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Hedhli O, Marra G, Karam G, Glemain P, Chelghaf I, De Vergie S, Perrouin Verbe MA, Biancone L, Gontero P, Bouchot O, Rigaud J, Branchereau J. Prostate cancer in solid organ transplant recipients: Results from a multicenter series. THE FRENCH JOURNAL OF UROLOGY 2025; 35:102841. [PMID: 39643043 DOI: 10.1016/j.fjurol.2024.102841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 09/30/2024] [Accepted: 11/28/2024] [Indexed: 12/09/2024]
Abstract
INTRODUCTION Prostate cancer incidence in immunosuppressed transplant recipients increases as life expectancy improves in this population. However, the management of treatments and immunosuppressive (IS) regimens for solid organ transplant recipients diagnosed with prostate cancer remains poorly defined. Therefore, we conducted a multicentric study to investigate these parameters more thoroughly. METHOD This multicentric, retrospective study includes all kidney, heart, liver, or combined transplant recipients, diagnosed with prostate cancer between 1998 and 2020. IS regimen management, demographic, oncological and survival outcomes were studied here. RESULTS A prostate cancer was diagnosed among 87 SOTRs: 70 RTRs, 10 HTRs, 2 LTRs and 5 combined transplant recipients. The mean age at diagnosis was 64.3years with 10.7years mean time from transplantation to PCa. A 38% low risk, 45% intermediate risk and 11% high risk were recorded at diagnosis. Fifty-six patients underwent radical prostatectomy, 11 patients underwent radiotherapy combined with ADT, 4 patients underwent radiotherapy alone, 6 patients underwent ADT alone, 1 patient underwent brachytherapy, 3 patients underwent watchful waiting, 1 patient was treated by HIFU and 5 patients were under active surveillance. Sixteen patients had complementary treatment following biochemical recurrence or positive margins. IS regimen was modified for 69% of patients. Twelve deaths occurred in total (14%) with a 92% and 86%, 3- and 5-year overall survival respectively. Three- and 5-year progression-free survival were 89% and 83% respectively. There was no significant PFS difference between patients treated with radiotherapy and prostatectomy (P=0.94), and patients with or without a change in immunosuppressants (P=0.88). CONCLUSION Guidelines for diagnosis and management of prostate cancer in the general population appears to apply in SOTRs with good oncological outcomes. Active surveillance should also be considered in this population. LEVEL OF EVIDENCE Low.
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Affiliation(s)
- Oussama Hedhli
- Departments of Urology and Renal Transplantation, Nantes University Hospital Center, Nantes, France.
| | - Giancarlo Marra
- Departments of Urology, and Nephrology and Renal Transplantation, Molinette Hospital, University of Studies of Turin, Turin, Italy
| | - Georges Karam
- Departments of Urology and Renal Transplantation, Nantes University Hospital Center, Nantes, France
| | - Pascal Glemain
- Departments of Urology and Renal Transplantation, Nantes University Hospital Center, Nantes, France
| | - Ismaël Chelghaf
- Departments of Urology and Renal Transplantation, Nantes University Hospital Center, Nantes, France
| | - Stéphane De Vergie
- Departments of Urology and Renal Transplantation, Nantes University Hospital Center, Nantes, France
| | | | - Luigi Biancone
- Departments of Urology, and Nephrology and Renal Transplantation, Molinette Hospital, University of Studies of Turin, Turin, Italy
| | - Paolo Gontero
- Departments of Urology, and Nephrology and Renal Transplantation, Molinette Hospital, University of Studies of Turin, Turin, Italy
| | - Olivier Bouchot
- Departments of Urology and Renal Transplantation, Nantes University Hospital Center, Nantes, France
| | - Jérôme Rigaud
- Departments of Urology and Renal Transplantation, Nantes University Hospital Center, Nantes, France
| | - Julien Branchereau
- Departments of Urology and Renal Transplantation, Nantes University Hospital Center, Nantes, France
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Zhu Y, Yang H, An Z. Skin cancer associated with calcineurin inhibitors treatment: analysis of FAERS database. Expert Opin Drug Saf 2024:1-7. [PMID: 39714133 DOI: 10.1080/14740338.2024.2443783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 10/31/2024] [Accepted: 11/08/2024] [Indexed: 12/24/2024]
Abstract
BACKGROUND Several studies have indicated a potential link between calcineurin inhibitors (CNIs) and skin cancers. However, comprehensive evidence of CNI-induced skin cancers remains lacking. RESEARCH DESIGN AND METHODS We conducted an observational retrospective pharmacovigilance study utilizing the FAERS database to identify potential risk signals associated with skin cancers with CNIs treatment, encompassing data from its inception to the third quarter of 2023. The assessment was carried out using the Information Component (IC) and Reporting Odds Ratio (ROR). RESULTS We identified 1339 cases of skin cancers linked to CNIs use. The frequency of skin cancers associated with both CsA and Tac was significantly higher compared to all other drugs in the database, especially for nonmelanoma skin cancer (NMSC). There was no significant difference in the risk of CsA-related melanoma skin cancer (MSC) and NMSC compared to Tac. Additionally, the development of MSC appeared to have a higher risk of fatal outcomes in individuals of Caucasian descent and patients aged 40-79 years. CONCLUSIONS Our study has provided new real-world evidence regarding the safety of CNIs concerning skin cancers. It is recommended that clinicians remain vigilant about CNI-associated skin cancers and implement early surveillance to prevent adverse outcomes.
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Affiliation(s)
- Yuezhen Zhu
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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Ge Y, Saad M, Nemani S, Shi Y, Lineaweaver WC, Yang Y. Diagnosis and Treatment of Skin Lesions in Renal Transplant Recipients: A Retrospective Review. Ann Plast Surg 2024; 93:S51-S54. [PMID: 39101849 DOI: 10.1097/sap.0000000000003930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/06/2024]
Abstract
BACKGROUND Immunosuppressive therapy is essential for to prevent graft rejection in renal transplant patients; however, it is associated with elevating the risk of several pathologies in these patients particularly infectious and neoplastic conditions. In this study, we explore the diagnosis and treatment of skin lesions in renal transplant patients. METHODS A retrospective chart review of 12 renal transplant recipients referred to plastic and reconstructive surgery with skin lesions from 2000 to 2020 was performed. RESULTS The mean age of the 12 patients was 49.6 years. Time to plastic surgery after renal transplantation ranged between 1 and 16 years. Nine cases of basal cell carcinoma, 2 cases of squamous cell carcinoma, and 1 case of skin and soft tissue infection of the lower extremity and cutaneous extranodal NK/T-cell lymphoma, nasal type was observed. Flaps, skin grafts, and artificial dermis grafts constitute the main reconstructive methods. There were no postoperative infections or wound dehiscence. CONCLUSIONS Cutaneous infections and skin malignancy account for most of the skin lesions developing after renal transplantation. Posttransplant lymphoproliferative disorder warrants equal attention and should not be disregarded. Early diagnosis and treatment significantly improve prognosis as patients with longer duration of transplant were found to have more aggressive tumors. Plastic and reconstructive surgery offers a safe therapeutic method of treatment in these cases.
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Affiliation(s)
- Yining Ge
- From the Department of Plastic and Reconstructive Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mariam Saad
- Department of Plastic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Sriya Nemani
- Department of Plastic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Yuedong Shi
- From the Department of Plastic and Reconstructive Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - William C Lineaweaver
- Department of Plastic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Yanwen Yang
- From the Department of Plastic and Reconstructive Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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Yeoh HL, Shingles H, Paul E, Levvey BJ, Schwarz M, Voskoboynik M, Haydon AM, Shackleton M, Snell GI, Andrews MC. Malignancy risk and mortality after lung transplantation: A single-institution experience over 31 years. JHLT OPEN 2024; 4:100094. [PMID: 40144262 PMCID: PMC11935466 DOI: 10.1016/j.jhlto.2024.100094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/28/2025]
Abstract
Background Malignancy is a long-term complication of lung transplantation (LTx); however, contemporary Australian data and detailed evaluation of nonreportable cancers are lacking. Methods Retrospective review of LTx recipients' medical records and registry data linkage were performed to identify histologically proven malignancies. Baseline clinico-demographic variables were collected, and cancer incidence was compared with reported data for the general Australian population. Results There were 1,715 LTx in 1,631 patients between 1989 and 2021, with a follow-up of 9,696 person-years. Eight hundred and ninety-three (54.8%) patients were male, and the median age at first LTx was 54.7 years. There were 886 deaths with a median overall survival of 7.5 years (95% confidence intervals (CI) 6.8-8.3 years). One thousand seven hundred and seventy-four separate invasive cancer events occurred across 407 patients, of which, 1,588 (89.5%) were nonmelanoma skin cancers (NMSCs). This translated to a 9-fold increased incidence of NMSCs and a 4-fold increased incidence of other cancers compared with the general population. Cancer mortality reached parity with chronic lung allograft dysfunction 10 years postfirst transplant and was independently associated with age (hazard ratios (HR) per year increase in age 1.02 [95% CI 1.01-1.03], p = 0.001), Epstein-Barr virus primary mismatch (HR 3.24 [95% CI 1.68-6.25], vs nonmismatch, p = 0.002), and cancer count (HR per cancer event 1.19 [95% CI 1.13-1.24], p < 0.0001), but was not associated with a pretransplant malignancy history. Conclusions Our 31-year single-center experience demonstrates that malignancies are a significant mortality burden to long-term LTx survivors, dominated by NMSCs that are poorly reported in cancer datasets. A history of pretransplant malignancy was associated with a shorter time to post-transplant malignancy but was not associated with cancer death.
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Affiliation(s)
- Hui-Ling Yeoh
- Department of Medical Oncology, Alfred Health, Melbourne, Victoria, Australia
| | - Helen Shingles
- Lung Transplant Service, Alfred Health, Melbourne, Victoria, Australia
| | - Eldho Paul
- Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
- Department of Clinical Haematology, Alfred Health, Melbourne, Victoria, Australia
| | - Bronwyn J. Levvey
- Lung Transplant Service, Alfred Health, Melbourne, Victoria, Australia
| | - Max Schwarz
- Department of Medical Oncology, Alfred Health, Melbourne, Victoria, Australia
- Department of Medicine, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Mark Voskoboynik
- Department of Medical Oncology, Alfred Health, Melbourne, Victoria, Australia
- Department of Medicine, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Andrew M. Haydon
- Department of Medical Oncology, Alfred Health, Melbourne, Victoria, Australia
- Department of Medicine, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Mark Shackleton
- Department of Medical Oncology, Alfred Health, Melbourne, Victoria, Australia
- Department of Medicine, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Gregory I. Snell
- Lung Transplant Service, Alfred Health, Melbourne, Victoria, Australia
| | - Miles C. Andrews
- Department of Medical Oncology, Alfred Health, Melbourne, Victoria, Australia
- Department of Medicine, Central Clinical School, Monash University, Melbourne, Victoria, Australia
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Bellini A, Finocchietti M, Rosa AC, Nordio M, Ferroni E, Massari M, Spila Alegiani S, Masiero L, Bedeschi G, Cardillo M, Lucenteforte E, Piccolo G, Leoni O, Pierobon S, Ledda S, Garau D, Davoli M, Addis A, Belleudi V, on behalf of CESIT study group. Effectiveness and safety of immunosuppressive regimens used as maintenance therapy in kidney transplantation: The CESIT study. PLoS One 2024; 19:e0295205. [PMID: 38165971 PMCID: PMC10760756 DOI: 10.1371/journal.pone.0295205] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 11/16/2023] [Indexed: 01/04/2024] Open
Abstract
Maintenance immunosuppressive therapy used in kidney transplantation typically involves calcineurin inhibitors, such as tacrolimus or cyclosporine, in combination with mycophenolate or mechanistic target of rapamycin (mTORi) with or without corticosteroids. An Italian retrospective multicentre observational study was conducted to investigate the risk-benefit profile of different immunosuppressive regimens. We identified all subjects who underwent kidney transplant between 2009 and 2019, using healthcare claims data. Patients on cyclosporine and tacrolimus-based therapies were matched 1:1 based on propensity score, and effectiveness and safety outcomes were compared using Cox models (HR; 95%CI). Analyses were also conducted comparing mTORi versus mycophenolate among tacrolimus-treated patients. Patients treated with cyclosporine had a higher risk of rejection or graft loss (HR:1.69; 95%CI:1.16-2.46) and a higher incidence of severe infections (1.25;1.00-1.55), but a lower risk of diabetes (0.66;0.47-0.91) compared to those treated with tacrolimus. Among tacrolimus users, mTORi showed non-inferiority to MMF in terms of mortality (1.01;0.68-1.62), reject/graft loss (0.61;0.36-1.04) and severe infections (0.76;0.56-1.03). In a real-life setting, tacrolimus-based immunosuppressive therapy appeared to be superior to cyclosporine in reducing rejection and severe infections, albeit with an associated increased risk of diabetes. The combination of tacrolimus and mTORi may represent a valid alternative to the combination with mycophenolate, although further studies are needed to confirm this finding.
