Post-transplantation Malignancy After Kidney Transplantation in Turkey Y. Kelesa, S. Tekinb,c, M. Duzenlic, Y. Yukselc, L. Yücetinc, L. Dosemecic,d, A. Sengulc, A. Demirbas¸c, and M. Tuncerc,e,* a Department of Radiation Oncology, Medical Park Antalya, Antalya, Turkey; bDepartment of General Surgery, Istanbul Kemerburgaz University, Istanbul, Turkey; cOrgan Transplant Center, Medical Park Antalya, Antalya, Turkey; dDepartment of Anesthesiology, Istanbul Kemerburgaz University, Istanbul, Turkey; and eDepartment of Nephrology, Istanbul Kemerburgaz University, Istanbul, Turkey
ABSTRACT Objective. Kidney transplantation is the best treatment option for end-stage renal disease patients. Increased incidence of post-transplantation malignancy can be caused by immunosuppressive drugs and some oncogenic infections. The aim of this study is to show the incidence of post-transplantation malignancy in patients who had surgery and were followed up in the Organ Transplant Center, Medical Park Antalya, Antalya, Turkey. Method. The study was based on 2100 kidney transplantation patients who had surgery between May 2008 and December 2012 and also on 1900 patients who had surgery by members of our team in other centers and who were followed up routinely. In all of our patients, the type of malignancy, the time that malignancy developed, immunosuppressive regimens, and viral status (Epstein-Barr virus and cytomegalovirus) were investigated. Results. Malignancy was developed in 30 patients (60% of them were male, median age was 52.1 years). Post-transplantation malignancy development time was a median of 5.1 years. The types of malignancies were as follows: non-melanoma skin cancer in 12 patients (40%), urogenital cancer in 7 patients (24%), breast cancer in 4 patients (14%), lymphoproliferative disease in 3 patients (10%), thyroid cancer in 2 patients (6%), and lung cancer in 2 patients (6%). Discussion. In this study, we did not find any increased post-transplantation malignancy risk in our patients. This finding could be due to the low-dosage immunosuppressive protocols that we used.
K
IDNEY transplantation is the best treatment option for end-stage renal disease patients. Development of post-transplantation malignancy is an important reason for morbidity and mortality in kidney transplant recipients [1e4]. Post-transplantation malignancies comprise the third important disease group for mortality in these patients [5]. Incidence of post-transplantation malignancy has been investigated in many studies [1e3]. Ninety-two percent of our patients have come to our transplantation center from outside of Antalya. Therefore, our patient population could be considered representative of all over Turkey. We aimed to investigate the post-transplantation malignancy incidence, development time, and risk factors in kidney transplant recipients.
MATERIALS AND METHODS The study was based on 2100 kidney transplant patients who had surgery between May 2008 and December 2012 and also on 1900 patients who had surgery by members of our team in other centers and were followed up routinely. In all patients, type of malignancy, the time that malignancy developed, immunosuppressive regimens, and viral status (Epstein Barr virus [EBV] and cytomegalovirus [CMV]) were investigated. Patients were followed up for at least 1 year post-transplantation and at the time of diagnosis of cancer, all had well-functioning grafts.
