mycophenolic-acid 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

Subcutaneous panniculitis-like T-cell lymphoma is a rare, indolent cutaneous cytotoxic alpha-beta T-cell lymphoma, where no specific therapy regimen is defined. We present a case with a diagnostically challenging association with anti-double stranded DNA and provides one of the first reports of a successful treatment with mycophenolate mofetil and glucocorticosteroids.

Topics: Humans; Lymphoma, T-Cell; Lymphoma, T-Cell, Cutaneous; Mycophenolic Acid; Panniculitis; Skin Neoplasms

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

In the last few years, melanoma treatment has been revolutionized by the development of immune checkpoint-blocking antibodies or immune checkpoint inhibitors including ipilimumab, vemurafenib, dabrafenib, trametinib, nivolumab, and pembrolizumab. Although they have shown promising results, they also have caused multiple adverse events (AEs), particularly immune-related AEs (irAEs). Specialists should be familiar with these AEs.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Drug Eruptions; Gastrointestinal Diseases; Humans; Hypophysitis; Hypothyroidism; Imidazoles; Immunosuppressive Agents; Indoles; Ipilimumab; Melanoma; Mycophenolic Acid; Nivolumab; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Sweet Syndrome; Thyrotoxicosis; Tumor Necrosis Factor-alpha; Vemurafenib; Vitiligo

There are multiple therapeutic options for the treatment of moderate to severe psoriasis. The process of choosing among potential treatment options requires both the physician and the patient to weigh the benefits of individual modalities against their potential risks. Traditional systemic therapies for psoriasis, including methotrexate (MTX) and cyclosporine (CsA), have a well-documented array of toxicities, particularly end-organ toxicities. Over the past several years, the use of biologic therapies for the treatment of moderate to severe psoriasis has been a major clinical and research focus. With the advent of these novel immunosuppressive therapies, one of the central safety issues surrounding these agents is their potential to increase the risk of malignancy.. Our objective was to review the risk of malignancy associated with therapies for moderate to severe psoriasis, including phototherapy, traditional systemic therapies, and biologic therapies. We reviewed the existing body of literature in order to define the known incidence of malignancy associated with psoralen and ultraviolet A (PUVA), narrowband and broadband ultraviolet B (UVB), MTX, CsA, mycophenolate mofetil (MMF), and biologic therapies, including alefacept, efalizumab, infliximab, etanercept, adalimumab, and ustekinumab.. PUVA, when given long term, is associated with increased risks of cutaneous squamous cell carcinoma and malignant melanoma. Reviews of studies on UVB, both narrowband and broadband, do not indicate any increased risk of nonmelanoma skin cancer or melanoma. The traditional systemic psoriasis therapies-MTX, CsA, and MMF-may be associated with an increased risk of lymphoproliferative disorders during treatment, demonstrated in clinical trials in patients with rheumatoid arthritis and documented in case reports concerning psoriasis patients. The risk of malignancy with biologic therapy is still unclear. However, the majority of studies examining this carcinogenic risk suggest that tumor necrosis factor-alpha inhibitors may cause a slightly increased risk of cancer, including nonmelanoma skin cancer and hematologic malignancies.. The majority of studies cited in this review lack the power and randomization of large clinical trials, as well as the long-term follow-up periods which would further substantiate the hypothetical link between these antipsoriatic treatment regimens and the potential for malignancy. Because of the substantial lack of clinical data, the majority of studies evaluated focus on the treatment of patients with rheumatoid arthritis, which is a systemic inflammatory disorder comparable to psoriasis. Additionally, the increased risk of malignancy associated with psoriasis itself is a confounding factor.. Many of the therapies for moderate to severe psoriasis, including PUVA, traditional systemic therapies, and some biologic therapies, may increase the risk of malignancy. Appropriate patient counseling and selection, as well as clinical follow-up, are necessary to maximize safety with these agents. Further long-term study is necessary to more precisely quantify the risks associated with biologic therapies.

