tacrolimus and Neoplasms

Atopic dermatitis is a prevalent condition in children and can be effectively managed with medications such as topical calcineurin inhibitors (pimecrolimus or tacrolimus). A key unresolved safety concern is whether use of topical calcineurin inhibitors is associated with cancer. We systematically reviewed the risk of cancer in patients with atopic dermatitis exposed to topical calcineurin inhibitors.. As part of the 2022 American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters atopic dermatitis guidelines, we searched MEDLINE, Embase, the Latin American and Caribbean Health Sciences Literature database, the Índice Bibliográfico Espanhol de Ciências da Saúde database, the Global Resource of Eczema Trials database, WHO's International Clinical Trials Registry Platform, the US Food and Drug Administration database, the European Medicines Agency database, company registers, and relevant citations from inception to June 6, 2022. We included randomised controlled trials and comparative and non-comparative non-randomised studies in any language addressing cancer risk in patients with atopic dermatitis using topical calcineurin inhibitors. We excluded split-body studies and studies with less than 3 weeks of follow-up. Paired reviewers independently screened records, extracted data, and assessed risk of bias in duplicate. We used Bayesian models to estimate the probability for cancer due to topical calcineurin inhibitor exposure and the GRADE approach to determine the certainty of the evidence. Patients, advocacy groups, and care providers set a priori thresholds of important effects. This study is registered with Open Science Framework, https://osf.io/v4bfc.. We identified and analysed 110 unique studies (52 randomised controlled trials and 69 non-randomised studies [11 were non-randomised study extensions of randomised controlled trials]) including 3·4 million patients followed up for a mean of 11 months (range 0·7-120). The absolute risk of any cancer with topical calcineurin inhibitor exposure was not different from controls (absolute risk 4·70 per 1000 with topical calcineurin inhibitors vs 4·56 per 1000 without; odds ratio 1·03 [95% credible interval 0·94-1·11]; moderate certainty). For all age groups and using data from observational studies and randomised controlled trials, the use of pimecrolimus (OR 1·05 [95% credible interval 0·94-1·15]) or tacrolimus (0·99 [0·89-1·09]) is likely to have had little to no association with cancer compared with no topical calcineurin inhibitor exposure. For pimecrolimus versus tacrolimus, the finding was similar (0·95 [95% credible interval 0·83-1·07]). Findings were similar in infants, children, and adults, and robust to trial sequential, subgroup, and sensitivity analyses.. Among individuals with atopic dermatitis, moderate-certainty evidence shows that topical calcineurin inhibitors do not increase the risk of cancer. These findings support the safe use of topical calcineurin inhibitors in the optimal treatment of patients with atopic dermatitis.. American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology via the Joint Task Force on Practice Parameters.

Topics: Adult; Asthma; Bayes Theorem; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Hypersensitivity; Infant; Neoplasms; Randomized Controlled Trials as Topic; Tacrolimus

Various immunosuppressive regimens have been developed for the treatment of lupus nephritis (LN). This study aimed to compare the efficacy and safety of immunosuppressive regimens in adults with LN.. We systematically searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases, including conference proceedings, trial registries, and reference lists, from inception until July 10, 2022. The effects of treatment were compared and ranked using the surface under the cumulative ranking curve (SUCRA). The primary endpoint was total remission. The secondary endpoints were complete remission, systemic lupus erythematosus disease activity index (SLEDAI), relapse, all-cause mortality, end-stage renal disease (ESRD), infection, herpes zoster, ovarian failure, myelosuppression, and cancer.. Sixty-two trials reported in 172 studies involving 6,936 patients were included in the network meta-analysis. The combination of tacrolimus (TAC), mycophenolate mofetil (MMF), and glucocorticoid (GC) provided the best result for the total remission rate (SUCRA, 86.63%) and SLEDAI (SUCRA, 91.00%), while the combination of voclosporin (VCS) , MMF and GC gave the best improvement in the complete remission rate (SUCRA, 90.71%). The combination of cyclophosphamide (CYC), MMF and GC was associated with the lowest risk of relapse (SUCRA, 85.57%) and cancer (SUCRA, 85.14%), while the combination of obinutuzumab (OTB), MMF and GC was associated with the lowest risk of all-cause mortality (SUCRA, 84.07%). Rituximab (RTX) plus MMF plus GC was associated with the lowest risk of ESRD (SUCRA, 83.11%), while the risk of infection was lowest in patients treated with azathioprine (AZA) plus CYC plus GC (SUCRA, 68.59%). TAC plus GC was associated with the lowest risk of herpes zoster (SUCRA, 87.67%) and ovarian failure (SUCRA, 73.60%). Cyclosporine (CsA) plus GC was associated with the lowest risk of myelosuppression (SUCRA, 79.50%), while AZA plus GC was associated with the highest risk of myelosuppression (SUCRA, 16.25%).. This study showed that a combination of TAC, MMF and GC was the best regimen for improving the total remission rate. The optimal regimen for specific outcomes should be highlighted for high-risk patients.

Topics: Adult; Azathioprine; Bone Marrow Diseases; Cyclophosphamide; Glucocorticoids; Herpes Zoster; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Nephritis; Mycophenolic Acid; Neoplasms; Network Meta-Analysis; Recurrence; Tacrolimus; Treatment Outcome

Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen sulfide (H

Topics: Animals; Cystathionine beta-Synthase; Down Syndrome; Enzyme Inhibitors; Humans; Hydrogen Sulfide; Neoplasms; Tacrolimus

FK506 binding (FKBP) proteins are part of the highly conserved immunophilin family and its members have fundamental roles in the regulation of signalling pathways involved in inflammation, adaptive immune responses, cancer and developmental biology. The original member of this family, FKBP12, is a well-known binding partner for the immunosuppressive drugs tacrolimus (FK506) and sirolimus (rapamycin). FKBP12 and its analog, FKBP12.6, function as cis/trans peptidyl prolyl isomerases (PPIase) and they catalyse the interconversion of cis/trans prolyl conformations. Members of this family uniquely contain a PPIase domain, which may not be functional. The larger FKBPs, such as FKBP51, FKBP52 and FKBPL, contain extra regions, including tetratricopeptide repeat (TPR) domains, which are important for their versatile protein-protein interactions with inflammation-related signalling pathways. In this review we focus on the pivotal role of FKBP proteins in regulating glucocorticoid signalling, canonical and non-canonical NF-κB signalling, mTOR/AKT signalling and TGF-β signalling. We examine the mechanism of action of FKBP based immunosuppressive drugs on these cell signalling pathways and how off target interactions lead to the development of side effects often seen in the clinic. Finally, we discuss the latest advances in the role of FKBPs as therapeutic targets and the development of novel agents for a range of indications of unmet clinical need, including glucocorticoid resistance, obesity, stress-induced inflammation and novel cancer immunotherapy.

Topics: Animals; Drug Development; Humans; Immunosuppressive Agents; Inflammation; Neoplasms; Signal Transduction; Sirolimus; Tacrolimus; Tacrolimus Binding Proteins

Kidney transplantation (KT) is the most effective way to decrease the high morbidity and mortality of patients with end-stage renal disease. However, KT does not completely reverse the damage done by years of decreased kidney function and dialysis. Furthermore, new offending agents (in particular, immunosuppression) added in the post-transplant period increase the risk of complications. Cardiovascular (CV) disease, the leading cause of death in KT recipients, warrants pre-transplant screening based on risk factors. Nevertheless, the screening methods currently used have many shortcomings and a perfect screening modality does not exist. Risk factor modification in the pre- and post-transplant periods is of paramount importance to decrease the rate of CV complications post-transplant, either by lifestyle modification (for example, diet, exercise, and smoking cessation) or by pharmacological means (for example, statins, anti-hyperglycemics, and so on). Post-transplantation diabetes mellitus (PTDM) is a major contributor to mortality in this patient population. Although tacrolimus is a major contributor to PTDM development, changes in immunosuppression are limited by the higher risk of rejection with other agents. Immunosuppression has also been implicated in higher risk of malignancy; therefore, proper cancer screening is needed. Cancer immunotherapy is drastically changing the way certain types of cancer are treated in the general population; however, its use post-transplant is limited by the risk of allograft rejection. As expected, higher risk of infections is also encountered in transplant recipients. When caring for KT recipients, special attention is needed in screening methods, preventive measures, and treatment of infection with BK virus and cytomegalovirus. Hepatitis C virus infection is common in transplant candidates and in the deceased donor pool; however, newly developed direct-acting antivirals have been proven safe and effective in the pre- and post-transplant periods. The most important and recent developments on complications following KT are reviewed in this article.

Topics: Antiviral Agents; Cardiovascular Diseases; Diabetes Mellitus; Hepatitis C, Chronic; Humans; Immunotherapy; Kidney Failure, Chronic; Kidney Transplantation; Mortality; Neoplasms; Postoperative Complications; Risk Factors; Tacrolimus

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

FK506-binding proteins (FKBPs) are intracellular receptors for FK506 and rapamycin, immunosuppressants that have recently been utilized as anticancer drugs. In the cytoplasm, FKBPs and these drugs modulate signal transduction pathways. However, recent reports reveal novel functions of FKBPs in the nucleus, which include regulation of transcription factors, histone chaperone activity, and modifications of chromatin structure. These activities are known to affect gene expression, DNA repair, and DNA replication. Therefore, elucidation of the nuclear functions of FKBPs will help researchers and clinicians better understand how immunosuppressants work as anticancer drugs, which might in turn lead to novel designs of cancer therapy.

Topics: Animals; Antineoplastic Agents; Chromatin; Drug Design; Humans; Immunosuppressive Agents; Neoplasms; Signal Transduction; Sirolimus; Tacrolimus; Tacrolimus Binding Proteins

Cutaneous side effects of epidermal growth factor receptor inhibitors (EGFRIs) are very frequent and well known. The aim of our study was to investigate the efficacy and safety of pimecrolimus 1% cream in the treatment of papulopustular eruption caused by EGFRIs and to review the relevant literature on therapeutic approaches.. Twenty cancer patients being treated with EGFRIs were included in the study. Nine of the patients showed grade 1 and 11 showed grade 2 papulopustular eruption. All patients were treated with pimecrolimus 1% cream, which was applied twice daily. Patients with grade 2 eruption also received systemic minocycline 100 mg/day.. All patients with grade 1 eruption responded to treatment, with 4/9 experiencing complete resolution of the lesions 2 weeks after the initiation of treatment. Five out of 11 patients with grade 2 eruption had more than 50% improvement in erythema and pustules, and 1 had complete resolution of the skin lesions. Two patients did not respond to treatment but were significantly improved after substitution of pimecrolimus 1% cream with metronidazole 1% cream. No side effects were recorded.. Our case series shows that pimecrolimus cream may be an effective and safe approach in the management of papulopustular eruption related to EGFRIs.

Topics: Aged; Antineoplastic Agents; Dermatologic Agents; Drug Eruptions; ErbB Receptors; Female; Humans; Male; Metronidazole; Middle Aged; Minocycline; Neoplasms; Ointments; Prospective Studies; Protein Kinase Inhibitors; Rosacea; Tacrolimus; Treatment Outcome

FK506 binding proteins (FKBPs) are the intracellular ligands of FK506 and rapamycin, two natural compounds with powerful and clinically efficient immunosuppressive activity. In recent decades, a relevant role for immunosuppressants as anticancer agents has emerged. Especially, rapamycin and its derivatives are used, with successful results, across a variety of tumors. Of note, rapamycin and FK506 bind to FKBP12, and the resulting complexes interfere with distinct intracellular signaling pathways driven, respectively, by the mammalian target of rapamycin and calcineurin phosphatase. These pathways are related to T-cell activation and growth. Hyperactivation of the mammalian target of rapamycin (mTOR), particularly in cancers that have lost the tumor suppressor gene PTEN, plays an important pathogenetic role in tumor transformation and growth. The signaling pathway involving calcineurin and nuclear factors of activated T-lymphocytes is also involved in the pathogenesis of different cancer types and in tumor metastasis, providing a rationale for use of FK506 in anticancer therapy. Recent studies have focused on FKBPs in apoptosis regulation: Targeting of FKBP12 promotes apoptosis in chronic lymphocytic leukemia, FKBP38 knockdown sensitizes hepatoma cells to apoptosis, and FKBP51 silencing overcomes resistance to apoptosis in acute lymphoblastic leukemia, prostate cancer, melanoma, and glioma. Interestingly, derivatives of FK506 that have the same FKBP12-binding properties as FK506 but lack functional immunosuppressant activity, exert the same apoptotic effect as FK506 in chronic lymphocytic leukemia.These findings suggest that a direct FKBP inhibition represents a further mechanism of immunosuppressants.' anticancer activity. In this review, we focus on the role of FKBP members in apoptosis control and summarize the data on the antitumor effect of selective targeting of FKBP.

Topics: Antineoplastic Agents; Apoptosis; Humans; Immunosuppressive Agents; Neoplasms; Signal Transduction; Sirolimus; Tacrolimus; Tacrolimus Binding Proteins

Atopic dermatitis is a chronic inflammatory skin disease characterized by recurrent intense pruritus and a distinctive distribution of skin lesions. The topical calcineurin inhibitors tacrolimus and pimecrolimus were approved in the USA, as an ointment and a cream, respectively, for the treatment of atopic dermatitis in 2000 and 2001, respectively. In 2005, the Pediatric Advisory Committee of the US FDA implemented a 'black box' warning for tacrolimus ointment and pimecrolimus cream due to the lack of long-term safety data and the potential risk of the development of malignancies. This article focuses on the safety aspects of these agents by discussing the findings from preclinical and clinical studies and postmarketing reports with regard to malignancies occurring after the use of tacrolimus ointment and pimecrolimus cream.

Topics: Administration, Cutaneous; Adverse Drug Reaction Reporting Systems; Animals; Calcineurin Inhibitors; Child; Clinical Trials as Topic; Dermatitis, Atopic; Drug Evaluation, Preclinical; Drug Labeling; Humans; Immunosuppressive Agents; Neoplasms; Tacrolimus; United States; United States Food and Drug Administration

Topical treatment with tacrolimus is more effective than the placebo and the low potency corticosteroids in the treatment of atopic dermatitis (AD) in both adults and children while it has a similar potency as some topical corticosteroids of medium potency. Since it was put on the market, more evidence has been accumulating to make our previous statements and it has been demonstrated to have greater effectivity than topical pimecrolimus and oral cyclosporine. It is a safe drug and its side effects are of little importance. Specifically no side effects have been demonstrated due to its systemic absorption nor has there been any increase in skin infections. The most frequent side effect is burning sensation or increased pruritus in the area where the product is applied. It is more frequent if the lesions treated are very acute and is generally transitory, not causing the treatment to be discontinued. Furthermore, with the current information, it cannot be associated to an increase of any type of neoplasms.

Topics: Adrenal Cortex Hormones; Adult; Child; Clinical Trials as Topic; Cost-Benefit Analysis; Cyclosporine; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Meta-Analysis as Topic; Middle Aged; Neoplasms; Pruritus; Retrospective Studies; Spain; Tacrolimus; Young Adult

In this article there were regarded the most frequent side effects that appear in the patients who have been treated with topical tacrolimus, and the association between topical tacrolimus and the development of tumors is unfolded. The irritation in the site of application of the tacrolimus can manifiest as pruritus, sensation of burning and/or eritema located to the area of the application. It is the most frequent side effect, independently of the duration of the study. The cutaneous infections, especially the viral ones, tend to be more numerous in patients with atopic dermatitis that receive topic tacrolimus. After reviewing the medical literature one concludes that nowadays there doesn t exist scientific evidence of an increase of skin cancer, lymphomas or systemic immunosuppression in those patients that use or have used topical tacrolimus. Nevertheless, it is not possible to exclude the possibility that there appear cutaneous and/or systemic long-term side effects.

