mycophenolic-acid and Neoplasms

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

Mycophenolic acid (MPA) is an immunosuppressive drug commonly used for prophylaxis of graft rejection in solid organ transplant recipients. The main concern with the prolonged use of immunosuppressive drugs is the risk of developing cancer. However, it remains unclear whether the immunosuppressive regimens containing MPA confer an increased degree of cancer risk. The present study aimed to determine the association between MPA exposure and the incidence of cancer in solid organ transplant recipients.. A systematic search was performed on the PubMed, EMBASE and Cochrane Library databases. Relevant articles that had findings on the incidence (or event) of cancer in cohorts with and without MPA exposure were retrieved for data extraction. A meta-analysis was conducted by means of the random-effects model, and the relative risk (RR) and its 95% confidence interval (95% CI) were used as a summary effect measure.. A total of 39 studies were eligible for inclusion, with 32 studies that enabled meta-analysis. MPA exposure was significantly associated with a lower risk of cancer when compared to azathioprine exposure (RR = 0.66, 95% CI = 0.53-0.81, P < .001) or no exposure to any additional treatments (RR = 0.85, 95% CI = 0.73-0.99, P = .04). There was no significant difference in cancer risk for the comparison between MPA exposure and mammalian target of rapamycin (mTOR) inhibitor exposure (RR = 1.54, 95% CI = 0.96-2.46, P = .07).. MPA exposure was not associated with an increased risk of cancer and may even be associated with a lower risk of cancer when compared to azathioprine or no treatment.

Topics: Azathioprine; Graft Rejection; Humans; Immunosuppressive Agents; Mycophenolic Acid; Neoplasms; Organ Transplantation; Risk

Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil (MMF), an immunosuppressive drug approved for the prophylaxis of allograft rejection in transplant recipients. Recent advances in the role of the type II isoform of inosine-5'-monophosphate dehydrogenase (IMPDH2) in the tumorigenesis of various types of cancer have called for a second look of MPA, the first IMPDH2 inhibitor discovered a hundred years ago, to be repurposed as an anticancer agent. Over a half century, a number of in vitro and in vivo experiments have consistently shown anticancer activity of MPA against several cell lines obtained from different malignancies and murine models. However, a few clinical trials have been conducted to investigate its anticancer activity in humans, and most of which have shown unsatisfactory results. Understanding of available evidence and underlying mechanism of action is a key step to be done so as to facilitate further investigations of MPA to reach its full therapeutic potential as an anticancer agent. This article provides a comprehensive review of non-clinical and clinical evidence available to date, with the emphasis on the molecular mechanism of action in which MPA exerts its anticancer activities: induction of apoptosis, induction of cell cycle arrest, and alteration of tumor microenvironment. Future perspective for further development of MPA to be an anticancer agent is extensively discussed, with the aim of translating the anticancer property of MPA from bench to bedside.

Topics: Animals; Antibiotics, Antineoplastic; Humans; IMP Dehydrogenase; Mycophenolic Acid; Neoplasms

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

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

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

Over the last 4 decades, cardiac transplantation has become the preferred therapy for select patients with end-stage heart disease. Heart transplantation is indicated in patients with heart failure despite optimal medical and device therapy, manifesting as intractable angina, refractory heart failure, or intractable ventricular arrhythmias. This article provides an overview of heart transplantation in the current era, focusing on the evaluation process for heart transplantation, the physiology of the transplanted heart, immunosuppressive regimens, and early and long-term complications.

Topics: Allografts; Azathioprine; Cardiotonic Agents; Contraindications; Graft Occlusion, Vascular; Graft Rejection; Heart; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Long-Term Care; Mycophenolic Acid; Neoplasms; Opportunistic Infections; Postoperative Care; Steroids

The prevailing notion in dermatology is that mycophenolate mofetil (MMF) is safer than cyclosporine (CsA), but that CsA has greater efficacy. This literature review evaluates the available long-term safety data of MMF and CsA. Literature in the fields of dermatology, autoimmune disease, and transplantation were retrieved from PubMed. Data regarding immunosuppressive and non-immunosuppressive side effects of MMF and CsA are presented along with available pregnancy safety data. Surprisingly, there is a paucity of data on long-term MMF monotherapy. Transplant data is presented separately due to the concomitant use of other immunosuppressants along with MMF. Trends that can be identified include a less discernable cancer or end-organ damage risk in MMF compared to CsA. However, MMF appears to have a greater risk in pregnancy and increased reports of herpes simplex and zoster infection compared to CsA.

Topics: Adult; Cyclosporine; Dermatologic Agents; Female; Humans; Immunosuppressive Agents; Infections; Long-Term Care; Mycophenolic Acid; Neoplasms; Pregnancy; Psoriasis; Safety

Prolonged waiting times for renal transplantation, an increase in the average age of recipients, decreased acute rejection rates due to use of newer potent immunosuppressives and improving long-term transplant survival have raised concerns in the transplant community regarding posttransplant cancer. In view of the fact that transplant recipients are living longer, it is of paramount importance that we continue to translate discoveries at the bench to the bedside and document cancers in the posttransplant recipient registries. Analysis of data will help in optimizing patient management.. Recent evidence indicates that sirolimus is associated with a decreased incidence of posttransplant de-novo cancer and remission of Kaposi's sarcoma and nonmelanoma skin cancer. Mycophenolate mofetil has been shown to have an antiproliferative activity against leukemia and lymphoma and an anti-tumor effect against colon and prostate cancer. Clinically it has been shown to be associated with a reduced incidence of cancers like posttransplant lymphoproliferative disorder.. Appropriate selection of transplant candidates, pretransplant and posttransplant cancer surveillance and judicious evidence-based use of newer immunosuppressants may help reduce the incidence and improve the outcome of posttransplant cancer.

