Table of Contents Author Guidelines Submit a Manuscript
Journal of Transplantation
Volume 2016, Article ID 4369574, 11 pages
http://dx.doi.org/10.1155/2016/4369574
Review Article

Everolimus and Malignancy after Solid Organ Transplantation: A Clinical Update

1Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Postboks 4950 Nydalen, 0424 Oslo, Norway
2Hepatobiliary Surgery & Liver Transplantation, Azienda Ospedaliero-Universitaria Pisana, 5412 Pisa, Italy
3Department of Cardiac Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria

Received 7 June 2016; Accepted 25 August 2016

Academic Editor: Frans H. J. Claas

Copyright © 2016 Hallvard Holdaas et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. E. A. Engels, R. M. Pfeiffer, J. F. Fraumeni Jr. et al., “Spectrum of cancer risk among US solid organ transplant recipients,” The Journal of the American Medical Association, vol. 306, no. 17, pp. 1891–1901, 2011. View at Publisher · View at Google Scholar · View at Scopus
  2. P. Piselli, D. Serraino, G. P. Segoloni et al., “Risk of de novo cancers after transplantation: results from a cohort of 7217 kidney transplant recipients, Italy 1997–2009,” European Journal of Cancer, vol. 49, no. 2, pp. 336–344, 2013. View at Publisher · View at Google Scholar · View at Scopus
  3. B. L. Kasiske, J. J. Snyder, D. R. Gilbertson, and C. Wang, “Cancer after kidney transplantation in the United States,” American Journal of Transplantation, vol. 4, no. 6, pp. 905–913, 2004. View at Publisher · View at Google Scholar
  4. S. A. Acuna, K. A. Fernandes, C. Daly et al., “Cancer mortality among recipients of solid organ transplants in Ontario, Canada,” Journal of the American Medical Association Oncology, vol. 2, no. 4, pp. 463–469, 2016. View at Google Scholar
  5. US Renal Data System, “2014 annual data report: epidemiology of kidney disease in the United States,” American Journal of Kidney Diseases, vol. 66, supplement 1, pp. S1–S306, 2015. View at Publisher · View at Google Scholar
  6. G. Tessari, L. Naldi, L. Boschiero et al., “Incidence of primary and second cancers in renal transplant recipients: a multicenter cohort study,” American Journal of Transplantation, vol. 13, no. 1, pp. 214–221, 2013. View at Publisher · View at Google Scholar · View at Scopus
  7. I. Rama and J. M. Grinyó, “Malignancy after renal transplantation: the role of immunosuppression,” Nature Reviews Nephrology, vol. 6, no. 9, pp. 511–519, 2010. View at Publisher · View at Google Scholar · View at Scopus
  8. M. Hojo, T. Morimoto, M. Maluccio et al., “Cyclosporine induces cancer progression by a cell-autonomous mechanism,” Nature, vol. 397, no. 6719, pp. 530–534, 1999. View at Publisher · View at Google Scholar · View at Scopus
  9. M. Castello, M. Gregorini, T. Rampino et al., “A retrospective analysis of dermatological lesions in kidney transplant patients,” Indian Journal of Medical Research, vol. 137, no. 6, pp. 1188–1192, 2013. View at Google Scholar · View at Scopus
  10. V. Pendón-Ruiz de Mier, M. D. Navarro Cabello, S. Martínez Vaquera et al., “Incidence and long-term prognosis of cancer after kidney transplantation,” Transplantation Proceedings, vol. 47, no. 9, pp. 2618–2621, 2015. View at Publisher · View at Google Scholar · View at Scopus
  11. C. Carenco, E. Assenat, S. Faure et al., “Tacrolimus and the risk of solid cancers after liver transplant: a dose effect relationship,” American Journal of Transplantation, vol. 15, no. 3, pp. 678–686, 2015. View at Publisher · View at Google Scholar · View at Scopus
  12. M. G. Crespo-Leiro, L. Alonso-Pulpón, J. A. Vázquez de Prada et al., “Malignancy after heart transplantation: incidence, prognosis and risk factors,” American Journal of Transplantation, vol. 8, no. 5, pp. 1031–1039, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. R. Rivinius, M. Helmschrott, A. Ruhparwar et al., “Analysis of malignancies in patients after heart transplantation with subsequent immunosuppressive therapy,” Drug Design, Development and Therapy, vol. 9, pp. 93–102, 2015. View at Publisher · View at Google Scholar
