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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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2
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Bigotte Vieira M, Arai H, Nicolau C, Murakami N. Cancer Screening and Cancer Treatment in Kidney Transplant Recipients. KIDNEY360 2024; 5:1569-1583. [PMID: 39480669 PMCID: PMC11556922 DOI: 10.34067/kid.0000000000000545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/02/2024]
Abstract
As the population ages and post-transplant survival improves, pretransplant and post-transplant malignancy are becoming increasingly common. In addition, rapid advances in cancer therapies and improving outcomes prompt us to rethink pretransplant cancer-free wait time and screening strategies. Although kidney transplant recipients (KTRs) are at higher risk of developing cancer, epidemiological data on how to best screen and treat cancers in KTRs are incomplete. Thus, current recommendations are still largely on the basis of studies in the general population, and their validity in KTRs is uncertain. Kidney transplant candidates without prior cancer should be evaluated for latent malignancies even in the absence of symptoms. Conversely, individuals with a history of malignancy require thorough monitoring to detect potential recurrences or de novo malignancies. When treating KTRs with cancer, reducing immunosuppression can enhance antitumor immunity, yet this also increases the risk of graft rejection. Optimal treatment and immunosuppression management remains undefined. As the emergence of novel cancer therapies adds complexity to this challenge, individualized risk-benefit assessment is crucial. In this review, we discuss up-to-date data on pretransplant screening and cancer-free wait time, as well as post-transplant cancer screening, prevention strategies, and treatment, including novel therapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies.
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Affiliation(s)
- Miguel Bigotte Vieira
- Nephrology Department, Hospital Curry Cabral, Unidade Local de Saúde São José, Lisbon, Portugal
- NOVA Medical School, Universidade NOVA de Lisboa, Lisbon, Portugal
| | - Hiroyuki Arai
- Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Carla Nicolau
- Nephrology Department, Hospital Curry Cabral, Unidade Local de Saúde São José, Lisbon, Portugal
| | - Naoka Murakami
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
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3
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de Jong E, Genders R, Harwood CA, Green AC, Plasmeijer EI, Proby C, Geissler E, Ferrándiz-Pulido C, Ducroux E, Euvrard S, Geusau A, Jahn-Bassler K, Borik-Heil L, Rácz E, Nägeli M, Hofbauer GFL, Piaserico S, Russo I, Mackintosh L, Borges-Costa J, Angeliki-Gkini M, Zavattaro E, Savoia P, Imko-Walszuk B, Dębska-Slizień A, Garmyn M, van Kelst S, Ricar J, Cetkovska P, Matin R, Güleç AT, Seçkin D, Anene CA, Oliveira WRP, Rademaker M, Goeman J, van Geloven N, Ruiz E, Murad F, Karn E, Schmults CD, Bouwes Bavinck JN. Cumulative incidence and risk factors for cutaneous squamous cell carcinoma metastases in organ transplant recipients: The Skin Care in Organ Transplant Patients in Europe-International Transplant Skin Cancer Collaborative metastases study, a prospective multicenter study. J Am Acad Dermatol 2024; 90:1200-1209. [PMID: 38301923 DOI: 10.1016/j.jaad.2024.01.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 11/23/2023] [Accepted: 01/07/2024] [Indexed: 02/03/2024]
Abstract
INTRODUCTION Solid organ transplant recipients (SOTRs) are believed to have an increased risk of metastatic cutaneous squamous cell carcinoma (cSCC), but reliable data are lacking regarding the precise incidence and associated risk factors. METHODS In a prospective cohort study, including 19 specialist dermatology outpatient clinics in 15 countries, patient and tumor characteristics were collected using standardized questionnaires when SOTRs presented with a new cSCC. After a minimum of 2 years of follow-up, relevant data for all SOTRs were collected. Cumulative incidence of metastases was calculated by the Aalen-Johansen estimator. Fine and Gray models were used to assess multiple risk factors for metastases. RESULTS Of 514 SOTRs who presented with 623 primary cSCCs, metastases developed in 37 with a 2-year patient-based cumulative incidence of 6.2%. Risk factors for metastases included location in the head and neck area, local recurrence, size > 2 cm, clinical ulceration, poor differentiation grade, perineural invasion, and deep invasion. A high-stage tumor that is also ulcerated showed the highest risk of metastasis, with a 2-year cumulative incidence of 46.2% (31.9%-68.4%). CONCLUSIONS SOTRs have a high risk of cSCC metastases and well-established clinical and histologic risk factors have been confirmed. High-stage, ulcerated cSCCs have the highest risk of metastasis.
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Affiliation(s)
- Estella de Jong
- Department of Dermatology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
| | - Roel Genders
- Department of Dermatology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Catherine A Harwood
- Department of Dermatology, Royal London Hospital, Barts Health NHS Trust, London, United Kingdom
| | - Adèle C Green
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Elsemieke I Plasmeijer
- Department of Dermatology, Leiden University Medical Center (LUMC), Leiden, The Netherlands; Department of Dermatology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Charlotte Proby
- Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, United Kingdom
| | - Edward Geissler
- Division of Experimental Surgery, Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | | | - Emilie Ducroux
- Department of Dermatology, Edouard Herriot Hospital, Lyon, France
| | - Sylvie Euvrard
- Department of Dermatology, Edouard Herriot Hospital, Lyon, France
| | - Alexandra Geusau
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Karin Jahn-Bassler
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Liliane Borik-Heil
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Emõke Rácz
- Department of Dermatology, University Medical Centre Groningen (UMCG), University of Groningen, Groningen, The Netherlands
| | - Mirjam Nägeli
- Department of Dermatology, University Hospital of Zürich, University of Zürich, Zürich, Switzerland
| | - Günther F L Hofbauer
- Department of Dermatology, University Hospital of Zürich, University of Zürich, Zürich, Switzerland
| | - Stefano Piaserico
- Unit of Dermatology, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Irene Russo
- Unit of Dermatology, Department of Medicine (DIMED), University of Padua, Padua, Italy; Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, IOV-IRCSS, Padua, Italy
| | - Lorna Mackintosh
- Department of Dermatology, NHS Greater Glasgow and Clyde, Glasgow, United Kingdom
| | - João Borges-Costa
- Department of Dermatology, Hospital de Santa Maria and Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Maria Angeliki-Gkini
- Department of Dermatology, Royal London Hospital, Barts Health NHS Trust, London, United Kingdom
| | - Elisa Zavattaro
- Dermatology Unit, Departments of Translational Medicine and Health Science, University of Eastern Piedmont, Novara, Italy
| | - Paola Savoia
- Dermatology Unit, Departments of Translational Medicine and Health Science, University of Eastern Piedmont, Novara, Italy
| | - Beata Imko-Walszuk
- N Dermatology and STD Outpatient Clinic, Copernicus Medical Centre, Gdansk, Poland
| | - Alicja Dębska-Slizień
- Department of Nephrology, Transplantology and Internal Medicine, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland
| | - Marjan Garmyn
- Department of Dermatology, University Hospitals Leuven, Leuven, Belgium
| | - Sofie van Kelst
- Department of Dermatology, University Hospitals Leuven, Leuven, Belgium
| | - Jan Ricar
- Department of Dermatovenereology, Charles University Hospital, Pilsen, Czech Republic
| | - Petra Cetkovska
- Department of Dermatovenereology, Charles University Hospital, Pilsen, Czech Republic
| | - Rubeta Matin
- Department of Dermatology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Ayşe Tülin Güleç
- Department of Dermatology, Faculty of Medicine, Baskent University, Ankara, Turkey
| | - Deniz Seçkin
- Department of Dermatology, Faculty of Medicine, Baskent University, Ankara, Turkey
| | - Chinedu Anthony Anene
- Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; Centre for Cancer Biology and Therapy, School of Applied Sciences, London South Bank University, London, United Kingdom
| | | | - Marius Rademaker
- Department of Dermatology, Waikato Clinical Campus, University of Auckland, Hamilton, New Zealand
| | - Jelle Goeman
- Department of Biomedical Data Sciences, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Nan van Geloven
- Department of Biomedical Data Sciences, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Emily Ruiz
- Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Fadi Murad
- Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Emily Karn
- Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts
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Alves FFC, de Jesus LCB, Cristelli MP, Enokihara MMSES, Hirata SH, Facina ADS, Tomimori J. Metastasis of skin squamous cell carcinoma in kidney transplant recipients. Int J Dermatol 2024; 63:560-564. [PMID: 38263692 DOI: 10.1111/ijd.17029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 12/14/2023] [Accepted: 01/04/2024] [Indexed: 01/25/2024]
Abstract
Cutaneous squamous cell carcinoma (cSCC) is the most common skin malignancy in kidney transplant recipients (KTRs) as a result of immunosuppression. A worldwide increase in kidney transplantation justifies the determination of prognostic biomarkers by collecting detailed patient data on metastasis development. This study aims to characterize the clinical, epidemiological, and histopathological profiles of KTRs who developed metastasis of cSCC. We conducted a retrospective single-center study on 18 KTRs and 21 immunocompetent patients (ICs) with metastatic cSCC, using data from 2004 to 2021. ICs were older (median age 70.5 years) than KTRs (median age: 59.5 years). Both groups were predominantly male with Fitzpatrick skin phototype I/II. The primary tumor appeared around 83.5 months post-transplant, usually in sun-exposed areas (61.1%), though some non-exposed areas in ICs (23.8%) contradicted literature findings. KTRs took longer to develop metastasis (median: 11.0 months) compared to ICs (median: 5.5 months). The mean size of the primary tumor was smaller in KTRs (2.50 cm2) compared to ICs (4.55 cm2). The main lymph node chain affected by metastasis was parotid lymph nodes in KTRs (27.8%) and cervical/axillar lymph nodes in ICs (both 19.0%). Both groups exhibited similar primary tumor grades and metastasis evolution, but KTRs had a higher prevalence of lymphovascular invasion. Metastasis of cSCC was more common in males with low skin phototype, in KTRs, particularly on the head and neck. The study suggests a possible link between lymphovascular invasion and metastasis development in KTRs.
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Affiliation(s)
| | - Laura C B de Jesus
- Department of Medicine, Post Graduate Program in Translational Medicine, São Paulo, Brazil
| | | | - Milvia M S E S Enokihara
- Department of Pathology - Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Sérgio H Hirata
- Department of Dermatology - Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP) and Hospital São Paulo, São Paulo, Brazil
| | - Anamaria da Silva Facina
- Department of Dermatology - Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP) and Hospital São Paulo, São Paulo, Brazil
| | - Jane Tomimori
- Department of Dermatology - Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP) and Hospital São Paulo, São Paulo, Brazil
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Hanna GJ, Dharanesswaran H, Giobbie-Hurder A, Harran JJ, Liao Z, Pai L, Tchekmedyian V, Ruiz ES, Waldman AH, Schmults CD, Riella LV, Lizotte P, Paweletz CP, Chandraker AK, Murakami N, Silk AW. Cemiplimab for Kidney Transplant Recipients With Advanced Cutaneous Squamous Cell Carcinoma. J Clin Oncol 2024; 42:1021-1030. [PMID: 38252908 PMCID: PMC10950183 DOI: 10.1200/jco.23.01498] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/24/2023] [Accepted: 10/03/2023] [Indexed: 01/24/2024] Open
Abstract
PURPOSE Cemiplimab is approved for treating locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC). Solid organ transplant recipients have been excluded from immunotherapy trials, given concern for allograft rejection despite their increased risk of skin cancers. Chronic immunosuppression is necessary to prevent organ rejection but may attenuate antitumor response with PD-1 inhibitors. METHODS We report a phase I study of cemiplimab for kidney transplant recipients (KTRs) with advanced CSCC. After cross-taper to a mammalian target of rapamycin (mTOR) inhibitor and pulsed dose corticosteroids (prednisone 40 mg once daily, the day before and on days 1-3 of each cycle, followed by 20 mg once daily on days 4-6, then 10 mg once daily until the day before each subsequent cycle), patients received cemiplimab 350 mg intravenously once every 3 weeks for up to 2 years and were assessed for response every 8 weeks. The primary end point was the rate of kidney rejection, with key secondary end points including rate and duration of response, and survival. RESULTS Twelve patients were treated. No kidney rejection or loss was observed. A response to cemiplimab was observed in five of 11 evaluable patients (46%; 90% CI, 22 to 73), including two with durable responses beyond a year. Median follow-up was 6.8 months (range, 0.7-29.8). Treatment-related grade 3 or greater adverse events occurred in five patients (42%), including diarrhea, infection, and metabolic disturbances. One patient died of angioedema and anaphylaxis attributed to mTOR inhibitor cross-taper. CONCLUSION mTOR inhibitor and corticosteroids represent a favorable immunosuppressive regimen for KTRs with advanced CSCC receiving immunotherapy. This combination resulted in durable antitumor responses with no kidney rejection events (funded by Regeneron Pharmaceuticals [ClinicalTrials.gov identifier: NCT04339062]).