Topics: Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Neoplasms; Population Surveillance; Sirolimus

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Disease Susceptibility; Drug Administration Schedule; Hemolytic-Uremic Syndrome; Humans; Hypertension; Immunocompromised Host; Immunosuppressive Agents; Incidence; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Neoplasms; Postoperative Complications; Sirolimus

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

Conventional allografting produces considerable regimen-related toxicities that generally limit this treatment to patients younger than 55 years and in otherwise good medical condition. T cell-mediated graft-versus-tumor (GVT) effects are known to play an important role in the elimination of malignant disease after allotransplants. A minimally myelosuppressive regimen that relies on immunosuppression for allogeneic engraftment was developed to reduce toxicities while optimizing GVT effects. Pre-transplant total-body irradiation (200 cGy) followed by post-transplant immunosuppression with cyclosporine (CSP) and mycophenolate mofetil (MMF) permitted human leukocyte antigen (HLA)-matched sibling donor hematopoietic cell engraftment in 82% of patients (n = 55) without prior high-dose therapy. The addition of fludarabine (90 mg/m2) facilitated engraftment in all 28 subsequent patients. Overall, fatal progression of underlying disease occurred in 20% of patients after transplant. Non-relapse mortality occurred in 11% of patients. Toxicities were low. Grade 2-4 acute graft-versus-host disease (GVHD) associated with primary engraftment developed in 47% of patients, and was readily controlled in all but two patients. Donor lymphocyte infusions (DLI) were not very effective at converting a low degree of mixed donor/host chimerism to full donor chimerism; however, the addition of fludarabine reduced the need for DLI. With a median follow-up of 244 days, 68% of patients were alive, with 42% of patients in complete remission, including molecular remissions. Remissions occurred gradually over periods of weeks to a year. If long-term efficacy is demonstrated, such a strategy would expand treatment options for patients who would otherwise be excluded from conventional allografting.

Topics: Adult; Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cyclosporine; Disease Progression; Dogs; Forecasting; Graft Enhancement, Immunologic; Graft Survival; Graft vs Host Disease; Graft vs Tumor Effect; Hematopoietic Stem Cell Transplantation; Histocompatibility; Humans; Immunosuppressive Agents; Lymphocyte Transfusion; Methotrexate; Middle Aged; Mycophenolic Acid; Neoplasms; Prednisone; Radiation Chimera; T-Lymphocytes, Cytotoxic; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine; Whole-Body Irradiation

In vertebrates, the glucuronidation of small lipophilic agents is catalyzed by the endoplasmic reticulum UDP-glucuronosyltransferases (UGTs). This metabolic pathway leads to the formation of water-soluble metabolites originating from normal dietary processes, cellular catabolism, or exposure to drugs and xenobiotics. This classic detoxification process, which led to the discovery nearly 50 years ago of the cosubstrate UDP-glucuronic acid (19), is now known to be carried out by 15 human UGTs. Characterization of the individual gene products using cDNA expression experiments has led to the identification of over 350 individual compounds that serve as substrates for this superfamily of proteins. This data, coupled with the introduction of sophisticated RNA detection techniques designed to elucidate patterns of gene expression of the UGT superfamily in human liver and extrahepatic tissues of the gastrointestinal tract, has aided in understanding the contribution of glucuronidation toward epithelial first-pass metabolism. In addition, characterization of the UGT1A locus and genetic studies directed at understanding the role of bilirubin glucuronidation and the biochemical basis of the clinical symptoms found in unconjugated hyperbilirubinemia have uncovered the structural gene polymorphisms associated with Crigler-Najjar's and Gilbert's syndrome. The role of the UGTs in metabolism and different disease states in humans is the topic of this review.

Topics: Autoimmunity; Chromosome Mapping; Glucuronides; Glucuronosyltransferase; Humans; Hyperbilirubinemia; Neoplasms; Steroids; Terminology as Topic

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Asparaginase; Bleomycin; Dactinomycin; Daunorubicin; Diethylstilbestrol; Humans; Hydroxyprogesterones; Mitomycins; Mycophenolic Acid; Nandrolone; Neoplasms; Nitrosourea Compounds; Olivomycins; Steroids; Streptonigrin

Topics: Alkylating Agents; Anti-Bacterial Agents; Antibody Formation; Antigen-Antibody Reactions; Antineoplastic Agents; Autoimmune Diseases; Binding Sites, Antibody; Enzymes; Hormones; Humans; Hydrazines; Immune System Diseases; Immunosuppression Therapy; Immunosuppressive Agents; Infections; Mitosis; Molecular Biology; Mycophenolic Acid; Neoplasms; Nitrosourea Compounds; Poly I-C; Pyrans; Transplantation, Homologous

Kidney transplant recipients are at a high risk of developing cancers after transplantation. Switching from calcineurin inhibitors to sirolimus has been shown to prevent secondary nonmelanoma skin cancer but whether everolimus with reduced exposure to calcineurin inhibitors has similar anti-cancer effects remains unknown. Therefore, we compared the risk of incident cancer over seven years of follow-up among kidney transplant recipients randomized to everolimus plus reduced exposure cyclosporine versus mycophenolate sodium and standard exposure cyclosporine. Using the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), we assessed the seven-year risk of incident cancer and other graft outcomes among a subgroup of recipients who had participated in the A2309 study using adjusted Cox proportional hazard models. Of 95 recipients, 66 were randomized to everolimus (1.5 mg or 3 mg) with reduced cyclosporine and 29 received mycophenolate sodium and standard exposure cyclosporine. Compared to mycophenolate sodium and standard exposure cyclosporine, everolimus treatment was associated with unadjusted hazard ratios of 0.28 (95% confidence interval 0.11-0.74), 0.39 (0.16-0.98) and 0.41 (0.23-0.71), respectively for nonmelanoma skin cancer, non-skin cancers and any cancers. Interestingly, the adjusted hazard ratios were 0.34 (0.13-0.91), 0.35 (0.09-1.25) and 0.32 (0.15-0.71), respectively. There was no association between treatment groups and rejection, graft loss or death. Compared to standard-exposure cyclosporine, everolimus with reduced exposure to cyclosporine may be associated with a reduced risk of cancer, particularly for non-melanoma skin cancer. Thus, if confirmed in larger patient cohorts, de novo use of everolimus with reduced exposure to calcineurin inhibitors may enable a reduction in cancer burden after transplantation.