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Affiliation(s)
- Arianna Bellini
- Department of Epidemiology, Lazio Regional Health Service, Rome, Italy
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | | | | | | | | | - Marco Massari
- National Centre for Drug Research and Evaluation, Istituto Superiore Di Sanità, Rome, Italy
| | | | - Lucia Masiero
- Italian National Transplant Centre, Istituto Superiore di Sanità, Rome, Italy
| | - Gaia Bedeschi
- Italian National Transplant Centre, Istituto Superiore di Sanità, Rome, Italy
| | - Massimo Cardillo
- Italian National Transplant Centre, Istituto Superiore di Sanità, Rome, Italy
| | - Ersilia Lucenteforte
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Olivia Leoni
- Department of Health of Lombardy Region, Epidemiology Observatory, Milan, Italy
| | | | - Stefano Ledda
- General Directorate for Health, Sardinia Region, Italy
| | | | - Marina Davoli
- Department of Epidemiology, Lazio Regional Health Service, Rome, Italy
| | - Antonio Addis
- Department of Epidemiology, Lazio Regional Health Service, Rome, Italy
| | - Valeria Belleudi
- Department of Epidemiology, Lazio Regional Health Service, Rome, Italy
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Veitch M, Beaumont K, Pouwer R, Chew HY, Frazer IH, Soyer HP, Campbell S, Dymock BW, Harvey A, Cock TA, Wells JW. Local blockade of tacrolimus promotes T-cell-mediated tumor regression in systemically immunosuppressed hosts. J Immunother Cancer 2023; 11:e006783. [PMID: 37678918 PMCID: PMC10496666 DOI: 10.1136/jitc-2023-006783] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/30/2023] [Indexed: 09/09/2023] Open
Abstract
BACKGROUND Immunosuppressive drugs such as tacrolimus have revolutionized our ability to transplant organs between individuals. Tacrolimus acts systemically to suppress the activity of T-cells within and around transplanted organs. However, tacrolimus also suppresses T-cell function in the skin, contributing to a high incidence of skin cancer and associated mortality and morbidity in solid organ transplant recipients. Here, we aimed to identify a compound capable of re-establishing antitumor T-cell control in the skin despite the presence of tacrolimus. METHODS In this study, we performed time-resolved fluorescence resonance energy transfer to identify molecules capable of antagonizing the interaction between tacrolimus and FKBP12. The capacity of these molecules to rescue mouse and human T-cell function in the presence of tacrolimus was determined in vitro, and the antitumor effect of the lead compound, Q-2361, was assessed in "regressor" models of skin cancer in immunosuppressed mice. Systemic CD8 T-cell depletion and analyses of intratumoral T-cell activation markers and effector molecule production were performed to determine the mechanism of tumor rejection. Pharmacokinetic studies of topically applied Q-2361 were performed to assess skin and systemic drug exposure. RESULTS Q-2361 potently blocked the interaction between tacrolimus and FKBP12 and reversed the inhibition of the nuclear factor of activated T cells activation by tacrolimus following T-cell receptor engagement in human Jurkat cells. Q-2361 rescued T-cell function in the presence of tacrolimus, rapamycin, and everolimus. Intratumoral injection of Q-2361-induced tumor regression in mice systemically immune suppressed with tacrolimus. Mechanistically, Q-2361 treatment permitted T-cell activation, proliferation, and effector function within tumors. When CD8 T cells were depleted, Q-2361 could not induce tumor regression. A simple solution-based Q-2361 topical formulation achieved high and sustained residence in the skin with negligible drug in the blood. CONCLUSIONS Our findings demonstrate that the local application of Q-2361 permits T-cells to become activated driving tumor rejection in the presence of tacrolimus. The data presented here suggests that topically applied Q-2361 has great potential for the reactivation of T-cells in the skin but not systemically, and therefore represents a promising strategy to prevent or treat skin malignancies in immunosuppressed organ transplant recipients.
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Affiliation(s)
- Margaret Veitch
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Kimberly Beaumont
- Queensland Emory Drug Discovery Initiative, UniQuest, The University of Queensland, Brisbane, Queensland, Australia
| | - Rebecca Pouwer
- Queensland Emory Drug Discovery Initiative, UniQuest, The University of Queensland, Brisbane, Queensland, Australia
| | - Hui Yi Chew
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Ian H Frazer
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - H Peter Soyer
- Frazer Institute, Dermatology Research Centre, The University of Queensland, Brisbane, Queensland, Australia
- Department of Dermatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Scott Campbell
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
- Department of Nephrology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Brian W Dymock
- Queensland Emory Drug Discovery Initiative, UniQuest, The University of Queensland, Brisbane, Queensland, Australia
| | - Andrew Harvey
- Queensland Emory Drug Discovery Initiative, UniQuest, The University of Queensland, Brisbane, Queensland, Australia
| | - Terrie-Anne Cock
- Queensland Emory Drug Discovery Initiative, UniQuest, The University of Queensland, Brisbane, Queensland, Australia
| | - James W Wells
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
- Frazer Institute, Dermatology Research Centre, The University of Queensland, Brisbane, Queensland, Australia
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Bommakanti KK, Kosaraju N, Tam K, Chai-Ho W, St John M. Management of Cutaneous Head and Neck Squamous and Basal Cell Carcinomas for Immunocompromised Patients. Cancers (Basel) 2023; 15:3348. [PMID: 37444461 DOI: 10.3390/cancers15133348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/11/2023] [Accepted: 06/15/2023] [Indexed: 07/15/2023] Open
Abstract
The incidence of non-melanoma skin cancer (NMSC) continues to rise, and more than one million cases are diagnosed in the United States each year. The increase in prevalence has been attributed to increased lifespan and improvements in survival for conditions that increase the risk of these malignancies. Patients who are immunocompromised have a higher risk of developing NMSC compared to the general population. In immunosuppressed patients, a combination of prevention, frequent surveillance, and early intervention are necessary to reduce morbidity and mortality. In this review, we collate and summarize current knowledge regarding pathogenesis of head and neck cutaneous SCC and BCC within immunocompromised patients, examine the potential role of the immune response in disease progression, and detail the role of novel immunotherapies in this subset of patients.
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Affiliation(s)
- Krishna K Bommakanti
- Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
- UCLA Head and Neck Cancer Program (HNCP), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
| | - Nikitha Kosaraju
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
| | - Kenric Tam
- Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
- UCLA Head and Neck Cancer Program (HNCP), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
| | - Wanxing Chai-Ho
- UCLA Head and Neck Cancer Program (HNCP), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
| | - Maie St John
- Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
- UCLA Head and Neck Cancer Program (HNCP), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
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Kulbat A, Richter K, Stefura T, Kołodziej-Rzepa M, Kisielewski M, Wojewoda T, Wysocki WM. Systematic Review of Calcineurin Inhibitors and Incidence of Skin Malignancies after Kidney Transplantation in Adult Patients: A Study of 309,551 Cases. Curr Oncol 2023; 30:5727-5737. [PMID: 37366913 PMCID: PMC10296938 DOI: 10.3390/curroncol30060430] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 05/26/2023] [Accepted: 06/07/2023] [Indexed: 06/28/2023] Open
Abstract
The purpose of this systematic review and meta-analysis was to compare the risk of non-melanoma skin cancer (NMSC) and melanoma development in renal transplant recipients who receive calcineurin inhibitors to that of patients treated with other immunosuppressive agents, and investigate the possible association between the type of maintenance immunosuppression and the incidence of NSMC and melanoma in this group of patients. The authors searched databases such as PubMed, Scopus, and Web of Science for articles that would help establish the influence of calcineurin inhibitors on skin cancer development. The inclusion criteria for the study consisted of randomized clinical trials, cohort studies, and case-control studies that compared patients who received kidney transplants and were treated with a calcineurin inhibitor (CNI), such as cyclosporine A (CsA) or tacrolimus (Tac), to those who received alternative immunosuppressants and did not receive a CNI. Seven articles were analyzed overall. The results revealed a correlation between CNI treatment in renal transplant recipients and increased total skin cancer risk (OR 1.28; 95% CI: 0.10-16.28; p < 0.01), melanoma risk (OR 1.09; 95% CI: 0.25-4.74; p < 0.01), and NMSC risk (OR 1.16; 95% CI: 0.41-3.26; p < 0.01). In conclusion, the calcineurin inhibitors used after kidney transplantation are associated with a higher risk of skin cancer-both non-melanoma and melanoma-when compared with other immunosuppressive therapies. This finding suggests that careful monitoring for skin lesions in post-transplant patients must be conducted. However, the decision on the kind of immunotherapy used should always be considered on an individual basis for each renal transplant recipient.
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Affiliation(s)
- Aleksandra Kulbat
- The Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland;
- Department of General, Oncological and Vascular Surgery, 5th Military Clinical Hospital in Kraków, 30-901 Kraków, Poland
- Department of Medical Education, Jagiellonian University Medical College, 30-688 Kraków, Poland
| | - Karolina Richter
- Chair of Surgery, Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Kraków University, 30-705 Kraków, Poland;
| | - Tomasz Stefura
- Department of General, Oncological and Vascular Surgery, 5th Military Clinical Hospital in Kraków, 30-901 Kraków, Poland
- Department of Medical Education, Jagiellonian University Medical College, 30-688 Kraków, Poland
| | - Marta Kołodziej-Rzepa
- Department of General, Oncological and Vascular Surgery, 5th Military Clinical Hospital in Kraków, 30-901 Kraków, Poland
- Chair of Surgery, Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Kraków University, 30-705 Kraków, Poland;
| | - Michał Kisielewski
- Department of General, Oncological and Vascular Surgery, 5th Military Clinical Hospital in Kraków, 30-901 Kraków, Poland
- Chair of Surgery, Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Kraków University, 30-705 Kraków, Poland;
| | - Tomasz Wojewoda
- Department of General, Oncological and Vascular Surgery, 5th Military Clinical Hospital in Kraków, 30-901 Kraków, Poland
- Chair of Surgery, Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Kraków University, 30-705 Kraków, Poland;
| | - Wojciech M. Wysocki
- The Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland;
- Department of General, Oncological and Vascular Surgery, 5th Military Clinical Hospital in Kraków, 30-901 Kraków, Poland
- Chair of Surgery, Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Kraków University, 30-705 Kraków, Poland;
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Russomanno K, Abdel Azim S, Patel VA. Immunomodulators for Non-Melanoma Skin Cancers: Updated Perspectives. Clin Cosmet Investig Dermatol 2023; 16:1025-1045. [PMID: 37095898 PMCID: PMC10122480 DOI: 10.2147/ccid.s362171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 03/20/2023] [Indexed: 04/26/2023]
Abstract
Non-melanoma skin cancers (NMSCs) are the most common cancers worldwide and may be associated with significant morbidity and mortality, especially in immunosuppressed populations. Successful management of NMSC must take primary, secondary and tertiary prevention strategies into consideration. In response to an improved understanding of the pathophysiology of NMSC and associated risk factors, multiple systemic and topical immunomodulatory drugs have been developed and integrated into clinical practice. Many of these drugs are efficacious in the prevention and treatment of precursor lesions (actinic keratoses; AKs), low-risk NMSC, and advanced disease. The identification of patients at high risk for the development of NMSC is critical in reducing disease morbidity. Understanding the various treatment options available and their comparative effectiveness is paramount for developing a personalized treatment regimen for such patients. This review article provides an updated overview of the various topical and systemic immunomodulatory drugs available for the prevention and treatment of NMSC, and the published data supporting their use in clinical practice.
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Affiliation(s)
- Kristen Russomanno
- Department of Dermatology, Medstar Georgetown University Hospital/Medstar Medical Group, Washington, DC, USA
| | - Sara Abdel Azim
- School of Medicine, Georgetown University, Washington, DC, USA
| | - Vishal A Patel
- Department of Dermatology, George Washington University, Washington, DC, USA
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10
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Kreher MA, Noland MMB, Konda S, Longo MI, Valdes-Rodriguez R. Risk of melanoma and nonmelanoma skin cancer with immunosuppressants, part I: Calcineurin inhibitors, thiopurines, IMDH inhibitors, mTOR inhibitors, and corticosteroids. J Am Acad Dermatol 2023; 88:521-530. [PMID: 36460257 DOI: 10.1016/j.jaad.2022.11.044] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/29/2022] [Accepted: 11/15/2022] [Indexed: 12/05/2022]
Abstract
Immunosuppression is a well-documented risk factor for skin cancer, as exemplified by the 65- to 250-fold higher squamous cell carcinoma risk, 10-fold higher basal cell carcinoma risk, and 0 to 8-fold higher melanoma risk in solid organ transplant recipients (SOTRs) receiving potent, prolonged courses of immunosuppressive therapies. Numerous immune system components have been shown to either suppress or promote tumor growth, and immunosuppressive drugs may have additional effects on proliferative pathways independent of the immune system. Thus, evaluation of the specific regimen by the dermatologist is key for assessing skin cancer risk in each patient. In the present manuscript, the immune-mediated mechanisms of skin cancer development and regression are first reviewed. Next, a synthesis of the evidence shows the differing effects of immunosuppressive agents commonly used in SOTRs on melanoma and nonmelanoma skin cancer risk. These include systemic calcineurin inhibitors, thiopurines, IMDH (inosine monophosphate dehydrogenase) inhibitors, mTOR (mammalian target of rapamycin) inhibitors, and systemic corticosteroids. Finally, recommendations for skin cancer screening in SOTRs are discussed. We further offer recommendations for select nontransplant patients who may benefit from routine skin cancer screening due to risks associated with specific immunosuppressant exposure, and we propose evidence-based strategies for minimizing high-risk immunosuppressant use in clinical practice.