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Affiliation(s)
- Glenn J. Hanna
- Center for Head and Neck Oncology, Dana-Farber Cancer Institute, Boston, MA
| | | | | | - John J. Harran
- Center for Cutaneous Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Zixi Liao
- Center for Cutaneous Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Lori Pai
- Department of Hematology/Oncology, Tufts Medical Center, Boston, MA
| | | | - Emily S. Ruiz
- Center for Cutaneous Oncology, Dana-Farber Cancer Institute, Boston, MA
| | | | | | - Leonardo V. Riella
- Department of Medicine, Renal Division, Massachusetts General Hospital, Boston, MA
| | - Patrick Lizotte
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA
| | - Cloud P. Paweletz
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA
| | | | - Naoka Murakami
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA
| | - Ann W. Silk
- Center for Cutaneous Oncology, Dana-Farber Cancer Institute, Boston, MA
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Zavattaro E, Veronese F, Airoldi C, DI Cristo N, Savoia P. Epidemiology and risk factors for multiple squamous cell carcinomas in a cohort of organ transplant recipients from northern Italy: a single center study. Ital J Dermatol Venerol 2023; 158:379-387. [PMID: 37916398 DOI: 10.23736/s2784-8671.23.07551-5] [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: 11/03/2023]
Abstract
BACKGROUND Keratinocyte cancers account for the most frequent oncological complication in organ transplant recipients. To date, many different risk factors have been reported, unless variability among the studies exist. We aimed to determine the incidence and risk factors for keratinocyte neoplasms in a cohort of kidney transplant and liver transplant recipients. METHODS A cohort of 338 patients were included in this retrospective study and followed-up from transplantation until the end of December 2021, with a 2-year minimum transplant time. Each skin cancer was collected in a specific database, together with all the demographic data and dermatological history and feature of patients. RESULTS In our cohort, liver transplant patients presented a higher keratinocyte cancer incidence compared to kidney transplant recipients. Regarding the risk factors for skin cancer in the entire group of patients, we observed a significant association with the detection of actinic keratosis and solar lentigo, and such relation was stronger when considering patients developing multiple skin cancers, in which fair skin types and occupational sun exposure were also associated. Furthermore, while actinic keratosis and a history of previous dialysis were significantly associated with the development of a least one squamous cell carcinoma, the presence of keratotic lesions and azathioprine intake resulted connected with the appearance of multiple squamous neoplasms. CONCLUSIONS We report here that, in our cohort, factors potentially leading to immune dysfunction were found to play a causative role in the development of the more aggressive histotype of keratinocyte tumors, and such association seemed more convincing in case of multiple squamous cell carcinomas.
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Affiliation(s)
- Elisa Zavattaro
- Department of Health Sciences, University of Eastern Piedmont, Novara, Italy
| | | | - Chiara Airoldi
- Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Nunzia DI Cristo
- Department of Health Sciences, University of Eastern Piedmont, Novara, Italy
| | - Paola Savoia
- Department of Health Sciences, University of Eastern Piedmont, Novara, Italy -
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Moseley I, Ahmed F, Lin E, Lim R, Hoang M, Baranwal N, Robinson-Bostom L, Libby T, Wisco O, Qureshi A, Cho E. Host and primary tumor factors for the development of multiple cutaneous squamous cell carcinomas among a retrospective cohort in Rhode Island. J Am Acad Dermatol 2023; 89:511-518. [PMID: 37011813 DOI: 10.1016/j.jaad.2023.03.038] [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: 08/16/2022] [Revised: 02/16/2023] [Accepted: 03/06/2023] [Indexed: 04/03/2023]
Abstract
INTRODUCTION Risk factors for a primary cutaneous squamous cell carcinoma (CSCC) are well-established; however, the host and primary tumor risk factors for subsequent CSCC have not been fully explored. METHODS We performed a retrospective chart review of patients diagnosed with CSCC in an academic dermatology clinic in Rhode Island from 2016-2019. Logistic regression was used to evaluate the associations between host factors and multiple CSCC and between primary tumor characteristics and the risk of subsequent CSCC. Adjusted odds ratios (aORs) and 95% CIs were calculated. RESULTS A total of 1312 patients with CSCC diagnoses were included. Host risk factors significantly associated with multiple CSCCs included: aged >80 years (aOR, 2.18; 95% CI, 1.46-3.31); history of: solid organ transplant (aOR, 2.41; 95% CI, 1.20-4.80); skin cancer (aOR, 1.96; 95% CI, 1.52-2.54); other cancer (aOR, 1.49; 95% CI, 1.11-2.00); family history of skin cancer (aOR, 1.36; 95% CI, 1.03-1.78); and actinic keratosis (aOR, 1.52; 95% CI, 1.18-1.95). Tumor location, diameter, histologic differentiation, and treatment were not significant predictors of subsequent CSCCs. LIMITATIONS Study patients were predominantly White and from a single institution, limiting the generalizability of results. CONCLUSIONS Certain host characteristics were associated with the development of subsequent CSCC, which may inform clinical guidelines for follow-up.
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Affiliation(s)
- Isabelle Moseley
- Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Fadwa Ahmed
- Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Erica Lin
- Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Rachel Lim
- Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Megan Hoang
- Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Navya Baranwal
- Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Leslie Robinson-Bostom
- Department of Dermatology, the Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Tiffany Libby
- Department of Dermatology, the Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Oliver Wisco
- Department of Dermatology, the Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Abrar Qureshi
- Department of Dermatology, the Warren Alpert Medical School of Brown University, Providence, Rhode Island; Department of Epidemiology, School of Public Health, Brown University, Providence, Rhode Island
| | - Eunyoung Cho
- Department of Dermatology, the Warren Alpert Medical School of Brown University, Providence, Rhode Island; Department of Epidemiology, School of Public Health, Brown University, Providence, Rhode Island; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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8
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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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9
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Gjersvik P, Falk RS, Roscher I, Rizvi SMH, Mjøen G, Gude E, Leuckfeld I, Boberg KM, Veierød MB, Robsahm TE. Rates of Second Tumor, Metastasis, and Death From Cutaneous Squamous Cell Carcinoma in Patients With and Without Transplant-Associated Immunosuppression. JAMA Dermatol 2023; 159:923-929. [PMID: 37466985 PMCID: PMC10357356 DOI: 10.1001/jamadermatol.2023.2029] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 05/12/2023] [Indexed: 07/20/2023]
Abstract
Importance Cutaneous squamous cell carcinoma (cSCC) may occur with multiple primary tumors, metastasize, and cause death both in immunocompetent and immunosuppressed patients. Objective To study the rates of second cSCC, metastasis, and death from cSCC in patients with and without organ transplant-associated immunosuppressive treatment. Design, Setting, and Participants This population-based, nationwide cohort study used Cancer Registry of Norway data from 47 992 individuals diagnosed with cSCC at 18 years or older between January 1, 1968, and December 31, 2020. Data were analyzed between November 24, 2021, and November 15, 2022. Exposures Receipt of a solid organ transplant at Oslo University Hospital between 1968 and 2012 followed by long-term immunosuppressive treatment. Main Outcomes and Measures Absolute rates of second cSCC, metastasis, and death from cSCC were calculated per 1000 person-years with 95% CIs. Hazard ratios (HRs) estimated using Cox proportional hazard regression were adjusted for age, sex, and year of first cSCC diagnosis. Results The study cohort comprised 1208 organ transplant recipients (OTRs) (median age, 66 years [range, 27-89 years]; 882 men [73.0%] and 326 women [27.0%]) and 46 784 non-OTRs (median age, 79 years [range, 18-106 years]; 25 406 men [54.3%] and 21 378 women [45.7%]). The rate of a second cSCC per 1000 person-years was 30.9 (95% CI, 30.2-31.6) in non-OTRs and 250.6 (95% CI, 232.2-270.1) in OTRs, with OTRs having a 4.3-fold increased rate in the adjusted analysis. The metastasis rate per 1000 person-years was 2.8 (95% CI, 2.6-3.0) in non-OTRs and 4.8 (95% CI, 3.4-6.7) in OTRs, with OTRs having a 1.5-fold increased rate in the adjusted analysis. A total of 30 451 deaths were observed, of which 29 895 (98.2%) were from causes other than cSCC. Death from cSCC was observed in 516 non-OTRs (1.1%) and 40 OTRs (3.3%). The rate of death from cSCC per 1000 person-years was 1.7 (95% CI, 1.5-1.8) in non-OTRs and 5.4 (95% CI, 3.9-7.4) in OTRs, with OTRs having a 5.5-fold increased rate in the adjusted analysis. Conclusions and Relevance In this cohort study, OTRs with cSCC had significantly higher rates of second cSCC, metastasis, and death from cSCC than non-OTRs with cSCC, although most patients with cSCC in both groups died from causes other than cSCC. These findings are relevant for the planning of follow-up of patients with cSCC and for skin cancer services.
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Affiliation(s)
- Petter Gjersvik
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Dermatology, Oslo University Hospital, Oslo, Norway
| | - Ragnhild S. Falk
- Oslo Centre for Biostatistics and Epidemiology, Research Support Services, Oslo University Hospital, Oslo, Norway
| | - Ingrid Roscher
- Department of Dermatology, Oslo University Hospital, Oslo, Norway
| | | | - Geir Mjøen
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Einar Gude
- Department of Cardiology, Oslo University Hospital, Oslo, Norway
| | - Inga Leuckfeld
- Department of Respiratory Medicine, Oslo University Hospital, Oslo, Norway
| | - Kirsten Muri Boberg
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Marit B. Veierød
- Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
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10
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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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11
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Voloshyna D, Shaik TA, Shrestha S, Ansari A, Saleem F, Ghaffari MAZ. Coexistence of Cutaneous Squamous Cell Carcinoma and Basal Cell Carcinoma in a Renal Transplant Recipient: A Case Report. Cureus 2022; 14:e28764. [PMID: 36211087 PMCID: PMC9531703 DOI: 10.7759/cureus.28764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/01/2022] [Indexed: 11/18/2022] Open
Abstract
In solid organ transplant patients, non-melanoma skin cancer remains a leading cause of mortality. The most common skin malignancies in solid organ transplant patients are squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In organ transplant patients, SCC is 100 times more prevalent, and BCC is 10 times more prevalent than in the general population. Many risk factors for developing such malignancies are equivalent to those in the general population. However, in the transplant population, such cancers occur at an earlier age, act more aggressively, and often appear at multiple locations. Thus, assiduousness on the patient's part and healthcare providers is the highest priority. The concurrence of SCC and BCC together is rarely encountered in a post-transplant individual. We report a rare case of coexistence of SCC and BCC in the same patient. A 63-year-old man had been diagnosed with SCC and BCC simultaneously by a punch biopsy performed at two different scalp lesions of different diameters. This review describes an unusual occurrence of both skin cancers concurrently in a kidney transplant recipient.
