Development of oncological diseases after organ transplantation
https://doi.org/10.23873/2074-0506-2022-14-4-476-487
Abstract
With the increase in the population of patients with transplanted organs, the risk of developing oncological diseases has become proportionally high, which may be the cause of poor quality of life, and also of a high mortality among the patients with transplanted organs. The review examines the risk factors, incidence, and the impact of malignant neoplasms on the survival in patients with transplanted organs. The rapid development of clinical transplantology, the use of new drugs and immunosuppression regimens poses new challenges for oncologists and transplantologists. The analysis of oncopathology incidence in patients with transplanted organs allows us to conclude about its impact on the long-term life prognosis and the need to include preventive measures in transplantation practice.
About the Authors
A. V. Babkina
N.V. Sklifosovsky Research Institute for Emergency Medicine; Department of Transplantology and Artificial Organs, A.I. Yevdokimov Moscow State University of Medicine and Dentistry
Russian Federation
Russian Federation
Anna V. Babkina, Assoc. Prof., Cand. Sci. (Med.), Gynecologist of the Urgent Gynecology Department; Associate Professor
3 Bolshaya Sukharevskaya Sq., Moscow 129090
20 Bldg. 1 Delegatskaya St., Moscow 127473
M. Sh. Khubutiya
N.V. Sklifosovsky Research Institute for Emergency Medicine; Department of Transplantology and Artificial Organs, A.I. Yevdokimov Moscow State University of Medicine and Dentistry
Russian Federation
Russian Federation
Mogeli Sh. Khubutiya, Academician of the Russian Academy of Sciences, Prof., Dr. Sci. (Med.), President; Head of the Department
3 Bolshaya Sukharevskaya Sq., Moscow 129090
20 Bldg. 1 Delegatskaya St., Moscow 127473
References
1. Abaeva OP, Romanov SV, Ryabova EN. Quality of life of patients who underwent kidney and liver transplant surgery. Profilakticheskaya Meditsina. 2020;23(1):121–126. (In Russ.). https://doi.org/10.17116/profmed202023011121
2. Gautier SV, Khomyakov SM. Organ donation and transplantation in the Russian Federation in 2020 13th Report from the Registry of the Russian Transplant Society. Russian Journal of Transplantology and Artificial Organs. 2021;23(3):8–34. (In Russ.). https://doi.org/10.15825/1995-1191-2021-3-8-34
3. ANZDATA 39th Annual Report 2016 (Data to 2015). Australia; 2016. Available at: https://www.anzdata.org.au/report/anzdata-39th-annual-report-2016/ [Accessed September 29, 2022].
4. Bos S, Vos R, Van Raemdonck DE, Verleden GM. Survival in adult lung transplantation: where are we in 2020? Curr Opin Organ Transplant. 2020;25(3):268–273. PMID: 32332197 https://doi.org/10.1097/mot.0000000000000753
5. Graham CN, Watson C, Barlev A, Stevenson M, Dharnidharka V. Mean lifetime survival estimates following solid organ transplantation in the US and UK. J Med Econ. 2022;25(1):230–237. PMID: 35068310 http://doi.org/10.1080/13696998.2022.2033050
6. Gallagher MP, Kelly PJ, Jardine M, Perkovic V, Cass A, Craig JC, et al. Longterm cancer risk of immunosuppressive regimens after kidney transplantation. J Am Soc Nephrol. 2010;21(5):852– 858. PMID: 20431040 https://doi.org/10.1681/asn.2009101043
7. Tessari G, Naldi L, Boschiero L, Minetti E, Sandrini S, Nacchia F, et al. Incidence of primary and second cancers in renal transplant recipients: a multicenter cohort study. Am J Transplant. 2013;13(1):214–221. PMID: 23057816 https://doi.org/10.1111/j.16006143.2012.04294.x