Topics: Adult; Australia; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Intention to Treat Analysis; Kaplan-Meier Estimate; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; New Zealand; Proportional Hazards Models; Protective Factors; Registries; Risk Assessment; Risk Factors; Time Factors; 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

In a clinical phase I/II trial, pediatric patients with high-risk malignancies were treated with ex vivo IL-2-stimulated donor natural killer (NK) cells after transplantation with haploidentical stem cells. To evaluate the potential negative effects of the immunosuppressive drug mycophenolate mofetil (MMF) used for immunotherapy, the functionality and signaling of ex vivo NK cells was investigated. Our results show that during NK cell expansion, long-term (9 days) incubation with mycophenolic acid (MPA), the active metabolite of MMF, in therapeutically relevant concentrations led to the severe inhibition of NK cell proliferation. This correlated with a significantly reduced cytokine/chemokine secretion and the inhibited acquisition of surface receptors regarding cytotoxicity (e.g., NKp30, NKp44, NKp46, NKG2D), adhesion/migration (e.g., ICAM-1/CD54, LFA-1/CD11a, CD62L, CXCR3) and activation (e.g., CD25). Moreover, MPA prevented phosphorylation of the central signaling molecules STAT-3/-4/-5, AKT and ERK1/2. In contrast, short-term (24 h) MPA incubation of IL-2-stimulated NK cells had no or only marginal effects on the activated NK cell phenotype, including receptor expression, cytokine/chemokine secretion and intracellular signaling. Further, short-term MPA incubation only moderately affected the highly cytotoxic activity of previously IL-2-stimulated NK cells. In conclusion, while long-term MPA incubation significantly compromised ex vivo NK cell functionality, previously IL-2-activated NK cells seemed to be rather resistant to short-term MPA treatment. This finding supports the use of IL-2-activated NK cells as immunotherapy, especially for patients treated with MMF after haploidentical stem cell transplantation.

Topics: Adolescent; Cell Growth Processes; Child, Preschool; Enzyme Inhibitors; Female; Humans; Immunotherapy, Adoptive; Infant; Interleukin-2; Killer Cells, Natural; Male; Mycophenolic Acid; Neoplasms

Inosine monophosphate dehydrogenase (IMPDH) is the target enzyme of mycophenolate mofetil (MMF). Single nucleotide polymorphisms (SNPs) in the IMPDH1 gene are reportedly relevant to acute rejection in renal transplant patients receiving MMF. The objective of this study was to identify the impact of IMPDH1 gene polymorphisms on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Four IMPDH1 gene SNPs (IVS7 +125 G>A, IVS8-106 G>A, exon15 1572 G>A, and 5' flanking intron-exon region C>T) were analyzed in 240 consecutive pairs of transplant recipients and their donors. The presence of the IMPDH1 IVS8-106 G/G genotype in recipients was associated with a significantly higher incidence of acute graft-versus-host disease (aGVHD) than other genotypes, in both unrelated and sibling transplantation cohorts (unrelated cohort: 83.3% vs 63.9%, P = .048; sibling cohort: 47.6% vs 17.3%, P = .008). Multivariate analysis confirmed that recipients with the IVS8-106 G/G genotype were at significantly higher risk of developing aGVHD (relative risk [RR] = 2.018, 95% confidence interval [CI]: 1.354-3.009, P = .001) and grades II-IV aGVHD (RR = 2.232, 95% CI: 1.352-3.685, P = .002). There was no association among IVS7 +125, exon15 1572, and 5' flanking intron-exon region genotypes and the risk of aGVHD. These results represent the first report of an association between IMPDH1 gene polymorphisms and the risk of aGVHD in allo-HSCT.

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Agents; Child; Exons; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; IMP Dehydrogenase; Introns; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Polymorphism, Single Nucleotide; Retrospective Studies; Risk Factors; Siblings; Transplantation, Homologous

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

Background and objective. We investigated immune recovery in 50 patients given either unmanipulated or CD8-depleted allogeneic peripheral blood stem cells after non-myeloablative conditioning.. Fifty patients were randomized to receive either CD8-depleted (n=22) or non-manipulated (n=28) peripheral blood stem cells. The median patients age was 57 (range 36-69) years. The conditioning regimen consisted of 2 Gy total body irradiation with or without added fludarabine. Twenty patients received grafts from related donors, 14 from 10/10 HLA-allele matched unrelated donors, and 16 from HLA-mismatched unrelated donors. Graft-versus-host disease pro-phylaxis consisted of mycophenolate mofetil and cyclosporine. Immune recovery during the first year after hematopoietic cell transplantation was assessed by flow cytometry phenotyping, analyses of the diversity of the TCRBV repertoire, and quantification of signal-joint T-cell receptor excision circles (sjTREC).. CD8-depletion of the graft reduced the recovery of CD8(+) T-cell counts in the first 6 months following transplantation (p<0.0001) but had no significant impact on the restoration of other T-cell subsets. Both sjTREC concentration and CD3(+) T-cell counts increased significantly between day 100 and 365 (p=0.010 and p=0.0488, respectively) demonstrating neo-production of T cells by the thymus. Factors associated with high sjTREC concentration 1 year after transplantation included an HLA-matched unrelated donor (p=0.029), a high content of T cells in the graft (p=0.002), and the absence of chronic graft-versus-host disease (p<0.0001).. Our data suggest that while immune recovery is mainly driven by peripheral expansion of the graft-contained mature T cells during the first months after non-myeloablative transplantation, T-cell neo-generation by the thymus plays an important role in long term immune reconstitution in transplanted patients.