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12
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Multiple Basal Cell Carcinomas in Immunocompetent Patients. Cancers (Basel) 2022; 14:cancers14133211. [PMID: 35804983 PMCID: PMC9264959 DOI: 10.3390/cancers14133211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/28/2022] [Accepted: 06/29/2022] [Indexed: 11/20/2022] Open
Abstract
Simple Summary It is widely known that long-term treatment with immunosuppressive drugs represents a risk factor for the onset of malignancies, including multiple basal cell carcinomas. However, multiple basal carcinomas are ao found in the general population, and even in the absence of specific predisposing genetic mutations. This paper aims, through the retrospective evaluation of all patients diagnosed and surgically treated for basal cell carcinomas during 5 years at our Dermatological Division, to identify the characteristics of these subjects and any possible risk factors, useful for outlining specific surveillance programs. In our experience, multiple carcinomas were identified in over 24% of the subjects analyzed, with several lesions removed, ranging from 2 to 11, confirming the relevance of this phenomenon. Abstract Background: The onset of multiple BCCs is a relatively common condition, not only among patients undergoing chronic treatment with immunosuppressant drugs, but also in the general population, although specific risk factors for immunocompetent patients have not been identified. A putative role of somatic mutations in the hedgehog pathway should be considered. Methods: This study is a retrospective observation of all patients diagnosed and surgically treated for BCCs during 5 years at our Dermatological Division. For these patients, we evaluated clinical and histopathological characteristics and data about possible risk factors for BCC. Results: Five-hundred and six patients affected by multiple BCCs, accounting for the 24.2% of the entire sample, have been identified. In these patients, the total number of BCCs was 1516, ranging from 2 to 11. Subjects affected by multiple BCCs were more frequently males, with an older age at diagnosis; multiple BCCs developed mainly on the trunk and were often represented by a nodular histotype. The multivariate analysis highlighted that male gender, older age, nodular BCC, or face involvement at the first diagnosis are risk factors for the development of multiple BCCs. Conclusions: The frequency of multiple BCCs even among the non-immunocompromised population underlines the need to subject patients to a close surveillance program, to allow early diagnosis and treatment of additional cancers.
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13
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de Jong E, Lammerts MUPA, Genders RE, Bouwes Bavinck JN. Update of advanced cutaneous squamous cell carcinoma. J Eur Acad Dermatol Venereol 2021; 36 Suppl 1:6-10. [PMID: 34855246 PMCID: PMC9299882 DOI: 10.1111/jdv.17728] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 10/07/2021] [Indexed: 12/20/2022]
Abstract
The incidence of cutaneous squamous cell carcinoma (cSCC) is rapidly increasing. A growing part of this patient group is formed by immunocompromised patients, for example organ-transplant recipients (OTR). Although over 90% of the cSCC show a relatively harmless clinical behaviour, there is also a chance of developing advanced cSCC and metastases. Locally advanced cSCC are defined as cSCC that have locally advanced progression and are no longer amenable to surgery or radiation therapy. Better understanding of the clinical behaviour of cSCC is essential to discriminate between low- and high-risk cSCC. Staging systems are important and have recently been improved. Genetic characterisation of SCC will likely become an important tool to help distinguish low and high-risk cSCC with an increased potential to metastasise in the near future. Available treatments for high-risk and advanced cSCC include surgery, radiotherapy, chemotherapy and targeted therapy with epidermal growth factor receptors inhibitors. Anti-PD-1 antibodies show promising results with response rates of up to 50% in both locally advanced and metastatic cSCC but, in its present form, is not suitable for OTR.
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Affiliation(s)
- E de Jong
- Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands
| | - M U P A Lammerts
- Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands
| | - R E Genders
- Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands
| | - J N Bouwes Bavinck
- Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands
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14
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Wehner MR, Niu J, Wheless L, Baker LX, Cohen OG, Margolis DJ, Giordano SH, Shin TM. Risks of Multiple Skin Cancers in Organ Transplant Recipients: A Cohort Study in 2 Administrative Data Sets. JAMA Dermatol 2021; 157:1447-1455. [PMID: 34668933 DOI: 10.1001/jamadermatol.2021.4148] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Importance There are limited reports on the risks of multiple primary skin cancers in organ transplant recipients (OTRs). Objective To determine the risks over time and risk factors for OTRs developing (1) any skin cancer posttransplant, (2) a subsequent skin cancer after the first posttransplant skin cancer in the data sets used in the study, and (3) 10 or more skin cancers. Design, Setting, and Participants This retrospective cohort study used data from Optum deidentified electronic health record data set (7.7 million patients) and Truven Health MarketScan insurance claims data set (161 million patients) from 2007 to 2017. Skin cancers were identified using diagnosis plus treatment codes for basal cell carcinoma, squamous cell carcinoma, and melanoma; OTRs were identified using 4 or more diagnosis codes for organ transplant. Data analysis took place from January 1, 2007, to December 31, 2017. Main Outcomes and Measures Cumulative risks of (1) any skin cancer treatment posttransplant, (2) a subsequent skin cancer treatment after the first posttransplant skin cancer treatment in our data, and (3) 10 or more skin cancer treatments in OTRs. A Wei-Lin-Weissfeld marginal model was used to evaluate risk factors for any skin cancer. Results A total of 7390 OTRs in Optum and 133 651 in MarketScan were identified, 4.5% and 13.3% of which had had at least 1 skin cancer treatment, respectively. At 2 years after the initial posttransplant skin cancer in the data sets, OTRs had a 44.0% to 57.0% risk of a subsequent skin cancer treatment and a 3.7% to 6.6% risk of having 10 or more skin cancer treatments. Statistically significant risk factors for any skin cancer included age, history of skin cancer, and history of actinic keratosis in both data sets, and male sex and thoracic transplant in MarketScan. Conclusions and Relevance In this retrospective cohort study, approximately half of the OTRs who developed at least 1 posttransplant skin cancer developed a subsequent skin cancer within 2 years, and approximately 1 in 20 developed 10 or more skin cancers. Identifying OTRs at highest risk for multiple primary skin cancers may help target strategies for prevention and early detection.
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Affiliation(s)
- Mackenzie R Wehner
- Department of Dermatology, University of Pennsylvania, Philadelphia.,Department of Health Services Research, University of Texas MD Anderson Cancer Center, Houston.,Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston
| | - Jiangong Niu
- Department of Health Services Research, University of Texas MD Anderson Cancer Center, Houston
| | - Lee Wheless
- Department of Dermatology, Vanderbilt University, Nashville, Tennessee
| | - Laura X Baker
- Department of Dermatology, Vanderbilt University, Nashville, Tennessee
| | - Olivia G Cohen
- Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - David J Margolis
- Department of Dermatology, University of Pennsylvania, Philadelphia
| | - Sharon H Giordano
- Department of Health Services Research, University of Texas MD Anderson Cancer Center, Houston
| | - Thuzar M Shin
- Department of Dermatology, University of Pennsylvania, Philadelphia
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15
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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: 4] [Impact Index Per Article: 1.0] [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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16
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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: 3] [Impact Index Per Article: 0.8] [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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17
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Ritter A, Badir S, Mansour M, Segal Z, Ad-El D, Bachar G, Shpitzer T, Popovtzer A, Mizrachi A. Solid organ transplantation worsens the prognosis of patients with cutaneous squamous cell carcinoma of the head and neck region-Comparison between solid organ transplant recipients and immunocompetent patients. Head Neck 2020; 43:884-894. [PMID: 33247523 DOI: 10.1002/hed.26546] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 10/25/2020] [Accepted: 11/09/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Cutaneous squamous cell carcinoma of the head and neck (CSCC-HN) appears to behave more aggressively in immunosuppressed patients. We aimed to investigate this hypothesis by comparing solid organ transplant recipients (SOTR) with CSCC-HN to immunocompetent patients. METHODS A retrospective comparative study was conducted for SOTR and immunocompetent patients who were treated for CSCC-HN. RESULTS A total of 177 SOTR and 157 immunocompetent patients with CSCC-HN were included. Lymph node metastases were more common in the SOTR group (9% vs 3%), and distant metastases occurred only in SOTR (3% of patients). SOTR had a higher rate of recurrences (19% vs 10%), which were mostly regional (7%) and distant (3%). The 2-year disease-specific survival of SOTR was lower (93% vs 100%). CONCLUSIONS SOTR with CSCC-HN has significantly worse outcomes compared to immunocompetent patients. Solid-organ transplantation should be regarded as a negative prognostic factor in patients with CSCC-HN.
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Affiliation(s)
- Amit Ritter
- Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Samih Badir
- Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Muhammad Mansour
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Plastic Surgery and Burns, Rabin Medical Center, Petah Tikva, Israel
| | - Zvi Segal
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Plastic Surgery and Burns, Rabin Medical Center, Petah Tikva, Israel
| | - Dean Ad-El
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Plastic Surgery and Burns, Rabin Medical Center, Petah Tikva, Israel
| | - Gideon Bachar
- Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Thomas Shpitzer
- Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Aron Popovtzer
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel
| | - Aviram Mizrachi
- Department of Otolaryngology Head and Neck Surgery, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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18
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Way M, Marquart L, Chambers DC, Hopkins P, Miura K, Jiyad Z, Plasmeijer EI, Ferguson LE, Davis M, Whiteman DC, Soyer HP, O'Rourke P, Green AC. Skin cancer multiplicity in lung transplant recipients: a prospective population-based study. Br J Dermatol 2020; 183:503-508. [PMID: 31853948 DOI: 10.1111/bjd.18812] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/16/2019] [Indexed: 12/30/2022]
Abstract
BACKGROUND Lung transplant recipients are at high risk of skin cancer, but precise annual incidence rates of treated skin cancers per patient are unknown. OBJECTIVES To perform a prospective assessment of the total burden of histologically confirmed squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) and associated factors in lung transplant recipients. METHODS A population-based cohort of 125 Queensland lung transplant recipients aged 18 years and over, recruited between 2013 and 2015, were followed to the end of 2016. All underwent dermatological skin examinations at baseline and annually thereafter and patients self-reported all interim treated skin cancers, which were verified against pathology databases. Standard skin cancer risk factors were obtained via questionnaire, and details of medications were acquired from hospital records. RESULTS During a median follow-up time of 1·7 years, 29 (23%) and 30 (24%) lung transplant recipients with a median duration of immunosuppression of 3·3 years developed SCC and BCC, respectively. The general population age-standardized incidence rates of SCC and BCC were 201 and 171 per 1000 person-years, respectively (based on first primary SCC or BCC during follow-up); however, on accounting for multiple primary tumours, corresponding incidence rates were 447 and 281 per 1000 person-years. Risk of multiple SCCs increased around sixfold in those aged ≥ 60 years and in those with previous skin cancer, and increased around threefold in those treated with the antifungal medication voriconazole. Multiple BCC risk rose threefold from age 60 years and tenfold for patients with previous skin cancer. CONCLUSIONS Lung transplant recipients have very high incidence of multiple primary skin cancers. Close surveillance and assiduous prevention measures are essential. Linked Comment: Proby and Harwood. Br J Dermatol 2020; 183:416-417.
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Affiliation(s)
- M Way
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.,Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - L Marquart
- Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - D C Chambers
- Queensland Lung Transplant Service, Prince Charles Hospital; and School of Medicine, University of Queensland, Brisbane, Australia
| | - P Hopkins
- Queensland Lung Transplant Service, Prince Charles Hospital; and School of Medicine, University of Queensland, Brisbane, Australia
| | - K Miura
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Z Jiyad
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.,Institute of Cardiovascular and Cell Sciences (Dermatology Unit), St George's University of London, London, U.K
| | - E I Plasmeijer
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.,Department of Dermatology, Erasmus Medical Centre, Erasmus University, Rotterdam, the Netherlands
| | - L E Ferguson
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - M Davis
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - D C Whiteman
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - H P Soyer
- Department of Dermatology, Princess Alexandra Hospital, Brisbane, Australia.,Dermatology Research Centre, University of Queensland, University of Queensland Diamantina Institute, Brisbane, Australia
| | - P O'Rourke
- Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - A C Green
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.,CRUK Manchester Institute and Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, U.K
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19
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Phan K, Moloney FJ, Hogarty DT, Lenane P, McColl D, Yazdabadi A. Mammalian target of rapamycin (mTOR) inhibitors and skin cancer risk in nonrenal solid organ transplant recipients: systematic review and meta-analysis. Int J Dermatol 2020; 59:91-98. [PMID: 31228256 DOI: 10.1111/ijd.14549] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 04/06/2019] [Accepted: 05/20/2019] [Indexed: 01/24/2023]
Abstract
BACKGROUND Solid organ transplant recipients have an increased risk of malignancy compared with the general population. Mammalian target of rapamycin (mTOR) inhibitors have been used as immunosuppressants in transplant recipients. There remains a lack of evidence of this treatment in nonrenal solid organ transplantation. We aimed to perform a systematic review and meta-analysis to assess the effects of mTOR inhibitors on secondary nonmelanoma skin cancer (NMSC) malignancies in nonrenal transplant recipients. METHODS A systematic review and meta-analysis was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eligible studies for the present systematic review and meta-analysis included those in which patient cohorts underwent heart, liver, lung, and pancreas (i.e. nonrenal solid organ) transplantation, with treatment group being those treated with an mTOR inhibitor such as sirolimus or everolimus, and control group being placebo, or alternative non-mTOR inhibitor treatment such as calcineurin inhibitors or as per standard treatment protocol. RESULTS From the six included studies, we found no significant difference in the odds of either primary or secondary NMSC (OR 0.73, 95% CI 0.41-1.29, P = 0.28). Pooled analysis of patients with secondary NMSC demonstrated a trend toward significant benefit with mTOR inhibitor treatment (OR 0.61, 95% CI 0.37-1.02, P = 0.06) but no protective effect for primary NMSC (OR 0.53, 95% CI 0.03-9.96, P = 0.67). CONCLUSIONS Our results suggest that in nonrenal transplant recipients, mTOR inhibitors may have a protective effect against secondary NMSC but not primary NMSC posttransplantation. Extrapolating the findings of reduced NMSC in renal transplant populations to nonrenal transplant cases should be cautioned.
