Controversies in Pathology Reporting and Staging

Reference work entry

Abstract

Following surgery for pancreatic cancer, it is the histopathologist who examines, dissects, and samples the resection specimen for microscopic (histologic) assessment, with the aim of producing a final pathology report that includes all the relevant prognostic information and accurate tumor staging. However, there is no universally agreed pathology protocol for the handling and sampling of pancreatic cancer resection specimens, particularly pancreatoduodenectomy specimens, and pathologists have differing opinions over what is a resection margin and when it should be considered involved. The increasing use of neoadjuvant therapy has also led to new challenges for the pathologist. Differences in interpretation of the TNM staging system can mean that two pathologists stage the same pancreatic cancer resection specimen quite differently. This chapter discusses the pathology reporting and staging of pancreatic cancer resection specimens, with particular emphasis on the challenges and areas of controversy for the pathologist.

Keywords

Pathology Pancreas Cancer Margin Staging Tumor regression Neoadjuvant therapy 

References

  1. 1.
    Cameron JL, He J. Two thousand consecutive pancreaticoduodenectomies. J Am Coll Surg. 2015;220:530–6.CrossRefGoogle Scholar
  2. 2.
    Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.Google Scholar
  3. 3.
    Sobin LH, Gospodarowicz MK, Wittekind C. UICC: TNM classification of malignant tumours. 7th ed. Oxford: Wiley-Blackwell; 2009.Google Scholar
  4. 4.
    IARC, Bosman FT, Carneiro F, Hruban RH, Tniese ND. WHO classification of tumors of the digestive system. 4th ed. Lyon: IARC Press; 2010.Google Scholar
  5. 5.
    Carpelan-Holmstrom M, Nordling S, Pukkala E, Sankila R, Lüttges J, Klöppel G, et al. Does anyone survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the Finnish cancer registry. Gut. 2005;54:385–7.CrossRefGoogle Scholar
  6. 6.
    Verbeke CS. Resection margins and R1 rates in pancreatic cancer – are we there yet? Histopathology. 2008;52:787–96.CrossRefGoogle Scholar
  7. 7.
    Rau BM, Moritz K, Schuschan S, Alsfasser G, Prall F, Klar E. R1 resection in pancreatic cancer has significant impact on long-term outcome in standardized pathology modified for routine use. Surgery. 2012;152:S103–11.CrossRefGoogle Scholar
  8. 8.
    Kamposioras K, Anthoney A, Fernández Moro C, Cairns A, Smith AM, Liaskos C, et al. Impact of intrapancreatic or extrapancreatic bile duct involvement on survival following pancreatoduodenectomy for common bile duct cancer. Br J Surg. 2014;101:89–99.CrossRefGoogle Scholar
  9. 9.
    Pomianowska E, Grzyb K, Westgaard A, Clausen OP, Gladhaug IP. Reclassification of tumour origin in resected periampullary adenocarcinomas reveals underestimation of distal bile duct cancer. Eur J Surg Oncol. 2012;38:1043–50.CrossRefGoogle Scholar
  10. 10.
    Janot MS, Kersting S, Belyaev O, Matuschek A, Chromik AM, Suelberg D, et al. Can the new RCP R0/R1 classification predict the clinical outcome in ductal adenocarcinoma of the pancreatic head? Langenbeck's Arch Surg. 2012;397:917–25.CrossRefGoogle Scholar
  11. 11.
    Verbeke CS, Leitch D, Menon KV, McMahon MJ, Guillou PJ, Anthoney A. Redefining the R1 resection in pancreatic cancer. Br J Surg. 2006;93:1232–7.CrossRefGoogle Scholar
  12. 12.
    Chandrasegaram MD, Goldstein D, Simes J, Gebski V, Kench JG, Gill AJ, et al. Meta-analysis of radical resection rates and margin assessment in pancreatic cancer. Br J Surg. 2015;102:1459–72.CrossRefGoogle Scholar
  13. 13.
    Feakins R, Campbell F, Verbeke CS. Survey of UK histopathologists’ approach to the reporting of resection specimens for carcinomas of the pancreatic head. J Clin Pathol. 2013;66:715–7.CrossRefGoogle Scholar
  14. 14.