  14. A. O. Doesch, S. Müller, M. Konstandin et al., “Malignancies after heart transplantation: incidence, risk factors, and effects of calcineurin inhibitor withdrawal,” Transplantation Proceedings, vol. 42, no. 9, pp. 3694–3699, 2010. View at Publisher · View at Google Scholar · View at Scopus
  15. M. Guba, P. von Breitenbuch, M. Steinbauer et al., “Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor,” Nature Medicine, vol. 8, no. 2, pp. 128–135, 2002. View at Publisher · View at Google Scholar · View at Scopus
  16. Á. Gutiérrez-Dalmau and J. M. Campistol, “The role of proliferation signal inhibitors in post-transplant malignancies,” Nephrology Dialysis Transplantation, vol. 22, supplement 1, pp. i11–i16, 2007. View at Publisher · View at Google Scholar · View at Scopus
  17. M. Bhat, N. Sonenberg, and G. J. Gores, “The mTOR pathway in hepatic malignancies,” Hepatology, vol. 58, no. 2, pp. 810–818, 2013. View at Publisher · View at Google Scholar · View at Scopus
  18. M. Majewski, M. Korecka, P. Kossev et al., “The immunosuppressive macrolide RAD inhibits growth of human Epstein-Barr virus-transformed B lymphocytes in vitro and in vivo: a potential approach to prevention and treatment of posttransplant lymphoproliferative disorders,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 8, pp. 4285–4290, 2000. View at Publisher · View at Google Scholar · View at Scopus
  19. P. K. Majumder, P. G. Febbo, R. Bikoff et al., “mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways,” Nature Medicine, vol. 10, no. 6, pp. 594–601, 2004. View at Publisher · View at Google Scholar · View at Scopus
  20. F. L. Luan, M. Hojo, M. Maluccio, K. Yamaji, and M. Suthanthiran, “Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy,” Transplantation, vol. 73, no. 10, pp. 1565–1572, 2002. View at Publisher · View at Google Scholar
  21. P. Frost, F. Moatamed, B. Hoang et al., “In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model,” Blood, vol. 104, no. 13, pp. 4181–4187, 2004. View at Publisher · View at Google Scholar · View at Scopus
  22. R. J. Motzer, B. Escudier, S. Oudard et al., “Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial,” The Lancet, vol. 372, no. 9637, pp. 449–456, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. R. J. Motzer, B. Escudier, S. Oudard et al., “Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors,” Cancer, vol. 116, no. 18, pp. 4256–4265, 2010. View at Publisher · View at Google Scholar · View at Scopus
  24. J. C. Yao, M. H. Shah, T. Ito et al., “Everolimus for advanced pancreatic neuroendocrine tumors,” The New England Journal of Medicine, vol. 364, no. 6, pp. 514–523, 2011. View at Publisher · View at Google Scholar · View at Scopus
  25. D. N. Franz, E. Belousova, S. Sparagana et al., “Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial,” The Lancet, vol. 381, no. 9861, pp. 125–132, 2013. View at Publisher · View at Google Scholar · View at Scopus
  26. A. Günther, P. Baumann, R. Burger et al., “Activity of everolimus (RAD001) in relapse and/or refractory multiple myeloma: a phase I study,” Haematologica, vol. 100, no. 4, pp. 541–547, 2015. View at Google Scholar
  27. R. Buzzoni, S. Pusceddu, E. Bajetta et al., “Activity and safety of RAD001 (everolimus) in patients affected by biliary tract cancer progressing after prior chemotherapy: a phase II ITMO study,” Annals of Oncology, vol. 25, no. 8, Article ID mdu175, pp. 1597–1603, 2014. View at Publisher · View at Google Scholar · View at Scopus
  28. K. Tobinai, M. Ogura, D. Maruyama et al., “Phase I study of the oral mammalian target of rapamycin inhibitor everolimus (RAD001) in Japanese patients with relapsed or refractory non-Hodgkin lymphoma,” International Journal of Hematology, vol. 92, no. 4, pp. 563–570, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. F. André, R. O'Regan, M. Ozguroglu et al., “Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial,” The Lancet Oncology, vol. 15, no. 6, pp. 580–591, 2014. View at Publisher · View at Google Scholar · View at Scopus
