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Manasa T, Meyyappan V, Sandeep P, Mylarappa P, Ramesh D, Jayakumar V, Penmetsa GK. Incidence, management and treatment outcomes of renal malignancy in a post-transplant recipient at a tertiary care centre: A 16-year experience. JOURNAL OF CLINICAL UROLOGY 2022. [DOI: 10.1177/20514158221081814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Introduction and Objective: Although the incidence of malignancy in renal transplant recipients is on the rise owing to boom in the post-transplant immunosuppressive therapy, there is paucity of literature regarding their reporting and management. In this study, we report the incidence of de novo renal malignancies, post-renal transplantation at our centre over a 16-year period and discuss their management. Methods: All patients who underwent renal transplantation at our department between March 2004 and February 2020 were included and retrospectively reviewed. We analysed the incidence of renal malignancy both in the native kidney and the graft, histological subtype, time to and type of treatment. Results: A total of 376 patients underwent renal transplantation. Mean age of recipients was 48.2 and 52.15 years among those who developed cancer. 13 (2.93%) of 376 recipients developed urogenital malignancy, of whom 8 had renal cell carcinoma (RCC) in their native kidneys and 1 in the allograft. Transitional cell carcinoma (TCC) of renal pelvis was noted in three patients with one concomitant TCC of bladder. No treatment-related graft losses occurred in the native kidney malignancy. Patients with RCC underwent nephrectomy while TCC of renal pelvis underwent nephroureterectomy with bladder cuff excision. Transurethral resection was done for bladder tumour. All patients were followed up as per standard protocol. Conclusion: A rise in urological post-transplant malignancies mandates regular surveillance after renal transplantation to ensure early detection of de novo malignancies and early initiation of treatment. Goal should be to minimise adverse graft outcomes with no compromise on oncological outcomes. Level of evidence: Not applicable
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Affiliation(s)
- T Manasa
- Department of Urology, Ramaiah Medical College, India
| | | | | | | | - D Ramesh
- Department of Urology, Ramaiah Medical College, India
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Musquera M, Sierra A, Diekmann F, Perez M, Mercader C, Peri L, Esforzado N, Paredes D, Alcaraz A. Increasing kidney grafts for transplantation. World J Urol 2020; 39:2795-2800. [PMID: 33000340 DOI: 10.1007/s00345-020-03463-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 09/18/2020] [Indexed: 11/28/2022] Open
Abstract
INTRODUCTION The current pool of organs available for transplantation does not cover requirements, for this reason non-standard risk donors need to be incorporated into the pool. In this way, donors with small renal tumour are considered for transplantation after bench tumour excision. The aim of our study was to analyse our experience in using these grafts for transplantation. MATERIALS AND METHODS Retrospective analysis from our prospective accrued database of donors with incidental renal mass used for kidney transplantation between January 2007 and August 2018. RESULTS Twenty kidney transplantations were performed, thirteen cases received the affected kidney (after tumour removal) and seven the contralateral kidney; from six living and eleven deceased donors. Donor and recipient median age was 58 years (range 22-82) and 56.5 years (range 38-74), respectively. Mean tumour diameter was 12.7 mm (SD 9.5). Tumours resulted in two benign lesions and fifteen renal cell carcinoma. Surgical margins were negative. Two cases presented with bleeding after reperfusion was solved without repercussion. One case presented with immediate vein thrombosis. None of them present delayed graft function. After a 69 month follow-up none of the donors or the recipients presented tumour recurrence. CONCLUSIONS Kidneys with small incidental tumours seem to be a good option for kidney transplantation in selected patients after bench surgery excision with good functional and oncologic results. More studies and longer follow-up are needed to confirm these results.
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Affiliation(s)
- Mireia Musquera
- Hospital Clinic de Barcelona, Instituto Clínic de Nefrología y Urología, Urology, Villarroel 170, 08036, Barcelona, Spain.
| | - Alba Sierra
- Hospital Clinic de Barcelona, Instituto Clínic de Nefrología y Urología, Urology, Villarroel 170, 08036, Barcelona, Spain
| | - Fritz Diekmann
- Hospital Clinic de Barcelona, Instituto Clínic de Nefrología y Urología, Nefrology, Villarroel 170, 08036, Barcelona, Spain
| | - Meritxell Perez
- Hospital de Terrassa. Torrebonica, s/n, 08227 Terrassa, Barcelona, Spain
| | | | - Lluis Peri
- Hospital Clinic de Barcelona, Instituto Clínic de Nefrología y Urología, Urology, Villarroel 170, 08036, Barcelona, Spain
| | - Nuria Esforzado
- Hospital Clinic de Barcelona, Instituto Clínic de Nefrología y Urología, Nefrology, Villarroel 170, 08036, Barcelona, Spain
| | - David Paredes
- Hospital Clinic de Barcelona, Coordination Unit, Villarroel 170 Barcelona, 08036, Catalunya, Spain
| | - Antonio Alcaraz
- Hospital Clinic de Barcelona, Instituto Clínic de Nefrología y Urología, Urology, Villarroel 170, 08036, Barcelona, Spain
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Sakai K, Oguchi H, Muramatsu M, Shishido S. Protocol graft biopsy in kidney transplantation. Nephrology (Carlton) 2018; 23 Suppl 2:38-44. [DOI: 10.1111/nep.13282] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2018] [Indexed: 01/15/2023]
Affiliation(s)
- Ken Sakai
- Department of Nephrology, Faculty of Medicine; Toho University; Tokyo Japan
| | - Hideyo Oguchi
- Department of Nephrology, Faculty of Medicine; Toho University; Tokyo Japan
| | - Masaki Muramatsu
- Department of Nephrology, Faculty of Medicine; Toho University; Tokyo Japan
| | - Seiichiro Shishido
- Department of Nephrology, Faculty of Medicine; Toho University; Tokyo Japan
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Conversion to mammalian target of rapamycin inhibitors in kidney transplant recipients with de novo cancers. Oncotarget 2018; 8:44833-44841. [PMID: 28160552 PMCID: PMC5546523 DOI: 10.18632/oncotarget.14908] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 01/17/2017] [Indexed: 11/25/2022] Open
Abstract
Objective: To investigate the impact of mammalian target of rapamycin (mTOR) inhibitor conversion together with minimization of calcineurin inhibitor on allograft outcome and patient survival in kidney transplant recipients with post-transplant cancers. Methods: A retrospective study of all kidney transplant recipients diagnosed to have post-transplant cancers between the period 1/1/1994 and 30/6/2015. Patients were divided into 2 groups: mTOR inhibitor group and non-conversion group. Outcome included allograft function, patient survival, graft survival, acute rejection and cancer recurrence. Results: 115 patients (56 in mTOR inhibitor group and 59 in non-conversion group) were analyzed. Median follow up was 28 months (range: 1 month – 20 years). The allograft function at 1-year remained similar between both groups. There was no significant difference in the patient survival, graft survival and rejection free survival between both groups. More patients in the non-conversion group developed recurrence of cancers than mTOR inhibitor group but statistically not significant. Conclusions: Use of mTOR inhibitors together with calcineurin inhibitor minimization offer a reasonable option in kidney transplant recipients who developed post-transplant cancers in view of stable renal function, low rejection rate and low cancer recurrence rate.
