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      Melanoma risk and survival among organ transplant recipients

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          Abstract

          Solid organ transplant recipients, who are medically immunosuppressed to prevent graft rejection, have increased melanoma risk, but risk factors and outcomes are incompletely documented. We evaluated melanoma incidence among 139,991 non-Hispanic white transplants using linked U.S. transplant-cancer registry data (1987–2010). We used standardized incidence ratios (SIRs) to compare incidence to the general population, and incidence rate ratios (IRRs) from multivariable Poisson models to assess risk factors. Separately, we compared post-melanoma survival among transplant recipients (N=182) and non-recipients (N=131,358) using multivariable Cox models. Among transplant recipients, risk of invasive melanoma (N=519) was elevated (SIR=2.20, 95%CI 2.01-2.39), especially for regional stage tumors (SIR=4.11, 95%CI 3.27–5.09). Risk of localized tumors was stable over time after transplantation, but higher with azathioprine maintenance therapy (IRR=1.35, 95%CI 1.03–1.77). Risk of regional/distant stage tumors peaked within 4 years following transplantation and increased with polyclonal antibody induction therapy (IRR=1.65, 95%CI 1.02–2.67). Melanoma-specific mortality was higher among transplant recipients than non-recipients (HR 2.98, 95%CI 2.26–3.93). Melanoma exhibits increased incidence and aggressive behavior under transplant-related immunosuppression. Some localized melanomas may result from azathioprine, which acts synergistically with ultraviolet radiation, while T-cell depleting induction therapies may promote late stage tumors. Our findings support sun safety practices and skin screening for transplant recipients.

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          Most cited references42

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          Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma.

          To determine whether density and distribution of tumor-infiltrating lymphocytes (TILs; TIL grade) is an independent predictor of sentinel lymph node (SLN) status and survival in patients with clinically localized primary cutaneous melanoma. From the Melanoma Institute Australia database, 1,865 patients with a single primary melanoma ≥ 0.75 mm in thickness were identified. The associations of clinical and pathologic factors with SLN status, recurrence-free survival (RFS), and melanoma-specific survival (MSS) were analyzed. The majority of patients had either no (TIL grade 0; 35.4%) or few (TIL grade 1; 45.1%) TILs, with a minority showing moderate (TIL grade 2; 16.3%) or marked (TIL grade 3; 3.2%) TILs. Tumor thickness, mitotic rate, and Clark level were inversely correlated with TIL grade (each P < .001). SLN biopsy was performed in 1,138 patients (61.0%) and was positive in 252 (22.1%). There was a significant inverse association between SLN status and TIL grade (SLN positivity rates for each TIL grade: 0, 27.8%; 1, 20.1%; 2, 18.3%; 3, 5.6%; P < .001). Predictors of SLN positivity were decreasing age (P < .001), decreasing TIL grade (P < .001), ulceration (P = .003), increasing tumor thickness (P = .01), satellitosis (P = .03), and increasing mitoses (P = .03). The 5-year MSS and RFS rates were 83% and 76%, respectively (median follow-up, 43 months). Tumor thickness (P < .001), ulceration (P < .001), satellitosis (P < .001), mitotic rate (P = .003), TIL grade (P < .001), and sex (P = .01) were independent predictors of MSS. Patients with TIL grade 3 tumors had 100% survival. TIL grade is an independent predictor of survival and SLN status in patients with melanoma. Patients with a pronounced TIL infiltrate have an excellent prognosis.
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            Cancer after kidney transplantation in the United States.

            Previous reports of cancer after kidney transplantation have been limited by small numbers of patients in single-center studies and incomplete ascertainment of cases in large registries. We examined rates of malignancies among first-time recipients of deceased or living donor kidney transplantations in 1995-2001 (n = 35 765) using Medicare billing claims. For most common tumors, e.g. colon, lung, prostate, stomach, esophagus, pancreas, ovary and breast, cancer rates were roughly twofold higher after kidney transplantation compared with the general population. Melanoma, leukemia, hepatobiliary tumors, cervical and vulvovaginal tumors were each approximately fivefold more common. Testicular and bladder cancers were increased approximately threefold, while kidney cancer was approximately 15-fold more common. Kaposi's sarcoma, non-Hodgkin's lymphomas, and nonmelanoma skin cancers were more than 20-fold increased than in the general population. Compared with patients on the waiting list, several tumors were more common after transplantation (p < 0.01): nonmelanoma skin cancers (2.6-fold), melanoma (2.2-fold), Kaposi's sarcoma (9.0-fold), non-Hodgkin's lymphoma (3.3-fold), cancer of the mouth (2.2-fold), and cancer of the kidney (39% higher). The rates for most malignancies are higher after kidney transplantation compared with the general population. Cancer should continue to be a major focus of prevention in kidney transplantation.
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              Azathioprine and UVA light generate mutagenic oxidative DNA damage.

              Oxidative stress and mutagenic DNA lesions formed by reactive oxygen species (ROS) are linked to human malignancy. Clinical treatments inducing chronic oxidative stress may therefore carry a risk of therapy-related cancer. We suggest that immunosuppression by azathioprine (Aza) may be one such treatment. Aza causes the accumulation of 6-thioguanine (6-TG) in patients' DNA. Here we demonstrate that biologically relevant doses of ultraviolet A (UVA) generate ROS in cultured cells with 6-TG-substituted DNA and that 6-TG and UVA are synergistically mutagenic. A replication-blocking DNA 6-TG photoproduct, guanine sulfonate, was bypassed by error-prone, Y-family DNA polymerases in vitro. A preliminary analysis revealed that in five of five cases, Aza treatment was associated with a selective UVA photosensitivity. These findings may partly explain the prevalence of skin cancer in long-term survivors of organ transplantation.
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                Author and article information

                Journal
                0426720
                4839
                J Invest Dermatol
                J. Invest. Dermatol.
                The Journal of investigative dermatology
                0022-202X
                1523-1747
                12 August 2015
                13 August 2015
                November 2015
                01 May 2016
                : 135
                : 11
                : 2657-2665
                Affiliations
                [1 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
                [2 ]Cancer Prevention Institute of California, Fremont, California, USA; Department of Health Research and Policy, Stanford University School of Medicine and Stanford Cancer Institute, Palo Alto, California, USA
                [3 ]Department of Dermatology, University of California, San Francisco, San Francisco, California, USA
                [4 ]Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
                [5 ]New York State Cancer Registry, Albany, New York, USA
                [6 ]University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii, USA
                [7 ]New Jersey State Cancer Registry, Trenton, New Jersey, USA, and Rutgers School of Public Health, Piscataway, New Jersey, USA
                [8 ]Department of Epidemiology, University of Iowa, Iowa City, Iowa, USA
                [9 ]Department of Medicine, Hennepin County Medical Center, University of Minnesota, Minneapolis, Minnesota, USA
                [10 ]Scientific Registry of Transplant Recipients, Minneapolis Medical Research Foundation, Minneapolis, Minnesota, USA
                Author notes
                Corresponding author: Hilary A. Robbins, 9609 Medical Center Drive, 6-E228, Bethesda, MD 20892. (240) 276-7187; hilary.robbins@ 123456jhmi.edu

                Current affiliation: HAR is currently affiliated with the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

                Article
                NIHMS714827
                10.1038/jid.2015.312
                4640996
                26270022
                d65a17a4-c766-48b1-9eed-99a43a4e86a3

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                Dermatology
                Dermatology

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