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Affiliation(s)
| | | | - Sailesh Konda
- Department of Dermatology, University of Florida, Gainesville, Florida
| | - Maria I Longo
- Department of Dermatology, University of Florida, Gainesville, Florida
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11
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Berman H, Shimshak S, Reimer D, Brigham T, Hedges MS, Degesys C, Tolaymat L. Skin Cancer in Solid Organ Transplant Recipients: A Review for the Nondermatologist. Mayo Clin Proc 2022; 97:2355-2368. [PMID: 36334939 DOI: 10.1016/j.mayocp.2022.07.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/29/2022] [Accepted: 07/07/2022] [Indexed: 11/06/2022]
Abstract
Solid organ transplant recipients (SOTRs) are at increased risk for the development of skin cancer compared with the general population, which requires consistent monitoring and management from a multidisciplinary team. The aim of this review is to provide a comprehensive overview for nondermatologist clinicians, outlining skin cancer diagnosis, treatment pearls, and skin cancer prevention strategies as they relate to SOTRs. A comprehensive search of the literature was conducted through the MEDLINE database with search terms including organ transplantation, transplant recipient, skin cancer, cutaneous neoplasms, management, and therapies. The search was limited to the English language and dates ranging from January 1, 2011, to December 28, 2021. All studies were reviewed for inclusion. Skin cancer will develop in more than half of SOTRs at some point in their life, most often nonmelanoma skin cancer such as basal cell carcinoma or squamous cell carcinoma. Melanoma and rarer cutaneous malignant neoplasms, such as Merkel cell carcinoma and Kaposi sarcoma, are also more frequent among SOTRs. A multidisciplinary effort at skin cancer screening and patient education is invaluable to prevent skin cancer-related morbidity and mortality in this population of patients. Reduction in immunosuppressive medications and surgical intervention are effective therapeutic approaches, and more novel systemic therapies including G protein-coupled receptor inhibitors and immune checkpoint inhibitors are possible options when traditional treatment approaches are not feasible. Checkpoint inhibitor therapy, however, comes with the risk of allograft rejection. With a growing and aging SOTR population, it is essential that SOTRs have support from dermatologists and nondermatologists alike in skin cancer prevention and treatment.
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Affiliation(s)
- Hannah Berman
- Department of Dermatology, Mayo Clinic, Jacksonville, FL
| | | | | | - Tara Brigham
- Mayo Clinic Medical Library, Mayo Clinic College of Medicine and Science, Jacksonville, FL
| | - Mary S Hedges
- Department of Internal Medicine, Division of Community Internal Medicine, Mayo Clinic, Jacksonville, FL
| | | | - Leila Tolaymat
- Department of Dermatology, Mayo Clinic, Jacksonville, FL.
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12
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Liu SW, Wang WM, Chiang CP, Chung CH, Tsao CH, Chien WC, Hung CT. Risk of skin cancer in kidney, liver and heart recipients: A nationwide population-based study in Taiwan. Indian J Dermatol Venereol Leprol 2022; 89:372-377. [DOI: 10.25259/ijdvl_366_2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 03/01/2022] [Indexed: 11/04/2022]
Abstract
Background
Previous population-based studies in western countries had revealed increased skin cancer risk among transplant recipients compared to the general population. However, population-based studies in Asia on skin cancer among recipients of different transplanted organs were lacking in the literature.
Aims
This study aims to estimate skin cancer risk among recipients in Taiwan, examine the association between each specific type of skin cancer and each type of transplanted organ, and compare skin cancer risk between different immunosuppressive regimens.
Methods
This population-based retrospective cohort study identified 7550 patients with heart, lung, kidney or liver transplantation and 30,200 controls matched for gender, age and comorbidity index from the National Health Insurance Research Database in Taiwan between 2000 and 2015. Using multivariable Cox proportional hazard models, we estimated the hazard ratios and 95% confidence intervals for the correlation of skin cancer with organ transplantation as well as immunosuppressive regimen.
Results
Organ transplant recipients in Taiwan had an increased risk of skin cancer with adjusted hazard ratios of 4.327 (95% confidence intervals 2.740-6.837, P < 0.001), with the greatest risk, observed among heart recipients (adjusted hazard ratios 6.348, 95% confidence intervals 3.080-13.088, P < 0.001). The risk of non-melanoma skin cancer and melanoma was 4.473 (95% confidence intervals 2.568-7.783, P < 0.001) and 3.324 (95% confidence intervals 1.300-8.172, P < 0.001), respectively. When comparing immunosuppressants, those with calcineurin inhibitors carried the highest risk of skin cancer (adjusted hazard ratios 4.789, 95% confidence intervals 3.033-7.569, P < 0.001), followed by those with antimetabolites (adjusted hazard ratios 4.771, 95% confidence intervals 3.025-7.541, P < 0.001).
Limitations
We could not evaluate confounding behavioural risk factors of skin cancers that were not documented in the database, nor could we recognize patients’ compliance with immunosuppressants.
Conclusion
Organ recipients have a greater risk of skin cancer. Clinicians should inform recipients of the importance of photoprotection and regular dermatologic follow-up.
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Affiliation(s)
| | | | | | - Chi-Hsiang Chung
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chang-Huei Tsao
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Wu-Chien Chien
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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13
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Tong SH, Huang YJ, Yang YC, Lin HC, Jou YC. Hepatic Angiosarcoma Post-Renal Transplantation: A Case Report. Transplant Proc 2022; 54:1597-1600. [PMID: 35868873 DOI: 10.1016/j.transproceed.2022.05.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/05/2022] [Accepted: 05/21/2022] [Indexed: 01/20/2023]
Abstract
BACKGROUND DNA damage and oncogenic viruses increase the risk of cancer post-kidney transplantation, including skin cancer, Kaposi's sarcoma, oral cancer, and non-Hodgkin lymphoma. Here we report an uncommon case of liver angiosarcoma that occurred 8 years after kidney transplantation. This study strictly complied with the Helsinki Congress and the Istanbul Declaration regarding donor source. CASE REPORT A 57-year-old female patient received a cadaver kidney transplantation 8 years ago. She followed a long-term regimen of tacrolimus, mycophenolate sodium, and everolimus, with good renal function. She received annual regular abdominal ultrasound examinations after kidney transplantation, which showed no findings. The patient suffered from several symptoms for approximately 2 weeks before a scheduled abdominal ultrasound: diarrhea, epigastric pain, abdominal fullness, tea-colored urine, and little stool passage. The abdominal computerized tomography showed multiple hepatic tumors in both the hepatic lobes with engorged vasculatures and mild hemoperitoneum. A liver biopsy revealed the histopathology of angiosarcoma. The patient suffered multiple organ failure within one month of treatment. CONCLUSIONS Various post-transplant malignancies are not uncommon after transplantation, warranting periodic screenings for any symptoms in these patients.
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Affiliation(s)
- Show-Hwa Tong
- Department of Pharmacy, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan
| | - Yen-Ju Huang
- Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan
| | - Yung-Cheng Yang
- Department of Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan
| | - Hui-Chuan Lin
- Department of Pharmacy, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan
| | - Yeong-Chin Jou
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan; Division of Urology, Department of Surgery, St. Martin De Porres Hospital, Chia-Yi City, Taiwan.
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14
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Quaresma MV, Azevedo LS, Pereira NV, Saldanha MG, David-Neto E, Sotto MN. Lymphocyte subsets and Langerhans cells in the skin of kidney transplant recipients under three different immunosuppressive regimens. J Eur Acad Dermatol Venereol 2022; 36:2466-2472. [PMID: 35841306 DOI: 10.1111/jdv.18430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/10/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Renal transplant recipients (RTRs) are at increased risk of developing skin cancer; however, the role of immunosuppression is not yet fully understood. In this study, we evaluated the immunohistochemical changes in the skin of RTRs under three different immunosuppression regimens: mTOR inhibitors (mTORi), sirolimus or everolimus, mycophenolic acid (MPA) precursors such as mycophenolate sodium or mofetil, or azathioprine (AZA). METHODS We evaluated biopsies of sun-exposed and sun-protected skin for immunohistochemical quantification of B lymphocytes (CD20+), T lymphocytes (CD3+, CD4+, and CD8+), and Langerhans cells (LCs) (CD1a+) in 30 RTRs and 10 healthy controls. The RTRs were divided into three groups: mTORi (n = 10), MPA (n = 10), and AZA (n = 10). RESULTS No differences were observed in the number of B lymphocytes. However, a significant decrease in the number of T lymphocytes and LCs was observed in both sun-protected and sun-exposed skin in the AZA and MPA groups, although to a lesser degree in the latter group. The skin of the mTORi group did not differ from that of the control group in terms of the number of B and T lymphocytes and LCs. CONCLUSIONS Patients treated with mTORi exhibit preserved cellular elements related to cutaneous immune surveillance. The use of AZA induced a greater degree of skin immunosuppression than in the control group, as demonstrated by the decrease in T lymphocytes and LCs.
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Affiliation(s)
- Maria Victória Quaresma
- Department of Dermatology, Hospital das Clínicas, University of São Paulo Medical School, São Paulo, Brazil
| | - Luiz S Azevedo
- Renal Transplantation Service, Hospital das Clínicas, University of São Paulo Medical School, São Paulo, Brazil
| | - Naiura V Pereira
- Department of Dermatology, Hospital das Clínicas, University of São Paulo Medical School, São Paulo, Brazil
| | - Maíra G Saldanha
- Department of Gynecology, Federal University of São Paulo, São Paulo, Brazil
| | - Elias David-Neto
- Renal Transplantation Service, Hospital das Clínicas, University of São Paulo Medical School, São Paulo, Brazil
| | - Mírian N Sotto
- Department of Dermatology, Hospital das Clínicas, University of São Paulo Medical School, São Paulo, Brazil.,Department of Pathology, University of São Paulo Medical School, São Paulo, Brazil
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15
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Gluck M, Hodak E, Davidovici B. Mammalian Target of Rapamycin Inhibitors for prolonged secondary prevention of non-melanoma skin cancer in solid organ transplant recipients. Dermatol Ther 2022; 35:e15649. [PMID: 35716099 DOI: 10.1111/dth.15649] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 05/30/2022] [Accepted: 06/16/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Immunosuppressive agents are essential for graft survival in solid-organ transplant recipients (SOTRs), but they have substantial durable side effects, including a higher incidence of aggressive non-melanoma skin cancers (NMSCs). Hitherto, only one class of immunosuppressants, mammalian target of rapamycin inhibitors (mTORi), may inhibit skin tumor formation, however their durable effectiveness is controversial. OBJECTIVE To evaluate the sustained effectiveness of mTORi in reducing NMSCs' incidence in SOTRs. METHODS A retrospective study was conducted in a specialized dermatology clinic for SOTRs of a tertiary university-affiliated medical center. SOTRs with a history of at least one histologically proven NMSC, were followed for 6 years: 3 years after transplantation, before initiation of mTORi, and 3 years under mTORi treatment. RESULTS The cohort consisted of 44 SOTRs. Treatment with mTORi was initiated on average 6.27 (3.34-6.34) years following transplantation. In the 3 years before mTORi treatment initiation, the mean number of new NMSCs per patient was 2.11 (1-14). This value decreased to 1.2 (0-19) in the 3 years under mTORi treatment (P=0.0007). Analysis by NMSC type yielded a significant decrease in both SCCs and BCCs. CONCLUSION This study found that mTORi are effective for prolonged secondary prevention of NMSCs in SOTRs. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Mirit Gluck
- Devision of Dermatology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel
| | - Emmillia Hodak
- Devision of Dermatology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Batya Davidovici
- Devision of Dermatology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel
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16
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Thai AA, Lim AM, Solomon BJ, Rischin D. Biology and Treatment Advances in Cutaneous Squamous Cell Carcinoma. Cancers (Basel) 2021; 13:5645. [PMID: 34830796 PMCID: PMC8615870 DOI: 10.3390/cancers13225645] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/08/2021] [Accepted: 11/08/2021] [Indexed: 12/24/2022] Open
Abstract
Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer diagnosed worldwide. CSCC is generally localized and managed with local therapies such as excision and/or radiotherapy. For patients with unresectable or metastatic disease, recent improvements in our understanding of the underlying biology have led to significant advancements in treatment approaches-including the use of immune checkpoint inhibition (ICI)-which have resulted in substantial gains in response and survival compared to traditional cytotoxic approaches. However, there is a lack of understanding of the biology underpinning CSCC in immunocompromised patients, in whom the risk of developing CSCC is hundreds of times higher compared to immunocompetent patients. Furthermore, current ICI approaches are associated with significant risk of graft rejection in organ transplant recipients who make up a significant proportion of immunocompromised patients. Ongoing scientific and clinical research efforts are needed in order to maintain momentum to increase our understanding and refine our therapeutic approaches for patients with CSCC.
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Affiliation(s)
- Alesha A. Thai
- Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan St., Parkville, Melbourne, VIC 3000, Australia; (A.M.L.); (B.J.S.); (D.R.)
