tacrolimus and Skin-Neoplasms

Heart transplant recipients experience high rates of skin cancer, likely due to greater length or dosage of immunosuppression. We review the impact of immunosuppressive medications on development of nonmelanoma skin cancer (NMSC) in heart transplant recipients. The authors searched keywords "heart transplant" and "nonmelanoma skin cancer" on PubMed in October 2022 for eligible articles available in English. Articles were selected for inclusion based on relevance to heart transplantation and NMSC. If any cited articles within included articles were related to our search they were also included. Of the 29 identified articles, 18 met the inclusion criteria with a total of 11,699 patients. Two studies found that tacrolimus and azathioprine increased the risk of NMSC. Five studies demonstrated that tacrolimus, everolimus, sirolimus, azathioprine and mycophenolate mofetil decreased the risk of NMSC. Three studies described that cyclosporine, tacrolimus, everolimus, sirolimus, azathioprine, mycophenolate mofetil and prednisone had no significant association with the development in NMSC. Two studies did not specify the correlation between immunosuppressant use and NMSC development. Ten studies did not discuss the association of immunosuppressants use with the development of NMSC. Our review highlights the commonly used immunosuppressive drugs that can impact the development of NMSC in heart transplant recipients. A management strategy in immunosuppression-associated skin cancers may ultimately involve adjusting the immunosuppressive regimen. This review serves as a summary of the most commonly used immunosuppressive drugs in heart transplant patients and their tumorigenic mechanisms to guide recommendations for dermatologic follow-up in heart transplant recipients.

Topics: Azathioprine; Everolimus; Heart Transplantation; Humans; Immunosuppressive Agents; Mycophenolic Acid; Sirolimus; Skin Neoplasms; Tacrolimus

The use of the calcineurin inhibitors (CNI) cyclosporine (CsA) and tacrolimus remains a cornerstone in post-transplantation immunosuppression. Although these immunosuppressive agents have revolutionized the field of transplantation medicine, its increased skin cancer risk poses a major concern. A key contributor to this phenomenon is a reduced capacity to repair DNA damage caused by exposure to ultraviolet (UV) wavelengths of sunlight. CNIs decrease DNA repair by mechanisms that remain to be fully explored. Though CsA is known to decrease the abundance of key DNA repair enzymes, less is known about how tacrolimus yields this effect. CNIs hold the capacity to inhibit both of the main catalytic calcineurin isoforms (CnAα and CnAβ). However, it is unknown which isoform regulates UV-induced DNA repair, which is the focus of this review. It is with hope that this insight spurs investigative efforts that conclusively addresses these gaps in knowledge. Additionally, this research also raises the possibility that newer CNIs can be developed that effectively blunt the immune response while mitigating the incidence of skin cancers with immunosuppression.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Cyclosporine; DNA Damage; DNA Repair; Humans; Protein Isoforms; Skin Neoplasms; Tacrolimus; Ultraviolet Rays

Atopic dermatitis (AD) requires long-term management, mainly with topical anti-inflammatory agents. Topical corticosteroids (TCS) and tacrolimus ointment (TAC-O) are recommended as first-line treatments for AD. However, the long-term use of TCS is limited by cutaneous adverse events such as skin atrophy. For TAC-O, Japanese and US labelings were updated in 2003 and 2006, respectively, to include a boxed warning about a theoretical risk of skin cancer and lymphoma in patients treated with topical calcineurin inhibitors. However, TAC-O has been used worldwide for longer than 15 years to treat adult and pediatric patients with AD. Available data suggest that TAC-O is effective and well tolerated, and can improve quality of life. TAC-O has successfully been used in the proactive management of AD consisting of long-term intermittent use to prevent, delay or reduce the occurrence of AD flares. Systemic drug absorption after TAC-O application is negligible and unlikely to result in systemic immunosuppression. There is currently no strong evidence of an increased rate of malignancy in treated patients, and observational data from postmarketing surveillance studies have shown no safety concerns. In the absence of robust evidence, the warning about the carcinogenic potential in the Japanese labeling for TAC-O does not appear justified and should be reconsidered. This mitigation of description would allow adult and pediatric patients with AD to receive the effective treatment more appropriately.

Topics: Administration, Cutaneous; Adult; Atrophy; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Dermatologic Agents; Glucocorticoids; Humans; Ointments; Skin; Skin Neoplasms; Tacrolimus; Treatment Outcome

Immune checkpoint inhibition with the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibodies nivolumab and pembrolizumab has improved survival in metastatic melanoma, lung cancer and renal cancer. Use of these agents holds promise in other malignancies. The augmented immune response enabled by these agents has led to a particular group of side effects called immune-related adverse events (irAEs). The main irAEs include diarrhea, colitis, hepatitis, skin toxicities and endocrinopathies such as hypophysitis and thyroid dysfunction. The anti-PD-1 antibodies have a different toxicity profile to ipilimumab with fewer high grade events. This article identifies the rates of common and uncommon irAEs associated with each immune checkpoint inhibitor (ICPI) and their timing of onset, focusing mainly on the experience in melanoma and lung cancer. An approach to management for each class of irAE is provided.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Antineoplastic Agents; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Colitis; CTLA-4 Antigen; Cyclosporine; Diarrhea; Drug Eruptions; Humans; Immunosuppressive Agents; Infliximab; Ipilimumab; Kidney Neoplasms; Lung Neoplasms; Melanoma; Mycophenolic Acid; Neoplasms; Nivolumab; Pituitary Diseases; Programmed Cell Death 1 Receptor; Skin Neoplasms; Tacrolimus; Thyroiditis

Kidney transplant recipients (KTRs) have a 65- to 250-fold greater risk than the general population of developing nonmelanoma skin cancer. Immunosuppressive drugs combined with traditional risk factors such as UV radiation exposure are the main modifiable risk factors for skin cancer development in transplant recipients. Genetic variation affecting immunosuppressive drug pharmacokinetics and pharmacodynamics has been associated with other transplant complications and may contribute to differences in skin cancer rates between KTRs. Genetic polymorphisms in genes encoding the prednisolone receptor, GST enzyme, MC1R, MTHFR enzyme and COX-2 enzyme have been shown to increase the risk of nonmelanoma skin cancer in KTRs. Genetic association studies may improve our understanding of how genetic variation affects skin cancer risk and potentially guide immunosuppressive treatment and skin cancer screening in at risk individuals.

Topics: Azathioprine; Calcineurin Inhibitors; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Pharmacogenetics; Prednisolone; Prednisone; Skin Neoplasms; Tacrolimus

There is controversy regarding a potential increased risk of lymphoma in patients with atopic dermatitis (AD).. To assess the risk of lymphoma and the role of topical treatments in patients with AD.. A systematic literature search and a separate meta-analysis were performed on case control and cohort studies.. Of the 3979 articles retrieved, 24 references met the inclusion criteria. In cohort studies, the risk of lymphoma was slightly increased, with a relative risk (RR) of 1.43 (95% confidence interval [CI], 1.12-1.81). In case control studies, no significant increased risk of lymphoma was found, with an odds ratio (OR) of 1.18 (95% CI, 0.94-1.47). Severity of AD was a significant risk factor. Highly potent topical steroids were associated with an increased risk of lymphoma. For topical calcineurin inhibitors (TCIs), a significant association between tacrolimus and mostly skin lymphoma was found in 1 study.. Confusion between severe AD and cutaneous T-cell lymphoma may account for part of the increased risk of lymphoma in patients with AD.. This systematic literature review shows a slightly increased risk of lymphoma in patients with AD. Severity of AD appears to be a significant risk factor. The role of topical steroids and TCIs is unlikely to be significant.

Topics: Administration, Topical; Adrenal Cortex Hormones; Age Distribution; Calcineurin Inhibitors; Comorbidity; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Incidence; Lymphoma, T-Cell, Cutaneous; Male; Prognosis; Risk Assessment; Severity of Illness Index; Sex Distribution; Skin Neoplasms; Tacrolimus

Cases of lymphoma or cutaneous cancer have been observed following use of topical calcineurin inhibitors (TCIs), but it is unclear whether TCI use increases cancer risk. We used published literature to assess the extent to which atopic dermatitis (AD) or TCI use is associated with lymphoma, melanoma, basal cell carcinoma and squamous cell carcinoma. We searched the literature and summarized the results of all studies that provided data on the absolute or relative frequency of any malignancy among patients with AD or eczema or among patients using TCIs. The relative risk for all lymphoma in broad populations of AD or eczema ranged from 0·7 to 1·8. Available data on lymphoma following TCI use were inconsistent and insufficient to draw a conclusion about the causal role of TCIs. We found no evidence indicating that melanoma or nonmelanoma skin cancer is associated with TCI use. A bias analysis showed that cutaneous T-cell lymphomas initially misdiagnosed and treated as AD would lead to overestimation of the association between TCI use and lymphoma. However, there are only sparse data on specific malignancies among TCI-treated patients. The short duration of typical TCI exposure hinders conclusions about longer exposure. There is insufficient evidence in the epidemiological literature to infer whether TCIs do or do not cause malignancy.

Topics: Administration, Topical; Calcineurin Inhibitors; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Dermatitis, Atopic; Dermatologic Agents; Humans; Lymphoma; Melanoma; Risk Factors; Skin Neoplasms; Tacrolimus

There have been many new developments in therapeutic modalities for the treatment of pediatric dermatological diseases in the past year. Advances in the treatment of atopic dermatitis, psoriasis, infantile hemangiomas and dystrophic epidermolysis bullosa will be discussed. The following review will update the reader on these exciting new possibilities for patient care and future directions for research to improve the lives of children suffering from skin diseases.. This review will discuss recent articles describing the use of topical tacrolimus for maintenance of remission in atopic dermatitis, utility of nurse educators in atopic dermatitis, safety and efficacy of etanercept for the treatment of psoriasis in children, narrow band ultraviolet B phototherapy for atopic dermatitis and psoriasis, use of topical timolol for infantile hemangiomas and bone marrow transplantation for dystrophic epidermolysis bullosa.. There are many new interesting, potentially useful therapeutic modalities emerging in pediatric dermatology. New treatments for atopic dermatitis, psoriasis, infantile hemangiomas and dystrophic epidermolysis bullosa are reviewed.

Topics: Adrenergic beta-Antagonists; Child; Dermatitis, Atopic; Epidermolysis Bullosa Dystrophica; Etanercept; Hemangioma; Humans; Immunoglobulin G; Immunosuppressive Agents; Pediatrics; Psoriasis; Receptors, Tumor Necrosis Factor; Skin Diseases; Skin Neoplasms; Tacrolimus; Timolol; Ultraviolet Therapy; Vitamin D; Vitamins

Tacrolimus ointment has shown efficacy as monotherapy in both short- and long-term studies in atopic dermatitis. Absorption of tacrolimus after topical application is dependent on the barrier function of the skin. Absorption through the intact epidermis is very low and eczematic skin a little higher. In comparison to systemic tacrolimus used for prevention and treatment of rejection after organ transplantation, the bioavailability of topical tacrolimus in patients with atopic dermatitis is between 3 and 4%. Long-term safety studies of up to 4 years have not shown adverse events associated with systemic use of immunosuppressive agents, that is, increased risk of infections, lymphomas or skin cancers. Despite these findings, many physicians remain concerned about possible long-term malignancies associated with long-term treatment with a topical calcineurin inhibitor.. To identify in the published literature possible long-term safety issues associated with topical tacrolimus treatment.. PubMed was used to identify studies of atopic dermatitis therapy in which tacrolimus ointment was used for at least 6 months. We evaluated the safety data available from these studies. In addition, some safety data were evaluated from clinical follow-up of our own patients who have used tacrolimus ointment intermittently for up to 14 years.. During a follow-up period of 4 years in clinical studies, no increased risk of infections or cancer was associated with long-term use of tacrolimus ointment. Only short-term adverse events were detected. They included increased burning and stinging of the skin, and a temporary increase in skin infections. No signs of immunosuppression were observed after 1 - 4 years of intermittent treatment with tacrolimus ointment.