    Esposito I, Kleeff J, Bergmann F, Reiser C, Herpel E, Friess H, et al. Most pancreatic cancer resections are R1 resections. Ann Surg Oncol. 2008;15:1651–60.CrossRefGoogle Scholar
  15. 15.
    Campbell F, Smith RA, Whelan P, Sutton R, Raraty M, Neoptolemos JP, et al. Classification of R1 resections for pancreatic cancer: the prognostic relevance of tumour involvement within 1 mm of a resection margin. Histopathology. 2009;55:277–83.CrossRefGoogle Scholar
  16. 16.
    Jamieson NB, Foulis AK, Oien KA, Going JJ, Glen P, Dickson EJ, et al. Positive mobilization margins alone do not influence survival following pancreatico-duodenectomy for pancreatic ductal adenocarcinoma. Ann Surg. 2010;251:1003–10.CrossRefGoogle Scholar
  17. 17.
    Verbeke CS, Gladhaug IP. Dissection of pancreatic resection specimens. Surg Pathol. 2016;9:523–8.CrossRefGoogle Scholar
  18. 18.
    Westgaard A, Laronningen S, Mellem C, Eide TJ, Clausen OP, Møller B, et al. Are survival predictions reliable? Hospital volume versus standardisation of histopathologic reporting for accuracy of survival estimates after pancreatoduodenectomy for adenocarcinoma. Eur J Cancer. 2009;45:2850–9.CrossRefGoogle Scholar
  19. 19.
    Verbeke CS, Gladhaug IP. Resection margin involvement and tumour origin in pancreatic head cancer. Br J Surg. 2012;99:1036–49.CrossRefGoogle Scholar
  20. 20.
    Luttges J, Zamboni G, Kloppel G. Recommendation for the examination of pancreaticoduodenectomy specimens removed from patients with carcinoma of the exocrine pancreas. A proposal for a standardized pathological staging of pancreaticoduodenectomy specimens including a checklist. Dig Surg. 1999;16(4):291–6.CrossRefGoogle Scholar
  21. 21.
    Campbell F, Verbeke CS. Pathology of the pancreas – a practical approach. London: Springer; 2013. p. 27–43.Google Scholar
  22. 22.
    Hruban RH, Klimstra DS, Pitman MB. Tumors of the pancreas, AFIP atlas of tumor pathology. 6th ed. Washington, DC: American Registry of Pathology in collaboration with the Armed Forces Institute of Pathology; 2007.Google Scholar
  23. 23.
    Japan Pancreas Society. Classification of pancreatic cancer. 3rd ed. Tokyo: Kanehara; 2011.Google Scholar
  24. 24.
    Adsay V, Ohike N, Tajiri T, Kim GE, Krasinskas A, Balci S, et al. Ampullary region carcinomas: definition and site specific classification with delineation of four clinicopathologically and prognostically distinct subsets in an analysis of 249 cases. Am J Surg Pathol. 2012;36(11):1592–608.CrossRefGoogle Scholar
  25. 25.
    Chatelain D, Fléjou JF. Pancreatectomy for adenocarcinoma: prognostic factors, recommendations for pathological reports. Ann Pathol. 2002;22:422–31.PubMedGoogle Scholar
  26. 26.
    Cancer of the Exocrine Pancreas, Ampulla of Vater and Distal Common Bile Duct. The Royal College of Pathologists of Australasia. 2014. Available from: https://www.rcpa.edu.au/
  27. 27.
    Bockhorn M, Uzunoglu FG, Adham M, Imrie C, Milicevic M, Sandberg AA, et al. Borderline resectable pancreatic cancer: a consensus statement by the international study Group of Pancreatic Surgery (ISGPS). Surgery. 2014;155:977–88.CrossRefGoogle Scholar
  28. 28.
    Hruban RH, Adsay NV, Albores-Saavedra J, Compton C, Garrett ES, Goodman SN, et al. Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol. 2001;25:579–86.CrossRefGoogle Scholar
  29. 29.