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3000, Australia
| | - Annette M. Lim
- Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan St., Parkville, Melbourne, VIC 3000, Australia; (A.M.L.); (B.J.S.); (D.R.)
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3000, Australia
| | - Benjamin J. Solomon
- Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan St., Parkville, Melbourne, VIC 3000, Australia; (A.M.L.); (B.J.S.); (D.R.)
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3000, Australia
| | - Danny Rischin
- Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan St., Parkville, Melbourne, VIC 3000, Australia; (A.M.L.); (B.J.S.); (D.R.)
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3000, Australia
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17
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Abstract
Benefits of solid organ transplantation in end stage organ diseases are indisputable. Malignancy is a feared complication of solid organ transplantation and is a leading cause of mortality in patients with organ transplantation. Iatrogenic immunosuppression to prevent graft rejection plays a crucial role in the cancer development in solid organ transplant recipients. Chronic exposure to immunosuppression increases the malignancy burden through deregulation of host immune defense mechanisms and unchecked proliferation of oncogenic viruses and malignancies associated with these viruses. Vigorous screening of candidates undergoing transplant evaluation for malignancies, careful assessment of donors, and vigilant monitoring of transplant recipients are necessary to prevent, detect, and manage this life-threatening complication.
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18
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Schaper-Gerhardt K, Hansel A, Walter A, Grimmelmann I, Gutzmer R. Sirolimus diminishes the expression of GRO-α (CXCL-1) /CXCR2 axis in human keratinocytes and cutaneous squamous cell carcinoma cells. J Dermatol Sci 2021; 104:30-38. [PMID: 34479772 DOI: 10.1016/j.jdermsci.2021.08.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 08/13/2021] [Accepted: 08/24/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND Organ transplant recipients show a high incidence for the formation of cutaneous squamous cell carcinoma (cSCC), while sirolimus appears to reduce the risk. GRO-α is a chemokine, which is overexpressed in many tumor entities and associated with malignant transformation. However, little is known about the expression and function of GRO-α in human cSCC. OBJECTIVE Our aim was to investigate the relevance of the GRO-α (CXCL-1)/ CXCR2 axis in human cSCC and the potential impact of sirolimus. METHODS We analyzed the GRO-α expression in human keratinocytes, different cSCC cell lines as well as cSCC tissue and investigated its effect on cell proliferation and migration. Additionally, we incubated cells with sirolimus and measured the expression of GRO-α and its receptor CXCR2. RESULTS We showed that both constitutive as well as induced GRO-α expression is higher in in cSCC cell lines compared to keratinocytes and that GRO-α protein is detectable in human cSCC tissue. By GRO-α exposure and shRNA knock down, we identified GRO-α as a driving factor in proliferation and migration. Moreover, in a dermis equivalent GRO-α knocked down cSCC cell lines displayed a reduced capacity in tumor nest formation. Incubation with sirolimus significantly inhibited GRO-α expression in keratinocytes as well as tumor cell lines. Moreover, sirolimus decreased the expression of the corresponding receptor CXCR2. CONCLUSION Taken together, our results suggest that the GRO-α/CXCR2 axis plays a role in human keratinocyte carcinogenesis and might represent a molecular mechanism for the preventive effect of mTOR inhibitors in cSCC development.
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Affiliation(s)
- Katrin Schaper-Gerhardt
- Skin Cancer Center Hannover, Departement of Dermatology and Allergy, Hannover Medical School, Hannover, Germany; Department of Dermatology, Ruhr University Bochum, Campus Minden, Minden, Germany.
| | - Annika Hansel
- Skin Cancer Center Hannover, Departement of Dermatology and Allergy, Hannover Medical School, Hannover, Germany
| | - Antje Walter
- Skin Cancer Center Hannover, Departement of Dermatology and Allergy, Hannover Medical School, Hannover, Germany
| | - Imke Grimmelmann
- Skin Cancer Center Hannover, Departement of Dermatology and Allergy, Hannover Medical School, Hannover, Germany
| | - Ralf Gutzmer
- Skin Cancer Center Hannover, Departement of Dermatology and Allergy, Hannover Medical School, Hannover, Germany; Department of Dermatology, Ruhr University Bochum, Campus Minden, Minden, Germany
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19
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Combined surgery and radiofrequency ablation for the treatment of EBV-associated smooth muscle tumors after liver transplantation in a child. JOURNAL OF PEDIATRIC SURGERY CASE REPORTS 2021. [DOI: 10.1016/j.epsc.2021.101957] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
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20
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Wojciechowski D, Wiseman A. Long-Term Immunosuppression Management: Opportunities and Uncertainties. Clin J Am Soc Nephrol 2021; 16:1264-1271. [PMID: 33853841 PMCID: PMC8455033 DOI: 10.2215/cjn.15040920] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The long-term management of maintenance immunosuppression in kidney transplant recipients remains complex. The vast majority of patients are treated with the calcineurin inhibitor tacrolimus as the primary agent in combination with mycophenolate, with or without corticosteroids. A tacrolimus trough target 5-8 ng/ml seems to be optimal for rejection prophylaxis, but long-term tacrolimus-related side effects and nephrotoxicity support the ongoing evaluation of noncalcineurin inhibitor-based regimens. Current alternatives include belatacept or mammalian target of rapamycin inhibitors. For the former, superior kidney function at 7 years post-transplant compared with cyclosporin generated initial enthusiasm, but utilization has been hampered by high initial rejection rates. Mammalian target of rapamycin inhibitors have yielded mixed results as well, with improved kidney function tempered by higher risk of rejection, proteinuria, and adverse effects leading to higher discontinuation rates. Mammalian target of rapamycin inhibitors may play a role in the secondary prevention of squamous cell skin cancer as conversion from a calcineurin inhibitor to an mammalian target of rapamycin inhibitor resulted in a reduction of new lesion development. Early withdrawal of corticosteroids remains an attractive strategy but also is associated with a higher risk of rejection despite no difference in 5-year patient or graft survival. A major barrier to long-term graft survival is chronic alloimmunity, and regardless of agent used, managing the toxicities of immunosuppression against the risk of chronic antibody-mediated rejection remains a fragile balance.
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Affiliation(s)
- David Wojciechowski
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
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21
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Duran-Ortiz S, List EO, Basu R, Kopchick JJ. Extending lifespan by modulating the growth hormone/insulin-like growth factor-1 axis: coming of age. Pituitary 2021; 24:438-456. [PMID: 33459974 PMCID: PMC8122064 DOI: 10.1007/s11102-020-01117-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/10/2020] [Indexed: 02/06/2023]
Abstract
Progress made in the years of aging research have allowed the opportunity to explore potential interventions to slow aging and extend healthy lifespan. Studies performed in yeast, worms, flies and mice subjected to genetic and pharmacological interventions have given insight into the cellular and molecular mechanisms associated with longevity. Furthermore, it is now possible to effectively modulate pathways that slow aging at different stages of life (early life or at an adult age). Interestingly, interventions that extend longevity in adult mice have had sex-specific success, suggesting a potential link between particular pathways that modulate aging and sex. For example, reduction of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis at an adult age extends lifespan preferentially in females. Moreover, several postnatal dietary interventions tested by the 'Intervention Testing Program (ITP)' from the National Institute of Aging (NIA) have shown that while pharmacological interventions like rapamycin affect the IGF-1/insulin pathway and preferentially extend lifespan in females; dietary compounds that target other cellular pathways are effective only in male mice-indicating mutually exclusive sex-specific pathways. Therefore, a combination of interventions that target non-overlapping aging-related pathways appears to be an effective approach to further extend healthy lifespan in both sexes. Here, we review the germline and postnatal mouse lines that target the GH/IGF-1 axis as a mechanism to extend longevity as well as the dietary compounds that tested positive in the NIA program to increase lifespan. We believe that the interventions reviewed in this paper could constitute feasible combinations for an extended healthy lifespan in both male and female mice.
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Affiliation(s)
- Silvana Duran-Ortiz
- Edison Biotechnology Institute, Ohio University, Athens, USA
- Department of Biological Sciences, College of Arts and Sciences, Ohio University, Athens, USA
- Molecular and Cellular Biology Program, Ohio University, Athens, USA
| | - Edward O List
- Edison Biotechnology Institute, Ohio University, Athens, USA
| | - Reetobrata Basu
- Edison Biotechnology Institute, Ohio University, Athens, USA
| | - John J Kopchick
- Edison Biotechnology Institute, Ohio University, Athens, USA.
- Molecular and Cellular Biology Program, Ohio University, Athens, USA.
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, 45701, USA.
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22
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Wilken R, Carucci J, Stevenson ML. Skin Cancers and Lung Transplant. Semin Respir Crit Care Med 2021; 42:483-496. [PMID: 34030209 DOI: 10.1055/s-0041-1728798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
It is well known that solid-organ transplant recipients (SOTRs) have a 65- to 100-fold increase in the risk of developing skin cancer, namely, nonmelanoma skin cancers (NMSCs) such as cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC). In addition, these patients are also at increased risk for development of melanoma as well as other less common cutaneous malignancies (Merkel's cell carcinoma, Kaposi's sarcoma). SOTRs with NMSC (namely cSCC) are also at significantly increased risk of poor clinical outcomes including local recurrence, nodal and distant metastasis, and disease-specific death relative to patients who are not immunosuppressed. Increased surveillance and monitoring in patients at risk of aggressive disease and poor outcomes who are on immunosuppression is essential in patients with lung transplants given the high degree of immunosuppression. Increased awareness of risks, treatments, and management allows for improved outcomes in these patients. This article will provide an overview of the risk factors for the development of cutaneous malignancies in organ transplant recipients as well as a detailed discussion of various immunosuppressant and prophylactic medications used in this patient population that contribute to the risk of developing cutaneous malignancies, with an emphasis on NMSC (cSCC and BCC) in lung transplant recipients. Finally, this article includes a discussion on the clinical and dermatologic management of this high-risk immunosuppressed population including a review of topical and systemic agents for field therapy of actinic damage and chemoprevention of keratinocyte carcinomas. In addition, indications for additional treatment and preventive measures such as adjuvant radiation treatment after surgical management of cutaneous malignancies and potential modification of immunosuppressive medication regimens are discussed.
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Affiliation(s)
- Reason Wilken
- The Ronald O. Perelman Department of Dermatology, NYU Langone Health, New York, New York
| | - John Carucci
- The Ronald O. Perelman Department of Dermatology, NYU Langone Health, New York, New York
| | - Mary L Stevenson
- The Ronald O. Perelman Department of Dermatology, NYU Langone Health, New York, New York
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23
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Buxeda A, Redondo-Pachón D, Pérez-Sáez MJ, Crespo M, Pascual J. Sex differences in cancer risk and outcomes after kidney transplantation. Transplant Rev (Orlando) 2021; 35:100625. [PMID: 34020178 DOI: 10.1016/j.trre.2021.100625] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 02/06/2023]
Abstract
Kidney transplant recipients (KTRs) experience a two- to four-fold increased risk of developing and dying from cancer compared with the general population. High cancer risk results from the interaction of both modifiable and non-modifiable factors. This mapping review explores the impact of sex disparity on cancer's increased incidence and mortality after kidney transplantation (KT). In terms of age, population-based studies indicate that younger recipients of both sexes experience a higher risk of cancer, but this is more pronounced in young women. On the contrary, older men are more likely to be diagnosed with cancer, although their increased risk is not statistically significant compared with the general population. Regarding cancer type, studies show an increased risk of Kaposi sarcoma, gynecologic and lung cancer in women, and bladder and kidney cancer in men. Immune-related cancers such as pos-transplant lymphoproliferative disorders and melanoma are increased in both sexes. Mortality also shows differences between sexes. Although cancer is the second cause of death in both male and female KTRs, studies show higher overall mortality in men and elderly recipients. However, the relative risk of cancer mortality compared with the general population is higher at a younger age, with disparate results regarding sex. Female KTRs appear to die at a younger age than males when compared with the general population. Differences in cancer rates by sex after renal transplantation need further studies. A better understanding of sex-specific differences in cancer epidemiology after KT could help nephrologists to better address pre-transplant counseling, to establish early surveillance programs, and to plan modifiable risk factors such as immunosuppression.