Topics: Administration, Topical; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Ointments; Skin Diseases; Skin Neoplasms; Tacrolimus

This article reviews if local immunosuppression of atopic dermatitis is associated with an increased risk of cancer - as implicated by a warning issued by the FDA and EMEA health authorities because systemic immunosuppression of transplanted patients leads to a significant increase of non-melanoma skin cancer and lymphoma. So far, no studies support that the use of topical immunosuppression increases the risk of local or systemic cancer.

Topics: Administration, Topical; Adult; Child; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Lymphoma; Risk Factors; Skin Neoplasms; Tacrolimus

Pimecrolimus (SDZ ASM 981), nonsteroid anty-inflammatory ackomycin-derived drug has more and more indications in dermatology. It has been recommended in therapy of atopic and contact dermatitis at the beginning. Nowadays pimecrolimus is used in the treatment of seborrhoic dermatitis, post-steroidal rosacea, bullous diseases etc. News reporting higher incidence of skin cancers after pimecrolimus application has not been proved clinically. The common use of mentioned medication forced us to detailed analysis of references concerning that problem.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Causality; Comorbidity; Dermatitis, Atopic; Dermatitis, Contact; Dermatologic Agents; Humans; Incidence; Skin Neoplasms; Tacrolimus

More than five years have passed since tacrolimus (Protopic) has been put on the market in Spain. This is sufficient time to reevaluate the successes and failures that this product has had after the great expectations created prior to the time when it was put on the market based on its extensive experimentation in clinical trials and very encouraging results. It is also time to reconsider the future of the indications and uses of tacrolimus, to reconsider our personal experiences with it and to offer answers to the new questions that have arisen after five years of using the product. Tacrolimus was sold for topical use in the treatment of atopic dermatitis. Since atopic dermatitis (AD) is a disease that affects children more frequently, tacrolimus is a product oriented directly toward use in children. This entails some added concerns. In this article, we review the most relevant findings that have arisen in the last five years in regards to the treatment of AD with tacrolimus in children.

Topics: Adolescent; Adrenal Cortex Hormones; Age Factors; Calcineurin Inhibitors; Child; Child, Preschool; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Infant; Lymphoma; Retrospective Studies; Skin Neoplasms; Spain; Tacrolimus

Topics: Azathioprine; Carcinoma, Squamous Cell; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Risk Factors; Skin Neoplasms; Tacrolimus; Ultraviolet Rays

Tacrolimus ointment is a nonsteroid treatment for atopic dermatitis which is both effective and has a minimal side-effect profile. However, some clinicians may be reluctant to use tacrolimus ointment due to the "unknown risks", meaning those that have not been uncovered in human studies conducted thus far. Therefore, the available animal data regarding the "unknown risks" of topical tacrolimus therapy are reviewed, and a discussion of the interpretation of this available but limited data is presented.. Some of the fear on the part of clinicians regarding the use of topical tacrolimus may come from the results of animal studies which showed an increase in lymphoma and UV-induced skin cancer after treatment with topical tacrolimus in animal models of carcinogenesis. However, rigorous assessment of these studies suggest that it is somewhat likely that these represent a species-specific response to tacrolimus in an animal already predisposed to tumor formation, and therefore may not be relevant in assessing the possibility of an increased human health risk.. Animal and human studies suggest that topical tacrolimus is a safe alternative to topical steroids, with the major known adverse effect being a transient burning sensation, compared with the known adverse effects of topical steroids, including long-lasting ones. Therefore, in the opinion of the authors, currently available data, including animal studies, does not suggest that "unknown risks" of topical tacrolimus need be any more concerning than the known side-effects of the topical steroids.

Topics: Administration, Topical; Animals; Dermatitis, Atopic; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Lymphoma; Skin Absorption; Skin Neoplasms; Tacrolimus; Ultraviolet Rays

In this review the controversy regarding the association between topical pimecrolimus and tacrolimus and the development of tumors is unfolded. After reviewing the literature we conclude that, currently, there is no scientific evidence of an increased incidence of skin cancer, lymphomas or systemic immunosuppression in those patients that use or have used topical calcineurin inhibitors. Published studies lack adequate number of patients and/or the follow-up time is short enough to conclude that topical use of calcineurin inhibitors might be associated with the reported cases of skin cancer and lymphoma. Nevertheless the possibility of long term cutaneous and/or systemic side effects cannot be excluded.

Topics: Administration, Topical; Animals; Calcineurin Inhibitors; Humans; Risk Factors; Skin Neoplasms; Tacrolimus

The topical immunomodulators tacrolimus and pimecrolimus were approved for the treatment of atopic dermatitis in 2000 and 2001, respectively. However, on 20 January 2006, the US FDA approved a 'black box' warning for these agents because of concerns regarding a possible link to development of malignancy. These concerns were based upon the known mechanism of action of this drug class, the results of animal studies, and case reports. This article provides an overview of the data that led to the approval by the FDA of a 'black box' warning and concludes that physicians, patients, and caregivers should feel confident about using tacrolimus and pimecrolimus for atopic dermatitis so long as they follow the FDA guidelines.

Topics: Administration, Topical; Animals; Carcinogenicity Tests; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Lymphoma; Models, Animal; Skin Neoplasms; Tacrolimus; Ultraviolet Rays

Tacrolimus ointment is a topical calcineurin inhibitor (TCI) that was developed specifically for the treatment of atopic dermatitis (AD). It is one of the most extensively tested dermatological products, with more than 19 000 patients (including approximately 7600 children) having participated in the tacrolimus ointment clinical development programme. Recent regulatory reviews have focused on the potential risk of malignancy with TCIs, based on their mode of action and the effects of systemic tacrolimus when given to transplant recipients. Studies have shown, however, that the systemic absorption of tacrolimus when applied topically is very low, with blood concentrations being below the level of quantification in most patients. Moreover, TCIs are not associated with a decrease in immunocompetence in the skin and there is no increase in the incidence of infections with long-term treatment. More than 5.4 million prescriptions for tacrolimus ointment have been issued worldwide, with no evidence of an increased risk of malignancy in adults or children compared with the general population. Similarly, epidemiological studies have failed to demonstrate an increased incidence of skin cancer in patients using TCIs. The most common adverse events (AEs) that occur with tacrolimus ointment treatment are transient application-site reactions, such as burning or pruritus. These complications are related to disease severity, and decrease in frequency over time as AD improves. The incidence of nonapplication-site AEs does not increase with long-term treatment, and most such events occurring in clinical trials were considered to be unrelated to therapy. Although it is important that clinicians are aware of the recent changes in product labelling, extensive clinical trials continue to show that tacrolimus ointment is well tolerated, and is generally an effective therapy for suitable patients with AD.

Topics: Administration, Topical; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Ointments; Skin Neoplasms; Tacrolimus; Treatment Outcome

Patient survival time following renal and other solid organ transplantation has been increasing recently, in part due to modern immunosuppressive regimens. However, the probability of malignant tumor formation is also increasing proportionally to survival time, as a side effect of long-term immunosuppression. The primary factor of increased tumor risk is the deficient antitumoral and antiviral function of the immune system. The frequency of posttransplantation tumors is 2 to 4-fold compared to the non-transplanted population, and the distribution of tumor types is also different. The most frequent tumor types--skin cancer, lymphoma, Kaposi's sarcoma, oral cancer, anogenital tumors, etc.--are often associated with oncogenic viruses. Treatment options and the prognosis of posttransplant tumors are worse than in the normal population. The increasing frequency of posttransplantation tumors is an important factor determining the long-term fate of transplant patients. The reduction of carcinogenic agents, the early diagnosis and treatment of tumors and precancerous conditions, low dose immunosuppression and the usage of immunosuppressive agents with an oncologically favorable, anti-proliferative effect will help reduce the risk of posttransplant tumor formation.

Topics: Adrenal Cortex Hormones; Azathioprine; Calcineurin Inhibitors; Cyclosporine; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphoproliferative Disorders; Muromonab-CD3; Neoplasms; Prognosis; Sarcoma, Kaposi; Skin Neoplasms; Tacrolimus

Atopic eczema is a chronic inflammatory skin disorder with a relapsing and remitting course. For many decades,topical corticosteroids have been the mainstay therapy for atopic dermatitis. After the introduction of calcineurin inhibitors as a corticosteroid-free alternative, there were high expectations. After the black box warning from the FDA regarding the potential theoretical risk for developing neoplasia under treatment with calcineurin inhibitors, patients and physicians became uncertain about its safety, regardless of the fact that current scientific data do not support increased concern for risk of malignancy.

Topics: Administration, Topical; Adult; Animals; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Enzyme Inhibitors; Humans; Immunosuppressive Agents; Infant; Lymphoma; Product Surveillance, Postmarketing; Skin Neoplasms; Tacrolimus

Topics: Administration, Topical; Adult; Adverse Drug Reaction Reporting Systems; Allergy and Immunology; Attitude of Health Personnel; Attitude to Health; Causality; Child; Dermatitis, Atopic; Drug Labeling; Fear; Humans; Lymphoma; Lymphoproliferative Disorders; Neoplasms; Patient Acceptance of Health Care; Patients; Physicians; Quality of Life; Skin Neoplasms; Societies, Medical; Tacrolimus

As newer immunosuppressive regimens have steadily reduced the incidence of acute rejection and have extended the life expectancy of allograft recipients, posttransplant malignancy has become an important cause of mortality. In fact, it is expected that cancer will surpass cardiovascular complications as the leading cause of death in transplant patients within the next 2 decades. An understanding of the underlying pathobiology and how to minimize cancer risks in transplant recipients are essential. The etiology of posttransplant malignancy is believed to be multifactorial and likely involves impaired immunosurveillance of neoplastic cells as well as depressed antiviral immune activity with a number of common posttransplant malignancies being viral-related. Although calcineurin inhibitors and azathioprine have been linked with posttransplant malignancies, newer agents such as mycophenolate mofetil and sirolimus have not and indeed may have antitumor properties. Long-term data are needed to determine if the use of these agents will ultimately lower the mortality due to malignancy for transplant recipients.

Topics: Azathioprine; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Cyclosporine; Hepatitis, Viral, Human; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphoproliferative Disorders; Mycophenolic Acid; Neoplasms; Sirolimus; Skin Neoplasms; Tacrolimus; Transplantation Immunology; Transplantation, Homologous

Topical Calcineurin Inhibitors (TCIs) used for the treatment of atopic eczema modify the immune regulatory function of the skin and may have the potential to enhance immunosuppressive ultraviolet (UV) effects. Current recommendations on UV protection in eczema patients treated with PCIs are inconsistent and have given rise to uncertainty and anxiety in patients. Therefore, the European Dermatology Forum (EDF) developed a position statement which reviews critically the available data with regard to the problem, especially analysing and commenting the limitations of rodent models for the human situation. There is no conclusive evidence from rodent trials to indicate that long-term application of TCIs is photococarcinogenic. There is a need for further studies to investigate the validity of mouse models as well as long-term cohort studies in patients using TCIs. Available data suggest that long-term application of TCIs is safe, that there is no evidence of increased skin cancer risk and that it is ethical to treat patients with TCIs when indicated.

Topics: Administration, Topical; Animals; Calcineurin Inhibitors; Cocarcinogenesis; Dermatitis, Atopic; Disease Models, Animal; Humans; Immunosuppressive Agents; Mice; Neoplasms, Radiation-Induced; Skin Neoplasms; Tacrolimus; Ultraviolet Rays

Within the last decade, healthcare providers have had a larger selection of effective novel topical immunomodulatory agents to treat many dermatologic conditions. Novel mechanisms of action of newer topical agents have facilitated differentiation from well-established topical agents such as corticosteroids and 5-fluorouracil. Further, because of a growing understanding of the immune mechanisms within the skin, the opportunity has arisen to use the body's immune system to effectively treat many dermatologic conditions, such as condyloma acuminata, actinic keratosis, basal cell carcinoma, and atopic dermatitis, while maintaining a favorable safety profile. Imiquimod 5% cream, an immune response modifier, is safe and effective in the treatment of condyloma acuminata, actinic keratosis, and primary superficial basal cell carcinoma (sBCC). Pimecrolimus cream 1% and tacrolimus ointment (0.1% and 0.03%) are safe and effective in the treatment of atopic dermatitis. This review highlights newer data on approved and investigational indications for these topical immunomodulatory agents.