Topics: Biological Products; Cyclosporine; Dermatologic Agents; Humans; Methotrexate; Mycophenolic Acid; Psoriasis; PUVA Therapy; Skin Neoplasms; Ultraviolet Therapy

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

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

To evaluate the safety of mycophenolate mofetil (MMF) versus azathioprine (Aza) in renal transplantation, we compared their side effects using evidence-based methods.. Medline, Embase, Cochrane library, and Chinese Biomedicine database (CBM) were searched to select randomized clinical trials that had one group using MMF and another group using Aza as an immunosuppressive drugs. Safety analysis consist of the following factors: diarrhea, abdominal pain, vomiting, nausea, constipation, CMV infection, leukopenia, anemia, thrombocytopenia or skin malignancy. RevMan 4.11 software was used for the systematic review analysis.. Twenty trials including 6387 patients were identified. The diarrhea incidence with MMF (3 g/d) was higher than for Aza at 1 and 3 years (P < .05). Diarrhea on MMF (2 g/d) was higher than for Aza within 6 months (P < .05). CMV infection incidence on MMF (3 g/d) was higher than for Aza's at 3 years (P < .05), but MMF (2 g/d) did not show a statistical significance compared with Aza. Leukopenia incidence on MMF (3 g/d) was higher than that on Aza, whereas the incidence with MMF (2 g/d) was not significantly different from Aza. Skin malignancy incidence showed no statistical difference between MMF 3 g/d, MMF 2 g/d, or Aza.. The use of MMF is associated with slight increases in gastrointestinal adverse effects, some hematologic adverse events, and CMV infections compared with Aza. Larger sample sizes of randomized controlled trials are needed to evaluate the safety of MMF.

Topics: Azathioprine; Cytomegalovirus Infections; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Mycophenolic Acid; Pain; Postoperative Complications; Randomized Controlled Trials as Topic; Retrospective Studies; Safety; Skin Neoplasms; Time Factors; Vomiting

Immune checkpoint inhibitor (IO) induced colitis is primarily managed with corticosteroids. Most patients have a rapid resolution of symptoms and do not require additional immunosuppressants. Many patients, however, require prolonged corticosteroid courses to maintain control of toxicity. Mycophenolate mofetil (MMF) is the prodrug of mycophenolic acid; which in turn directly inhibits activated T and B lymphocytes. MMF, in addition to corticosteroids, may enable reduction of corticosteroids without precipitating resurgence of colitis. Metastatic melanoma patients between 1 January 2017 and 31 December 2017 with combination IO-induced colitis were managed with a novel treatment algorithm: upfront oral enteric-coated MMF alongside high-dose corticosteroids. Outcome measures included incidence of colitis flare, time to grade 1 colitis, time to patient-reported normal bowel habit and overall cumulative corticosteroid exposure. Thirteen patients developed high-grade combination IO-induced colitis; 11 were managed with the combination of high-dose corticosteroid and MMF. Median patient age was 59 (range: 28-73) years. Four (36%) developed flare of colitis; flares occurred at a median of 11 (interquartile range: 4.5-16.75) days. All colitis flares responded fully to infliximab (5 mg/kg). The remaining seven patients did not develop colitis flare during corticosteroid wean. All patients were successfully weaned from corticosteroids and none had a resurgence of colitis at 8 weeks following discontinuation of MMF. Concomitant enteric-coated MMF alongside high-dose corticosteroids may hasten the improvement of high-grade colitis to normal bowel habit and reduce the incidence of colitis flare.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colitis; Disease Management; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Ipilimumab; Male; Melanoma; Middle Aged; Mycophenolic Acid; Nivolumab; Prognosis; Prospective Studies; Skin Neoplasms

