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Algarin YA, Jambusaria-Pahlajani A, Ruiz E, Patel VA. Advances in Topical Treatments of Cutaneous Malignancies. Am J Clin Dermatol 2023; 24:69-80. [PMID: 36169917 DOI: 10.1007/s40257-022-00731-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/12/2022] [Indexed: 01/26/2023]
Abstract
Surgical excision has been the preferred treatment for cutaneous malignancies, but can be affected by various considerations. Noninvasive, self-administered topical treatments represent an alternative option. The aim of this review was to evaluate and summarize evidence-based recommendations for topical treatments of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (CSCC), in situ melanoma (MIS), and extramammary Paget's disease (EMPD). Studies were reviewed on PubMed. Included studies were summarized, assessed for biases, and assigned a level of evidence to develop treatment recommendations. For the treatment of superficial BCC, complete clearance rates ranged from 90 to 93% for 5% 5-fluorouracil (5-FU) and 71 to 76% for imiquimod (IMQ). For the treatment of nodular BCC, clearance rates for photodynamic therapy (PDT) were 91% at 3 months, with a sustained lesion clearance response rate of 76% after 5 years of follow-up. Clearance rates were 53 to 76% with IMQ. For squamous cell carcinoma in situ, clearance rates ranged from 52 to 98% for PDT, 67 to 92% for 5-FU, and 75 to 93% for IMQ. For MIS, clearance rates ranged from 53 to 92% for IMQ. For EMPD, 54% of 110 patients in cohort studies and case series had a clinical complete response with IMQ. While surgical intervention remains the standard of care for skin cancer, non-invasive, self-administered topical treatments are highly desirable alternative options. Ultimately, the patient and provider should find a treatment modality that aligns with the patient's expectations and maintenance of quality of life.
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Affiliation(s)
| | | | - Emily Ruiz
- Department of Dermatology, Brigham and Women's Hospital, Boston, MA, USA
| | - Vishal A Patel
- Department of Dermatology, The George Washington School of Medicine and Health Sciences, 2150 Pennsylvania Avenue 2B, NW, Washington, DC, 20037, USA.
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De Novo Carcinoma after Solid Organ Transplantation to Give Insight into Carcinogenesis in General-A Systematic Review and Meta-Analysis. Cancers (Basel) 2021; 13:cancers13051122. [PMID: 33807849 PMCID: PMC7961956 DOI: 10.3390/cancers13051122] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/20/2021] [Accepted: 03/02/2021] [Indexed: 11/21/2022] Open
Abstract
Simple Summary Patients receiving a solid organ transplantation, such as a kidney, liver, or lung transplantation, inevitably have to take drugs to suppress the immune system in order to prevent rejection of the transplanted organ. However, these drugs are known to cause malignancies in the long term. This study focuses specifically on newly developed carcinomas in patients who use those drugs after a solid organ transplantation. This systematic review and meta-analysis of published data show a 20-fold risk to develop a carcinoma after solid organ transplantation compared to the general population, with specifically increased risks in patients who receive cyclosporine or azathioprine. By comparing the different pathways involved in immunosuppression and the occurrence of carcinoma development, new insights can be discovered for future research and understanding of carcinoma development in transplantation patients and the general population as well. Abstract Immunosuppressive therapy after solid organ transplantation leads to the development of cancer in many recipients. Analysis of the occurrence of different types of de novo carcinomas in relation to specific immunosuppressive drugs may give insight into their carcinogenic process and carcinogenesis in general. Therefore, a systematic search was performed in Embase and PubMed. Studies describing over five de novo carcinomas in patients using immunosuppressive drugs after solid organ transplantation were included. Incidence per 1000 person-years was calculated with DerSimonian–Laird random effects model and odds ratio for developing carcinomas with the Mantel–Haenszel test. Following review of 5606 papers by title and abstract, a meta-analysis was conducted of 82 studies. The incidence rate of de novo carcinomas was 8.41. Patients receiving cyclosporine developed more de novo carcinomas compared to tacrolimus (OR1.56, 95%CI 1.00–2.44) and mycophenolate (OR1.26, 95%CI 1.03–1.56). Patients receiving azathioprine had higher odds to develop de novo carcinomas compared to mycophenolate (OR3.34, 95%CI 1.29–8.65) and head and neck carcinoma compared to tacrolimus (OR3.78, 95%CI 1.11–12.83). To conclude, patients receiving immunosuppressive drugs after solid organ transplantation have almost a 20-fold increased likelihood of developing carcinomas, with the highest likelihood for patients receiving cyclosporine A and azathioprine. Looking into altered immune pathways affected by immunosuppressive drugs might lead to better understanding of carcinogenesis in general.
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Kemp Bohan PM, Mankaney G, Vreeland TJ, Chick RC, Hale DF, Cindass JL, Hickerson AT, Ensley DC, Sohn V, Clifton GT, Peoples GE, Burke CA. Chemoprevention in familial adenomatous polyposis: past, present and future. Fam Cancer 2021; 20:23-33. [PMID: 32507936 PMCID: PMC7276278 DOI: 10.1007/s10689-020-00189-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 05/18/2020] [Indexed: 01/05/2023]
Abstract
Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome characterized by colorectal adenomas and a near 100% lifetime risk of colorectal cancer (CRC). Prophylactic colectomy, usually by age 40, is the gold-standard therapy to mitigate this risk. However, colectomy is associated with morbidity and fails to prevent extra-colonic disease manifestations, including gastric polyposis, duodenal polyposis and cancer, thyroid cancer, and desmoid disease. Substantial research has investigated chemoprevention medications in an aim to prevent disease progression, postponing the need for colectomy and temporizing the development of extracolonic disease. An ideal chemoprevention agent should have a biologically plausible mechanism of action, be safe and easily tolerated over a prolonged treatment period, and produce a durable and clinically meaningful effect. To date, no chemoprevention agent tested has fulfilled these criteria. New agents targeting novel pathways in FAP are needed. Substantial preclinical literature exists linking the molecular target of rapamycin (mTOR) pathway to FAP. A single case report of rapamycin, an mTOR inhibitor, used as chemoprevention in FAP patients exists, but no formal clinical studies have been conducted. Here, we review the prior literature on chemoprevention in FAP, discuss the rationale for rapamycin in FAP, and outline a proposed clinical trial testing rapamycin as a chemoprevention agent in patients with FAP.