*Address correspondence to Murat Tuncer, MD, Organ Transplant Center, Medical Park Antalya, Medical Park Hasta lu caddesi, 07030, Lara, Antalya, Türkiye. E-mail: nesi, Tekeliog [email protected]
0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.04.010
ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1418
Transplantation Proceedings, 47, 1418e1420 (2015)
POST-TRANSPLANTATION MALIGNANCY
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Table 1. Demographic Features and Clinical Events of Patients Malignancy Type
Number of Patients
Non-melanoma skin Basal cell Squamous cell Kaposi sarcoma Urogenital Bladder Renal cell Prostate Vulvar Endometrial Ovarian Breast Lymphoproliferative Non-Hodgkin lymphoma Chronic myeloid leukemia Lung Thyroid All
12 (40%) 5 4 3 7 (23.3%) 2 1 1 1 1 1 4 (13.3%) 3 (10%) 2 1 2 (6.6%) 2 (6.6%) 30 (100%)
Pretransplantation education concerning cigarette smoking and sunlight was given to all patients [6,7]. Abdominal ultrasonography and chest x-rays were investigated yearly in all patients. Mammography, gynecological examinations, and PAP smears were performed yearly in female patients older than 40 years. Prostate examination and carcinoma markers were investigated yearly in male patients older than 50 years. In all patients, antiviral drugs (valganciclovir or valaciclovir) were administered for 3 to 6 months post-transplantation. The incidence of cancer increases with increasing time on immunosuppression and with dose of immunotherapy. The calcineurin inhibitors cyclosporine and tacrolimus have been associated with the development of malignancies in renal transplantation patients [5]. One study has shown that the incidence of cancer was significantly higher in a group of patients who received higher cyclosporine doses than in a group receiving lower doses [8]. As immunosuppression, low-dose treatment regimens were administered (trough levels for tacrolimus: 3e6 ng/mL, for cyclosporine 25e50 ng/mL, for sirolimus 3e6 ng/mL with no loading dosage) from the start of the operation and antithymocyte globulin was administered according to CD3 levels (when the activated CD3 count is lower than 10%, antithymocyte globulin was not used). Azathioprine was not used in any patient.
Statistical Analysis IBM SPSS Statistics 19 package program (IBM, Armonk, NY, USA) was used for data analysis. All results were given as mean standard deviation. The unpaired Student t test was used to analyze numeric values and categorical values were compared using the c2 test. P < .05 was accepted as statistically significant.
RESULTS
Malignancy was developed in 30 patients (0.75% of all patients, 60% of them were male, median age was 52.1 years [range, 31e69 y]). The post-transplantation malignancy development time was a median of 5.1 years. The types of malignancies were non-melanoma skin cancer in 12 patients (40%), urogenital cancer in 7 patients (23.3%), breast cancer in 4 patients (13.3%), lymphoproliferative disease in 3 patients (10%),
Malignancy Development Time (Post-transplantation Year: min-max)
Age (y; minimum-maximum)
1e10
31e64
1e12
40e69
2e9 8e10
40e67 47e61
2e10 2e3 1e12 (median, 5.1)
46e65 53e65 31e69 (median, 52.1)
thyroid cancer in 2 patients (6.6%), and lung cancer in 2 patients (6.6%; Table 1). In non-melanoma skin cancers, basal cell carcinoma, squamous cell carcinoma and Kaposi sarcoma were diagnosed in 5, 4, and 3 patients, respectively. For urogenital cancers; urinary bladder cancer, renal cell carcinoma, prostate carcinoma, vulvar carcinoma, and endometrial carcinoma were diagnosed in 2, 1, 1, 1, and 1 patients, respectively. The earliest diagnosed cancer types were Kaposi sarcoma and prostate cancer (in the first year after transplantation) and urinary bladder carcinoma was diagnosed after 12th post-transplantation year. Four patients died during study follow-up (due to non-Hodgkin lymphoma, chronic myeloid leukemia, urinary bladder cancer, and lung cancer, respectively). At the time of malignancy diagnosis, 20 patients were on tacrolimus, 7 patients were on cyclosporine, and 3 patients were on sirolimus therapy as an immunosuppressive agent. As an anti-proliferative agent, no patients were on azathioprine, all were using mycophenolate mofetil or mycophenolate sodium. After diagnosis of malignancy, tacrolimus or cyclosporine were switched to everolimus in all patients. Thirteen patients have received antithymocyte globulin for acute rejection episodes. There was no statistically significant relationship between immunosuppression and development of malignancy (P ¼ .715; Table 2). Table 2. Relationship Between Immunosuppressive Drugs and Malignancy Development Among Our Cases* Drug
Malignancy Development (Present/Absent)
Total
Antithymocyte globulin Tacrolimus Cyclosporine Sirolimus
13/397 20/2380 7/1193 3/397
410 2400 1200 400
*P ¼ .715.