8. Wong G, Chapman JR, Craig JC. Death from cancer: a sobering truth for patients with kidney transplants. Kidney Int. 2014;85(6):1262-1264. PMID: 24875547 https://doi.org/10.1038/ki.2013.494
9. Rashti SL. Themes in literature related to incidence, risk, and prevention of cancer in solid-organ transplantation recipients on immunosuppressive therapy. Cancer Nurs. 2019;42(1):E28–E35. PMID: 29334522 http://doi.org/10.1097/NCC.0000000000000558
10. Guillemin A, Rousseau B, Neuzillet C, Joly C, Boussion H, Grimbert P, et al. De novo cancer after solid organ transplantation: epidemiology, prognosis and management. Bull Cancer. 2017;104(3):245–257. PMID: 28237352 https://doi.org/10.1016/j.bulcan.2016.12.008
11. Huo Z, Li C, Xu X, Ge F, Wang R, Wen Y, et al. Cancer risks in solid organ transplant recipients: results from a comprehensive analysis of 72 cohort studies. Oncoimmunology. 2020;9(1):1848068. PMID: 33299661 http://doi.org/10.1080/2162402X.2020.1848068
12. van Leeuwen MT, Grulich AE, Webster AC, McCredie MR, Stewart JH, McDonald SP, et al. Immunosuppression and other risk factors for early and late non-Hodgkin lymphoma after kidney transplantation. Blood. 2009;114(3):630– 637. PMID: 19443660 https://doi.org/10.1182/blood-2009-02-202507
13. Elfimova AYu. Klinicheskiy sluchay vozniknoveniya posttransplantatsionnogo limfoproliferativnogo zabolevaniya s porazheniem tsentral'noy nervnoy sistemy posle transplantatsii pochki. Russian Journal of Pediatric Hematology and Oncology. 2019;6(S1):91–92. (In Russ.).
14. Sultanov PK, Khadjibaev FA, Ergashev DN, Ismatov AA. Analysis of complications after kidney transplantation. The Bulletin of Emergency Medicine. 2021;14(1):55–64. (In Russ.).
15. Engels EA, Pfeiffer RM, Fraumeni JF Jr, Kasiske BL, Israni AK, Snyder JJ, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA. 2011;306(17):1891– 1901. PMID: 22045767 https://doi.org/10.1001/jama.2011.1592
16. Berastegui C, LaPorta R, López-Meseguer M, Romero L, Gómez-Ollés S, Riera J, et al. Epidemiology and risk factors for cancer after lung transplantation. Transplant Proc. 2017;49(10):2285– 2291. PMID: 29198662 https://doi.org/10.1016/j.transproceed.2017.09.043
17. Sprangers B, Nair V, Launay-Vacher V, Riella LV, Jhaveri KD. Risk factors associated with post-kidney transplant malignancies: an article from the Cancer-Kidney International Network. Clin Kidney J. 2018;11(3):315–329. PMID: 29942495 https://doi.org/10.1093/ckj/sfx122
18. Sherston SN, Carroll RP, Harden PN, Wood Kathryn J. Predictors of cancer risk in the long-term solidorgan transplant recipient. Transplantation. 2014;97(6):605–611. PMID: 24202142 http://doi.org/10.1097/01.TP.0000436907.56425.5c
19. Schrem H, Schneider V, Kurok M, Goldis A, Dreier M, Kaltenborn A, et al. Independent pre-transplant recipient cancer risk factors after kidney transplantation and the utility of g-chart analysis for clinical process control. PLoS One. 2016;11(7):0158732. PMID: 27398803 https://doi.org/10.1371/journal.pone.0158732
20. Kluijfhout WP, Drake FT, Pasternak JD, Beninato T, Mitmaker EJ, Gosnell JE, et al. De novo thyroid cancer following solid organ transplantation-A 25-year experience at a high-volume institution with a review of the literature. J Surg Oncol. 2017;115(2):105–108. PMID: 28054345 https://doi.org/10.1002/jso.24495