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Affiliation(s)
- Phillip M Kemp Bohan
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA.
| | - Gautam Mankaney
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland, OH, USA
| | - Timothy J Vreeland
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | - Robert C Chick
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | - Diane F Hale
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | - Jessica L Cindass
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | - Annelies T Hickerson
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | - Daniel C Ensley
- Department of Urology, Brooke Army Medical Center, Ft. Sam Houston, TX, USA
| | - Vance Sohn
- Department of Surgery, Madigan Army Medical Center, Joint Base Lewis-McChord, Tacoma, WA, USA
| | - G Travis Clifton
- Department of Surgery, Brooke Army Medical Center, 3551 Roger Brooke Dr., Ft Sam Houston, TX, 78234, USA
| | | | - Carol A Burke
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland, OH, USA
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Rapamycin inhibits lung squamous cell carcinoma growth by downregulating glypican-3/Wnt/β-catenin signaling and autophagy. J Cancer Res Clin Oncol 2020; 147:499-505. [PMID: 33225417 DOI: 10.1007/s00432-020-03422-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 10/08/2020] [Indexed: 12/21/2022]
Abstract
PURPOSE There is not much progress in the treatment for lung squamous cell carcinoma LSCC in the past few years. Rapamycin Rapa, an inhibitor of mammalian target of rapamycin mTOR, has exhibited antitumor efficacy in a variety of malignant tumors. It has recently been reported that Rapamycin can induce autophagy signaling pathway in lung cancer and Glypican-3GPC3 can promote the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling pathway. The aim of this study is to investigate the mechanisms of rapamycin's antitumor efficacy in relation to GPC3/Wnt/β-catenin pathway and autophagy in LSCC. METHODS SK-MES-1 cells, a LSCC cell line, were treated with various concentrations of rapamycin with or without Glypican-3 GPC3-targeting siRNA. SK-MES-1 cell proliferation was determined by MTT assay. Protein expression levels of GPC3, β-catenin, Beclin-1 were checked via western blotting. We established the xenograft mice model to investigate the suppression effect of rapamycin on LSCC. In addition, we further testified the metabolism protein of autophagy process using the xenograft tumor tissue. RESULTS Rapamycin could inhibit the SK-MES-1 cell proliferation in a concentration-dependent manner both in vitro and in vivo by decreasing the GPC3 expression and downregulating the glypican-3/Wnt/β-catenin signaling pathway. In addition, we found that GPC3 silencing can activate the glypican-3/Wnt/β-catenin pathway and autophagy, which contribute to the suppression of tumor growth both in vitro and in vivo. CONCLUSION Rapamycin suppresses the growth of lung cancer through down-regulating glypican-3/Wnt/β-catenin signaling, which mediates with activation of autophagy. This study suggests GPC3 is a new promising target for rapamycin in the treatment of lung cancer.
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Imko-Walczuk B, Roskosz-Stożkowska M, Szymańska K, Kadylak D, Dębska-Ślizień A. Skin cancer in children after organ transplantation. Postepy Dermatol Alergol 2019; 36:649-654. [PMID: 31997989 PMCID: PMC6986283 DOI: 10.5114/ada.2019.82680] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 12/17/2019] [Indexed: 01/20/2023] Open
Abstract
Skin cancer is the second most common complication of organ transplantation in children. The frequency of skin cancer incidence after organ transplantation is different in paediatric and adult populations. The post-transplant lymphoproliferative disease is the most common group of malignancies after organ transplantation in paediatric population. The majority of researchers who examined children with kidney, liver, heart or lungs grafts observed that the risk of skin cancer was three times higher than in the general population whereas in adults even200 times higher. The occurrence of skin cancer in children after transplantation is extremely rare during childhood. The risk increases in early adulthood. Malignancies occurring after solid organ transplantation result from many different factors. These include the immunological condition of the child, dose and time of immunosuppression, and oncogenic viruses. The increased risk of skin cancer following paediatric transplantation requires prevention and adequate education of children and their parents. These involve avoiding sun exposure and protection such as sunscreens and protective clothing. The early detection of cancer in transplant recipients is very important. Prevention of cancer includes regular dermatological examination.
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Affiliation(s)
- Beata Imko-Walczuk
- Dermatology and STD Outpatient Clinic, Copernicus Medical Centre, Gdansk, Poland
| | | | | | - Damian Kadylak
- Dermatology and STD Outpatient Clinic, Copernicus Medical Centre, Gdansk, Poland
| | - Alicja Dębska-Ślizień
- Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdansk, Gdansk, Poland
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Sprangers B, Nair V, Launay-Vacher V, Riella LV, Jhaveri KD. Risk factors associated with post-kidney transplant malignancies: an article from the Cancer-Kidney International Network. Clin Kidney J 2018; 11:315-329. [PMID: 29942495 PMCID: PMC6007332 DOI: 10.1093/ckj/sfx122] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 09/15/2017] [Indexed: 12/13/2022] Open
Abstract
In kidney transplant recipients, cancer is one of the leading causes of death with a functioning graft beyond the first year of kidney transplantation, and malignancies account for 8-10% of all deaths in the USA (2.6 deaths/1000 patient-years) and exceed 30% of deaths in Australia (5/1000 patient-years) in kidney transplant recipients. Patient-, transplant- and medication-related factors contribute to the increased cancer risk following kidney transplantation. While it is well established that the overall immunosuppressive dose is associated with an increased risk for cancer following transplantation, the contributive effect of different immunosuppressive agents is not well established. In this review we will discuss the different risk factors for malignancies after kidney transplantation.
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Affiliation(s)
- Ben Sprangers
- Department of Microbiology and Immunology, KU Leuven and Division of Nephrology, University Hospitals Leuven, Leuven, Belgium
- Department of Microbiology and Immunology, KU Leuven and Laboratory of Experimental Transplantation, University Hospitals Leuven, Leuven, Belgium
- Cancer-Kidney International Network, Brussels, Belgium
| | - Vinay Nair
- Department of Medicine, Division of Kidney Diseases and Hypertension, Hofstra Northwell School of Medicine, Hempstead, NY, USA
| | - Vincent Launay-Vacher
- Cancer-Kidney International Network, Brussels, Belgium
- Service ICAR and Department of Nephrology, Pitié-Salpêtrière University Hospital, Paris, France
| | - Leonardo V Riella
- Department of Medicine, Schuster Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Boston, MA, USA
| | - Kenar D Jhaveri
- Cancer-Kidney International Network, Brussels, Belgium
- Department of Medicine, Division of Kidney Diseases and Hypertension, Hofstra Northwell School of Medicine, Hempstead, NY, USA
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Mazzoni E, Rotondo JC, Marracino L, Selvatici R, Bononi I, Torreggiani E, Touzé A, Martini F, Tognon MG. Detection of Merkel Cell Polyomavirus DNA in Serum Samples of Healthy Blood Donors. Front Oncol 2017; 7:294. [PMID: 29238698 PMCID: PMC5712532 DOI: 10.3389/fonc.2017.00294] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 11/16/2017] [Indexed: 12/27/2022] Open
Abstract
Merkel cell polyomavirus (MCPyV) has been detected in 80% of Merkel cell carcinomas (MCC). In the host, the MCPyV reservoir remains elusive. MCPyV DNA sequences were revealed in blood donor buffy coats. In this study, MCPyV DNA sequences were investigated in the sera (n = 190) of healthy blood donors. Two MCPyV DNA sequences, coding for the viral oncoprotein large T antigen (LT), were investigated using polymerase chain reaction (PCR) methods and DNA sequencing. Circulating MCPyV sequences were detected in sera with a prevalence of 2.6% (5/190), at low-DNA viral load, which is in the range of 1–4 and 1–5 copies/μl by real-time PCR and droplet digital PCR, respectively. DNA sequencing carried out in the five MCPyV-positive samples indicated that the two MCPyV LT sequences which were analyzed belong to the MKL-1 strain. Circulating MCPyV LT sequences are present in blood donor sera. MCPyV-positive samples from blood donors could represent a potential vehicle for MCPyV infection in receivers, whereas an increase in viral load may occur with multiple blood transfusions. In certain patient conditions, such as immune-depression/suppression, additional disease or old age, transfusion of MCPyV-positive samples could be an additional risk factor for MCC onset.