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Affiliation(s)
- Anna Buxeda
- Department of Nephrology, Hospital del Mar, Barcelona, Spain.
| | | | | | - Marta Crespo
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
| | - Julio Pascual
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
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Murray SL, Daly FE, O'Kelly P, O'Leary E, Deady S, O'Neill JP, Dudley A, Rutledge NR, McCormick A, Houlihan DD, Williams Y, Morris PG, Ni Raghallaigh S, Moloney FJ, Sexton DJ, Conlon PJ. The impact of switching to mTOR inhibitor-based immunosuppression on long-term non-melanoma skin cancer incidence and renal function in kidney and liver transplant recipients. Ren Fail 2021; 42:607-612. [PMID: 32605413 PMCID: PMC7946013 DOI: 10.1080/0886022x.2020.1785499] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Solid organ transplantation is associated with increased risk of non-melanoma skin cancer. Studies with short follow up times have suggested a reduced occurrence of these cancers in recipients treated with mammalian target of rapamycin inhibitors as maintenance immunosuppression. We aimed to describe the occurrence of skin cancers in renal and liver transplant recipients switched from calcineurin inhibitor to sirolimus-based regimes. Methods We performed a retrospective study of sirolimus conversion within the Irish national kidney and liver transplant programs. These data were linked with the National Cancer Registry Ireland to determine the incidence of NMSC among these recipients. The incidence rate ratio (IRR) for post versus pre-conversion NMSC rates are referred in this study as an effect size with [95% confidence interval]. Results Of 4,536 kidney transplants and 574 liver transplants functioning on the 1 January 1994 or transplanted between 1 January 1994 and 01 January 1994 and 01 January 2015, 85 kidney and 88 liver transplant recipients were transitioned to sirolimus-based immunosuppression. In renal transplants, the rate of NMSC was 131 per 1000 patient years pre-switch to sirolimus, and 68 per 1000 patient years post switch, with adjusted effect size of 0.48 [0.31 − 0.74] (p = .001) following the switch. For liver transplant recipients, the rate of NMSC was 64 per 1,000 patient years pre-switch and 30 per 1,000 patient years post switch, with an adjusted effect size of 0.49 [0.22 − 1.09] (p .081). Kidney transplant recipients were followed up for a median 3.4 years. Liver transplants were followed for a median 6.6 years. Conclusions In this study, the conversion of maintenance immunosuppression from calcineurin inhibitors to mTOR inhibitors for clinical indications did appear to reduce the incidence of NMSC in kidney and liver transplant recipients.
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Affiliation(s)
- Susan L Murray
- Department of Nephrology & Transplantation, Beaumont Hospital, Dublin, Ireland.,Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Fergus E Daly
- Department of Nephrology & Transplantation, Beaumont Hospital, Dublin, Ireland
| | - Patrick O'Kelly
- Department of Nephrology & Transplantation, Beaumont Hospital, Dublin, Ireland
| | - Eamonn O'Leary
- National Cancer Registry Ireland, Cork Airport Business Park, Cork, Ireland
| | - Sandra Deady
- National Cancer Registry Ireland, Cork Airport Business Park, Cork, Ireland
| | - James P O'Neill
- Department of Otolaryngology, Head & Neck Surgery, Beaumont Hospital, and Royal College of Surgeons, Ireland, Ireland
| | - Alexander Dudley
- Hepatology & Liver Transplant Department, St Vincent's University Hospital, Dublin, Ireland
| | - Nicholas R Rutledge
- Hepatology & Liver Transplant Department, St Vincent's University Hospital, Dublin, Ireland
| | - Aiden McCormick
- Hepatology & Liver Transplant Department, St Vincent's University Hospital, Dublin, Ireland
| | - Diarmuid D Houlihan
- Hepatology & Liver Transplant Department, St Vincent's University Hospital, Dublin, Ireland
| | - Yvonne Williams
- Department of Nephrology & Transplantation, Beaumont Hospital, Dublin, Ireland
| | | | | | - Fergal J Moloney
- Department of Dermatology, Mater Misericordia University Hospital University College, Dublin, Ireland
| | - Donal J Sexton
- Department of Nephrology & Transplantation, Beaumont Hospital, Dublin, Ireland
| | - Peter J Conlon
- Department of Nephrology & Transplantation, Beaumont Hospital, Dublin, Ireland.,Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
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25
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Growth and Viability of Cutaneous Squamous Cell Carcinoma Cell Lines Display Different Sensitivities to Isoform-Specific Phosphoinositide 3-Kinase Inhibitors. Int J Mol Sci 2021; 22:ijms22073567. [PMID: 33808215 PMCID: PMC8036316 DOI: 10.3390/ijms22073567] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 03/19/2021] [Indexed: 12/20/2022] Open
Abstract
Cutaneous squamous cell carcinomas (cSCCs) account for about 20% of keratinocyte carcinomas, the most common cancer in the UK. Therapeutic options for cSCC patients who develop metastasis are limited and a better understanding of the biochemical pathways involved in cSCC development/progression is crucial to identify novel therapeutic targets. Evidence indicates that the phosphoinositide 3-kinases (PI3Ks)/Akt pathway plays an important role, in particular in advanced cSCC. Questions remain of whether all four PI3K isoforms able to activate Akt are involved and whether selective inhibition of specific isoform(s) might represent a more targeted strategy. Here we determined the sensitivity of four patient-derived cSCC cell lines to isoform-specific PI3K inhibitors to start investigating their potential therapeutic value in cSCC. Parallel experiments were performed in immortalized keratinocyte cell lines. We observed that pan PI3Ks inhibition reduced the growth/viability of all tested cell lines, confirming the crucial role of this pathway. Selective inhibition of the PI3K isoform p110α reduced growth/viability of keratinocytes and of two cSCC cell lines while affecting the other two only slightly. Importantly, p110α inhibition reduced Akt phosphorylation in all cSCC cell lines. These data indicate that growth and viability of the investigated cSCC cells display differential sensitivity to isoform-specific PI3K inhibitors.
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Préterre J, Visentin J, Saint Cricq M, Kaminski H, Del Bello A, Prezelin-Reydit M, Merville P, Kamar N, Couzi L. Comparison of two strategies based on mammalian target of rapamycin inhibitors in secondary prevention of non-melanoma skin cancer after kidney transplantation, a pilot study. Clin Transplant 2021; 35:e14207. [PMID: 33369772 DOI: 10.1111/ctr.14207] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 12/10/2020] [Accepted: 12/16/2020] [Indexed: 01/05/2023]
Abstract
After kidney transplantation, withdrawal of calcineurin inhibitors (CNI) and conversion to sirolimus (SRL) may reduce the occurrence of new non-melanoma skin cancer (NMSC). Conversely, a reduced CNI exposure with everolimus (EVR) is an alternative strategy that has not been thoroughly evaluated. We retrospectively compared the occurrence of newly diagnosed NMSCs in two cohorts of kidney transplant recipients (KTR) with at least one NMSC: 35 patients were converted to EVR with reduced CNI exposure (CNI/EVR group), whereas 46 patients were converted to SRL in association with mycophenolic acid (MPA) (SRL/MPA group). Two years after conversion, survival free of new NMSC was similar between the two cohorts (p = .37), with 19 KTR (54.3%) in the CNI/EVR group and 22 (47.8%) in the SRL/MPA group being diagnosed of at least one new NMSC. Half of the KTR from both groups showed adverse events, leading to mTORi discontinuation for 37.1% of KTR in the CNI/EVR group and 21.7% in the SRL/MPA group (p = .09). The incidence of rejections was similar between the two groups. In a retrospective cohort of KTR with at least one post-transplant NMSC, the outcome of the patients converted to a CNI/EVR regimen was not different from those converted to a SRL/MPA regimen.
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Affiliation(s)
- Julie Préterre
- CHU de Bordeaux, Service de Néphrologie-Transplantation-Dialyse-Aphérèse, Hôpital Pellegrin, Bordeaux, France
| | - Jonathan Visentin
- CHU de Bordeaux, Service d'Immunologie et Immunogénétique, Hôpital Pellegrin, Bordeaux, France.,Université de Bordeaux, CNRS "ImmunoConcEpT" UMR 5164, Bordeaux, France
| | - Morgane Saint Cricq
- Department of Nephrology, Dialysis and Organ Transplantation, Hôpital Rangueil, CHU de Toulouse, Toulouse, France
| | - Hannah Kaminski
- CHU de Bordeaux, Service de Néphrologie-Transplantation-Dialyse-Aphérèse, Hôpital Pellegrin, Bordeaux, France.,Université de Bordeaux, CNRS "ImmunoConcEpT" UMR 5164, Bordeaux, France
| | - Arnaud Del Bello
- Department of Nephrology, Dialysis and Organ Transplantation, Hôpital Rangueil, CHU de Toulouse, Toulouse, France.,Centre de Physiopathologie Toulouse Purpan, University Paul Sabatier, INSERM U1043, Toulouse, France
| | - Mathilde Prezelin-Reydit
- CHU de Bordeaux, Service de Néphrologie-Transplantation-Dialyse-Aphérèse, Hôpital Pellegrin, Bordeaux, France
| | - Pierre Merville
- CHU de Bordeaux, Service de Néphrologie-Transplantation-Dialyse-Aphérèse, Hôpital Pellegrin, Bordeaux, France.,Université de Bordeaux, CNRS "ImmunoConcEpT" UMR 5164, Bordeaux, France
| | - Nassim Kamar
- Department of Nephrology, Dialysis and Organ Transplantation, Hôpital Rangueil, CHU de Toulouse, Toulouse, France.,Centre de Physiopathologie Toulouse Purpan, University Paul Sabatier, INSERM U1043, Toulouse, France
| | - Lionel Couzi
- CHU de Bordeaux, Service de Néphrologie-Transplantation-Dialyse-Aphérèse, Hôpital Pellegrin, Bordeaux, France.,Université de Bordeaux, CNRS "ImmunoConcEpT" UMR 5164, Bordeaux, France
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Lim LM, Kung LF, Kuo MC, Huang AM, Kuo HT. Timing of mTORI usage and outcomes in kidney transplant recipients. Int J Med Sci 2021; 18:1179-1184. [PMID: 33526978 PMCID: PMC7847621 DOI: 10.7150/ijms.53655] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 12/18/2020] [Indexed: 12/17/2022] Open
Abstract
The introduction of mammalian target of rapamycin inhibitors (mTORi) as immunosuppressive agents has changed the landscape of calcineurin inhibitor-based immunosuppressive regimens. However, the timing of mTORi conversion and its associated outcomes in kidney transplantation have conflicting results. This study investigated the effect of early or late mTORi post-transplant initiation on major transplant outcomes, including post-transplant malignancy, in kidney transplant recipients in our center. We enrolled 201 kidney transplant recipients with surviving function grafts of >3 months between 1983 and 2016. Patients were divided into three groups: early mTORi (initiated within 6 months of kidney transplantation), late mTORi, (mTORi initiation >6 months after kidney transplantation) and no mTORi. The mean creatinine at conversion was 1.46 ± 0.48 mg/dL and 1.30 ± 0.53 mg/dL for the early and late mTORi groups, respectively. During the study period, 10.5% of mTORi users and 19.2% of mTORi nonusers developed malignancy, mainly urothelial carcinoma. After adjustment for confounding factors, mTORi users were found to have a lower incidence of post-transplant malignancy than did nonusers (adjusted OR: 0.28, P = 0.04). No significant difference was observed between early and late mTORi users. Our results verified the potential advantages of mTORi usage in reducing cancer incidence after kidney transplantation. However, no significant result was found related to the timing of mTORi introduction. Future studies should include a longer observation period with a larger cohort.
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Affiliation(s)
- Lee-Moay Lim
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Lan-Fang Kung
- Department of Nursing, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Mei-Chuan Kuo
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.,Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - A-Mei Huang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Biochemistry, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hung-Tien Kuo
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.,Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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29
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Naik MG, Arns W, Budde K, Diekmann F, Eitner F, Gwinner W, Heyne N, Jürgensen JS, Morath C, Riester U, Heller KM, Fischereder M. Sirolimus in renal transplant recipients with malignancies in Germany. Clin Kidney J 2020; 14:2047-2058. [PMID: 34476091 PMCID: PMC8406058 DOI: 10.1093/ckj/sfaa262] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 11/23/2020] [Indexed: 12/29/2022] Open
Abstract
Background Renal transplant recipients have an increased cancer risk. The mammalian target of rapamycin inhibitor sirolimus (SRL) has immunosuppressive and antitumour activities but knowledge about its use in recipients with cancer is limited. Methods We retrospectively analysed 726 renal allograft recipients converted to SRL from 10 German transplant centres. Patient and graft survival were analysed depending on malignancy status prior to conversion and tumour entity. Results Malignancy before conversion to SRL was reported in 230 patients, with 137 patients having skin cancers and 101 having solid cancers. Cancer occurred 4.6 ± 9.4 (median 3.0) years after transplantation. Basal cell carcinoma, squamous cell carcinoma and Bowen’s disease were the most prevalent skin cancers, while carcinomas of the kidney, colon and breast were the most prevalent solid cancers before conversion. Patients with prior malignancy were older and had better renal function at conversion compared with patients without a history of cancer. After conversion to SRL, cancer incidence rates (IRs) of all tumours were lower compared with rates before conversion. Cancer IRs after conversion were higher in patients with malignancy before conversion compared with those without. Patient survival was worse in patients with solid cancers compared with patients with skin cancers or without malignancies. Biopsy-proven acute rejections in the first year after conversion were less frequent in patients with malignancy compared with those without. Graft survival and renal function in all cancer types were better than in patients converted to SRL without cancers. Conclusions Conversion to SRL in patients with a history of cancer is safe regarding renal function and graft survival, while patient survival is largely dependent on tumour entity.