21. Lengwiler E, Stampf S, Zippelius A, Salati E, Zaman K, Schäfer N, et al. The Swiss Transplant Cohort Study. Solid cancer development in solid organ transplant recipients within the Swiss Transplant Cohort Study. Swiss Med Wkly. 2019;149:w20078. PMID: 31104307 https://doi.org/10.4414/smw.2019.20078
22. Park GH, Chang SE, Won CH, Lee MW, Choi JH, Moon KC, et al. Incidence of primary skin cancer after organ transplantation: an 18-year singlecenter experience in Korea. J Am Acad Dermatol. 2014;70(3):465–472. PMID: 24342756 https://doi.org/10.1016/j.jaad.2013.10.024
23. Ekstrоm M, Riise GC, Tanash HA. Risk of cancer after lung transplantation for COPD. Int J Chron Obstruct Pulmon Dis. 2017;12:2841–2847. PMID: 29042765 https://doi.org/10.2147/copd.s147065
24. Hart A, Smith JM, Skeans MA, Gustafson SK, Wilk AR, Robinson A, et al. OPTN/SRTR 2016 Annual data report: kidney. Am J Transplant. 2018;18(Suppl 1):18–113. PMID: 29292608 https://doi.org/10.1111/ajt.14557
25. Kim WR, Lake JR, Smith JM, Schladt DP, Skeans MA, Harper AM, et al. OPTN/SRTR 2016 Annual data report: liver. Am J Transplant. 2018;18(Suppl 1):172–253. PMID: 29292603 https://doi.org/10.1111/ajt.14559
26. McCaughan JA, Courtney AE. The clinical course of kidney transplant recipients after 20 years of graft function. Am J Transplant. 2015;15(3):734– 740. PMID: 25683898 https://doi.org/10.1111/ajt.13041
27. Yusen RD, Edwards LB, Dipchand AI, Goldfarb SB, Kucheryavaya AY, Levvey BJ, et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-third adult lung and heart-lung transplant report-2016; focus theme: primary diagnostic indications for transplant. J Heart Lung Transplant. 2016;35(10):1170–1184. PMID: 27772669 https://doi.org/10.1016/j.healun.2016.09.001
28. Lim WH, Badve SV, Wong G. Long-term allograft and patient outcomes of kidney transplant recipients with and without incident cancer – a population cohort study. Oncotarget. 2017;8(44):77771–77782. PMID: 29100424 https://doi.org/10.18632/oncotarget.20781
29. Sigel K, Veluswamy R, Krauskopf K, Mehrotra A, Mhango G, Sigel C, et al. Lung cancer prognosis in elderly solid organ transplant recipients. Transplantation. 2015;99(10):2181–2189. PMID: 25839704 https://doi.org/10.1097/tp.0000000000000715
30. Farrugia D, Mahboob S, Cheshire J, Begaj I, Khosla S, Ray D, et al. Malignancy-related mortality following kidney transplantation is common. Kidney Int. 2014;85(6):1395–1403. PMID: 24257690 https://doi.org/10.1038/ki.2013.458
31. Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA, et al. Kidney Disease: Improving Global O. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int. 2010;77(4):299–311. PMID: 19847156 https://doi.org/10.1038/ki.2009.377
32. Doycheva I, Amer S, Watt KD. Denovo malignancies after transplantation: risk and surveillance strategies. Med Clin North Am. 2016;100(3):551–567. PMID: 27095645 https://doi.org/10.1016/j.mcna.2016.01.006
33. Krynitz B, Edgren G, Lindelof B, Baecklund E, Brattstrom C, Wilczek H, et al. Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008--a Swedish population-based study. Int J Cancer. 2013;132(6):1429–1438. PMID: 22886725 https://doi.org/10.1002/ijc.27765
34. Acuna SA, Huang JW, Daly C, Shah PS, Kim SJ, Baxter NN. Outcomes of solid organ transplant recipients with preexisting malignancies in remission: a systematic review and meta-analysis. Transplantation. 2017;101(3):471–481. PMID: 27101077 https://doi.org/10.1097/tp.0000000000001192