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Affiliation(s)
- Elisa Mazzoni
- Laboratories of Cell Biology and Molecular Genetics, Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy
| | - John C Rotondo
- Laboratories of Cell Biology and Molecular Genetics, Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy
| | - Luisa Marracino
- Laboratories of Cell Biology and Molecular Genetics, Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy
| | - Rita Selvatici
- Department of Medical Sciences, Section of Microbiology and Medical Genetics, University of Ferrara, Ferrara, Italy
| | - Ilaria Bononi
- Laboratories of Cell Biology and Molecular Genetics, Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy
| | - Elena Torreggiani
- Laboratories of Cell Biology and Molecular Genetics, Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy
| | - Antoine Touzé
- UMR INRA 1282 ISP, Faculté des Sciences Pharmaceutiques, Université Francois Rabelais, Tours, France
| | - Fernanda Martini
- Laboratories of Cell Biology and Molecular Genetics, Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy
| | - Mauro G Tognon
- Laboratories of Cell Biology and Molecular Genetics, Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy
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Zhang J, Fu JZ, Hong SF, Jiang H, Qi ZQ, Huang ZS, Xia JJ. Toxicity of rapamycin and its derivatives to pancreatic islets. Shijie Huaren Xiaohua Zazhi 2016; 24:2667-2675. [DOI: 10.11569/wcjd.v24.i17.2667] [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] [Indexed: 02/06/2023] Open
Abstract
The development of islet transplantation has been promoted by the proposal of the Edmonton protocol. Rapamycin, as a recommended immunosuppressive medicine of the Edmonton protocol, has been getting extraordinarily popular. At the same time, derivatives of rapamycin (everolimus, deforolimus, zotarolimus and temsirolimus) have also garnered great interest. While the immunosuppressive and anti-cancer effects of rapalogs were being discussed actively, researchers discovered their cytotoxic effect on pancreatic islets. Whether they could be ideal drugs for anti-rejection after islet transplantation needs further study. This review aims to elucidate the function and application of rapalogs as well as their toxicity to pancreatic islets.
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Mukthinuthalapati PK, Gotur R, Ghabril M. Incidence, risk factors and outcomes of de novo malignancies post liver transplantation. World J Hepatol 2016; 8:533-544. [PMID: 27134701 PMCID: PMC4840159 DOI: 10.4254/wjh.v8.i12.533] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Revised: 03/08/2016] [Accepted: 04/06/2016] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) is associated with a 2 to 7 fold higher, age and gender adjusted, risk of de novo malignancy. The overall incidence of de novo malignancy post LT ranges from 2.2% to 26%, and 5 and 10 years incidence rates are estimated at 10% to 14.6% and 20% to 32%, respectively. The main risk factors for de novo malignancy include immunosuppression with impaired immunosurveillance, and a number of patient factors which include; age, latent oncogenic viral infections, tobacco and alcohol use history, and underlying liver disease. The most common cancers after LT are non-melanoma skin cancers, accounting for approximately 37% of de novo malignancies, with a noted increase in the ratio of squamous to basal cell cancers. While these types of skin cancer do not impact patient survival, post-transplant lymphoproliferative disorders and solid organ cancer, accounting for 25% and 48% of malignancies, are associated with increased mortality. Patients developing these types of cancer are diagnosed at more advanced stages, and their cancers behave more aggressively compared with the general population. Patients undergoing LT for primary sclerosing cholangitis (particularly with inflammatory bowel disease) and alcoholic liver disease have high rates of malignancies compared with patients undergoing LT for other indications. These populations are at particular risk for gastrointestinal and aerodigestive cancers respectively. Counseling smoking cessation, skin protection from sun exposure and routine clinical follow-up are the current approach in practice. There are no standardized surveillance protocol, but available data suggests that regimented surveillance strategies are needed and capable of yielding cancer diagnosis at earlier stages with better resulting survival. Evidence-based strategies are needed to guide optimal surveillance and safe minimization of immunosuppression.
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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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Purani JM, Purani HJ. Treatment of geographic tongue with topical tacrolimus. BMJ Case Rep 2014; 2014:bcr-2013-201268. [PMID: 25085945 DOI: 10.1136/bcr-2013-201268] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Geographic tongue is an inflammatory condition of the dorsal surface and lateral border of the tongue, which may be asymptomatic. This article presents a case of geographic tongue in a 6-year-old child. Successful management was achieved with topical application of 0.1% tacrolimus.
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Affiliation(s)
- Jigar M Purani
- Department of Oral Pathology, Faculty of Dental Science, Nadiad, Gujarat, India
| | - Hiral J Purani
- Department of Periodontia, Faculty of Dental Science, Nadiad, Gujarat, India
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Merkel cell carcinoma in immunosuppressed patients. Cancers (Basel) 2014; 6:1328-50. [PMID: 24978436 PMCID: PMC4190543 DOI: 10.3390/cancers6031328] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Revised: 05/22/2014] [Accepted: 06/09/2014] [Indexed: 02/07/2023] Open
Abstract
Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy. The infectivity of Merkel cell polyomavirus (MCPyV), an apparent agent in MCC development, may be exacerbated with impaired immune responses. This paper reviews relevant data regarding the role of immunosuppression in the development of MCC and describes modes of immunodeficient states. Because of the inherently low incidence rate of MCC, several case studies and series are also briefly mentioned to provide a more comprehensive summary of MCC in the setting of immunosuppression. We describe immunosuppressed patients who have experienced excessive UV radiation, organ transplantation, human immunodeficiency virus infection/AIDS, autoimmune diseases, and lymphoproliferative disorders. Iatrogenic forms of immunosuppression are also highlighted. Studies that quantify risks consistently report that individuals with a history of solid organ transplantation, autoimmune diseases, AIDS, and/or lymphoproliferative diseases have a significantly elevated risk of developing MCC. Overall, immunocompromised patients also appear to have an early onset and more aggressive course of MCC, with poorer outcomes. Recommendations for multidisciplinary approaches are proposed to effectively prevent and manage MCC in these patients.