Topics: Adjuvants, Immunologic; Administration, Topical; Aminoquinolines; Condylomata Acuminata; Dermatitis, Atopic; Dermatitis, Seborrheic; Humans; Hutchinson's Melanotic Freckle; Imiquimod; Keratosis; Melanoma; Membrane Glycoproteins; Receptors, Cell Surface; Skin Diseases; Skin Diseases, Viral; Skin Neoplasms; Tacrolimus; Toll-Like Receptors

Skin cancer is the most common malignancy arising in the posttransplantation setting. Multiple factors contribute to the high risk for cutaneous carcinoma in immunosuppressed organ-transplant recipients. We review the phenomenon of skin cancer in solid-organ transplant recipients and further delineate the problem in the context of liver transplantation. Skin cancer is a significant medical and surgical problem for organ-transplant recipients. With prolonged allograft function and patient survival, the majority of solid-organ transplant recipients will eventually develop skin cancer. Although squamous cell carcinoma is the most common cutaneous malignancy in this population, basal cell carcinoma, melanoma, and Kaposi's sarcoma, as well as uncommon skin malignancies, may occur. Highly susceptible patients may develop hundreds of squamous cell carcinomas, which may be life threatening. Management strategies focus on regular full-skin and nodal examination, aggressive treatment of established malignancies, and prophylactic measures to reduce the risk for additional photodamage and malignant transformation. Skin cancer is a substantial cause of morbidity and even mortality among solid-organ transplant recipients. As a byproduct of immunosuppression, liver transplant recipients experience a high incidence of skin cancer and should be educated and managed accordingly.

Topics: Animals; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cyclosporine; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Keratosis; Liver Transplantation; Postoperative Complications; Skin Neoplasms; Tacrolimus

The calcineurin pathway is often activated in mycosis fungoides. We aimed to assess the activity and safety of topical pimecrolimus, a calcineurin inhibitor, in patients with early mycosis fungoides.. PimTo-MF was a single-arm, multicentre, phase 2 trial done at six medical centres in Spain. Patients (aged ≥18 years) had histologically confirmed early mycosis fungoides (stages IA-IIA) and an Eastern Cooperative Oncology Group performance status of 0-1. Key exclusion criteria included the use of concurrent treatments for mycosis fungoides, including sunbathing, topical or systemic corticosteroids, and other calcineurin inhibitors. Patients applied topical pimecrolimus 1% cream on their skin lesions twice daily for 16 weeks (1 g per 2% of body surface), with subsequent follow-up of 12 months. Dosage modifications were not allowed. To evaluate adherence to the treatment, patients were instructed to return all empty tubes to the hospital (as per drug accountability protocols). The primary endpoint was the overall response ratein the intention-to-treat population. PimTo-MF is registered with EudraCT, 2014-001377-14, and is complete.. Between March 1, 2015, and Sept 30, 2016, 39 patients were enrolled. All patients were assessable, with a median age of 51·5 years (IQR 45-62), and the population was predominantly male (24 male [62%], 15 female [38%]). Median follow-up after baseline was 5·7 years (IQR 5·7-6·2). 22 (56%) of 39 patients had an overall response (one complete response, 21 partial responses). Responses were observed across IA (14 [54%] of 26 patients) and IB (eight [73%] of 11 patients) clinical stages, but not IIA. Topical pimecrolimus was well tolerated and no patient required a dose reduction or discontinued treatment because of unacceptable drug-related toxicity. No patients were lost to follow-up or discontinued treatment. 13 (33%) of 39 patients reported adverse events; transitory mild burning or pruritus (grade 1) was the most common, seen in eight (21%) patients. In three (8%) of these patients, the burning or pruritus was considered related to treatment. No grade 4 or 5 adverse events were observed.. Pimecrolimus 1% cream seems active and safe in patients with early stage mycosis fungoides. Our findings should be taken with caution until long-term follow-up data are obtained that confirm the safety of this treatment. Further controlled clinical trials are warranted to confirm these results.. Instituto de Salud Carlos III and the European Regional Development Fund.. For the Spanish translation of the abstract see Supplementary Materials section.

Topics: Adolescent; Adult; Female; Humans; Male; Middle Aged; Mycosis Fungoides; Pruritus; Skin Neoplasms; Tacrolimus

Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare infiltrative vascular tumors. Currently, no standard treatment regimens exist for KHE/TA. The purpose of our study was to evaluate the efficacy and safety of topical application of tacrolimus for superficial KHE/TA. We examined six patients with superficial KHE/TA. All patients were treated with tacrolimus 0.1% ointment twice daily for at least 12 months. The response rate was 100%, including three nearly complete remissions. Only one patient experienced local pruritus during treatment. The data constituted an intriguing rationale for clinical trials of topical tacrolimus in the treatment of superficial KHE/TA.

Topics: Administration, Cutaneous; Biopsy; Child, Preschool; Female; Hemangioendothelioma; Hemangioma; Humans; Infant; Kasabach-Merritt Syndrome; Male; Off-Label Use; Ointments; Photography; Pruritus; Sarcoma, Kaposi; Skin; Skin Neoplasms; Tacrolimus; Treatment Outcome

Transplant recipients in whom cutaneous squamous-cell carcinomas develop are at high risk for multiple subsequent skin cancers. Whether sirolimus is useful in the prevention of secondary skin cancer has not been assessed.. In this multicenter trial, we randomly assigned transplant recipients who were taking calcineurin inhibitors and had at least one cutaneous squamous-cell carcinoma either to receive sirolimus as a substitute for calcineurin inhibitors (in 64 patients) or to maintain their initial treatment (in 56). The primary end point was survival free of squamous-cell carcinoma at 2 years. Secondary end points included the time until the onset of new squamous-cell carcinomas, occurrence of other skin tumors, graft function, and problems with sirolimus.. Survival free of cutaneous squamous-cell carcinoma was significantly longer in the sirolimus group than in the calcineurin-inhibitor group. Overall, new squamous-cell carcinomas developed in 14 patients (22%) in the sirolimus group (6 after withdrawal of sirolimus) and in 22 (39%) in the calcineurin-inhibitor group (median time until onset, 15 vs. 7 months; P=0.02), with a relative risk in the sirolimus group of 0.56 (95% confidence interval, 0.32 to 0.98). There were 60 serious adverse events in the sirolimus group, as compared with 14 such events in the calcineurin-inhibitor group (average, 0.938 vs. 0.250). There were twice as many serious adverse events in patients who had been converted to sirolimus with rapid protocols as in those with progressive protocols. In the sirolimus group, 23% of patients discontinued the drug because of adverse events. Graft function remained stable in the two study groups.. Switching from calcineurin inhibitors to sirolimus had an antitumoral effect among kidney-transplant recipients with previous squamous-cell carcinoma. These observations may have implications concerning immunosuppressive treatment of patients with cutaneous squamous-cell carcinomas. (Funded by Hospices Civils de Lyon and others; TUMORAPA ClinicalTrials.gov number, NCT00133887.).

Topics: Adult; Aged; Aged, 80 and over; Calcineurin Inhibitors; Carcinoma, Squamous Cell; Cyclosporine; Enzyme Inhibitors; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Sirolimus; Skin Neoplasms; Tacrolimus

To determine whether atopic dermatitis (AD) patients treated with tacrolimus ointment experienced an increased risk of non-melanoma skin cancer (NMSC).. Data were collected from 9813 adult and paediatric patients with AD who applied 0.03% or 0.1% tacrolimus ointment twice daily and were examined every 3 months during the tacrolimus ointment development programme.. Thirteen adult patients were diagnosed with NMSC during the follow-up period. All patients with NMSC were white adults and 12 were over 40 years of age. Based on 1718 patient-years of tacrolimus ointment exposure in patients 40 years of age, the calculated incidence of NMSC did not suggest an increased risk of first NMSC over that of a similarly aged US cohort.. This study does not indicate an increased risk for the development of NMSC in patients with AD treated with tacrolimus ointment for a mean duration of 208 days with a maximum observation period of 1479 days.

Topics: Administration, Topical; Adult; Aged; Dermatitis, Atopic; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Skin Neoplasms; Tacrolimus; Treatment Outcome

Although conventional immunosuppression after liver transplantation consists of cyclosporine A (CsA), steroids, and azathioprine, recently introduced protocols entail CsA-based quadruple induction protocols or tacrolimus-based combinations. These protocols aim to reduce the rejection rate and the considerable morbidity related to the side effects of additional immunosuppressive treatment, but have not yet been analyzed regarding their long term de novo neoplastic risk.. From September 1988 to May 1994, 500 liver transplantations were performed in 458 patients. The median follow-up was 50 months (range, 0.3-97 months) for all patients. Conventional triple therapy was implemented in 25 patients, CsA-based quadruple induction therapy using an antilymphocyte globulin preparation (ATG) in 190 patients, an interleukin-2 receptor antibody (BT563) in 141 patients, and tacrolimus-based dual or triple immunosuppression in 102 patients. The different protocols were evaluated in four randomized and two nonrandomized prospective trials.. De novo neoplasias were detected in 33 patients (7.2%) and were comprised of lymphomas (n = 7), skin malignancies (n = 8 lesions in 7 patients), intraepithelial neoplasias of the cervix uteri (n = 7), breast carcinoma (n = 3), lung carcinoma (n = 3), and other malignancies (n = 6). The incidence of de novo neoplasias did not differ in the different trial arms. Only a positive T-crossmatch and a low CD4+/CD8+ ratio in patients receiving CsA-based immunosuppression demonstrated a significant correlation with the development of a de novo tumor in a multivariant logistic regression analysis.. The development of de novo neoplastic diseases after liver transplantation with the use of CsA-based quadruple induction protocols or tacrolimus-based regimens for immunosuppresion was assessed over the long term. Recently introduced immunosuppressive protocols did not alter the posttransplant de novo tumor rate. Patients with a low CD4+/CD8+ ratio during CsA-based therapy or a positive T-crossmatch were identified to be at an increased risk for the development of a de novo malignancy.

Topics: Antibodies, Monoclonal; Antilymphocyte Serum; Clinical Trials as Topic; Cyclosporine; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoma; Neoplasms, Second Primary; Prospective Studies; Randomized Controlled Trials as Topic; Receptors, Interleukin-2; Skin Neoplasms; Tacrolimus; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

The cancer risks associated with treatment with topical calcineurin inhibitors (TCIs) in patients with atopic dermatitis (AD) remain controversial, and limited evidence exists regarding the cancer risks among patients with AD treated with TCIs in Asian populations.. This study identified the association between TCI use and the risks of developing all cancers, lymphoma, skin cancers, and other cancers.. This study was a nationwide, population-based, retrospective cohort study.. Taiwan's National Health Insurance Research Database.. Patients diagnosed at least twice with ICD-9 code 691 or at least one time with ICD-9 codes 691 or 692.9 within 1 year between 1 January 2003 and 31 December 2010 were included and followed until 31 December 2018. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using the Cox proportional hazard ratio model.. Patients using tacrolimus or pimecrolimus were identified in the National Health Insurance Research Database and compared with patients using topical corticosteroids (TCSs).. The main outcomes were hazard ratios (HRs) of cancer diagnoses and associated outcomes obtained from the Taiwan Cancer Registry database.. After propensity score (PS) matching, the final cohort included 195,925 patients with AD, including 39,185 who were initial TCI users and 156,740 who were TCS users. Propensity score matching was performed according to age, sex, index year, and Charlson Comorbidity Index using a ratio of 1:4. Except for leukemia, HR and 95% CI showed no significant associations between TCI use and the risk of developing all cancer, lymphoma, skin cancers, and other cancers. Sensitivity analysis showed that the lag time HRs for every cancer subtype continued to show no significant association between TCI use and cancer risk, except for leukemia.. Our study found no evidence to support an association between TCI use and the risks of almost all cancers compared with TCS use in patients with AD, but physicians should be aware of potentially higher risks of leukemia with TCI use. This study represents the first population-based study focused on the cancer risk of TCI use among patients with AD in an Asian population.