Choice of immunosuppression may modify the risk of cancer after kidney transplantation, however, long-term data are lacking. Using the Australian and New Zealand Dialysis and Transplant Registry, we compared the 9-year risk of incident cancer, non-melanoma skin cancer (NMSC), and death attributed to cancer among participants from Australia and New Zealand in four randomized-controlled trials which compared de novo or early switch to an everolimus-containing regimen with calcineurin-inhibitor-based triple therapy. An adjusted Cox-model with random effects was used to determine such risks. Two hundred seventy-nine patients (192 everolimus, 87 control) were followed for a median of 9 years (IQR 6.7, 11.2). Compared with control, everolimus use was not associated with a reduction in the risk of incident cancer, NMSC, or cancer-related death (unadjusted HR [95% CI] 0.86 [0.49-1.48], 0.58 [0.30-1.12], and 1.18 [0.32-4.38], respectively). Subgroup analyses showed a 56% reduction for NMSC in patients randomized to everolimus + reduced-dose calcineurin-inhibitor versus control (unadjusted HR 0.44 [0.21-0.92]), which remained significant after adjusting for age, gender and smoking (adjusted HR 0.45 [0.21-0.96]). Although de novo or early switch to everolimus did not alter the 9-year risk of incident cancer or cancer-related death, everolimus with reduced-dose calcineurin-inhibitor strategy may reduce the long-term risk of NMSC.

Topics: Australia; Cyclosporine; Everolimus; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Risk Factors; Sirolimus; Skin Neoplasms; Transplant Recipients

The immunosuppressant mycophenolate mofetil (MMF; CellCept) has greatly improved transplant recipients' clinical outcomes, but its efficacy may be limited by dose adjustments due to adverse events (AEs). An enteric-coated formulation of mycophenolate sodium (EC-MPS; myfortic), designed to improve gastrointestinal tolerability is now available. This Latin-American, prospective, multicenter, open-label, 6-month trial assessed the safety and tolerability of converting renal transplant recipients from MMF to EC-MPS. In total, 237 renal transplant recipients (stable > or = 3 months' posttransplant) receiving MMF (< or =1000 mg b.i.d.) were enrolled. Adults (n = 218) were converted to EC-MPS 720 mg b.i.d. (equimolar to MMF 1000 mg b.i.d.) even if they were initially receiving <1000 mg MMF b.i.d. (ie, 47 adults received a higher than equimolar dose of EC-MPS). Children (n = 19) were converted to EC-MPS 450 or 432 mg/m2 b.i.d. Patients also received cyclosporine microemulsion (Neoral) and corticosteroids. There were three acute rejections and no graft failures. The incidence of AEs was 59.9% (in those receiving a higher than equimolar EC-MPS dose it was 57.4%). In all, 22% of patients had gastrointestinal AEs, 37% had infections, and 4.8% had hematological AEs. Only 24 patients (10%) had an AE-related dose reduction. Seven of these patients had received higher than equimolar doses of EC-MPS. Patients can be safely converted from different doses of MMF to a standard dose of EC-MPS. The requirement for EC-MPS dose reduction to manage AEs was relatively low. Use of EC-MPS is a valid alternative for renal transplant recipients receiving maintenance MMF treatment.

Topics: Adolescent; Adult; Child; Creatinine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Latin America; Male; Mycophenolic Acid; Postoperative Complications; Safety; Skin Neoplasms; Tablets, Enteric-Coated

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

After kidney transplantation, withdrawal of calcineurin inhibitors (CNI) and conversion to sirolimus (SRL) may reduce the occurrence of new non-melanoma skin cancer (NMSC). Conversely, a reduced CNI exposure with everolimus (EVR) is an alternative strategy that has not been thoroughly evaluated. We retrospectively compared the occurrence of newly diagnosed NMSCs in two cohorts of kidney transplant recipients (KTR) with at least one NMSC: 35 patients were converted to EVR with reduced CNI exposure (CNI/EVR group), whereas 46 patients were converted to SRL in association with mycophenolic acid (MPA) (SRL/MPA group). Two years after conversion, survival free of new NMSC was similar between the two cohorts (p = .37), with 19 KTR (54.3%) in the CNI/EVR group and 22 (47.8%) in the SRL/MPA group being diagnosed of at least one new NMSC. Half of the KTR from both groups showed adverse events, leading to mTORi discontinuation for 37.1% of KTR in the CNI/EVR group and 21.7% in the SRL/MPA group (p = .09). The incidence of rejections was similar between the two groups. In a retrospective cohort of KTR with at least one post-transplant NMSC, the outcome of the patients converted to a CNI/EVR regimen was not different from those converted to a SRL/MPA regimen.