  30. N. Maass, N. Harbeck, C. Mundhenke et al., “Everolimus as treatment for breast cancer patients with bone metastases only: results of the phase II RADAR study,” Journal of Cancer Research and Clinical Oncology, vol. 139, no. 12, pp. 2047–2056, 2013. View at Publisher · View at Google Scholar · View at Scopus
  31. T. Bachelot, C. Bourgier, C. Cropet et al., “Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study,” Journal of Clinical Oncology, vol. 30, no. 22, pp. 2718–2724, 2012. View at Publisher · View at Google Scholar · View at Scopus
  32. S. Mourah, R. Porcher, M. Battistella et al., “Paradoxical simultaneous regression and progression of lesions in a phase II study of everolimus in classic Kaposi sarcoma,” British Journal of Dermatology, vol. 173, no. 5, pp. 1284–1287, 2016. View at Publisher · View at Google Scholar · View at Scopus
  33. J. J. Bissler, J. C. Kingswood, E. Radzikowska et al., “Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial,” The Lancet, vol. 381, no. 9869, pp. 817–824, 2013. View at Publisher · View at Google Scholar · View at Scopus
  34. M. E. Pavel, J. D. Hainsworth, E. Baudin et al., “Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study,” The Lancet, vol. 378, no. 9808, pp. 2005–2012, 2011. View at Publisher · View at Google Scholar · View at Scopus
  35. J. Yao, J. Y. Wang, Y. Liu et al., “A randomized phase II study of everolimus for advanced pancreatic neuroendocrine tumors in Chinese patients,” Medical Oncology, vol. 31, no. 12, p. 251, 2014. View at Google Scholar
  36. G. B. Klintmalm, S. Saab, J. C. Hong, and B. Nashan, “The role of mammalian target of rapamycin inhibitors in the management of post-transplant malignancy,” Clinical Transplantation, vol. 28, no. 6, pp. 635–648, 2014. View at Publisher · View at Google Scholar · View at Scopus
  37. J. Klawitter, B. Nashan, and U. Christians, “Everolimus and sirolimus in transplantation-related but different,” Expert Opinion on Drug Safety, vol. 14, no. 7, pp. 1055–1070, 2015. View at Publisher · View at Google Scholar · View at Scopus
  38. S. J. Chadban, J. M. Eris, J. Kanellis et al., “A randomized, controlled trial of everolimus-based dual immunosuppression versus standard of care in de novo kidney transplant recipients,” Transplant International, vol. 27, no. 3, pp. 302–311, 2014. View at Publisher · View at Google Scholar · View at Scopus
  39. H. Tedesco Silva Jr., D. Cibrik, T. Johnston et al., “Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients,” American Journal of Transplantation, vol. 10, no. 6, pp. 1401–1413, 2010. View at Publisher · View at Google Scholar · View at Scopus
  40. K. Budde, F. Lehner, C. Sommerer et al., “Five-year outcomes in kidney transplant patients converted from cyclosporine to everolimus: the randomized ZEUS study,” American Journal of Transplantation, vol. 15, no. 1, pp. 119–128, 2015. View at Publisher · View at Google Scholar · View at Scopus
  41. H. Holdaas, L. Rostaing, D. Serón et al., “Conversion of long-term kidney transplant recipients from calcineurin inhibitor therapy to everolimus: a randomized, multicenter, 24-month study,” Transplantation, vol. 92, no. 4, pp. 410–418, 2011. View at Google Scholar
  42. L. Fischer, F. Saliba, G. M. Kaiser et al., “Three-year outcomes in de novo liver transplant patients receiving everolimus with reduced tacrolimus: follow-up results from a randomized, multicenter study,” Transplantation, vol. 99, no. 7, pp. 1455–1462, 2015. View at Publisher · View at Google Scholar · View at Scopus
  43. M. Sterneck, G. M. Kaiser, N. Heyne et al., “Everolimus and early calcineurin inhibitor withdrawal: 3-year results from a randomized trial in liver transplantation,” American Journal of Transplantation, vol. 14, no. 3, pp. 701–710, 2014. View at Publisher · View at Google Scholar
  44. H. J. Eisen, J. Kobashigawa, R. C. Starling et al., “Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial,” American Journal of Transplantation, vol. 13, no. 5, pp. 1203–1216, 2013. View at Publisher · View at Google Scholar · View at Scopus