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Affiliation(s)
- Kevin Phan
- Department of Dermatology, Liverpool Hospital, Liverpool, Sydney, Australia
| | - Fergal J Moloney
- Department of Dermatology, Mater Misericordiae University Hospital, University College Dublin, Dublin, Ireland
| | - Daniel T Hogarty
- Medical School, Monash University, Victoria, Melbourne, Australia
| | - Patsy Lenane
- Department of Dermatology, Mater Misericordiae University Hospital, University College Dublin, Dublin, Ireland
| | - Douglas McColl
- Department of Dermatology, Northern Health, Victoria, Melbourne, Australia
| | - Anousha Yazdabadi
- Department of Dermatology, Northern Health, Victoria, Melbourne, Australia.,Department of Dermatology, Eastern Health, Victoria, Melbourne, Australia.,Department of Dermatology, Alfred Health, Victoria, Melbourne, Australia.,Department of Dermatology, Deakin University, Victoria, Melbourne, Australia.,Department of Dermatology, Melbourne University, Victoria, Melbourne, Australia
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20
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Identification of Risk Factors for Multiple Non-Melanoma Skin Cancers in Italian Kidney Transplant Recipients. ACTA ACUST UNITED AC 2019; 55:medicina55060279. [PMID: 31208110 PMCID: PMC6631054 DOI: 10.3390/medicina55060279] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 04/07/2019] [Accepted: 06/07/2019] [Indexed: 01/10/2023]
Abstract
Background and objectives: Non-melanoma skin cancers (NMSCs) represent the most frequently encountered malignancy in organ transplant recipients and their incidence increases proportionally to the duration of immunosuppression. Furthermore, patients of this group often develop multiple and more aggressive cancers and, to date, risk factors for the development of multiple NMSCs have not been yet established. The present study aimed to identify risk factors for multiple NMSCs in a cohort of Italian kidney transplant recipients (KTRs). Materials and Methods: We consecutively included all KTRs referring to two post-transplant outpatient clinics of North-Western Italy between 2001 and 2017. In this cohort, we evaluated different clinical (endogenous and exogenous) risk factors in order to establish their correlation with NMSCs. Results: 518 KTRs were included, of which 148 (28.6%) developed keratinocyte cancers, with a single tumor in 77 subjects, two skin cancers in 31 patients, 3 in 21 patients, whereas at least 4 NMSCs developed in 19 KTRs. We observed an increased risk of the development of cutaneous neoplasms for the male gender, old age at transplantation (>50 years), light phototype, solar lentigo, history of sunburns, or chronic actinic damage. Considering patients affected by multiple keratinocyte neoplasms, we observed a significant association of actinic damage and solar lentigo with an increased risk of NMSCs; their significance was confirmed even at the multivariable model. Conclusions: Our results confirm the role played by chronic cutaneous actinic damage in carcinogenesis on KTRs and highlight the significance of individualized periodic dermatological screening.
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21
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Peters FS, Peeters AMA, van den Bosch TPP, Mooyaart AL, van de Wetering J, Betjes MGH, Baan CC, Boer K. Disrupted regulation of serpinB9 in circulating T cells is associated with an increased risk for post-transplant skin cancer. Clin Exp Immunol 2019; 197:341-351. [PMID: 31059128 PMCID: PMC6693965 DOI: 10.1111/cei.13309] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2019] [Indexed: 12/14/2022] Open
Abstract
Cutaneous squamous cell carcinoma (cSCC) is a serious complication after organ transplantation and patients benefit from an early risk assessment. We hypothesized that functional differences in circulating T cells may represent risk factors for post‐transplant cSCC development. Here, we analysed genome‐wide DNA methylation of circulating T cells of kidney transplant recipients before the clinical onset of cSCC, to identify differences associated with post‐transplant cSCC development. This analysis identified higher DNA methylation of SERPINB9, which is an intracellular inhibitor of granzyme B, a protein that induces apoptosis in target cells. High DNA methylation of SERPINB9 in circulating T cells was confirmed in a second patient cohort during recurrent cSCC, indicating that high SERPINB9 methylation represents a persistent risk factor for cSCC development. At the functional level, the inverse correlation between DNA methylation and messenger RNA expression present in non‐cSCC patients was absent in the cSCC patients. Also, a significant difference in serpinB9 protein expression between cSCC patients and non‐cSCC patients was observed. It was concluded that disturbed regulation of serpinB9 in circulating T cells represents a novel risk factor for post‐transplant cSCC in kidney transplant recipients.
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Affiliation(s)
- F S Peters
- Rotterdam Transplant Group, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - A M A Peeters
- Rotterdam Transplant Group, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - T P P van den Bosch
- Department of Pathology, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - A L Mooyaart
- Department of Pathology, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - J van de Wetering
- Rotterdam Transplant Group, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - M G H Betjes
- Rotterdam Transplant Group, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - C C Baan
- Rotterdam Transplant Group, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - K Boer
- Rotterdam Transplant Group, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
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22
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Chan AW, Fung K, Austin PC, Kim SJ, Singer LG, Baxter NN, Alhusayen R, Rochon PA. Improved keratinocyte carcinoma outcomes with annual dermatology assessment after solid organ transplantation: Population-based cohort study. Am J Transplant 2019; 19:522-531. [PMID: 29900669 DOI: 10.1111/ajt.14966] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 06/04/2018] [Accepted: 06/04/2018] [Indexed: 01/25/2023]
Abstract
Solid organ transplant recipients have a high risk of keratinocyte carcinoma (non-melanoma skin cancer). Consensus-based transplant guidelines recommend annual dermatological examination but the impact on skin cancer-related outcomes is unclear. We conducted a population-based, retrospective, inception cohort study using administrative health databases in Ontario, Canada to evaluate the association between adherence to annual dermatology assessments (time-varying exposure) and keratinocyte carcinoma-related morbidity and mortality after transplantation. The primary outcome was the time to first advanced (highly morbid or fatal) keratinocyte carcinoma. Among 10 183 adults receiving their first transplant from 1994 to 2012 and followed for a median of 5.44 years, 4.9% developed an advanced keratinocyte carcinoma after transplant. Adherence to annual dermatology assessments for at least 75% of the observation time after transplant was associated with a 34% reduction in keratinocyte carcinoma-related morbidity or death compared with adherence levels below 75% (adjusted hazard ratio 0.66, 95% CI 0.48-0.92). Adherence levels were universally low (median proportion of time spent in adherence 0%, inter-quartile range 0-27%). Only 45% of transplant recipients had ever seen a dermatologist and 2.1% were fully adherent during the entire observation period. Strategies are needed to improve adherence rates in order to help decrease long-term morbidity after transplant.
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Affiliation(s)
- An-Wen Chan
- Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada.,Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada.,Division of Dermatology, Women's College Hospital, Toronto, Ontario, Canada.,Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Kinwah Fung
- Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
| | - Peter C Austin
- Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
| | - S Joseph Kim
- Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada.,Department of Medicine, University of Toronto, Toronto, Ontario, Canada.,Division of Nephrology, University Health Network, Toronto, Ontario, Canada
| | - Lianne G Singer
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada.,Division of Respirology, University Health Network, Toronto, Ontario, Canada
| | - Nancy N Baxter
- Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada.,Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.,Department of Surgery, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Raed Alhusayen
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada.,Division of Dermatology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Paula A Rochon
- Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada.,Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada.,Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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23
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Ritter A, Bachar G, Feinmesser R, Shpitzer T, Popovtzer A, Rabinovics N. Nonmelanoma skin cancer of the head and neck region in solid organ transplant recipients. Head Neck 2018; 41:374-380. [DOI: 10.1002/hed.25467] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Accepted: 08/17/2018] [Indexed: 01/20/2023] Open
Affiliation(s)
- Amit Ritter
- Department of Otolaryngology, Head and Neck SurgeryRabin Medical Center Petach Tikva Israel
| | - Gideon Bachar
- Department of Otolaryngology, Head and Neck SurgeryRabin Medical Center Petach Tikva Israel
| | - Raphael Feinmesser
- Department of Otolaryngology, Head and Neck SurgeryRabin Medical Center Petach Tikva Israel
| | - Thomas Shpitzer
- Department of Otolaryngology, Head and Neck SurgeryRabin Medical Center Petach Tikva Israel
| | - Aron Popovtzer
- Institute of Oncology, Davidoff CenterRabin Medical Center Petach Tikva Israel
| | - Naomi Rabinovics
- Department of Otolaryngology, Head and Neck SurgeryRabin Medical Center Petach Tikva Israel
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24
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Dantal J, Morelon E, Rostaing L, Goffin E, Brocard A, Tromme I, Broeders N, Del Marmol V, Chatelet V, Dompmartin A, Kessler M, Serra A, Hofbauer GFL, Kamar N, Pouteil-Noble C, Kanitakis J, Roux A, Decullier E, Euvrard S. Sirolimus for Secondary Prevention of Skin Cancer in Kidney Transplant Recipients: 5-Year Results. J Clin Oncol 2018; 36:2612-2620. [PMID: 30016177 DOI: 10.1200/jco.2017.76.6691] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Purpose Transplant recipients who develop cutaneous squamous cell carcinomas are at high risk for multiple subsequent skin cancers. Sirolimus has been shown to reduce the occurrence of secondary skin cancers, but no study included a follow-up exceeding 2 years. We extended at 5 years the TUMORAPA randomized trial of sirolimus-based immunosuppressive regimen versus calcineurin inhibitor-based immunosuppression. Methods Kidney transplant recipients receiving calcineurin inhibitors who had at least one cutaneous squamous cell carcinoma were randomly assigned to receive sirolimus as a substitute for calcineurin inhibitors (n = 64) or to maintain their initial treatment (n = 56). The primary end point was survival free of squamous cell carcinoma at 5 years. Secondary end points included the occurrence of other skin cancers, renal function, patient and graft survival, and treatment tolerance. Results Survival free of cutaneous squamous cell carcinoma was significantly longer in the sirolimus group than in the calcineurin inhibitor group ( P = .007). In the sirolimus group, the number of patients with new skin cancers was significantly lower compared with the calcineurin inhibitor group: 22% versus 59% for squamous cell carcinomas ( P < .001), 34% versus 66% for other skin cancers ( P < .001), and 20% versus 37.5% for basal cell carcinomas ( P < .05). Kidney graft function, patients, and graft survival were similar in both groups. In the sirolimus group, the mean number of serious adverse effects per patient decreased from 1.16 during the first 2 years, to 0.83 between years 2 and 5. Conclusion In kidney transplant recipients with previous cutaneous squamous cell carcinomas, the antitumoral effect of conversion from calcineurin inhibitors to sirolimus was maintained at 5 years, and sirolimus tolerance was satisfactory.