Topics: Administration, Cutaneous; Animals; Calcineurin Inhibitors; Clinical Trials as Topic; Dermatitis, Atopic; Flushing; Humans; Immunosuppressive Agents; Neoplasms; Neoplasms, Experimental; Organ Transplantation; Postoperative Complications; Pruritus; Retrospective Studies; Skin Absorption; Skin Diseases, Viral; Spain; Tacrolimus

Many recombinant growth factors have failed in clinical trials due to off-target effects. We describe a method for circumventing off-target effects that involves equipping cells with a conditionally active signaling protein that can be specifically activated by an exogenously administered synthetic ligand. We believe that this approach will have many applications in gene and cell therapy.

Topics: Anemia; Animals; Cell Proliferation; Cell Transplantation; Gene Expression Regulation; Genetic Engineering; Genetic Therapy; Hematopoiesis; Humans; Neoplasms; Organic Chemicals; Receptors, Erythropoietin; Tacrolimus

Since the introduction of cyclosporin A (CsA) in the early 1980s, the use of immunosuppressants has markedly increased. Already established drugs have proved effective in the treatment of a wide range of diseases outside transplantation medicine and new immunosuppressants have been developed for more specific indications such as psoriasis and atopic dermatitis. Patients in transplantation medicine as well as in dermatology have benefited significantly from systemic and topical application of both new and established drugs. But are these drugs without risks? Cancer-protecting effects have been reported for some of the available immunosuppressants. Conversely, other publications and the issue of a black box warning by the US Food and Drug Administration have increased concerns about cancer-promoting effects. Knowledge of the specific effects as well as adverse effects is paramount to ensure an application that is safe and beneficial for the patient. Here we review the mechanisms of action and therapeutic potential, and critically review recent literature with respect to possible carcinogenic side effects of systemic and topical CsA, tacrolimus, pimecrolimus and rapamycin.

Topics: Calcineurin Inhibitors; Carcinogens; Cyclosporine; DNA Repair; Humans; Immunosuppressive Agents; Models, Biological; Neoplasms; Protein Kinases; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases; Ultraviolet Rays

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

In this report, we review the data on the safety and tolerability of pimecrolimus cream 1% (Elidel) from clinical trials and post-marketing surveillance in patients with atopic dermatitis. These data demonstrate that topically applied pimecrolimus is minimally absorbed through the skin and has a favourable safety margin. The most common treatment-related adverse events are transient local reactions, particularly skin burning (16.1 and 12.9 events per 1,000 patient-months of follow-up in adults and children, respectively). When compared to the vehicle, the use of pimecrolimus cream 1% is associated with an increased incidence of herpes simplex virus infections in children (relative risk: 2.5; 95% confidence interval: 1.2-5.8; p = 0.017). However, pimecrolimus cream 1% does not increase the incidence of any skin infection in comparison with moderately potent topical corticosteroids and lacks other corticosteroid-related side effects such as skin atrophy. While cases of malignancy have been reported in patients who have used pimecrolimus cream 1%, there is no clinical evidence to establish that treatment with pimecrolimus cream 1% increases the risk of malignancy.

Topics: Administration, Cutaneous; Animals; Calcineurin Inhibitors; Clinical Trials as Topic; Dermatitis, Atopic; Glucocorticoids; Humans; Immunosuppressive Agents; Neoplasms; Product Surveillance, Postmarketing; Skin Absorption; Skin Diseases, Infectious; Tacrolimus

Topics: Administration, Topical; Calcineurin Inhibitors; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Neoplasms; Risk Factors; Safety; Tacrolimus; United States; United States Food and Drug Administration

Topical calcineurin inhibitors (pimecrolimus, Elidel, East Hanover, NJ; and tacrolimus, Protopic, Tokyo, Japan) have been approved for the use in atopic dermatitis since the year 2000. These compounds represent a relatively safe class of topical anti-inflammatory, nonsteroidal therapy. However, in January of 2006, the US Food and Drug Administration issued a black box warning on these compounds about possible concerns of increased long-term malignancy risk due to systemic immunosuppression. To date, studies from clinical trials, systemic absorption, and post-marketing surveillance show no evidence for this systemic immunosuppression or increased risk for any malignancy.

Topics: Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Drug-Related Side Effects and Adverse Reactions; Immunosuppression Therapy; Immunosuppressive Agents; Neoplasms; Tacrolimus; Time Factors; United States; United States Food and Drug Administration

Post-transplant de novo malignancies are reviewed in three time periods: (i) the azathioprine (AZA) era from 1962 to 1980-1981, (ii) the cyclosporine (CYA) era (1980 to present) in which the calcineurin inhibitors, CYA and tacrolimus (TAC), were the mainstay of recipient immunosuppression, and (iii) the TOR inhibitor era starting in the year 2000. Both transplant registry and transplant center reports on malignancies occurring in the AZA era are reviewed. Reports from transplant centers and from the Cincinnati Transplant Tumor Registry (CTTR) in both the early CYA era (1980s) and the 1900-2000 CYA era are reported. Cancer incidence associated with AZA versus CYA, CYA versus TAC, and AZA versus mycophenolate mofetil (MMF) is compared in both transplant center and registry reports including new, unreported Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) data from 1998 to 2003. The malignancy incidence associated with lymphocyte-depleting antibody and corticosteroid immunosuppression is discussed. Reduced malignancy incidence recently reported with TOR inhibitors is compared with that of conventional immunosuppression. Important nondrug factors influencing the incidence of post-transplant malignancies from seven single and three registry reports are detailed. The substantial role that de novo malignancies play in post-transplant mortality is discussed. Finally, management recommendations for recipients who develop de novo post-transplant malignancies are briefly presented.

Topics: Antilymphocyte Serum; Azathioprine; Cyclosporine; Europe; Female; History, 20th Century; History, 21st Century; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Neoplasms; Ohio; Registries; Sirolimus; Tacrolimus; United States

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

Topics: Administration, Cutaneous; Animals; Dermatologic Agents; Disease Models, Animal; Humans; Immunosuppressive Agents; Neoplasms; 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

Thrombotic microangiopathy (TMA) after hematopoietic stem-cell transplantation (HSCT) or solid-organ transplantation is a serious complication that may be associated with diverse clinical conditions. The reported incidence varies widely, in part due to different diagnostic criteria. Currently, the diagnosis is based mostly on clinical features and is often uncertain; many disease or therapy-related complications in transplantation and malignancy can manifest clinical features of TMA. Risk factors for TMA post HSCT include the type of conditioning regimen, the presence graft-versus-host disease (GVHD), the use of calcineurin inhibitors (cyclosporine and tacrolimus) for GVHD prophylaxis, and infection. Cyclosporin and tacrolimus are the most commonly reported agents associated with TMA in solid-organ (mainly kidney) transplantations. Cancer-related TMA may be associated with chemotherapy or the malignancy itself. Compared with idiopathic TMA (thrombotic thrombocytopenic purpura), the outcome for patients with TMA post-HSCT or disseminated malignancy is poor. The efficacy of plasma exchange in the treatment of TMA post-HSCT or malignancy is uncertain. In the future, objective criteria integrating laboratory features (including tissue pathology, quantitative hematology, and endothelial cell functionality) with clinical features may assist in the diagnostic accuracy of TMA post HSCT, which would allow better evaluation of treatment modalities and better prediction of prognosis and outcomes.

Topics: Cyclosporine; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Neoplasms; Plasma Exchange; Prognosis; Purpura, Thrombotic Thrombocytopenic; Risk Factors; Tacrolimus; Treatment Outcome

Currently, expected 10-year first graft survival rates for kidneys from HLA-identical sibling, 1-haplotype-matched relative, and cadaver donors are 74, 51, and 40%, respectively. Histocompatibility, immunological conditioning with blood products, and immunosuppression with glucocorticoids, azathioprine, cyclosporin, and the antithymocyte (antilymphocyte) antibody preparations have been significant factors in the gradual improvement of kidney graft survival rates. Nearly all immunosuppression regimens are cyclosporin-based. Antithymocyte antibody induction therapy with delayed administration of cyclosporin is widely practised to avoid cyclosporin nephrotoxicity while the kidney graft is recovering from preservation injury. Late cyclosporin withdrawal results in inferior cadaver kidney transplant survival rates. Rejection crises usually respond to high dose glucocorticoid therapy. Glucocorticoid-resistant rejection usually responds to treatment with antithymocyte antibody. FK-506 is a promising new immunosuppressant that has properties similar to cyclosporin. Prophylaxis against viral, bacterial and fungal infections is necessary to reduce the morbidity of immunosuppression. The incidence of malignant conditions associated with viral infections is significantly increased with immunosuppression. New immunopharmacological agents and advances in genetic procedures may allow the induction of specific transplantation tolerance and successful xenotransplantation within the next decade.

Topics: Antilymphocyte Serum; Azathioprine; Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunocompromised Host; Immunosuppressive Agents; Infections; Kidney Transplantation; Neoplasms; Prednisolone; Tacrolimus

Topics: Diabetes Mellitus; Humans; Kidney; Neoplasms; Nervous System Diseases; Tacrolimus

Atopic dermatitis is a prevalent condition in children and can be effectively managed with medications such as topical calcineurin inhibitors (pimecrolimus or tacrolimus). A key unresolved safety concern is whether use of topical calcineurin inhibitors is associated with cancer. We systematically reviewed the risk of cancer in patients with atopic dermatitis exposed to topical calcineurin inhibitors.. As part of the 2022 American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters atopic dermatitis guidelines, we searched MEDLINE, Embase, the Latin American and Caribbean Health Sciences Literature database, the Índice Bibliográfico Espanhol de Ciências da Saúde database, the Global Resource of Eczema Trials database, WHO's International Clinical Trials Registry Platform, the US Food and Drug Administration database, the European Medicines Agency database, company registers, and relevant citations from inception to June 6, 2022. We included randomised controlled trials and comparative and non-comparative non-randomised studies in any language addressing cancer risk in patients with atopic dermatitis using topical calcineurin inhibitors. We excluded split-body studies and studies with less than 3 weeks of follow-up. Paired reviewers independently screened records, extracted data, and assessed risk of bias in duplicate. We used Bayesian models to estimate the probability for cancer due to topical calcineurin inhibitor exposure and the GRADE approach to determine the certainty of the evidence. Patients, advocacy groups, and care providers set a priori thresholds of important effects. This study is registered with Open Science Framework, https://osf.io/v4bfc.. We identified and analysed 110 unique studies (52 randomised controlled trials and 69 non-randomised studies [11 were non-randomised study extensions of randomised controlled trials]) including 3·4 million patients followed up for a mean of 11 months (range 0·7-120). The absolute risk of any cancer with topical calcineurin inhibitor exposure was not different from controls (absolute risk 4·70 per 1000 with topical calcineurin inhibitors vs 4·56 per 1000 without; odds ratio 1·03 [95% credible interval 0·94-1·11]; moderate certainty). For all age groups and using data from observational studies and randomised controlled trials, the use of pimecrolimus (OR 1·05 [95% credible interval 0·94-1·15]) or tacrolimus (0·99 [0·89-1·09]) is likely to have had little to no association with cancer compared with no topical calcineurin inhibitor exposure. For pimecrolimus versus tacrolimus, the finding was similar (0·95 [95% credible interval 0·83-1·07]). Findings were similar in infants, children, and adults, and robust to trial sequential, subgroup, and sensitivity analyses.. Among individuals with atopic dermatitis, moderate-certainty evidence shows that topical calcineurin inhibitors do not increase the risk of cancer. These findings support the safe use of topical calcineurin inhibitors in the optimal treatment of patients with atopic dermatitis.. American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology via the Joint Task Force on Practice Parameters.

Topics: Adult; Asthma; Bayes Theorem; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Hypersensitivity; Infant; Neoplasms; Randomized Controlled Trials as Topic; Tacrolimus

Everolimus is a drug from the class of mammalian target of rapamycin inhibitors used for both immunosuppressant and oncological indications. We postulate that there is room for improvement of dosing, as the optimal immunosuppressive dose in calcineurin-free regimens is unknown and since the once daily dosing regimen for oncological indications is often associated with treatment-limiting toxicity.. We developed a mechanistic population pharmacokinetic model for everolimus in cancer and transplant patients and explored alternative dosing regimens.. We found that formulation did not influence bioavailability and that use of >20 mg prednisolone daily increased everolimus clearance. In transplant patients, the approved dose of 0.75-1 mg twice daily (BID) results in subtherapeutic trough levels (<6 μg l. For oncological indications, our results encourage the investigation of dosing everolimus 3.75 mg BID in terms of superiority in safety and noninferiority in efficacy.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Everolimus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Neoplasms; Prednisolone; Tacrolimus; TOR Serine-Threonine Kinases; Transplantation, Homologous; Treatment Outcome

In a phase 2 study, kidney transplant recipients of low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept had improved kidney function at 12 months postconversion versus those continuing CNI therapy, with a low rate of acute rejection and no transplant loss.. 36-month follow-up of the intention-to-treat population.. CNI-treated adult kidney transplant recipients with stable transplant function (estimated glomerular filtration rate [eGFR], 35-75mL/min/1.73m. At 6 to 36 months posttransplantation, patients were randomly assigned to switch to belatacept-based immunosuppression (n=84) or continue CNI-based therapy (n=89).. Safety was the primary outcome. eGFR, acute rejection, transplant loss, and death were also assessed.. Treatment exposure-adjusted incidence rates for safety, repeated-measures modeling for eGFR, Kaplan-Meier analyses for efficacy.. Exploratory post hoc analysis with a small sample size.. Switching patients from a CNI to belatacept may represent a safe approach to immunosuppression and is being further explored in an ongoing phase 3b trial.

Topics: Abatacept; Adult; Calcineurin Inhibitors; Cyclosporine; Drug Substitution; Female; Graft Rejection; Graft Survival; Humans; Immunocompromised Host; Immunosuppressive Agents; Infections; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mortality; Neoplasms; Tacrolimus; Treatment Outcome

Only a few studies in children have evaluated the efficacy of prophylactic regimens using tacrolimus on acute graft-versus-host disease (aGVHD). As a result, optimal tacrolimus levels in children after matched sibling donor allogeneic hematopoietic cell transplantation (alloHCT) are not well defined. We measured the association between subtherapeutic levels (<10 ng/mL) during weeks 1 to 4 after alloHCT and the cumulative incidence of grades II to IV aGVHD in children. Additionally, we identified optimal lower cutoff levels for tacrolimus. Sixty patients (median age, 8 years) received tacrolimus/mycophenolate mofetil between March 2003 and September 2012. Twenty-three had a malignant disease and 37 nonmalignant disorders. The stem cell source included peripheral blood stem cells (n = 12) and bone marrow or cord blood (n = 48). Conditioning regimen varied. Specifically, 38.3% received a myeloablative regimen, 36.7% receiving a reduced-toxicity regimen, and 25% receiving a reduced-intensity regimen. Tacrolimus was initiated at .03 mg/kg/day via continuous i.v. infusion or .12 mg/kg/day orally. The dose was adjusted to maintain daily steady state concentrations within a range of 10 to 20 ng/mL. The overall incidence of grades II to IV aGVHD was 33.3%. On multivariate analysis, a mean tacrolimus level < 10 ng/mL during week 3 (P = .042; 95% confidence interval, 1.051 to 14.28) was significantly associated with increased incidence of grades II to IV aGVHD. Using weekly receiver operator curves, the optimal lower cutoff for tacrolimus levels was 10 to 11.2 ng/mL. Further prospective studies are warranted to study the incidence of aGVHD comparing the conventional tacrolimus levels of 5 to 15 versus 10 to 15 ng/mL.

