysis. J Magn Reson Imaging 7: 120-124, 1997. 91. Tanimoto A, Yuasa Y, Shinmoto H, Jinzaki M, Imai Y, Okuda S, and Kuribayashi S. Superparamagnetic iron oxide-mediated hepatic signal intensity change in patients with and without cirrhosis: pulse sequence effects and Kupffer cell function. Radiology 222: 661-666, 2002. 92. Thomas JD. Magnetization transfer in magnetic resonance imaging. Radiol Technol 67: 297-306, 1996. 93. Tsukamoto H, Matsuoka M, and French SW. Experimental models of hepatic fibrosis: a review. Semin Liver Dis 10: 56-65, 1990. 94. Van de Graaff KM. Digestive system, 2000. 95. Wang YX, Hussain SM, and Krestin GP. Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging. Eur Radiol 11: 2319-2331, 2001. 96. Wanless IR. Physioanatomic considerations. Philadelphia: Lippincott- Raven, 1999. 97. Weissleder R, Stark DD, Engelstad BL, Bacon BR, Compton CC, White DL, Jacobs P, and Lewis J. Superparamagnetic iron oxide: pharmacokinetics and toxicity. AJR Am J Roentgenol 152: 167-173, 1989. 98. Wolff SD and Balaban RS. Magnetization transfer contrast [MTC] and tissue water proton relaxation in vivo. Magn Reson Med 10: 135-144, 1989. 99. Wolff SD, Chesnick S, Frank JA, Lim KO, and Balaban RS. Magnetization transfer contrast: MR imaging of the knee. Radiology 179: 623-628, 1991.
摘要: 
肝纖維化是因肝細胞外基質過度累積所造成,其最主要的成分是膠原蛋白,而嚴重肝纖維化會演變成肝硬化;肝硬化是台灣人民十大死因之一,傳統的確診方法是以肝穿刺為主,但它具侵入性且較具危險性;而磁振造影(Magnetic resonance imaging; MRI)因可提供良好的組織特性、強烈的組織對比、多種切面影像、不具游離輻射及不具侵入性之檢測,其臨床價值是優於其他傳統的影像診斷模式;並可結合超順磁性氧化鐵(Superparamagnetic iron oxide ; SPIO)對比劑之特性,應用於肝臟生理機制之評估;故可藉由大鼠肝纖維化之組織形態上的變化,對應於MRI之組織參數特性的活體研究,來探討有關肝纖維化的MRI參數改變,評估其在肝臟實質病變之臨床診斷價值,並提供組織內不同的成分及彼此間交互作用的訊息,以做為早期診斷的指標。本研究以16、12、8週齡之雄性SD Rat,分別誘導4, 8, 12週為誘導組,並以正常20週齡之雄性SD Rat為對照組(n=8),誘導藥物為50 % CCl4(劑量為2 mL/kg/次/隻);以MRI掃描Rat肝臟,分別計算其T1 & T2 relaxation time及Magnetization transfer ratio(MTR);並於Rat尾靜脈注射SPIO後再掃描,檢測其訊號強度(signal intensity ;SI),以計算其Relative enhancement(RE%);並檢測hepatic kupffer cell吞噬鐵粒子的程度,以評估其活性;動物犧牲時抽血檢測其血液生化值(GOT、GPT),再解剖檢查肉眼及組織病理變化,測量肝、脾臟器官重量/體重之比值,並做肝臟膠原蛋白之定量分析及以西方氏墨點偵測法(western blot)分析α-smooth muscle actin(α-SMA)之表現量,以評估肝纖維化程度與MRI影像訊號之相關性。實驗結果在T1 & T2 relaxation time方面:各誘導組相對於對照組皆有延長的現象,而各誘導組間的差異不大;但誘導12週結束後,讓其病況回復1、2、4、8、15天後,再以MRI掃描,檢測其T1 & T2 relaxation time皆有變短的趨勢,且與對照組無顯著差異。而在MTR方面:誘導4週組相對於對照組有些許下降的趨勢,誘導8週組相對於誘導4週組有回升的趨勢,但誘導12週組相對於誘導8週組其數值的差異不大,推測有可能因肝臟內部仍有些微發炎反應存在,干擾其MT效應所導致;而在回復後,再檢測其MT effect,發現MTR有明顯增高的趨勢。在注射SPIO對比劑後,其對照組的MRI影像呈現明顯黑化,表示Kupffer cell活性很好;誘導4、8、12週組,只有些微的黑化情形,表示Kupffer cell活性明顯降低。綜合實驗結果可知,以MRI並配合對比劑之應用,證實經由CCl4誘導大鼠肝纖維化,且經過15天的回復,使誘導期間的發炎程度趨緩後,其膠原蛋白有明顯的增生,而利用MRI檢測能真正反應出肝纖維化在MRI中的組織特性,其確實不失為一種有效的診斷肝纖維化程度之工具。

Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases, advanced liver fibrosis results in cirrhosis, and liver cirrhosis was one of ten leading causes of death in Taiwan. The conventional method in diagnosis was based on the liver biopsy, but this method was invasive and not cost-effective. Magnetic resonance imaging (MRI) is a non-invasive diagnostic modality, with the advantages of non-ionizing radiation, high sensitivity and specificity in tissue characterization, and that technology feasible and provided the distinct tissue contrast in anatomic structure and obtained the imagings in multiple slices. The clinical performance of MRI is superior to other conventional imaging modalities. In this experiment, we tried to explode the MRI findings of liver fibrosis in rats induced by oral administration of CCl4 for various durations(4, 8 and 12wks). Serum biochemicological and histopathological studies were also performed before and after sacrifice of rats. The results showed significant prolongation of both T1 and T2 relaxation times, higher magnetization transfer(MT)indices in fibrotic rat livers. After intravenous administration of superparamagnetic iron oxide (SPIO)liver-specific contrast agent, the descent of signal attenuation of hepatic parenchyma in the disease rat liver expressed the impairment of the cellular activity of Kupffer cells in rat liver. In conclusion, MRI is a potentially powerful technique for diagnosing fibrotic liver diseases.
URI: http://hdl.handle.net/11455/13407
其他識別: U0005-2308200718460100
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