    Agoff SN, Crispin DA, Bronner MP, Dail DH, Hawes SE, Haggitt RC. Neoplasms of the ampulla of Vater with concurrent pancreatic intraductal neoplasia: a histological and molecular study. Mod Pathol. 2001;14:139–46.CrossRefGoogle Scholar
  30. 30.
    Campbell F, Verbeke CS. Pathology of the pancreas – a practical approach. London: Springer; 2013. p. 111–51.Google Scholar
  31. 31.
    Ang DC, Shia J, Tang LH, Katabi N, Klimstra DS. The utility of immunohistochemistry in subtyping adenocarcinoma of the ampulla of Vater. Am J Surg Pathol. 2014;38:1371–9.CrossRefGoogle Scholar
  32. 32.
    Washington K, Berlin J, Branton P, Burgart LJ, Carter DK, Compton CC, et al. Protocol for the examination of specimens from patients with carcinoma of the exocrine pancreas. College of American Pathologists. 2016. Available from: www.cap.org
  33. 33.
    Raut CP, Tseng JF, Sun CC, Wang H, Wolff RA, Crane CH, et al. Impact of resection status on pattern of failure and survival after pancreaticoduodenectomy for pancreatic adenocarcinoma. Ann Surg. 2007;246:52–6.CrossRefGoogle Scholar
  34. 34.
    Staley CA, Cleary KR, Abbruzzese JL, Lee JE, Ames FC, Fenoglio CJ, Evans DB. The need for standardized pathologic staging of pancreaticoduodenectomy specimens. Pancreas. 1996;4:373–80.CrossRefGoogle Scholar
  35. 35.
    Nagakawa T, Sanada H, Inagaki M, Sugama J, Ueno K, Konishi I, et al. Long-term survivors after resection of carcinoma of the head of the pancreas: significance of histologically curative resection. J Hepato-Biliary-Pancreat Surg. 2004;11:402–8.CrossRefGoogle Scholar
  36. 36.
    Campbell F, Foulis AK, Verbeke CS. Dataset for the histopathological reporting of carcinomas of the pancreas, ampulla of Vater and common bile duct. The Royal College of Pathologists. 2010. Available from: www.rcpath.org
  37. 37.
    Pancreatic adenocarcinoma. NCCN clinical practice guidelines in oncology. 2015. Available from: www.nccn.org/patients
  38. 38.
    Quirke P, Dudley P, Dixon MF, Williams NS. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathologic study of lateral tumour spread and surgical excision. Lancet. 1986;2:996–9.CrossRefGoogle Scholar
  39. 39.
    Quirke P, Dixon MF. The prediction of local recurrence in rectal adenocarcinoma by histopathological examination. Int J Colorect Dis. 1988;3:127–31.CrossRefGoogle Scholar
  40. 40.
    Verbeke CS, Knapp J, Gladhaug IP. Tumour growth is more dispersed in pancreatic head cancers than in rectal cancer: implications for resection margin assessment. Histopathology. 2011;59:1111–21.CrossRefGoogle Scholar
  41. 41.
    Chang DK, Johns AL, Merrett ND, Gill AJ, Colvin EK, Scarlett CJ, et al. Margin clearance and outcome in resected pancreatic cancer. J Clin Oncol. 2009;27:2855–62.CrossRefGoogle Scholar
  42. 42.
    Jamieson NB, Chan NI, Foulis AK, Dickson EJ, McKay CJ, Carter CR. The prognostic influence of resection margin clearance following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. J Gastrointest Surg. 2013;17(3):511–21.CrossRefGoogle Scholar
  43. 43.
    Gebauer F, Tachezy M, Vashist YK, Marx AH, Yekebas E, Izbicki JR, et al. Resection margin clearance in pancreatic cancer after implementation of the Leeds pathology protocol (LEEPP): clinically relevant or just academic? World J Surg. 2015;39(2):493–9.CrossRefGoogle Scholar
  44. 44.
    Amin MB, Edge S, Greene F, editors. AJCC cancer staging manual. 8th ed. New York: Springer; 2016.Google Scholar
  45. 45.