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Affiliation(s)
- Marcel G Naik
- Division of Nephrology, Charité University-Mitte, Berlin, Germany.,Berliner Institut für Gesundheitsforschung/Berlin Institute of Health (BIH) Körperschaft des öffentlichen Rechts Anna-Louisa-Karsch-Str. 2 10178 Berlinn, Germany
| | - Wolfgang Arns
- Transplant Centre Cologne, Cologne General Hospital, Cologne, Germany
| | - Klemens Budde
- Division of Nephrology, Charité University-Mitte, Berlin, Germany
| | - Fritz Diekmann
- Department of Nephrology and Kidney Transplantation, Hospital Clinic, Barcelona, Spain
| | - Frank Eitner
- Division of Nephrology and Immunology, Kidney Diseases Research, RWTH Aachen University Hospital, Bayer AG, Wuppertal, Germany
| | - Wilfried Gwinner
- Division of Nephrology, Hannover Medical School, Hannover, Germany
| | - Nils Heyne
- Division of Nephrology, University of Tübingen, Tübingen, Germany
| | | | - Christian Morath
- Division of Nephrology, University of Heidelberg, Heidelberg, Germany
| | | | - Katharina M Heller
- Department of Medicine, Division of Nephrology, University of Erlangen, Erlangen, Germany
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González-Cruz C, Ferrándiz-Pulido C, García-Patos Briones V. Melanoma in Solid Organ Transplant Recipients. ACTAS DERMO-SIFILIOGRAFICAS 2020; 112:216-224. [PMID: 33197437 DOI: 10.1016/j.ad.2020.11.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 10/20/2020] [Accepted: 11/02/2020] [Indexed: 12/19/2022] Open
Abstract
In this review, we analyze the 3 clinical scenarios related to the development of melanoma in solid organ transplant recipients: melanoma in patients with a history of the tumor prior to a transplant, de novo melanoma following a transplant, and melanoma of donor origin. The main factors to consider in organ-transplant candidates with a history of melanoma are tumor stage, presence or absence of residual disease, and time from diagnosis to transplantation. Solid organ transplant recipients have a greater risk of melanoma than immunocompetent individuals. Mortality is also higher in this population, especially in patients with advanced melanoma, as treatment is especially challenging. Clinical history and physical examination provide the most useful information for preventing donor-to-recipient transmission of melanoma. Donor-derived melanoma has a very poor prognosis.
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Affiliation(s)
- C González-Cruz
- Servicio de Dermatología, Hospital Universitari Vall d'Hebron. Facultad de Medicina, Universitat Autònoma de Barcelona, Barcelona, España.
| | - C Ferrándiz-Pulido
- Servicio de Dermatología, Hospital Universitari Vall d'Hebron. Facultad de Medicina, Universitat Autònoma de Barcelona, Barcelona, España
| | - V García-Patos Briones
- Servicio de Dermatología, Hospital Universitari Vall d'Hebron. Facultad de Medicina, Universitat Autònoma de Barcelona, Barcelona, España
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Abstract
Cancer is an important cause of morbidity and mortality after liver transplantation and can occur through three mechanisms: recurrence of a recipient's pre-transplant malignancy, donor-related transmission and de novo development. Currently, the decision to list a patient with a history of malignancy is an individual one. Screening guidelines for potential donors and for recipients after transplant are still widely based on general population guidelines, while the role of chronic immunosuppression remains controversial. These shortcomings mean that patients present at diagnosis with advanced stages of the disease, often precluding curative treatments. The present review summarizes current recommendations for the screening of recipients and donors for pre- and post-transplant malignancies, and current management of recipients who develop cancer after a liver transplant.
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He B, Ng ZQ, Mou L, Delriviere L, Jaques B, Tuke J, Musk GC, Lim W. Long-term outcome of kidney transplant by using restored kidney grafts after tumour ex vivo excision - a prospective study. Transpl Int 2020; 33:1253-1261. [PMID: 32589771 DOI: 10.1111/tri.13682] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/26/2020] [Accepted: 06/22/2020] [Indexed: 01/10/2023]
Abstract
The aim of this study is to report long-term outcomes of kidney transplantation by using the kidney graft after a small tumour ex vivo excision. A structured programme was established to use the restored kidney graft from urological referral after radical nephrectomy. The criteria were defined as tumour size ≤3 cm, margin clear on frozen section and recipients aged ≥60 years or those on the urgent list for transplantation as a result of imminent lack of dialysis access. The recipients were followed up regularly for surveillance of tumour recurrence. Between February 2007 and February 2018, 28 recipients had kidney transplantation by using the restored kidney grafts. The tumour size was 2.6 ± 0.7 cm. The follow-up was median 7 years without evidence of tumour recurrence. The patient and graft survival was satisfactory. Kidney transplantation by using restored kidneys after a small tumour excision is a novel source for selected recipients. The long-term patient and graft survival is satisfactory. Although there is a risk of tumour recurrence, it is rare event. Together with literature review, we would support use of kidney graft after a small tumour excision for selected recipients.
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Affiliation(s)
- Bulang He
- WA Liver and Kidney Transplant Service, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.,Faculty of Health and Medical Sciences, Medical School, The University of Western Australia, Crawley, WA, Australia.,Alfred Hospital, Monash University, Prahran, Vic., Australia
| | - Zi Qin Ng
- WA Liver and Kidney Transplant Service, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
| | - Lingjun Mou
- WA Liver and Kidney Transplant Service, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
| | - Luc Delriviere
- WA Liver and Kidney Transplant Service, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.,Faculty of Health and Medical Sciences, Medical School, The University of Western Australia, Crawley, WA, Australia
| | - Bryon Jaques
- WA Liver and Kidney Transplant Service, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.,Faculty of Health and Medical Sciences, Medical School, The University of Western Australia, Crawley, WA, Australia
| | - Jonathan Tuke
- School of Mathematical Sciences, University of Adelaide, Adelaide, SA, Australia
| | - Gabrielle C Musk
- Animal Care Services, The University of Western Australia, Crawley, WA, Australia
| | - Wai Lim
- Faculty of Health and Medical Sciences, Medical School, The University of Western Australia, Crawley, WA, Australia.,Department of Nephrology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
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Determinants of Successful Use of Sirolimus in Renal Transplant Patients. Transplant Proc 2020; 52:3103-3111. [PMID: 32493677 DOI: 10.1016/j.transproceed.2020.02.159] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 02/13/2020] [Indexed: 01/03/2023]
Abstract
BACKGROUND Sirolimus is an established immunosuppressant in renal transplantation with antineoplastic and antiviral features, but side effects like proteinuria limit its use. The aim of this retrospective multicenter observational study is to define predictors for determining which patients most likely benefit from a sirolimus-based therapy. METHODS All patients from 10 German centers that were switched to a sirolimus-containing maintenance immunosuppression in 2000 to 2008 after 3 months or later post-transplantation were enrolled (n = 726). Observation times after switching to sirolimus ranged from 4 days to 9 years (median: 24.3 months). With multinomial logistic regression, risk factors for the endpoints terminal graft failure and withdrawal of sirolimus therapy compared to successful therapy were identified. RESULTS Successful sirolimus therapy was observed in 304 patients. Forty patients died with functioning graft. Therapy failures included graft loss (n = 106) and sirolimus-discontinuation for various reasons (n = 276). Successful sirolimus-use was predicted in 83% and graft failure in 65%, whereas prediction of deliberate sirolimus-discontinuation was poor (48%). Most favorable results for sirolimus-use were observed in patients switched in 2006 to 2008. Using ROC analysis, an estimated glomerular filtration rate (eGFR) below 32 mL/min was shown to be the cut-off in patients withdrawing from therapy as a result of renal reasons, as well as in patients with graft loss. Proteinuria above 151 mg/L was shown to be predictive for patients with graft failure. CONCLUSIONS eGFR and proteinuria are the major determinants for successful sirolimus-therapy. Our findings help stratifying patients who will benefit most from this therapy and avoid toxicities in patients without potential benefits for this therapy.
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Lopez-Soler RI, Chen P, Nair L, Ata A, Patel S, Conti DJ. Sirolimus use improves cancer-free survival following transplantation: A single center 12-year analysis. TRANSPLANTATION REPORTS 2020. [DOI: 10.1016/j.tpr.2020.100040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Interventions to Prevent Nonmelanoma Skin Cancers in Recipients of a Solid Organ Transplant: Systematic Review of Randomized Controlled Trials. Transplantation 2020; 103:1206-1215. [PMID: 31246934 DOI: 10.1097/tp.0000000000002641] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Organ transplant recipients are at high risk of developing skin cancer. The benefits and harms of interventions to prevent nonmelanoma skin cancer in solid organ transplant recipients have not been summarized. METHODS We searched MEDLINE, Embase, and CENTRAL through April 2018. Risk of bias was assessed using the Cochrane tool, and evidence certainty was evaluated using the Grades of Recommendation, Assessment, Development, and Evaluation process. Prespecified outcomes were nonmelanoma skin cancer, clearance and prevention of keratotic skin lesions, and intervention-specific adverse events. RESULTS Ninety-two trials (20 012 participants) were included. The evaluated treatments were cancer-specific interventions (acitretin, imiquimod, photodynamic therapy, nicotinamide, topical diclofenac, and selenium) and immunosuppression regimes (azathioprine, mycophenolate mofetil, calcineurin inhibitors, mammalian target of rapamycin [mTOR] inhibitors, belatacept, induction agents, and withdrawal of calcineurin inhibitors or corticosteroids). Effects on nonmelanoma skin cancer were uncertain for photodynamic therapy (3 trials, 93 participants, risk ratio [RR] 1.42 [95% confidence interval (CI), 0.65-3.11]; low certainty evidence), nicotinamide (2 trials, 60 participants), acitretin (2 trials, 61 participants), and imiquimod (1 trial, 20 participants) compared to control. mTOR inhibitors probably reduced skin cancer compared to calcineurin inhibitors (12 trials, 2225 participants, RR 0.62 [95% CI, 0.45-0.85]; moderate certainty evidence). Photodynamic therapy may cause pain at the treatment site (4 trials, 95 patients, RR 17.09 [95% CI, 4.22-69.26]; low certainty evidence). CONCLUSIONS There is limited evidence for the efficacy and safety of specific treatments to prevent nonmelanoma skin cancers among solid organ transplant recipients.
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James LJ, Saglimbene V, Wong G, Tong A, Luu LDW, Craig J, Howard K, Howell M. Behavioural and pharmaceutical interventions for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomised controlled trials. BMJ Open 2020; 10:e029265. [PMID: 32423925 PMCID: PMC7239542 DOI: 10.1136/bmjopen-2019-029265] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVES Solid organ transplant recipients are at increased risk of skin cancer, affecting more than 50% of recipients. We aimed to determine the effectiveness of interventions for behavioural change for sun protection or skin cancer prevention in solid organ transplant recipients. DESIGN Systematic review. DATA SOURCES We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL) and CINAHL from inception to November 2019. ELIGIBILITY CRITERIA We included randomised controlled trials that evaluated the effect of behavioural or pharmaceutical interventions on behavioural change or skin cancer prevention in solid organ transplant recipients. DATA EXTRACTION AND SYNTHESIS Risks of bias and evidence certainty were assessed using Cochrane and the Grading of Recommendations Assessment Development and Evaluation framework. RESULTS Twenty trials (n=2295 participants) were included. It is uncertain whether behavioural interventions improve sun protection behaviour (n=3, n=414, standardised mean difference (SMD) 0.89, 95% CI -0.84 to 2.62, I2=98%) and knowledge (n=4, n=489, SMD 0.50, 95% CI 0.12 to 0.87, I2= 76%) as the quality of evidence is very low. We are uncertain of the effects of mammalian target of rapamaycin inhibitors on the incidence of non-melanocytic skin cancer (n=5, n=1080, relative risk 0.46, 95% CI 0.28 to 0.75, I2 =72%) as the quality of evidence is very low. CONCLUSIONS Behavioural and pharmaceutical preventive interventions may improve sun protective behaviour and knowledge, and reduce the incidence of non-melanocytic skin cancer, but the overall quality of the evidence is very low and insufficient to guide decision-making and clinical practice. PROSPERO REGISTRATION NUMBER CRD42017063962.