Topics: Calcineurin Inhibitors; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Pilot Projects; Retrospective Studies; Secondary Prevention; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases

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

Topics: Antirheumatic Agents; Female; Histiocytoma, Benign Fibrous; Humans; Lung Diseases, Interstitial; Middle Aged; Mycophenolic Acid; Pyridones; Scleroderma, Systemic; Skin; Skin Neoplasms

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

Chronic immunosuppression after solid-organ transplantation is a risk factor for cutaneous squamous cell carcinoma (cSCC) development. Certain immunosuppressant drugs, namely azathioprine and calcineurin inhibitors, increase this risk more than others. We investigated incidence of cSCC in a Dutch lung transplant recipient (LTR) cohort and analyzed associated risk factors.. All LTRs with post-transplant survival of >30 days were included. Data included indication for lung transplantation and duration of medication use. Skin cancer data were extracted from the Dutch nationwide registry of histopathology (PALGA). Uni- and multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression analyses.. Five hundred forty-four patients were included with a median survival of 11.05 years. Fifty-two (9.6%) LTRs developed at least one cSCC, with a cumulative incidence of 3.9% and 15.3% after 5 and 10 years, respectively. Multivariate analyses showed that the sequential use of azathioprine and mycophenolate mofetil (MMF), both at for least 1 year, was associated with a lower risk of developing cSCC (hazard ratio [HR] 0.24; 95% confidence interval [CI] 0.10 to 0.56) compared with azathioprine use only. Furthermore, age at transplantation (HR 3.42; 95% CI 1.33 to 8.79), male gender (HR 1.75; 95% CI 1.00 to 3.05), previous skin cancer (HR 4.75; 95% CI 1.14 to 19.76), and history of smoking (HR 3.30; 95% CI 1.69 to 6.44) were associated with increased risk of developing cSCC in univariate analyses.. Apart from known risk factors, we found that switching from azathioprine to MMF is associated with reduced incidence of cSCC in LTR, prompting a discussion of whether switching azathioprine to MMF should be considered in high-risk patients.

Topics: Adolescent; Adult; Aged; Azathioprine; Carcinoma, Squamous Cell; Child; Drug Substitution; Female; Humans; Immunosuppressive Agents; Incidence; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Risk Assessment; Risk Factors; Skin Neoplasms; Time Factors; Young Adult

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

With advances in immunosuppressive therapy, heart transplantation is currently recommended as the only established surgical treatment for refractory heart failure. However, chronic immunosuppression increases the risk for malignancy. Everolimus (EVR) is a potent mammalian target of rapamycin inhibitor that is used after transplantation and to treat advanced malignancies, as we have done in Taiwan after heart transplantation since 2004. Mycophenolate mofetil (MMF) and EVR are frequently used as cell-cycle inhibitors to optimize post-transplantation outcomes.. We retrospectively analyzed the characteristics and outcomes of 454 patients who received either MMF (n = 232) or EVR (n = 222) after heart transplantation at the National Taiwan University Hospital from March 1, 1990, to March 1, 2015. Patient characteristics and Kaplan-Meier survival curves were compared between groups.. During a median follow-up of 69.2 months, malignancy was diagnosed in 27 patients receiving MMF (n = 23) or EVR (n = 4). There was a significant difference in malignancy risk between groups (9.91% vs 1.80%, P = .001). The most common malignancies were non-Hodgkin lymphoma, skin cancers, and lung squamous cell carcinoma. The 2-year overall survival after malignancy was 50% in the EVR group and 47% in the MMF group (P = .745).. EVR treatment after heart transplant is associated with a lower risk of malignancy than is MMF treatment. The 2-year survival rate after malignancy was similar between EVR and MMF groups.