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Keaney TC, Bhutani T, Sivanesan P, Bandow GD, Weinstein SB, Cheung LC, Malick F, Koo J. Open-label, pilot study examining sequential therapy with oral tacrolimus and topical tacrolimus for severe atopic dermatitis. J Am Acad Dermatol 2012; 67:636-41. [DOI: 10.1016/j.jaad.2011.10.033] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2010] [Revised: 10/11/2011] [Accepted: 10/23/2011] [Indexed: 01/10/2023]
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Kuschal C, Thoms KM, Schubert S, Schäfer A, Boeckmann L, Schön MP, Emmert S. Skin cancer in organ transplant recipients: effects of immunosuppressive medications on DNA repair. Exp Dermatol 2012; 21:2-6. [PMID: 22151386 DOI: 10.1111/j.1600-0625.2011.01413.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
UV-induced skin cancers comprise a major problem in organ transplant recipients (OTRs). Cyclosporin A, a calcineurin inhibitor, is used as a standard immunosuppressant and clearly increases the skin cancer risk. Azathioprine does not appear to result in such an increase in skin cancer risk, and mTOR inhibitors are associated with an even lesser skin cancer risk. The underlying molecular mechanisms of these clinically important differences among immunosuppressants are still unclear and may relate to other than immunological effects. Insights may be gained by the multistep skin cancer theory and xeroderma pigmentosum, where defective nucleotide excision repair (NER) results in a cellular mutator phenotype and cutaneous carcinogenesis. This viewpoint assay summarizes current knowledge about the influence of the most commonly used immunosuppressive drugs in OTRs on DNA repair. Calcineurin inhibition results in a 200-fold increased skin cancer risk compared with the normal population and inhibits NER. The skin cancer risk under azathioprine is threefold less compared with calcineurin inhibitors, which may relate to inhibition of only the last step of NER, i.e. gap filling. mTOR inhibitors do not reduce NER in the global genome and can inhibit the growth of already initiated tumors, which may account for the markedly reduced skin cancer risk compared with calcineurin inhibitors. We conclude that OTRs may benefit from treatment regimens other than calcineurin inhibitors and speculate that a targeted modulation of calcineurin-dependent signalling may prevent UV-induced tumor formation by enhancing NER not only in OTRs but also in the general population, at least in part.
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Affiliation(s)
- Christiane Kuschal
- Department of Dermatology, Venerology, and Allergology, Georg-August-University, Goettingen, Germany
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Vivarelli M, Risaliti A. Liver transplantation for hepatocellular carcinoma on cirrhosis: Strategies to avoid tumor recurrence. World J Gastroenterol 2011; 17:4741-6. [PMID: 22147974 PMCID: PMC3229622 DOI: 10.3748/wjg.v17.i43.4741] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2011] [Revised: 06/21/2011] [Accepted: 06/28/2011] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent neoplasms worldwide and in most cases it is associated with chronic liver disease. Liver transplantation (LT) is potentially the optimal treatment for those patients with HCC who have a poor functional hepatic reserve due to their underlying chronic liver disease. However, due to the limited availability of donors, only those patients whose oncologic profile is favorable can be considered for LT. Despite the careful selection of candidates based on strict rules, 10 to 20% of liver transplant recipients who have HCC in the native cirrhotic liver develop tumor recurrence after transplantation. The selection criteria presently employed to minimize the risk of recurrence are based on gross tumor characteristics defined by imaging techniques; unfortunately, the accuracy of imaging is far from being optimal. Furthermore, microscopic tumor features that are strictly linked with prognosis can not be assessed prior to transplantation. Pre-transplantation tumor downstaging may allow transplantation in patients initially outside the selection criteria and seems to improve the prognosis; it also provides information on tumor biology. The main peculiarity of the transplantation setting, when this is compared with other modalities of treatment, is the need for pharmacological immunosuppression: this is based on drugs that have been demonstrated to increase the risk of tumor development. As HCC is an aggressive malignancy, immunosuppression has to be handled carefully in patients who have HCC at the time of transplantation and new categories of immunosuppressive agents should be considered. Adjuvant chemotherapy following transplantation has failed to show any significant advantage. The aim of the present study is to review the possible strategies to avoid recurrence of HCC after liver transplantation based on the current clinical evidence and the more recent developments and to discuss possible future directions.
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16
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Thoms KM, Kuschal C, Oetjen E, Mori T, Kobayashi N, Laspe P, Boeckmann L, Schön MP, Emmert S. Cyclosporin A, but not everolimus, inhibits DNA repair mediated by calcineurin: implications for tumorigenesis under immunosuppression. Exp Dermatol 2011; 20:232-6. [PMID: 21323745 DOI: 10.1111/j.1600-0625.2010.01213.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Unlike other immunosuppressive drugs including everolimus, cyclosporin A causes a dramatic increase of UV-induced skin cancer, a feature that is reminiscent of xeroderma pigmentosum (XP), where defective nucleotide excision repair (NER) of UV-induced DNA damage results in cutaneous carcinogenesis. The molecular basis of the clinically important differential activities of cyclosporin A and everolimus is still unclear. We measured post-UV cell survival of cyclosporin A- and everolimus-treated human fibroblasts and lymphoblasts using a cell proliferation assay (MTT). The cellular NER capacity was assessed by host cell reactivation. Using an ELISA and specific antibodies, cyclobutane pyrimidine and pyrimidine-6,4-pyrimidone photoproduct removal from the cellular genome was measured. The effect of calcineurin on NER was investigated using a calcineurin A expression vector and specific RNAi. Cyclosporin A led to a dose dependent decrease in post-UV cell survival, inhibited NER and blocked photoproduct removal. In contrast, none of these effects where seen in everolimus-treated cells. Overexpression of calcineurin A resulted in increased NER and complemented the Cyclosporin A-induced reduction of NER. Downregulation of calcineurin using RNAi inhibited NER comparable to cyclosporin A-treatment. We conclude that cyclosporin A, but not everolimus, leads to an increased skin cancer risk via a calcineurin signalling-dependent impairment of NER.
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Affiliation(s)
- Kai-Martin Thoms
- Department of Dermatology, Venerology, and Allergology, Georg-August-University, Goettingen, Germany
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17
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Zavos G, Karidis NP, Tsourouflis G, Bokos J, Diles K, Sotirchos G, Theodoropoulou E, Kostakis A. Nonmelanoma skin cancer after renal transplantation: a single-center experience in 1736 transplantations. Int J Dermatol 2011; 50:1496-500. [PMID: 21790552 DOI: 10.1111/j.1365-4632.2011.04939.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND Renal transplantation is associated with an increased incidence of nonmela-noma skin cancer (NMSC) caused by immunosuppression. Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), the two major histological types of NMSC, exhibit more aggressive biological and clinical courses in renal transplant recipients (RTRs), with higher rates of recurrence and mortality than in the general population. METHODS We retrospectively analyzed our experience of NMSC in 1736 renal transplantations performed over a 25-year period. All cases of skin cancer after renal transplantation were included except those of skin cancer resulting from melanoma and mesenchymal skin tumors. RESULTS In our series, the overall incidence of NMSC after transplantation was 2.2% (n = 39), and SCC represented the most frequent skin malignancy (64.1%), followed by BCC (17.9%), Bowen's disease (10.2%), basosquamous carcinoma (5.1%), and a rare case of invasive sebaceous carcinoma (2.6%). A shift to newer immunosuppressive regimens after the initial diagnosis of NMSC had been implemented in eight cases (20.5%). The recurrence rate after initial treatment was 41% (n = 16), and distant metastatic disease was diagnosed in 15.4% (n = 6) of NMSC patients. The NMSC-specific mortality rate was 25.6% (n = 10). CONCLUSIONS Nonmelanoma skin cancer remains a significant source of morbidity and mortality in RTRs, and post-transplant surveillance should be increased.