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Affiliation(s)
- Laura J James
- Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia
- Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
| | - Valeria Saglimbene
- Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia
- Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
| | - Germaine Wong
- Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia
- Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
- Centre for Transplant and Renal Research, Westmead Hospital, Westmead, NSW, Australia
| | - Allison Tong
- Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia
- Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
| | - Laurence Don Wai Luu
- Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia
- Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
| | - Jonathan Craig
- College of Medicine and Public Health, Flinders University Faculty of Medicine Nursing and Health Sciences, Adelaide, South Australia, Australia
| | - Kirsten Howard
- Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Martin Howell
- Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia
- Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
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Malignancy After Lung Transplantation: How to Manage Immunosuppression? Transplant Proc 2020; 52:315-320. [DOI: 10.1016/j.transproceed.2019.09.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 08/29/2019] [Accepted: 09/26/2019] [Indexed: 02/07/2023]
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Cucchiari D, Ríos J, Molina-Andujar A, Montagud-Marrahi E, Revuelta I, Ventura-Aguiar P, Piñeiro GJ, De Sousa-Amorim E, Esforzado N, Cofán F, Torregrosa JV, Ugalde-Altamirano J, Ricart MJ, Rovira J, Torres F, Solè M, Campistol JM, Diekmann F, Oppenheimer F. Combination of calcineurin and mTOR inhibitors in kidney transplantation: a propensity score analysis based on current clinical practice. J Nephrol 2019; 33:601-610. [PMID: 31853792 DOI: 10.1007/s40620-019-00675-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Accepted: 11/18/2019] [Indexed: 12/12/2022]
Abstract
INTRODUCTION The TRANSFORM study demonstrated that an immunosuppression based on a combination of calcineurin inhibitors and de-novo mTOR inhibitors (mTORi) is safe and effective in kidney transplant recipients. However, data that validate this approach in clinical practice are currently missing. MATERIALS AND METHODS Analysis of 401 kidney transplant recipients transplanted from June 2013 to December 2016. All patients received tacrolimus with prednisone in combination with either mycophenolate (n = 186) or mTORi (either everolimus or sirolimus, n = 215). A propensity score to receive mTORi was calculated based on the inverse probability of treatment weighting (IPTW) from the following parameters: age and sex of donor and recipient, BMI, previous transplants, diabetes, cPRA, dialysis before transplantation, dialysis vintage, type of donor, ABO-incompatibility, HLA-mismatches, induction and ischemia time. Median follow-up was 2.6 [1.9; 3.7] years. RESULTS Cox-regression analysis suggests good results for mTORi versus MPA in terms of 1-year biopsy-proven acute rejection (BPAR, P = 0.063), 1-year graft loss (P = 0.025) and patient survival (P < 0.001). Results observed for BPAR and graft failure were largely attributed to those patients that would have been excluded by the TRANSFORM because of some exclusion criteria (52.9% of the population, P = 0.003 for 1-year BPAR and P = 0.040 for graft loss). In patients who met selection criteria for TRANSFORM, no effect of treatment for BPAR or graft failure was observed, while the beneficial effect on overall survival persisted. CONCLUSIONS In a real-life setting, a protocol based on de-novo mTORi with tacrolimus and prednisone could be employed as a standard immunosuppressive regimen and was associated with good outcomes.
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Affiliation(s)
- David Cucchiari
- Renal Transplant Unit, Hospital Clínic, Carrer Villaroel 170, 08023, Barcelona, Spain.
| | - José Ríos
- Medical Statistics Core Facility, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Alicia Molina-Andujar
- Renal Transplant Unit, Hospital Clínic, Carrer Villaroel 170, 08023, Barcelona, Spain
| | | | - Ignacio Revuelta
- Renal Transplant Unit, Hospital Clínic, Carrer Villaroel 170, 08023, Barcelona, Spain
- Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Red de Investigación Renal (REDINREN), Madrid, Spain
| | - Pedro Ventura-Aguiar
- Renal Transplant Unit, Hospital Clínic, Carrer Villaroel 170, 08023, Barcelona, Spain
| | - Gastón J Piñeiro
- Renal Transplant Unit, Hospital Clínic, Carrer Villaroel 170, 08023, Barcelona, Spain
| | - Erika De Sousa-Amorim
- Renal Transplant Unit, Hospital Clínic, Carrer Villaroel 170, 08023, Barcelona, Spain
| | - Nuria Esforzado
- Renal Transplant Unit, Hospital Clínic, Carrer Villaroel 170, 08023, Barcelona, Spain
| | - Frederic Cofán
- Renal Transplant Unit, Hospital Clínic, Carrer Villaroel 170, 08023, Barcelona, Spain
| | | | | | - Maria José Ricart
- Renal Transplant Unit, Hospital Clínic, Carrer Villaroel 170, 08023, Barcelona, Spain
| | - Jordi Rovira
- Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Red de Investigación Renal (REDINREN), Madrid, Spain
| | - Ferran Torres
- Medical Statistics Core Facility, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Manel Solè
- Pathology Unit, Hospital Clínic, Barcelona, Spain
| | - Josep M Campistol
- Renal Transplant Unit, Hospital Clínic, Carrer Villaroel 170, 08023, Barcelona, Spain
| | - Fritz Diekmann
- Renal Transplant Unit, Hospital Clínic, Carrer Villaroel 170, 08023, Barcelona, Spain.
- Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
- Red de Investigación Renal (REDINREN), Madrid, Spain.
| | - Frederic Oppenheimer
- Renal Transplant Unit, Hospital Clínic, Carrer Villaroel 170, 08023, Barcelona, Spain
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Pontrelli P, Rascio F, Zaza G, Accetturo M, Simone S, Infante B, Furian L, Castellano G, Ditonno P, Battaglia M, Cormio L, Carrieri G, Lupo A, Rigotti P, Gesualdo L, Stallone G, Grandaliano G. Interleukin-27 is a potential marker for the onset of post-transplant malignancies. Nephrol Dial Transplant 2019; 34:157-166. [PMID: 30059989 DOI: 10.1093/ndt/gfy206] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 05/21/2018] [Indexed: 12/12/2022] Open
Abstract
Background Malignancies represent the third leading cause of post-transplant mortality worldwide. The main challenge for transplant physicians is a timely diagnosis of this condition. The aim of the study was to identify a soluble diagnostic marker for monitoring the development of post-transplant malignancies. Methods This is a multicentre, observational, perspective, case-control study. We enrolled 47 patients with post-transplant solid neoplasia. As a control group we employed 106 transplant recipients without a history of neoplasia and matched them with cases for the main demographic and clinical features. We investigated the transcriptomic profiles of peripheral blood mononuclear cells from kidney graft recipients with and without post-transplant malignancies enrolled in two of the participating centres, randomly selected from the whole study population. Microarray results were confirmed by quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) in the remaining patients from the same transplant centres and validated in a further independent group enrolled in two different transplant centres. Results We identified 535 differentially expressed genes comparing patients with and without post-transplant malignancies (fold change ≥2.5; false discovery rate <5%). The cancer pathway was closely related to gene expression data, and one of the most down-regulated genes in this pathway was interleukin-27 (IL-27), a cytokine regulating anti-tumour immunity. Quantitative PCR and ELISA confirmed the microarray data. Interestingly, IL-27 plasma levels were able to discriminate patients with post-transplant neoplasia with a specificity of 80% and a sensitivity of 81%. This observation was confirmed in an independent set of patients from two different transplant centres. Conclusions Our data suggest that IL-27 may represent a potential immunological marker for the timely identification of post-transplant neoplasia.
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Affiliation(s)
- Paola Pontrelli
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Federica Rascio
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gianluigi Zaza
- Department of Clinical Medicine, University of Verona, Verona, Italy
| | - Matteo Accetturo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Simona Simone
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Barbara Infante
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Lucrezia Furian
- Kidney and Pancreas Transplantation Unit, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Pasquale Ditonno
- Andrology, Urology and Kidney Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Michele Battaglia
- Andrology, Urology and Kidney Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Luigi Cormio
- Urology and Kidney Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Giuseppe Carrieri
- Urology and Kidney Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Antonio Lupo
- Department of Clinical Medicine, University of Verona, Verona, Italy
| | - Paolo Rigotti
- Kidney and Pancreas Transplantation Unit, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Giuseppe Grandaliano
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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Tran AP, Martins PN, Papazian ZG, Vanguri VK, Movahedi B, Fan PY, Bodziak KA, Yates JK, Sokoloff MH, Bozorgzadeh A. Transplantation of Renal Allograft After Removal of Renal Cell Carcinoma: Case Report and Review of the Literature. EXP CLIN TRANSPLANT 2019; 19:732-735. [PMID: 31580237 DOI: 10.6002/ect.2018.0215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
With the rising incidence of end-stage renal disease in the United States, patients needing renal transplants are waiting longer for increasingly scarce grafts. Formerly, the general practice was to avoid organs with tumors for transplant because of the risk of malignancy transmission to the recipient. However, with comprehensive donor selection and a small-sized primary tumor, the positive outcomes of transplant outweigh the risks of transmission after a partial nephrectomy. In our case, a 31-year-old woman, the daughter of the recipient, underwent a laparoscopic nephrectomy with an existing 8-mm tumor later confirmed as renal cell carcinoma. An ex vivo tumor enucleation was performed before the allograft was transplanted into the 69-year-old patient with endstage renal disease. At last follow-up, graft function has remained excellent with no evidence of local recurrence or metastasis in both the donor and recipient. Here, we describe our case and perform a literature review on the incidence and management of renal allografts with incidentally detected renal cell carcinoma during transplant.
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Affiliation(s)
- Anthony P Tran
- From the Department of Surgery, Division of Organ Transplantation, University of Massachusetts Medical School and UMass Memorial Medical Center, Worcester, Massachusetts, USA
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Mammalian Target of Rapamycin Inhibitors Combined With Calcineurin Inhibitors as Initial Immunosuppression in Renal Transplantation: A Meta-analysis. Transplantation 2019; 103:2031-2056. [DOI: 10.1097/tp.0000000000002769] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Manzia TM, Angelico R, Gazia C, Lenci I, Milana M, Ademoyero OT, Pedini D, Toti L, Spada M, Tisone G, Baiocchi L. De novo malignancies after liver transplantation: The effect of immunosuppression-personal data and review of literature. World J Gastroenterol 2019; 25:5356-5375. [PMID: 31558879 PMCID: PMC6761240 DOI: 10.3748/wjg.v25.i35.5356] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 08/08/2019] [Accepted: 08/24/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Immunosuppression has undoubtedly raised the overall positive outcomes in the post-operative management of solid organ transplantation. However, long-term exposure to immunosuppression is associated with critical systemic morbidities. De novo malignancies following orthotopic liver transplants (OLTs) are a serious threat in pediatric and adult transplant individuals. Data from different experiences were reported and compared to assess the connection between immunosuppression and de novo malignancies in liver transplant patients. AIM To study the role of immunosuppression on the incidence of de novo malignancies in liver transplant recipients. METHODS A systematic literature examination about de novo malignancies and immunosuppression weaning in adult and pediatric OLT recipients was described in the present review. Worldwide data were collected from highly qualified institutions performing OLTs. Patient follow-up, immunosuppression discontinuation and incidence of de novo malignancies were reported. Likewise, the review assesses the differences in adult and pediatric recipients by describing the adopted immunosuppression regimens and the different type of diagnosed solid and blood malignancy. RESULTS Emerging evidence suggests that the liver is an immunologically privileged organ able to support immunosuppression discontinuation in carefully selected recipients. Malignancies are often detected in liver transplant patients undergoing daily immunosuppression regimens. Post-transplant lymphoproliferative diseases and skin tumors are the most detected de novo malignancies in the pediatric and adult OLT population, respectively. To date, immunosuppression withdrawal has been achieved in up to 40% and 60% of well-selected adult and pediatric recipients, respectively. In both populations, a clear benefit of immunosuppression weaning protocols on de novo malignancies is difficult to ascertain because data have not been specified in most of the clinical experiences. CONCLUSION The selected populations of tolerant pediatric and adult liver transplant recipients greatly benefit from immunosuppression weaning. There is still no strong clinical evidence on the usefulness of immunosuppression withdrawal in OLT recipients on malignancies. An interesting focus is represented by the complete reconstitution of the immunological pathways that could help in decreasing the incidence of de novo malignancies and may also help in treating liver transplant patients suffering from cancer.
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Affiliation(s)
- Tommaso Maria Manzia
- HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Roberta Angelico
- Division of Abdominal Transplantation and HPB Surgery, Bambino Gesù Children's Hospital IRCCS, Rome 00165, Italy
| | - Carlo Gazia
- HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC 27101, United States
| | - Ilaria Lenci
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
| | - Martina Milana
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
| | | | - Domiziana Pedini
- Division of Abdominal Transplantation and HPB Surgery, Bambino Gesù Children's Hospital IRCCS, Rome 00165, Italy
| | - Luca Toti
- HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Marco Spada
- Division of Abdominal Transplantation and HPB Surgery, Bambino Gesù Children's Hospital IRCCS, Rome 00165, Italy
| | - Giuseppe Tisone
- HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Leonardo Baiocchi
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
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Pretransplant Cancer in Kidney Recipients in Relation to Recurrent and De Novo Cancer Incidence Posttransplantation and Implications for Graft and Patient Survival. Transplantation 2019; 103:581-587. [PMID: 30418430 DOI: 10.1097/tp.0000000000002459] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Whether kidney transplant recipients who were treated for a malignant tumor before transplantation are at an increased risk of developing a tumor posttransplantation has not been adequately quantified and characterized. METHODS We studied more than 270 000 patients on whom pretransplant and posttransplant malignancy data were reported to the Collaborative Transplant Study. More than 4000 of these patients were treated for pretransplant malignancy. The posttransplant tumor incidence in these patients was compared to that in recipients without a pretransplant tumor. Cox regression, considering multiple confounders, was applied. RESULTS Significant increases in posttransplant tumor incidence with hazard ratio ranging from 2.10 to 5.47 (all P < 0.001) were observed for tumors in the site-specific pretransplant locations, suggesting tumor recurrences. There were also significantly increased de novo tumors in new locations with hazard ratio ranging from 1.28 to 1.89. Pretransplant basal cell carcinoma of the skin and male genital cancer were associated with significantly increased death-censored graft survival, suggesting impaired immune responsiveness against transplanted kidneys. Time interval from pretransplant tumor occurrence to transplantation and posttransplant mammalian target of rapamycin inhibitor treatment was not found to be of significant relevance in this study. CONCLUSIONS Patients who experienced a pretransplant tumor are at significant risk of tumor recurrence, regardless of the length of interval between tumor treatment and transplantation. There is also some increased risk for de novo tumors, suggesting impaired immune surveillance. Impaired tumor immunity appears to extend to a lower rate of transplant rejection because patients with pretransplant tumors tended to show improved death-censored graft survival.