Topics: Adult; Aged; Anesthesia Recovery Period; CD8-Positive T-Lymphocytes; Cyclosporine; Female; Flow Cytometry; Graft vs Host Disease; Histocompatibility Testing; Humans; Immunosuppressive Agents; Lymphocyte Depletion; Male; Middle Aged; Mycophenolic Acid; Myeloablative Agonists; Neoplasms; Peripheral Blood Stem Cell Transplantation; Receptors, Antigen, T-Cell, alpha-beta; Thymus Gland; Time Factors; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation

The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of >/=3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p < 0.001), as were median levels of serum creatinine (TAC/SRL = 1.5 mg/dL, TAC/MMF = 1.3 mg/dL, CYA/MMF = 1.5 mg/dL; p = 0.032) and triglycerides (TAC/SRL = 162 mg/dL, TAC/MMF = 126 mg/dL, CYA/MMF = 154 mg/dL; p = 0.028). The TAC/SRL group encountered fewer viral infections but more fungal infections and impaired wound healing. These secondary endpoints suggest that the TAC/MMF combination appears to offer more advantages than TAC/SRL or CYA/MMF in cardiac transplant patients, including fewer >/=3A rejections or hemodynamic compromise rejections and an improved side-effect profile.

Topics: Adult; Antiviral Agents; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft Rejection; Heart Transplantation; Heart-Lung Transplantation; Humans; Hypolipidemic Agents; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Patient Selection; Postoperative Complications; Sirolimus; Treatment Outcome; United States

A large-scale, controlled clinical study has shown that enteric-coated mycophenolate sodium (EC-MPS) is therapeutically equivalent to mycophenolate mofetil (MMF) in de novo renal transplant patients. Safety and efficacy outcomes from an open-label extension of this core study (n = 122) were compared to those of the MMF arm of two well-controlled randomized studies (RAD B251, n = 141, and RAD B201, n = 150) for the 12- to 36-month posttransplant period. During this period, 33 (27%) EC-MPS patients experienced one or more drug-related adverse event. Sixteen patients (13%) discontinued the extension study due to adverse events. The incidence of all safety parameters was similar in the EC-MPS patients and the MMF-treated patients in the RAD B201 and RAD B251 studies during the 12- to 36-month posttransplant period, as was the frequency of adverse events, infections, malignancies, and hematological abnormalities. During the 24 months of the EC-MPS extension study, four patients died and two lost their graft. Biopsy-proven acute rejection (BPAR) occurred in four patients (3.3%). BPAR, graft loss, and death occurred in a similar proportion of MMF-treated patients in the RAD B201 and RAD B251 studies during months 12 to 36 posttransplant. These findings confirm the safety and efficacy of EC-MPS in maintenance transplant patients at least 1 year posttransplant and suggest that outcomes with EC-MPS are comparable to MMF in this population when used in combination with CsA-ME and steroids.

Topics: Adult; Cytomegalovirus Infections; Female; Follow-Up Studies; Graft Rejection; Hematologic Diseases; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Postoperative Complications; Tablets, Enteric-Coated; Time Factors

Topics: Adult; Chronic Disease; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Mycophenolic Acid; Neoplasms; Treatment Outcome

Kidney grafts from suboptimal donors are more likely to suffer the nephrotoxic side-effects of cyclosporine than kidneys from standard donors. In an attempt to avoid the use of cyclosporine, we carried out a prospective study in low-immunological risk recipients of suboptimal kidneys, using an immunosuppressive protocol combining Thymoglobuline in induction with a bi-therapy of mycophenolate mofetil (MMF) and steroids. Patients with panel reactive antibodies (PRA) <50% receiving a first renal transplant from a suboptimal donor (age >or=50, non heart beating, arterial hypertension, or acute renal failure) or a kidney at risk of delayed graft function (DGF) because of a prolonged cold ischaemia time (CIT) of 24 h or more, were eligible for this trial. Between September 1996 and December 1999, 30 patients were enrolled for the trial and treated with MMF 2 g orally, pre-operatively, and 3 g daily, post-operatively; Thymoglobuline 2 mg/kg IV pre-operatively, 1.5 mg/kg IV the next day, and for doses of 1 mg/kg IV given on alternate days; and prednisolone 0.25 mg/kg per day, reduced progressively from the end of the first month to 0.1 mg/kg per day by 3 months post-transplant. Cyclosporine was added only if rejection grade II or higher, or a reduction in MMF below 1 g daily, occurred. Ten patients (30%) suffered from DGF, and one kidney suffered primary non function. Seven patients (24%) suffered acute rejection (six were biopsy proven, 3 grade I and 3 grade II). MMF dosage was reduced in 28 patients because of adverse events, and calcineurin inhibitors were introduced in 16 patients. There were 14 episodes of opportunistic infection (cytomegalovirus (CMV 10), Herpes zoster 2, Listeria monocytogenes 1, Pseudomonas aeuruginosa 1), and 7 malignancies (skin 2, thyroid 1, lung 1, Kaposi's sarcoma 2, post-transplantation lymphoproliferative disorder 1). Mean serum creatinine was 178, 199, 213, and 218 micromol/l at 1, 2, 3 and 5 years after transplantation, respectively. Actuarial patient and graft (after censoring for death) survival was 94% and 83% after 1 year and 79% and 65% after 5 years, respectively. These results show that with the combination of MMF, Thymoglobuline and steroids the use of cyclosporine can be delayed, and in a few cases completely avoided, with good efficacy in terms of prevention of rejection and recovery of renal function. Regardless of acceptable patient and graft survival, side-effects of MMF at the doses used in this protocol were common

Topics: Adult; Aged; Antilymphocyte Serum; Cadaver; Calcineurin Inhibitors; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Opportunistic Infections; Prospective Studies; Survival Analysis; Tissue Donors