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Affiliation(s)
- George Zavos
- Transplantation Unit, Laiko General Hospital, Athens, Greece
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18
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Abstract
Cutaneous squamous cell carcinoma (SCC) is the second most common human cancer and can behave aggressively. Mohs micrographic surgery offers the highest cure rates for high-risk SCCs and is particularly useful for SCCs on challenging anatomic sites.
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Affiliation(s)
- Daniel Belkin
- Department of Dermatology, Weill Cornell Medical College, 1305 York Avenue, New York, NY 10021, USA
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19
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Alam M, Brown RN, Silber DH, Mullen GM, Feldman DS, Oren RM, Yancy CW. Increased incidence and mortality associated with skin cancers after cardiac transplant. Am J Transplant 2011; 11:1488-97. [PMID: 21718441 DOI: 10.1111/j.1600-6143.2011.03598.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Skin cancer incidence has been shown to be increased in the context of transplant-associated immunosuppression. There is, however, limited information specifically about the incidence of skin cancer after cardiac transplantation in the United States. A 10-year retrospective cohort study of 6271 heart transplants at 32 US transplant centers revealed increased postprocedure incidence of nonmelanoma and melanoma skin cancers, especially cutaneous squamous cell carcinoma, for which the incidence increased from 4- to 30-fold compared to the age and gender equivalent general population. Incidence of skin cancer in this study was consistent with prior single-center data regarding cardiac transplant patients. Comparison of all-cause mortality statistics for patients with basal cell carcinoma, squamous cell carcinoma and melanoma, respectively, demonstrated increased mortality associated with melanoma. Skin cancer screening and prophylaxis may be of some utility in reducing morbidity and mortality in cardiac transplant patients.
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Affiliation(s)
- M Alam
- Departments of Dermatology, Otolaryngology, and Surgery (Transplant), Northwestern University, Chicago, IL, USA.
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20
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Kuschal C, Thoms KM, Boeckmann L, Laspe P, Apel A, Schön MP, Emmert S. Cyclosporin A inhibits nucleotide excision repair via downregulation of the xeroderma pigmentosum group A and G proteins, which is mediated by calcineurin inhibition. Exp Dermatol 2011; 20:795-9. [PMID: 21707758 DOI: 10.1111/j.1600-0625.2011.01320.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Cyclosporin A (CsA) inhibits nucleotide excision repair (NER) in human cells, a process that contributes to the skin cancer proneness in organ transplant patients. We investigated the mechanisms of CsA-induced NER reduction by assessing all xeroderma pigmentosum (XP) genes (XPA-XPG). Western blot analyses revealed that XPA and XPG protein expression was reduced in normal human GM00637 fibroblasts exposed to 0.1 and 0.5 μm CsA. Interestingly, the CsA treatment reduced XPG, but not XPA, mRNA expression. Calcineurin knockdown in GM00637 fibroblasts using RNAi led to similar results suggesting that calcineurin-dependent signalling is involved in XPA and XPG protein regulation. CsA-induced reduction in NER could be complemented by the overexpression of either XPA or XPG protein. Likewise, XPA-deficient fibroblasts with stable overexpression of XPA (XP2OS-pCAH19WS) did not show the inhibitory effect of CsA on NER. In contrast, XPC-deficient fibroblasts overexpressing XPC showed CsA-reduced NER. Our data indicate that the CsA-induced inhibition of NER is a result of downregulation of XPA and XPG protein in a calcineurin-dependent manner.
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Affiliation(s)
- Christiane Kuschal
- Department of Dermatology, Venerology, and Allergology, Georg-August-University, Goettingen, Goettingen, Germany
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21
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Rama I, Grinyó JM. Malignancy after renal transplantation: the role of immunosuppression. Nat Rev Nephrol 2011; 6:511-9. [PMID: 20736984 DOI: 10.1038/nrneph.2010.102] [Citation(s) in RCA: 138] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Outcomes of kidney transplantation, in terms of graft and patient survival, have improved over the past few decades, partly as a result of the introduction of new immunosuppressive drugs. Many immunosuppressive agents are associated with an increased risk of cardiovascular events and an increased risk of cancer, however, which can compromise patient survival. Cancer is more common among solid-organ transplant recipients than it is in the general population or in patients on dialysis. In fact, malignancy is the third most common cause of death in renal transplant recipients. Immunosuppressive treatments used in renal transplant recipients can cause malignancy by supporting oncogenesis caused by certain viruses or by impairing immune surveillance thereby enabling faster tumor growth. In this Review, we describe the epidemiological and clinical characteristics of common tumor types occurring after kidney transplantation, and the etiopathogenetic factors that lead to their appearance, with a particular focus on the relationship between immunosuppressive treatment and malignancy. Immunosuppressive drugs associated with an increased risk of malignancy after transplantation are also discussed, as are immunosuppressive drugs that seem to have antioncogenic properties.
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Affiliation(s)
- Inés Rama
- Hospital Universitari de Bellvitge, Feixa Llarga s/n 08907, L'Hospitalet de Llobregat, Barcelona, Spain
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22
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Toll-like receptors: role in dermatological disease. Mediators Inflamm 2010; 2010:437246. [PMID: 20847936 PMCID: PMC2933899 DOI: 10.1155/2010/437246] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2010] [Revised: 04/27/2010] [Accepted: 07/01/2010] [Indexed: 01/04/2023] Open
Abstract
Toll-like receptors (TLRs) are a class of conserved receptors that recognize pathogen-associated molecular patterns (PAMPs) present in microbes. In humans, at least ten TLRs have been identified, and their recognition targets range from bacterial endotoxins to lipopeptides, DNA, dsRNA, ssRNA, fungal products, and several host factors. Of dermatological interest, these receptors are expressed on several skin cells including keratinocytes, melanocytes, and Langerhans cells. TLRs are essential in identifying microbial products and are known to link the innate and adaptive immune systems. Over the years, there have been significant advances in our understanding of TLRs in skin inflammation, cutaneous malignancies, and defence mechanisms. In this paper, we will describe the association between TLRs and various skin pathologies and discuss proposed TLR therapeutics.
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23
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Lonsdorf AS, Becker MR, Stockfleth E, Schäkel K, Ulrich C. [Primary and secondary prevention of skin cancer in organ transplant recipients]. DER HAUTARZT 2010; 61:195-206. [PMID: 20177652 DOI: 10.1007/s00105-009-1858-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Skin cancer constitutes the most frequently reported post-transplant malignancy in solid organ transplant recipients (OTR) worldwide. Whereas the risk for malignant melanoma is only moderately increased, non-melanoma skin cancers (NMSC) seem to thrive on chronic immunosuppression and account for up to 95% of post-transplant cutaneous malignancies. Compared to the general population cutaneous squamous cell carcinoma (SCC) and actinic keratoses (AK) characteristically show even higher incidences than basal cell carcinoma (BCC) and act as an indicator for the development of multiple primary cutaneous neoplasias and locally recurrent cancers (field cancerization). Early diagnosis and therapy of pre-malignant cutaneous lesions is crucial for the secondary prophylaxis of further invasive and highly aggressive skin cancers. High quality interdisciplinary care and prophylactic modalities, including consistent and sufficient UV protection, topical immunmodulatory therapies of UV-damaged skin areas, retinoid chemoprevention as well as tapering immunosuppressive treatment or the selection of immunosuppressants with proposed antiangiogenic properties like mTor-inhibitors may help to reduce the multiplicity of subsequent primary skin cancers in high-risk patients. Apart from the continuous need for educational intervention of OTR in the primary prophylaxis of post-transplant skin cancers, dermatologic care occupies a central position within the field of transplantation medicine in terms of pre- and post-transplantation dermatologic evaluation and therapy as well as the implication of timely and effective secondary preventive approaches in the management of this high-risk patient population.