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Affiliation(s)
- Jacques Dantal
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Emmanuel Morelon
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Lionel Rostaing
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Eric Goffin
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Anabelle Brocard
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Isabelle Tromme
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Nilufer Broeders
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Véronique Del Marmol
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Valérie Chatelet
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Anne Dompmartin
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Michèle Kessler
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Andreas Serra
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Günther F L Hofbauer
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Nassim Kamar
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Claire Pouteil-Noble
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Jean Kanitakis
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Adeline Roux
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Evelyne Decullier
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
| | - Sylvie Euvrard
- Jacques Dantal and Anabelle Brocard, Nantes University Hospital, Nantes; Emmanuel Morelon, Claire Pouteil-Noble, Jean Kanitakis, and Sylvie Euvrard, Hospices Civils de Lyon, Edouard Herriot Hospital Group; Adeline Roux and Evelyne Decullier, Hospices Civils de Lyon, Unité de Recherche Clinique, Lyon; Lionel Rostaing and Nassim Kamar, Toulouse University Hospital, Toulouse; Valérie Chatelet and Anne Dompmartin, University Hospital of Caen, Caen; Michèle Kessler, University Hospital of Nancy, Vandœuvre-lès-Nancy, France; Eric Goffin and Isabelle Tromme, St Luc University Hospital, Woluwe-Saint-Lambert; Nilufer Broeders and Véronique del Marmol, Université Libre de Bruxelles, Bruxelles, Belgium; and Andreas Serra and Günther F.L. Hofbauer, Zürich University Hospital, Zürich, Switzerland
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Ankudowicz A, Król E, Dębska-Ślizień A, Czernych R. Level of Education and Knowledge of Skin Cancer Risk Factors in Patients Undergoing Maintenance Hemodialysis. Transplant Proc 2018; 50:1621-1624. [DOI: 10.1016/j.transproceed.2018.02.098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Accepted: 02/06/2018] [Indexed: 11/24/2022]
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26
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Peters FS, Peeters AMA, Mandaviya PR, van Meurs JBJ, Hofland LJ, van de Wetering J, Betjes MGH, Baan CC, Boer K. Differentially methylated regions in T cells identify kidney transplant patients at risk for de novo skin cancer. Clin Epigenetics 2018; 10:81. [PMID: 29946375 PMCID: PMC6006560 DOI: 10.1186/s13148-018-0519-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 06/11/2018] [Indexed: 01/08/2023] Open
Abstract
Background Cutaneous squamous cell carcinoma (cSCC) occurs 65–200 times more in immunosuppressed organ transplant patients than in the general population. T cells, which are targeted by the given immunosuppressive drugs, are involved in anti-tumor immune surveillance and are functionally regulated by DNA methylation. Prior to kidney transplantation, we aim to discover differentially methylated regions (DMRs) in T cells involved in de novo post-transplant cSCC development. Methods We matched 27 kidney transplant patients with a future de novo cSCC after transplantation to 27 kidney transplant patients without cSCC and studied genome-wide DNA methylation of T cells prior to transplantation. From 11 out of the 27 cSCC patients, the DNA methylation of T cells after transplantation was also examined to assess stability of the observed differences in DNA methylation. Raw methylation values obtained with the 450k array were confirmed with pyrosequencing. Results We found 16 DMRs between patients with a future cSCC and those who do not develop this complication after transplantation. The majority of the DMRs were located in regulatory genomic regions such as flanking bivalent transcription start sites and bivalent enhancer regions, and most of the DMRs contained CpG islands. Examples of genes annotated to the DMRs are ZNF577, coding for a zinc-finger protein, and FLOT1, coding for a protein involved in T cell migration. The longitudinal analysis revealed that DNA methylation of 9 DMRs changed significantly after transplantation. DNA methylation of 5 out of 16 DMRs was relatively stable, with a variation in beta-value lower than 0.05 for at least 50% of the CpG sites within that region. Conclusions This is the first study demonstrating that DNA methylation of T cells from patients with a future de novo post-transplant cSCC is different from patients without cSCC. These results were obtained before transplantation, a clinically relevant time point for cSCC risk assessment. Several DNA methylation profiles remained relatively stable after transplantation, concluding that these are minimally affected by the transplantation and possibly have a lasting effect on post-transplant cSCC development. Electronic supplementary material The online version of this article (10.1186/s13148-018-0519-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Fleur S Peters
- 1Neprology and Transplantation, Department of Internal Medicine, Rotterdam Transplant Group, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Annemiek M A Peeters
- 1Neprology and Transplantation, Department of Internal Medicine, Rotterdam Transplant Group, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Pooja R Mandaviya
- 2Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Joyce B J van Meurs
- 2Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Leo J Hofland
- 3Endocrinology, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Jacqueline van de Wetering
- 1Neprology and Transplantation, Department of Internal Medicine, Rotterdam Transplant Group, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Michiel G H Betjes
- 1Neprology and Transplantation, Department of Internal Medicine, Rotterdam Transplant Group, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Carla C Baan
- 1Neprology and Transplantation, Department of Internal Medicine, Rotterdam Transplant Group, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Karin Boer
- 1Neprology and Transplantation, Department of Internal Medicine, Rotterdam Transplant Group, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
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Farshchian M, Nissinen L, Siljamäki E, Riihilä P, Piipponen M, Kivisaari A, Kallajoki M, Grénman R, Peltonen J, Peltonen S, Quint KD, Bavinck JNB, Kähäri VM. Tumor cell-specific AIM2 regulates growth and invasion of cutaneous squamous cell carcinoma. Oncotarget 2018; 8:45825-45836. [PMID: 28526809 PMCID: PMC5542230 DOI: 10.18632/oncotarget.17573] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 04/18/2017] [Indexed: 12/20/2022] Open
Abstract
Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. Inflammation is a typical feature in cSCC progression. Analysis of the expression of inflammasome components in cSCC cell lines and normal human epidermal keratinocytes revealed upregulation of the expression of AIM2 mRNA and protein in cSCC cells. Elevated levels of AIM2 mRNA were noted in cSCCs in vivo compared with normal skin. Strong and moderate tumor cell specific expression of AIM2 was detected with immunohistochemistry (IHC) in sporadic human cSCCs in vivo, whereas expression of AIM2 was moderate in cSCC in situ (cSCCIS) and low or absent in actinic keratosis (AK) and normal skin. IHC of cSCCs, cSCCIS and AKs from organ transplant recipients also revealed strong and moderate tumor cell specific expression of AIM2 in cSCCs. Knockdown of AIM2 resulted in reduction in viability of cSCC cells and onset of apoptosis. RNA-seq and pathway analysis after knockdown of AIM2 in cSCC cells revealed downregulation of the biofunction category Cell cycle and upregulation of the biofunction category Cell Death and Survival. Knockdown of AIM2 also resulted in reduction in invasion of cSCC cells and downregulation in production of invasion proteinases MMP1 and MMP13. Knockdown of AIM2 resulted in suppression of growth and vascularization of cSCC xenografts in vivo. These results provide evidence for the role of AIM2 in the progression of cSCC and identify AIM2 inflammasome function as a potential therapeutic target in these invasive and metastatic tumors.
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Affiliation(s)
- Mehdi Farshchian
- Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland.,MediCity Research Laboratory, University of Turku, Turku, Finland
| | - Liisa Nissinen
- Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland.,MediCity Research Laboratory, University of Turku, Turku, Finland
| | - Elina Siljamäki
- Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland.,MediCity Research Laboratory, University of Turku, Turku, Finland
| | - Pilvi Riihilä
- Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland.,MediCity Research Laboratory, University of Turku, Turku, Finland
| | - Minna Piipponen
- Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland.,MediCity Research Laboratory, University of Turku, Turku, Finland
| | - Atte Kivisaari
- Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland.,MediCity Research Laboratory, University of Turku, Turku, Finland
| | - Markku Kallajoki
- Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland
| | - Reidar Grénman
- Department of Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Turku, Finland
| | - Juha Peltonen
- Department of Cell Biology and Anatomy, University of Turku, Turku, Finland
| | - Sirkku Peltonen
- Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland
| | - Koen D Quint
- Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.,DDL Diagnostic Laboratory, Rijswijk, The Netherlands
| | | | - Veli-Matti Kähäri
- Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland.,MediCity Research Laboratory, University of Turku, Turku, Finland
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Abstract
Basal cell carcinoma (BCC) is the most common malignancy worldwide, arising from non-keratinizing cells within the basal layer of the epidermis. The incidence of BCC continues to rise annually, increasing the burden of management of these carcinomas and the morbidity associated with their treatment. While surgical interventions such as Mohs micrographic surgery and surgical excision are the standard of care and yield the highest cure rates, the number of non-surgical interventions approved for the treatment of BCC continues to expand. We review various surgical and non-surgical approaches to the treatment of BCC, focusing on targeted molecular therapies that are approved for locally advanced or recurrent disease.
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Affiliation(s)
- Mariam Totonchy
- Department of Dermatology, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208059, New Haven, CT 06520-8059, Connecticut, USA
| | - David Leffell
- Department of Dermatology, Section of Cutaneous Oncology and Dermatologic Surgery , Yale University School of Medicine, 40 Temple Street 5A, New Haven, Connecticut, USA
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29
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Madeleine M, Patel N, Plasmeijer E, Engels E, Bouwes Bavinck J, Toland A, Green A. Epidemiology of keratinocyte carcinomas after organ transplantation. Br J Dermatol 2017; 177:1208-1216. [DOI: 10.1111/bjd.15931] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2017] [Indexed: 12/14/2022]
Affiliation(s)
| | - N.S. Patel
- University of South Florida Tampa FL U.S.A
| | - E.I. Plasmeijer
- QIMR Berghofer Medical Research Institute Queensland Australia
| | | | | | - A.E. Toland
- The Ohio State University Medical Center Columbus OH U.S.A
| | - A.C. Green
- QIMR Berghofer Medical Research Institute Queensland Australia
- CRUK Manchester Institute and University of Manchester Manchester Academic Health Sciences Centre Manchester U.K
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Effector Antitumor and Regulatory T Cell Responses Influence the Development of Nonmelanoma Skin Cancer in Kidney Transplant Patients. Transplantation 2017; 101:2102-2110. [PMID: 28403126 DOI: 10.1097/tp.0000000000001759] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Chronic immunosuppression promotes nonmelanocytic squamous cell carcinoma (SCC) after kidney transplantation. Adaptive and innate immunity play a key role controlling tumor growth and are influenced by different immunosuppressive agents. We hypothesized that functional impairment of tumor-specific T cell responses due to calcineurin inhibitors (CNI) could contribute to SCC development, whereas conversion to mammalian target of rapamycin inhibitors (mTOR-i) could recover this protective immune response. METHODS Peripheral tumor-specific T cell responses against main SCC-derived antigens using the IFN-γ enzyme-linked immunospot assay and intratumor (IT) and circulating immune phenotypes (CD4 + T, CD8 + T, CD20 + B, CD56 + NK, FOXP3 + regulatory T [Treg] cells) were explored in a cross-sectional analysis in 59 kidney transplant patients with SCC on CNI (KT-CNI-SCC) or mTOR-i (KT-mTORi-SCC), 25 nontransplants developing SCC (NoKT-SCC) and 6 healthy controls. Moreover, 25 KT-CNI-SCC were switched to mTOR-i and evaluated after 12 months. RESULTS Kidney transplant patients showed lower IT infiltrates and tumor-specific T cell responses than NoKT-SCC, and intratumoral and circulating FOXP3 + Treg cells were higher in KT-mTORi-SCC (P < 0.05). Tumor-specific T cell responses were significantly lower in KT-CNI-SCC than KT-mTORi-SCC and NoKT-SCC and predicted SCC relapses (area under the curve = 0.837; P < 0.05). One-year after mTOR-i conversion, a significant increase in FOXP3 + Treg cell numbers and tumor-specific T cell responses were observed, reaching similar levels than KT-mTORi-SCC and NoKT-SCC patients. CONCLUSIONS Tumor-specific T cell responses are strongly impaired in CNI-treated patients but recover after mTOR-i conversion, reducing SCC relapses.
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Mittal A, Colegio OR. Skin Cancers in Organ Transplant Recipients. Am J Transplant 2017; 17:2509-2530. [PMID: 28556451 DOI: 10.1111/ajt.14382] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 05/05/2017] [Accepted: 05/19/2017] [Indexed: 02/06/2023]
Abstract
Long-term utilization of immunosuppression in organ transplant recipients (OTRs) leads to decreased immune-mediated tumor surveillance and development of malignant tumors. A delicate balance needs to be maintained in the intensity of immunosuppression to keep the risk of malignancy low without jeopardizing life-saving graft function. OTRs are prone to developing skin cancers that exhibit unique epidemiologic, pathophysiologic, and prognostic characteristics. In this review, we discuss the most commonly reported skin cancers in OTRs: squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Kaposi sarcoma, Merkel cell carcinoma, and malignant melanoma (MM). Tumors in this high-risk population are aggressive and may respond poorly to standard therapies; however, new targeted therapies are promising. Checkpoint inhibitor antibodies have been used for treatment of cutaneous SCC, Merkel cell carcinoma, and MM; epidermal growth factor receptor inhibitors have been used for cutaneous SCC; hedgehog pathway inhibitors have been used for BCC; and BRAF and MEK inhibitors are being used increasingly in the management of MM. Guidelines for dermatologic screening are variable and primarily based on expert opinion. Prospective evidence-based trials by multidisciplinary groups are needed to better define surveillance schedules for pre- and posttransplant cutaneous malignancies.