1420
In all patients, preoperative EBV and CMV immunoglobulin M (IgM) and IgG status were investigated. CMV IgG was positive in all malignancy developed patients. EBV IgG was positive in 25 (83.3%) malignancy developed patients. In all three patients with lymphoproliferative disease, EBV IgG was positive. There is no statistically significant relationship between viral status and malignancy development. DISCUSSION
There is a 3- to 5-times increased risk of malignancy development after kidney transplantation compared with the general population in many studies [1,2,6,9]. There are many factors that may cause malignancy after kidney transplantation, such as viral infections, some immunosuppressive drugs, advanced age, and cigarette smoking [10e12]. Ramsay et al showed that at least 50% of kidney transplantation patients may have skin neoplasm at 10 years after transplantation. More than 80% of lesions were found in head and neck region of patients [13]. Age, male gender, and duration of immunosuppressive drug usage were found to be related with development of skin neoplasms in many studies [14,15]. In our patients, basal cell carcinoma is the most common skin neoplasm. Lesions generally were found in the head and neck region. All patients were educated about the disturbing effects of sunlight before the transplantation and creams preventing effects of sunlight were used in all patients. Increased relative risk of breast cancer in transplant patients was found to be 0.7 by Agraharkar et al [16]. In our study, breast cancer was found in four patients. One patient is using trastuzumab after chemotherapy and the other patients are on hormone therapy. Lung cancer development risk was found to be 0.78% in transplantation patients and occurrence time was found to be a median of 6.6 years by Génébès et al [17]. In our two patients with lung cancer, cancer occurrence times were at 2 and 10 years post-transplantation. Thyroid cancer risk was found to be 6.9% cancer occurrence time was a median of 6 years and cancer type was mainly papillary carcinoma by Karamchandani et al [18]. In our two patients with thyroid cancer, malignancy occurrence times were at 2 and 6 years post-transplantation and both have papillary carcinoma. Post-transplantation non-hodgkin lymphoma (NHL) development is generally seen within the first year after transplantation. EBV positivity, high-dose immunosuppressive usage, and long duration of immunosuppressive usage are risk factors [19]. NHL was diagnosed at 6 and 10 years after transplantation. One patient was died after autologous bone marrow transplantation. The malignancy occurrence was not increased compared to the general population in our study group [20]. According to the International Agency for Research on Cancer, the malignancy development incidence in Turkey is 245.5 per 100.000 population for males and 157.5 per 100.000 population for females [20]. We believe this finding is due to
KELES, TEKIN, DUZENLI ET AL
pretransplantation education concerning cancer risk factors especially cigarette smoking and sunlight, antiviral prophylaxis, and low-dose immunosuppressive treatment regimes that all of our patients have received. REFERENCES [1] Penn I. Occurrence of cancers in immunosuppressed organ transplant recipients. Clin Transpl 1998:147e58. [2] Penn I. De novo malignencies in pediatric organ transplant recipients. Pediatr Transplant 1998;2:56e63. [3] Davison AM. Epidemiology of cancer in patients with renal transplants. Adv Nephrol Necker Hosp 1998;28:171e94. [4] Kasiske BL, Vazquez MA, Harmon WE, et al. Clinical Practice Guidelines of the American Society of Transplantation. Recommendation for the outpatients surveillance of renal transplant recipients. VII. Cancers. J Am Soc Nephrol 2000;11(suppl 15):S1e86. [5] Penn I. Posttransplant malignancy: the role of immunosuppression. Drug Saf 2000;23:101e13. [6] Birkeland