Topics: Acute Disease; Adolescent; Adult; Child; Child, Preschool; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Male; Mycophenolic Acid; Neoplasms; Retrospective Studies; Siblings; Survival Rate; Tacrolimus; Transplantation Conditioning

Several studies suggest that the introduction of tacrolimus (TRL), mycophenolic acid (MPA) and interleukin 2 receptor antibodies (IL2Ra) as single drugs more than a decade ago has not increased the risk of malignancy after renal transplantation. However, only limited data are available on their carcinogenic effects when used in combination as a potent immunosuppressive regimen.. A retrospective single-centre cohort study on 929 adult renal transplant recipients. Investigation of the effect of two consecutive immunosuppressive regimens [1993-98, N = 405, anti-lymphocyte antibodies, cyclosporine and azathioprine (AZA); 1999-2007, N = 524, predominantly IL2Ra, TRL and MPA] on the incidence rate of skin cancer, solid tumours and post-transplant lymphoproliferative disease (PTLD).. In total, 365 malignancies developed among 113 patients. As compared to the previous cyclosporine and AZA-based immunosuppression, the introduction of the new immunosuppressive regimen did not increase the incidence rate of skin cancer [rate ratio 0.84; 95% confidence interval (CI) 0.48-1.46], solid tumours (0.89; 95% CI 0.46-1.67) and PTLD (0.82; 95% CI 0.28-2.21). Patients treated with the more recent regimens less frequently developed multiple skin cancers and invasive squamous cell cancer. Skin cancer after transplantation was strongly associated with the development of solid tumours (odds ratio 5.2; P < 0.0001). The introduction of the new immunosuppressive drugs reduced the incidence of first year acute rejection from 34.8 to 13.2% (P < 0.0001).. Although significantly more efficient in the prevention of acute rejection, the introduction of TRL, MPA and IL2Ra-based immunosuppression after kidney transplantation was not associated with an increased incidence of skin cancer, solid tumours or PTLD.

Topics: Adult; Antibiotics, Antineoplastic; Antibodies, Anti-Idiotypic; Drug Combinations; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Prognosis; Receptors, Interleukin-2; Retrospective Studies; Survival Rate; Tacrolimus

Pediatric allogeneic stem cell transplant (AlloSCT) patients are at substantial risk of developing kidney injury (KI), and KI contributes to transplant-related morbidity and mortality. We compared the estimated creatinine clearance (eCrCl) at 1, 3, 6, 9, and 12 months post-AlloSCT in 170 patients following reduced toxicity conditioning (RTC) versus myeloablative conditioning (MAC) to baseline. eCrCl was calculated using the Schwartz equation. Patients with ≥ 50% drop in eCrCl from the baseline were considered to have KI. Patients received tacrolimus and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis. The logistic regression model was used for assessing risk factors for KI. Seventy-six patients (median age = 10.6 years) received RTC AlloSCT; 94 patients (median age = 8.5 years) received MAC AlloSCT. The incidence of KI at 1 month post-AlloSCT was significantly higher in MAC versus RTC AlloSCT (43/94 [45.7%] versus 13/76 [17.1%] P < .0001). There was no statistical difference in KI at 3, 6, 9, and 12 months post-AlloSCT between the 2 conditioning groups. On multivariate analysis, only MAC was a significant risk factor for KI (odds radio [OR] 3.44, 95% confidence interval [CI] 1.59-7.42, P = .002). In multivariate analysis for risk factors affecting overall survival (OS), the following were statistically significant: MAC versus RTC (hazard ratio [HR] 2.66, P = .0008), average versus poor-risk disease status (HR 2.09, P = .004), matched sibling donor (MSD) and matched unrelated donor (MUD) versus umbilical cord blood (UCB) (HR 2.31, P = .013), no KI versus KI (HR 2.00, P = .005). In children, MAC is associated with significant risk of KI in the first month after transplant, and KI in the first month post-AlloSCT is associated with a significantly decreased OS.

Topics: Adolescent; Child; Child, Preschool; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Male; Mycophenolic Acid; Neoplasms; Retrospective Studies; Risk Factors; Stem Cell Transplantation; Survival Rate; Tacrolimus; Time Factors; Transplantation Conditioning; Transplantation, Homologous

Cutaneous side effects of epidermal growth factor receptor inhibitors (EGFRIs) are very frequent and well known. The aim of our study was to investigate the efficacy and safety of pimecrolimus 1% cream in the treatment of papulopustular eruption caused by EGFRIs and to review the relevant literature on therapeutic approaches.. Twenty cancer patients being treated with EGFRIs were included in the study. Nine of the patients showed grade 1 and 11 showed grade 2 papulopustular eruption. All patients were treated with pimecrolimus 1% cream, which was applied twice daily. Patients with grade 2 eruption also received systemic minocycline 100 mg/day.. All patients with grade 1 eruption responded to treatment, with 4/9 experiencing complete resolution of the lesions 2 weeks after the initiation of treatment. Five out of 11 patients with grade 2 eruption had more than 50% improvement in erythema and pustules, and 1 had complete resolution of the skin lesions. Two patients did not respond to treatment but were significantly improved after substitution of pimecrolimus 1% cream with metronidazole 1% cream. No side effects were recorded.. Our case series shows that pimecrolimus cream may be an effective and safe approach in the management of papulopustular eruption related to EGFRIs.

Topics: Aged; Antineoplastic Agents; Dermatologic Agents; Drug Eruptions; ErbB Receptors; Female; Humans; Male; Metronidazole; Middle Aged; Minocycline; Neoplasms; Ointments; Prospective Studies; Protein Kinase Inhibitors; Rosacea; Tacrolimus; Treatment Outcome

The efficacy and safety of converting maintenance renal transplant recipients from calcineurin inhibitors (CNIs) to sirolimus (SRL) was evaluated.. Eight hundred thirty renal allograft recipients, 6 to 120 months posttransplant and receiving cyclosporine or tacrolimus, were randomly assigned to continue CNI (n=275) or convert from CNI to SRL (n=555). Primary endpoints were calculated Nankivell glomerular filtration rate (GFR; stratified at baseline: 20-40 vs. >40 mL/min) and the cumulative rates of biopsy-confirmed acute rejection (BCAR), graft loss, or death at 12 months. Enrollment in the 20 to 40 mL/min stratum was halted prematurely because of a higher incidence of safety endpoints in the SRL conversion arm.. Intent-to-treat analyses at 12 and 24 months showed no significant treatment difference in GFR in the baseline GFR more than 40 mL/min stratum. On-therapy analysis of this cohort showed significantly higher GFR at 12 and 24 months after SRL conversion. Rates of BCAR, graft survival, and patient survival were similar between groups. Median urinary protein-to-creatinine ratios (UPr/Cr) were similar at baseline but increased significantly after SRL conversion. Malignancy rates were significantly lower at 12 and 24 months after SRL conversion. Post hoc analyses identified a subgroup with baseline GFR more than 40 mL/min and UPr/Cr less than or equal to 0.11, whose risk-benefit profile was more favorable after conversion than that for the overall SRL conversion cohort.. At 2 years, SRL conversion among patients with baseline GFR more than 40 mL/min was associated with excellent patient and graft survival, no difference in BCAR, increased urinary protein excretion, and a lower incidence of malignancy compared with CNI continuation. Superior renal function was observed among patients who remained on SRL through 12 to 24 months, particularly in the subgroup of patients with baseline GFR more than 40 mL/min and UPr/Cr less than or equal to 0.11.

Topics: Adolescent; Adult; Aged; Biopsy; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Neoplasms; Prospective Studies; Sirolimus; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome; Young Adult

To evaluate the efficacy and safety of a tacrolimus-based immunosuppressive regimen with and without induction therapy using daclizumab in first cadaveric renal transplant recipients.. Since January 2001, we studied the effect of daclizumab in a non-randomized and prospective study of 36 sequential first cadaveric renal transplant recipients. They were compared with a historical control group of 21 sequential first cadaveric renal transplant recipients without induction therapy. All patients received tacrolimus, azathioprine and corticosteroids as concomitant immunosuppressive therapy. Daclizumab was given at 1 mg/kg infusion 2 h before transplantation and then every 14 days for four more doses. Outcomes measured included incidence of acute rejection, patient survival, graft survival, annualized change in creatinine clearance (CrCl), cardiovascular risk profile, infection and malignancy.. Fewer biopsy proven acute rejections were observed in the induction treatment group: 11.1% (4/36) versus 19% (4/21) but the rejection free survival was similar (P = 0.37). The patient survival and graft survival were comparable. The renal function was similar in both groups. There were also no significant difference in infection, malignancy and cardiovascular risk profile in both groups.. Adding daclizumab to a tacrolimus-based therapy is safe but cannot further improve clinical efficacy.

Topics: Acute Disease; Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Cardiovascular Diseases; Creatinine; Daclizumab; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Neoplasms; Opportunistic Infections; Prospective Studies; Tacrolimus; Time Factors; Treatment Outcome

Blockade of costimulation and adhesion signaling is an attractive approach to interfere with graft rejection. Between January 1997 and May 1999, forty adults having benign liver diseases were included in a prospective, randomized study comparing tacrolimus plus low-dose short-term steroids without (n=20, TAC group) or with a 10-day course of antihuman CD2 monoclonal antibody (n=20, BTI group).. At day 7, histological rejection expressed by mean Banff scores (2.3+/-1.6 vs. 5.4+/-1.6 in the TAC group; P<0.0001) and incidence of moderate to severe rejection (score>or=6) (0 vs. 10 [50%] in the TAC group; P<0.001) were significantly lower in the BTI group. Rejection was treated in 10% (two patients) of BTI patients during the first 3 months and in 15% during the whole follow-up and in 25% (five patients) of TAC patients (P=NS). None of the BTI-patients presented with an adverse event. Three-month, 1-year, and 5-year actual patient survival rates were 100%, 95%, and 95% in the BTI group and 100%, 100%, and 85% in the TAC group. Graft survival rates were 100%, 90%, and 90% in the BTI group and 95%, 95%, and 80% in the TAC group (P=NS). The mAb had no negative impact on infectious or tumor events.. Antihuman CD2 monoclonal antibody is a safe immunosuppressive drug which has a favorable impact on early immunological follow-up of liver transplanted patients. The antibody had no impact on late patient and graft survival.

Topics: Adult; Aged; Antibodies, Monoclonal; CD2 Antigens; Dose-Response Relationship, Drug; Drug Administration Schedule; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Infections; Liver Failure; Liver Transplantation; Lymphocyte Count; Middle Aged; Neoplasms; Postoperative Period; Steroids; Survival Analysis; Tacrolimus

To determine whether myalgias/arthralgias occurring in cancer patients who receive quinupristin/dalfopristin are associated with biliary tract dysfunction.. We studied 56 patients with vancomycin-resistant enterococcal infections who were treated with quinupristin/dalfopristin 7.5 mg/kg every 8 h for a mean duration of 12 days (range 2-52 days). Liver function tests, including a test for alkaline phosphatase, were performed before, during and after the end of therapy. All patients were followed for 1 month after completion of therapy.. Thirty-eight (68%) of the 56 patients responded. Myalgias/arthralgias were the leading adverse events occurring in 20 (36%) of the patients. Patients with myalgias/arthralgias had significantly higher levels of alkaline phosphatase (mean 318.7 IU/L) during the mid-term therapy cycle compared with patients without any joint or muscular pain (mean 216.3 IU/L, P = 0.05). In addition, 3/18 (16.6%) patients with myalgias/arthralgias had more than five-fold the normal levels of alkaline phosphatase, which did not occur in any of the other patients who did not develop myalgias/arthralgias (P = 0.04). All myalgias/arthralgias resolved after the discontinuation of quinupristin/dalfopristin. By univariate analysis, other factors associated with myalgias/arthralgias were relapse of haematological malignancy (P = 0.01), receiving tacrolimus within 1 month prior to treatment (P = 0.04) and receiving methotrexate during antimicrobial therapy (P = 0.05).. Myalgias/arthralgias occur frequently in cancer patients receiving quinupristin/dalfopristin and may be associated with biliary tract dysfunction, as measured by alkaline phosphatase or other factors that could lead to intra-hepatic cholestasis, such as relapse of haematological malignancy or treatment with tacrolimus or methotrexate.

Topics: Aged; Alkaline Phosphatase; Anti-Bacterial Agents; Antimetabolites, Antineoplastic; Antineoplastic Agents; Arthralgia; Biliary Tract Diseases; Enterococcus; Female; Gram-Positive Bacterial Infections; Humans; Immunosuppressive Agents; Liver Function Tests; Male; Methotrexate; Middle Aged; Muscular Diseases; Neoplasms; Pain; Recurrence; Risk Factors; Tacrolimus; Virginiamycin

Topics: Adolescent; Adult; Aged; Azathioprine; Cyclosporine; Drug Therapy, Combination; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Methylprednisolone; Middle Aged; Neoplasms; Postoperative Complications; Survival Rate; Tacrolimus; Time Factors

Belatacept is employed alongside calcineurin inhibitor (CNI) therapy to prevent graft rejection in kidney transplant patients who are Epstein-Barr virus (EBV) seropositive. Preliminary data suggested that rates of post-transplant lymphoproliferative disorder (PTLD) were higher in individuals treated with belatacept compared to CNI therapy alone.. The records of 354 adults who underwent kidney only transplantation from January 2015 through September 2021 at one medical center were evaluated. Patients underwent treatment with either low-doses of mycophenolate, tacrolimus and sirolimus (B. Non-belatacept (MMF, tacrolimus and sirolimus) and belatacept-based (MMF, tacrolimus and belatacept) regimens do not appear to pose any increased risk of early onset PTLD. Both cohorts benefited from low rates of rejection, malignancy, mortality and graft failure. Recipients will continue to be monitored as PTLD can manifest as a long-term complication.

Topics: Abatacept; Adult; Calcineurin Inhibitors; Epstein-Barr Virus Infections; Graft Rejection; Graft Survival; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Neoplasms; Sirolimus; Tacrolimus

Apatinib is widely used in Chinese cancer patients. As the in vivo drug disposition of apatinib has large individual differences, adverse events are prone to occur. Cytochrome P450 (CYP)3A5 and cancer types maybe the main factors affecting this individual differences. The objective of our study was to establish a population pharmacokinetics (PK) model of apatinib in adult cancer patients, and to explore optimal dosage regimens for individualized treatment.. Adult patients with various types of cancer treated with apatinib were enrolled. The concentration of apatinib in plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. CYP3A5 genotype was determined using TaqMan allelic discrimination technique. The population PK model was developed by NONMEM V7.4. The dosing regimen was optimized based on Monte Carlo simulations.. A population PK model of apatinib in adult cancer patient was established. CYP3A5 genotype and systemic cancer type (digestive system cancers, nondigestive system cancers) were the most significant covariates for PK parameters. Patients with CYP3A5*1 expressers (CYP3A5*1/*1 and CYP3A5*1/*3) had lower apparent clearance and apparent volume of distribution than patients who do not express CYP3A5*1 (CYP3A5*3/*3). Patients with nondigestive system cancer had higher apparent volume of distribution and absorption rate constant than digestive system cancer. The results of dose simulation suggest that the apatinib dose in patients who do not express CYP3A5*1 should be 33.33-50.00% higher than that in CYP3A5*1 expressers.. A population PK model of apatinib in adult cancer patients was established. CYP3A5 genotype and systemic cancer type had concurrent effects on PK parameters. CYP3A5 patients who do not express CYP3A5*1 required higher doses.