35. van de Wetering J, Roodnat JI, Hemke AC, Hoitsma AJ, Weimar W. Patient survival after the diagnosis of cancer in renal transplant recipients: a nested case-control study. Transplantation. 2010;90(12):1542–1546. PMID: 21076383 https://doi.org/10.1097/tp.0b013e3181ff1458
36. Noone AM, Pfeiffer RM, Dorgan JF, Magder LS, Bromberg JS, Lynch CF, et al. Cancer-attributable mortality among solid organ transplant recipients in the United States: 1987 through 2014. Cancer. 2019;125(15):2647–2655. PMID: 31034602 https://doi.org/10.1002/cncr.32136
37. Acuna SA, Fernandes KA, Daly C, Hicks LK, Sutradhar R, Kim SJ, et al. Cancer mortality among recipients of solid-organ transplantation in Ontario, Canada. JAMA Oncol. 2016;2(4):463–469. PMID:26746479 https://doi.org/10.1001/jamaoncol.2015.5137
38. Asch WS, Perazella MA. Cancer and mortality in solid-organ transplantation: preventable or inevitable? Am J Kidney Dis. 2016;68(6):839–842. PMID: 27405594 https://doi.org/10.1053/j. ajkd.2016.06.009
39. D'Arcy ME, Coghill AE, Lynch CF, Koch LA, Li J, Pawlish KS, et al. Survival after a cancer diagnosis among solid organ transplant recipients in the United States. Cancer. 2019;125(6):933– 942. PMID: 30624768 https://doi.org/10.1002/cncr.31782
40. Wise J. Organ transplantation may link to deaths from cancer, study finds. BMJ. 2016;352:i83. PMID: 26755734 https://doi.org/10.1136/bmj.i83
41. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007;370(9581):59–67. PMID: 17617273 https://doi.org/10.1016/S0140-6736(07)61050-2
42. Gutierrez-Dalmau A, Campistol JM. Immunosuppressive therapy and malignancy in organ transplant recipients: a systematic review. Drugs. 2007;67(8):1167–1198. PMID: 17521218 https://doi.org/10.2165/00003495200767080-00006
43. Kamdar KY, Rooney CM, Heslop HE. Posttransplant lymphoproliferative disease following liver transplantation. Curr Opin Organ Transplant. 2011;16(3):274–280. PMID: 21467936 https://doi. org/10.1097/mot.0b013e3283465715
44. Sampaio MS, Cho YW, Qazi Y, Bunnapradist S, Hutchinson IV, Shah T. Posttransplant malignancies in solid organ adult recipients: an analysis of the U.S. National Transplant Database. Transplantation. 2012;94(10):990–998. PMID: 23085553 https://doi.org/10.1097/tp.0b013e318270bc7b
45. Tsai HI, Lee CW, Kuo CF, See LC, Liu FC, Chiou MJ, et al. De Novo malignancy in organ transplant recipients in Taiwan: a nationwide cohort population study. Oncotarget. 2017;8(22):36685–36695. PMID: 27821818 https://doi.org/10.18632/oncotarget.13124
46. Na R, Grulich AE, Meagher NS, McCaughan GW, Keogh AM, Vajdic CM. Comparison of de novo cancer incidence in Australian liver, heart and lung transplant recipients. Am J Transplant. 2013;13(1):174–183. PMID: 23094788 https://doi.org/10.1111/j.16006143.2012.04302.x
47. Chapman JR, Webster AC, Wong G. Cancer in the transplant recipient. Cold Spring Harb Perspect Med. 2013;3(7):a015677. PMID: 23818517 https://doi.org/10.1101/cshperspect.a015677
48. Liao JB, Fisher CE, Madeleine MM. Gynecologic cancers and solid organ transplantation. Am J Transplant. 2019;19(5):1266–1277. PMID: 30725527 https://doi.org/10.1111/ajt.15292
49. Wielgos AA, Pietrzak B. Human papilloma virus-related premalignant and malignant lesions of the cervix and anogenital tract in immunocompromised women. Ginekol Pol. 2020;91(1):32–37. PMID: 32039466 https://doi.org/10.5603/gp.2020.0008
50. de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective crosssectional world-wide study. Lancet Oncol. 2010;11(11):1048–1056. PMID: 20952254 https://doi.org/10.1016/s1470-2045(10)70230-8