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Affiliation(s)
- A Mittal
- Departments of Dermatology, Yale University School of Medicine, New Haven, CT
| | - O R Colegio
- Departments of Dermatology, Yale University School of Medicine, New Haven, CT.,Departments of Pathology, Yale University School of Medicine, New Haven, CT.,Departments of Surgery, Yale University School of Medicine, New Haven, CT.,Yale Cancer Center, Yale University School of Medicine, New Haven, CT.,Yale-New Haven Transplantation Center, Yale University School of Medicine, New Haven, CT
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Smith A, Niu W, Desai A. The Effect of Conversion from a Calcineurin Inhibitor to Sirolimus on Skin Cancer Reduction in Post-renal Transplantation Patients. Cureus 2017; 9:e1564. [PMID: 29057176 PMCID: PMC5640387 DOI: 10.7759/cureus.1564] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
In kidney transplant patients, skin cancer is the most commonly involved neoplasm. More than 90% of post-transplantation skin cancers are nonmelanoma skin cancers (NMSCs). The majority of them are squamous cell carcinomas and basal cell carcinomas. Calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus are immunosuppressive agents given after solid organ transplantation, but they can also promote tumor growth. Sirolimus is a novel class of immunosuppressants and has been proven to have antineoplastic properties. We review clinical trials and meta-analyses studying if conversion from CNI to sirolimus in post-renal transplantation patients decreases the development of NMSCs. A critical appraisal of the literature demonstrated that, while smaller scale studies tended to yield no clinically significant data, larger clinical trials and meta-analyses supported the conclusion that converting to sirolimus in post-renal transplant patients leads to reductions in skin cancer development. As a result, we conclude that conversion to sirolimus likely reduces NMSC in post-renal transplantation patients. Larger scale clinical trials with more rigorous stratification and less patient dropout rate are needed for more definitive conclusions.
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Affiliation(s)
- Aaron Smith
- College of Medicine, University of Central Florida
| | - Wei Niu
- College of Medicine, University of Central Florida
| | - Anand Desai
- College of Medicine, University of Central Florida
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Abstract
Malignancy is the second most common single cause of death observed in organ transplant recipients. The excess cancer risk is related to intensity and duration of immunosuppressive therapy and inversely to recipient age. Immunodeficiency and (chronic/oncogenic) viral infections together constitute a major risk. Nonmelanoma skin cancer, Kaposi sarcoma, and posttransplant lymphoproliferative disease have standardized incidence ratios exceeding 10- or 50-fold. The mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, are increasingly used after organ transplantation with potential advantages in virus-associated posttransplant malignancies as well as anti-cancer properties. Despite a seemingly clear mechanism of action and solid rationale for their use in cancer therapy, mTORis have met only modest success rates in clinical trials with advanced malignancies except for specific tumors, such as Kaposi sarcoma and mantle cell lymphoma. Because mTORis are primarily cytostatic, not cytotoxic, the observed clinical efficacy is a reflection of disease stabilization rather than tumor regression. Nonmelanoma skin cancers, in particular cutaneous squamous cell carcinoma, have the highest standardized incidence ratios in transplant recipients. Recent meta-analyses and randomized trials on secondary prevention of squamous cell carcinoma observed a reduction in cumulative tumor load, suggesting most benefit to be gained by early conversion to an mTOR inhibitor-based maintenance regime. There is ongoing debate on the mechanisms involved including withdrawal of the carcinogenic effects of calcineurin inhibitors and/or their impact on chronic (oncogenic) viral infections. At present, there is, however, insufficient evidence for the primary use of mTORis as protective agents against most other cancer types.
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34
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Pinho A, Gouveia M, Cardoso JC, Xavier MM, Vieira R, Alves R. Non-melanoma skin cancer in Portuguese kidney transplant recipients - incidence and risk factors. An Bras Dermatol 2017; 91:455-62. [PMID: 27579740 PMCID: PMC4999103 DOI: 10.1590/abd1806-4841.20164891] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 11/09/2015] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Cancer is currently among the three leading causes of death after solid organ transplantation and its incidence is increasing. Non-melanoma skin cancer - squamous cell carcinoma and basal cell carcinoma - is the most common malignancy found in kidney transplant recipients (KTRs). The incidence of non-melanoma skin cancer in KTRs has not been extensively studied in Portugal. OBJECTIVES To determine the incidence of non-melanoma skin cancer in KTRs from the largest Portuguese kidney transplant unit; and to study risk factors for non-melanoma skin cancer. METHODS Retrospective analysis of clinical records of KTRs referred for the first time for a dermatology consultation between 2004 and 2013. A case-control study was performed on KTRs with and without non-melanoma skin cancer. RESULTS We included 288 KTRs with a median age at transplantation of 47 years, a male gender predominance (66%) and a median transplant duration of 3.67 years. One fourth (n=71) of KTRs developed 131 non-melanoma skin cancers, including 69 (53%) squamous cell carcinomas and 62 (47%) basal cell carcinomas (ratio squamous cell carcinoma: basal cell carcinoma 1.11), with a mean of 1.85 neoplasms per patient. Forty percent of invasive squamous cell carcinomas involved at least two clinical or histological high-risk features. The following factors were associated with a higher risk of non-melanoma skin cancer: an older age at transplantation and at the first consultation, a longer transplant duration and the presence of actinic keratosis. KTRs treated with azathioprine were 2.85 times more likely to develop non-melanoma skin cancer (p=0.01). CONCLUSION Non-melanoma skin cancer was a common reason for dermatology consultation in Portuguese KTRs. It is imperative for KTRs to have access to specialized dermatology consultation for early referral and treatment of skin malignancies.
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Affiliation(s)
- André Pinho
- Centro Hospitalar e Universitário de Coimbra - Coimbra, Portugal
| | - Miguel Gouveia
- Centro Hospitalar e Universitário de Coimbra - Coimbra, Portugal
| | | | | | - Ricardo Vieira
- Centro Hospitalar e Universitário de Coimbra - Coimbra, Portugal
| | - Rui Alves
- Centro Hospitalar e Universitário de Coimbra - Coimbra, Portugal
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Comparison of the incidence of skin cancers in patients on dialysis and after kidney transplantation. Postepy Dermatol Alergol 2017; 34:138-142. [PMID: 28507493 PMCID: PMC5420606 DOI: 10.5114/ada.2017.67078] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 04/05/2016] [Indexed: 01/20/2023] Open
Abstract
INTRODUCTION Kidney transplant (KTx) patients on immunosuppressive therapy are predisposed to the development of infections and cancers. AIM To compare the incidence and type of malignant skin lesions in kidney transplant patients and the dialyzed population based on the initiated dermatologic screening. MATERIAL AND METHODS The study included 598 patients: 486 kidney transplant recipients and 112 patients on maintenance dialysis. All the patients underwent dermatological examination. Only histologically confirmed cancers were included in this study. Age, gender and immunosuppressive therapy administration were also considered. Patients were followed up by a dermatologist for a period of 5 years. RESULTS Fifty-eight skin cancers; 39 basal cell carcinomas (BCC), 13 squamous cell carcinomas (SCC), 1 Bowen disease, 2 Kaposi sarcoma, 1 malignant melanoma, 1 Merkel cell carcinoma, and 1 fibrosarcoma protuberans were diagnosed in 30 (6.2%) kidney transplant patients, and 8 lesions (7 BCC and 1 SCC) were found in 4 (3.6%) patients on dialysis. CONCLUSIONS The initiated dermatologic screening program indicates that the risk of skin cancer incidence in post kidney transplant patients receiving immunosuppressive therapy was significantly higher than in patients on dialysis.
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Oh C, Hofbauer G, Serra A, Harwood C, Mitchell L, Proby C, Olasz E, Mosel D, Piaserico S, Fortina A, Geusau A, Jahn-Bassler K, Gerritsen M, Seçkin D, Güleç A, Cetkovská P, Ricar J, Imko-Walczuk B, Dębska-Ślizień A, Bouwes Bavinck J. Painful skin lesions and squamous cell carcinoma predict overall mortality risk in organ transplant recipients: a cohort study. Br J Dermatol 2017; 176:1179-1186. [DOI: 10.1111/bjd.15269] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2016] [Indexed: 11/29/2022]
Affiliation(s)
- C.C. Oh
- Department of Dermatology; University Hospital Zürich; Zürich Switzerland
| | - G.F.L. Hofbauer
- Department of Dermatology; University Hospital Zürich; Zürich Switzerland
| | - A.L. Serra
- Epidemiology, Biostatistics and Prevention Institute; University of Zürich; Zürich Switzerland
| | - C.A. Harwood
- Barts and The London School of Medicine and Dentistry; Queen Mary University of London; London U.K
| | - L. Mitchell
- Barts and The London School of Medicine and Dentistry; Queen Mary University of London; London U.K
| | - C.M. Proby
- Barts and The London School of Medicine and Dentistry; Queen Mary University of London; London U.K
- Division of Cancer Research; University of Dundee; Ninewells Hospital and Medical School; Dundee U.K
| | - E.B. Olasz
- Medical College of Wisconsin; Milwaukee WI U.S.A
| | - D.D. Mosel
- Medical College of Wisconsin; Milwaukee WI U.S.A
| | - S. Piaserico
- Department of Medicine; University of Padua; Padua Italy
| | - A.B. Fortina
- Department of Medicine; University of Padua; Padua Italy
| | - A. Geusau
- Department of Dermatology; Medical University of Vienna; Vienna Austria
| | - K. Jahn-Bassler
- Department of Dermatology; Medical University of Vienna; Vienna Austria
| | | | - D. Seçkin
- Başkent University Faculty of Medicine; Ankara Turkey
| | - A.T. Güleç
- Başkent University Faculty of Medicine; Ankara Turkey
| | - P. Cetkovská
- University Hospital Pilsen; Pilsen Czech Republic
| | - J. Ricar
- University Hospital Pilsen; Pilsen Czech Republic
| | | | - A. Dębska-Ślizień
- Department of Nephrology, Transplantology and Internal Medicine; Medical University of Gdańsk; Gdańsk Poland
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Ducroux E, Martin C, Bouwes Bavinck JN, Decullier E, Brocard A, Westhuis-van Elsäcker ME, Lebbé C, Francès C, Morelon E, Legendre C, Joly P, Kanitakis J, Jullien D, Euvrard S, Dantal J. Risk of Aggressive Skin Cancers After Kidney Retransplantation in Patients With Previous Posttransplant Cutaneous Squamous Cell Carcinomas: A Retrospective Study of 53 Cases. Transplantation 2017; 101:e133-e141. [PMID: 28099404 PMCID: PMC7228575 DOI: 10.1097/tp.0000000000001644] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 12/05/2016] [Accepted: 12/09/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND The course of skin cancer after retransplantation in organ-transplant recipients who have already developed posttransplant skin cancer has not been assessed. METHODS This retrospective multicentric study included 53 patients with a history of cutaneous squamous cell carcinoma (SCC) after a first kidney transplantation who received a second kidney transplantation. The primary endpoint was the occurrence of aggressive cutaneous SCC after the second transplantation. Secondary endpoints included the course of skin cancers over 3 periods (first transplantation, return to dialysis, second transplantation), the time to occurrence, and risk factors for aggressive SCC after retransplantation. RESULTS The first SCC developed in 47 patients with a functional graft and in 6 after return to dialysis. After the first transplantation, 17 (33.3%) patients developed SCC in dialysis and 39 (73.6%) after the second transplantation, respectively. Twenty aggressive SCC developed over the study period. They occurred in 14 (26.4%) patients after retransplantation vs 5 (9.4%) after the first transplantation with a median delay of 50 months and were responsible for 5 deaths. Fair skin type, multiple tumors before retransplantation, treatment with azathioprine, T cell-depleting antibodies, and delayed revision of immunosuppression were associated with an increased risk of aggressive cutaneous SCC after retransplantation. CONCLUSIONS Candidates to retransplantation with a history of posttransplant SCC have a high risk of aggressive SCC. Our data suggest that the risk could be reduced by a tailored immunosuppression. A wait period may be required depending on the clinicopathological characteristics of the previous SCC and discussed on an individual patient basis.