Topics: Adult; Cytochrome P-450 CYP3A; Genotype; Humans; Immunosuppressive Agents; Neoplasms; Pharmacogenetics; Pyridines; Tacrolimus

Co-treatment with calcineurin inhibitors, such as tacrolimus and cyclosporin A, can sensitize chemotherapy-resistant cancer cells with P-glycoprotein (P-gp)-over-expression. Pimecrolimus (PIME) is a clinically available calcineurin inhibitor with a structure similar to that of tacrolimus. Whether PIME can sensitize P-gp-over-expressing resistant cancer cells remains unclear.. Cell viability assay, annexin V analyses, cellular morphology and density observation with a microscope, western-blotting, fluorescence-activated cell sorting (FACS), and analysis for P-gp inhibitory activity were performed to investigate the mechanism of action.. PIME, currently used in clinics, can be repositioned for treating patients with P-gp-over-expressing resistant cancer (stem) cells.

Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Calcineurin Inhibitors; Cyclosporine; Humans; Neoplasms; Rhodamine 123; Tacrolimus

Patients after heart transplantation are at increased risk for malignancy secondary to immunosuppression and oncogenic viral infections. Most common among children is posttransplant lymphoproliferative disorder (PTLD), occurring in 5% to 10% of patients. We used a national database to examine the incidence and risk factors for posttransplant malignancy.. The United Network for Organ Sharing database was queried for pediatric (<18 years) heart transplant recipients from October 1987 through November 2019. Freedom from malignancy after transplant was assessed with Kaplan-Meier analysis. Cox regression was performed to generate hazard ratios (HRs) and 95% CIs for risk of malignancy development.. Of 8581 pediatric heart transplant recipients, malignancy developed in 8.1% over median follow-up time of 6.3 years, with PTLD compromising 86.4% of the diagnosed cancers. The incidence of PTLD development was 1.3% at 1 year and 4.5% at 5 years. Older age at the time of transplant was protective against the development of malignancy (HR, 0.98; 95% CI, 0.96-0.99; P < .001), whereas a history of previous malignancy (HR, 1.9; 95% CI, 1.2-3.0; P = .007) and Ebstein-Barr virus (EBV) recipient-donor mismatch (HR, 1.7; 95% CI, 1.3-2.2; P < .001) increased the risk. Induction therapy, used in 78.9% of the cohort, did not increase malignancy risk (P = .355) nor did use of maintenance tacrolimus (P = .912).. PTLD occurred after 7% of pediatric heart transplants, with risk increased by younger age and EBV mismatch, highlighting the importance of PTLD monitoring in EBV-seronegative recipients. Induction therapy, used in most of the pediatric heart transplants, does not seem to increase posttransplant malignancy nor does tacrolimus, the most commonly used calcineurin inhibitor.

Topics: Calcineurin Inhibitors; Child; Epstein-Barr Virus Infections; Heart Transplantation; Herpesvirus 4, Human; Humans; Induction Chemotherapy; Lymphoproliferative Disorders; Neoplasms; Risk Factors; Tacrolimus

Elderly liver transplant (LTx) recipients at a lower risk of acute rejection compared to younger recipients due to immunosenescence. As such, they may benefit from reduced immunosuppression (IS) to minimize infectious and malignant complications. We aimed to evaluate outcomes in LTx recipients ≥60 years compared to a younger group of LTx recipients aged 18-59 years maintained on a similar level of IS. This was a single-center retrospective evaluation of adult LTx recipients from 2013 to 2018 who received methylprednisolone induction and were maintained on tacrolimus, mycophenolate mofetil (MMF), and a prednisone taper. A total of 143 LTx recipients were evaluated. Mean age in the older group was 65 ± 3.8 compared to 49 ± 10.4 years in the younger group (p < 0.0001). Mean tacrolimus levels and the duration of MMF and steroids were comparable. Both groups had a similar incidence of first rejection within 1 year (19.2% in the elderly group vs. 23.1% in the younger group, p = 0.57). There were no statistical difference in terms of infection, malignancy, or patient survival. In conclusion, our data suggests that elderly LTx recipients, when treated with a similar level of IS, had similar 1 year incidence of rejection, infection, malignancy, and patient survival as younger LTx recipients.

Topics: Adolescent; Adult; Aged; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Middle Aged; Mycophenolic Acid; Neoplasms; Retrospective Studies; Tacrolimus; Young Adult

To evaluate whether combinatorial use of abatacept (ABT) and tacrolimus (Tac) increases the risk of adverse events compared to their individual use in Japanese rheumatoid arthritis (RA) patients. We conducted a retrospective cohort study of RA patients using the Japanese multicenter database and analyzed the data of RA patients registered from April 2010 to March 2019 by comparing three treatment groups who received Tac, ABT, or a combination of both. We included patients who had initiated treatment with ABT or Tac and excluded patients who used tumor necrosis factor inhibitors, IL-6 inhibitors, and Jak inhibitors in the first year of our study. The primary outcome was the occurrence of adverse events such as infections that required hospitalization, newly diagnosed malignancy, or death from any cause after initiation of ABT or Tac. Of the 27,032 RA patients in the registry, 2009 patients were included. The Tac, ABT, and combination groups consisted of 1328, 563, and 118 patients, respectively. Primary outcome occurred in 149 (13.4%), 62 (13.5%), and 14 (13.9%) patients of the Tac, ABT, and combination groups, respectively. The incidence of adverse events between groups was not significantly different (p = 0.638). A Cox regression analysis which was adjusted for potential confounders such as age, disease activity, and concomitant use of prednisolone revealed no significant differences between groups. The combinatorial use of ABT and Tac, or ABT alone does not increase the risk of adverse events when compared to the use of Tac alone in RA patients in Japan. Key Points • This study included Japanese rheumatoid arthritis data and found that there was no significant risk when patients were treated with a combination of Tac and ABT or each drug alone.

Topics: Abatacept; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Japan; Neoplasms; Retrospective Studies; Tacrolimus; Treatment Outcome

Immunosuppressive-drugs are needed after solid organ transplantation to prevent allograft rejection but induce severe side effects. Understanding the alloimmune response is critical to modulate it and to achieve graft operational tolerance. The role of regulatory T cells and tolerogenic dendritic cells (Tol-DCs) is undoubtedly essential in tolerance induction. Tacrolimus is considered as the cornerstone of immunosuppression in solid organ transplantation. mTOR inhibitor such as rapamycin are thought to induce tolerance and are used as anticancer drugs in several cancers. The aim of this study was to better understand the effect of these immunosuppressive drugs on the differentiation, maturation and function of human monocyte derived dendritic cells (DCs).. DCs were differentiated from monocytes of healthy donors with either rapamycin (Rapa-DCs) or tacrolimus (Tac-DCs). The phenotype was evaluated by flow cytometry analysis. The production of pro- and anti-inflammatory cytokines was assessed by ELISA. The mRNA expression level of IDO and PD-L1 was assessed by RTqPCR. Mixed leukocytes reactions were performed to analyse suppressive activity of DCs.. Rapa-DC were characterised by a lower expression of the co-stimulatory molecules and CD83 than control-DCs (CTR-DC) (p < 0.05). In contrast, tacrolimus had no effect on the expression of surface markers compared to CTR-DCs. Rapamycin reduced both IL-12 and IL-10 secretions (p < 0.05). Rapa-DCs had a suppressive effect on CD4. Rapa-DCs exhibit an incomplete phenotypic tolerogenic profile. To our knowledge this is the first paper showing a reduction of expression of pro-tolerogenic enzyme IDO in DCs. Tacrolimus does not change the phenotypical or functional characteristics of moDCs.

Topics: B7-H1 Antigen; Cell Differentiation; Cells, Cultured; Cytokines; Dendritic Cells; Forkhead Transcription Factors; Healthy Volunteers; Humans; Immune Tolerance; Immunomodulation; Immunosuppressive Agents; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation Mediators; Monocytes; Neoplasms; Organ Transplantation; Phenotype; Sirolimus; T-Lymphocytes, Regulatory; Tacrolimus

Tacrolimus is an essential immunosuppressant for successful allogeneic haematopoietic stem cell transplantation (Allo-HSCT). This study aimed to examine the change in the blood concentration of tacrolimus during switching from intravenous to oral administration in allo-HSCT for paediatric cancer to predict the optimal dosage.. We retrospectively examined the medical records of 63 patients who received allo-HSCT and were administered tacrolimus. To compare bioavailability among different dose ranges, the blood concentration was divided by the dose (C/D).. Thirty-nine patients (age range=children 1-15 years, adults 17-67 years) were switched to oral administration of tacrolimus. The C/D after switching was significantly lower in children than in adults (p=0.039). There was a strong positive correlation between age and C/D in children, whereas no correlation was observed in adults.. In paediatric cancer patients, switching tacrolimus administration route may result in reduced blood concentrations. This tendency is more prominent in younger children.

Topics: Administration, Intravenous; Administration, Oral; Adolescent; Adult; Aged; Blood Physiological Phenomena; Child; Child, Preschool; Female; Humans; Infant; Male; Middle Aged; Neoplasms; Pediatrics; Tacrolimus; Young Adult

Topics: Humans; Liver Transplantation; Neoplasms; Nicotiana; Tacrolimus

Long-term safety of topical calcineurin inhibitors is not well understood. APPLES (A Prospective Pediatric Longitudinal Evaluation to Assess the Long-Term Safety of Tacrolimus Ointment for the Treatment of Atopic Dermatitis; NCT00475605) examined incidence of lymphoma and other cancers in a pediatric population with atopic dermatitis.. To quantify incident malignancies during 10 years in children with atopic dermatitis who used topical tacrolimus for ≥6 weeks.. Standardized incidence ratios for cancer events were analyzed relative to sex-, age-, and race-matched control data from national cancer registries.. There were 7954 eligible patients enrolled at 314 sites in 9 countries. During 44,629 person-years, 6 confirmed incident cancers occurred (standardized incidence ratio, 1.01; 95% confidence interval, 0.37-2.20). No lymphomas occurred.. Observational prospective cohort study.. The cancer incidence was as expected, given matched background data. This finding provides no support for the hypothesis that topical tacrolimus increases long-term cancer risk in children with atopic dermatitis.

Topics: Administration, Topical; Adolescent; Age Factors; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Incidence; Infant; Longitudinal Studies; Male; Neoplasms; Prospective Studies; Registries; Risk Assessment; Risk Factors; Sex Factors; Tacrolimus

Topics: Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Incidence; Neoplasms; Tacrolimus

Researchers have estimated that about 50% of pediatric patients with chronic illness adhere to tacrolimus therapy, a medication responsible for preventing critical side effects in patients undergoing hematopoietic stem cell transplantation (HSCT).. The purpose of this study was to describe patient adherence to tacrolimus by reviewing documentation from the electronic health record and therapeutic drug levels.. This retrospective descriptive study examined 357 clinic visits by 57 patients undergoing HSCT. Direct (tacrolimus levels) and indirect (subjective reporting) measures were evaluated.. The authors found that, in 51% of visits, adherence was not documented. The overall nontherapeutic drug level rate was 60%. Because of the small sample size, nonadherence did not statistically correlate with nontherapeutic levels. The findings highlight the need for adherence awareness, assessment, and documentation in clinical practice.

Topics: Child; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Medication Adherence; Neoplasms; Retrospective Studies; Tacrolimus

Resistance to a drug and the suppression of inflammatory disorders with immunosuppressive drugs might have happened upon exposure to natural compounds during evolution. Streptomycetes are soil bacteria, but they produce therapeutic drugs. They have been reported to be the low-abundant members of mucosal microbiomes with a higher prevalence in nonhumans ingesting soil compared with humans. Their lower abundance in the human microbiome might be the representations of our current hygienic lifestyle. We suggest that the Streptomyces bacteria producing antiproliferative/immunosuppressive compounds (e.g., rapamycin and tacrolimus) contribute to the rapalog resistance of certain mucosal tumours (e.g., colon cancer) and the 'hygiene hypothesis'. If so, the shortage of exposure to these compounds in the current lifestyle might be an underlying reason for the increase of inflammatory diseases, such as inflammatory bowel diseases (IBD). An investigation on adding certain Streptomycetes (e.g., S. hygroscopicus and S. tubercidicus) to the list of probiotics against inflammatory diseases would be an interesting research area in the future.

Topics: Biological Evolution; Drug Resistance; Humans; Hygiene Hypothesis; Immunosuppressive Agents; Neoplasms; Sirolimus; Streptomyces; Tacrolimus

Immunosuppressive therapy plays a major role in the development of post-transplant cancer. In this nested case-control study of kidney transplant recipients (KTRs), we investigated whether the incidence of post-transplant cancer is associated with the level of tacrolimus exposure over time.. We screened the Rabin Medical Center database for adults who received kidney transplants between 2001 and 2014 and developed post-transplant cancer (excluding basal and squamous cell skin cancers). They were matched against KTRs without cancer. All patients received a maintenance immunosuppressive treatment with tacrolimus, mycophenolate mofetil and corticosteroids. The degree of exposure to tacrolimus was estimated as the time-weighted average (tTWA) value of tacrolimus blood levels. The tTWA was calculated as the area under the curve divided by time at 1, 6, and 12 months after transplantation and at time of cancer diagnosis.. Thirty-two cases were matched against 64 controls. tTWA values above 11 ng/mL at 6 and 12 months after transplantation were associated with odds ratio (OR) of 3.1 (95% CI 1.1-9) and 11.7 (95% CI = 1.3-106), respectively, for post-transplant cancer; and with OR of 5.2 (95% CI 1.3-20.5) and 14.1 (95% CI = 1.5-134.3), respectively, for cancer diagnosed more than 3 years after transplantation.. Exposure to a tacrolimus time-weighted average level above 11 ng/mL at 6 or 12 months after kidney transplantation is associated with an increased risk of developing cancer.

Topics: Adult; Aged; Case-Control Studies; Female; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Neoplasms; Odds Ratio; Tacrolimus

De novo malignancies (DNMs) are one of the leading causes of late mortality after liver transplantation (LT). We analyzed 1616 consecutive patients who underwent LT between 1988 and 2006 at our institution. All patients were prospectively observed over a study period of 28 years by our own outpatient clinic. Complete follow-up data were available for 96% of patients, 3% were incomplete, and only 1% were lost to follow-up. The median follow-up of the patients was 14.1 years. Variables with possible prognostic impact on the development of DNMs were analyzed, as was the incidence of malignancies compared with the nontransplant population by using standardized incidence ratios. In total, 266 (16.5%) patients developed 322 DNMs of the following subgroups: hematological malignancies (n = 49), skin cancer (n = 83), and nonskin solid organ tumors (SOT; n = 190). The probability of developing any DNM within 10 and 25 years was 12.9% and 23.0%, respectively. The respective probability of developing SOT was 7.8% and 16.2%. Mean age at time of diagnosis of SOT was 57.4 years (range, 18.3-81.1 years). In the multivariate analysis, an increased recipient age (hazard ratio [HR], 1.03; P < 0.001) and a history of smoking (HR, 1.92; P < 0.001) were significantly associated with development of SOT. Moreover, the development of SOT was significantly increased in cyclosporine A-treated compared with tacrolimus-treated patients (HR, 1.53; P = 0.03). The present analysis shows a disproportionate increase of de novo SOT with an increasing follow-up period. Increased age and a history of smoking are confirmed as major risk factors. Moreover, the importance of immunosuppression is highlighted. Liver Transplantation 23 1404-1414 2017 AASLD.