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Bieniasz M, Chmura A, Kwapisz M, Czerwińska M, Kieszek R, Domagała P, Wszoła M, Serwańska-Świętek M, Górnicka B, Durlik M, Pączek L, Kwiatkowski A. Renal Tumor in Allogeneic Kidney Transplant Recipient. Transplant Proc 2017; 48:1849-54. [PMID: 27496506 DOI: 10.1016/j.transproceed.2016.01.051] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 01/21/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND Malignancies will be a leading cause of mortality in renal transplant recipients in the next 20 years. Renal cell cancer (RCC) is the most common urologic cancer in kidney transplant recipients. The risk of RCC development in kidney transplant recipients is 15-100 times higher than in the general population. The purpose of the current retrospective study was to assess the frequency of nephrectomies performed because of renal tumors in the native kidneys in kidney transplant recipients in the Department of General and Transplantation Surgery at the Medical University of Warsaw between 2010 and 2014 year; the identification of kidney recipients diagnosed with RCC; and epidemiologic, clinical, and histopathological aspects associated with RCC. PATIENTS AND METHODS A total of 319 nephrectomies were performed in the Department of General and Transplantation Surgery at the Medical University of Warsaw between 2010 and 2014 year. Renal tumors were diagnosed in 25 renal transplant recipients. RESULTS Among malignant tumors, 13 cases of RCC and 1 case of post-transplant lymphoproliferative disorder (PTLD) were observed. There was no significant difference between age and duration of pretransplantation dialysis in patients with RCC and patients with benign tumors (P = .14 and P = .91, respectively). Body mass index was significantly higher in patients with RCC than in patients with benign tumors (P = .04). CONCLUSIONS Renal cell cancer is more common among male kidney recipients. There is a good Polish screening system allowing detection of kidney cancer in native kidney. We recommend performing periodic screening for kidney cancers to obtain an early diagnosis.
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Affiliation(s)
- M Bieniasz
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland.
| | - A Chmura
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
| | - M Kwapisz
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
| | - M Czerwińska
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
| | - R Kieszek
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
| | - P Domagała
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
| | - M Wszoła
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
| | - M Serwańska-Świętek
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
| | - B Górnicka
- Department of Pathology, Medical University of Warsaw, Warsaw, Poland
| | - M Durlik
- Department of Transplantation Medicine and Nephrology, Medical University of Warsaw, Warsaw, Poland
| | - L Pączek
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - A Kwiatkowski
- Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland
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6
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Kleinclauss F, Thuret R, Murez T, Timsit M. Transplantation rénale et cancers urologiques. Prog Urol 2016; 26:1094-1113. [DOI: 10.1016/j.purol.2016.08.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2016] [Accepted: 08/22/2016] [Indexed: 12/18/2022]
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Morgan M, Kenten C, Deedat S, Farsides B, Newton T, Randhawa G, Sims J, Sque M. Increasing the acceptability and rates of organ donation among minority ethnic groups: a programme of observational and evaluative research on Donation, Transplantation and Ethnicity (DonaTE). PROGRAMME GRANTS FOR APPLIED RESEARCH 2016. [DOI: 10.3310/pgfar04040] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BackgroundBlack, Asian and minority ethnic (BAME) groups have a high need for organ transplantation but deceased donation is low. This restricts the availability of well-matched organs and results in relatively long waiting times for transplantation, with increased mortality risks.ObjectiveTo identify barriers to organ donor registration and family consent among the BAME population, and to develop and evaluate a training intervention to enhance communication with ethnic minority families and identify impacts on family consent.MethodsThree-phase programme comprising (1) community-based research involving two systematic reviews examining attitudes and barriers to organ donation and effective interventions followed by 22 focus groups with minority ethnic groups; (2) hospital-based research examining staff practices and influences on family consent through ethics discussion groups (EDGs) with staff, a study on intensive care units (ICUs) and interviews with bereaved ethnic minority families; and (3) development and evaluation of a training package to enhance cultural competence among ICU staff.SettingCommunity focus group study in eight London boroughs with high prevalence of ethnic minority populations. Hospital studies at five NHS hospital trusts (three in London and two in Midlands).Participants(1) Community studies: 228 focus group participants; (2) hospital studies: 35 nurses, 28 clinicians, 19 hospital chaplains, 25 members of local Organ Donation Committees, 17 bereaved family members; and (3) evaluation: 66 health professionals.Data sourcesFocus groups with community residents, systematic reviews, qualitative interviews and observation in ICUs, EDGs with ICU staff, bereaved family interviews and questionnaires for trial evaluation.Review methodsSystematic review and narrative synthesis.Results(1) Community studies: Organ Donor Register – different ethnic/faith and age groups were at varying points on the ‘pathway’ to organ donor registration, with large numbers lacking knowledge and remaining at a pre-contemplation stage. Key attitudinal barriers were uncertainties regarding religious permissibility, bodily concerns, lack of trust in health professionals and little priority given to registration, with the varying significance of these factors varying by ethnicity/faith and age. National campaigns focusing on ethnic minorities have had limited impact, whereas characteristics of effective educational interventions are being conducted in a familiar environment; addressing the groups’ particular concerns; delivery by trained members of the lay community; and providing immediate access to registration. Interventions are also required to target those at specific stages of the donation pathway. (2) Hospital studies: family consent to donation – many ICU staff, especially junior nurses, described a lack of confidence in communication and supporting ethnic minority families, often reflecting differences in emotional expression, faith and cultural beliefs, and language difficulties. The continuing high proportion of family donation discussions that take place without the collaboration of a specialist nurse for organ donation (SNOD) reflected consultants’ views of their own role in family consent to donation, a lack of trust in SNODs and uncertainties surrounding controlled donations after circulatory (or cardiac) death. Hospital chaplains differed in their involvement in ICUs, reflecting their availability/employment status, personal interests and the practices of ICU staff. (3) Evaluation: professional development package – a digital versatile disc-based training package was developed to promote confidence and skills in cross-cultural communication (available at:www.youtube.com/watch?v=ueaR6XYkeVM&feature=youtu.be). Initial evaluation produced positive feedback and significant affirmative attitudinal change but no significant difference in consent rate over the short follow-up period with requirements for longer-term evaluation.LimitationsParticipants in the focus group study were mainly first-generation migrants of manual socioeconomic groups. It was not permitted to identify non-consenting families for interview with data regarding the consent process were therefore limited to consenting families.ConclusionsThe research presents guidance for the effective targeting of donation campaigns focusing on minority ethnic groups and provides the first training package in cultural competence in the NHS.Future workGreater evaluation is required of community interventions in the UK to enhance knowledge of effective practice and analysis of the experiences of non-consenting ethnic minority families.FundingThe National Institute for Health Research Programme Grants for Applied Research programme.