The kidney transplant program at the Ospedali Riuniti of Bergamo, Italy was established in 1989. Since its inception, 367 patients have been transplanted, including 357 kidney transplants from cadaveric donors and 10 from living-related donors. Overall 8-year patient and graft survival rates were 94% and 77%, respectively. By 1995 our unit co-ordinated the activity of the Department of Immunology and Clinics of Organ Transplantation, Ospedali Riuniti--Mario Negri Institute for Pharmacological Research, Bergamo. The dual "marginal" kidney transplant program in the same recipient was launched in August 1997, as a part of an international cooperative network which established the "Double Kidney Transplant Group" (DKG). To date, 19 dual kidney transplants have been successfully performed in our center. Four combined heart-kidney transplants and 2 combined liver-kidney transplants have also been performed. During the past 4 years several studies involving conventional antirejection drugs were carried out, particularly focussing our attention on cyclosporine (CsA) through pharmacokinetic and pharmacodynamic approaches: 1) a simplified method to evaluate daily exposure to CsA has been set up; 2) the monitoring of calcineurin activity in whole blood samples was evaluated as a way to optimize CsA dosing. As for the new immunosuppressants, studies are ongoing with mycophenolate mofetil (MMF). We are co-ordinating a prospective multicenter randomized trial of steroid sparing in kidney transplant recipients given MMF or azathioprine as a part of their immunosuppression therapy (MY.S.S. study). This involves 9 Italian transplant centers and 2 European centers. Up to now 325 patients have been randomized. Moreover we have set up an HPLC method for measuring plasma mycophenolic acid (MPA), and examined the possibility of optimizing MMF dosing by drug pharmacokinetic monitoring. Further studies have been addressed to chronic allograft nephropathy. The nature and mediators of renal lesions in kidney transplant patients given CsA have been explored taking into account the gene expression of endothelin-1, RANTES and MCP-1 in graft specimens from patients who had evidence of CsA nephrotoxicity, chronic rejection, or no lesions at histological examination. The impact of percutaneous transluminal angioplasty and stenting of posttransplant renal artery stenosis on renal function recovery was also recently examined. From this study we conclude that the procedure is safe and effe

Topics: Academic Medical Centers; Animals; Calcineurin; Cyclosporine; Genetic Therapy; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; In Vitro Techniques; Infections; Italy; Kidney Transplantation; Mycophenolic Acid; Neoplasms; Randomized Controlled Trials as Topic; Renal Artery Obstruction; Survival Rate; Swine; Tissue and Organ Procurement; Transplantation, Heterologous

Mycophenolate mofetil (MMF) is a new immunosuppressive drug that selectively inhibits de novo purine synthesis. It has been tested in three large double-blind controlled trials for the prevention of rejection in renal transplant patients. These studies indicate that the use of MMF dramatically decreases the incidence of biopsy-proven rejection, the use of multiple courses of steroids for rejection, and the use of antilymphocyte preparations for treatment of rejection. The drug was well tolerated with an acceptable safety profile. The main side effects were gastrointestinal (nausea, vomiting, diarrhea), but seldom resulted in the cessation of drug therapy. Hematologic side effects similar to those with azathioprine occurred and were reversible. There was a slight increase in CMV-invasive disease with the use of MMF, but no deaths. Rates of malignancy were within published ranges for transplant recipients. Mycophenolate mofetil is a safe and efficacious drug for prevention of rejection in kidney transplant recipients.

Topics: Antilymphocyte Serum; Azathioprine; Cytomegalovirus Infections; Diarrhea; Double-Blind Method; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Mycophenolic Acid; Nausea; Neoplasms; Opportunistic Infections; Placebos; Purines; Safety; Steroids; Vomiting

Topics: Adult; Aged; Alkenes; Antibiotics, Antineoplastic; Caproates; Carcinoma; Clinical Trials as Topic; Female; Humans; Lactones; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Phenols; Phthalic Acids

To determine the incidence of all-cause and cancer mortality (CM) in association with immunosuppression.. Retrospective cohort study at ocular inflammatory disease (OID) subspecialty centers. We harvested exposure and covariate data retrospectively from clinic inception (earliest in 1979) through 2010 inclusive. Then we ascertained overall and cancer-specific mortalities by National Death Index linkage. We constructed separate Cox models to evaluate overall and CM for each class of immunosuppressant and for each individual immunosuppressant compared with person-time unexposed to any immunosuppression.. Patients with noninfectious OID, excluding those with human immunodeficiency infection or preexisting cancer.. Tumor necrosis factor (TNF) inhibitors (mostly infliximab, adalimumab, and etanercept); antimetabolites (methotrexate, mycophenolate mofetil, azathioprine); calcineurin inhibitors (cyclosporine); and alkylating agents (cyclophosphamide) were given when clinically indicated in this noninterventional cohort study.. Overall mortality and CM.. Over 187 151 person-years (median follow-up 10.0 years), during which 15 938 patients were at risk for mortality, we observed 1970 deaths, 435 due to cancer. Both patients unexposed to immunosuppressants (standardized mortality ratio [SMR] = 0.95, 95% confidence interval [CI], 0.90-1.01) and those exposed to immunosuppressants but free of systemic inflammatory diseases (SIDs) (SMR = 1.04, 95% CI, 0.95-1.14) had similar mortality risk to the US population. Comparing patients exposed to TNF inhibitors, antimetabolites, calcineurin inhibitors, and alkylating agents with patients not exposed to any of these, we found that overall mortality (adjusted hazard ratio [aHR] = 0.88, 0.89, 0.90, 1.11) and CM (aHR = 1.25, 0.89, 0.86, 1.23) were not significantly increased. These results were stable in sensitivity analyses whether excluding or including patients with SID, across 0-, 3-, or 5-year lags and across quartiles of immunosuppressant dose and duration.. Our results, in a cohort where the indication for treatment was proven unassociated with mortality risk, found that commonly used immunosuppressants-especially the antimetabolites methotrexate, mycophenolate mofetil, and azathioprine; the TNF inhibitors adalimumab and infliximab, and cyclosporine-were not associated with increased overall and CM over a median cohort follow-up of 10.0 years. These results suggest the safety of these agents with respect to overall and CM for patients treated with immunosuppression for a wide range of inflammatory diseases.. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Topics: Adalimumab; Alkylating Agents; Antimetabolites; Azathioprine; Calcineurin Inhibitors; Cohort Studies; Cyclosporine; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infliximab; Methotrexate; Mycophenolic Acid; Neoplasms; Retrospective Studies; Tumor Necrosis Factor Inhibitors