51. Smith JS, Backes DM, Hoots BE, Kurman RJ, Pimenta JM. Human papillomavirus type-distribution in vulvar and vaginal cancers and their associated precursors. Obstet Gynecol. 2009;113(4):917– 924. PMID: 19305339 https://doi.org/10.1097/aog.0b013e31819bd6e0
52. De Vuyst H, Clifford GM, Nascimento MC, Madeleine MM, Franceschi S. Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis. Int J Cancer. 2009;124(7):1626–1636. PMID: 19115209 https://doi.org/10.1002/ijc.24116
53. Hinten F, Meeuwis KA, van Rossum MM, de Hullu JA. HPV-related (pre)malignancies of the female anogenital tract in renal transplant recipients. Crit Rev Oncol Hematol. 2012;84(2):161–180. PMID: 22425015 https://doi.org/10.1016/j.critrevonc.2012.02.008
54. Adey DB. Women and kidney transplantation. Adv Chronic Kidney Dis. 2013;20(5):427–432. PMID: 23978549 https://doi.org/10.1053/j.ackd.2013.06.008
55. Hibberd AD, Trevillian PR, Wlodarczyk JH, Kemp DG, Stein AM, Gillies AH, et al. Effect of immunosuppression for primary renal disease on the risk of cancer in subsequent renal transplantation: a populationbased retrospective cohort study. Transplantation. 2013;95(5):122–127. PMID: 23238532 https://doi.org/10.1097/tp.0b013e3182782f59
56. Koyawala N, Silber JH, Rosenbaum PR, Wang W, Hill AS, Reiter JG, et al. Comparing outcomes between antibody induction therapies in kidney transplantation. J Am Soc Nephrol. 2017;28(7):2188–2200. PMID: 28320767 https://doi.org/10.1681/asn.2016070768
57. Wang X, Dong M. Malignancy after lung transplantation: how to manage immunosuppression? Transplant Proc. 2020;52(1):315–320. PMID: 31948800 https://doi.org/10.1016/j.transproceed.2019.09.012
58. Hall EC, Engels EA, Pfeiffer RM, Segev DL. Association of antibody induction immunosuppression with cancer after kidney transplantation. Transplantation. 2015;99(5):1051–1057. PMID: 25340595 https://doi.org/10.1097/tp.0000000000000449
59. Koff JL, Waller EK. Improving cancer-specific outcomes in solid organ transplant recipients: where to begin? Cancer. 2019;125(6):838–842. PMID: 30624770 https://doi.org/10.1002/cncr.31963
60. Graham RC, Mella JS, Mangus RS. De novo head and neck cancer after liver transplant with antibody-based immunosuppression induction. Transplant Proc. 2018;50(10):3661–3666. PMID: 30577252 https://doi.org/10.1016/j.transproceed.2018.06.033
61. Alberu J, Pascoe MD, Campistol JM, Schena FP, Rial Mdel C, Polinsky M, et al. Lower malignancy rates in renal allograft recipients converted to sirolimusbased, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial. Transplantation. 2011;92(3):303–310. PMID: 21792049 https://doi.org/10.1097/tp.0b013e3182247ae2
62. Kao CC, Liu JS, Lin MH, Hsu CY, Chang FC, Lin YC, et al. Impact of mTOR inhibitors on cancer development in kidney transplantation recipients: a population-based study. Transplant Proc. 2016;48(3):900–904. PMID: 27234763 https://doi.org/10.1016/j.transproceed.2016.01.017
63. Karpe KM, Talaulikar GS, Walters GD. Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients. Cochrane Database Syst Rev. 2017;7(7):CD006750. PMID: 28730648 https://doi.org/10.1002/14651858.cd006750.pub2
64. Geissler EK, Schlitt HJ, Thomas G. mTOR, cancer and transplantation. Am J Transplant. 2008;8(11):2212–2218. PMID: 18785960 https://doi.org/10.1111/j.16006143.2008.02391.x
65. Vatazin AV, Shcherbakova EO, Prokopenko EI. Opyt primeneniya everolimusa u bol'nykh s renal'nym transplantatom. Nephrology and Dialysis. 2013;15(4):356. (In Russ.).