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Affiliation(s)
- Myfanwy Morgan
- Division of Health and Social Care Research, King’s College London, London, UK
| | - Charlotte Kenten
- Division of Health and Social Care Research, King’s College London, London, UK
| | - Sarah Deedat
- Division of Health and Social Care Research, King’s College London, London, UK
| | - Bobbie Farsides
- Brighton and Sussex Medical School, University of Sussex, Brighton, UK
| | - Tim Newton
- Dental Institute, King’s College London, London, UK
| | - Gurch Randhawa
- Institute for Health Research, University of Bedfordshire, Luton, UK
| | - Jessica Sims
- Division of Health and Social Care Research, King’s College London, London, UK
| | - Magi Sque
- Faculty of Education, Health and Wellbeing, University of Wolverhampton and Royal Wolverhampton NHS Trust, Wolverhampton, UK
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8
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Demir T, Ozel L, Gökçe AM, Ata P, Kara M, Eriş C, Özdemir E, Titiz MI. Cancer Screening of Renal Transplant Patients Undergoing Long-Term Immunosuppressive Therapy. Transplant Proc 2016; 47:1413-7. [PMID: 26093731 DOI: 10.1016/j.transproceed.2015.04.073] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
OBJECTIVE With this study we aimed to research the effects of immunosuppressive drugs, their cumulative doses, and viral infections on development of malign tumors in patients who have undergone treatment for 5 years. METHODS We examined 100 patients who underwent renal transplantation from 2004 to 2009. Patients had mycophenolate mofetil and steroid in addition to cyclosporine, sirolimus, or tacrolimus as immunosuppressive treatment. For malignancy screening, physical examination, radiologic and endoscopic screening were done, and immunosuppressive drugs and their cumulative doses, age, sex, body mass index (BMI), dialysis history, and viral infection history were investigated. RESULTS The mean age of patients was 42.03 ± 11.30 years. There were 1 colon cancer patient, 1 retroperitoneal liposarcoma, 1 renal oncocytoma, 3 Kaposi sarcoma patients treated with cyclosporine; in those treated with Tac there were 1 basal cell carcinoma, 1 Kaposi sarcoma, 2 thyroid carcinoma, 1 breast carcinoma, 1 bladder carcinoma, 1 renal cell carcinoma, and 1 colon carcinoma patients. The mean age of patients having carcinoma was statistically significant compared with those without cancer (P < .01). The prednisolone cumulative dose was significantly higher in carcinoma patients than in patients without carcinoma (P < .01). RESULTS The use of long-term chronic immunosuppressive therapy may increase the development of cancer. The risk of carcinoma increases with increasing drug dose and time period of the immunosuppressive drug. There was not a negative effect on cancer prevalence in patients with cyclosporine or tacrolimus. But the cumulative dose of steroids significantly increased malignancy occurence.
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Affiliation(s)
- T Demir
- Department of General Surgery and Transplantation, Haydarpasa Numune Training and Research Hospital, Uskudar, Istanbul, Turkey
| | - L Ozel
- Department of General Surgery and Transplantation, Haydarpasa Numune Training and Research Hospital, Uskudar, Istanbul, Turkey.
| | - A M Gökçe
- Department of Urology and Transplantation, Haydarpasa Numune Training and Research Hospital, Uskudar, Istanbul, Turkey
| | - P Ata
- Department of Medical Genetics, Faculty of Medicine, Marmara University, Istanbul, Turkey; Tissue Typing Laboratory, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey
| | - M Kara
- Department of General Surgery and Transplantation, Haydarpasa Numune Training and Research Hospital, Uskudar, Istanbul, Turkey
| | - C Eriş
- Department of General Surgery and Transplantation, Haydarpasa Numune Training and Research Hospital, Uskudar, Istanbul, Turkey
| | - E Özdemir
- Department of General Surgery and Transplantation, Haydarpasa Numune Training and Research Hospital, Uskudar, Istanbul, Turkey
| | - M I Titiz
- Department of General Surgery and Transplantation, Haydarpasa Numune Training and Research Hospital, Uskudar, Istanbul, Turkey
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Manito N, Delgado JF, Crespo-Leiro MG, Arizón JM, Segovia J, González-Vílchez F, Mirabet S, Lage E, Pascual-Figal D, Díaz B, Palomo J, Rábago G, Sanz M, Blasco T, Roig E. Twelve-month efficacy and safety of the conversion to everolimus in maintenance heart transplant recipients. World J Transplant 2015; 5:310-319. [PMID: 26722659 PMCID: PMC4689942 DOI: 10.5500/wjt.v5.i4.310] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 07/31/2015] [Accepted: 10/13/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To determine the clinical reasons for conversion to everolimus (EVL) and long-term outcomes in heart transplant (HT) recipients.
METHODS: A retrospective 12-mo study has been carried out in 14 Spanish centres to assess the efficacy and safety of conversion to EVL in maintenance HT recipients.
RESULTS: Two hundred and twenty-two patients were included (mean age: 53 ± 10.5 years; mean time from HT: 8.1 ± 4.5 years). The most common reasons for conversion were nephrotoxicity (30%), chronic allograft vasculopathy (20%) and neoplasms (17%). The doses and mean levels of EVL at baseline (conversion to EVL) and after one year were 1.3 ± 0.3 and 1.2 ± 0.6 mg/d and 6.4 ± 3.4 and 5.6 ± 2.5 ng/mL, respectively. The percentage of patients receiving calcineurin inhibitors (CNIs) at baseline and on the final visit was 95% and 65%, respectively. The doses and mean levels of CNIs decreased between baseline and month 12 from 142.2 ± 51.6 to 98.0 ± 39.4 mg/d (P < 0.001) and from 126.1 ± 50.9 to 89.2 ± 47.7 ng/mL (P < 0.001), respectively, for cyclosporine, and from 2.9 ± 1.8 to 2.6 ± 1.9 mg/d and from 8.3 ± 4.0 to 6.5 ± 2.7 ng/mL (P = 0.011) for tacrolimus. In the subgroup of patients converted because of nephrotoxicity, creatinine clearance increased from 34.9 ± 10.1 to 40.4 ± 14.4 mL/min (P < 0.001). There were 37 episodes of acute rejection in 24 patients (11%). The most frequent adverse events were oedemas (12%), infections (9%) and gastrointestinal problems (6%). EVL was suspended in 44 patients (20%). Since the database was closed at the end of the study, no further follow-up data is available.
CONCLUSION: Conversion to EVL in maintenance HT recipients allowed minimisation or suspension of the CNIs, with improved kidney function in the patients with nephrotoxicity, after 12 mo.
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Kato T, Kakuta Y, Abe T, Yamanaka K, Imamura R, Okumi M, Ichimaru N, Takahara S, Nonomura N. The benefits of cancer screening in kidney transplant recipients: a single-center experience. Cancer Med 2015; 5:153-8. [PMID: 26686199 PMCID: PMC4735786 DOI: 10.1002/cam4.568] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 09/22/2015] [Accepted: 09/23/2015] [Indexed: 12/19/2022] Open
Abstract
The frequency of malignancy is increasing in kidney transplant recipients. Posttransplant malignancy (PTM) is a major cause of long-term graft survival inhibition. In this study, we evaluated the frequency and prognosis of PTM at our center and examined the efficacy of cancer screening. Between 1972 and 2013, 750 patients were followed-up at our center. Annual physical examinations and screenings were performed to detect PTM. We investigated the detail of two distinctive cancer groups: screening-detected cancers and symptom-detected cancers. Seventy-seven PTM were identified during the follow-up period. The mean age at the initial PTM detection was 43.6 ± 12.8 years. The mean interval from transplantation to cancer diagnosis was 134.5 ± 11.3 months. Among the 77 patients, posttransplant lymphoproliferative disease (PTLD) was the most common cancer (19.5%, 15/77), followed by renal cell carcinoma (15.6%, 12/77). Of the cancer cases, 46.8% (36/77) were detected via screening. The most frequently screening-detected cancer was renal cell carcinoma of the native kidney and breast cancer (22.2%, 8/36). However, it was difficult to detect PTLD, urothelial carcinoma, and colorectal cancer via screening. Interestingly, Cox proportional regression analyses revealed nonscreened recipients to be a significant prognostic factor for PTM (P < 0.001). This study is the first to report that appropriate screening tests play a key role in early PTM diagnosis and lead to reduce the mortality rate in kidney transplant recipients. These findings support the provision of long-term appropriate screening for kidney transplant recipients.