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Affiliation(s)
- A S Lonsdorf
- Universitätshautklinik, Hauttumorzentrum, Vossstr. 2, 69115, Heidelberg.
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24
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Hofbauer G. [Immunosuppressive therapy after transplantation. Dermatologic relevance and pathomechanisms]. Hautarzt 2010; 61:214-9. [PMID: 20145903 DOI: 10.1007/s00105-009-1861-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Immunosuppressive therapy keeps rejection in check following solid organ transplantation. Drug reactions, inflammatory and infectious skin conditions frequently follow. Specific side effects can be avoided by switching individual agents. In addition to UV light, immunosuppressants are the most important driver for squamous cell carcinoma of the skin (SCC). Beyond immunosuppression, cyclosporine A promotes carcinogenesis by TGF beta and VEGF, while mTOR inhibitors are antiproliferative. Azathioprine photosensitizes to UVA and enables UVA to damage DNA directly. To fight skin cancer, global reduction of immunosuppression is the most effective measure. Switching calcineurin inhibitors to mTOR inhibitors is probably to be recommended, while omitting azathioprine may potentially be advisable in recurrent SCC.
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Affiliation(s)
- G Hofbauer
- Dermatologische Klinik, Universitätsspital Zürich, Gloriastr. 31, 8091, Zürich, Schweiz.
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25
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Perrett CM, Harwood CA, McGregor JM, Karran P. Carcinogenic mechanisms related to immunosuppressive therapy. Cancer Treat Res 2009; 146:123-32. [PMID: 19415198 DOI: 10.1007/978-0-387-78574-5_11] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Conal M Perrett
- Centre for Cutaneous Research, Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, 4 Newark Street, London, UK, E1 2AT
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26
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Morelon E, Mahe E, Touraine JL. The role of the transplant physician in the management of skin cancers after organ transplantation. Cancer Treat Res 2009; 146:377-390. [PMID: 19415217 DOI: 10.1007/978-0-387-78574-5_30] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Affiliation(s)
- Emmanuel Morelon
- Département de Transplantation, Université Claude-Bernard Lyon 1, Hôpital Edouard Herriot, Pavillon P, Lyon, France
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27
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Affiliation(s)
- Jean Kanitakis
- Department of Dermatology, Edouard Herriot Hospital, 60437 Lyon Cedex 03, France
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28
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Wulff BC, Kusewitt DF, VanBuskirk AM, Thomas-Ahner JM, Duncan FJ, Oberyszyn TM. Sirolimus reduces the incidence and progression of UVB-induced skin cancer in SKH mice even with co-administration of cyclosporine A. J Invest Dermatol 2008; 128:2467-73. [PMID: 18463679 DOI: 10.1038/jid.2008.121] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Transplant immunosuppressants have been implicated in the increased incidence of non-melanoma skin cancer in transplant recipients, most of whom harbor considerable UVB-induced DNA damage in their skin prior to transplantation. This study was designed to evaluate the effects of two commonly used immunosuppressive drugs, cyclosporine A (CsA) and sirolimus (SRL), on the development and progression of UVB-induced non-melanoma skin cancer. SKH-1 hairless mice were exposed to UVB alone for 15 weeks, and then were treated with CsA, SRL, or CsA+SRL for 9 weeks following cessation of UVB treatment. Compared with vehicle, CsA treatment resulted in enhanced tumor size and progression. In contrast, mice treated with SRL or CsA+SRL had decreased tumor multiplicity, size, and progression compared with vehicle-treated mice. CsA, but not SRL or combined treatment, increased dermal mast cell numbers and TGF-beta1 levels in the skin. These findings demonstrate that specific immunosuppressive agents differentially alter the cutaneous tumor microenvironment, which in turn may contribute to enhanced development of UVB-induced skin cancer in transplant recipients. Furthermore, these results suggest that CsA alone causes enhanced growth and progression of skin cancer, whereas co-administration of SRL with CsA causes the opposite effect. JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article please go to http://network.nature.com/group/jidclub
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Affiliation(s)
- Brian C Wulff
- Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA
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29
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Herman S, Rogers HD, Ratner D. Immunosuppression and squamous cell carcinoma: a focus on solid organ transplant recipients. Skinmed 2007; 6:234-8. [PMID: 17786101 DOI: 10.1111/j.1540-9740.2007.06174.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
As transplant medicine advances, new immunosuppressive regimens are increasing the long-term survival of solid organ transplant recipients (SOTRs). This growing population is at significantly increased risk for developing cutaneous malignancies, particularly squamous cell carcinoma (SCC), as a result of chronic immunosuppression. Conventional risk factors for the development of skin cancer, including fair skin type, advanced age, sun exposure, and genetic predisposition, also play a crucial role in the initiation and progression of SCC in SOTRs. Immunosuppressed patients develop more aggressive and more numerous SCCs than immunocompetent individuals, however. It is important to understand the mechanisms underlying immunosuppression-mediated SCC development to identify prognostic markers and to develop effective prevention and treatment strategies. This article addresses the fundamental differences between SCC in SOTRs and those in the general population, focusing on the role that immunosuppression plays in the pathogenesis of this malignancy.
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Affiliation(s)
- Sara Herman
- Department of Dermatology, Columbia University Medical Center, 161 Fort Washington Avenue, New York, NY 10012, USA
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30
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Kopelovich L, Fay JR, Sigman CC, Crowell JA. The mammalian target of rapamycin pathway as a potential target for cancer chemoprevention. Cancer Epidemiol Biomarkers Prev 2007; 16:1330-40. [PMID: 17626998 DOI: 10.1158/1055-9965.epi-07-0045] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The mammalian target of rapamycin (mTOR) is a key signaling node coordinating cell cycle progression and cell growth in response to genetic, epigenetic, and environmental conditions. Pathways involved in mTOR signaling are dysregulated in precancerous human tissues. These findings, together with the intriguing possibility that mTOR suppression may be associated with antitumor actions of caloric restriction, suggest that mTOR signaling may be an important target for chemopreventive drugs.