  45. A. K. Andreassen, B. Andersson, F. Gustafsson et al., “Everolimus initiation with early calcineurin inhibitor withdrawal in de novo heart transplant recipients: three-year results from the randomized SCHEDULE study,” American Journal of Transplantation, vol. 16, no. 4, pp. 1238–1247, 2016. View at Google Scholar
  46. H. M. Kauffman, S. W. Cherikh, Y. Cheng, D. W. Hanto, and B. D. Kahan, “Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with reduced incidence of de novo malignancies,” Transplantation, vol. 80, no. 7, pp. 883–889, 2005. View at Google Scholar
  47. C. Chiurchiu, C. A. Carreño, R. Schiavelli et al., “Results of the conversion to everolimus in renal transplant recipients with posttransplantation malignancies,” Transplantation Proceedings, vol. 42, no. 1, pp. 277–279, 2010. View at Publisher · View at Google Scholar · View at Scopus
  48. E. González, A. Andrés, N. Polanco et al., “Everolimus represents an advance in immunosuppression for patients who have developed cancer after renal transplantation,” Transplantation Proceedings, vol. 41, no. 6, pp. 2332–2333, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. P. Ruangkanchanasetr, B. Kanjanapayak, and K. Jungmeechoke, “Prolonged survival in renal transplant recipient with advanced renal cell carcinoma by everolimus and sorafenib,” Nephrology, vol. 16, no. 1, pp. 118–119, 2011. View at Publisher · View at Google Scholar · View at Scopus
  50. C. A. Carreño and M. Gadea, “Case report of a kidney transplant recipient converted to everolimus due to malignancy: resolution of bronchiolitis obliterans organizing pneumonia without everolimus discontinuation,” Transplantation Proceedings, vol. 39, no. 3, pp. 594–595, 2007. View at Publisher · View at Google Scholar · View at Scopus
  51. A. Fernández, R. Marcén, J. Pascual et al., “Conversion from calcineurin inhibitors to everolimus in kidney transplant recipients with malignant neoplasia,” Transplantation Proceedings, vol. 38, no. 8, pp. 2453–2455, 2006. View at Publisher · View at Google Scholar · View at Scopus
  52. J. M. Campistol and F. P. Schena, “Kaposi's sarcoma in renal transplant recipients—the impact of proliferation signal inhibitors,” Nephrology Dialysis Transplantation, vol. 22, supplement 1, pp. i17–i22, 2007. View at Publisher · View at Google Scholar · View at Scopus
  53. Kidney Disease Improving Global Outcomes (KDIGO) Transplant Work Group, “KDIGO Clinical practice guideline for the care of kidney transplant recipients,” American Journal of Transplantation, vol. 9, supplement 3, pp. S1–S155, 2009. View at Google Scholar
  54. G. Stallone, A. Schena, B. Infante et al., “Sirolimus for Kaposi's sarcoma in renal-transplant recipients,” The New England Journal of Medicine, vol. 352, no. 13, pp. 1317–1323, 2005. View at Publisher · View at Google Scholar · View at Scopus
  55. G. Basu, A. Mohapatra, M. T. Manipadam, S. E. Mani, and G. T. John, “Leflunomide with low-dose everolimus for treatment of Kaposi's sarcoma in a renal allograft recipient,” Nephrology Dialysis Transplantation, vol. 26, no. 10, pp. 3412–3415, 2011. View at Publisher · View at Google Scholar · View at Scopus
  56. D. Detroyer, K. Deraedt, P. Schöffski et al., “Resolution of diffuse skin and systemic Kaposi's sarcoma in a renal transplant recipient after introduction of everolimus: a case report,” Transplant Infectious Disease, vol. 17, no. 2, pp. 303–307, 2015. View at Publisher · View at Google Scholar · View at Scopus
  57. M. B. Lund, V. Paulsen, and P. Aukrust, “Intestinal Kaposi sarcoma in a lung transplant recipient: therapy with mammalian target of rapamycin inhibitor and immunosuppression reduction,” The Journal of Heart and Lung Transplantation, vol. 32, no. 3, pp. 376–377, 2013. View at Publisher · View at Google Scholar · View at Scopus
  58. S. Krengel, I. Satzger, M. Alter, A. Kapp, and R. Gutzmer, “Remission of an iatrogenic kaposi sarcoma in a patient with myasthenia gravis after switching immunosuppressive therapy to the mTOR inhibitor everolimus,” Hautarzt, vol. 63, no. 7, pp. 573–576, 2012 (German). View at Publisher · View at Google Scholar · View at Scopus