    Wittekind C, Compton CC, Greene FL, Sobin LH. TNM residual tumour classification revisited. Cancer. 2002;94:2511–6.CrossRefGoogle Scholar
  46. 46.
    Brierley JD, Gospodarowicz MK, Wittekind C. UICC: TNM classification of malignant tumours. 8th ed. Oxford: Wiley-Blackwell; 2017.Google Scholar
  47. 47.
    Adsay NV, Basturk O, Saka B, Bagci P, Ozdemir D, Balci S, et al. Whipple made simple for surgical pathologists: orientation, dissection, and sampling of pancreaticoduodenectomy specimens for a more practical and accurate evaluation of pancreatic, distal common bile duct, and ampullary tumors. Am J Surg Pathol. 2014;38:480–93.CrossRefGoogle Scholar
  48. 48.
    Isaji S, Kawarada Y, Uemoto S. Classification of pancreatic cancer: comparison of Japanese and UICC classifications. Pancreas. 2004;28:231–4.CrossRefGoogle Scholar
  49. 49.
    Tanaka M, Fernández-del Castillo C, Adsay V, Chari S, Falconi M, Jang JY, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology. 2012;12:183–97.CrossRefGoogle Scholar
  50. 50.
    Adsay V, Mino-Kenudson M, Furukawa T, Basturk O, Zamboni G, Marchegiani G, et al. Pathologic evaluation and reporting of intraductal papillary mucinous neoplasms of the pancreas and other tumoral intraepithelial neoplasms of pancreatobiliary tract: recommendations of Verona consensus meeting. Ann Surg. 2016;263(1):162–77.CrossRefGoogle Scholar
  51. 51.
    Sobin LH, Wittekind C. UICC: TNM classification of malignant tumours. 5th ed. Oxford: Wiley-Blackwell; 1997.Google Scholar
  52. 52.
    Lüttges J, Vogel I, Menke M, Henne-Bruns D, Kremer B, Klöppel G. The retroperitoneal resection margin and vessel involvement are important factors determining survival after pancreaticoduodenectomy for ductal adenocarcinoma of the head of the pancreas. Virchows Arch. 1998;433:237–42.CrossRefGoogle Scholar
  53. 53.
    Adsay NV, Bagci P, Tajiri T, Oliva I, Ohike N, Balci S, et al. Pathologic staging of pancreatic, ampullary, biliary, and gallbladder cancers: pitfalls and practical limitations of the current AJCC/UICC TNM staging system and opportunities for improvement. Sem Diagn Pathol. 2012;29:127–41.CrossRefGoogle Scholar
  54. 54.
    Saka B, Balci S, Basturk O, Bagci P, Postlewait LM, Maithel S, et al. Pancreatic ductal adenocarcinoma is spread to the peripancreatic soft tissue in the majority of resected cases, rendering the AJCC T-stage protocol (7th edition) inapplicable and insignificant: a size-based staging system (pT1: ≤2, pT2: >2-≤4, pT3: >4 cm) is more valid and clinically relevant. Ann Surg Oncol. 2016;23(6):2010–8.CrossRefGoogle Scholar
  55. 55.
    Allen PJ, Kuk D, Castillo CF, Basturk O, Wolfgang CL, Cameron JL, et al. Multi-institutional validation study of the American joint commission on cancer (8th edition) changes for T and N staging in patients with pancreatic adenocarcinoma. Ann Surg. 2017;265(1):185–91.CrossRefGoogle Scholar
  56. 56.
    House MG, Gönen M, Jarnagin WR, D'Angelica M, DeMatteo RP, Fong Y, et al. Prognostic significance of pathologic nodal status in patients with resected pancreatic cancer. J Gastrointest Surg. 2007;11(11):1549–55.CrossRefGoogle Scholar
  57. 57.
    Huebner M, Kendrick M, Reid-Lombardo KM, Que F, Therneau T, Qin R, et al. Number of lymph nodes evaluated: prognostic value in pancreatic adenocarcinoma. J Gastrointest Surg. 2012;16(5):920–6.CrossRefGoogle Scholar
  58. 58.