Topics: Adult; Age Factors; Aged; Cyclosporine; End Stage Liver Disease; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Liver Transplantation; Male; Middle Aged; Neoplasms; Prognosis; Proportional Hazards Models; Prospective Studies; Risk Factors; Smoking; Tacrolimus; Young Adult

BACKGROUND Lung transplant (LTx) recipients suffer from high rates of malignancy. Exposure to immunosuppressive medication such as tacrolimus has been proposed as a risk factor for tumorigenesis. We hypothesized that chronically high levels of tacrolimus would be associated with risk of malignancy. MATERIAL AND METHODS The study was performed in a transplant center in Israel, with a nested case-control design. Cases were LTx recipients who were diagnosed with any solid or hematological malignancy except non-melanoma skin cancer. Controls were tumor-free during their entire follow-up after LTx and had at least the same follow-up time as their matched case. Controls were matched to cases by age and type of transplant received (single/double). Tacrolimus levels were extracted and analyzed for median drug level and also integrated over time (area under the curve - AUC-tacrolimus). RESULTS We reviewed 412 LTx recipients in our registry. Thirty-nine cases of malignancy were diagnosed and 160 controls were matched, giving a crude tumor incidence rate of 26/100 000/year. Lung cancers were the commonest diagnosis. Cases and controls were well matched by age, smoking status, and LTx type. Median tacrolimus levels were 11.0 ng/ml and 11.3 ng/ml in cases and controls, respectively (p=0.88). The median log (AUC-tacrolimus) was 9.4 in the cases and 9.5 in the controls (p=0.59). CONCLUSIONS In this nested case-control study, exposure to tacrolimus was similar in tumor cases and non-tumor controls. These data, based on a cohort with modest size, suggest either that tumorigenesis in LTx recipients is unrelated to tacrolimus exposure or that levels in these patients are above an unknown threshold at which the dose-response effect is saturated.

Topics: Case-Control Studies; Female; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Neoplasms; Registries; Retrospective Studies; Risk Factors; Tacrolimus; Transplant Recipients

Topics: Absorption, Physiological; Administration, Topical; Humans; Immunosuppressive Agents; Lichen Planus; Lichen Planus, Oral; Neoplasms; Tacrolimus

GVHD and graft failure are serious problems in CBT. PES after CBT also occurs frequently and is associated with transplantation-related complications such as acute GVHD. We reviewed medical records for 70 consecutive child CBT recipients between December 1997 and April 2015. Forty-nine patients received prophylaxis against GVHD with CsA or Tac in combination with mPSL from day +7 (mPSL group), and 21 patients received CsA or Tac with MTX on day +1 and day +3 (MTX group). Neutrophil engraftment was detected in 59 patients (84.3%). Neutrophil engraftment rate in the MTX group was significantly higher than that in the mPSL group (21/21 (100%) and 38/49 (77.6%), respectively, p = 0.027). PES developed in 35 patients, and the incidence of PES in the mPSL group was significantly higher than that in the MTX group (p = 0.036). The incidence of severe acute GVHD (grade III or IV) in the MTX group was significantly lower than that in the mPSL group (p = 0.049). Although this study was a small-scale study, the results showed that increase in the rate of engraftment and decrease in the incidence of early immune reactions such as PES and severe acute GVHD could be achieved by early commencement of immunosuppression using MTX.

Topics: Adolescent; Child; Child, Preschool; Cord Blood Stem Cell Transplantation; Cyclosporine; Disease-Free Survival; Female; Graft Survival; Graft vs Host Disease; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Infant; Infant, Newborn; Male; Methotrexate; Neoplasms; Neutrophils; Retrospective Studies; Tacrolimus; Time Factors; Transplantation Conditioning; Treatment Outcome

Background Solid organ transplant recipients are at increased risk of developing malignancies. The objective of this prospective, observational, one-armed study was to study the feasibility to add a mammalian target of rapamycin (mTOR) inhibitor to the immunosuppressive regimen in transplanted patients with post-transplant malignancies. During the trial the need to improve identification of post-transplant malignancies and to reassure adequate oncological treatment of these patients became evident. Multidisciplinary team (MDT) evaluation of oncological and immunosuppressive treatments was implemented for all patients with malignancies after renal or combined renal and pancreas transplantation because of the trial. Material and methods At Uppsala University Hospital, Sweden, a MDT consisting of transplant surgeons, nephrologists, oncologists and dermatologists evaluated 120 renal or combined renal and pancreas-transplanted recipients diagnosed with malignancies from September 2006 to July 2012. To identify all malignancies, the population was linked to the Regional Tumor Registry (RTR). We recorded to which extent a switch to mTOR inhibitors was possible and how often the originally planned oncological managements were adjusted. All patients were followed for three years. (ClinicalTrials.gov: NCT02241564). Results In 76 of 120 patients (63%) a switch to mTOR inhibitors was possible. Immunosuppression was interrupted in seven patients (6%), reduced in three patients (2%) and remained unchanged in 34 of 120 patients (28%). Identification of post-transplant malignancies increased significantly after linkage to RTR (p = 0.015). The initially recommended oncological treatment was adjusted in 23 of 44 patients (52%) with solid or hematological malignancies; 36 of these patients (82%) were treated according to national guidelines. Conclusion In two thirds of the patients the immunosuppressive treatment could be changed to an mTOR inhibitor with anti-tumor effects in transplanted patients with post-transplant malignancies. The use of regional tumor registers considerably improved the identification of patients with post-transplant malignancies indicating that post-transplant malignancies might be timely underreported in transplant registers.

Topics: Antineoplastic Agents; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Neoplasms; Prospective Studies; Tacrolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Pharmacokinetics is the link between genetic data and the use of treatments. It can be use on several relevant aspects in the clinic, including the treatment selection, efficacy or toxicity prediction and the choice of the dose. Pharmacogenetics has been applied in clinical nephrology since a long time by the genetic prediction of azathiorpine associated myelotoxicity. However, despite an extensive literature describing the links between genetics and metabolism and transport of drugs, genetic tests are little used in clinical practice. One reason for this poor implementation is the current lack of evidence of improved clinical outcomes with pharmacogenetic tests. In addition, with an effective therapeutic drug monitoring, it is possible to correct the effect of genotype on the pharmacokinetic differences, thus reducing the usefulness of the assay based on the genotype. The future of pharmacogenetics will be treatment models in which patient characteristics are combined with data on polymorphisms in multiple genes including pharmacodynamic parameters, drug transporter proteins, and predictors of toxicity.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Azathioprine; Cyclosporine; Everolimus; Genotype; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Mycophenolic Acid; Neoplasms; Nephrology; Pharmacogenetics; Polymorphism, Genetic; Tacrolimus; Treatment Outcome

Cancer risk associated with topical calcineurin inhibitors (TCIs) remains unclear.. To evaluate the association between TCIs and cancer among patients with atopic and endogenous eczema.. Incident cancers were identified from the National Cancer Registry. Data were analyzed using the Cox proportional hazards model to estimate hazard ratios (HRs) and 95% confidence intervals.. 880 unique cases of cancer developed in 66 176 patients from 2004 to 2012. The adjusted HRs for overall malignancy were 0.82 (95%CI 0.44-1.39) for tacrolimus-exposed and 1.30 (95%CI 0.59-2.45) for pimecrolimus-exposed. The only significant cancer association observed was lymphoid leukemia among the tacrolimus-exposed: HR 7.58 (95%CI 1.64-25.8). All affected patients had young-onset B-cell leukemia. Subgroup analysis of pediatric patients (≤16 years) showed significant association between tacrolimus use and B-cell leukemia: HR 26.4 (95%CI 4.77-146).. In this first Asian study on the risk of TCIs and malignancies, we do not find an association between use of tacrolimus and pimecrolimus in atopic and endogenous eczema and the overall development of malignancies. However, the use of topical tacrolimus was found to be associated with the development of B-cell acute lymphoid leukemia in pediatric eczema patients; further studies are required to investigate if a true association indeed occurs.

Topics: Administration, Topical; Asian People; Calcineurin Inhibitors; Child; Cohort Studies; Eczema; Female; Humans; Immunosuppressive Agents; Male; Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk; Tacrolimus

The aim of this study was to evaluate the association between cancer occurrence and risk of graft failure in kidney transplant recipients. From November 1998 to November 2013, 672 adult patients received their first kidney transplant from a deceased donor and had a minimum follow-up of 6 months. During a median follow-up of 4.7 years (3523 patient-years), 47 patients developed a nonmelanoma skin cancer (NMSC) and 40 a noncutaneous malignancy (NCM). A total of 59 graft failures were observed. The failure rate was 6 per 100 patient-year (pt-yr) after NCM versus 1.5 per 100 pt-yr in patients without NCM. In a time-dependent multivariable model, the occurrence of NCM appeared to be associated with failure (HR = 3.27; 95% CI = 1.44-7.44). The effect of NCM on the cause-specific graft failure was different (P = 0.002) when considering events due to chronic rejection (HR = 0.55) versus other causes (HR = 15.59). The reduction of the immunosuppression after NCM was not associated with a greater risk of graft failure. In conclusion, our data suggest that post-transplant NCM may be a strong risk factor for graft failure, particularly for causes other than chronic rejection.

Topics: Adult; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Neoplasms; Prospective Studies; Retrospective Studies; Risk; Tacrolimus; Time Factors

Increased rates of solid organ cancers post-liver transplantation have been reported, but the contribution of environmental factors and immunosuppressive therapy is not clear. This study's aims were to compare the incidence of de novo solid organ cancers after liver transplantation; identify risk factors independent of immunosuppressive therapy associated with these cancers; and assess the influence of calcineurin inhibitors on the appearance of these cancers.. This single-centre study from 1991 to 2008 included 465 liver recipients who had survived for ≥1 year. Gross incidence rates were standardized by age and sex, using the global population as a reference. In addition, 322 of the 465 patients treated for ≥1 year with calcineurin inhibitors were studied.. Sixty-five (13.9%) of the 465 patients developed de novo solid cancers. The overall relative risk was 3.7. Significantly increased relative risks were observed for digestive, oesophageal, colorectal, oral and lung cancers, but not for genito-urinary and breast cancers. Among the 65 patients who developed solid organ cancers, 43 died (66.1%), 41 from cancer. The two independent risk factors were pretransplant smoking [P < 0.0001; odds ratio = 5.5 (.5; 12)] and obesity [P = 0.0184; odds ratio = 2.2 (1.1; 4.3)]. Of the 322 patients on calcineurin inhibitors, 55 (17%) developed de novo solid cancers. Tacrolimus exposure level was a risk factor for de novo solid cancers [P < 0.0001; OR = 15.3 (4.5; 52.2)].. We recommend a change in immunosuppressive protocols with lifestyle/dietary guidelines and smoking cessation.

Topics: Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Female; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Male; Middle Aged; Multivariate Analysis; Neoplasms; Obesity; Risk Factors; Smoking; Tacrolimus; Transplant Recipients

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

A black box warning describes a potential risk of malignancy associated with topical use of pimecrolimus to treat atopic dermatitis due to its similarity to oral calcineurin inhibitors used in solid-organ transplantation and spontaneous reporting of malignancies, including lymphomas and cutaneous malignancies.. To evaluate the risk of malignancy in a postmarketing study of children exposed to pimecrolimus.. A longitudinal cohort study among a nationwide ongoing long-term cohort of children enrolled in the Pediatric Eczema Elective Registry (PEER) who had a history of atopic dermatitis and pimecrolimus use with data available up through May 2014.. Reports of malignancy among those in the PEER compared with expected rates from the Surveillance, Epidemiology, and End Results (SEER) program.. Overall, 7457 children were enrolled in the PEER, for a total of 26,792 person-years. Children used a mean (SD) of 793 (1356) g of pimecrolimus when enrolled in the study. As of May 2014, five malignancies had been reported. These include 2 leukemias, 1 osteosarcoma, and 2 lymphomas. No skin cancers were reported. The standardized incidence ratio for all malignancies (primary outcome) based on the age-standardized SEER population was 1.2 (95% CI, 0.5-2.8). As secondary analyses, the standardized incidence ratios (based on 2 cases for each) were 2.9 (95% CI, 0.7-11.7) for lymphoma and 2.0 (95% CI, 0.5-8.2) for leukemia. None of these findings were statistically significant.. Based on more than 25,000 person-years of follow-up, it seems unlikely that topical pimecrolimus as it was used in the PEER cohort to treat atopic dermatitis is associated with an increased risk of malignancy.

Topics: Administration, Cutaneous; Adolescent; Child; Child, Preschool; Cohort Studies; Dermatitis, Atopic; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Longitudinal Studies; Male; Neoplasms; Registries; Risk; SEER Program; Tacrolimus

Topics: Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Neoplasms; Tacrolimus

Full-dose sirolimus (SRL) therapy without a calcineurin inhibitor (CNI) reduces the incidence of malignancy after renal transplantation, but with significant side effects. We hypothesized that de novo therapy with low-dose SRL combined with a CNI could still prevent cancer in renal transplant recipients.. A retrospective case-control study was performed to assess the cancer incidence among renal transplant patients who had undergone surgery in our transplant centers between January 2000 and June 2012. Patients who received low-dose SRL and a CNI (SRL group, n = 189) were compared with patients receiving conventional CNI-based therapy in the same hospitals (Conventional group, n = 271).. The 5-year graft and patient survival rates were comparable between the two groups. Seven patients in the SRL group and 24 patients in the Conventional group developed malignancies during mean follow-up periods of 68.2 ± 37.5 months and 81.7 ± 51.4 months, respectively. The cancer incidence at 5 years was significantly lower in the SRL group (1.9%), than that in the Conventional group (6.7%; p = 0.04). By multivariate analyses, SRL therapy (p = 0.04), male sex (p = 0.04), and younger age (p = 0.01) were significantly associated with a lower risk of malignancy after kidney transplantation.. De novo therapy with low-dose SRL combined with a CNI was associated with reduced risk of post-transplant cancer in renal transplant recipients. De novo cancer prevention using a low-dose proliferation signal inhibitor such as SRL could be effective for renal transplant recipients.