Topics: Adolescent; Adult; Aged; Animals; Child; Child, Preschool; Everolimus; Female; Follow-Up Studies; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Infant; Kaplan-Meier Estimate; Lymphoma, Non-Hodgkin; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Skin Neoplasms; Survival Rate; Taiwan; Young Adult

Skin malignancies are the most prevalent neoplasms seen in organ transplant recipients (OTRs). Immunosuppressive treatment has been attributed to play a causative role in malignancy development. The aim of the study was to assess cytokine concentrations involved in cytotoxic and regulatory responses in patients after organ transplantation (Tx). We compared two OTR subgroups: those with malignant skin tumors and those without any known changes developed after Tx.. We enrolled 102 patients, 63: 3-360 (median: min-max) months after Tx, aged 54.3 ± 9.9 (mean ± SD) years (38.2% females). Seventeen patients were diagnosed with malignant skin neoplasms. The most frequent treatment schemes were cyclosporine A - mycophenolate mofetil - glucocorticosteroids (GS) (37.4%), mycophenolate mofetil-tacrolimus - GS (15.2%), and azathioprine-cyclosporine A-GS (14.1%). A 5-mL sample of venous blood was obtained from participants of two subgroups: those with malignant skin tumors and those without any known changes. The blood was tested for interleukin 2 (IL-2), interferon gamma, IL-10, and transforming growth factor beta concentrations (Multicytokine Flex Set, ELISA). The Kruskal-Wallis test was used to compare variables; P < .05 was considered valid.. Age, gender distribution, and time from transplantation did not differ across the two subgroups. We found significantly lower blood concentrations of IL-2 and IL-10 in patients with post-transplantation skin cancers versus patients without any known skin changes (0 pgmL(-1) vs. 21.22 pgmL(-1), and 4.93 pgmL(-1) vs. 7.36 pgmL(-1), respectively). The differences between interferon gamma and transforming growth factor beta levels were insignificant across studied groups.. Our findings suggest that immunosuppressive response assessed by cytokine IL-2 and IL-10 levels may be used in the risk stratification for the development of skin cancer in organ recipient patients.

Topics: Adult; Azathioprine; Case-Control Studies; Cyclosporine; Cytokines; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Interferon-gamma; Interleukin-10; Interleukin-2; Male; Middle Aged; Mycophenolic Acid; Organ Transplantation; Postoperative Complications; Skin Neoplasms; Transforming Growth Factor beta

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: 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 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: Aged; Combined Modality Therapy; Female; Fluorescein Angiography; Humans; Lymph Node Excision; Lymphatic Metastasis; Melanoma; Multimodal Imaging; Mycophenolic Acid; Optic Nerve Diseases; Paraneoplastic Syndromes, Ocular; Plasmapheresis; Positron-Emission Tomography; Prednisone; Skin Neoplasms; Tomography, X-Ray Computed; Visual Acuity; Visual Field Tests; Visual Fields