To compare the efficacy and safety of different-course corticosteroids plus mycophenolate mofetil (MMF) as maintenance therapy in autoimmune encephalitis (AE) with neuronal surface antibodies (NSAbs) without tumor and explore the optimal course of corticosteroids.. Fifty-five patients with definite AE without tumor were enrolled consecutively between June 2015 and November 2020 and retrospectively divided three groups according to the course of treatment with corticosteroid, i.e., a group of patients with a course of 3-6 months (Group 3-6mo), 6-12 months (Group 6-12mo), and >12 months (Group >12mo). Demographic data, clinical manifestation and ancillary tests results were recorded. The dosage and courses of corticosteroid treatment, the recovery of neurological function, the occurrence of adverse effects, and relapses were followed up.. A total of 55 patients were included in the final analysis. The numbers of patients in Group 3-6 mo, Group 6-12 mo, and Group >12 mo was 14, 17, and 24, respectively. A significantly higher proportion of patients in Group >12 mo showed a decreased level of consciousness at the onset (12, 50%) than in Group 3-6 mo and Group 6-12 mo (2,14.3%; 3, 17.6%) (p = 0.033). The incidence of MRI abnormalities was significantly higher in Group 6-12 mo and Group >12 mo (10, 58.8%; 16, 66.7%) than in Group 3-6 mo (3, 21.4%) (P=0.023). Ordinal regression analysis indicated that decreased level of consciousness was associated with the course of corticosteroid (OR=3.838, 95% CI: 1.103-13.323, P=0.035). No significant difference was observed between the three groups regarding the cumulative dose of corticosteroids administered during the first three months of long-term treatment (P>0.05). Additionally, no significant difference in the cumulative dosage of corticosteroids was found between patients in Group 6-12 months and Group >12 months during the first 6 months after beginning long-term treatment. The mRS scores of the three groups were not statistically significant before and after first-line treatment or at the last follow-up. Bonferroni multiple comparison test indicated that the mRS scores of patients in Group 6-12 months and Group >12 months were not statistically significant at 3 months and 12 months after the start of long-term treatment. During the follow-up, 50 (90.9%) patients achieved satisfactory neurological function (mRS score ≤2). Five patients (9.1%) experienced a first relapse and 2 of them were overlapped with both anti-NMDA receptor and glial antibodies. The incidence of adverse effects was significantly higher in Group >12 mo (17, 70.8%) than in Group 3-6 mo (3, 21.4%) and Group 6-12 mo (5, 29.4%) (P=0.003).. The beneficial effects of oral corticosteroid treatment may do not persist beyond 12 months and may even contribute to an increased incidence of adverse effects. In order to optimize the effectiveness and safety of treatment, we recommend a corticosteroid course of 3-12 months. Patients with reduced levels of consciousness may be more inclined to choose longer courses of corticosteroids for long-term treatment. Patients with an "overlapping syndrome" may require more intense immunotherapy to prevent relapse.

Topics: Adrenal Cortex Hormones; Autoimmune Diseases of the Nervous System; Humans; Mycophenolic Acid; Neoplasms; Recurrence; Retrospective Studies

Topics: Azathioprine; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Mycophenolic Acid; Neoplasms

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

Systemic Lupus Erythematosus (SLE) an autoimmune rheumatic disease with a complex pathogenesis, remains potentially life-threatening. SLE patients have increased morbidity and premature mortality compared to non-SLE patients. The five-year survival rate has improved from <50% in the 1950s to >90% in the 1980s. Lupus patients still have a mortality risk three times that of the general population.. To provide a detailed analysis of the causes of death, main characteristics and trends in the management of the deceased SLE patients from the lupus clinic at the University College London Hospital (UCLH); during the past four decades.. This was a non-interventional, retrospective study based on historical real-world data from paper and electronic records of patients followed up at UCLH. The analysis focused on data collected between 1st January 1978 and 31th December 2018. We collected the: causes of death, duration of disease, key laboratory and clinical parameters and the treatment received. We compared the results from the four decades to ascertain trends in the causes of mortality. All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS), version 22.0. The 95% confidence intervals for the means of data were calculated.. 111 SLE patients (15%), died during follow-up. Their median age was 51 years (interquartile range (IQR) = 38-63 years) and the median duration of disease, 15 years (IQR = 8.5-24 years). The main causes of death in the past 40 years were infection (31.7%), cancer (26.7%) and cardiovascular disease (CVD) (21.8%). 93.6% of these patients were immunosupressed. During the 40-year period, there were several therapeutic developments notably the introduction of mycophenolate mofetil (MMF) and rituximab; the latter initially only given to patients when more conventional inmunosupressants had failed, but more recently offered to patients at diagnosis. There was a statistically significant increase in the use of hydroxycloroquine (HCQ), MMF and rituximab. In contrast, the use of Azathioprine (AZA) and steroids, hardly changed over time.. This retrospective review shows how epidemiological factors, causes of death and treatment of SLE patients have changed during the last 40 years in the UCLH cohort.

Topics: Adult; Antirheumatic Agents; Azathioprine; Cardiovascular Diseases; Cause of Death; Cohort Studies; Enzyme Inhibitors; Female; Humans; Hydroxychloroquine; Immunocompromised Host; Infections; Lupus Erythematosus, Systemic; Male; Middle Aged; Morbidity; Mortality, Premature; Mycophenolic Acid; Neoplasms; Retrospective Studies; Risk Factors; Rituximab; Steroids; Survival Rate; Time Factors; United Kingdom

Novel immune-modulating anticancer drugs are being used with increasing frequency. With increased use, there are more frequent cases of toxicities caused by these drugs, termed immune-related adverse events (irAEs). We present a case in which we successfully treated a case of severe, steroid-refractory, nivolumab-induced myocarditis with therapeutic plasma exchange (TPE). Nivolumab is an immune checkpoint inhibitor (ICI) which blocks programmed death receptor-1 (PD-1). This blockade allows for enhanced T-cell function and increased anti-tumor response. The patient presented with signs and symptoms of heart failure and was found to have a significantly depressed cardiac ejection fraction. Over the course of her five TPE procedures, she improved clinically and was discharged home with improved left ventricular ejection function. This case suggests an emerging role of TPE in the management of severe ICI-induced toxicity, such as myocarditis.