  59. D. Rukasz, M. Krajewska, H. Augustyniak-Bartosik et al., “Effective treatment of Kaposi sarcoma with everolimus in a patient with membranous glomerulonephritis,” Internal Medicine Journal, vol. 45, no. 2, pp. 230–231, 2015. View at Publisher · View at Google Scholar
  60. T. Uno, S. Ito, A. Nakazawa, O. Miyazaki, T. Mori, and K. Terashima, “Successful treatment of kaposiform hemangioendothelioma with everolimus,” Pediatric Blood and Cancer, vol. 62, no. 3, pp. 536–538, 2015. View at Publisher · View at Google Scholar · View at Scopus
  61. S. Euvrard, J. Kanitakis, and A. Claudy, “Skin cancers after organ transplantation,” The New England Journal of Medicine, vol. 348, no. 17, pp. 1681–1691, 2003. View at Publisher · View at Google Scholar · View at Scopus
  62. J. W. de Fijter, “Use of proliferation signal inhibitors in non-melanoma skin cancer following renal transplantation,” Nephrology Dialysis Transplantation, vol. 22, supplement 1, pp. i23–i26, 2007. View at Publisher · View at Google Scholar · View at Scopus
  63. S. Euvrard, J. Kanitakis, E. Decullier et al., “Subsequent skin cancers in kidney and heart transplant recipients after the first squamous cell carcinoma,” Transplantation, vol. 81, no. 8, pp. 1093–1100, 2006. View at Publisher · View at Google Scholar · View at Scopus
  64. G. A. Knoll, M. B. Kokolo, R. Mallick et al., “Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data,” British Medical Journal, vol. 349, Article ID g6679, 2014. View at Publisher · View at Google Scholar
  65. L. Caroti, M. Zanazzi, N. Paudice et al., “Conversion from calcineurin inhibitors to everolimus with low-dose cyclosporine in renal transplant recipients with squamous cell carcinoma of the skin,” Transplantation Proceedings, vol. 44, no. 7, pp. 1926–1927, 2012. View at Publisher · View at Google Scholar · View at Scopus
  66. J. Pascual, A. M. Fernández, R. Marcén, and J. Ortuño, “Conversion to everolimus in a patient with arterial hypertension and recurrent cutaneous neoplasia—a case report,” Nephrology Dialysis Transplantation, vol. 21, supplement 3, pp. iii38–iii41, 2006. View at Publisher · View at Google Scholar · View at Scopus
  67. M. Alter, I. Satzger, H. Schrem, A. Kaltenborn, A. Kapp, and R. Gutzmer, “Non-melanoma skin cancer is reduced after switch of immunosuppression to mTOR-inhibitors in organ transplant recipients,” Journal der Deutschen Dermatologischen Gesellschaft, vol. 12, no. 6, pp. 480–488, 2014. View at Publisher · View at Google Scholar · View at Scopus
  68. S. Euvrard, P. Boissonnat, A. Roussoulières et al., “Effect of everolimus on skin cancers in calcineurin inhihitor-treated heart transplant recipients,” Transplant International, vol. 23, no. 8, pp. 855–857, 2010. View at Publisher · View at Google Scholar · View at Scopus
  69. P. De Simone, P. Carrai, L. Coletti, D. Ghinolfi, D. Campani, and F. Filipponi, “Everolimus-based immunosuppression is associated with a reduced risk of new-onset malignancies after liver transplantation,” American Journal of Transplantation, vol. 15, supplement 3, abstract 1284, 2015. View at Google Scholar
  70. J. Gomez-Camarero, M. Salcedo, D. Rincon et al., “Use of everolimus as a rescue immunosuppressive therapy in liver transplant patients with neoplasms,” Transplantation, vol. 84, no. 6, pp. 786–791, 2007. View at Publisher · View at Google Scholar · View at Scopus
  71. E. Thimonier, O. Guillaud, T. Walter et al., “Conversion to everolimus dramatically improves the prognosis of de novo malignancies after liver transplantation for alcoholic liver disease,” Clinical Transplantation, vol. 28, no. 12, pp. 1339–1348, 2014. View at Publisher · View at Google Scholar · View at Scopus
  72. I. Bilbao, M. Salcedo, M. A. Gómez et al., “Renal function improvement in liver transplant recipients after early everolimus conversion: a clinical practice cohort study in Spain,” Liver Transplantation, vol. 21, no. 8, pp. 1056–1065, 2015. View at Publisher · View at Google Scholar · View at Scopus