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Affiliation(s)
- Taigo Kato
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yoichi Kakuta
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Toyofumi Abe
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kazuaki Yamanaka
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryoichi Imamura
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Masayoshi Okumi
- Department of Urology, Tokyo Women's Medical University Graduate School of Medicine, Shinjyuku, Japan
| | - Naotsugu Ichimaru
- Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Suita, Japan
| | - Shiro Takahara
- Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Suita, Japan
| | - Norio Nonomura
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan
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11
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Abstract
From the early days of transplantation onwards, increased cancer development in transplant recipients, who require immunosuppression to avoid graft rejection, has been recognized. Registry data indicate that approximately 10-30% of deaths are attributed to post-transplant malignancy, with an upward trend in this incidence as more patients have been exposed to chronic lifelong immunosuppression. In this Review, the overall incidence and most frequent types of cancer encountered are summarized, along with information about which transplant recipients are at the greatest risk of malignancy. Reasons for why differences exist in susceptibility to cancer in this patient population are examined, and approaches that might improve our understanding of the options available for reducing the incidence of this adverse effect of immunosuppression are described. Whether anti-rejection drugs have been successful in diminishing overall immunosuppressive burden, and consequently show any promise for decreasing post-transplant malignancies is also discussed. The topic shifts to one class of conventional anti-rejection drugs, the mammalian target of rapamycin (mTOR) inhibitors, which paradoxically have both immunosuppressive and anti-neoplastic properties. The complex activities of mTOR are reviewed in order to provide context for how these seemingly opposing effects are possible, and the latest clinical data on use of mTOR inhibitors in the clinic are discussed. The current and future perspectives on how best to normalize these unacceptably high rates of post-transplantation malignancies are highlighted.
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12
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Xie X, Jiang Y, Lai X, Xiang S, Shou Z, Chen J. mTOR inhibitor versus mycophenolic acid as the primary immunosuppression regime combined with calcineurin inhibitor for kidney transplant recipients: a meta-analysis. BMC Nephrol 2015; 16:91. [PMID: 26126806 PMCID: PMC4486141 DOI: 10.1186/s12882-015-0078-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2014] [Accepted: 05/21/2015] [Indexed: 01/01/2023] Open
Abstract
Background A number of studies have provided information regarding the risks and benefits of mammalian target of rapamycin inhibitors (mTOR-I) combined with calcineurin inhibitors (CNI) versus mycophenolic acid (MPA). Methods Medline, Embase and the Cochrane Central Register of Controlled Trials were searched. Randomized controlled trials comparing mTOR-I to MPA as the primary immunosuppressive regimen in combination with CNI were selected and meta-analyzed. Results Eleven randomized controlled trials consisting of 4930 patients in total were included. No significant difference was observed in the risk of biopsy-proven acute rejection and patient death between the two groups. However, an increased risk of graft loss (relative risk (RR) = 1.20) and inferior graft function (creatinine clearance, weighted mean difference (WMD) = −2.41 μmol/L) were demonstrated in mTOR-I-treated patients. Patients treated with mTOR-I had a higher risk of new-onset diabetes mellitus (RR = 1.32), dyslipidemia, proteinuria (RR = 1.79), peripheral edema (RR = 1.34), thrombocytopenia (RR = 1.97) and lymphocoele (RR = 1.80), but a lower risk of cytomegalovirus infection (RR = 0.40), malignancy (RR = 0.64) and leucopenia (RR = 0.43). There was no difference in diarrhea, anemia, urinary tract infection, polyoma virus infection and impaired wound healing when mTOR-I was compared with MPA. Conclusions mTOR-I showed no particular superiority to MPA. Notably, mTOR-I had an increased risk of graft loss when combined with CNI, even when combined with a reduced dose of CNI. Therefore, the optimal dosage strategies for mTOR-I and CNI need to be further explored. Electronic supplementary material The online version of this article (doi:10.1186/s12882-015-0078-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xishao Xie
- Kidney Disease Center, The First Affiliated Hospital, Medical School of Zhejiang University, Qingchun Rd, Hangzhou, Zhejiang, China.
| | - Yan Jiang
- Kidney Disease Center, The First Affiliated Hospital, Medical School of Zhejiang University, Qingchun Rd, Hangzhou, Zhejiang, China.
| | - Xiuxiu Lai
- Kidney Disease Center, The First Affiliated Hospital, Medical School of Zhejiang University, Qingchun Rd, Hangzhou, Zhejiang, China.
| | - Shilong Xiang
- Kidney Disease Center, The First Affiliated Hospital, Medical School of Zhejiang University, Qingchun Rd, Hangzhou, Zhejiang, China.
| | - Zhangfei Shou
- Kidney Disease Center, The First Affiliated Hospital, Medical School of Zhejiang University, Qingchun Rd, Hangzhou, Zhejiang, China.
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, Medical School of Zhejiang University, Qingchun Rd, Hangzhou, Zhejiang, China.
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Kato T, Kakuta Y, Yamanaka K, Okumi M, Abe T, Imamura R, Ichimaru N, Takahara S, Nonomura N. Early diagnosis and treatment of breast cancer in Japanese kidney transplant recipients: a single center experience. SPRINGERPLUS 2015; 4:196. [PMID: 25992308 PMCID: PMC4431989 DOI: 10.1186/s40064-015-0946-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Accepted: 03/25/2015] [Indexed: 01/20/2023]
Abstract
Background The incidence of malignancies in kidney transplant recipients is increasing. Breast cancer is a common malignancy after kidney transplantation and can be more aggressive in kidney transplant recipients than in the general population. In this study, we evaluated the incidence and prognosis of breast cancer in kidney transplant recipients. Findings Between 1993 and 2013, 750 kidney transplant patients were followed-up at our center. Since 1999, annual physical examination, mammography, and breast ultrasonography have been performed for such patients. Diagnostic studies, including core needle or mammotome biopsy, were performed for suspected malignancies. Patients with malignant neoplasm were administered the appropriate treatment and followed-up to assess tumor response and symptoms. Nine patients were diagnosed with breast cancer during the follow-up period. The mean age at the initial detection of the breast cancer was 47.7 ± 8.4 years. The mean interval from transplantation to diagnosis was 148.7 ± 37.1 months. Of the 9 patients, 8 were detected through the screening test; 7 were treated with breast conservative surgery and 1 was treated with modified radical mastectomy. The cancer stages were 0 (n = 2), I (n = 6), and II (n = 1). The incidence of breast cancer tended to be unchanged with time between transplantation and diagnosis, inconsistent with the increase in the duration of immunosuppression. Conclusion Annual screening tests are crucial in the early diagnosis of breast cancer. Early treatment of breast cancer can result in an excellent prognosis in kidney transplant recipients.