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

Increased skin cancer risk in organ transplant recipients has been experimentally emulated with enhanced UV carcinogenesis from administering conventional immunosuppressants. However, newer generation immunosuppressive drugs, rapamycin (Rapa) and mycophenolate mofetil (MMF), have been shown to impair angiogenesis and outgrowth of tumor implants. To ascertain the overall effect on UV carcinogenesis, Rapa and MMF were admixed into the food pellets of hairless SKH1 mice receiving daily sub-sunburn UV dosages. With immunosuppressive blood levels neither of the drugs affected onset of tumors (<2 mm), but in contrast to MMF, Rapa significantly increased latency of large tumors (>or=4 mm, medians of 190 vs 125 days) and reduced their multiplicity (1.6 vs 4.5 tumors per mouse at 200 days). Interestingly, tumors (>2 mm) from the Rapa-fed group showed a reduction in UV-signature p53 mutations (39% vs 90%) in favor of mutations from putative base oxidation. This shift in mutation spectrum was not essentially linked to the reduction in large tumors because it was absent in large tumors similarly reduced in number when feeding Rapa in combination with MMF, possibly owing to an antioxidant effect of MMF. Significantly fewer tumor cells were Vegf-positive in the Rapa-fed groups, but a correspondingly reduced expression of Hif1alpha target genes (Vegf, Ldha, Glut1, Pdk1) that would indicate altered glucose metabolism with increased oxidative stress was not found. Remarkably, we observed no effect of the immunosuppressants on UV-induced tumor onset, and with impaired tumor outgrowth Rapa could therefore strongly reduce skin carcinoma morbidity and mortality rates in organ transplant recipients.

Topics: Angiogenic Proteins; Animals; Blotting, Western; Diet; Female; Immunoenzyme Techniques; Immunosuppressive Agents; Male; Mice; Mice, Hairless; Mutation; Mycophenolic Acid; Neoplasms, Radiation-Induced; Neovascularization, Pathologic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sirolimus; Skin; Skin Neoplasms; Tumor Suppressor Protein p53; Ultraviolet Rays; Whole-Body Irradiation

The objectives of the present study were to evaluate the incidence of malignancies and to describe the effects of immunosuppression on survival and recurrence of malignancies after heart transplantation (HTX). Data were analyzed in 211 cardiac allograft recipients, in whom HTX was performed between 1989 and 2005. All of these patients survived for more than 2 years after HTX and received induction therapy with antithymocyte globulin (RATG) guided by T-cell monitoring since 1994. An immunosuppressive regimen consisting of cyclosporine A (CsA) combined with azathioprine was followed by CsA and mycophenolate mofetil (MMF) in 2001; mammalian target of rapamycin (mTOR) inhibitors (everolimus/sirolimus) were used since 2003. Mean patient age at HTX was 51.4 ± 10.5 years; mean follow-up time after HTX 9.2 ± 4.7 years. Overall incidence of neoplasias was 30.8%. Individual risk factors associated with a higher risk of malignancy after HTX were higher age at transplantation (P = .003), male gender (P = .005) and ischemic cardiomyopathy before HTX (P = .04). Administration of azathioprine (P < .0001) or a calcineurin inhibitor (CNI) (P = .02) for more than 1 year was associated with development of malignancy, whereas significantly fewer malignancies were noticed in patients receiving an mTOR-inhibitor (P < .0001). Kaplan-Meier analysis demonstrated a strong statistical trend toward an improved survival in patients with a noncutaneous neoplasia switched to a CNI-free protocol (P = .05). This study demonstrated the impact of a variety of individual risk factors and immunosuppressive drugs on development of malignancy after HTX. Markedly fewer patients with noncutaneous malignancies died after switch to a CNI-free regimen, not quite reaching statistical significance by Kaplan-Meier analysis, however.

Topics: Adolescent; Adult; Azathioprine; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Germany; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Skin Neoplasms; Survival Rate; Time Factors; TOR Serine-Threonine Kinases; Transplantation, Homologous; Treatment Outcome; Young Adult

Topics: Anti-Inflammatory Agents, Non-Steroidal; Carcinoma, Squamous Cell; Drug Therapy, Combination; Female; Humans; Iatrogenic Disease; Immunocompromised Host; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Risk Assessment; Scleroderma, Systemic; Skin; Skin Neoplasms