SA, Lokkegaard H, Storm HH. Cancer risk in patients on dialysis and after renal transplantation. Lancet 2000;355:1886e7. [7] Newstead CG. Assessment of risk of cancer after renal transplantation. Lancet 1998;351:610e1. [8] Dantal J, Hourmant M, Cantarovich D, et al. Effect of longterm immunosuppression in kidney-graft recipients on cancer incidence: randomized comparison of two cyclosporine regimens. Lancet 1998;351:623e8. [9] Ojo AO, Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY, Port FK. Long-term survival in renal transplant recipients with graft function. Kidney Int 2000;57:307e13. [10] Yavuz A, Tuncer M, Gurkan A, et al. Cigarette smoking in renal transplant recipients. Transplant Proc 2004;36(1):108e10. [11] Akbas SH, Yavuz A, Tuncer M, et al. Serum cystatin C as an index of renal function in kidney transplant patients. Transplant Proc 2004;36(1):99e101. [12] Hirsch HH, Friman S, Wiecek A, et al. Prospective study of polyomavirus BK viruria and viremia in de novo renal transplantation. Am J Transplant 2007;7:150. [13] Ramsay HM, Fryer AA, Hawley CM, et al. Non-melanoma skin cancer risk in the Queensland renal transplant population. Br J Dermatol 2002;147:950e6. [14] Alamartine E, Diab N, De Filippis JP, Berthoux F. Cancer risk factors in transplantation. In: Touraine JL, editor. Cancer in Transplantation. Prevention and Treatment, 27. Dordrecht, The Netherlands: Kluwer Academic Publishers; 1996. p. 123e9. [15] Naldi L, Fortin AB, Lovati S, et al. Risk of nonmelanoma skin cancer in Italian organ transplant recipieints. Transplantation 2000;70:1479e84. [16] Agraharkar ML, Cinclair RD, Kuo YF, et al. Risk of malignancy with long-term immunosuppression in renal transplant recipients. Kidney Int 2004;66:383e9. [17] Génébès C, Brouchet L, Kamar N, et al. Characteristics of thoracic malignancies that occur after solid-organ transplantation. J Thorac Oncol 2010;5(11):1789e95. [18] Karamchandani D, Arias-Amaya R, Donaldson N, et al. Thyroid cancer and renal transplantation: a meta-analysis. Endocr Relat Cancer 2010;17:159e67. [19] Timuragaoglu A, Ugur-Bilgin A, Colak D, et al. Posttransplant lymphoproliferative disorders in transplant recipients. Transplant Proc 2006;38(2):641e5. [20] Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer incidence and Mortality Worldwide: IARC Cancer Base No.11. Web site. Available at: globocan.iarc.fr.
ABSTRACT Objective. Kidney transplantation is the best treatment option for end-stage renal disease patients. Increased incidence of post-transplantation malignancy can be caused by immunosuppressive drugs and some oncogenic infections. The aim of this study is to show the incidence of post-transplantation malignancy in patients who had surgery and were followed up in the Organ Transplant Center, Medical Park Antalya, Antalya, Turkey. Method. The study was based on 2100 kidney transplantation patients who had surgery between May 2008 and December 2012 and also on 1900 patients who had surgery by members of our team in other centers and who were followed up routinely. In all of our patients, the type of malignancy, the time that malignancy developed, immunosuppressive regimens, and viral status (Epstein-Barr virus and cytomegalovirus) were investigated. Results. Malignancy was developed in 30 patients (60% of them were male, median age was 52.1 years). Post-transplantation malignancy development time was a median of 5.1 years. The types of malignancies were as follows: non-melanoma skin cancer in 12 patients (40%), urogenital cancer in 7 patients (24%), breast cancer in 4 patients (14%), lymphoproliferative disease in 3 patients (10%), thyroid cancer in 2 patients (6%), and lung cancer in 2 patients (6%). Discussion. In this study, we did not find any increased post-transplantation malignancy risk in our patients. This finding could be due to the low-dosage immunosuppressive protocols that we used.
K
IDNEY transplantation is the best treatment option for end-stage renal disease patients. Development of post-transplantation malignancy is an important reason for morbidity and mortality in kidney transplant recipients [1e4]. Post-transplantation malignancies comprise the third important disease group for mortality in these patients [5]. Incidence of post-transplantation malignancy has been investigated in many studies [1e3]. Ninety-two percent of our patients have come to our transplantation center from outside of Antalya. Therefore, our patient population could be considered representative of all over Turkey. We aimed to investigate the post-transplantation malignancy incidence, development time, and risk factors in kidney transplant recipients.
MATERIALS AND METHODS The study was based on 2100 kidney transplant patients who had surgery between May 2008 and December 2012 and also on 1900 patients who had surgery by members of our team in other centers and were followed up routinely. In all patients, type of malignancy, the time that malignancy developed, immunosuppressive regimens, and viral status (Epstein Barr virus [EBV] and cytomegalovirus [CMV]) were investigated. Patients were followed up for at least 1 year post-transplantation and at the time of diagnosis of cancer, all had well-functioning grafts.
*Address correspondence to Murat Tuncer, MD, Organ Transplant Center, Medical Park Antalya, Medical Park Hasta lu caddesi, 07030, Lara, Antalya, Türkiye. E-mail: nesi, Tekeliog [email protected]
0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.04.010
ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1418
Transplantation Proceedings, 47, 1418e1420 (2015)
POST-TRANSPLANTATION MALIGNANCY
1419
Table 1. Demographic Features and Clinical Events of Patients Malignancy Type
Number of Patients
Non-melanoma skin Basal cell Squamous cell Kaposi sarcoma Urogenital Bladder Renal cell Prostate Vulvar Endometrial Ovarian Breast Lymphoproliferative Non-Hodgkin lymphoma Chronic myeloid leukemia Lung Thyroid All
12 (40%) 5 4 3 7 (23.3%) 2 1 1 1 1 1 4 (13.3%) 3 (10%) 2 1 2 (6.6%) 2 (6.6%) 30 (100%)
Pretransplantation education concerning cigarette smoking and sunlight was given to all patients [6,7]. Abdominal ultrasonography and chest x-rays were investigated yearly in all patients. Mammography, gynecological examinations, and PAP smears were performed yearly in female patients older than 40 years. Prostate examination and carcinoma markers were investigated yearly in male patients older than 50 years. In all patients, antiviral drugs (valganciclovir or valaciclovir) were administered for 3 to 6 months post-transplantation. The incidence of cancer increases with increasing time on immunosuppression and with dose of immunotherapy. The calcineurin inhibitors cyclosporine and tacrolimus have been associated with the development of malignancies in renal transplantation patients [5]. One study has shown that the incidence of cancer was significantly higher in a group of patients who received higher cyclosporine doses than in a group receiving lower doses [8]. As immunosuppression, low-dose treatment regimens were administered (trough levels for tacrolimus: 3e6 ng/mL, for cyclosporine 25e50 ng/mL, for sirolimus 3e6 ng/mL with no loading dosage) from the start of the operation and antithymocyte globulin was administered according to CD3 levels (when the activated CD3 count is lower than 10%, antithymocyte globulin was not used). Azathioprine was not used in any patient.
Statistical Analysis IBM SPSS Statistics 19 package program (IBM, Armonk, NY, USA) was used for data analysis. All results were given as mean standard deviation. The unpaired Student t test was used to analyze numeric values and categorical values were compared using the c2 test. P < .05 was accepted as statistically significant.