  73. I. Yokoyama, B. Carr, H. Saitsu, S. Iwatsuki, and T. E. Starzl, “Accelerated growth rates of recurrent hepatocellular carcinoma after liver transplantation,” Cancer, vol. 68, no. 10, pp. 2095–2100, 1991. View at Publisher · View at Google Scholar · View at Scopus
  74. C. Duvoux and C. Toso, “mTOR inhibitor therapy: does it prevent HCC recurrence after liver transplantation?” Transplantation Reviews, vol. 29, no. 3, pp. 168–174, 2015. View at Publisher · View at Google Scholar · View at Scopus
  75. E. Cholongitas, C. Mamou, K. I. Rodríguez-Castro, and P. Burra, “Mammalian target of rapamycin inhibitors are associated with lower rates of hepatocellular carcinoma recurrence after liver transplantation: a systematic review,” Transplant International, vol. 27, no. 10, pp. 1039–1049, 2014. View at Publisher · View at Google Scholar · View at Scopus
  76. M. Masetti, R. Montalti, G. Rompianesi et al., “Early withdrawal of calcineurin inhibitors and everolimus monotherapy in de novo liver transplant recipients preserves renal function,” American Journal of Transplantation, vol. 10, no. 10, pp. 2252–2262, 2010. View at Publisher · View at Google Scholar · View at Scopus
  77. L. Fischer, J. Klempnauer, S. Beckebaum et al., “A randomized, controlled study to assess the conversion from calcineurin-inhibitors to everolimus after liver transplantation—PROTECT,” American Journal of Transplantation, vol. 12, no. 7, pp. 1855–1865, 2012. View at Publisher · View at Google Scholar · View at Scopus
  78. P. De Simone, F. Nevens, L. De Carlis et al., “Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial,” American Journal of Transplantation, vol. 12, no. 11, pp. 3008–3020, 2012. View at Publisher · View at Google Scholar · View at Scopus
  79. G. Junge, F. Saliba, P. De Simone et al., “Everolimus impact on hepatocellular carcinoma recurrence after liver transplantation—12, 24 and 36 months data from 719 liver transplant recipients,” American Journal of Transplantation, vol. 14, no. 694, abstract A376, 2014. View at Google Scholar
  80. A. O. Ferreiro, M. A. Vazquez-Millán, F. S. López, M. G. Gutiérrez, S. P. Diaz, and M. J. L. Patiño, “Everolimus-based immunosuppression in patients with hepatocellular carcinoma at high risk of recurrence after liver transplantation: a case series,” Transplantation Proceedings, vol. 46, no. 10, pp. 3496–3501, 2014. View at Publisher · View at Google Scholar · View at Scopus
  81. H.-S. Shiah, C.-Y. Chen, C.-Y. Dai et al., “Randomised clinical trial: comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma,” Alimentary Pharmacology and Therapeutics, vol. 37, no. 1, pp. 62–73, 2013. View at Publisher · View at Google Scholar · View at Scopus
  82. A. X. Zhu, T. A. Abrams, R. Miksad et al., “Phase 1/2 study of everolimus in advanced hepatocellular carcinoma,” Cancer, vol. 117, no. 22, pp. 5094–5102, 2011. View at Publisher · View at Google Scholar · View at Scopus
  83. K. Yamanaka, M. Petrulionis, S. Lin et al., “Therapeutic potential and adverse events of everolimus for treatment of hepatocellular carcinoma—systematic review and meta-analysis,” Cancer Medicine, vol. 2, no. 6, pp. 862–871, 2013. View at Publisher · View at Google Scholar · View at Scopus
  84. A. X. Zhu, M. Kudo, E. Assenat et al., “Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial,” Journal of the American Medical Association, vol. 312, no. 1, pp. 57–67, 2014. View at Google Scholar
  85. P. De Simone, L. Crocetti, D. Pezzati et al., “Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation,” Transplantation Proceedings, vol. 46, no. 1, pp. 241–244, 2014. View at Publisher · View at Google Scholar · View at Scopus
  86. A. Valdivieso, J. Bustamante, M. Gastaca et al., “Management of hepatocellular carcinoma recurrence after liver transplantation,” Transplantation Proceedings, vol. 42, no. 2, pp. 660–662, 2010. View at Publisher · View at Google Scholar · View at Scopus