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

Calcineurin inhibitors (CNIs) are frequently associated with side effects such as nephrotoxicity and hypertension, so CNI withdrawal from immunosuppressive regimens is desirable in certain cases. The proliferation signal inhibitors/mammalian target of rapamycin inhibitors everolimus and sirolimus may play an important role in achieving CNI withdrawal. Studies on sirolimus have shown that conversion from CNIs is associated with improvements in renal function and hypertension. A case report is presented of a renal transplant recipient who experienced hypertension and recurrent cutaneous neoplasia while receiving a ciclosporin (CsA)-based immunosuppressive regimen. After transplantation, the patient received full-dose CsA and prednisolone. After 7 years, the patient's serum creatinine increased from 1.9 mg/dl to 2.5 mg/dl, and mycophenolate mofetil (MMF, 1000 mg/day) was introduced, enabling the CsA dose to be reduced to 100 mg b.i.d. The patient also required resection of five cutaneous neoplastic lesions; this led to the decision to stop CsA and start treatment with everolimus 1.5 mg/day, which was increased to 3.0 mg/day to achieve target trough blood levels of 3 ng/ml. To avoid over-immunosuppression, the MMF dose was reduced to 500 mg/day. After conversion, the patient experienced a substantial improvement in blood pressure, from 175/85 mmHg to 155/70 mmHg. Serum creatinine levels decreased to 1.6 mg/dl, and there has been no recurrence of cutaneous neoplasia in 9 months of follow-up. Therefore, conversion to everolimus from CsA in a renal transplant recipient led to improvements in blood pressure and resolution of recurrent cutaneous neoplasia, with no evidence of rejection or changes in renal function.

Topics: Blood Pressure; Calcineurin Inhibitors; Creatinine; Cyclosporine; Drug Therapy, Combination; Everolimus; Humans; Hypertension; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasm Recurrence, Local; Postoperative Complications; Prednisolone; Sirolimus; Skin Neoplasms; Treatment Outcome; Withholding Treatment

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

With the establishment of kidney transplant centres in Nigeria and increase in the number of kidney transplant recipients returning home for follow up after successful transplant abroad, an increasing number of patients with post transplant complications are likely to be seen. There is the need for physicians vested with the care of these patients to be aware of the post transplant complications so that early diagnosis and effective treatment can be instituted so as to save both the patient and the allograft. Two out of seventeen renal transplant recipients followed up in our unit had post renal transplant Kaposi's sarcoma. Both were successfully treated with withdrawal of cyclosporin, reduction of other immunosuppressives and introduction of low dose Mycophenolate Mofetil (MMF). One had a course of radiotherapy followed by weekly intravenous vincristine and the other only had vincristine with complete remission of the lesions in both patients. Post transplant Kaposi's sarcoma occurs in Nigerian transplant patients and this report highlights the need for increased awareness and high index of suspicion of post transplant Kaposi's sarcoma among kidney transplant recipients.

Topics: Clinical Competence; Early Diagnosis; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Nigeria; Sarcoma, Kaposi; Skin Neoplasms; Time Factors

Topics: Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Postoperative Complications; Remission, Spontaneous; Retreatment; Sarcoma, Kaposi; Skin Neoplasms

Kaposi's sarcoma (KS) is an human herpesvirus 8-associated tumor, occurring in immunocompromised patients. We report here an increased incidence of KS among kidney graft recipients (KGRs) during the last 2 years, concomitant to the introduction of the immunosuppressant mycophenolate mofetil (MMF).. A total of 1835 KGRs, receiving organs between 1987 and 1997, were surveyed for the development of KS. A total of 371 patients received therapy including MMF (group A), whereas 1464 patients were treated with an MMF-free protocol (group B).. 3/371 patients (0.8%) of group A versus 2/1464 patients (0.1%) of group B developed KS. In group A, KS became evident 7+/-2 months after initiation of MMF therapy.. At our center, during the last 2 years, the incidence of KS has increased in KGRs, and it is not clear whether the introduction of MMF contributes to the phenomenon.

Topics: Drug Therapy, Combination; Extremities; Fatal Outcome; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Neoplasms; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Postoperative Complications; Radiography; Sarcoma, Kaposi; Skin Neoplasms