Topics: Calcineurin Inhibitors; Dermatitis, Atopic; Humans; Leukemia; Lymphoma; Retrospective Studies; Skin Neoplasms; Tacrolimus

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.. 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.. 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.. 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.

Topics: Animals; Humans; Immunocompromised Host; Immunosuppressive Agents; Mice; Skin Neoplasms; Tacrolimus; Tacrolimus Binding Protein 1A

Mycosis fungoides (MF) in solid-organ transplant recipients (SOTRs) is rare, with limited data on disease characteristics.. The aim was to study the characteristics of MF in SOTRs with an emphasis on the immunosuppressive therapy.. A retrospective cohort of patients diagnosed with MF, who were also SOTRs, were followed at 3 cutaneous lymphoma outpatient clinics, between January 2010 and February 2022.. Ten patients were included (7 male; median ages at transplantation and at diagnosis of MF were 33 and 48 years, respectively; 40% were diagnosed before the age of 18 years). Median time from transplantation to diagnosis of MF was 8 years (range 0.5-22). Transplanted organs and immunosuppressive treatments included: liver (n = 5; 4 treated with tacrolimus, 1 with tacrolimus and prednisone), kidney (n = 3), liver and kidney (n = 1), and heart (n = 1), all treated with mycophenolic acid, tacrolimus, and prednisone. Nine had early-stage MF (IA - 4, IB - 5; 40% with early folliculotropic MF), treated with skin-directed therapies, in 2 combined with acitretin, achieving partial/complete response. One patient had advanced-stage MF (IIIA) with folliculotropic erythroderma, treated with ultraviolet A and narrow-band ultraviolet B with acitretin, achieving partial response. Immunosuppression was modified in 3. At last follow-up (median 4 years, range 1-8), no stage progression was observed; 5 had no evidence of disease, 5 had active disease (IA/IB - 4, III - 1).. MF in SOTRs is usually diagnosed at an early stage, with overrepresentation of folliculotropic MF, and of children. Immunosuppressive therapy alterations, not conducted in most patients, should be balanced against the risk of organ compromise/rejection. Disease course was similar to MF in immunocompetent patients, during the limited time of follow-up.

Topics: Acitretin; Adolescent; Child; Humans; Male; Mycosis Fungoides; Organ Transplantation; Prednisone; Retrospective Studies; Skin Neoplasms; Tacrolimus

Topics: Humans; Mycosis Fungoides; Skin Neoplasms; Tacrolimus

Topics: Humans; Mycosis Fungoides; Skin Neoplasms; Tacrolimus

Mucosal melanoma, or so-called mucosal-oral melanoma is a rare but serious diagnostic and therapeutic problem. The "primary mixed" mucocutaneous forms of melanoma, which affect both the mucosa and the adjacent skin, are also particularly problematic and rare. Given that the staging, diagnosis, and treatment of mucosal (oral) melanoma differs from that of cutaneous melanoma, staging in mixed melanoma (primary mucocutaneous melanoma) as well as decisions for each subsequent diagnostic and therapeutic step should be individualized and modified according to the recommendations of the respective two classifications (for cutaneous but also mucosal melanomas), while at the same time or at least to a large extent overlapping with them. In practice, the following paradoxes occur during staging - there are melanomas with the same tumor thickness, but in different stages, which should be treated in a different, consensus-based way. At the same time, it would be appropriate for the surgical interventions to be in accordance with the patient's wishes for minimal trauma/reduced risk of developing facial disproportion. We present the case of a 69-year-old patient with a newly-developed lesion in the area of the mucosa of the upper lip and adjacent skin, which was identified as a primary mucocutaneous form of melanoma after surgical removal. The complex pathogenesis of the disease is discussed herein, emphasizing the role of UV radiation, iatrogenic immunosuppression with mycophenolate mofetil, tacrolimus, and prednisolone (due to severe glomerulonephritis leading to kidney transplantation), as well as the potential possible but speculative pathogenetic role of acetyl salicylic acid, etc. Primary mucosal and mucocutaneous forms of melanoma remain a challenge for clinicians, and steps for their diagnosis and treatment should be an expression of multidisciplinary, consensual solutions.

Topics: Aged; Humans; Melanoma; Mouth Neoplasms; Mycophenolic Acid; Prednisolone; Salicylic Acid; Skin Neoplasms; Tacrolimus

Topics: Administration, Topical; Hemangioma; Humans; Immunosuppressive Agents; Ointments; ortho-Aminobenzoates; Skin Neoplasms; Steroids; Tacrolimus; Treatment Outcome

Epidermolytic acanthomas (EA) are rare benign tumors of unclear etiology that present as flat, sometimes slightly keratotic, pale or whitish papules that are usually asymptomatic. Not uncommonly, their clinical appearance in the anogenital area might lead to misdiagnosis as other lesions that commonly develop at this site, such as condylomata acuminata. Though mainly asymptomatic, there are also reports of EA presenting with persistent genital pruritus. We describe the first reported case of pruritic scrotal EA successfully treated with topical pimecrolimus.

Topics: Acanthoma; Dermatologic Agents; Dosage Forms; Humans; Male; Middle Aged; Pruritus; Scrotum; Skin Neoplasms; Tacrolimus; Treatment Outcome

Topics: Aged; Carcinoma, Basal Cell; Female; Glucocorticoids; Humans; Immune System; Immunosuppressive Agents; Keratoacanthoma; Kidney Transplantation; Mycophenolic Acid; Polycystic Kidney Diseases; Skin Neoplasms; Tacrolimus

Topics: Administration, Topical; Adult; Calcineurin Inhibitors; Carcinoma; Dermatitis, Atopic; Humans; Keratinocytes; Skin Neoplasms; Tacrolimus

Topics: Hemangioma; Humans; Pain; Skin Neoplasms; Tacrolimus

Topics: Administration, Topical; Adrenal Cortex Hormones; Aged; Antimalarials; Calcineurin Inhibitors; Carcinoma, Squamous Cell; Clofazimine; Diabetic Retinopathy; Drug Therapy, Combination; Ear; Humans; Leprostatic Agents; Lupus Erythematosus, Discoid; Lymph Node Excision; Male; Middle Aged; Neoplasm Staging; Skin Neoplasms; Tacrolimus; Treatment Outcome

Organ transplantation is a significant risk factor for the development of skin cancer. The impact of skin type, immunosuppressive regimens, and photosensitizing agents requires further study.. The objective of this study was to compare skin cancer development between Caucasian and non-Caucasian transplant recipients at the University of Southern California.. We performed a retrospective chart review of lung and liver transplantations to determine the incidence of post-transplant skin cancer. Participants included patients who underwent lung or liver transplantation between 2005 and 2013 at our institution. Patients included in the study were limited to those who survived through the study observation period.. We analyzed 475 patients who underwent transplantation, including 370 liver transplant recipients and 105 lung transplant recipients. Among these, 46.3% identified as Caucasian, while 53.7% were non-Caucasian. Over a mean follow-up of 7.9 years, 11.8% of Caucasian patients developed at least one skin cancer, compared with 2.7% of non-Caucasians (p < 0.001). However, irrespective of race, skin cancer development was significantly greater in lung compared with liver transplant recipients (20.0% vs. 3.2%, p < 0.001). The standard immunosuppressive and prophylactic regimens were mycophenolate mofetil and tacrolimus based for both transplants. Mycophenolate mofetil was maintained throughout the course in lung transplant patients, whereas this agent was reduced and terminated when possible in liver transplant recipients. In addition, during the years examined, voriconazole, a known photosensitizing agent, was used in lung transplant recipients to prevent aspergillosis.. Fair skin type increases post-transplant skin cancer development, irrespective of the immunosuppressive regimen. A higher risk of skin cancer is associated with different regimens; in particular photosensitizing agents may increase risk in transplant recipients.

Topics: Adult; Aged; Female; Humans; Incidence; Liver Transplantation; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Skin Neoplasms; Tacrolimus; Transplant Recipients

Skin lesions are very common among organ transplant recipients (OTR), particularly infections and tumors, because of the immunosuppressive state these patients are put in.. 177 OTR were examined. Skin lesions were categorized into neoplastic, infectious, and inflammatory diseases.. The mean age of OTR was 52 years, the mean age at transplantation was 42.7 years, and kidney was the most common organ transplanted (72%). Skin lesions were found in 147 patients (83%). Cutaneous infections were seen in 106 patients (60%). Warts (30%) had the larger incidence and were associated with azathioprine (P = 0.026), cyclosporine (P = 0.006), and tacrolimus (P = 0.009). Superficial mycoses occurred in 16% of OTR, mostly onychomycosis, which was associated with tacrolimus (P = 0.040). Actinic keratosis (AK) occurred in 31% of patients and cutaneous tumors in 56%. Squamous cell carcinoma (SCC) was the most common tumor type affecting 36% of OTR (n = 64), with invasive SCC predominating over in situ SCC, whereas basal cell carcinoma (BCC) accounted for 17%. Both SCC and BCC were more numerous in patients' skin type I (P < 0.05). SCC was more frequent (36%) in combined kidney and liver recipients (P = 0.004), and BCC was associated with cyclosporine (P = 0.047). Inflammatory complications (acne, alopecia, hypertrichosis, and gingival overgrowth) were observed in 17.5% of patients.. Organ transplant recipients must be regularly evaluated by dermatologists, who should be alert to the onset of infections and skin (pre)malignant diseases in these patients.

Topics: Adolescent; Adult; Aged; Azathioprine; Brazil; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Child; Cyclosporine; Dermatomycoses; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Keratosis, Actinic; Male; Middle Aged; Organ Transplantation; Risk Factors; Skin Diseases, Infectious; Skin Neoplasms; Tacrolimus; Warts; Young Adult

Systemic therapeutic management of post-transplant Kaposi sarcoma (KS) is mainly based on 3 axes: reduction of immunosuppression, conversion to mammalian target of rapamycin (mTOR) inhibitors, chemotherapy, or a combination of these.. To obtain an overview of clinical strategies about the current treatment of KS.. We conducted a multicenter retrospective cohort study including 145 solid organ transplant recipients diagnosed with KS between 1985 and 2011 to collect data regarding first-line treatment and response at 6 months.. Overall, 95%, 28%, and 16% of patients had reduction of immunosuppression, conversion to mTOR inhibitor, and chemotherapy, respectively. Patients treated with chemotherapy or mTOR inhibitor conversion were more likely to have visceral KS. At 6 months, 83% of patients had response, including 40% complete responses.. The retrospective design of the study.. Currently available therapeutic options seem to be effective to control KS in most patients. Tapering down the immunosuppressive regimen remains the cornerstone of KS management.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Substitution; Europe; Female; Graft Survival; Humans; Immunosuppressive Agents; Male; Middle Aged; Organ Transplantation; Retrospective Studies; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Survival Rate; Tacrolimus; TOR Serine-Threonine Kinases

Alcohol-related liver disease (ALD) is one of the main indications for liver transplantation (LT). For 20 years, tacrolimus (Tac) is the cornerstone immunosuppressive drug used after LT and is very efficient for the prevention of rejection. Nevertheless, the major drawback of long-term use of Tac is the risk for developing dose-dependent adverse effects.. The aim of the present study was to assess the impact of Tac exposure (trough concentrations and concentration/dose (C/D) ratio) during the first year after LT, on short- and long-term complications after LT for ALD.. All patients who underwent a LT for ALD at Lyon Edouard Herriot Hospital from October 1990 to September 2010, and who were treated with Tac for at least one year after LT, were analyzed.. The study population consisted in 251 patients, mean age 53.4 ± 7.3 years, and followed during 11.6 ± 4.8 years. Post-LT complications included severe infectious events (44.6%), malignancies (41.4%), arterial hypertension (49.4%) dyslipidemia (44.2%), diabetes (18.7%) and cardiovascular events (15.5%). De novo hypertension, cardiovascular event, CMV infection, non-melanoma skin cancers and HCC recurrence after transplantation were significantly associated with higher Tac trough blood concentration. In addition, Tac fast-metabolizers (defined as C/D < 1.8) had significantly more impaired renal function at 1, 5, and 10 years and more cardiovascular events, PTLD, diabetes and hypertension than slow-metabolizers.. Our results strongly support that, in addition to blood trough concentrations, Tac metabolism, as estimated by the simple C/D ratio, could be an efficient parameter in daily practice to identify LT patients at risk to develop long term general complications of Tac.