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Affiliation(s)
- Emilie Ducroux
- 1 Department of Dermatology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France. 2 Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands. 3 Hospices Civils de Lyon, Pôle Information Médicale Evaluation Recherche, Unité de Recherche Clinique, Lyon, France. 4 Université de Lyon, Laboratoire Santé Individu Société, Lyon, France. 5 Department of Dermatology, Nantes University Medical Center, Nantes, France. 6 Department of Dermatology, Saint Louis Hospital, APHP, University Paris VII, Paris, France. 7 Department of Dermatology, Tenon Hospital, APHP, University Paris VI, Paris, France. 8 Department of Transplantation and Nephrology, Edouard Herriot Hospital, Université de Lyon, Lyon, France. 9 Department of Nephrology-Transplantation, Necker Hospital, APHP, Paris, France. 10 Department of Dermatology, Charles-Nicolle University Medical Center, Rouen, France. 11 Department of Renal Medicine and Transplantation, Nantes University Medical Center, Nantes, France
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Verkouteren J, Ramdas K, Wakkee M, Nijsten T. Epidemiology of basal cell carcinoma: scholarly review. Br J Dermatol 2017; 177:359-372. [DOI: 10.1111/bjd.15321] [Citation(s) in RCA: 133] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/07/2016] [Indexed: 12/21/2022]
Affiliation(s)
- J.A.C. Verkouteren
- Department of Dermatology; Erasmus MC Cancer Institute; Burgemeester s'Jacobplein 51 3015 CA Rotterdam the Netherlands
| | - K.H.R. Ramdas
- Department of Dermatology; Erasmus MC Cancer Institute; Burgemeester s'Jacobplein 51 3015 CA Rotterdam the Netherlands
| | - M. Wakkee
- Department of Dermatology; Erasmus MC Cancer Institute; Burgemeester s'Jacobplein 51 3015 CA Rotterdam the Netherlands
| | - T. Nijsten
- Department of Dermatology; Erasmus MC Cancer Institute; Burgemeester s'Jacobplein 51 3015 CA Rotterdam the Netherlands
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Bostom AG, Merhi B, Walker J, Robinson-Bostom L. More than skin deep? Potential nicotinamide treatment applications in chronic kidney transplant recipients. World J Transplant 2016; 6:658-664. [PMID: 28058215 PMCID: PMC5175223 DOI: 10.5500/wjt.v6.i4.658] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 10/03/2016] [Accepted: 11/02/2016] [Indexed: 02/05/2023] Open
Abstract
Non-melanoma cutaneous carcinomas, or skin cancers, predominantly squamous cell carcinomas (SCCs), are the most common malignancies occurring in kidney transplant recipients (KTRs). Squamous cell carcinoma risk is dramatically elevated in KTRs, occurring at rates of up 45-250 times those reported in general populations. New non-melanoma skin cancers in KTRs with a prior non-melanoma skin cancer also develop at 3-times the rate reported in non-KTRs with the same clinical history. The unique aggressiveness of SCCs in KTRs increases patient morbidity, due to the high rate of new lesions requiring treatment, frequently surgical excision. Oral nicotinamide shows promise in the chemoprevention of the especially aggressive non-melanoma skin cancers which occur in KTRs. This benefit might be conferred via its inhibition of sirtuin enzymatic pathways. Nicotinamide’s concurrent hypophosphatemic effect may also partially ameliorate the disturbed calcium-phosphorus homeostasis in these patients-a putative risk factor for mortality, and graft failure. Conceivably, a phase 3 trial of nicotinamide for the prevention of non-melanoma skin cancers in KTRs, lasting at least 12-mo, could also incorporate imaging and laboratory measures which assess nicotinamide’s impact on subclinical cardiovascular and chronic kidney disease risk, and progression.
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Jiyad Z, Olsen CM, Burke MT, Isbel NM, Green AC. Azathioprine and Risk of Skin Cancer in Organ Transplant Recipients: Systematic Review and Meta-Analysis. Am J Transplant 2016; 16:3490-3503. [PMID: 27163483 DOI: 10.1111/ajt.13863] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Revised: 04/12/2016] [Accepted: 05/02/2016] [Indexed: 01/25/2023]
Abstract
Azathioprine, a purine antimetabolite immunosuppressant, photosensitizes the skin and causes the production of mutagenic reactive oxygen species. It is postulated to increase the risk of squamous cell carcinoma (SCC) and other skin cancers in organ transplant recipients (OTRs), but evidence from multiple, largely single-center studies to date has been inconsistent. We aimed to resolve the issue of azathioprine's carcinogenicity by conducting a systematic review of the relevant literature and pooling published risk estimates to evaluate the risks of SCC, basal cell carcinoma (BCC), keratinocyte cancers (KCs) overall and other skin cancers in relation to azathioprine treatment. Twenty-seven studies were included in total, with risk estimates from 13 of these studies able to be pooled for quantitative analysis. The overall summary estimate showed a significantly increased risk of SCC in relation to azathioprine exposure (1.56, 95% confidence interval [CI] 1.11-2.18). No significant associations between azathioprine treatment and BCC (0.96, 95% CI 0.66-1.40) or KC (0.84, 95% CI 0.59-1.21) risk were observed. There was significant heterogeneity between studies for azathioprine risk estimates and the outcomes of SCC, BCC and KC. The pooled findings of available evidence support the contention that treatment with azathioprine increases the risk of SCC in OTRs.
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Affiliation(s)
- Z Jiyad
- Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,Institute of Cardiovascular and Cell Sciences (Dermatology Unit), St. George's University of London, London, United Kingdom
| | - C M Olsen
- Cancer Control Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,School of Public Health, University of Queensland, Brisbane, Queensland, Australia
| | - M T Burke
- Department of Nephrology, University of Queensland at Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - N M Isbel
- Department of Nephrology, University of Queensland at Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - A C Green
- Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,CRUK Manchester Institute and Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom
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Koyfman SA, Cooper JS, Beitler JJ, Busse PM, Jones CU, McDonald MW, Quon H, Ridge JA, Saba NF, Salama JK, Siddiqui F, Smith RV, Worden F, Yao M, Yom SS. ACR Appropriateness Criteria(®) Aggressive Nonmelanomatous Skin Cancer of the Head and Neck. Head Neck 2016; 38:175-82. [PMID: 26791005 DOI: 10.1002/hed.24171] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 06/11/2015] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Aggressive nonmelanomatous skin cancer (NMSC) of the head and neck presents an increasingly common therapeutic challenge for which prospective clinical trials are lacking. METHODS The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. RESULTS The American College of Radiology Expert Panel on Radiation Oncology - Head and Neck Cancer developed consensus recommendations for guiding management of aggressive NMSC. CONCLUSION Multidisciplinary assessment is vital to guiding the ideal use of surgery, radiation, and systemic therapy in this disease.
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Affiliation(s)
| | | | | | - Paul M Busse
- Massachusetts General Hospital, Boston, Massachusetts
| | | | - Mark W McDonald
- Indiana University School of Medicine, Indianapolis, Indiana
| | - Harry Quon
- Johns Hopkins University, Baltimore, Maryland
| | - John A Ridge
- Fox Chase Cancer Center, Philadelphia, Pennsylvania, American College of Surgeons
| | - Nabil F Saba
- Emory University, Atlanta, Georgia, American Society of Clinical Oncology
| | | | | | - Richard V Smith
- Montefiore Medical Center, Bronx, New York, American College of Surgeons
| | - Francis Worden
- University of Michigan, Ann Arbor, Michigan, American Society of Clinical Oncology
| | - Min Yao
- University Hospitals Case Medical Center, Cleveland, Ohio
| | - Sue S Yom
- University of California San Francisco, San Francisco, California
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Krynitz B, Olsson H, Lundh Rozell B, Lindelöf B, Edgren G, Smedby KE. Risk of basal cell carcinoma in Swedish organ transplant recipients: a population-based study. Br J Dermatol 2015; 174:95-103. [PMID: 26333521 DOI: 10.1111/bjd.14153] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2015] [Indexed: 11/27/2022]
Abstract
BACKGROUND Risk of basal cell carcinoma (BCC) has been reported to be several-fold increased among organ transplant recipients (OTRs). However, due to lack of reliable BCC registration, population-based risk estimates are scarce. OBJECTIVES To characterize risk of BCC among OTRs compared with the general population, and contrast with risk of cutaneous squamous cell carcinoma (SCC). SUBJECTS AND METHODS OTRs transplanted during 2004-2011 were identified through national healthcare registers and linked with the nationwide Swedish BCC Register initialized in 2004. Relative risk of BCC was expressed as standardized incidence ratios (SIR) with 95% confidence intervals (CI). RESULTS Altogether, 4023 transplanted patients developed 341 BCCs during follow-up. Compared with the general population, the relative risk of BCC was increased sixfold (SIR 6·1, 95% CI 5·4-6·9). The risk was higher in kidney and heart/lung than in liver recipients (SIRkidney 7·2, 6·3-8·3; SIRheart/lung 5·8, 4·0-8·2; SIRliver 2·6, 1·7-4·0), and risk increased with time since transplantation (Ptrend < 0·01). The SCC to BCC ratio was 1 : 1·7 and BCC developed earlier after transplantation than SCC. Distribution of anatomical sites and histological types did not differ substantially between OTR- and population-BCCs. CONCLUSIONS Risk of BCC was strikingly elevated in OTRs compared with the general population. Risk was higher in kidney recipients and increased with follow-up time. These findings support a tumour-promoting effect of immunosuppressive drugs in BCC development. The low SCC to BCC ratio was possibly attributed to short follow-up time.
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Affiliation(s)
- B Krynitz
- Department of Pathology and Cytology, F46, Karolinska University Laboratories, Huddinge, 14186, Stockholm, Sweden. .,Dermatology and Venereology Unit, Karolinska Institutet, Stockholm, Sweden.
| | - H Olsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.,Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - B Lundh Rozell
- Department of Clinical Pathology and Clinical Genetics, Linköping University, Linköping, Sweden.,Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - B Lindelöf
- Dermatology and Venereology Unit, Karolinska Institutet, Stockholm, Sweden.,Department of Dermatology, Karolinska University Hospital, Stockholm, Sweden
| | - G Edgren
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.,Hematology Centre, Karolinska University Hospital, Stockholm, Sweden
| | - K E Smedby
- Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.,Hematology Centre, Karolinska University Hospital, Stockholm, Sweden
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Bottomley MJ, Harden PN, Wood KJ. CD8+ Immunosenescence Predicts Post-Transplant Cutaneous Squamous Cell Carcinoma in High-Risk Patients. J Am Soc Nephrol 2015; 27:1505-15. [PMID: 26563386 DOI: 10.1681/asn.2015030250] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 08/05/2015] [Indexed: 01/19/2023] Open
Abstract
Most morbidity associated with malignancy in long-term renal transplant recipients is due to cutaneous squamous cell carcinoma (SCC). Previously identified measures to stratify SCC risk have limited use, however. We hypothesized that an increased proportion of senescent, terminally differentiated CD8(+) T cells would identify renal transplant recipients at elevated SCC risk. Peripheral blood lymphocytes were isolated from 117 stable transplant recipients at high risk of SCC and analyzed phenotypically by flow cytometry. Participants were followed up prospectively for SCC development. The predictive value of variables was assessed using Cox regression. Age at transplant and enrollment, dialysis duration, and previous disease were predictive of SCC development during follow-up. Previously published clinical phenotype-based risk scores lost predictive value with the removal of age as a covariate. The percentage of CD57-expressing CD8(+) T cells was the strongest immunologic predictor of future SCC and correlated with increasing CD8(+) T cell differentiation. We dichotomized participants into those with a majority (CD57hi) and a minority (CD57lo) of CD8(+) T cells expressing CD57; CD57hi participants were more likely to develop SCC during follow-up (hazard ratio, 2.9; 95% confidence interval, 1.0 to 8.0), independent of potential confounders, and tended to develop earlier recurrence. The CD57hi phenotype was stable with time and associated with increasing age and cytomegalovirus seropositivity. Our results show that the CD57hi phenotype is a strong predictor of SCC development and recurrence in this cohort of long-term, high-risk renal transplant recipients. This information may allow identification of recipients who may benefit from intensive dermatologic screening and immunosuppression reduction.