Topics: Adult; Calcineurin Inhibitors; Case-Control Studies; Cyclosporine; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Neoplasms; Postoperative Complications; Proportional Hazards Models; Retrospective Studies; Risk Factors; Sirolimus; Survival Rate; Tacrolimus; Taiwan; Treatment Outcome

With this study we aimed to research the effects of immunosuppressive drugs, their cumulative doses, and viral infections on development of malign tumors in patients who have undergone treatment for 5 years.. We examined 100 patients who underwent renal transplantation from 2004 to 2009. Patients had mycophenolate mofetil and steroid in addition to cyclosporine, sirolimus, or tacrolimus as immunosuppressive treatment. For malignancy screening, physical examination, radiologic and endoscopic screening were done, and immunosuppressive drugs and their cumulative doses, age, sex, body mass index (BMI), dialysis history, and viral infection history were investigated.. The mean age of patients was 42.03 ± 11.30 years. There were 1 colon cancer patient, 1 retroperitoneal liposarcoma, 1 renal oncocytoma, 3 Kaposi sarcoma patients treated with cyclosporine; in those treated with Tac there were 1 basal cell carcinoma, 1 Kaposi sarcoma, 2 thyroid carcinoma, 1 breast carcinoma, 1 bladder carcinoma, 1 renal cell carcinoma, and 1 colon carcinoma patients. The mean age of patients having carcinoma was statistically significant compared with those without cancer (P < .01). The prednisolone cumulative dose was significantly higher in carcinoma patients than in patients without carcinoma (P < .01).. The use of long-term chronic immunosuppressive therapy may increase the development of cancer. The risk of carcinoma increases with increasing drug dose and time period of the immunosuppressive drug. There was not a negative effect on cancer prevalence in patients with cyclosporine or tacrolimus. But the cumulative dose of steroids significantly increased malignancy occurence.

Topics: Adult; Breast Neoplasms; Carcinoma; Colonic Neoplasms; Cyclosporine; Early Detection of Cancer; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Retroperitoneal Neoplasms; Sarcoma, Kaposi; Sirolimus; Steroids; Tacrolimus; Thyroid Neoplasms; Time Factors; Urologic Neoplasms

Using Taiwan's National Health Insurance Research Database, this large population-based study was conducted to explore the incidences and risk factors of post-transplant malignancy in Asian renal transplant recipients.. A total of 642 patients who firstly underwent renal transplant between January 1, 2000 and December 31, 2008 were identified from a 2 million cohort. The primary endpoint was a subsequent hospitalization with a primary diagnosis of malignancy (ICD-9-CM code: 140.xx-239.xx) after renal transplantation. All patients were followed until the occurrence of endpoints or the end of the study (December 31, 2010), whichever came first. Adjusted risks of post-transplant cancer were analyzed using Cox proportional hazards regression model. All models were adjusted for baseline characteristics, comorbid diseases, transplant year, and exposure to immunosuppressive agents.. Among 642 renal transplant patients, 54 cancers (8.4 %) were identified. The median time between transplant and cancer diagnosis was 46.2 (range 8.5-107.4) months. Cancers of kidney and other unspecified urinary organs was the most common cancer sites, accounted for 18.5 % of the malignancies diagnosed. The next most common cancer sites were trachea, bronchus, and lung (14.8 %), bladder (13.0 %), liver and intrahepatic bile ducts (11.1 %), colon (5.6 %), and prostate (5.6 %). Age at transplantation was a statistically significant risk factor of post-transplant cancer in our study. Increased risks of post-transplant cancer were observed in patients who received immunosuppression agents (cyclosporine (HR 1.26, 95 % CI 0.58-2.77, p = 0.5603), tacrolimus (HR 1.99, 95 % CI 0.66-6.00, p = 0.2197), and mycophenolate (HR 1.00, 95 % CI 0.40-2.45, p = 0.9874)) although the estimates were not statistically significant.. Our population-based cohort study offers additional insight into post-transplant cancers in Asian population. Further studies are warranted to assess the association between specific immunosuppression agents and post-transplant cancers.

Topics: Adult; Age Factors; Aged; Asian People; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Risk Factors; Tacrolimus; Taiwan; Time Factors

De novo malignancies are a major cause of late death after liver transplantation. Aim of the present study was to determine whether use of cyclosporine versus tacrolimus affects long-term tumor incidence considering potential confounders. De novo malignancies in 609 liver transplant recipients at Munich Transplant Centre between 1985 and 2007 were registered. In 1996, the standard immunosuppressive regimen was changed from cyclosporine to tacrolimus. Different effects of those drugs on long-term tumor incidence were analyzed in multivariate analysis. During 3765 patient years of follow-up (median 4.78 years), 87 de novo malignancies occurred in 71 patients (mean age 47.5 ± 13.3 years, mean time after liver transplantation 5.7 ± 3.7 years). The cumulative incidence of de novo malignancies was 34.7% for all tumor entities after 15 years as compared to 8.9% for a nontransplanted population. The most frequent tumors observed were nonmelanoma skin cancers (44.83%). Moreover, post-transplant lymphoid disease, oropharyngeal cancer (n = 6, 6.9%), upper gastrointestinal tract cancer (n = 4, 4.6%), lung cancer (n = 4, 4.6%), gynecological malignancies (n = 4, 4.6%), and kidney cancer (n = 3, 3.45%) were detected. Multivariate analysis revealed recipient age [hazards ratio (HR) 1.06], male gender (HR 1.73), and tacrolimus-based immunosuppression (HR 2.06) as significant risk factors. Based on those results, a tacrolimus-based immunosuppression should be discussed especially in older male patients. Whether reducing tacrolimus target levels may reduce the risk for de novo malignancies has yet to be determined in prospective trials.

Topics: Adult; Cyclosporine; Female; Follow-Up Studies; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Liver Failure; Liver Transplantation; Male; Middle Aged; Multivariate Analysis; Neoplasms; Proportional Hazards Models; Risk Factors; Sex Factors; Tacrolimus; Treatment Outcome

Hemophagocytic lymphohistiocytosis (HLH) is associated with hypercytokinemia in children. Although HLH can be also observed after hematopoietic stem cell transplantation (HSCT), the incidence and clinical features of HLH after HSCT remain obscure.. The clinical features of HLH after HSCT (post-HSCT HLH) were investigated in children with malignancies, immune deficiencies, or aplastic anemia. The HLH/Langerhans Cell Histiocytosis (LCH) Committee of the Japanese Society of Pediatric Hematology (JSPH) sent questionnaires to hospitals with JPSH members asking for details of cases in which HLH occurred after HSCT between 1998 and 2008.. Among 42 children who were diagnosed with post-HSCT HLH between 1998 and 2008 in Japan, 37 fulfilled our inclusion criteria; of these, 26 were classified as early-onset (onset <30 days after HSCT) and 11 were classified as late-onset (onset >30 days after HSCT). In the early-onset group, the presence of respiratory symptoms, high levels of total bilirubin, and triglycerides at onset and the lack of control of GVHD with tacrolimus were significantly associated with non-resolution of HLH (P < 0.05). The survival rate was significantly higher in patients with resolution of HLH than in those without resolution (59% vs. 14%, P < 0.05).. These findings suggest that early-onset post-HSCT HLH is a specific entity of HLH, and appropriate diagnosis and prompt management need to be established.

Topics: Anemia, Aplastic; Bilirubin; Child; Child, Preschool; Common Variable Immunodeficiency; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Japan; Lymphohistiocytosis, Hemophagocytic; Male; Neoplasms; Surveys and Questionnaires; Survival Rate; Tacrolimus; Transplantation, Homologous; Triglycerides

This retrospective single-center study evaluated long-term renal function after conversion from calcineurin inhibitors to sirolimus-based immunosuppression in kidney transplant recipients.. From 2001 to 2009, one hundred fifty kidney transplant recipients were converted from calcineurin inhibitors to sirolimus at least 3 months after transplant.. After a mean follow-up of 171 weeks, 56.7% of converted patients remained on sirolimus. The 5-year survival rate of the patients (including intent-to-treat) and grafts was 85.5% and 83.6%. Patients on sirolimus showed significant improvement in renal function with a creatinine clearance of 50.9 ± 20.7 and 52.9 ± 20.8 mL/minute at month 0 and month 24. Independent predictive factors associated with a stable estimated glomerular filtration rate at the last follow-up of sirolimus patients were (1) having a living donor, (2) absence of anti-HLA alloantibodies at month 0, and (3) cyclosporine versus tacrolimus used before conversion. Adverse effects were reported in 134 patients (89.3%). They included (1) hospitalization for infection (n=52), (2) de novo proteinuria (n=40), and (3) eight patients with biopsy-proven acute rejection. Sirolimus was stopped and replaced by calcineurin inhibitors in 37 patients after a mean of 16 months treatment. After stopping sirolimus, renal-allograft function remained stable at 2 years.. Conversion of calcineurin inhibitors to sirolimus in kidney transplant recipients was associated with improved renal function. The reintroduction of calcineurin inhibitors was safe in patients who were withdrawn from sirolimus owing to adverse effects.

Topics: Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Enzyme Inhibitors; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Neoplasms; Opportunistic Infections; Postoperative Complications; Proteinuria; Retrospective Studies; Sirolimus; Tacrolimus

Topics: Aging; Animals; Apoptosis; Cell Division; Cell Transformation, Neoplastic; Cellular Senescence; Cytokines; Disease Susceptibility; Genes, p16; Genes, Tumor Suppressor; Humans; Mice; Models, Biological; Neoplasms; Oncogenes; Tacrolimus; Tumor Suppressor Protein p14ARF

Although newer immunosuppressive agents, such as mTOR (mammalian target of rapamycin) inhibitors, have lowered the occurrence of malignancies after transplantation, cancer is still a leading cause of death late after heart transplantation. Statins may have an impact on clinical outcomes beyond their lipid-lowering effects. The aim of the present study was to delineate whether statin therapy has an impact on cancer risk and total mortality after heart transplantation.. A total of 255 patients who underwent heart transplantation at the University Hospital Zurich between 1985 and 2007 and survived the first year were included in the present study. The primary outcome measure was the occurrence of any malignancy; the secondary end point was overall survival. During follow-up, a malignancy was diagnosed in 108 patients (42%). The cumulative incidence of tumors 8 years after transplantation was reduced in patients receiving a statin (34% versus 13%; 95% confidence interval, 0.25-0.43 versus 0.07-0.18; P<0.003). Statin use was associated with improved cancer-free and overall survival (both P<0.0001). A Cox regression model that analyzed the time to tumor formation with or without statin therapy, adjusted for age, male sex, type of cardiomyopathy, and immunosuppressive therapy (including switch to mTOR inhibitors or tacrolimus), demonstrated a superior survival in the statin group. Statins reduced the hazard of occurrence of any malignancy by 67% (hazard ratio, 0.33; 95% confidence interval, 0.21-0.51; P<0.0001).. Although it is not possible to adjust for all potential confounders because of the very long follow-up period, this registry suggests that statin use is associated with improved cancer-free and overall survival after cardiac transplantation. These data will need to be confirmed in a prospective trial.

Topics: Adult; Female; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Postoperative Complications; Proportional Hazards Models; Retrospective Studies; Risk Factors; Tacrolimus

New cases have been reported in France and elsewhere. Epidemiological studies show an increased risk of lymphoma.

Topics: Administration, Cutaneous; Eczema; Humans; Immunosuppressive Agents; Neoplasms; Risk Assessment; Risk Factors; Tacrolimus

The goal of this study was to determine the risk factors for de novo cancer after liver transplantation (LTx). Retrospective analyses were performed in 385 LTx patients who underwent transplantation between 1986 and 2007. In total, 50 (13.0%) recipients developed de novo malignancy. The cumulative incidence of de novo cancer at 1, 5, 10, and 15 years after LTx was 2.9% +/- 0.9%, 10.5% +/- 1.8%, 19.4% +/- 3.0%, and 33.6% +/- 6.8%, respectively. The standardized incidence ratio of malignancy in LTx patients compared to the general population was 2.2 (95% confidence interval: 1.6-2.8). After excluding posttransplant lymphoproliferative disorder and skin cancer, patients with de novo cancer had a significantly lower survival rate compared to recipients who remained cancer-free. The identified univariate risk factors for de novo cancer were cyclosporine A (CsA) treatment, time period of LTx, and recipient age. In multivariate analysis, only CsA treatment emerged as an independent risk factor for de novo cancer, which was attributed to more aggressive cancer types. A surprising finding was that CsA treatment specifically enhanced cancer risk in patients who underwent transplantation after 2004, when C(2) monitoring (blood concentration at 2 hours postdose) was introduced. In addition, these patients showed a significantly lower acute rejection rate, which might reflect a more robust immunosuppressive status caused by the CsA-C(2) regimen. When age was considered, only patients < or =50 years had a higher cancer rate when treated with CsA compared to treatment with tacrolimus. Our data suggest that, compared to tacrolimus treatment, CsA treatment with C(2) monitoring or in younger patients of < or =50 years is associated with a higher early de novo cancer risk after LTx.

Topics: Adolescent; Adult; Age Factors; Aged; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Liver Transplantation; Male; Middle Aged; Monitoring, Immunologic; Monitoring, Physiologic; Neoplasms; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus; Young Adult

The risk of malignancies in renal transplant recipients is considerably greater than in the general population. The purpose of the present study was to investigate the effects on the appearance of malignancies of 3 immunosuppressive periods: azathioprine (AZA), cyclosporine (CsA), and tacrolimus (TAC).. This study included 1029 first renal transplant recipients of mean age at transplantation of 44.6±14.9 years with a mean follow-up of 95.6±84.2 months. Initial immunosuppression was AZA-based (n=198), CsA-based (n=524), and TAC (n=307). A total of 280 recipients were also treated with mycophenolate mofetil or mycophenolic acid.. There were 157 patients (15.3%) who displayed≥1 malignancy; there were 95 skin (9.2%) and 74 (7.8%) non-skin malignancies with presentations at 74±62 and 107±77 months, respectively (P=.003). The skin malignancies included squamous cell carcinomas (n=41), basal cell carcinomas (n=41), Kaposi sarcomas (n=7), and melanomas (n=4). Among the solid tumors, lymphoproliferative disorders (n=15), digestive tract (n=14), kidney and urinary tract (n=11), lung (n=10), and breast (n=3) carcinomas. The cumulative incidences at 5, 10, and 15 years were 6%, 10%, and 18% for skin and 3%, 7%, and 14% for non-skin malignancies, respectively. Multivariate analysis showed that age at transplant in years (P=.000) and male gender (P=.000) were the only variables associated with skin malignancies; age at transplant in years (P=.004) and treatment with OKT3 (P=.000) were associated with non-skin malignancies. Malignancies were the cause of death in 18% of recipients who died with functioning grafts.. Malignancies are an important cause of morbidity and mortality among renal transplant recipients. The new immunosuppressive agents do not increase the risk of malignancies. Special surveillance is needed for older, male recipients.

Topics: Adult; Azathioprine; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Neoplasms; Tacrolimus

Topics: Administration, Cutaneous; Humans; Immunosuppressive Agents; Neoplasms; Skin Diseases, Infectious; Tacrolimus

The best induction agent for simultaneous pancreas-kidney transplantation (SPKT) remains the subject of debate. Alemtuzumab is effective in preventing acute cellular rejection (ACR) in SPK recipients and has been used to prevent antibody-mediated rejection (AMR) in sensitized kidney transplant candidates.. A retrospective cohort study was performed including 136 SPK recipients receiving maintenance immunosuppression with tacrolimus, mycophenolic acid prodrugs, and prednisone. Two groups were compared: those who received induction with alemtuzumab (n=97) and those induced with basiliximab (n=39).. Kidney ACR was more frequent in SPKT induced with basiliximab (2-year 12.8% vs. 3.1%, P=0.04), but the incidence of AMR was similar (2-year 18% with basiliximab vs. 13.8% with alemtuzumab, P=NS). Kidney rejection was associated with clinical pancreas rejection in 70% of cases, without differences between the groups. Postrejection kidney graft survival was similar in both groups (2-year basiliximab/alemtuzumab 94.7%/91.2%), but death-censored kidney graft survival was lower with alemtuzumab (100%/91.2%, P=0.056). In the basiliximab group, the predominant cause of kidney loss was death-with-function, whereas in the alemtuzumab group AMR accounted for all losses. Pancreas graft survival was similar in both groups, yet more pancreas losses due to acute rejection occurred in alemtuzumab-treated patients (4 vs. 1).. Kidney AMR is more common than ACR in SPKT recipients treated with alemtuzumab, tacrolimus, mycophenolic acid, and steroids. ACR is better prevented by alemtuzumab than basiliximab, but no relevant difference is found in prevention of AMR. Despite the high incidence of AMR, survival rates are excellent in both groups.