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Affiliation(s)
- Taigo Kato
- Department of Urology, Osaka University Graduate School of Medicine, 2-2 E4 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Yoichi Kakuta
- Department of Urology, Osaka University Graduate School of Medicine, 2-2 E4 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Kazuaki Yamanaka
- Department of Urology, Osaka University Graduate School of Medicine, 2-2 E4 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Masayoshi Okumi
- Department of Urology, Tokyo Women's Medical University Graduate School of Medicine, 8-1 Kawada-cho, Shinjyuku-ku, Tokyo, 162-8666 Japan
| | - Toyofumi Abe
- Department of Urology, Osaka University Graduate School of Medicine, 2-2 E4 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Ryoichi Imamura
- Department of Urology, Osaka University Graduate School of Medicine, 2-2 E4 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Naotsugu Ichimaru
- Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Shiro Takahara
- Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Norio Nonomura
- Department of Urology, Osaka University Graduate School of Medicine, 2-2 E4 Yamadaoka, Suita, Osaka, 565-0871 Japan
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14
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Geissler EK. The influence of mTOR inhibitors on immunity and the relationship to post-transplant malignancy. Transplant Res 2013; 2:S2. [PMID: 24565200 PMCID: PMC3834556 DOI: 10.1186/2047-1440-2-s1-s2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
The known role of mammalian target of rapamycin (mTOR) in the immune response has been rapidly evolving, from what was once thought to be a simple immunosuppressive antiproliferative effect on T cells to a very complex central role that serves to integrate multiple signals given to T cells, B cells and antigen-presenting cells. The complexity of this topic is demonstrated by recent data suggesting that mTOR inhibition can either inhibit or promote certain aspects of immune responses, depending on the nature of the antigenic stimulus, and the environmental conditions cueing the cellular immunological players. There is even evidence that, under mTOR inhibition, an immune response to one foreign entity (for example, an organ transplant) may be simultaneously completely different to that of another (for example, tumour or microorganism). To understand how this might be possible, it is necessary to investigate the central role that mTOR seems to have in shaping the immune response. This review is aimed at examining how mTOR controls the development and function of key immune cells, and puts this information primarily in the context of organ transplant rejection and post-transplant malignancy.
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Halleck F, Friedersdorff F, Fuller T, Matz M, Huber L, Dürr M, Schütz M, Budde K. New Perspectives of Immunosuppression. Transplant Proc 2013; 45:1224-31. [DOI: 10.1016/j.transproceed.2013.02.033] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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16
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Spanogle JP, Kudva YC, Dierkhising RA, Kremers WK, Roenigk RK, Brewer JD, Prieto M, Otley CC. Skin cancer after pancreas transplantation. J Am Acad Dermatol 2012; 67:563-9. [DOI: 10.1016/j.jaad.2011.11.939] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2011] [Accepted: 11/08/2011] [Indexed: 10/28/2022]
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17
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Halleck F, Duerr M, Waiser J, Huber L, Matz M, Brakemeier S, Liefeldt L, Neumayer HH, Budde K. An evaluation of sirolimus in renal transplantation. Expert Opin Drug Metab Toxicol 2012; 8:1337-56. [PMID: 22928953 DOI: 10.1517/17425255.2012.719874] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Sirolimus is a powerful antiproliferative immunosuppressive drug approved for the prevention of kidney allograft rejection. By its unique mechanism of action, sirolimus provides a multitude of clinical potential and has been used effectively in different drug combinations. Extensive experience has been gained regarding the best timing of its application, side effect profile and potential benefits and limitations compared with other immunosuppressive drugs. AREAS COVERED The authors evaluate the recent experience with sirolimus in kidney transplantation. Pivotal randomized controlled trials were used to provide an overview with special attention to pharmacokinetic and dynamic aspects of sirolimus, its current clinical use as well as perspectives for its future role. EXPERT OPINION Sirolimus enriches the possibilities of immunosuppressive therapies after renal transplantation. Beneficial effects toward kidney function by allowing CNI sparing, lower incidence of malignancies and less viral infections have been suggested. Sirolimus should be used cautiously in de novo patients for reasons of wound healing. An early conversion to a sirolimus-based CNI-free regimen has shown promising results, whereas late conversion is more challenging. Finally, sirolimus-associated side effects are causing tolerability concerns and frequent discontinuations. Future research should aim to better define the therapeutic window and those patients most likely to benefit.
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Affiliation(s)
- Fabian Halleck
- Department of Nephrology, Charité Universitätsmedizin, Berlin, Germany.
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18
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Campistol JM, Cuervas-Mons V, Manito N, Almenar L, Arias M, Casafont F, Del Castillo D, Crespo-Leiro MG, Delgado JF, Herrero JI, Jara P, Morales JM, Navarro M, Oppenheimer F, Prieto M, Pulpón LA, Rimola A, Román A, Serón D, Ussetti P. New concepts and best practices for management of pre- and post-transplantation cancer. Transplant Rev (Orlando) 2012; 26:261-79. [PMID: 22902168 DOI: 10.1016/j.trre.2012.07.001] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Accepted: 07/01/2012] [Indexed: 02/06/2023]
Abstract
Solid-organ transplant recipients are at increased risk of developing cancer compared with the general population. Tumours can arise de novo, as a recurrence of a preexisting malignancy, or from the donated organ. The ATOS (Aula sobre Trasplantes de Órganos Sólidos; the Solid-Organ Transplantation Working Group) group, integrated by Spanish transplant experts, meets annually to discuss current advances in the field. In 2011, the 11th edition covered a range of new topics on cancer and transplantation. In this review we have highlighted the new concepts and best practices for managing cancer in the pre-transplant and post-transplant settings that were presented at the ATOS meeting. Immunosuppression plays a major role in oncogenesis in the transplant recipient, both through impaired immunosurveillance and through direct oncogenic activity. It is possible to transplant organs obtained from donors with a history of cancer as long as an effective minimization of malignancy transmission strategy is followed. Tumour-specific wait-periods have been proposed for the increased number of transplantation candidates with a history of malignancy; however, the patient's individual risk of death from organ failure must be taken into consideration. It is important to actively prevent tumour recurrence, especially the recurrence of hepatocellular carcinoma in liver transplant recipients. To effectively manage post-transplant malignancies, it is essential to proactively monitor patients, with long-term intensive screening programs showing a reduced incidence of cancer post-transplantation. Proposed management strategies for post-transplantation malignancies include viral monitoring and prophylaxis to decrease infection-related cancer, immunosuppression modulation with lower doses of calcineurin inhibitors, and addition of or conversion to inhibitors of the mammalian target of rapamycin.