Topics: Abatacept; Adrenal Cortex Hormones; Adrenal Gland Neoplasms; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Female; Humans; Immune Checkpoint Inhibitors; Immune System; Mycophenolic Acid; Myocarditis; Neoplasms; Nivolumab; Plasma Exchange; Programmed Cell Death 1 Receptor; Steroids

Post-transplantation cyclophosphamide (PTCy) demonstrated effectiveness to prevent GVHD after haploidentical hematopoietic cell transplantation (HCT). Reducing toxicities with a maximized efficacy is still challenging in HCT. In this retrospective study, we analyzed the safety and efficacy of transplantation from a 1-antigen HLA-mismatched unrelated donor (9/10 MMUD) in 80 patients with hematological disorders between 2010 and 2018; 22 patients received PTCy with a reduced dose of 40 mg/kg, cyclosporine A, and mycophenolate mofetil (MMF); 58 patients received anti-thymocyte globulin (ATG), cyclosporine A, and either methotrexate or MMF for GVHD prophylaxis. Cumulative incidence (CI) of acute GVHD grades II-IV in the PTCy group was significantly lower (15% vs. 50%, p = 0.006); however, CI of chronic GVHD was (not significantly) lower in the PTCy group (26% vs. 35%, p = 0.137). One-year OS was significantly longer (p = 0.008) in the PTCy group with a similar 1-year PFS (p = 0.114) in both groups. Rates of 1-year relapse and non-relapse mortality were similar. Median time to neutrophil engraftment was comparable in both GVHD prophylaxis groups (14 days vs. 16 days, respectively, p = 0.107). Our results show that a lower dose of PTCy-based prophylaxis is an effective and safe strategy to prevent acute GVHD in HCT with 9/10 MMUD compared to ATG.

Topics: Adult; Aged; Anemia, Aplastic; Antilymphocyte Serum; Bone Marrow Diseases; Bone Marrow Failure Disorders; Cyclophosphamide; Cyclosporine; Drug Evaluation; Female; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hemoglobinuria, Paroxysmal; Histocompatibility; HLA Antigens; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Retrospective Studies; T-Lymphocytes; Tissue Donors

Topics: Animals; Antineoplastic Agents; Benzene Derivatives; Cell Line, Tumor; Cell Survival; Drug Discovery; Enzyme Inhibitors; Humans; IMP Dehydrogenase; Mice; Molecular Docking Simulation; Neoplasms; NIH 3T3 Cells; Small Molecule Libraries; Structure-Activity Relationship

With the recent approval of 5 PD-1/PD-L1 inhibitors for a number of malignancies, PD-1 axis inhibition is drastically changing the treatment landscape of immunotherapy in cancer. As PD-1/PD-L1 are involved in peripheral immune tolerance, inhibition of this immune checkpoint has led to novel immune-related adverse events including colitis, hepatitis, pneumonitis, rash, and endocrinopathies among many others.. In this seminar, we will analyze the incidence of immune-related adverse events for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. Then, we will discuss the specific management of the most common immune-mediated adverse events including colitis, hepatitis, pneumonitis, rash, endocrinopathies, nephritis, and neurologic toxicities.. Immune-related adverse events are frequently treated with immunosuppressive medication such as steroids and mycofenolate mofetil.. There are specific immune-related adverse events which are frequently seen by the treating oncologist from checkpoint inhibitors. It is essential to understand the recommended treatment options to minimize toxicity and mortality from this important class of anti-neoplastic therapies.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; B7-H1 Antigen; Colitis; Exanthema; Hepatitis; Humans; Immunosuppressive Agents; Immunotherapy; Mycophenolic Acid; Neoplasms; Nephritis; Neurodegenerative Diseases; Nivolumab; Pneumonia; Programmed Cell Death 1 Receptor

BACKGROUND Immunosuppression increases the risk of malignancy in liver transplant recipients. The potential impact of mycophenolate mofetil monotherapy on this risk has not been studied. MATERIAL AND METHODS The incidence and risk factors for de novo malignancies of 392 liver transplant recipients with a survival higher than 3 months and a mean follow-up of 8.5 years were studied. RESULTS De novo malignancies were diagnosed in 126 patients (32.1%) (64 non-melanoma skin cancer and 81 other malignancies). Sixty-nine patients (18.1%) stopped receiving calcineurin inhibitors and were maintained on mycophenolate mofetil monotherapy. The proportion of time on mycophenolate mofetil monotherapy (obtained after dividing the time on monotherapy by the time until diagnosis of neoplasia/last follow-up) was independently associated with a lower risk of de novo malignancy (HR: 0.16, 95% CI: 0.05-0.48; P=0.001), non-melanoma skin cancer (HR: 0.17, 95% CI: 0.03-0.79; P=0.024), and other malignancies (HR: 0.23, 95% CI: 0.07-0.77; P=0.017). Older age and male sex were also associated with a higher risk of malignancy, and transplantation for hepatocellular carcinoma increased the risk of non-melanoma skin cancer. CONCLUSIONS Mycophenolate mofetil monotherapy is associated with a lower risk of cancer in liver transplant recipients compared with maintenance immunosuppression with calcineurin inhibitors.

Topics: Age Factors; Aged; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Risk; Sex Factors

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

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

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

To investigate the chemical constituents of the cultures of Laetiporus sulphureus (Bull.) Murrill.. Compounds were isolated and purified by various chromatographic techniques. The structure of the new compound was determined by interpretation of MS and 1D-, 2D-NMR spectroscopic data, while the known compounds were identified by comparison of their data with those reported.. Three mycophenolic acid derivatives, 6-((2E, 6E)-3, 7-dimethyldeca-2, 6-dienyl)-7-hydroxy-5-methoxy-4-methylphtanlan-1-one (1), 6-((2E, 6E)-3, 7, 11-trimethyldedoca-2, 6, 10-trienyl)-5, 7-dihydroxy-4-methylphtanlan-1-one (2), and 6-((2E, 6E)-3, 7, 11-trimethyldedoca-2, 6, 10-trienyl)-7-hydroxy-5-methoxy-4-methylphtanlan-1-one (3) were isolated.. Among them, compound 1 was new, and compound 2 exhibited moderate cytotoxicity against HL-60, SMMC-7721, A-549, and MCF-7 cells, with IC50 values of 39.1, 31.1, 27.4, and 35.7 μmol·L(-1), respectively.