  87. C. Gomez-Martin, J. Bustamante, J. F. Castroagudin et al., “Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation,” Liver Transplantation, vol. 18, no. 1, pp. 45–52, 2012. View at Publisher · View at Google Scholar · View at Scopus
  88. E. Kaplinsky, J. González-Costello, N. Manito et al., “Renal function improvement after conversion to proliferation signal inhibitors during long-term follow-up in heart transplant recipients,” Transplantation Proceedings, vol. 44, no. 9, pp. 2564–2566, 2012. View at Publisher · View at Google Scholar · View at Scopus
  89. S. Kusuki, Y. Hashii, N. Fukushima et al., “Pediatric post-transplant diffuse large B cell lymphoma after cardiac transplantation,” International Journal of Hematology, vol. 89, no. 2, pp. 209–213, 2009. View at Publisher · View at Google Scholar · View at Scopus
  90. L. Feldmeyer, G. F. L. Hofbauer, T. Böni, L. E. French, and J. Hafner, “Mammalian target of rapamycin (mTOR) inhibitors slow skin carcinogenesis, but impair wound healing,” British Journal of Dermatology, vol. 166, no. 2, pp. 422–424, 2012. View at Publisher · View at Google Scholar · View at Scopus
  91. J. Signorell, T. Hunziker, M. Martinelli, S. C. Koestner, and P. J. Mohacsi, “Recurrent non-melanoma skin cancer: remission of field cancerization after conversion from calcineurin inhibitor- to proliferation signal inhibitor-based immunosuppression in a cardiac transplant recipient,” Transplantation Proceedings, vol. 42, no. 9, pp. 3871–3875, 2010. View at Publisher · View at Google Scholar · View at Scopus
  92. M. Salvadori, M. P. Scolari, E. Bertoni et al., “Everolimus with very low-exposure cyclosporine A in de novo kidney transplantation: a multicenter, randomized, controlled trial,” Transplantation, vol. 88, no. 10, pp. 1194–1202, 2009. View at Publisher · View at Google Scholar · View at Scopus
  93. R. M. Langer, R. Hené, S. Vitko et al., “Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation,” Transplant International, vol. 25, no. 5, pp. 592–602, 2012. View at Publisher · View at Google Scholar · View at Scopus
  94. T. M. Manzia, R. Angelico, L. Toti et al., “The efficacy and safety of mammalian target of rapamycin inhibitors ab initio after liver transplantation without corticosteroids or induction therapy,” Digestive and Liver Disease, vol. 48, no. 3, pp. 315–320, 2016. View at Publisher · View at Google Scholar
  95. U. Herden, A. Galante, L. Fischer et al., “Early initiation of everolimus after liver transplantation: a single-center experience,” Annals of Transplantation, vol. 21, pp. 77–85, 2016. View at Publisher · View at Google Scholar
  96. K. Budde, T. Becker, W. Arns et al., “Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial,” The Lancet, vol. 377, no. 9768, pp. 837–847, 2011. View at Publisher · View at Google Scholar · View at Scopus
  97. L. Mjörnstedt, S. S. Sørensen, B. von Zur Mühlen et al., “Improved renal function after early conversion from a calcineurin inhibitor to everolimus: a randomized trial in kidney transplantation,” American Journal of Transplantation, vol. 12, no. 10, pp. 2744–2753, 2012. View at Publisher · View at Google Scholar · View at Scopus
  98. B. Nashan and F. Citterio, “Wound healing complications and the use of mammalian target of rapamycin inhibitors in kidney transplantation: a critical review of the literature,” Transplantation, vol. 94, no. 6, pp. 547–561, 2012. View at Publisher · View at Google Scholar · View at Scopus
  99. J. F. Trotter and L. Lizardo-Sanchez, “Everolimus in liver transplantation,” Current Opinion in Organ Transplantation, vol. 19, no. 6, pp. 578–582, 2014. View at Publisher · View at Google Scholar · View at Scopus
  100. H. Holdaas, K. Midtvedt, and A. Åsberg, “A drug safety evaluation of everolimus in kidney transplantation,” Expert Opinion on Drug Safety, vol. 11, no. 6, pp. 1013–1022, 2012. View at Publisher · View at Google Scholar · View at Scopus
  101. P. Ventura-Aguiar, J. M. Campistol, and F. Diekmann, “Safety of mTOR inhibitors in adult solid organ transplantation,” Expert Opinion on Drug Safety, vol. 15, no. 3, pp. 303–319, 2016. View at Publisher · View at Google Scholar