RESULTS
Malignancy was developed in 30 patients (0.75% of all patients, 60% of them were male, median age was 52.1 years [range, 31e69 y]). The post-transplantation malignancy development time was a median of 5.1 years. The types of malignancies were non-melanoma skin cancer in 12 patients (40%), urogenital cancer in 7 patients (23.3%), breast cancer in 4 patients (13.3%), lymphoproliferative disease in 3 patients (10%),
Malignancy Development Time (Post-transplantation Year: min-max)
Age (y; minimum-maximum)
1e10
31e64
1e12
40e69
2e9 8e10
40e67 47e61
2e10 2e3 1e12 (median, 5.1)
46e65 53e65 31e69 (median, 52.1)
thyroid cancer in 2 patients (6.6%), and lung cancer in 2 patients (6.6%; Table 1). In non-melanoma skin cancers, basal cell carcinoma, squamous cell carcinoma and Kaposi sarcoma were diagnosed in 5, 4, and 3 patients, respectively. For urogenital cancers; urinary bladder cancer, renal cell carcinoma, prostate carcinoma, vulvar carcinoma, and endometrial carcinoma were diagnosed in 2, 1, 1, 1, and 1 patients, respectively. The earliest diagnosed cancer types were Kaposi sarcoma and prostate cancer (in the first year after transplantation) and urinary bladder carcinoma was diagnosed after 12th post-transplantation year. Four patients died during study follow-up (due to non-Hodgkin lymphoma, chronic myeloid leukemia, urinary bladder cancer, and lung cancer, respectively). At the time of malignancy diagnosis, 20 patients were on tacrolimus, 7 patients were on cyclosporine, and 3 patients were on sirolimus therapy as an immunosuppressive agent. As an anti-proliferative agent, no patients were on azathioprine, all were using mycophenolate mofetil or mycophenolate sodium. After diagnosis of malignancy, tacrolimus or cyclosporine were switched to everolimus in all patients. Thirteen patients have received antithymocyte globulin for acute rejection episodes. There was no statistically significant relationship between immunosuppression and development of malignancy (P ¼ .715; Table 2). Table 2. Relationship Between Immunosuppressive Drugs and Malignancy Development Among Our Cases* Drug
Malignancy Development (Present/Absent)
Total
Antithymocyte globulin Tacrolimus Cyclosporine Sirolimus
13/397 20/2380 7/1193 3/397
410 2400 1200 400
*P ¼ .715.
1420
In all patients, preoperative EBV and CMV immunoglobulin M (IgM) and IgG status were investigated. CMV IgG was positive in all malignancy developed patients. EBV IgG was positive in 25 (83.3%) malignancy developed patients. In all three patients with lymphoproliferative disease, EBV IgG was positive. There is no statistically significant relationship between viral status and malignancy development. DISCUSSION
There is a 3- to 5-times increased risk of malignancy development after kidney transplantation compared with the general population in many studies [1,2,6,9]. There are many factors that may cause malignancy after kidney transplantation, such as viral infections, some immunosuppressive drugs, advanced age, and cigarette smoking [10e12]. Ramsay et al showed that at least 50% of kidney transplantation patients may have skin neoplasm at 10 years after transplantation. More than 80% of lesions were found in head and neck region of patients [13]. Age, male gender, and duration of immunosuppressive drug usage were found to be related with development of skin neoplasms in many studies [14,15]. In our patients, basal cell carcinoma is the most common skin neoplasm. Lesions generally were found in the head and neck region. All patients were educated about the disturbing effects of sunlight before the transplantation and creams preventing effects of sunlight were used in all patients. Increased relative risk of breast cancer in transplant patients was found to be 0.7 by Agraharkar et al [16]. In our study, breast cancer was found in four patients. One patient is using trastuzumab after chemotherapy and the other patients are on hormone therapy. Lung cancer development risk was found to be 0.78% in transplantation patients and occurrence time was found to be a median of 6.6 years by Génébès et al [17]. In our two patients with lung cancer, cancer occurrence times were at 2 and 10 years post-transplantation. Thyroid cancer risk was found to be 6.9% cancer occurrence time