    Sierzega M, Popiela T, Kulig J, Nowak K. The ratio of metastatic/resected lymph nodes is an independent prognostic factor in patients with node-positive pancreatic head cancer. Pancreas. 2006;33:240–5.CrossRefGoogle Scholar
  59. 59.
    Berger AC, Watson JC, Ross EA, Hoffman JP. The metastatic/examined lymph node ratio is an important prognostic factor after pancreaticoduodenectomy for pancreatic adenocarcinoma. Ann Surg. 2004;70:235–40.Google Scholar
  60. 60.
    Pawlik TM, Gleisner AL, Cameron JL, Winter JM, Assumpcao L, Lillemoe KD, et al. Prognostic relevance of lymph node ratio following pancreaticoduodenectomy for pancreatic cancer. Surgery. 2007;141:610–8.CrossRefGoogle Scholar
  61. 61.
    Han SS, Jang JY, Kim SW, Kim WH, Lee KU, Park YH. Analysis of long-term survivors after surgical resection for pancreatic cancer. Pancreas. 2006;32:271–5.CrossRefGoogle Scholar
  62. 62.
    Tomlinson JS, Jain S, Bentrem DJ, Sekeris EG, Maggard MA, Hines OJ, et al. Accuracy of staging node-negative pancreas cancer: a potential quality measure. Arch Surg. 2007;142:767–73.CrossRefGoogle Scholar
  63. 63.
    Valsangkar NP, Bush DM, Michaelson JS, Ferrone CR, Wargo JA, Lillemoe KD, et al. N0/N1, PNL, or LNR? The effect of lymph node number on accurate survival prediction in pancreatic ductal adenocarcinoma. J Gastroint Surg. 2013;17:257–66.CrossRefGoogle Scholar
  64. 64.
    Pai RK, Beck AH, Mitchem J, Linehan DC, Chang DT, Norton JA, et al. Pattern of lymph node involvement and prognosis in pancreatic adenocarcinoma: direct lymph node invasion has similar survival to node negative disease. Am J Surg Pathol. 2011;35:228–34.CrossRefGoogle Scholar
  65. 65.
    Buc E, Couvelard A, Kwiatkowski F, Dokmak S, Ruszniewski P, Hammel P, et al. Adenocarcinoma of the pancreas: does prognosis depend on mode of lymph node invasion? Eur J Surg Oncol. 2014;40:1578–85.CrossRefGoogle Scholar
  66. 66.
    Konstantinidis IT, Deshpande V, Zheng H, Wargo JA, Fernandez-del Castillo C, Thaver SP, et al. Does the mechanism of lymph node invasion affect survival in patients with pancreatic ductal adenocarcinoma? J Gastroint Surg. 2010;4:261–7.CrossRefGoogle Scholar
  67. 67.
    Prenzel KL, Holscher AH, Drebber U, Bollschweiler E, Gutschow CA, Stipple DL, et al. Extracapsular lymph node spread as a negative prognostic factor of adenocarcinoma of the pancreas and cancer of the papilla of Vater. Pancreas. 2014;43:64–8.CrossRefGoogle Scholar
  68. 68.
    Luchini C, Veronese N, Pea A, Sergi G, Manzato E, Nottegar A, et al. Extranodal extension in N1-adenocarcinoma of the pancreas and papilla of Vater: a systematic review and meta-analysis of its prognostic significance. Eur J Gastroenterol Hepatol. 2016;28:205–9.PubMedGoogle Scholar
  69. 69.
    Strobel O, Hinz U, Gluth A, Hank T, Hackert T, Bergmann F, et al. Pancreatic adenocarcinoma: number of positive nodes allows to distinguish several N categories. Ann Surg. 2015;261:961–9.CrossRefGoogle Scholar
  70. 70.
    Basturk O, Saka B, Balci S, Postlewait LM, Knight J, Goodman M, et al. Substaging of lymph node status in resected pancreatic ductal adenocarcinoma has strong prognostic correlations: proposal for a revised N classification for TNM staging. Ann Surg Oncol. 2015;22:S1187–95.CrossRefGoogle Scholar
  71. 71.
    Hermanek P. Staging of exocrine pancreatic carcinoma. Eur J Surg Oncol. 1991;17(2):167–72.PubMedGoogle Scholar
  72. 72.