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Affiliation(s)
- Matthew J Bottomley
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom; and Oxford Kidney Unit, Churchill Hospital, Oxford, United Kingdom
| | - Paul N Harden
- Oxford Kidney Unit, Churchill Hospital, Oxford, United Kingdom
| | - Kathryn J Wood
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom; and
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Gerber S, Seifert B, Inci I, Serra A, Kohler M, Benden C, Hofbauer G, Schuurmans M. Exposure to moxifloxacin and cytomegalovirus replication is associated with skin squamous cell carcinoma development in lung transplant recipients. J Eur Acad Dermatol Venereol 2015; 29:2451-7. [DOI: 10.1111/jdv.13389] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Accepted: 07/27/2015] [Indexed: 12/14/2022]
Affiliation(s)
- S.R. Gerber
- Division of Dermatology; University Hospital Zurich; Zurich Switzerland
- Division of Pulmonology; University Hospital Zurich; University of Zurich; Zurich Switzerland
| | - B. Seifert
- Epidemiology, Biostatistics, and Prevention Institute; University of Zurich; Zurich Switzerland
| | - I. Inci
- Division of Thoracic Surgery; University Hospital Zurich; Zurich Switzerland
| | - A.L. Serra
- Epidemiology, Biostatistics, and Prevention Institute; University of Zurich; Zurich Switzerland
| | - M. Kohler
- Division of Pulmonology; University Hospital Zurich; University of Zurich; Zurich Switzerland
| | - C. Benden
- Division of Pulmonology; University Hospital Zurich; University of Zurich; Zurich Switzerland
| | - G.F.L. Hofbauer
- Division of Dermatology; University Hospital Zurich; Zurich Switzerland
| | - M.M. Schuurmans
- Division of Pulmonology; University Hospital Zurich; University of Zurich; Zurich Switzerland
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Peripheral natural killer cell and allo-stimulated T-cell function in kidney transplant recipients associate with cancer risk and immunosuppression-related complications. Kidney Int 2015; 88:1374-1382. [PMID: 26266834 DOI: 10.1038/ki.2015.237] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 06/05/2015] [Accepted: 06/12/2015] [Indexed: 12/12/2022]
Abstract
Reducing immunosuppression has been proposed as a means of preventing cancer in kidney transplant recipients but this can precipitate graft rejection. Here we tested whether anti-tumor natural killer (NK) cell and allo-responsive T-cell function in kidney transplant recipients may predict cancer risk and define risk of rejection. NK cell function was measured by the release of lactate dehydrogenase and T-cell allo-response by interferon-γ quantification using a panel of reactive T-cell enzyme-linked immunospot (ELISPOT) in 56 kidney transplant recipients with current or past cancer and 26 kidney transplant recipients without cancer. NK function was significantly impaired and the allo-response was significantly lower in kidney transplant recipients with cancer. With prospective follow-up, kidney transplant recipients with poor NK cell function had a hazard ratio of 2.1 (95% confidence interval 0.97-5.00) for the combined end point of metastatic cancer, cancer-related death, or septic death. Kidney transplant recipients with low interferon-γ release were also more likely to reach this combined end point. Thus, posttransplant monitoring of allo-immunity and NK cell function is useful for assessing the risk of over immunosuppression for the development of malignancy and/or death from cancer or sepsis.
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Hayashida MZ, Fernandes VMC, Fernandes DRDM, Ogawa MM, Tomimori J. Epidemiology and clinical evolution of non-melanoma skin cancer in renal transplant recipients: a single-center experience in São Paulo, Brazil. Int J Dermatol 2015; 54:e383-8. [PMID: 25969871 DOI: 10.1111/ijd.12632] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2013] [Revised: 11/09/2013] [Accepted: 12/31/2013] [Indexed: 12/19/2022]
Abstract
BACKGROUND Non-melanoma skin cancer (NMSC) is very common among renal transplant recipients (RTRs) as a result of the immunosuppressed status of these patients and other factors. Few studies have examined the clinical characteristics and evolution of NMSC in RTRs in tropical countries. OBJECTIVES The aim of this study was to characterize the epidemiology and clinical evolution of NMSC in RTRs. METHODS We conducted a retrospective study including 68 RTRs with NMSC diagnosed from July 2004 to December 2009 with a minimum follow-up of three years. We analyzed demographic and transplant- and NMSC-related data. RESULTS The mean age of patients at the first diagnosis of NMSC was 51 years (range: 29-71 years). Most first diagnoses occurred within nine years post-transplant. The majority of patients (n = 48) had Fitzpatrick skin phototype II, although NMSC was also observed in those with skin phototypes III and IV. Forty-six (67.6%) RTRs had received a kidney from a living donor. Fifty-five (80.9%) RTRs had received cytotoxic immunosuppressives, 51 (75.0%) had received calcineurin inhibitors, and two (2.9%) had received mTOR inhibitors. Most of the RTRs developed about eight NMSC lesions, but up to 25 NMSC lesions were diagnosed in one patient. Most lesions (67.6%) were located on sun-exposed areas. Squamous cell carcinoma (SCC) represented the predominant tumor type, accounting for 70.6% of all tumors, whereas basal cell carcinoma accounted for 29.4% of all tumors. Invasive SCC predominated over in situ SCC. Finally, 48.5% of patients had a previous history of viral warts. CONCLUSIONS Long-term use of immunosuppressive therapy increases the risk for tumor occurrence. Multiple NMSC tumors can develop in patients in tropical countries, even in patients with a high skin phototype. Therefore, RTRs should understand the high risk for the development of malignant tumors and should be properly informed about the prevention and treatment of NMSC.
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Affiliation(s)
- Marina Zoega Hayashida
- Department of Dermatology, Escola Paulista de Medicina (Paulista School of Medicine), Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Victor Miguel Coutinho Fernandes
- Department of Dermatology, Escola Paulista de Medicina (Paulista School of Medicine), Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Diana Rosa de Melo Fernandes
- Department of Dermatology, Escola Paulista de Medicina (Paulista School of Medicine), Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Marília Marufuji Ogawa
- Department of Dermatology, Escola Paulista de Medicina (Paulista School of Medicine), Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Jane Tomimori
- Department of Dermatology, Escola Paulista de Medicina (Paulista School of Medicine), Federal University of São Paulo (UNIFESP), São Paulo, Brazil
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Ulrich C, Arnold R, Frei U, Hetzer R, Neuhaus P, Stockfleth E. Skin changes following organ transplantation: an interdisciplinary challenge. DEUTSCHES ARZTEBLATT INTERNATIONAL 2015; 111:188-94. [PMID: 24698074 DOI: 10.3238/arztebl.2014.0188] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Revised: 01/07/2014] [Accepted: 01/07/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND The immunosuppressants used in transplantation medicine significantly elevate the incidence of neoplasia, particularly in the skin. The cumulative incidence of non-melanocytic skin cancer (NMSC) in renal transplant recipients was 20.5% in a study carried out in German centers. Data on more than 35 000 renal transplant recipients in the USA document a cumulative NMSC incidence of over 7% after 3 years of immunosuppression. METHOD The authors selectively review publications obtained by a PubMed search to discuss the incidence of, and major risk factors for, skin tumors and infectious diseases of the skin in immunosuppressed patients. RESULTS The main risk factors for skin tumors are age at the time of transplantation, light skin color, previous and present exposure to sunlight, and the type and duration of immunosuppressive treatment. Squamous-cell carcinoma (SCC) is the most common kind of skin tumor in immunosuppressed patients. Human herpesvirus 8 and Merkel-cell polyoma virus also cause neoplasia more often in immunosuppressed patients than in the general population. Surgical excision is the treatment of choice. Actinic keratosis markedly elevates the risk that SCC will arise in the same skin area (odds ratio 18.36, 95% confidence interval 3.03-111). Patients with multiple actinic keratoses can be treated with photodynamic therapy or with acitretin. To lower the skin cancer risk, organ transplant recipients should apply medical screening agents with a sun protection factor of at least 50 to exposed skin areas every day. 55% to 97% of organ transplant recipients have skin infections; these are treated according to their respective types. CONCLUSION Squamous-cell carcinoma of the skin adds to the morbidity and mortality of transplant recipients and is therefore among the major oncological challenges in this patient group. Structured concepts for interdisciplinary care enable risk-adapted treatment.
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Affiliation(s)
- Claas Ulrich
- Outpatient Clinic for the Follow-up Care of Immunosuppressed Patients, Skin Tumor Center, Charité - Universitätsmedizin Berlin, Department of Hematology, Oncology, and Tumor Immunology Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Medical Director, Charité - Universitätsmedizin Berlin, Department of Cardiac, Cardiothoracic and Vascular Surgery, German Heart Institute Berlin, Department of General, Visceral, and Transplant Surgery, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin
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Exclusive Development of a Single Type of Keratinocyte Skin Cancer: Evidence from an Australian Population–Based Cohort Study. J Invest Dermatol 2015; 135:728-733. [DOI: 10.1038/jid.2014.410] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 08/11/2014] [Accepted: 08/26/2014] [Indexed: 11/08/2022]
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Savoia P, Cavaliere G, Fava P. Risk of infectious diseases and cutaneous tumours in solid organ recipients: A meta-analysis of literature. World J Meta-Anal 2015; 3:11-19. [DOI: 10.13105/wjma.v3.i1.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 09/08/2014] [Accepted: 11/19/2014] [Indexed: 02/05/2023] Open
Abstract
AIM: To compare the risk of cutaneous infections and tumours in kidney transplant recipients with data recently published about this topic.
METHODS: In the present work, we evaluated the incidence of bacterial, fungal and viral cutaneous infectious diseases and the development of skin cancers in a cohort of 436 patients who underwent a renal transplantation. The median age at transplantation of our patients was 50 years and the median duration of the immunosuppression was of 7.2 years. Data obtained from our cohort were compared with those obtained by a systematic review of the literature of the last 20 years about the same topic.
RESULTS: Infectious diseases were the most frequent dermatological disorders that were diagnosed after transplantation, affecting about the 16.5% of patients. Herpes virus reactivation occurs in about the 35% of patients and is more common within 6 mo from transplantation, whereas when the immunosuppression is reduced, skin infections are mainly represented by Human Papilloma Virus infections and localized mycosis, such as pityriasis versicolor and superficial candidiasis. Bacterial infections were relatively rare and occur mainly in the first months after transplantation. The cumulative risk to develop skin cancer enhance significantly over the time, as consequence of long-term immunosuppressive regiments. Endogenous and exogenous risk factors, as well as the schedule of immunosuppression can play a role and justify the different incidence of skin cancer in the various series.
CONCLUSION: Skin infections and cancer, commonly diagnosed in transplanted patients, impact on survival and life-quality, justifying the realization of follow-up programs for the early diagnosis and treatment.
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Hope CM, Coates PTH, Carroll RP. Immune profiling and cancer post transplantation. World J Nephrol 2015; 4:41-56. [PMID: 25664246 PMCID: PMC4317627 DOI: 10.5527/wjn.v4.i1.41] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 11/03/2014] [Accepted: 11/07/2014] [Indexed: 02/06/2023] Open
Abstract
Half of all long-term (> 10 year) australian kidney transplant recipients (KTR) will develop squamous cell carcinoma (SCC) or solid organ cancer (SOC), making cancer the leading cause of death with a functioning graft. At least 30% of KTR with a history of SCC or SOC will develop a subsequent SCC or SOC lesion. Pharmacological immunosuppression is a major contributor of the increased risk of cancer for KTR, with the cancer lesions themselves further adding to systemic immunosuppression and could explain, in part, these phenomena. Immune profiling includes; measuring immunosuppressive drug levels and pharmacokinetics, enumerating leucocytes and leucocyte subsets as well as testing leucocyte function in either an antigen specific or non-specific manner. Outputs can vary from assay to assay according to methods used. In this review we define the rationale behind post-transplant immune monitoring assays and focus on assays that associate and/or have the ability to predict cancer and rejection in the KTR. We find that immune monitoring can identify those KTR of developing multiple SCC lesions and provide evidence they may benefit from pharmacological immunosuppressive drug dose reductions. In these KTR risk of rejection needs to be assessed to determine if reduction of immunosuppression will not harm the graft.
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