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Veroux M, Tallarita T, Corona D, D’Assoro A, Gurrieri C, Veroux P. Sirolimus in solid organ transplantation: current therapies and new frontiers. Immunotherapy 2011; 3:1487-97. [DOI: 10.2217/imt.11.143] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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20
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Braconnier P, del Marmol V, Broeders N, Kianda M, Massart A, Lemy A, Ghisdal L, Le Moine A, Madhoun P, Racapé J, Abramowicz D, Wissing KM. Combined introduction of anti-IL2 receptor antibodies, mycophenolic acid and tacrolimus: effect on malignancies after renal transplantation in a single-centre retrospective cohort study. Nephrol Dial Transplant 2011; 27:2547-53. [DOI: 10.1093/ndt/gfr627] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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21
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22
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Basu A, Banerjee P, Contreras AG, Flynn E, Pal S. Calcineurin inhibitor-induced and Ras-mediated overexpression of VEGF in renal cancer cells involves mTOR through the regulation of PRAS40. PLoS One 2011; 6:e23919. [PMID: 21886838 PMCID: PMC3160347 DOI: 10.1371/journal.pone.0023919] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Accepted: 08/01/2011] [Indexed: 12/20/2022] Open
Abstract
Malignancy is a major problem in patients treated with immunosuppressive agents. We have demonstrated that treatment with calcineurin inhibitors (CNIs) can induce the activation of proto-oncogenic Ras, and may promote a rapid progression of human renal cancer through the overexpression of vascular endothelial growth factor (VEGF). Interestingly, we found that CNI-induced VEGF overexpression and cancer cell proliferation was inhibited by rapamycin treatment, indicating potential involvement of the mammalian target of rapamycin (mTOR) pathway in this tumorigenic process. Here, we examined the role of mTOR pathway in mediating CNI- and Ras-induced overexpression of VEGF in human renal cancer cells (786-0 and Caki-1). We found that the knockdown of raptor (using siRNA) significantly decreased CNI-induced VEGF promoter activity as observed by promoter-luciferase assay, suggesting the role of mTOR complex1 (mTORC1) in CNI-induced VEGF transcription. It is known that mTOR becomes activated following phosphorylation of its negative regulator PRAS40, which is a part of mTORC1. We observed that CNI treatment and activation of H-Ras (through transfection of an active H-Ras plasmid) markedly increased the phosphorylation of PRAS40, and the transfection of cells using a dominant-negative plasmid of Ras, significantly decreased PRAS40 phosphorylation. Protein kinase C (PKC)-ζ and PKC-δ, which are critical intermediary signaling molecules for CNI-induced tumorigenic pathway, formed complex with PRAS40; and we found that the CNI treatment increased the complex formation between PRAS40 and PKC, particularly (PKC)-ζ. Inhibition of PKC activity using pharmacological inhibitor markedly decreased H-Ras-induced phosphorylation of PRAS40. The overexpression of PRAS40 in renal cancer cells significantly down-regulated CNI- and H-Ras-induced VEGF transcriptional activation. Finally, it was observed that CNI treatment increased the expression of phosho-PRAS40 in renal tumor tissues in vivo. Together, the phosphorylation of PRAS40 is critical for the activation of mTOR in CNI-induced VEGF overexpression and renal cancer progression.
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Affiliation(s)
- Aninda Basu
- Division of Nephrology and Transplantation Research Center, Children's Hospital, Boston, Massachusetts, United States of America
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Pallavi Banerjee
- Division of Nephrology and Transplantation Research Center, Children's Hospital, Boston, Massachusetts, United States of America
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Alan G. Contreras
- Division of Nephrology and Transplantation Research Center, Children's Hospital, Boston, Massachusetts, United States of America
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Evelyn Flynn
- Division of Nephrology and Transplantation Research Center, Children's Hospital, Boston, Massachusetts, United States of America
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Soumitro Pal
- Division of Nephrology and Transplantation Research Center, Children's Hospital, Boston, Massachusetts, United States of America
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail:
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23
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Epailly E, Albanell J, Andreassen A, Bara C, Campistol JM, Delgado JF, Eisen H, Fiane AE, Mohacsi P, Schubert S, Sebbag L, Turazza FM, Valantine H, Zuckermann A, Potena L. Proliferation signal inhibitors and post-transplant malignancies in heart transplantation: practical clinical management questions. Clin Transplant 2011; 25:E475-86. [PMID: 21592231 DOI: 10.1111/j.1399-0012.2011.01476.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Although malignancy is a major threat to long-term survival of heart transplant (HT) recipients, clear strategies to manage immunosuppression in these patients are lacking. Several lines of evidences support the hypothesis of an anticancer effect of proliferation signal inhibitors (PSIs: mammalian target of rapamycin [mTOR] inhibitors) in HT recipients. This property may arise from PSI's ability to replace immunosuppressive therapies that promote cancer progression, such as calcineurin inhibitors or azathioprine, and/or through their direct biological actions in preventing tumor development and progression. Given the lack of randomized studies specifically exploring these issues in the transplant setting, a collaborative group reviewed current literature and personal clinical experience to reach a consensus aimed to provide practical guidance for the clinical conduct in HT recipients with malignancy, or at high risk of malignancy, with a special focus on advice relevant to potential role of PSIs.
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Affiliation(s)
- E Epailly
- Les Hôpitaux Universitaires de Strasbourg, Strasbourg, France
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24
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Cheung CY, Lam MF, Lee KC, Chan GSW, Chan KW, Chau KF, Li CS, Chan TM, Lai KN. Renal cell carcinoma of native kidney in Chinese renal transplant recipients: a report of 12 cases and a review of the literature. Int Urol Nephrol 2011; 43:675-80. [PMID: 21547472 PMCID: PMC3160549 DOI: 10.1007/s11255-011-9912-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2010] [Accepted: 02/05/2011] [Indexed: 11/29/2022]
Abstract
Objectives To present and discuss the epidemiological and clinical aspects, as well as therapeutic options and outcome of de novo renal cell carcinoma (RCC) of the native kidneys in a series of Chinese renal transplant recipients. Patients and Methods A retrospective, cohort study examining all renal transplant recipients with the diagnosis of RCC of native kidney followed up in two major regional hospitals in Hong Kong between January 2000 and December 2009. Clinical data included age, gender, cause of renal failure, symptoms at presentation, duration of transplantation, immunosuppressive therapy, and history of acquired cystic kidney disease (ACKD). Laboratory, radiographic, operative, and pathology reports were used to assess the tumor extent. Results Among the 1,003 renal transplant recipients recruited, 12 transplant recipients had a nephrectomy for a total of 13 RCC. The prevalence of de novo RCC was 1.3%. The mean age at diagnosis of RCC was 48.4 years, and the median time from transplantation to diagnosis was 6.1 years. ACKD was found in 6 (50%) of the patients. All patients except one were asymptomatic. pT1 disease was found in ten patients with a mean tumor size of 3.2 cm. All patients were treated successfully with radical nephrectomy. After a median follow-up of 38 months, two patients (16.7%) died. One died of sepsis, and the other died of metastatic carcinoma. Conclusions With increasing data showing a better prognosis if RCC is detected early by screening, it is time to consider screening all kidney transplant recipients for ACKD and RCC.
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Affiliation(s)
- Chi Yuen Cheung
- Renal Unit, Department of Medicine, Queen Elizabeth Hospital, Kowloon, Hong Kong
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25
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Rama I, Grinyó JM. Malignancy after renal transplantation: the role of immunosuppression. Nat Rev Nephrol 2011; 6:511-9. [PMID: 20736984 DOI: 10.1038/nrneph.2010.102] [Citation(s) in RCA: 138] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Outcomes of kidney transplantation, in terms of graft and patient survival, have improved over the past few decades, partly as a result of the introduction of new immunosuppressive drugs. Many immunosuppressive agents are associated with an increased risk of cardiovascular events and an increased risk of cancer, however, which can compromise patient survival. Cancer is more common among solid-organ transplant recipients than it is in the general population or in patients on dialysis. In fact, malignancy is the third most common cause of death in renal transplant recipients. Immunosuppressive treatments used in renal transplant recipients can cause malignancy by supporting oncogenesis caused by certain viruses or by impairing immune surveillance thereby enabling faster tumor growth. In this Review, we describe the epidemiological and clinical characteristics of common tumor types occurring after kidney transplantation, and the etiopathogenetic factors that lead to their appearance, with a particular focus on the relationship between immunosuppressive treatment and malignancy. Immunosuppressive drugs associated with an increased risk of malignancy after transplantation are also discussed, as are immunosuppressive drugs that seem to have antioncogenic properties.