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Affiliation(s)
- Levy Kopelovich
- Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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31
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Abstract
Since the introduction of cyclosporin A (CsA) in the early 1980s, the use of immunosuppressants has markedly increased. Already established drugs have proved effective in the treatment of a wide range of diseases outside transplantation medicine and new immunosuppressants have been developed for more specific indications such as psoriasis and atopic dermatitis. Patients in transplantation medicine as well as in dermatology have benefited significantly from systemic and topical application of both new and established drugs. But are these drugs without risks? Cancer-protecting effects have been reported for some of the available immunosuppressants. Conversely, other publications and the issue of a black box warning by the US Food and Drug Administration have increased concerns about cancer-promoting effects. Knowledge of the specific effects as well as adverse effects is paramount to ensure an application that is safe and beneficial for the patient. Here we review the mechanisms of action and therapeutic potential, and critically review recent literature with respect to possible carcinogenic side effects of systemic and topical CsA, tacrolimus, pimecrolimus and rapamycin.
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Affiliation(s)
- Maren Weischer
- Department of Dermatology and Venerology, Eberhard Karls University, Liebermeisterstrasse 25, D-72076 Tuebingen, Germany
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32
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Athar M, Tang X, Lee JL, Kopelovich L, Kim AL. Hedgehog signalling in skin development and cancer. Exp Dermatol 2006; 15:667-77. [PMID: 16881963 DOI: 10.1111/j.1600-0625.2006.00473.x] [Citation(s) in RCA: 139] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Basal cell carcinoma (BCC) is the most common human malignancy, affecting 750,000 Americans each year. The understanding of mutations that are known to activate hedgehog (Hh) signalling pathway genes, including PATCHED (PTCH), sonic hedgehog (Shh) and smoothened (Smo), has substantially expanded our current understanding of the genetic basis of BCC development. The Hh signalling pathway is one of the most fundamental signal transduction pathways in embryonic development. In skin, the Shh pathway is crucial for maintaining stem cell population, and for regulating hair follicle and sebaceous gland development. This pathway plays a minimal role in adult tissues, but is known to be activated in many neoplasms, including those arising in the skin. In this review, we attempt to summarize the results of published studies on some important aspects of the Shh pathway and its involvement in skin development and carcinogenesis. We also provide a description of various animal models that have been developed, based on our knowledge of the Shh pathway in human skin cancers. Additionally, we include a brief description of studies conducted in our laboratory and by others on the chemoprevention of BCCs. This review therefore provides a current understanding of the role of the Shh pathway in skin development and neoplasia. It also provides a basis for the molecular target-based chemoprevention and therapeutic management of skin cancer.
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Affiliation(s)
- Mohammad Athar
- Department of Dermatology, Columbia University, New York, NY 10032, USA.
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33
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Lewis KG, Jellinek N, Robinson-Bostom L. Skin Cancer After Transplantation: A Guide for the General Surgeon. Surg Clin North Am 2006; 86:1257-76, viii. [PMID: 16962413 DOI: 10.1016/j.suc.2006.06.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The success of organ transplantation has been accompanied by serious concerns regarding the incidence and management of potentially catastrophic cutaneous carcinogenesis in transplant recipients. Delivery of the highest quality of care requires a concerted effort toward collaboration between multiple surgical and medical specialties. The purpose of this review is to provide the general surgeon with a practical, user-friendly guide to the important components of comprehensive dermatologic care for organ transplant recipients (OTRs) with references to more detailed sources of information.
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Affiliation(s)
- Kevan G Lewis
- Department of Dermatology, Brown Medical School/Rhode Island Hospital, 593 Eddy Street, APC-10, Providence, RI 02903, USA
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34
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Becker JC, Houben R, Vetter CS, Bröcker EB. The carcinogenic potential of tacrolimus ointment beyond immune suppression: a hypothesis creating case report. BMC Cancer 2006; 6:7. [PMID: 16405733 PMCID: PMC1386691 DOI: 10.1186/1471-2407-6-7] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2005] [Accepted: 01/11/2006] [Indexed: 11/10/2022] Open
Abstract
Background Since tacrolimus ointment was approved by the U.S. Food and Drug Administration (FDA) as a promising treatment for atopic dermatitis, it has been approved in more than 30 additional countries, including numerous European Union member nations. Moreover, in the current clinical routine the use of this drug is no longer restricted to the approved indication, but has been extended to a wide variety of inflammatory skin diseases including some with the potential of malignant transformation. So far, the side-effects reported from the topical use of tacrolimus have been relatively minor (e.g. burning, pruritus, erythema). Recently, however, the FDA reviewed the safety of topical tacrolimus, which resulted in a warning that the use of calcineurin inhibitors may be associated with an increased risk of cancer. Case presentation Oral lichen planus (OLP) was diagnosed in a 56-year-old women in February 1999. After several ineffective local and systemic therapeutic measures an off-label treatment of this recalcitrant condition using Tacrolimus 0.1% ointment was initiated in May 2002. After a few weeks of treatment most of the lesions ameliorated, with the exception of the plaques on the sides of the tongue. Nevertheless, the patient became free of symptoms which, however, reoccurred once tacrolimus was weaned, as a consequence treatment was maintained. In April 2005, the plaques on the left side of the tongue appeared increasingly compact and a biopsy specimen confirmed the suspected diagnosis of an oral squamous cell carcinoma. Conclusion The suspected causal relationship between topical use of tacrolimus and the development of a squamous cell carcinoma prompted us to test the notion that the carcinogenicity of tacrolimus may go beyond mere immune suppression. To this end, tacrolimus has been shown to have an impact on cancer signalling pathways such as the MAPK and the p53 pathway. In the given case, we were able to demonstrate that these pathways had also been altered subsequent to tacrolimus therapy.
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Affiliation(s)
- Jürgen C Becker
- Department of Dermatology, Julius-Maximilians-University, Würzburg, Germany
| | - Roland Houben
- Department of Dermatology, Julius-Maximilians-University, Würzburg, Germany
| | - Claudia S Vetter
- Department of Dermatology, Julius-Maximilians-University, Würzburg, Germany
| | - Eva B Bröcker
- Department of Dermatology, Julius-Maximilians-University, Würzburg, Germany
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35
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Affiliation(s)
- Sylvie Euvrard
- Department of Dermatology, Edouard Herriot Hospital (Pav. R), 5 Place d'Arsonval, 69437 Lyon Cedex 03, France.
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36
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Ippoliti G, Rinaldi M, Pellegrini C, Viganò M. Incidence of cancer after immunosuppressive treatment for heart transplantation. Crit Rev Oncol Hematol 2005; 56:101-13. [PMID: 15979322 DOI: 10.1016/j.critrevonc.2005.03.013] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2004] [Revised: 03/16/2005] [Accepted: 03/17/2005] [Indexed: 01/10/2023] Open
Abstract
Prolonged or intensive immunosuppressive therapy used after organ transplantation is complicated by an increased incidence of cancer. Striking differences in incidence are observed in heart and heart-lung transplant recipients when compared with renal transplant patients. The most significant increase was in the incidence of lymphomas in cardiac versus renal patients. Moreover, a two-fold greater increase of all neoplasms was found in cardiac recipients, with nearly a six-fold increase in visceral tumors. Several factors may account for these differences. In cardiac allograft recipients, intensive immunosuppression is frequently used to reverse acute rejection and the highest number of cardiac transplants was performed in the era of polypharmacy, usually consisting of triple therapy.