was a median of 6 years and cancer type was mainly papillary carcinoma by Karamchandani et al [18]. In our two patients with thyroid cancer, malignancy occurrence times were at 2 and 6 years post-transplantation and both have papillary carcinoma. Post-transplantation non-hodgkin lymphoma (NHL) development is generally seen within the first year after transplantation. EBV positivity, high-dose immunosuppressive usage, and long duration of immunosuppressive usage are risk factors [19]. NHL was diagnosed at 6 and 10 years after transplantation. One patient was died after autologous bone marrow transplantation. The malignancy occurrence was not increased compared to the general population in our study group [20]. According to the International Agency for Research on Cancer, the malignancy development incidence in Turkey is 245.5 per 100.000 population for males and 157.5 per 100.000 population for females [20]. We believe this finding is due to
KELES, TEKIN, DUZENLI ET AL
pretransplantation education concerning cancer risk factors especially cigarette smoking and sunlight, antiviral prophylaxis, and low-dose immunosuppressive treatment regimes that all of our patients have received. REFERENCES [1] Penn I. Occurrence of cancers in immunosuppressed organ transplant recipients. Clin Transpl 1998:147e58. [2] Penn I. De novo malignencies in pediatric organ transplant recipients. Pediatr Transplant 1998;2:56e63. [3] Davison AM. Epidemiology of cancer in patients with renal transplants. Adv Nephrol Necker Hosp 1998;28:171e94. [4] Kasiske BL, Vazquez MA, Harmon WE, et al. Clinical Practice Guidelines of the American Society of Transplantation. Recommendation for the outpatients surveillance of renal transplant recipients. VII. Cancers. J Am Soc Nephrol 2000;11(suppl 15):S1e86. [5] Penn I. Posttransplant malignancy: the role of immunosuppression. Drug Saf 2000;23:101e13. [6] Birkeland SA, Lokkegaard H, Storm HH. Cancer risk in patients on dialysis and after renal transplantation. Lancet 2000;355:1886e7. [7] Newstead CG. Assessment of risk of cancer after renal transplantation. Lancet 1998;351:610e1. [8] Dantal J, Hourmant M, Cantarovich D, et al. Effect of longterm immunosuppression in kidney-graft recipients on cancer incidence: randomized comparison of two cyclosporine regimens. Lancet 1998;351:623e8. [9] Ojo AO, Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY, Port FK. Long-term survival in renal transplant recipients with graft function. Kidney Int 2000;57:307e13. [10] Yavuz A, Tuncer M, Gurkan A, et al. Cigarette smoking in renal transplant recipients. Transplant Proc 2004;36(1):108e10. [11] Akbas SH, Yavuz A, Tuncer M, et al. Serum cystatin C as an index of renal function in kidney transplant patients. Transplant Proc 2004;36(1):99e101. [12] Hirsch HH, Friman S, Wiecek A, et al. Prospective study of polyomavirus BK viruria and viremia in de novo renal transplantation. Am J Transplant 2007;7:150. [13] Ramsay HM, Fryer AA, Hawley CM, et al. Non-melanoma skin cancer risk in the Queensland renal transplant population. Br J Dermatol 2002;147:950e6. [14] Alamartine E, Diab N, De Filippis JP, Berthoux F. Cancer risk factors in transplantation. In: Touraine JL, editor. Cancer in Transplantation. Prevention and Treatment, 27. Dordrecht, The Netherlands: Kluwer Academic Publishers; 1996. p. 123e9. [15] Naldi L, Fortin AB, Lovati S, et al. Risk of nonmelanoma skin cancer in Italian organ transplant recipieints. Transplantation 2000;70:1479e84. [16] Agraharkar ML, Cinclair RD, Kuo YF, et al. Risk of malignancy with long-term immunosuppression in renal transplant recipients. Kidney Int 2004;66:383e9. [17] Génébès C, Brouchet L, Kamar N, et al. Characteristics of thoracic malignancies that occur after solid-organ transplantation. J Thorac Oncol 2010;5(11):1789e95. [18] Karamchandani D, Arias-Amaya R, Donaldson N, et al. Thyroid cancer and renal transplantation: a meta-analysis. Endocr Relat Cancer 2010;17:159e67. [19] Timuragaoglu A, Ugur-Bilgin A, Colak D, et al. Posttransplant lymphoproliferative disorders in transplant recipients. Transplant Proc 2006;38(2):641e5. [20] Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer incidence and Mortality Worldwide: IARC Cancer Base No.11. Web site. Available at: globocan.iarc.fr.