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Affiliation(s)
- Inés Rama
- Hospital Universitari de Bellvitge, Feixa Llarga s/n 08907, L'Hospitalet de Llobregat, Barcelona, Spain
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26
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Urological De Novo Malignancy After Kidney Transplantation: A Case for the Urologist. J Urol 2011; 185:428-32. [DOI: 10.1016/j.juro.2010.09.091] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2010] [Indexed: 01/20/2023]
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27
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Wéclawiak H, Kamar N, Ould-Mohamed A, Cardeau-Desangles I, Rostaing L. Biological agents in kidney transplantation: belatacept is entering the field. Expert Opin Biol Ther 2011; 10:1501-8. [PMID: 20726688 DOI: 10.1517/14712598.2010.514901] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
IMPORTANCE OF THE FIELD Kidney transplantation is the best treatment for end-stage kidney-disease patients. However, despite major breakthroughs in the last decades, and the progresses made with immunosuppressants, the long-term results still need to be improved. This is related to the increased risk of cardiovascular mortality, de novo post-transplant malignancies, and chronic kidney disease within the allograft. The last is multifactorial and includes immunological and non-immunological factors. Amongst the last is the calcineurin inhibitor (CNI) (cyclosporine A (CsA) and tacrolimus)-related nephrotoxicity. Kidney-allograft function at 1-year post-transplantation is a good surrogate marker of long-term allograft survival. AREAS COVERED IN THIS REVIEW Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4)-Ig, a fusion protein, presents as abatacept, which conserves the natural structure of CTLA4, and belatacept, which has enhanced activity thanks to two amino-acid substitutions. Abatacept and belatacept block CD86-CD28 interaction, but belatacept blocks them more powerfully. Abatacept is already approved for the treatment of rheumatoid arthritis and is marketed as Orencia(®) (Bristol-Myers Squibb, Princeton, NJ, USA), whereas belatacept is not yet approved. Herein, we review the current data available on the use of belatacept in Phase II and III kidney-transplantation trials. Note, though, that data from belatacept Phase II liver transplantation trials are not yet available. WHAT THE READER WILL GAIN The results show in de novo kidney transplant patients that as compared to CsA-treated patients, belatacept-treated patients showed: i) a significant better allograft function both at 1- and 2- year post-transplantation and ii) better cardiovascular and metabolic profiles. Regarding the safety data, Epstein-Barr virus (EBV) seronegative belatacept-treated patients experience more post-transplant lymphoproliferative disorders than the EBV seropositive belatacept-treated patients and the CsA-treated patients. TAKE HOME MESSAGE CNIs are potent immunosuppressants but have some degree of nephrotoxicity. Therefore, it is important to have strong data showing that belatacept-based therapy is as efficient as CsA-based therapy, but displaying at both 1- and 2-year post-transplantation a better allograft function, which might translate in the long-term into longer allograft survival.
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Affiliation(s)
- Hugo Wéclawiak
- Toulouse University Hospital, Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, 1 av. Jean Poulhès, TSA 50032, 31059 Toulouse Cédex 9, France
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de Gruijl FR, Koehl GE, Voskamp P, Strik A, Rebel HG, Gaumann A, de Fijter JW, Tensen CP, Bavinck JNB, Geissler EK. Early and late effects of the immunosuppressants rapamycin and mycophenolate mofetil on UV carcinogenesis. Int J Cancer 2010; 127:796-804. [PMID: 19998342 DOI: 10.1002/ijc.25097] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Increased skin cancer risk in organ transplant recipients has been experimentally emulated with enhanced UV carcinogenesis from administering conventional immunosuppressants. However, newer generation immunosuppressive drugs, rapamycin (Rapa) and mycophenolate mofetil (MMF), have been shown to impair angiogenesis and outgrowth of tumor implants. To ascertain the overall effect on UV carcinogenesis, Rapa and MMF were admixed into the food pellets of hairless SKH1 mice receiving daily sub-sunburn UV dosages. With immunosuppressive blood levels neither of the drugs affected onset of tumors (<2 mm), but in contrast to MMF, Rapa significantly increased latency of large tumors (>or=4 mm, medians of 190 vs 125 days) and reduced their multiplicity (1.6 vs 4.5 tumors per mouse at 200 days). Interestingly, tumors (>2 mm) from the Rapa-fed group showed a reduction in UV-signature p53 mutations (39% vs 90%) in favor of mutations from putative base oxidation. This shift in mutation spectrum was not essentially linked to the reduction in large tumors because it was absent in large tumors similarly reduced in number when feeding Rapa in combination with MMF, possibly owing to an antioxidant effect of MMF. Significantly fewer tumor cells were Vegf-positive in the Rapa-fed groups, but a correspondingly reduced expression of Hif1alpha target genes (Vegf, Ldha, Glut1, Pdk1) that would indicate altered glucose metabolism with increased oxidative stress was not found. Remarkably, we observed no effect of the immunosuppressants on UV-induced tumor onset, and with impaired tumor outgrowth Rapa could therefore strongly reduce skin carcinoma morbidity and mortality rates in organ transplant recipients.
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Affiliation(s)
- F R de Gruijl
- Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands
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29
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Jham BC, Montaner S. The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor: Lessons on dysregulated angiogenesis from a viral oncogene. J Cell Biochem 2010; 110:1-9. [PMID: 20213674 DOI: 10.1002/jcb.22524] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Tumor viruses can induce cell transformation by overcoming cellular defense mechanisms and promoting the ungoverned proliferation of infected cells. To this end, functionally related viral oncogenes have evolved in disparate viruses to over-ride key proliferative and survival intracellular pathways, thus assuring efficient viral replication and contributing to tumor formation. Indeed, the study of viral oncogenes has been a powerful tool for disclosing fundamental insights into these basic cellular processes. In this regard, the Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8), the etiological agent of Kaposi's sarcoma (KS), is an exemplary model of an oncogenic virus that includes within its genome several homologues of cellular genes implicated in the regulation of cell proliferation and apoptosis. However, emerging evidence now points to a single KSHV gene, ORF74, encoding for the viral G protein-coupled receptor (vGPCR), as essential for KS development. Expressed in only a fraction of cells within KS lesions, this viral receptor induces tumorigenesis through both autocrine and paracrine mechanisms. Indeed, work from several laboratories has demonstrated that vGPCR can promote cell proliferation, enhance cell survival, modulate cell migration, stimulate angiogenesis, and recruit inflammatory cells, both in expressing cells, as well as in neighboring (bystander) cells. Examination of this powerful viral oncogene may expose novel targets for the treatment of patients with KS and could ultimately provide a unique perspective into how GPCRs, and specifically chemokine receptors, contribute to angiogenesis and tumorigenesis.