66. Gerasimova OA, Granov DA, Zherebtsov FK. Everolimus in clinical practice after liver transplantation: a single-center experience. Russian Journal of Transplantology and Artificial Organs. 2017;19(2):34–40. (In Russ.). https://doi.org/10.15825/19951191-2017-2-34-40
67. de Fijter JW. Cancer and mTOR inhibitors in transplant recipients. Transplantation. 2017;101(1):45–55. PMID: 27547865 https://doi.org/10.1097/tp.0000000000001447
68. Hsiao FY, Hsu WW. Epidemiology of post-transplant malignancy in Asian renal transplant recipients: a population-based study. Int Urol Nephrol. 2014;46(4):833–838. PMID: 24009082 https://doi.org/10.1007/s11255-0130544-6
69. Buxeda A, Redondo-Pachón D, Pérez-Sáez María J, Crespo M, Pascual J. Sex differences in cancer risk and outcomes after kidney transplantation. Transplant Rev. (Orlando). 2021;35(3):100625. PMID: 34020178 https://doi.org/10.1016/j.trre.2021.100625
70. Pietrzak B, Mazanowska N, Ekiel AM, Durlik M, Martirosian G, Wielgos M, et al. Prevalence of high-risk human papillomavirus cervical infection in female kidney graft recipients: an observational study. Virol J. 2012;9:117. PMID: 22709394 https://doi.org/10.1186/1743-422x-9-117
71. Ribes J, Esteban L, Cleries R, Galceran J, Marcos-Gragera R, Gispert R, et al. Cancer incidence and mortality projections up to 2020 in Catalonia by means of Bayesian models. Clin Transl Oncol. 2014;16(8):714–724. PMID: 24338506 https://doi.org/10.1007/s12094-0131140-z
72. Webster AC, Wong G, Craig JC, Chapman JR. Managing cancer risk and decision making after kidney transplantation. Am J Transplant. 2008;8(11):2185– 2191. PMID: 18782291 https://doi.org/10.1111/j.1600-6143.2008.02385.x
73. Tanash HA, Ekström M, Wagner P, Piitulainen E. Cause-specific mortality in individuals with severe alpha 1-antitrypsin deficiency in comparison with the general population in Sweden. Int J Chron Obstruct Pulmon Dis. 2016;11:1663–1669. PMID: 27555756 https://doi.org/10.2147/copd.s109173
74. Opelz G, Dohler B. Influence of current and previous smoking on cancer and mortality after kidney transplantation. Transplantation. 2016;100(1):227–232. PMID: 26102616 https://doi.org/10.1097/tp.0000000000000804
75. Au E, Wong G, Chapman JR. Cancer in kidney transplant recipients. Nat Rev Nephrol. 2018;14(8):508–520. PMID: 29802400 https://doi.org/10.1038/s41581-018-0022-6
76. Wetmore JB, Calvet JP, Yu AS, Lynch CF, Wang CJ, Kasiske BL, et al. Polycystic kidney disease and cancer after renal transplantation. J Am Soc Nephrol. 2014;25(10):2335–2341. PMID: 24854270 https://doi.org/10.1681/ asn.2013101122
77. Ma MK, Lim WH, Turner RM, Chapman JR, Craig JC, Wong G. The risk of cancer in recipients of living-donor, standard and expanded criteria deceased donor kidney transplants: a registry analysis. Transplantation. 2014;98(12):1286–1293. PMID: 25119131 https://doi.org/10.1097/tp.0000000000000375
78. Wong G, Turner RM, Chapman JR, Howell M, Lim WH, Webster AC, et al. Time on dialysis and cancer risk after kidney transplantation. Transplantation. 2013;95(1):114–121. PMID: 23222892 https://doi.org/10.1097/tp.0b013e31827743b4
79. Acuna SA, Sutradhar R, Camacho X, Daly C, Del Giudice ME, Kim SJ, et al. Uptake of cancer screening tests among recipients of solid organ transplantation. Am J Transplant. 2017;17(9):2434– 2443. PMID: 28485086 https://doi.org/10.1111/ajt.14272
Review
For citations:
Babkina A.V., Khubutiya M.Sh. Development of oncological diseases after organ transplantation. Transplantologiya. The Russian Journal of Transplantation. 2022;14(4):476-487. https://doi.org/10.23873/2074-0506-2022-14-4-476-487
Views:
695
Email this article 