Topics: Acute Disease; Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Neoplasms; Pancreas Transplantation; Survival Rate; Tacrolimus

Topics: Administration, Topical; Contraindications; Dermatitis, Atopic; France; Humans; Neoplasms; Tacrolimus

The underlying mechanism regulating the expression of the cancer stem cell/tumor-initiating cell marker CD133/prominin-1 in cancer cells remains largely unclear, although knowledge of this mechanism would likely provide important biological information regarding cancer stem cells. Here, we found that the inhibition of mTOR signaling up-regulated CD133 expression at both the mRNA and protein levels in a CD133-overexpressing cancer cell line. This effect was canceled by a rapamycin-competitor, tacrolimus, and was not modified by conventional cytotoxic drugs. We hypothesized that hypoxia-inducible factor-1 alpha (HIF-1 alpha), a downstream molecule in the mTOR signaling pathway, might regulate CD133 expression; we therefore investigated the relation between CD133 and HIF-1 alpha. Hypoxic conditions up-regulated HIF-1 alpha expression and inversely down-regulated CD133 expression at both the mRNA and protein levels. Similarly, the HIF-1 alpha activator deferoxamine mesylate dose-dependently down-regulated CD133 expression, consistent with the effects of hypoxic conditions. Finally, the correlations between CD133 and the expressions of HIF-1 alpha and HIF-1 beta were examined using clinical gastric cancer samples. A strong inverse correlation (r = -0.68) was observed between CD133 and HIF-1 alpha, but not between CD133 and HIF-1 beta. In conclusion, these results indicate that HIF-1 alpha down-regulates CD133 expression and suggest that mTOR signaling is involved in the expression of CD133 in cancer cells. Our findings provide a novel insight into the regulatory mechanisms of CD133 expression via mTOR signaling and HIF-1 alpha in cancer cells and might lead to insights into the involvement of the mTOR signal and oxygen-sensitive intracellular pathways in the maintenance of stemness in cancer stem cells.

Topics: AC133 Antigen; Antigens, CD; Cell Line, Tumor; Chromones; Colorectal Neoplasms; Down-Regulation; Glycoproteins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Neoplasms; Morpholines; Neoplasms; Peptides; Protein Kinases; RNA, Messenger; Signal Transduction; Sirolimus; Stomach Neoplasms; Tacrolimus; TOR Serine-Threonine Kinases; Transcription, Genetic; Up-Regulation

Malignancy is a dreaded complication following organ transplantation. Immunosuppressive therapy-induced impairment of the host immune system is the prevailing hypothesis for the high incidence and aggressive progression of post-transplant neoplasm. We summarize our observations supporting an autonomous cellular mechanism for cyclosporine and tacrolimus associated metastases. Cyclosporine conferred tumor invasiveness by a direct effect on the tumor cells and promoted metastases in T-, B-, and NK cell deficient SCID- beige mice, and anti-TGF-beta antibodies reduced metastases. Tacrolimus, another calcineurin inhibitor widely used in transplantation, induced TGF-beta secretion by tumor cells and promoted metastases in the SCID- beige mice. The immunosuppressive macrolide rapamycin reversed an invasive phenotype to a non-invasive one, reduced circulating levels of TGF-beta1 and prevented tumor growth and metastases in the immocompetant BALB/c mice and in the SCID-beige mice. Our studies, in addition to demonstrating a cell autonomous mechanism for tumor progression, advance TGF-beta blockade as an anti-tumor strategy.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cell Line, Tumor; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Neoplasms; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Mice, SCID; Neoplasm Invasiveness; Neoplasms; Organ Transplantation; Phenotype; Sirolimus; Tacrolimus

Sirolimus, a macrolide with immunosuppressive properties, was introduced into clinical practice a decade ago. The optimal use of this drug remains controversial: It displays a wide range of organ and tissue toxicities owing to the critical role of its therapeutic site- the kinase mammalian target of rapamycin-in the signal transduction pathways of numerous cytokines, growth factors, hormones, and nutrients. However, it displays unique, recognized benefits for renal transplant recipients: synergistic interactions with cyclosporine and possibly tacrolimus, allowing marked reduction in exposure to the calcineurin inhibitor; reduction in the frequency of posttransplant malignancies, particularly lymphomas, Kaposi sarcomas, and hypernephromas; and modest nephrotoxicity in comparison with calcineurin inhibitors. Because of its inhibitory effects on endothelial and smooth muscle cell proliferation, sirolimus may be a useful tool to dampen chronic vasculo-obliterative processes that attenuate graft survival. With increasing experience with the drug, the true potential of sirolimus will be realized to be a critical element in the immunosuppressive matrix.

Topics: Calcineurin Inhibitors; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Kidney Transplantation; Neoplasms; Postoperative Complications; Sirolimus; Tacrolimus

The Food and Drug Administration has issued a public health advisory regarding cancer risk from topical calcineurin inhibitors.. To compare the rates of cancer among patients with common dermatologic conditions who were exposed or not exposed to topical calcineurin inhibitors.. A retrospective cohort observational study used data from an integrated healthcare delivery system on 953,064 subjects with diagnoses of atopic dermatitis or eczema between 2001 and December 2004. The main endpoint was initial cancer diagnosis. Chart review was performed to confirm cancer diagnosis in the subjects exposed to topical calcineurin inhibitors when any particular cancer rate was at least 3 times higher than that in unexposed subjects. Data were analyzed using the Cox proportional hazards model.. Age- and sex-adjusted hazard ratios for all cancers were 0.93 (95% CI 0.81 to 1.07; p = 0.306) for tacrolimus-exposed versus -unexposed subjects and 1.15 (95% CI 0.99 to 1.31; p = 0.054) for pimecrolimus-exposed versus -unexposed subjects. T-cell lymphoma was the only cancer associated with a significantly increased risk among subjects exposed to tacrolimus (HR = 5.04, 95% CI 2.39 to 10.63; p < 0.001) or pimecrolimus (HR = 3.76, 95% CI 1.71 to 8.28; p = 0.010). Subsequent chart review of subjects in the exposed group with T-cell lymphoma found that 4 of 16 had skin lesions that were suspected to be the early lesions of T-cell lymphoma prior to exposure to tacrolimus or pimecrolimus. After these 4 cases were excluded, the age and sex hazard ratio for T-cell lymphoma was 5.44 (95% CI 2.51 to 11.79; p < 0.001) for tacrolimus and 2.32 (95% CI 0.89 to 6.07; p = 0.086) for pimecrolimus. There was no statistically significantly increased risk for other subgroups of cancer, including melanoma.. Exposure to topical tacrolimus or pimecrolimus was not associated with an increase in the overall cancer rate. Use of topical tacrolimus may be associated with an increased risk of T-cell lymphoma.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Calcineurin Inhibitors; Child; Child, Preschool; Cohort Studies; Dermatitis, Atopic; Eczema; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Infant; Lymphoma, T-Cell; Male; Middle Aged; Neoplasms; Proportional Hazards Models; Retrospective Studies; Risk; Tacrolimus; Young Adult

Antiangiogenic therapies have shown varying results partly because each tumor type secretes a distinct panel of angiogenic factors to sustain its own microvascular network. In addition, recent evidence demonstrated that tumors develop resistance to antiangiogenic therapy by turning on alternate angiogenic pathways when one pathway is therapeutically inhibited. Here, we test the hypothesis that expression of a caspase-based artificial death switch in tumor-associated endothelial cells will disrupt tumor blood vessels and slow down tumor progression irrespective of tumor type. Adenoviral vectors expressing inducible Caspase-9 (iCaspase-9) under transcriptional regulation with the endothelial cell-specific vascular endothelial growth factor receptor-2 (VEGFR2) promoter (Ad-hVEGFR2-iCaspase-9) induced apoptosis of proliferating human dermal microvascular endothelial cells (HDMECs), but not human tumor cells (UM-SCC-17B, head and neck squamous cell carcinoma; HepG2, hepatocellular carcinoma; PC-3, prostate adenocarcinoma; SLK, Kaposi's sarcoma; MCF-7, breast adenocarcinoma). Notably, apoptosis was dependent upon activation of iCaspase-9 with the dimerizer drug AP20187. Local delivery of Ad-hVEGFR2-iCaspase-9 followed by intraperitoneal injection of AP20187 ablated tumor microvessels and inhibited xenografted tumor growth in all tumor models evaluated here. We conclude that a cancer gene therapy strategy based on a transcriptionally targeted viral vector expressing an inducible caspase allows for selective and controlled ablation of microvessels of histopathologically diverse tumor types.

Topics: Adenoviridae; Animals; Apoptosis; Caspase 9; Cell Line; Cell Line, Tumor; Endothelial Cells; Flow Cytometry; Genetic Therapy; Genetic Vectors; Humans; Mice; Mice, SCID; Neoplasms; Neovascularization, Pathologic; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; Tacrolimus; Transcription, Genetic; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays

Topics: Angiogenesis Inhibitors; Cyclosporine; Humans; Immunosuppressive Agents; Neoplasms; Organ Transplantation; Sarcoma, Kaposi; Sirolimus; Tacrolimus; United States

Among recipients of renal transplants, the incidences of renal cancer and gastrointestinal cancer are higher and that of skin cancer is much lower in Japan than in Europe and North America.. The risk factors for the development of malignant tumors were examined in Japanese recipients of renal transplants. A total of 556 patients underwent renal transplantation at the Department of Urology, Osaka University Faculty of Medicine between March 1, 1965, and April 31, 2004. Of these patients, 366 were retrospectively studied in whom risk factors potentially related to the development of malignancy could be evaluated on the basis of medical records. The incidence of malignancy, survival rate, and risk factors for malignancy were examined.. The overall incidence of malignancy was 6.8% (25/366 patients). Six of the 25 patients with malignancy died of cancer, but there was no correlation between the occurrence of malignancy and the survival rate (P = .8058, log-rank test). A Cox proportional-hazards model identified treatment with tacrolimus (hazard ratio [HR] = 4.376; 95% confidence interval [CI]: 1.647-11.627; P = .0031) and age at transplantation (HR = 1.562; 95% CI: 1.089-2.240; P = .0155) as risk factors for malignancy.. The results of multivariate analysis suggested that age at transplantation and the use of tacrolimus were independent risk factors for the development of malignancy in recipients of renal transplants.

Topics: Adult; Age Factors; Azathioprine; Cyclosporine; Female; Humans; Immunosuppressive Agents; Japan; Kidney Transplantation; Male; Neoplasms; Risk Factors; Survival Rate; Tacrolimus

With the development of new immunosuppressive agents, the majority of transplant recipients are surviving for over a decade, and malignancy has become a major burden on long-term survival. Reducing the incidence of post-transplant malignancies is especially important in heart transplantation where the risk of malignancies is higher than in other organ transplants. Everolimus and sirolimus, the proliferation signal inhibitors (PSIs) or mammalian target-of-rapamycin (mTOR) inhibitors, now provide new strategies for immunosuppression because of their proven efficacy that translates to a reduction in doses of calcineurin inhibitors needed to prevent acute rejection. In addition, the anti-proliferative effects of this class of drugs raise the possibility that they may be effective for reducing the risk of malignancies after solid-organ transplantation. Despite the paucity of direct clinical evidence for this effect in heart transplant patients, observations from renal transplant recipients suggest that the anti-proliferative actions of PSIs/mTOR inhibitors may also protect against malignancies in heart transplant recipients. This potential for an anti-cancer effect is further supported by the emerging data on the use of PSIs/mTOR inhibitors in non-transplant oncology patients. Reviewed in this article are the incidence rates of malignancies after solid-organ transplantation, and the evidence for anti-cancer effects of PSIs/mTOR inhibitors in renal transplant recipients and in non-transplant patients. Also discussed are the implications of these observational data for future studies on the reduction of malignancies after heart transplantation.

Topics: Azathioprine; Cyclosporine; Enzyme Inhibitors; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Neoplasms; Postoperative Complications; Protein Kinases; Risk; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases

Topics: Administration, Cutaneous; Adult; Adverse Drug Reaction Reporting Systems; Calcineurin Inhibitors; Child; Dermatologic Agents; Drug Approval; Drug Monitoring; Europe; Humans; Immunosuppressive Agents; Marketing; Neoplasms; Product Surveillance, Postmarketing; Risk Assessment; Risk Factors; Science; Tacrolimus; United States

This commentary is designed to provide a clinical viewpoint regarding the Food and Drug Administration (FDA) and its recent decision to imposed a "black box warning" on the topical calcineurin inhibitors, pimecrolimus and tacrolimus.. Select references were used to review the relevant data.. Although there is a theoretic risk of oncogenesis because of the trivial systemic absorption of these agents and there exist anecdotes of cancer occurring amongst the millions of people who have used these agents, human data from randomized controlled trials suggest a protective effect from cancer. Although results from randomized controlled trials provide the highest level of evidence, the FDA chose to warn the public on the basis of weak and likely faulty data. Subsequent to the FDA actions, utilization of the best-studied class of agents for atopic dermatitis has fallen significantly.. These actions represent a "death of common sense" and have profound impact both on our ability to safely and effectively care for patients and our medicolegal risk.

Topics: Administration, Topical; Calcineurin Inhibitors; Contraindications; Drug Labeling; Duty to Warn; Evidence-Based Medicine; Humans; Immunosuppressive Agents; Neoplasms; Randomized Controlled Trials as Topic; Risk; Tacrolimus; United States; United States Food and Drug Administration

Topics: Administration, Topical; Adolescent; Adult; Age Factors; Animals; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; Lymphoma; Mice; Neoplasms; Neoplasms, Experimental; Product Surveillance, Postmarketing; Tacrolimus

Topics: Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Neoplasms; Tacrolimus

Immunosuppression is often incriminated for the increased risk of post-transplant malignancies. To examine whether triple- (MMF+Tacro+CS) versus dual-drug therapy (Tacro+CS) is associated with an increased incidence of malignancy, or death due to malignancy, data from a large registry of liver transplant recipients were analyzed. Data from adult primary liver recipients reported to the Scientific Registry of Transplant Recipients between June 1, 1995, and April 30, 2004, and recorded at transplant on triple-drug (n = 9180) or dual-drug (n = 10 099) therapy were included. Kaplan-Meier survival analysis showed no significant differences in death due to malignancy 4 years post-transplantation between the treatment groups. Multivariable analysis using Cox proportional hazard models confirmed no differences in risk of death due to malignancy between the groups (HR: 0.83, p = 0.107). Incidence of any post-transplant malignancy was also not significantly different. Older recipient age and cause of liver disease were significantly associated with an increased risk of malignancy-related death. These data utilizing relatively short follow-up suggest the addition of MMF to Tacro+CS at transplant is not associated with death due to malignancy, at least in the short term. Individual recipient factors appear to be important risk factors for malignancy-related death; elucidating these risk factors can assist in identifying who should be monitored most aggressively for post-transplant malignancies.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Registries; Risk Factors; Survival Analysis; Tacrolimus

(1) Disturbing reports of cancers linked to topical application of tacrolimus or pimecrolimus have been published. Some involved children. Animal studies had already shown a dose-dependent increase in the incidence of lymphoma in mice and monkeys. (2) In practice, it is better to avoid topical application of these immunosuppressants, which have a negative risk-benefit balance.