Topics: Cytomegalovirus Infections; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; France; Humans; Hypertension; Immunosuppressive Agents; Liver Diseases, Alcoholic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Risk; Skin Neoplasms; Tacrolimus; Time Factors

Topics: Adult; Aged; Anti-Inflammatory Agents; Facial Dermatoses; Female; Humans; Hydroa Vacciniforme; Lymphoma, T-Cell, Cutaneous; Minocycline; Skin Neoplasms; Sunscreening Agents; Tacrolimus

Organ transplant recipients receiving immunosuppression have an increased risk of developing post-transplant lymphoproliferative diseases (PTLDs). Traditionally, PTLDs refer to Epstein-Barr virus (EBV)-induced B-cell lymphoma. However, post-transplant T-cell lymphoma may also occur and tends to have a poorer response to reduced immunosuppressive therapy. As such, additional therapy is often needed for post-transplant T-cell lymphoma, including post-transplant cutaneous T-cell lymphoma (PT-CTCL). We present only the third case of PT-CTCL occurring after liver transplantation. The patient was diagnosed with stage IB mycosis fungoides (MF). His lesions were refractory to multiple skin-directed therapies, and so he was given oral bexarotene 150 mg daily and his oral tacrolimus dose was decreased to 2 mg daily. Remarkably, his MF patches have demonstrated a complete response to oral bexarotene 75 mg daily without recurrence over 11 years of follow-up. He developed hypertriglyceridemia with bexarotene 150 mg, so his dose was decreased to 75 mg, without loss of response. Our report is the second to describe PT-CTCL demonstrating a long-term complete response to oral bexarotene. Given its anti-carcinogenic properties and favorable toxicity profile, oral bexarotene represents an appealing treatment option for PT-CTCL refractory to skin-directed therapies.

Topics: Administration, Oral; Anticarcinogenic Agents; Bexarotene; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycosis Fungoides; Skin Neoplasms; Tacrolimus; Tetrahydronaphthalenes; Treatment Outcome

Topics: Adult; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Sarcoma, Kaposi; Skin Neoplasms; Tacrolimus

Topics: Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Infant; Lymphoma; Skin Neoplasms; Sunlight; Tacrolimus

Organ transplant recipients (OTRs) have a substantially elevated risk of squamous cell skin carcinoma (SCSC), largely attributed to immunosuppressive medications used to prevent graft rejection, although data to support the role of newer drugs in SCSC risk are sparse. We investigated the association between immunosuppressive medications and SCSC risk among cardiac and renal transplant recipients in the SCOT cohort study. Incident cases were ascertained through medical record review after self-report of skin biopsy (n = 170). Controls without SCSC (n = 324) were matched to cases on sex, age, race, transplant year, hospital, donor type, organ transplanted, and time between transplantation and interview. Conditional logistic regression was used to evaluate the association between specific medications and SCSC. Users of the antimetabolite azathioprine were more than twice as likely to develop SCSC (odds ratio [OR] = 2.67, 95% confidence interval [CI] 1.23-5.76). In contrast, the newer antimetabolite preparations (i.e., mycophenolic acid [MPA]) were associated with lower SCSC risk (OR = 0.45, 95% CI 0.29-0.69). This inverse association between MPA and SCSC persisted among OTRs with no history of azathioprine use, even after adjustment for simultaneous use of the calcineurin inhibitor tacrolimus (OR = 0.52, 95% CI 0.32-0.84). Our data suggest that the increased risk of SCSC historically associated with azathioprine is not seen in OTRs prescribed newer regimens, including MPA and tacrolimus.

Topics: Antibiotics, Antineoplastic; Carcinoma, Squamous Cell; Case-Control Studies; Cohort Studies; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Risk Factors; Skin Neoplasms; Tacrolimus; Washington

Immune-checkpoint inhibitors have been approved for the treatment of metastatic melanoma based on several phase III trials. Patients after organ transplantation and patients with impaired renal function were excluded from these studies. Recently, allograft rejections were reported in organ transplant recipients receiving PD-1 blocking antibodies.. Four patients with metastatic melanoma and impaired kidney function (baseline serum creatinine 1.79-2.59 mg/dl) were treated with immune-checkpoint blockers, of which one was a kidney-transplant recipient receiving immunosuppressive therapy with tacrolimus and prednisolone. The patient was initially treated with the anti-CTLA-4 antibody ipilimumab after detailed explanation of the potential risk of allograft rejection. Upon disease progression, therapy was switched to the anti-PD-1 antibody nivolumab. The other three patients were treated with nivolumab or pembrolizumab, two of them after previous therapy with ipilimumab.. The patients received a median of six doses (range 3-21) of anti-PD-1 antibodies and 3-4 doses of ipilimumab. Kidney function tests remained stable throughout the course of checkpoint blockade. In the kidney transplant recipient, neither ipilimumab nor nivolumab led to an allograft rejection. Responses to anti-PD-1 treatment were divergent with two patients showing disease progression, one achieving a mixed response and one experiencing a complete response.. These cases show that checkpoint inhibitors can be a safe therapeutic option in patients with impaired kidney function. Furthermore, we report the first organ transplant patient with malignant melanoma who received ipilimumab followed by nivolumab without experiencing a kidney allograft rejection.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents; CTLA-4 Antigen; Graft Rejection; Humans; Immunosuppressive Agents; Ipilimumab; Kidney Failure, Chronic; Kidney Transplantation; Male; Melanoma; Middle Aged; Nivolumab; Patient Safety; Prednisolone; Programmed Cell Death 1 Receptor; Skin Neoplasms; Tacrolimus

The aim of this study was to analyze the distribution of malignancies in patients after heart transplantation (HTX) and to evaluate the risk factors including immunosuppressive therapy with regard to the development of malignancies and survival. Special emphasis was placed on the effects of a mammalian target of rapamycin (mTOR) containing immunosuppressive regimen.. A total of 381 patients (age ≥18 years) receiving HTX were included in the present analysis. All patients were followed-up at the University of Heidelberg Heart Center, Heidelberg, Germany. Data were retrieved from the Heidelberg Registry for Heart Transplantation being collected between 1989 and 2014. According to center standard, all patients received induction therapy with anti-thymocyte globulin guided by T-cell monitoring since 1994. The initial immunosuppressive regimen consisting of cyclosporine A (CsA) and azathioprine (AZA) was replaced by CsA and mycophenolate mofetil (MMF) in 2001 and by tacrolimus (TAC) and MMF in 2006. Additionally, mTOR inhibitors (everolimus/sirolimus) were applied since 2003.. Mean recipient age at HTX was 51.2±10.5 years and the mean follow-up period after HTX was 9.7±5.9 years. During follow-up, 130 patients developed a neoplasm (34.1% of total). Subgroup analysis revealed 58 patients with cutaneous malignancy only (15.2%), 56 patients with noncutaneous malignancy only (14.7%), and 16 patients with both cutaneous and noncutaneous malignancy (4.2%). Statistically significant risk factors associated with an increased risk of malignancy after HTX were older age (P<0.0001), male recipients (P=0.0008), dyslipidemia (P=0.0263), diabetes mellitus (P=0.0003), renal insufficiency (P=0.0247), and >1 treated rejection episode (TRE) in the first year after HTX (P=0.0091). Administration of CsA (P=0.0195), AZA (P=0.0008), or steroids (P=0.0018) for >1 year after HTX was associated with increased development of malignancy, whereas administration of MMF (P<0.0001) or mTOR inhibitors (P<0.0001) was associated with a lower risk for development of malignancy. Additionally, 5-year follow-up of cutaneous malignancy recurrence (P=0.0065) and noncutaneous malignancy mortality (P=0.0011) was significantly lower in patients receiving an mTOR inhibitor containing therapy after the development of a malignancy.. This study highlights the complexity of risk factors including immunosuppression with regard to the development of malignancies after HTX. mTOR-inhibitor-based immunosuppression is associated with a better outcome after HTX, particularly in cases with noncutaneous malignancy.

Topics: Adult; Azathioprine; Cyclosporine; Female; Follow-Up Studies; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Melanoma; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Neoplasms; Risk Factors; Skin Neoplasms; Survival Analysis; Tacrolimus

We present a case report of a patient with diffuse skin and systemic Kaposi's sarcoma (KS), 1 year after renal transplantation. A concomitant Pyrenochaeta romeroi granuloma of the right hallux was diagnosed and illustrated an important immunodysfunction in our patient. Four months after reduction in immunosuppression and switch to everolimus, a total regression of the KS was observed. Reduction in the immunosuppression and treatment with terbinafine cleared the P. romeroi infection, while lowering immunosuppression and changing the type of immunosuppressive therapy were important steps in the successful management of the KS. In recent years, evidence of the antitumor effects of everolimus is increasing: total regression of KS in combination with renal function preservation in renal graft recipients is possible with mammalian target of rapamycin (mTOR) inhibitor-based regimens. In addition, with increasing numbers of human immunodeficiency virus-positive transplant recipients, mTOR inhibitors may play a more crucial role in the management of KS.

Topics: Adult; Dermatomycoses; Drug Substitution; Everolimus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Neoplasms; Mycophenolic Acid; Sarcoma, Kaposi; Skin Neoplasms; Tacrolimus; Treatment Outcome

Topics: Adenocarcinoma; Aged; Colonic Neoplasms; Colostomy; Dermatitis; Diagnosis, Differential; Humans; Male; Postoperative Complications; Prednisone; Pyoderma Gangrenosum; Skin Neoplasms; Skin Ulcer; Surgical Stomas; Tacrolimus

Drug and chemically-induced immunosuppression has been implicated as a confounding factor for cancer development. Management of cancer in such situation is often a challenging task. We tested the efficacy of nordihydroguiaretic acid (NDGA) against immunosuppressant tacrolimus-induced augmentation of mouse skin tumorigenesis. It was observed that topical administration of tacrolimus significantly accelerated the tumor promotion events in dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA) promoted two-stage mouse skin carcinogenesis, which were accompanied by reduced CD4(+)/CD8(+) ratio of lymph nodes and serum IL-2 level. NDGA pre-treatment before each TPA application reduced the tumor incidence, its multiplicity and volume together with improvement in histopathological alterations and decrease in proliferating cell nuclear antigen (PCNA) labeling index (LI). However, NDGA had no significant influence on the immunosuppressive effect of tacrolimus. The present study demonstrates chemopreventive effect of NDGA in normal as well as in the condition of immunosuppression. Thus, NDGA has the potential to inhibit or delay the onset of tumor development during immunosuppressive regimen.

Topics: Animals; Anticarcinogenic Agents; Carcinogenesis; Female; Immunosuppressive Agents; Masoprocol; Mice; Skin; Skin Neoplasms; Tacrolimus

This study aims to investigate how immunosuppression influences the protein expression of antiapoptotic members of the Bcl-2 family-namely, Bcl-xL and Mcl-1-in nonmelanoma skin cancer (NMSC) and the peritumoral epidermis of renal transplant recipients.. NMSC and peritumoral epidermis protein expression of Bcl-xL and Mcl-1 were assessed by immunohistochemistry in renal transplant recipients receiving tacrolimus or sirolimus and the general population not receiving immunosuppression.. NMSC from renal transplant recipients compared with patients not receiving immunosuppressant medications had a reduced Bcl-xL expression intensity (P = .042). Mcl-1 expression intensity in NMSC was decreased in tacrolimus-treated patients compared with sirolimus-treated patients and the nonimmunosuppressed population (P = .024). Bcl-xL expression intensity was increased in peritumoral epidermis compared with NMSC (P = .002).. It was shown for the first time that Bcl-xL and Mcl-1 expression are widespread in the peritumoral epidermis and NMSC of renal transplant recipients. Importantly in NMSC, Bcl-xL expression was reduced with immunosuppression exposure, and Mcl-1 expression was reduced in tacrolimus-treated compared with sirolimus-treated patients.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; bcl-X Protein; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Female; Humans; Immunohistochemistry; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mitosis; Myeloid Cell Leukemia Sequence 1 Protein; Sirolimus; Skin Neoplasms; Tacrolimus; Transplant Recipients

Topics: Delayed Diagnosis; Herpesvirus 8, Human; Humans; Immunocompromised Host; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Sarcoma, Kaposi; Skin Neoplasms; Tacrolimus; Thorax

Topics: Administration, Oral; Aged; Antibodies, Monoclonal; Antineoplastic Agents; Dacarbazine; Drug Administration Schedule; Fluorodeoxyglucose F18; Humans; Immunosuppressive Agents; Ipilimumab; Kidney Transplantation; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Melanoma; Middle Aged; Mycophenolic Acid; Platinum Compounds; Positron-Emission Tomography; Prednisone; Radiopharmaceuticals; Skin Neoplasms; Tacrolimus; Temozolomide; Tomography, X-Ray Computed; Treatment Outcome

Topics: Antineoplastic Agents; Calcineurin Inhibitors; Carcinoma, Squamous Cell; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Risk Factors; Sirolimus; Skin Neoplasms; Tacrolimus; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Delayed Diagnosis; Dermatitis; Diagnostic Errors; Drug Substitution; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Postoperative Period; Prednisone; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Tacrolimus; Vinblastine

Topics: Acanthosis Nigricans; Adolescent; Female; Humans; Immunosuppressive Agents; Papilloma; Skin Neoplasms; Tacrolimus

Topics: Administration, Cutaneous; Animals; Dinitrofluorobenzene; Immunosuppressive Agents; Mice; Neoplasms, Radiation-Induced; Skin Neoplasms; Tacrolimus; Ultraviolet Rays

Cancer after heart transplant is recognized as a leading cause of morbidity and mortality. A man's clinical course after receiving a heart transplant is described, with emphasis on important clinical considerations in the care of heart transplant recipients.

Topics: Azathioprine; Carcinoma, Squamous Cell; Drug Therapy, Combination; Fatal Outcome; Glucocorticoids; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Neoplasms; Male; Mediastinal Neoplasms; Middle Aged; Mycophenolic Acid; Neoplasm Recurrence, Local; Pleural Neoplasms; Prednisone; Sirolimus; Skin Neoplasms; Tacrolimus

Kaposi's sarcoma (KS) is a vascular lesion of low-grade malignant potential caused by the complex interactions between geographic, genetic, environmental, and immunological factors. We recently experienced a rare case of KS associated with rheumatoid arthritis in a patient receiving corticosteroids and tacrolimus; the KS demonstrated unusually aggressive clinical behavior. We herein report the details of the clinical course and discuss the possible contribution of corticosteroids and tacrolimus to the development of aggressive KS in the present case.

Topics: Adrenal Cortex Hormones; Aged; Arthritis, Rheumatoid; Bone Neoplasms; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Male; Sarcoma, Kaposi; Skin Neoplasms; Tacrolimus

Tacrolimus is a macrolide immunosuppressive agent, and tacrolimus ointment has been used as therapy for atopic dermatitis worldwide. Given that the immunosuppressive action of tacrolimus raises at least the theoretical potential for an increased risk of skin cancer, accurate assessment of the risk of developing skin cancer by tacrolimus ointment is necessary. The objective of the present study is to investigate the skin tumorigenic potential of commercially available tacrolimus ointment. We conducted a skin carcinogenicity study using an initiation-promotion (I/P) mouse model. Our study consisted of six groups (26 mice/group): sham control, absorptive ointment (AO), macrogol ointment (MO), tacrolimus ointment (TO) vehicle control, TO 0.03%, and TO 0.1%. Following a single administration of 7,12-dimethylbenz[α] anthracene (DMBA) to the dorsal skin of mice as an initiator, 12-O-tetra-decanoylphorbol-13-acetate (TPA) as a promoter and the test drugs were topically administered for 18 weeks. The incidence of skin hyperplasia in the TO 0.03% and TO 0.1% groups was reduced compared with both control groups (P < 0.05). Further, the incidence of skin neoplasia in the TO 0.03% (P < 0.05) and TO 0.1% groups (P < 0.01) was reduced in a dose-dependent manner compared with the sham control group. Tumor promotion effects on skin carcinogenesis were observed in the AO group, whereas inhibitory effects were observed in the MO group. TO 0.03% and TO 0.1% dose-dependently inhibit tumor induction in an I/P mouse model of skin tumors.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogenicity Tests; Female; Immunosuppressive Agents; Mice; Mice, Inbred ICR; Ointments; Skin; Skin Neoplasms; Tacrolimus

Topics: Calcineurin Inhibitors; Child, Preschool; Female; Hemangioma; Humans; Immunosuppressive Agents; Infant; Male; Skin Neoplasms; Tacrolimus

Cutaneous T-cell lymphoma occurring in the context of posttransplant immunosuppression is rare, with 27 cases documented to date.. We report 2 new cases of posttransplant cutaneous T-cell lymphoma in patients treated at our institution. Both were male recipients of renal transplants who had undergone transplantation a mean of 5.3 years previously and were taking various multidrug immunosuppressive regimens, including cyclosporine, tacrolimus, mycophenolate mofetil, and prednisone.. These cases underscore the association of posttransplant cutaneous T-cell lymphoma with renal transplantation, cyclosporine and tacrolimus therapy, male sex, and later onset compared with B-cell posttransplant lymphoproliferative disease. Relative to the general population, the incidence of cutaneous T-cell lymphoma seems increased among transplant recipients receiving immunosuppressive medications.

Topics: Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoma, T-Cell, Cutaneous; Male; Risk Factors; Sex Factors; Skin Neoplasms; Tacrolimus

Non-melanoma skin cancers (NMSCs) are the most common malignancies after solid organ transplantation. Their incidence increases with time after transplantation. Calcineurin-inhibitors (CNIs) and azathioprine are known as skin neoplasia-initiating and -enhancing immunosuppressants. In contrast, increasing clinical experience suggests a relevant antiproliferative effect of mammalian target of rapamycin inhibitors, also named proliferation signal inhibitors (PSIs). We report the case of a cardiac allograft recipient with an impressive and consolidated reduction of recurrent NMSC, observed after conversion from CNI-therapy to a PSI-based protocol.

Topics: Calcineurin Inhibitors; Carcinoma, Squamous Cell; Cell Proliferation; Drug Therapy, Combination; Everolimus; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Neoplasm Recurrence, Local; Photochemotherapy; Signal Transduction; Sirolimus; Skin Neoplasms; Tacrolimus; Time Factors; TOR Serine-Threonine Kinases; Transplantation, Homologous; Treatment Outcome

Topics: Administration, Topical; Adult; Combined Modality Therapy; Female; Humans; Laser Therapy; Middle Aged; Risk Factors; Skin Neoplasms; Tacrolimus; Vitiligo

Pimecrolimus and tacrolimus are topical calcineurin inhibitors developed specifically for the treatment of atopic eczema. Experience with long-term use of topical calcineurin inhibitors is limited and the risk of rare but serious adverse events remains a concern. We have previously demonstrated the absence of carcinogenic effect of tacrolimus alone and in combination with simulated solar radiation (SSR) on hairless mice. The aim of this study is to determine whether pimecrolimus accelerates photocarcinogenesis in combination with SSR or pimecrolimus and tacrolimus accelerate photocarcinogenesis in combination with UVA. We used 11 groups of 25 hairless female C3.Cg/TifBomTac immunocompetent mice (n = 275). Pimecrolimus cream or tacrolimus ointment was applied on their dorsal skin three times weekly followed by SSR (2, 4, or 6 standard erythema doses, SED) or UVA (25 J/cm(2)) 3-4 h later. This was done up to 365 days in the SSR-treated groups and up to 500 days in the UVA-treated groups. Pimecrolimus did not accelerate the time for development of the first, second or third tumor in any of the groups. Median time to the first tumor was 240 days for the control-2SED group compared with pimecrolimus-2SED group (233 days), control-4SED group (156 days) compared with pimecrolimus-4SED group (163 days) and control-6SED group (162 days) compared with pimecrolimus-6SED group (170 days). Only one mouse in each of the three UVA groups developed a tumor. We conclude that pimecrolimus in combination with SSR and both pimecrolimus and tacrolimus in combination with UVA do not accelerate photocarcinogenesis in hairless mice.

Topics: Administration, Topical; Animals; Carcinoma, Squamous Cell; Disease Models, Animal; Disease Progression; Female; Immunosuppressive Agents; Mice; Mice, Hairless; Neoplasms, Radiation-Induced; Skin; Skin Neoplasms; Skin Pigmentation; Tacrolimus; Ultraviolet Rays

Liver transplant recipients are known to be at increased risk for the development of de novo neoplasms or the recurrence of preexisting malignancies, and this is possibly related to the use of immunosuppressive medication. Little is known about the effects of cytotoxic chemotherapy on graft function after transplantation. A retrospective chart and pathology database review was undertaken to identify post-liver transplant patients developing rejection during chemotherapy. All liver biopsies were reviewed by a hepatopathologist. Three patients were identified. All patients were diagnosed with cancer within 7 years of liver transplantation; two-thirds died soon after the diagnosis of malignancy. Rejection occurred soon after chemotherapy was started. All patients were receiving prednisone and tacrolimus (trough levels: 2.1-4.8 ng/mL). One patient developed plasma cell hepatitis (de novo autoimmune hepatitis). There was no histologic evidence of hepatotoxicity due to the chemotherapeutic agents. Cytotoxic chemotherapy should be used in liver transplant recipients with caution, and immunosuppressant doses should be maintained at therapeutic levels, as patients may be at risk for allograft rejection. Treatment of rejection or plasma cell hepatitis in this setting should be undertaken in a timely and aggressive fashion to prevent chronic ductopenic rejection.

Topics: Adult; Antineoplastic Agents; Biopsy; Cholangitis, Sclerosing; Colonic Neoplasms; Cytotoxins; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis, Biliary; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Prednisone; Retrospective Studies; Risk Factors; Skin Neoplasms; Tacrolimus

Malignancies are a serious long-term complication among liver transplant recipients, with an overall incidence of 4.5%-15%. Posttransplantation lymphoproliferative disease (PTLD) is one of the leading causes of late death. Its development is related to complex interactions between immunosuppressive drugs and environmental agents. The aim of this study was to analyze risk factors for PTLD and survival after orthotopic liver transplantation (OLT) compared with solid tumors.. We undertook a retrospective review of the clinical histories of adult patients who underwent OLT between July 1986 and February 2001, and who had been followed until 2005. This study comprised 528 adult recipients who survived more than 2 months after OLT. We excluded pediatric, partial-organ, and multiorgan recipients.. No differences were observed concerning gender, viral etiology of hepatitis, calcineurin inhibitor regimen, or steroid maintenance period. Treated acute rejection episodes accounted for 53.3% of patients who developed PTLD compared with 47.3% in the control group (P = .787). Patients with solid tumors were older at the time of diagnosis than those with PTLD (57.5 +/- 8.13 years vs 48.8 +/- 13.9; P = .002). The overall mortality rate for PTLD was 55.5%, which did not differ significantly from solid tumors.. PTLD develops in younger patients after OLT. Various immunosuppressive regimens do not seem to influence the incidence of PTLD or other solid tumors.

Topics: Adult; Carcinoma, Squamous Cell; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Liver Transplantation; Lymphoproliferative Disorders; Male; Retrospective Studies; Risk Factors; Skin Neoplasms; Survival Analysis; Survivors; Tacrolimus

Numerous studies have demonstrated the utility of topical tacrolimus ointment in atopic dermatitis. However, there is a concern that local immunosuppression by calcineurin inhibitors may enhance dermal photocarcinogenesis and carcinogenesis. Therefore, we investigated the influence of topical tacrolimus ointment on squamous cell carcinoma formation in hairless female C3.Cg/TifBomTac immunocompetent mice exposed to solar simulated radiation (SSR). In a first experiment, mice (n = 200) had tacrolimus applied on their dorsal skin three times weekly followed by SSR (2, 4 or 6 standard erythema doses, SED) 3-4 h later. Tacrolimus did not reduce the time to tumor development and in the group receiving 4 SED it even had a protective effect (156 days vs 170 days, P = 0.008). In a second experiment, mice (n = 50) were irradiated with 6 SED three times weekly for 3 months and subsequently treated five times weekly with topical tacrolimus to mimic the use of tacrolimus on sun-damaged skin. The median time to the first skin tumor was 234 days in SSR + tacrolimus group compared with 227 days in the only SSR-irradiated group (P = 0.160). In a third experiment, mice (n = 25) had tacrolimus applied on their dorsal skin every day for 1 month, thereafter the group was irradiated with 4 SED three times weekly. The median time to the first skin tumor was 142 days in tacrolimus + SSR group compared with 156 days in the only SSR-irradiated group from experiment 1 (P = 0.363). We conclude that tacrolimus ointment does not accelerate photocarcinogenesis or induce any dermal carcinogenicity in hairless mice.

Topics: Administration, Topical; Animals; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; Immunosuppressive Agents; Mice; Mice, Hairless; Neoplasms, Radiation-Induced; Skin; Skin Neoplasms; Skin Pigmentation; Tacrolimus; Ultraviolet Rays

Topics: Administration, Topical; Biopsy; Child; Disease Progression; Female; Forearm; Humans; Immunosuppressive Agents; Melanoma; Skin; Skin Neoplasms; Tacrolimus; Vitiligo

Topics: Female; Fetal Blood; Graft vs Host Disease; Humans; Leukemia, T-Cell; Lymphoma, T-Cell; Methotrexate; Middle Aged; Skin Neoplasms; Stem Cell Transplantation; Tacrolimus; Transplantation Conditioning; Treatment Outcome; Whole-Body Irradiation

Two topical calcineurin inhibitors (TCI) are available for the treatment of atopic dermatitis and there has been concern that their use could be associated with an increased risk of nonmelanoma skin cancer (NMSC).. To determine if TCI exposure is associated with an increased risk of NMSC in adults.. A case-control study using a questionnaire mailed to 5,000 adults with dermatitis.. We received responses from 70.7% of those surveyed by mail. Overall, 25.7% reported exposure to TCI. TCI exposure was 14.4% for the cases and 30.7% for the controls. Our primary analysis was a comparison between those with NMSC and those without. The unadjusted odds ratio was 0.38 (0.31-0.47) and the adjusted (age, gender, previous NMSC, history of atopic dermatitis) was 0.54 (0.41-0.69). The odds ratio of association for NMSC decreased as the number of tubes used and the potency of the agent increased.. This early study shows that TCI use is not associated with an increased risk of NMSC in adults.

Topics: Administration, Topical; Aged; Calcineurin Inhibitors; Case-Control Studies; Dermatitis, Atopic; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Skin Neoplasms; Tacrolimus

Immunosuppressive therapies allow long-term patient and transplant survival, but are associated with increased development of UV-induced skin cancers, particularly squamous cell carcinomas. The mechanisms by which CsA, MMF, tacrolimus (TAC) or sirolimus (SRL), alone or in dual combinations, influence tumor development and progression are not completely understood. In the current study, chronically UV-exposed mice treated with SRL alone or in combination with CsA or TAC developed more tumors than mice treated with vehicle or other immunosuppressants, but the tumors were significantly smaller and less advanced. Mice treated with CsA or TAC developed significantly larger tumors than vehicle-treated mice, and a larger percentage in the CsA group were malignant. The addition of MMF to CsA, but not to TAC, significantly reduced tumor size. Immunosuppressant effects on UVB-induced inflammation and tumor angiogenesis may explain these findings. CsA enhanced both UVB-induced inflammation and tumor blood vessel density, while MMF reduced inflammation. Addition of MMF to CsA reduced tumor size and vascularity. SRL did not affect inflammation, but significantly reduced tumor vascularity. Thus the choice of immunosuppressants has important implications for tumor number, size and progression, likely due to the influence of immunosuppressants on UVB-induced inflammation and angiogenesis.

Topics: Animals; Blood Vessels; Carcinoma, Squamous Cell; Cyclosporine; Disease Models, Animal; Drug Therapy, Combination; Female; Immunosuppressive Agents; Inflammation; Mice; Mice, Hairless; Mycophenolic Acid; Neoplasms, Radiation-Induced; Neovascularization, Pathologic; Sirolimus; Skin Neoplasms; Tacrolimus; Ultraviolet Rays

Topics: Acquired Immunodeficiency Syndrome; Administration, Topical; Adult; Dermatitis, Seborrheic; Humans; Immunosuppressive Agents; Male; Psoriasis; Sarcoma, Kaposi; Skin Neoplasms; Tacrolimus

Cutaneous plasmacytosis is a rare disease predominantly found in Japanese patients. We describe the case of a 75-year-old white female with cutaneous plasmacytosis of the face and involvement of the bone marrow. In contrast to other cases of cutaneous plasmacytosis, the patient revealed hypogammaglobulinemia and elevated levels of free light chains in the urine. Treatment with topical pimecrolimus 1%, which primarily targets T cells, led to almost complete clinical and histological remission of the skin lesions. Our report indicates that the therapeutically induced disappearance of the plasma cells was due to indirect T-cell-mediated effects.

Topics: Aged; B-Lymphocytes; Biopsy; Calcineurin Inhibitors; Female; Follow-Up Studies; Humans; Plasmacytoma; Skin Neoplasms; T-Lymphocytes; Tacrolimus

Cutaneous T cell lymphomas (CTCLs) are a heterogenous group of lymphoproliferative disorders caused by clonally-derived, skin-invasive T cells. A variety of skin-directed and systemic therapies are available to treat mycosis fungoides/Sézary syndrome (MF/SS), the therapeutic choices of which are guided by the stage of disease. A 29-year-old man presented at our clinic with pruritic, erythematous macules located on the sternum and the lower back. Histological findings and immunohistochemistry studies showed patch stage MF. The patient was treated with tacrolimus ointment 0.1% twice daily for one month, achieving complete remission. Three months after the first episode a relapse was successfully treated with the same therapeutic regimen. Tacrolimus is an immunomodulatory macrolide that reduces the stimulatory capacity toward T cells and is therefore worth investigating as a treatment of CTCL. Topical tacrolimus has been related to an unknown effect with the risk for secondary malignancies including CTCL. Also, black box warnings have been proposed by the FDA for the topical calcineurin inhibitors. Nevertheless, our results in the treatment of early stage MF are in agreement with other unpublished data that have observed its efficacy. To our knowledge, there is no other case of patch type mycosis fungoides treated with tacrolimus ointment 0.1% in the medical literature.

Topics: Administration, Cutaneous; Adult; Diagnosis, Differential; Humans; Immunosuppressive Agents; Male; Mycosis Fungoides; Ointments; Severity of Illness Index; Skin Neoplasms; Tacrolimus

Topics: Aged; Anastomosis, Surgical; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Drug Therapy, Combination; Ear Neoplasms; Ear, External; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Melanoma; Microsurgery; Mycophenolic Acid; Plastic Surgery Procedures; Scalp; Skin Neoplasms; Surgical Flaps; Tacrolimus; Transplantation, Homologous

Topics: Administration, Cutaneous; Humans; Immunosuppressive Agents; Neoplasms, Second Primary; Skin Neoplasms; Tacrolimus

Topics: Adult; Animals; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Eczema; Humans; Immunosuppressive Agents; Lymphoma; Skin Neoplasms; Tacrolimus

Topics: Animals; Child; Dermatitis, Atopic; Dermatologic Agents; Eczema; Haplorhini; Humans; Leukemia; Lymphoma; Mice; Skin Neoplasms; Tacrolimus

Topics: Acne Vulgaris; Animals; Child; Humans; Immunosuppressive Agents; Mice; Mice, Hairless; Skin Neoplasms; Steroids; Tacrolimus

The use of calcineurin inhibitors in solid organ transplantation results in an increased risk of skin cancer. We examined the effect of these drugs on DNA repair in normal human keratinocytes after ultraviolet B (UVB) irradiation. We found that both cyclosporine A (CsA) and ascomycin inhibited removal of cyclobutane pyrimidine dimers, and that they also inhibited UVB-induced apoptosis. We also observed that UVB induced nuclear localization of the transcription factor nuclear factor of activated T-cells (NFAT), and that this was blocked by CsA and ascomycin. These data suggest that the increased risk of skin cancer observed in organ-transplant patients may be as a result of not only systemic immune suppression but also the local inhibition of DNA repair and apoptosis in skin by calcineurin inhibitors. These findings may have implications for the use of topical calcineurin inhibitors in sun-exposed skin and eyes.

Topics: Active Transport, Cell Nucleus; Apoptosis; Calcineurin Inhibitors; Cell Nucleus; Cyclosporine; DNA; DNA Damage; DNA Repair; Enzyme Inhibitors; Humans; Keratinocytes; NFATC Transcription Factors; Pyrimidine Dimers; Skin Neoplasms; Tacrolimus; Ultraviolet Rays

Topics: Acquired Immunodeficiency Syndrome; Administration, Topical; Adult; Humans; Immunosuppressive Agents; Male; Sarcoma, Kaposi; Skin Neoplasms; Tacrolimus

Topics: Administration, Topical; Carcinoma, Squamous Cell; Diagnosis, Differential; Female; Humans; Lichen Sclerosus et Atrophicus; Precancerous Conditions; Risk Assessment; Skin Neoplasms; Tacrolimus; Vulvar Diseases

Topics: Animals; Cell Transformation, Neoplastic; Immunosuppressive Agents; Mice; Research Design; Skin Neoplasms; Tacrolimus

Immunomodulators include both immunostimulatory and immunosuppressive agents. Obligate contact sensitizers such as diphencyprone or dinitrochlorobenzene have been used against viral and autoimmune diseases. Newer agents such as the toll-like receptor agonists imiquimod and resiquimod have been clinically used to treat viral infections and skin cancers in immunocompetent and immunosuppressed patients. On the other hand, the topical immunosuppressive agents tacrolimus and pimecrolimus have been used with great success in the treatment of chronic inflammatory diseases in children and adults. The introduction of this new class of drugs (i.e. Calcineurin inhibitors) marked the beginning of the post-cortisone era in clinical dermatology. Toll-like receptor agonists and calcineurin antagonists will supplement corticosteroids to improve specific dermatological therapy. Topical immunotherapy with both immunostimulatory and immunosuppressive agents show potential for effective and patient-friendly treatment of inflammatory, infectious and neoplastic skin diseases. Long-term evaluation will define the tolerability and the safety profile.

Topics: Adjuvants, Immunologic; Administration, Topical; Adult; Aged; Aged, 80 and over; Aminoquinolines; Asthma; Autoimmune Diseases; Bowen's Disease; Child; Cyclopropanes; Dermatitis, Atopic; Dinitrochlorobenzene; Female; Follow-Up Studies; Herpes Simplex; Humans; Imidazoles; Imiquimod; Immunity, Cellular; Immunocompromised Host; Immunoglobulin A; Immunosuppressive Agents; Lichen Sclerosus et Atrophicus; Male; Molluscum Contagiosum; Papillomavirus Infections; Precancerous Conditions; Skin Diseases; Skin Diseases, Viral; Skin Neoplasms; Tacrolimus; Time Factors; Warts

Topics: Administration, Cutaneous; Adult; Dermatitis, Atopic; Diagnosis, Differential; Facial Dermatoses; Humans; Immunosuppressive Agents; Male; Ointments; Skin Neoplasms; Tacrolimus

Tacrolimus, produced by the fungus Streptomyces tsukabaensis, is a potent macrolide immunosuppressant widely used in liver and kidney transplantation. Topical tacrolimus has recently been found to be an effective treatment for atopic dermatitis (AD).. Because of the well-known association between T-cell immunosuppression and an increased risk of carcinogenesis, we investigated the effect of topical tacrolimus on skin carcinogenesis in 117 mice.. Approximately 8 cm2 of the shaved dorsal skin of 7-week-old female CD-1 mice was treated with 7,12-dimethylbenz[alpha]anthracene (DMBA) dissolved in acetone, which is in general use as a tumour initiator, or acetone alone, on day 1 of the experiment, followed by promoting treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) with or without tacrolimus, or acetone with or without tacrolimus, for 20 weeks. The mice were divided into six treatment groups: (1) DMBA followed by acetone; (2) DMBA followed by TPA; (3) DMBA followed by acetone + tacrolimus; (4) DMBA followed by TPA + tacrolimus; (5) acetone followed by acetone + tacrolimus; and (6) acetone followed by acetone (control).. The induction of skin tumours was significantly greater in the TPA-treated groups than in the absence of TPA. However, after 14 weeks there was marked synergy between tacrolimus and the DMBA/TPA regimen, with 0.47 +/- 0.13 (mean +/- SD) new tumours per mouse per week in group 4 vs. 0.10 +/- 0.025 in group 2 (P < 0.01), and 0.01 +/- 0.002 in group 3. A significant reduction in the CD4/CD8 ratio was found in axillary and inguinal lymph nodes in tacrolimus-treated mice, supporting the presumption that the immunosuppressive effect of the drug was responsible for its effect in promoting tumorigenesis. The major increase in tumours caused by topical tacrolimus was of papillomas, not squamous cell carcinomas. Papillomas are uncommon in humans, and are benign. However, 8.5% of the tumours found in the experiment were squamous cell carcinomas, and a considerable synergy between topical tacrolimus and conventional carcinogens was observed, raising the spectre of some risk of skin carcinogenesis in AD patients undergoing prolonged treatment with tacrolimus.. Caution and careful surveillance are required with regard to skin lesions in patients treated with tacrolimus for prolonged periods.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Cutaneous; Animals; Carcinogens; Carcinoma, Squamous Cell; CD4 Lymphocyte Count; Cell Transformation, Neoplastic; Female; Immunosuppressive Agents; Lymph Nodes; Mice; Mice, Inbred Strains; Papilloma; Skin Neoplasms; Tacrolimus

Topics: Facial Dermatoses; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Plasmacytoma; Skin Neoplasms; Tacrolimus

A standard therapy for advanced cutaneous T-cell lymphomas has not yet been defined. Bexarotene is a new retinoid x receptor-specific retinoid that has been approved for systemic second-line therapy for cutaneous T-cell lymphomas in the USA and Europe. In order to evaluate the efficacy of bexarotene in cutaneous T-cell lymphomas, a pilot trial was initiated.. In a pilot project 10 patients with advanced cutaneous T-cell lymphomas, who had received a variety of previous treatments, were treated with bexarotene at the departments of dermatology in Münster, Minden and Charité Berlin, Germany. The patients received bexarotene at a dose of 300 mg/m2 body surface daily. According to the percentage of tumour reduction and affected body surface, the response rates were divided in complete and partial remission, stable disease and progressive disease. Laboratory parameters i.e. cholesterol, triglycerides transaminases, T3, T4, and TSH were screened regularly.. In 2 patients a short partial remission was achieved; however, after a few weeks progression followed. In 4 patients a lasting stabilisation was obtained. The other 4 patients showed a progressive disease during therapy. 6 patients developed hypertriglyceridemia with levels up to 2000 mg/dl; therapy had to be suspended in 3 patients because of these adverse drug events.. Weighing benefits and risks, bexarotene can at present not be recommended as standard therapy in the treatment of patients with progressive cutaneous lymphomas.

Topics: Adult; Aged; Aminoquinolines; Anticarcinogenic Agents; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bexarotene; Combined Modality Therapy; Cyclophosphamide; Disease Progression; Doxorubicin; Female; Humans; Imiquimod; Immunosuppressive Agents; Interferons; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Neoplasm Staging; Pilot Projects; Prednisone; PUVA Therapy; Remission Induction; Skin; Skin Neoplasms; Tacrolimus; Tetrahydronaphthalenes; Time Factors; Treatment Outcome; Vincristine

Anetoderma is circumscribed atrophy of the skin due to a localized deficiency in elastic tissue. It can follow inflammatory skin diseases of several types, and occasionally is present in the skin around neoplasms. There are a few reports of anetoderma in the lesional skin of cutaneous lymphoma. We report on two patients who presented with multiple lesions of anetoderma and who later proved to have low-grade cutaneous B-cell lymphomas. One patient (Patient 1) is a 39-year-old man and the other patient is a 26-year-old woman who is a renal transplant recipient (Patient 2). Some biopsy specimens from the anetodermic skin of Patient 1 appeared to show an urticarial reaction, although plasma cells were present. A large nodule showed lymphoid follicles surrounded by plasmacytoid lymphocytes, with loss of elastic tissue in the adjacent dermis. The plasmacytoid cells stained overwhelmingly for lambda light chain, and staining of the urticarial lesions from this patient also showed a marked majority of lambda positive cells. Immunoglobulin heavy chain gene (IgH) rearrangements showed a dominant clonal pattern in the nodular lesion. We classified the disease in Patient 1 as marginal zone lymphoma and the disease in Patient 2 as a post-transplant lymphoproliferative disorder. Because of the intimate association of anetoderma and cutaneous B-cell lymphoproliferative disorders in these two patients, it seems possible that anetoderma could result from either a local effect of the neoplastic cells or associated inflammatory cells, especially neutrophils as in Case 1. The infiltrates of Case 1 had many interstitial neutrophils and only a few clonal plasmacytoid lymphocytes, indicating that this presentation of B-cell lymphoma can be a diagnostic pitfall. Given these two cases and similar ones in the literature, biopsy of lesional skin in anetoderma should be performed to ensure that lymphomatous infiltrates are not present. Even if plasma cells are sparse, studies to detect clonality are appropriate. Cutaneous B-cell lymphoma can be added to the list of associations of elastolysis and cutaneous lymphoma, which includes granulomatous slack skin (T-cell lymphoma) and cutis laxa (myeloma).

Topics: Adult; Atrophy; Cutis Laxa; Cyclosporine; DNA; Elastic Tissue; Female; Fluorescein-5-isothiocyanate; Gene Rearrangement, B-Lymphocyte, Heavy Chain; Herpesvirus 4, Human; Humans; Immunocompromised Host; Immunohistochemistry; In Situ Hybridization; Kidney Transplantation; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Lymphoproliferative Disorders; Male; Polymerase Chain Reaction; RNA, Viral; Skin Neoplasms; Tacrolimus

Topics: Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Leg; Middle Aged; Postoperative Complications; Retreatment; Sarcoma, Kaposi; Skin Neoplasms; Tacrolimus

Topics: Adult; Antineoplastic Agents; Cyclosporine; Doxorubicin; Drug Carriers; Humans; Immunosuppressive Agents; Kidney Transplantation; Liposomes; Male; Sarcoma, Kaposi; Skin Neoplasms; Tacrolimus

An increased incidence of de novo nonlymphoid malignancies has been shown in immunocompromised patients. However, the true risk over time compared to the general population has not been determined.. One thousand consecutive patients were carefully followed for an average of 77.8+/-11.1 (range, 56.3-96.3) months after primary liver transplantation at a single center. All de novo nonlymphoid malignancies were recorded. Each malignancy was compared with a standard Occupational Cohort Mortality Analysis Program population matched for age, sex, and length of follow-up using modified life table technique and surveillance epidemiology end result (SEER) data.. Fifty-seven patients accounted for de novo malignancies and contributed 4795.3 total person years, a mean+/-SD of 36+/-21 (median, 36; range, 6-74) months after liver transplantation. Twenty-two of these malignancies were skin malignancies including two melanomas. Oropharyngeal cancers (n=7) were found to be 7.6 times higher (P<0.05) and respiratory malignancies (n=8) were 1.7 times higher (P>0.05) compared to the SEER incidence rate. Female reproductive system malignancies including breast cancer (n=3) were 1.9 times lower (P>0.05) and genitourinary malignancies were (n=5) 1.5 times lower (P>0.05) than their matched cohorts. No differences was observed in gastrointestinal malignancies (n=5). There was a significant difference in survival of the patients after diagnosis of malignancy depending on the type of cancer. There were two Kaposi's sarcomas, two metastatic unknown primaries, one thyroid, one brain, and one ophthalmic malignancies in the series. Mortality for Kaposi's and metastatic disease of unknown primary was 100% within 5 months, while the 1-year mortality for oropharyngeal cancer was 57.1% and that for lung cancers was 62.5%. Long-term survival for skin cancer was highest: 86.4% at 3 years (P=0.015 by log-rank test).. An increased incidence of de novo cancers in the chronically immunocompromised patient demands careful long-term screening protocols which will help to facilitate the diagnosis at an early stage of the disease. This is particularly true for oropharyngeal cancers where the risk is more than 7 times higher compared to SEER incidence data matched for age, sex, and length of follow-up.

Topics: Adult; Aged; Female; Gastrointestinal Neoplasms; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Male; Middle Aged; Neoplasms; Oropharyngeal Neoplasms; Respiratory Tract Neoplasms; Skin Neoplasms; Tacrolimus; Urogenital Neoplasms

Topics: Female; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphomatoid Papulosis; Middle Aged; Skin Neoplasms; Tacrolimus

The effect of FK506, a potent immunosuppressive agent, on 7,12-dimethylbenz[alpha]anthracene-initiated and anthralin-promoted skin tumor formation was examined in CD-1 mice. A topical application of 0.1 mumol FK506 to mouse skin 15 min prior to each anthralin treatment markedly inhibited skin tumor formation. Anthralin stimulated IL-1 alpha production in primary cultured mouse epidermal cells, and the peak IL-1 alpha level was observed at 6 h after the stimulation. Anthralin also stimulated IL-1 alpha release into culture medium. Both production and release of Il-1 alpha were markedly inhibited by FK506 (0.1 or 1 microM). FK506 (1 microM) alone neither affected IL-1 alpha production nor its release. It may be possible that the inhibition of IL-1 alpha production by FK506 is related to its anti-tumor-promoting action.

Topics: Administration, Topical; Animals; Anthralin; Anticarcinogenic Agents; Carcinogens; Female; Interleukin-1; Mice; Skin Neoplasms; Tacrolimus

The effect of FK506, a potent immunosuppressive agent, on 7,12-dimethylbenz[a]anthracene-initiated and 12-O-tetradecanoylphorbol-13- acetate (TPA)-promoted skin papilloma formation was examined in CD-1 mice. A topical application of FK506 to mouse skin 15 min before each TPA treatment resulted in a dose-related inhibition of tumor formation. FK506 (1 mumol) almost completely inhibited tumor formation. This inhibitory effect of FK506 was not due to any damage inflicted on the initiated cells but due to its anti-tumor-promoting action. A topical application of FK506 also inhibited epidermal ornithine decarboxylase induction and skin inflammation caused by TPA in a dose-related manner. Significant inhibition by FK506 of TPA-induced endogenous protein phosphorylation in intact epidermal cells was not detected. These results indicate that FK506 inhibits TPA-induced tumor promotion at a step distal to the endogenous protein phosphorylation by TPA.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Dermatitis, Contact; Enzyme Induction; Female; Mice; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors; Papilloma; Phosphorylation; Skin Neoplasms; Tacrolimus; Tetradecanoylphorbol Acetate