    Sobin LH, Wittekind C. UICC: TNM classification of malignant tumours. 6th ed. Oxford: Wiley-Blackwell; 2002.Google Scholar
  73. 73.
    Chatterjee D, Katz MH, Rashid A, Estrella JS, Wang H, Varadhachary GR, et al. Pancreatic intraepithelial neoplasia and histological changes in non-neoplastic pancreas associated with neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma. Histopathology. 2013;63:841–51.CrossRefGoogle Scholar
  74. 74.
    Verbeke C, Löhr M, Karlsson JS, Del Chiaro M. Pathology reporting of pancreatic cancer following neoadjuvant therapy: challenges and uncertainties. Cancer Treatm Rev. 2015;41:17–26.CrossRefGoogle Scholar
  75. 75.
    Hartman DJ, Krasinskas AM. Assessing treatment effect in pancreatic cancer. Arch Pathol Lab Med. 2012;136(1):100–9.CrossRefGoogle Scholar
  76. 76.
    Ishikawa O, Ohhigashi H, Sasaki Y, Imaoka S, Iwanaga T, Teshima T, et al. The histopathological effect of preoperative irradiation in adenocarcinoma of the periampullary region. Nippin Gan Chir Gakkai Shi. 1988;23:720–7.Google Scholar
  77. 77.
    Evans DB, Rich TA, Byrd DR, Cleary KR, Connelly JH, Levin B, et al. Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg. 1992;127:1335–9.CrossRefGoogle Scholar
  78. 78.
    Breslin TM, Hess KR, Harbison DB, Jean ME, Cleary KR, Dackiw AP, et al. Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration. Ann Surg Oncol. 2001;8:123–32.CrossRefGoogle Scholar
  79. 79.
    White RR, Xie HB, Gottfried MR, Czito BG, Hurwitz HI, Morse MA, et al. Significance of histological response to preoperative chemoradiotherapy for pancreatic cancer. Ann Surg Oncol. 2005;12:214–21.CrossRefGoogle Scholar
  80. 80.
    Chatterjee D, Katz MH, Rashid A, Varadhachary GR, Wolff RA, Wang H, et al. Histologic grading of the extent of residual carcinoma following neoadjuvant chemoradiation in pancreatic ductal adenocarcinoma: a predictor for patient outcome. Cancer. 2012;118:3182–90.CrossRefGoogle Scholar
  81. 81.
    Zhao Q, Rashid A, Gong Y, Katz MH, Lee JE, Wolf R, et al. Pathologic complete response to neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma is associated with a better prognosis. Ann Diagn Pathol. 2012;16:29–37.CrossRefGoogle Scholar
  82. 82.
    Liu L, Katz MH, Lee SM, Fischer LK, Prakash L, Parker N, et al. Superior mesenteric artery margin of posttherapy pancreaticoduodenectomy and prognosis in patients with pancreatic ductal adenocarcinoma. Am J Surg Pathol. 2015;39:1395–403.CrossRefGoogle Scholar
  83. 83.
    Cross SS, Feeley KM, Angel CA. The effect of four interventions on the informational content of histopathology reports of resected colorectal carcinomas. J Clin Pathol. 1998;51:481–2.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Royal Liverpool University HospitalLiverpoolUK
  2. 2.Oslo University HospitalOsloNorway

Section editors and affiliations

  • James L. Abbruzzese
    • 1
  • Raul A. Urrutia
    • 2
  • John Neoptolemos
    • 3
  • Markus W. Büchler
    • 4
  • Thilo Hackert
    • 5
  1. 1.Duke University Medical CenterDurhamUSA
  2. 2.Mayo Clinic Cancer CenterMayo ClinicRochesterUSA
  3. 3.Division of Surgery and OncologyUniversity of LiverpoolLiverpoolUK
  4. 4.Department of General, Visceral and Transplantation SurgeryUniversity of HeidelbergHeidelbergGermany
  5. 5.Department of General, Visceral and Transplantation SurgeryUniversity of HeidelbergHeidelbergGermany

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