Topics: Administration, Topical; Adult; Child; Humans; Immunosuppressive Agents; Neoplasms; Tacrolimus

Malignancies are an important cause of morbidity and mortality among transplant patients. Tumor genesis is the consequence of non-specific immunosuppression that enhanced oncogenic virus replication, but may also be due to direct effects of immunosuppressants. Steroids are believed not to be involved in cancer genesis, in contrast to azathioprine, well known to reduce DNA repair ability, particularly in skin cells exposed to UV irradiation. Calcineurin inhibitors, cyclosporine and tacrolimus, are involved in tumor development through various mechanisms: they promote B-cell proliferation by increasing T lymphocyte IL6 secretion, decrease DNA repair ability and may be able to promote metastasis spreading by a direct cellular effect that is independent of their effect on the host's immune cells. In vitro anti-tumoral properties of mycophenolate mofetil have not been valided in animal models or in human. The last developed immunosuppressant mTOR inhibitors, sirolimus and everolimus, effectively control the proliferation of various tumor cell lines, promote tumor cell apoptosis and inhibit metastatic tumor growth and angiogenesis in in vivo mouse models by affecting VEGF production and effect. If these antitumoral features are confirmed in human, this new immunosuppressive family will offer the unique opportunity to reduce both the incidence of rejection and cancer in organ transplant recipients.

Topics: Azathioprine; Cyclosporine; DNA Repair; Glucocorticoids; Humans; Immunosuppressive Agents; Mycophenolic Acid; Neoplasms; Tacrolimus; Transplantation

Programmed cell death 4 (Pdcd4), originally identified as an inhibitor of murine cellular transformation, inhibits protein synthesis by directly interacting with eukaryotic initiation factor 4A (eIF4A) of the translation initiation complex. The relevance of Pdcd4 to a broad range of human cancers derived from multiple tissue sites is unknown. Protein expression patterns from the National Cancer Institute drug-screening panel of 60 human cancer cells (NCI60) were analyzed by Western blot methods and revealed frequent reduction of Pdcd4 protein levels in renal-, lung-, and glia-derived tumors. Greater than mean Pdcd4 protein levels correlated with the antitumor activity of geldanamycin and tamoxifen. Stable expression of antisense PDCD4 significantly reduced the sensitivity of MCF-7 breast cancer cells to geldanamycin and to tamoxifen. Sensitivity to geldanamycin significantly increased in UO-31 renal cancer cells expressing sense PDCD4 cDNA. Increased geldanamycin sensitivity was accompanied by enhanced cell cycle arrest and apoptosis. One primary mode of inactivation of Pdcd4 in human cancers appears to involve down-regulated expression, and this down-regulation causes a decreased sensitivity to geldanamycin cytotoxicity. Thus, up-regulating Pdcd4 expression may be promising for geldanamycin-based combination therapy.

Topics: Antineoplastic Agents; Apoptosis Regulatory Proteins; Benzoquinones; Cell Division; Cell Line, Tumor; Drug Screening Assays, Antitumor; G2 Phase; Humans; Kidney Neoplasms; Lactams, Macrocyclic; Mitosis; Neoplasms; Prognosis; Quinones; Retinoblastoma Protein; RNA-Binding Proteins; RNA, Messenger; Tacrolimus; Tamoxifen

In a retrospective study we analyzed the incidence and characteristics of de novo tumors developing in renal transplant recipients treated in our center. The 5% incidence de novo tumors developing among patients treated with azathioprine and prednisolone (n = 241) was similar to the 5.4% incidence of de novo tumors developing among patients treated with calcineurin-based immunosuppression (n = 1918). The most common malignancies among our patients were basal cell (21.7%) and squamous cell (13.9%) carcinomas of the skin, followed by urogenital (10.4%) and lung malformations (9.6%). A high incidence of Kaposi's sarcoma (9.6%; half cutaneous and half visceral) and a lower than expected incidence of posttransplant lymphoproliferative disorder (PTLD; 3.5%) was found. Among patients developing de novo tumors, the incidence of death with a functioning graft was higher than among recipients without tumors. Moreover, the incidence of tumor-related death was high among the de novo tumor recipients. Among our recipients, the most aggressive tumors were Kaposi's sarcoma, lung tumors, lymphomas, and gastrointestinal tumors, which occurred relatively early after transplantation and were the cause of death in most cases. Compared to tumor registry data, we found an inverse basal-to-squamous cell carcinoma ratio, a lower incidence of PTLD, and a higher incidence of Kaposi's sarcoma.

Topics: Azathioprine; Cyclosporine; Female; Humans; Hungary; Immunosuppressive Agents; Kidney Transplantation; Neoplasms; Postoperative Complications; Prednisolone; Retrospective Studies; Risk Factors; Tacrolimus

Immunosuppressive therapy is a risk factor for the increased incidence and metastatic progression of malignancies in organ graft recipients. Transforming growth factor (TGF)-beta(1) has been associated with tumor invasion and metastasis, and we have implicated cyclosporine-associated TGF-beta(1) hyperexpression in tumor progression in mice.. BALB/c mice or severe combined immunodeficient-beige mice were treated with 2 or 4 mg/kg of tacrolimus, and the effect of treatment on mouse renal cancer cell pulmonary metastasis was investigated. We also determined whether tacrolimus induces TGF-beta(1) expression. Spleens from tacrolimus-treated mice were analyzed for level of expression of TGF-beta(1) mRNA with the use of competitive-quantitative polymerase chain reaction assay, and circulating levels of TGF-beta(1) protein were measured with the use of an enzyme-linked immunosorbent assay.. Treatment with tacrolimus resulted in a dose-dependent increase in the number of pulmonary metastases in the BALB/c mice (197+/-16 in untreated mice, 281+/-26 in mice treated with 2 mg/kg of tacrolimus, and 339+/-25 in mice treated with 4 mg/kg of tacrolimus; no treatment vs. 4 mg/kg tacrolimus, Bonferroni's P<0.001) and in the severe combined immunodeficient-beige mice (117+/-18 in untreated mice, 137+/-19 in mice treated with 2 mg/kg of tacrolimus, and 216+/-29 in mice treated with 4 mg/kg of tacrolimus; no treatment vs. 4 mg/kg tacrolimus, P<0.05). Treatment with 4 mg/kg but not 2 mg/kg of tacrolimus resulted in a significant increase in the levels of expression of TGF-beta(1) mRNA and circulating levels of TGF-beta(1) protein.. Tacrolimus has a dose-dependent effect on tumor progression and TGF-beta(1) expression, and tacrolimus-induced TGF-beta(1) overexpression may be a pathogenetic mechanism in tumor progression.

Topics: Animals; Carcinoma, Renal Cell; Disease Progression; Dose-Response Relationship, Drug; Immunosuppressive Agents; Kidney Neoplasms; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, SCID; Neoplasm Metastasis; Neoplasms; Spleen; Tacrolimus; Transforming Growth Factor beta; Transforming Growth Factor beta1

Kidney transplant recipients require careful follow-up in both the early (< 6 months) and late posttransplant periods. Monitoring should focus on graft function and the most common complications of immunosuppression therapy. Infections, especially CMV infection, require particular attention in the first few months after transplantation, when immunosuppression is most intense. In both the early and the late posttransplant periods, an emphasis should be placed on intensive management of CVD risk factors (e.g., hypertension, hyperlipidemia, cigarette smoking). Screening for malignancies known to occur with a high incidence after transplantation is also important. With the improved short-term survival rates brought about by new, potent immunosuppressive agents, emphasis has now shifted to the prevention and treatment of posttransplant complications in kidney transplant recipients. A heightened awareness of these complications, along with a cooperative effort between primary care physicians and transplant programs, offers the best hope for further improvement in outcomes after kidney transplantation.

Topics: Cardiovascular Diseases; Cyclosporine; Cytomegalovirus Infections; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney Transplantation; Metabolic Diseases; Monitoring, Physiologic; Neoplasms; Risk Assessment; Sirolimus; Tacrolimus; Transplantation, Homologous

Treatment with cyclosporin A (CsA) in kidney-transplant recipients is associated with reduced DNA repair and enhanced cancer incidence. CsA is an inhibitor of the serine/threonine phosphatase calcineurin, also termed PP2B, which is a Ca(2+)/calmodulin-dependent phosphatase. In this study we sought to elucidate the role of calcineurin in DNA repair using CsA and tacrolimus; examine whether UV-induced DNA repair is associated with dephosphorylation; and investigate whether phosphatases other than calcineurin are active in DNA repair, in light of the fact that calcineurin inhibition only partially suppressed DNA repair. Peripheral blood mononuclear cells from healthy donors were used. In vitro, we assayed UV-induced DNA repair by measuring the incorporation of tritiated thymidine in UV-irradiated cells. We gauged phosphatase activity indirectly by measuring free inorganic phosphate (Pi) excreted into the medium. The phosphatase assay was performed under the same conditions and in parallel to the DNA-repair assay. Tacrolimus, like CsA, inhibited DNA repair in a dose-dependent fashion. DNA repair was associated with production of Pi, which correlated with the number of cells performing DNA repair. Phosphatase activity increased after UV irradiation. DNA repair correlated directly with phosphatase activity, whereas CsA reduced both DNA repair and Pi production. Inhibition of calmodulin by trifluoperazine and W7 [N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide] reduced DNA repair in part. We investigated the role of the Ca(2+)-independent phosphatases PP1 and PP2A using specific inhibitors. Calyculin A, which inhibits both phosphatases, reduced DNA repair. Endothall, a PP2A inhibitor, had no effect on DNA repair. Okadaic acid, which is mostly a PP2A inhibitor but also a weak inhibitor of PP1, reduced DNA repair only slightly. We suggest that DNA repair is mediated by way of Ca(2+)-dependent and Ca(2+)-independent pathways, with calcineurin and PP1 being the respective phosphatases involved in each pathway.

Topics: Calcineurin; Calcineurin Inhibitors; Cyclosporine; DNA Repair; Enzyme Inhibitors; Humans; Immunosuppressive Agents; In Vitro Techniques; Kidney Transplantation; Leukocytes, Mononuclear; Marine Toxins; Neoplasms; Oxazoles; Phosphates; Phosphoprotein Phosphatases; Signal Transduction; Tacrolimus; Ultraviolet Rays

Anti-angiogenic therapies based on targeted disruption of the tumor microvascular network have been proposed for cancer treatment. Inhibitors of the endothelial cell pro-survival pathway mediated by VEGF were shown to activate caspases and cause microvascular regression, but the efficacy of this strategy can be hindered by the engagement of redundant survival pathways. Alternatively, if direct activation of an apical pro-apoptotic caspase is sufficient to disrupt microvessels in vivo, such a strategy could potentially override upstream endothelial cell survival inputs and disrupt tumor neovascular networks. Here, we fused caspase-9 to a mutated FKBP12 domain to express an inducible caspase-9 molecule (iCaspase-9) that can be activated by a cell-permeable dimerizer drug, and transduced this construct into primary endothelial cells. We found that drug-induced dimerization of iCaspase-9 is sufficient to activate endogenous caspase-3 and trigger apoptosis even when endothelial cells are treated with the pro-survival factors VEGF or bFGF. A single intraperitoneal injection of the dimerizer drug induced apoptosis of endothelial cells expressing iCaspase-9 and elimination of human microvessels engineered in immunodeficient mice. These results demonstrate that the activation of iCaspase-9 disrupts microvessels in vivo, and suggest a novel anti-angiogenic strategy based on the expression and controlled activation of an inducible death gene in neovascular endothelial cells.

Topics: Animals; Apoptosis; Caspase 3; Caspase 9; Caspases; Cell Line; Dimerization; Endothelial Growth Factors; Endothelium, Vascular; Enzyme Activation; Enzyme Precursors; Fibroblast Growth Factor 2; Genetic Therapy; Genetic Vectors; Humans; Injections, Intraperitoneal; Lymphokines; Mice; Mice, SCID; Microcirculation; Models, Animal; Neoplasms; Neovascularization, Pathologic; Retroviridae; Tacrolimus; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Adolescent; Adult; Aged; Autoantibodies; Biomarkers; Child; Cyclosporine; Female; Gene Expression Regulation; Genes, p53; Humans; Kidney Transplantation; Male; Middle Aged; Neoplasms; Prednisone; Reference Values; Tacrolimus; Tumor Suppressor Protein p53

Alterations in gene expression may represent an underlying cause of undesired side-effects mediated by the immunosuppressant cyclosporin A (CsA). We employed the method of differential display PCR to identify new genes whose expression is modulated by CsA. Human peripheral blood mononuclear cells (PBMCs), or subpopulations thereof, were simultaneously stimulated with the phorbol ester 4beta-phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore ionomycin, in the presence or absence of therapeutic concentrations of CsA. We identify the gene encoding the DNA repair enzyme DNA polymerase beta (Pol beta) as a novel CsA-sensitive transcription unit. Our data show that transcription of pol beta mRNA is induced by Ca2+ and that CsA significantly inhibits PMA/ionomycin- and ionomycin-mediated upregulation of both pol beta mRNA and Pol beta protein. The CsA-mediated inhibition of pol beta upregulation is maintained for at least 21 h after gene activation and is exerted via the phosphatase calcineurin. FK506, another immunosuppressant that targets calcineurin, also inhibits pol beta upregulation, while rapamycin competes with FK506 action. This work identifies Ca2+ as an inducer of pol beta gene activity in primary blood cells. The demonstrated CsA sensitivity of this process suggests a novel molecular mechanism that may contribute to the increased tumor incidence in patients receiving CsA treatment.

Topics: Animals; Base Sequence; Calcineurin; Calcium; Cyclosporine; DNA Polymerase beta; DNA Primers; DNA Repair; Humans; Immunosuppressive Agents; In Vitro Techniques; Ionomycin; Ionophores; Leukocytes, Mononuclear; Neoplasms; RNA, Messenger; Tacrolimus; Tetradecanoylphorbol Acetate; Up-Regulation

BALB/c mice were infected with the lymphotropic mouse gammaherpesvirus (MHV-72). At late (7-12 months) post-infection intervals the latent virus was detected in the cells of lymphatic system (peripheral blood, lymphocytes and macrophages, thymocytes, lymph nodes, bone marrow, and peritoneal macrophages,) and in the spleen, lungs, liver, and kidney by cocultivation as well as by explantation. The MHV-72 infected mice, in which latency had been established, were treated with the immunosuppressive (IS) drug FK-506 (2 mg/kg/mouse for 30 days). This treatment increased the probability of virus reactivation by over two-fold. During the post-treatment observation period of 19 months, the incidence of lymphomas and the development of MHV-related lymphoproliferative and hemoblastic disorders raised to nearly five-fold in the drug treated mice as compared to untreated animals.

Topics: Animals; Gammaherpesvirinae; Herpesviridae Infections; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Mice; Mice, Inbred BALB C; Neoplasms; Tacrolimus; Tumor Virus Infections; Virus Latency

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: Carcinoma, Hepatocellular; Cyclosporine; Follow-Up Studies; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Lymphoma; Neoplasms; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors