Risk of melanoma and nonmelanoma skin cancer with immunosuppressants, part II: Methotrexate, alkylating agents, biologics, and small molecule inhibitors.

In solid organ transplant recipients, skin cancer risk associated with posttransplant immunosuppression has been well-described, and screening practices generally reflect these risks. In addition to agents used posttransplant, other classes of immunosuppressants also have the potential to raise the risk of nonmelanoma skin cancer (NMSC) or melanoma. In the present manuscript, the evidence for melanoma and NMSC risk associated with methotrexate, cyclophosphamide, biologic cytokine inhibitors including TNF (tumor necrosis factor)-alpha and interleukin inhibitors, costimulation blockers such as abatacept, integrin inhibitors such as natalizumab, targeted B-cell, and T-cell inhibitors including CD20 (cluster of differentiate 20), CD52, and BTK (Bruton's tyrosine kinase) inhibitors, and JAK (Janus kinase) inhibitors is reviewed. Based on the available data, we recommend regular skin cancer screening for select nontransplant patients receiving immunosuppressive regimens that are shown to raise the risk of NMSC or melanoma. We also offer suggestions for conscientious use of these therapies in high-risk patients. Finally, a comprehensive summary of the relative risk associated with each immunosuppressant class and associated recommendations is presented.

Risk of melanoma and nonmelanoma skin cancer with immunosuppressants, part I: Calcineurin inhibitors, thiopurines, IMDH inhibitors, mTOR inhibitors, and corticosteroids.

Immunosuppression is a well-documented risk factor for skin cancer, as exemplified by the 65- to 250-fold higher squamous cell carcinoma risk, 10-fold higher basal cell carcinoma risk, and 0 to 8-fold higher melanoma risk in solid organ transplant recipients (SOTRs) receiving potent, prolonged courses of immunosuppressive therapies. Numerous immune system components have been shown to either suppress or promote tumor growth, and immunosuppressive drugs may have additional effects on proliferative pathways independent of the immune system. Thus, evaluation of the specific regimen by the dermatologist is key for assessing skin cancer risk in each patient. In the present manuscript, the immune-mediated mechanisms of skin cancer development and regression are first reviewed. Next, a synthesis of the evidence shows the differing effects of immunosuppressive agents commonly used in SOTRs on melanoma and nonmelanoma skin cancer risk. These include systemic calcineurin inhibitors, thiopurines, IMDH (inosine monophosphate dehydrogenase) inhibitors, mTOR (mammalian target of rapamycin) inhibitors, and systemic corticosteroids. Finally, recommendations for skin cancer screening in SOTRs are discussed. We further offer recommendations for select nontransplant patients who may benefit from routine skin cancer screening due to risks associated with specific immunosuppressant exposure, and we propose evidence-based strategies for minimizing high-risk immunosuppressant use in clinical practice.

Reactive angioendotheliomatosis associated with antiphospholipid syndrome.

Reactive angioendotheliomatosis (RAE) is an uncommon, benign, antiproliferative condition associated with systemic diseases that may cause occlusion or inflammation of the vascular lumina. A link between antiphospholipid syndrome (APS) and RAE has been reported a few times in the literature. Herein, we present a unique case of RAE diagnosed in a patient with primary APS who was well-managed on warfarin and rituximab with no recent thrombotic events. As RAE can precede or follow a diagnosis of APS, the presence of the condition indicates a need to workup for APS and to ensure those with the condition are adequately anticoagulated. However, as demonstrated in this case, the condition can still occur in patients who are adequately anticoagulated.

Initial skin cancer screening for solid organ transplant recipients in the United States: Delphi method development of expert consensus guidelines.

Skin cancer is the most common malignancy affecting solid organ transplant recipients (SOTR), and SOTR experience increased skin cancer-associated morbidity and mortality. There are no formal multidisciplinary guidelines for skin cancer screening after transplant, and current practices are widely variable. We conducted three rounds of Delphi method surveys with a panel of 84 U.S. dermatologists and transplant physicians to establish skin cancer screening recommendations for SOTR. The transplant team should risk stratify SOTR for screening, and dermatologists should perform skin cancer screening by full-body skin examination. SOTR with a history of skin cancer should continue regular follow-up with dermatology for skin cancer surveillance. High-risk transplant patients include thoracic organ recipients, SOTR age 50 and above, and male SOTR. High-risk Caucasian patients should be screened within 2 years after transplant, all Caucasian, Asian, Hispanic, and high-risk African American patients should be screened within 5 years after transplant. No consensus was reached regarding screening for low-risk African American SOTR. We propose a standardized approach to skin cancer screening in SOTR based on multidisciplinary expert consensus. These guidelines prioritize and emphasize the need for screening for SOTR at greatest risk for skin cancer.

Use of Topical and Systemic Retinoids in Solid Organ Transplant Recipients: Update and Review of the Current Literature.

BACKGROUND: Solid organ transplant recipients (SOTRs) are at an increased risk of epithelial malignancies, mainly squamous cell carcinoma, and its precursor lesions such as actinic keratoses, warts, and porokeratosis, which may respond to retinoid therapy. OBJECTIVE: To review the published evidence on the efficacy and safety of topical and systemic retinoids for the treatment and prophylaxis of malignant and premalignant conditions that mostly afflict SOTRs. MATERIALS AND METHODS: Systematic review of the literature to summarize the level of evidence and grade of recommendation for retinoid therapy with emphasis in the SOTR population. RESULTS: Acitretin has the highest strength of recommendation (Grade A) for prophylaxis of nonmelanoma skin cancer (NMSC) and treatment and prophylaxis of actinic keratoses in SOTR. In nonimmunosuppressed patients, acitretin and isotretinoin have a Grade B recommendation for treatment of recalcitrant warts. Topical retinoids have not shown efficacy in preventing NMSC in immunocompetent patients. CONCLUSION: Retinoids constitute a highly efficacious alternative for the management of the most common conditions that affect SOTRs. Acitretin has the most robust evidence for chemoprophylaxis in SOTRs. Knowledge about the specific indications and expected side effects of topical and systemic retinoids may help optimize their therapeutic potential.

Isotretinoin and candida immunotherapy for recalcitrant warts in solid organ transplant recipients.

Treatment of recalcitrant warts in solid organ transplant recipients (SOTR) can pose a therapeutic challenge for dermatologists. Successful treatment of recalcitrant warts can serve as secondary prevention for skin cancer in those with chronic immunosuppression. Given the heterogeneity of associated comorbid conditions in SOTR, clinical trials are difficult to conduct in this high-risk population, therefore, our clinical practice is mostly driven by observed responses from studies in immunocompetent patients or from case reports of immunocompromised patients. The combination of systemic retinoids and candida immunotherapy likely provide the most effective treatment for recalcitrant warts in SOTR. However, many SOTR have chronic renal insufficiency and are not candidates for acitretin therapy. We provide two cases of recalcitrant warts in SOTR successfully treated with isotretinoin in the setting of impaired renal function.

Vorinostat interferes with the signaling transduction pathway of T-cell receptor and synergizes with phosphoinositide-3 kinase inhibitors in cutaneous T-cell lymphoma.

BACKGROUND: Vorinostat (suberoylanilide hydroxamic acid, SAHA), an inhibitor of class I and II histone deacetylases, has been approved for the treatment of cutaneous T-cell lymphoma. In spite of emerging information on the effect of vorinostat in many types of cancer, little is yet known about this drug's mechanism of action, which is essential for its proper use in combination therapy. We investigated alterations in gene expression profile over time in cutaneous T-cell lymphoma cells treated with vorinostat. Subsequently, we evaluated inhibitors of PI3K, PIM and HSP90 as potential combination agents in the treatment of cutaneous T-cell lymphoma. DESIGN AND METHODS: The genes significantly up- or down-regulated by vorinostat over different time periods (2-fold change, false discovery rate corrected P value<0.05) were selected using the short-time series expression miner. Cell viability was assessed in vitro in cutaneous T-cell lymphoma cells through measuring intracellular ATP content. Drug interactions were analyzed by the combination index method with CalcuSyn software. RESULTS: The functional analysis suggests that vorinostat modifies signaling of T-cell receptor, MAPK, and JAK-STAT pathways. The phosphorylation studies of ZAP70 (Tyr319, Tyr493) and its downstream target AKT (Ser473) revealed that vorinostat inhibits phosphorylation of these kinases. With regards to effects on cutaneous T-cell lymphoma cells, combining vorinostat with PI3K inhibitors resulted in synergy while cytotoxic antagonism was observed when vorinostat was combined with HSP90 inhibitor. CONCLUSIONS: These results demonstrate the potential targets of vorinostat, underlining the importance of T-cell receptor signaling inhibition following vorinostat treatment. Additionally, we showed that combination therapies involving histone deacetylase inhibitors and inhibitors of PI3K are potentially efficacious for the treatment of cutaneous T-cell lymphoma.