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Affiliation(s)
- Giovanbattista Ippoliti
- Divisione di Medicina Interna, Ospedale Civile, V. Volturno 14, 27048 Voghera, Pavia, Italy.
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Bécuwe C, Euvrard S, Bosshard S, Pouteil-Noble C, Garnier JL, Lefrançois N, Boillot O, Kanitakis J, Touraine JL, Claudy A. Maladie de Kaposi et transplantation d’organes : 22 cas. Ann Dermatol Venereol 2005; 132:839-43. [PMID: 16327712 DOI: 10.1016/s0151-9638(05)79501-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND The discovery of the Human Herpes virus 8 (HHV8) improved our knowledge of the pathogenesis of Kaposi's sarcoma. After organ transplantation, Kaposi's sarcoma exhibits distinctive features compared with other forms of the disease. PATIENTS AND METHODS We report 22 cases of post-transplant Kaposi's sarcoma (12 kidneys, 2 kidney-pancreas, 6 livers and 2 hearts). The aim of this retrospective study was to analyze clinical and virological characteristics in these transplant patients and to specify the frequency of HHV8 seroconversions in this population. RESULTS Twenty-one patients showed cutaneous lesions and 9 had visceral involvement. HHV8 serology was positive in 16/20 patients at transplantation and in 21/22 cases at the time of Kaposi's sarcoma diagnosis. Most cases corresponded to viral reactivations whereas seroconversions occurred in 2 cases and may have been linked to viral transmission by the graft. Treatment led to recovery in 68p. 100 of the cases. Two heart-transplant patients died from their disease. We included in our series two cases of re-transplanted patients without recurrence of Kaposi's sarcoma and one case of familial Kaposi's sarcoma. DISCUSSION Seroconversions after transplantation emphasize the interest of systematic screening of HHV8 serology in transplant recipients and their donors.
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Affiliation(s)
- C Bécuwe
- Service de Dermatologie, Hôpital Edouard Herriot, Lyon
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Durando B, Reichel J. The relative effects of different systemic immunosuppressives on skin cancer development in organ transplant patients. Dermatol Ther 2005; 18:1-11. [PMID: 15842607 DOI: 10.1111/j.1529-8019.2005.05007.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The immunosuppressive medications used in organ transplant recipients (OTRs) to prevent allograft rejection are associated with an increased incidence of skin cancer in this population. Several classes of immunosuppressive agents exist, and the selection of which medication to use varies by organ type and with time. The tumorigenic potential and relative effects of different immunosuppressive medications on skin cancer risk have been studied. This article reviewed the history of the immunosuppressive agents and their mechanisms of action. A summary of the current literature on the relationship between skin cancer and the different immunosuppressives were included. Guidelines for management of OTRs in dermatologic practice were discussed.
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Affiliation(s)
- Bianca Durando
- Division of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Nakamura H, Makino Y, Okamoto K, Poellinger L, Ohnuma K, Morimoto C, Tanaka H. TCR engagement increases hypoxia-inducible factor-1 alpha protein synthesis via rapamycin-sensitive pathway under hypoxic conditions in human peripheral T cells. THE JOURNAL OF IMMUNOLOGY 2005; 174:7592-9. [PMID: 15944259 DOI: 10.4049/jimmunol.174.12.7592] [Citation(s) in RCA: 125] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Peripheral T cells encounter rapid decrease in oxygen tension because they are activated by Ag recognition and migrate into inflammatory sites or tumors. Activated T cells, therefore, are thought to have such machineries that enable them to adapt to hypoxic conditions and execute immune regulation in situ. We have recently shown that survival of CD3-engaged human peripheral blood T cells is prolonged under hypoxic conditions and hypoxia-inducible factor-1 (HIF-1) and its target gene product adrenomedullin play a critical role for the process. It is also shown that hypoxia alone is not sufficient, but TCR-mediated signal is required for accumulation of HIF-1alpha in human peripheral T cells. In the present study, we showed that TCR engagement does not influence hypoxia-dependent stabilization but stimulates protein synthesis of HIF-1alpha, most possibly via PI3K/mammalian target of rapamycin system, and that expression of HIF-1alpha and its target genes is blocked by treatment with rapamycin. Since some of those gene products, e.g., glucose transporters and phosphoglycerokinase, are considered to be essential for glycolysis and energy production under hypoxic conditions and adequate immune reaction in T cells, this TCR-mediated synthesis of HIF-1alpha may play a pivotal role in peripheral immune response. Taken together, our results may highlight a novel aspect of downstream signal from Ag recognition by TCR and a unique pharmacological role of rapamycin as well.
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Affiliation(s)
- Hiroshi Nakamura
- Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
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Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C. Amelioration of Acute Renal Failure by Stem Cell Therapy—Paracrine SecretionVersusTransdifferentiation into Resident Cells. J Am Soc Nephrol 2005. [DOI: 10.1681/asn.2005030294] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
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Moloney FJ, de Freitas D, Conlon PJ, Murphy GM. Renal transplantation, immunosuppression and the skin: an update. PHOTODERMATOLOGY PHOTOIMMUNOLOGY & PHOTOMEDICINE 2005; 21:1-8. [PMID: 15634217 DOI: 10.1111/j.1600-0781.2005.00128.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Transplant medicine has seen many innovations over past decades and continues to evolve into the 21st century. Newer immunosuppressive strategies in renal transplantation are associated with better patient and graft survival rates; however, the adverse toxicities and long-term side effects associated with these agents present a number of challenges. Certain immunosuppressants are commonly used in dermatologic disorders, however, dermatologists may be less familiar with the clinical efficacy, side-effect profile, and dosage of newer immunosuppressive agents. A knowledge of the molecular and cellular mechanisms of action of these agents gives us a better understanding of how these agents contribute to the cutaneous and mucosal complications frequently seen post-transplant. With the advent of new immunosuppressive therapies and different treatment regimens, there is an increasing need for a multidisciplinary approach to balancing the risks and benefits of these medications to the individual transplant recipient. This review will highlight the different immunosuppressive agents and their effect on the skin while focusing on the evidence base to support the commonly used immunosuppressive regimes, newer protocols aimed at achieving maximum graft survival with minimal side effects, and important drug interactions with which all dermatologists should be familiar.
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Affiliation(s)
- F J Moloney
- Department of Dermatology, Beaumont Hospital, Dublin 9, Ireland.
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Koehl GE, Schlitt HJ, Geissler EK. Rapamycin and tumor growth: mechanisms behind its anticancer activity. Transplant Rev (Orlando) 2005. [DOI: 10.1016/j.trre.2005.01.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Why inhibitors of mammalian target of rapamycin will be important in organ transplantation. Curr Opin Organ Transplant 2004. [DOI: 10.1097/01.mot.0000146560.58398.e4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Lisik W, Kahan BD. Inhibitors of mammalian target of rapamycin: mechanism of action explains efficacy and toxicity. Curr Opin Organ Transplant 2004. [DOI: 10.1097/01.mot.0000146725.34815.ea] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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