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Horie K, Tsuchiya T, Iinuma K, Maekawa Y, Nakane K, Kato T, Mizutani K, Koie T. Risk factors and incidence of malignant neoplasms after kidney transplantation at a single institution in Japan. Clin Exp Nephrol 2019; 23:1323-1330. [PMID: 31372795 DOI: 10.1007/s10157-019-01769-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 07/16/2019] [Indexed: 12/31/2022]
Abstract
BACKGROUND The risk of malignant neoplasms increases in kidney transplantation (KT) recipients (KTRs). However, Japanese registry studies have not been reported since 2000. METHODS We retrospectively reviewed the medical records of 346 patients who underwent KT at Gifu University Hospital, Japan since 2000. Patients were divided into two groups based on whether they developed malignancy after KT or not. The incidence, type of malignancy, risk factors, and prognosis for malignancy were examined. RESULTS In this study, 22 de novo malignant neoplasms were identified in 20 KTRs (7.3%), with a median follow-up period of 8.2 years. Cumulative incidence of any malignant neoplasms was 1.1% within 1 year and 4.4% within 5 years. The 5-year overall survival (OS) rates were 71.8% in KTRs with malignant neoplasms and 98.6% in KTRs without malignant neoplasms. Uni- and multivariate analysis revealed that age at KT and acute rejection (AR) episode were significant predictors for incidence of malignancy. CONCLUSIONS The development of malignant neoplasms was associated with poor OS and graft survival. We consider that appropriate screening and investigation of symptoms are important for KTRs, particularly for older KTRs at transplantation and those with AR episode.
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Affiliation(s)
- Kengo Horie
- Department of Urology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Tomohiro Tsuchiya
- Department of Urology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1193, Japan.
| | - Koji Iinuma
- Department of Urology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Yuka Maekawa
- Department of Urology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Keita Nakane
- Department of Urology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Taku Kato
- Department of Urology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Kosuke Mizutani
- Department of Urology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Takuya Koie
- Department of Urology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1193, Japan
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Incidence of Malignancies in Patients Treated With Sirolimus Following Heart Transplantation. J Am Coll Cardiol 2019; 73:2676-2688. [DOI: 10.1016/j.jacc.2019.03.499] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 02/27/2019] [Accepted: 03/03/2019] [Indexed: 01/06/2023]
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Gender, Race and Disease Etiology Predict De Novo Malignancy Risk After Liver Transplantation: Insights for Future Individualized Cancer Screening Guidance. Transplantation 2019; 103:91-100. [PMID: 29377876 DOI: 10.1097/tp.0000000000002113] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Malignancy after liver transplant (LT) is a leading cause of mortality, but data is limited. The aim of this study was to identify patients at higher risk for de novo malignancies after LT in a large multicenter database. METHODS The Scientific Registry of Transplant Recipients database comprising all 108 412 LT recipients across the United States between 1987 and March 2015 was analyzed with a median follow-up of 6.95 years. Potential risk factors for malignancies after LT were assessed using Cox regression analysis for the outcome of time to first malignancy. RESULTS Mean age 51.9 ± 10.8 years, 64.6% male, 74.5% white, and 15.8% with previous malignancy. Malignancies during follow-up were 4,483 (41.3%) skin, 1519 (14.0%) hematologic, and 4842 (44.7%) solid organ. The 10-year probability of de novo malignancy was 11.5% (11.3-11.8%). On multivariable analysis, age by decade (hazard ratio [HR], 1.52; P < 0.001), male sex (HR, 1.28; P < 0.001), white race (compared with other races: HR, 1.45-2.04; P < 0.001), multiorgan transplant (HR, 1.35; P < 0.001), previous malignancy (HR, 1.34; P < 0.001), and alcoholic liver disease, autoimmune, nonalcoholic steatohepatitis (HR, 1.35; P < 0.001), and primary sclerosing cholangitis pre-LT (compared with hepatitis C virus, P < 0.001) were associated with higher risk of post-LT malignancy, but type of immunosuppression was not (P = NS). CONCLUSIONS This large data set demonstrates the effects of ethnicity/race and etiologies of liver disease, particularly nonalcoholic steatohepatitis as additional risk factors for cancer after LT. Patients with these high-risk characteristics should be more regularly and diligently screened.
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Buxeda A, Redondo-Pachón D, Pérez-Sáez MJ, Bartolomé Á, Mir M, Pascual-Dapena A, Sans A, Duran X, Crespo M, Pascual J. Gender differences in cancer risk after kidney transplantation. Oncotarget 2019; 10:3114-3128. [PMID: 31139324 PMCID: PMC6517099 DOI: 10.18632/oncotarget.26859] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 03/23/2019] [Indexed: 02/06/2023] Open
Abstract
Kidney transplant (KT) recipients are at greater risk of developing some cancers than the general population. Moreover, cancer is the only cause of death that is currently increasing after kidney transplantation. We analyzed incidence, risk factors and characteristics of post-transplant malignancies (solid organ tumors and lymphoproliferative disorders) at our center in 925 KT recipients (1979-2014). Sex differences were particularly assessed. One hundred and eight patients (11.7%) developed solid organ tumors (76.9%) or lymphoma (23.1%). Twenty-one percent of patients who reached 20 years after KT developed cancer, with a median post-KT time to diagnosis of 7.4 years. Most common solid organs affected were lung (30.1%), prostate (10.8%), bladder (9.6%), and native kidney (7.2%). When analyzing standardized incidence ratios (SIR) by gender compared to the general population, relative risk was increased in women (SIR = 1.81; 95%CI, 1.28-2.45) but not significantly increased in men (SIR = 1.22; 0.95-2.52). Regarding specific types, gynecological (SIR = 11.6; 4.2-22.7) and lung (SIR = 10.0; 4.3-18.2) in women, and bladder (SIR = 16.3; 5.9-32.1) in men were the most affected locations. Thymoglobulin, a polyclonal antibody that has been used as an immunosuppressive agent in kidney transplantation over the last decades, was a significant risk factor for developing cancer in adjusted regression analysis [IRR = 1.62, 1.02-2.57; p = 0.041], and was associated with lower patient survival. Compared with the general population, the incidence of post-KT non-skin cancer is almost two-fold higher in women but not significantly higher in men. Lung is the most common solid organ affected. Thymoglobulin induction therapy is associated with a greater risk.
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Affiliation(s)
- Anna Buxeda
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
| | | | | | - Álvaro Bartolomé
- Department of Medicine, University Autonoma Barcelona, Barcelona, Spain
- Department of Experimental and Health Sciences, University Pompeu-Fabra, Barcelona, Spain
| | - Marisa Mir
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
| | - Ana Pascual-Dapena
- Department of Medicine, University Autonoma Barcelona, Barcelona, Spain
- Department of Experimental and Health Sciences, University Pompeu-Fabra, Barcelona, Spain
| | - Anna Sans
- Department of Medicine, University Autonoma Barcelona, Barcelona, Spain
- Department of Experimental and Health Sciences, University Pompeu-Fabra, Barcelona, Spain
| | - Xavier Duran
- Methodology and Biostatistics Support Unit, Institute Hospital del Mar for Medical Research (IMIM), Barcelona, Spain
| | - Marta Crespo
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
- Department of Medicine, University Autonoma Barcelona, Barcelona, Spain
| | - Julio Pascual
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
- Department of Medicine, University Autonoma Barcelona, Barcelona, Spain
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Penney SW, Bishop BN, Howell DL. Treatment response with sirolimus for a pediatric patient with an EBV-associated smooth-muscle tumor after bone marrow transplantation. Pediatr Blood Cancer 2019; 66:e27585. [PMID: 30614215 DOI: 10.1002/pbc.27585] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 11/13/2018] [Accepted: 11/26/2018] [Indexed: 11/08/2022]
Abstract
Epstein-Barr virus-associated smooth-muscle tumors (EBV-SMTs) are unique and rare neoplasms described in immunocompromised patients. The case describes a nine-year-old female with a history of acute lymphoblastic leukemia with relapse and subsequent allogeneic bone marrow transplantation who presented with multiple EBV-SMTs of the liver. EBV utilizes the mammalian target of rapamycin (mTOR) pathway for tumor growth, and sirolimus, a mTOR inhibitor, has shown to result in a short-term response. We now report an extended treatment response with sirolimus in a pediatric patient with an EBV-SMT.
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Affiliation(s)
- Scott W Penney
- San Antonio Uniformed Services Health Education Consortium, Joint Base San Antonio-Fort Sam, Houston, Texas
| | - Bradie N Bishop
- San Antonio Uniformed Services Health Education Consortium, Joint Base San Antonio-Fort Sam, Houston, Texas
| | - Della L Howell
- San Antonio Uniformed Services Health Education Consortium, Joint Base San Antonio-Fort Sam, Houston, Texas
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49
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Risk Factors for Developing Nonmelanoma Skin Cancer after Lung Transplantation. J Skin Cancer 2019; 2019:7089482. [PMID: 30984427 PMCID: PMC6431522 DOI: 10.1155/2019/7089482] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 12/24/2018] [Accepted: 02/12/2019] [Indexed: 01/25/2023] Open
Abstract
Background Nonmelanoma skin cancer (NSMC) is the most common malignancy after organ transplantation. Lung transplant recipients (LTRs) are particularly prone to develop NMSC as compared to renal or hepatic transplant recipients due to higher dosages of immunosuppression needed. Everolimus, an immunosuppressant used in organ transplant recipients, is thought to inherit a lower risk for NMSC than calcineurin inhibitors, especially in renal transplant recipients. It is currently unknown whether this also applies to LTRs. Objectives To determine risk factors for NMSC and precancerous lesions after lung transplantation (LTx) and to characterize the effect of everolimus-based regimens regarding this risk. Materials and Methods 90 LTRs and former participants of the interventional trial “Immunosuppressive Therapy with Everolimus after Lung Transplantation”, who were randomized to receive either an everolimus- or mycophenolate mofetil- (MMF-) based regimen, were enrolled and screened in this retrospective, single-center cohort study. Results After a median follow-up of 101 months, we observed a prevalence of 38% for NMSC or precancerous lesions. 33% of the patients continuously receiving everolimus from LTx to dermatologic examination compared to 39% of all other patients, predominantly receiving an MMF-based regimen, were diagnosed with at least one NMSC or precancerous lesion (P=.66). Independent risk factors for NMSC or precancerous lesions after LTx were male sex and duration of voriconazole therapy. Conclusion NMSC or precancerous lesions were very common after LTx, and risk factors were similar to previous reports on LTRs. Everolimus did not decrease this risk under the given circumstances of this study. Patients should be counseled regarding their risk, perform vigorous sunscreen, and undergo regular dermatological controls, regardless of their immunosuppressive regimen.
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50
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Egeli T, Unek T, Ozbilgin M, Agalar C, Derici S, Akarsu M, Unek IT, Aysin M, Bacakoglu A, Astarcıoglu I. De Novo Malignancies After Liver Transplantation: A Single Institution Experience. EXP CLIN TRANSPLANT 2019; 17:74-78. [PMID: 29237362 DOI: 10.6002/ect.2017.0111] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Our objective was to analyze characteristics, risk factors, and incidence of de novo malignancies after liver transplant. MATERIALS AND METHODS The hospital records of 557 patients who underwent liver transplant were analyzed from the point of de novo malignancy development. We evaluated the demographic features and survival of these patients retrospectively. RESULTS The research covered 429 patients, 9 (2%) of whom developed de novo malignancy. All of these patients were male (100%), and their mean (SD) age was 51.33 (4.69) years (range, 45-65 y). Indications for transplant included alcohol related in 4 cases, chronic hepatitis B in 2 cases, chronic hepatitis B and C in 1 case, chronic hepatitis B and D in 1 case, and chronic hepatitis C and alcohol-related cirrhosis in 1 case. The mean (SD) time from transplant to cancer diagnosis was 63.41 (37.10) months (range, 17-122 mo). The types of tumors were lung cancer, lymphoma, neuroendocrine tumor of lung, nasopharyngeal cancer, and squamous cell carcinoma of the skin. Seven cases received chemotherapy with or without radiotherapy. Two cases received surgery and radiotherapy. One patient underwent surgical treatment. One patient died before treatment was started. CONCLUSIONS In recent years, improvements in surgical techniques and immunosuppressive therapies have helped prolong survival of patients who undergo liver transplant. However, this also has led to a rise in the incidence of long-term complications such as de novo malignancy. These patients are more likely to develop de novo malignancy than the general population, for which chronic immunosuppression is identified as a major risk factor. Early diagnosis and treatment of de novo malignancies can help obtain better prognosis and higher survival rates in these patients.
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Affiliation(s)
- Tufan Egeli
- From the Department of General Surgery, Liver Transplantation and Hepatopancreaticobiliary Surgery Unit, Dokuz Eylul University School of Medicine, Izmir, Turkey
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