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Affiliation(s)
- Bruno C Jham
- Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, Maryland 21201, USA
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30
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Fekecs T, Kádár Z, Battyáni Z, Kalmár-Nagy K, Szakály P, Wéber G, Horváth OP, Ferencz A. [Clinical study of non-melanoma skin cancer following human organ transplantation]. Magy Seb 2010; 63:84-90. [PMID: 20400400 DOI: 10.1556/maseb.63.2010.2.6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Increasing evidence suggests that non-melanoma skin cancers (NMSC) are the most frequent tumours in transplanted patients. In this study, we present the first Hungarian dermatological screening program to establish the incidence of NMSC after organ transplantations. PATIENTS AND METHODS 116 adult, "Caucasian" (white skin) transplanted (kidney, simultaneous-pancreas-kidney) patients (70 male and 46 female) of the Surgical Department of Pécs University were enrolled from September 2008. All patients underwent a a full skin examination by a dermatologist for NMSC as well as a standardized questionnaire was filled in to assess risk factors. RESULTS Screening resulted in 16 NMSC (13.8%, median age: 49.3 years, male : female = 1 : 1) diagnoses with a median duration from transplantation of 4.1 years. Histology showed 13 basal cell carcinoma (BBC), 3 squamous cell carcinoma (SCC), with a 4 : 1 ratio of BCC : SCC. Incidence of NMSC was significantly higher on patients who were treated with cyclosporine as immunosuppressant, who had more than 2 sunburns prior to transplantation, or had outdoor workplace ( p < 0.05). CONCLUSIONS These data confirm the importance of skin cancer surveillance in transplant recipients via a close cooperation between Transplantation and Dermatological Centres. Our results reflect the international data, except for the BCC : SCC ratio. Further studies needed to elucidate this difference.
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Affiliation(s)
- Tamás Fekecs
- Pécsi Tudományegyetem, Klinikai Központ Bor-, Nemikórtani és Onkodermatológiai Klinika 7624 Pécs Kodály Zoltán út 20.
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Sieber M, Baumgrass R. Novel inhibitors of the calcineurin/NFATc hub - alternatives to CsA and FK506? Cell Commun Signal 2009; 7:25. [PMID: 19860902 PMCID: PMC2774854 DOI: 10.1186/1478-811x-7-25] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2009] [Accepted: 10/27/2009] [Indexed: 01/16/2023] Open
Abstract
The drugs cyclosporine A (CsA) and tacrolimus (FK506) revolutionized organ transplantation. Both compounds are still widely used in the clinic as well as for basic research, even though they have dramatic side effects and modulate other pathways than calcineurin-NFATc, too. To answer the major open question - whether the adverse side effects are secondary to the actions of the drugs on the calcineurin-NFATc pathway - alternative inhibitors were developed. Ideal inhibitors should discriminate between the inhibition of (i) calcineurin and peptidyl-prolyl cis-trans isomerases (PPIases; the matchmaker proteins of CsA and FK506), (ii) calcineurin and the other Ser/Thr protein phosphatases, and (iii) NFATc and other transcription factors. In this review we summarize the current knowledge about novel inhibitors, synthesized or identified in the last decades, and focus on their mode of action, specificity, and biological effects.
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Affiliation(s)
- Matthias Sieber
- Deutsches Rheuma-Forschungszentrum Berlin, Charitéplatz 1, D-10117 Berlin, Germany.
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Pita-Fernandez S, Valdes-Cañedo F, Pertega-Diaz S, Seoane-Pillado MT, Seijo-Bestilleiro R. Cancer incidence in kidney transplant recipients: a study protocol. BMC Cancer 2009; 9:294. [PMID: 19698143 PMCID: PMC2745429 DOI: 10.1186/1471-2407-9-294] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2009] [Accepted: 08/22/2009] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Different publications show an increased incidence of neoplasms in renal transplant patients. The objective of this study is to determine the incidence of cancer in the recipients of renal transplants performed in the A Coruña Hospital (Spain) during the period 1981-2007. METHODS/DESIGN During the study period 1967 kidney transplants were performed, corresponding to 1710 patients. Patients with neoplasms prior to the transplant will be excluded (n = 38). A follow-up study was carried out in order to estimate cancer incidence after transplantation.For each patient, information included donor and recipient characteristics, patients and graft survival and cancer incidence after transplantation. Incident cancer is considered as new cases of cancer after the transplant with anatomopathological confirmation. Their location will be classified according to the ICD-9.The analysis will be calculated using the indirect standardisation method. Age-adjusted cancer incidence rates in the Spanish general population will be obtained from the Carlos III Health Institute, the National Epidemiology Centre of the Ministry of Science and Technology. Crude first, second and third-year post-transplantation cancer incidence rates will be calculated for male and female recipients. The number of cases of cancer at each site will be calculated from data in the clinical records. The expected number of cancers will be calculated from data supplied by the Carlos III Health Institute. For each tumour location we will estimate the standardized incidence ratios (SIRs), using sex-specific cancer incidence rates, by dividing the incidence rate for the transplant patients by the rate of the general population. The 95% confidence intervals of the SIRs and their associated p-values will be calculated by assuming that the observed cancers follow a Poisson distribution. Stratified analysis will be performed to examine the variation in the SIRs with sex and length of follow-up.Competing risk survival analysis methods will be applied to estimate the cumulative incidence of cancer and to identify variables associated to its occurrence. DISCUSSION Information about cancer incidence in kidney transplant patients could be useful to adapt the guidelines on post-kidney transplant follow-up on tumour screening, and evaluate the impact of intervention measures for the prevention of cancer in these patients.
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Affiliation(s)
- Salvador Pita-Fernandez
- Clinical Epidemiology and Biostatistics Unit, University Hospital Complex of A Coruña, Hotel de Pacientes 7a Planta, As Xubias, 84, 15006 A Coruña, Spain
| | | | - Sonia Pertega-Diaz
- Clinical Epidemiology and Biostatistics Unit, University Hospital Complex of A Coruña, Hotel de Pacientes 7a Planta, As Xubias, 84, 15006 A Coruña, Spain
| | - Maria Teresa Seoane-Pillado
- Clinical Epidemiology and Biostatistics Unit, University Hospital Complex of A Coruña, Hotel de Pacientes 7a Planta, As Xubias, 84, 15006 A Coruña, Spain
| | - Rocio Seijo-Bestilleiro
- Clinical Epidemiology and Biostatistics Unit, University Hospital Complex of A Coruña, Hotel de Pacientes 7a Planta, As Xubias, 84, 15006 A Coruña, Spain
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High Incidence of Transitional Cell Carcinoma in Kidney Transplant Recipients in Eastern Taiwan. Tzu Chi Med J 2009. [DOI: 10.1016/s1016-3190(09)60022-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Abstract
Sirolimus (SRL) is a non-nephrotoxic immunosuppressive drug blocking T-cell proliferation through mTOR inhibition. SRL can be used as (1) an early drug in a calcineurin inhibitor-free protocol in the first 3 months after transplantation, (2) in the early and late conversion protocols as suggested by the multicenter randomized CONVERT trial, and (3) in recipients from marginal donors, because calcineurin inhibitors can increase the preexisting renal damage induced by age, hypertension, and diabetes that are frequent in elderly cadaveric donors. In any case, SRL should be used in patients with a cutoff of proteinuria (<or=800 mg/24 hr) or proteinuria-to-creatinine ratio less than 0.11.
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