Topics: Agaricales; Biological Products; HL-60 Cells; Humans; MCF-7 Cells; Molecular Structure; Mycophenolic Acid; Neoplasms; Phenols; Polyporales

Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA) which has been widely used for the prevention of acute graft rejection, is a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) that is up-regulated in many tumors and potentially a target for cancer therapy. MPA is known to inhibit cancer cell proliferation and induces apoptosis; however, the underlying molecular mechanisms remain elusive.. We first demonstrated MPA's antiproliferative and proapoptotic activities using in vitro studies of 13 cancer cell lines and a xenograft model. Key proteins involved in cell cycle, proliferation and apoptosis were analyzed by Western blotting.. In vitro treatment of thirteen cancer cell lines indicated that five cell lines (AGS, NCI-N87, HCT-8, A2780 and BxPC-3) are highly sensitive to MPA (IC50 < 0.5 μg/ml), four cell lines (Hs746T, PANC-1, HepG2 and MCF-7) are very resistant to MPA (IC50 > 20 μg/ml) and the four other cell lines (KATO III, SNU-1, K562 and HeLa) have intermediate sensitivity. The anticancer activity of MPA was confirmed in vivo using xenograft model with gastric AGS cell line. Further in vitro analyses using AGS cells indicated that MPA can potently induce cell cycle arrest and apoptosis as well as inhibition of cell proliferation. Targeted proteomic analyses indicate that many critical changes responsible for MPA's activities occur at the protein expression and phosphorylation levels. MPA-induced cell cycle arrest is achieved through reduction of many cell cycle regulators such as CDK4, BUB1, BOP1, Aurora A and FOXM1. We also demonstrate that MPA can inhibit the PI3K/AKT/mTOR pathway and can induce caspase-dependent apoptosis.. These results suggest that MPA has beneficial activities for anticancer therapy through diverse molecular pathways and biological processes.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Hep G2 Cells; Humans; Inhibitory Concentration 50; Male; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Mycophenolic Acid; Neoplasms; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Signal Transduction; Time Factors; TOR Serine-Threonine Kinases; Tumor Burden; Xenograft Model Antitumor Assays

Previous studies demonstrated a 3-5-fold increased cancer risk in kidney allograft recipients compared with the general population. Our aim was to estimate cancer frequencies among kidney allograft recipients who were transplanted in 1997-2000 and who were immunosuppressed according to a more modern steroid-free standard protocol based on basixilimab, ciclosporine and mycophenolate mofetil.. This was a retrospective cohort study of patients receiving their first kidney allograft in 1997-2000 at Odense University Hospital, Denmark (n = 90). Histologically verified cancers were identified from a detailed search of the individual patient's medical records.. During an average follow-up time of 8.4 years, a total of 14 cancers were observed. The cancer incidence rate was 18.5 (95% confidence interval (CI): 11.0-31.3) per 1,000 years, and the cancer prevalence was 13.4% (95% CI: 5.6-21.2%) among survivors in 2007. The relative risk of prevalent cancer was 3.6 (95% CI: 2.0-6.5) compared with the general population. Patients with cancer had a poorer survival than patients without cancer.. The observed cancer incidence rate and prevalence were similar to figures derived from studies performed in the earlier eras of kidney transplantation. Reducing cancer rates after kidney transplantation remains an important challenge for nephrologists.. not relevant.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Confidence Intervals; Cyclosporine; Denmark; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Neoplasms; Prevalence; Recombinant Fusion Proteins; Retrospective Studies; Risk

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

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

Topics: Azathioprine; Calcineurin Inhibitors; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Mycophenolic Acid; Neoplasms; Organ Transplantation; Propylene Glycols; Protein Kinases; Sphingosine; TOR Serine-Threonine Kinases

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

The relative risk for the development of malignancies following solid organ transplantation seems to be decreased in patients treated with the immunosuppressive agent mycophenolic acid (MPA). However, the molecular mechanisms of the antineoplastic effects of MPA are not completely understood. Here, we report that human endothelial cells and fibroblasts are highly sensitive to MPA treatment. We found that U87 glioblastoma cells were resistant to MPA treatment in vitro. However, U87 tumor growth was markedly inhibited in vivo in BALB/c nude mice, suggesting that MPA exerted its antitumor effects via modulation of the tumor microenvironment. Accordingly, microvascular density and pericyte coverage were markedly reduced in MPA-treated tumors in vivo. Using functional in vitro assays, we showed that MPA potently inhibited endothelial cell and fibroblast proliferation, invasion/migration, and endothelial cell tube formation. To identify the genetic participants governing the antiangiogenic and antifibrotic effects of MPA, we performed genome-wide transcriptional analysis in U87, endothelial and fibroblast cells at 6 and 12 h after MPA treatment. Network analysis revealed a critical role for MYC signaling in endothelial cells treated with MPA. Moreover, we found that the antiangiogenic effects of MPA were organized by coordinated communications between MYC and NDRG1, YYI, HIF1A, HDAC2, CDC2, GSK3B, and PRKACB signaling. The regulation of these "hub nodes" was confirmed by real-time quantitative reverse transcription-PCR and protein analysis. The critical involvement of MYC in the antiangiogenic signaling of MPA was further shown by gene knockdown experiments. Together, these data provide a molecular basis for the antiangiogenic and antifibrotic effects of MPA, which warrants further clinical investigations.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cell Line; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Mice; Mice, Nude; Mycophenolic Acid; Neoplasms; Neovascularization, Pathologic; Proto-Oncogene Proteins c-myc; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; Transcription, Genetic; Xenograft Model Antitumor Assays

To critically assess potentially carcinogenic effects of immunosuppressive therapy in the ocular inflammation setting.. Focused evidence assessment.. Relevant publications were identified by MEDLINE and EMBASE queries and reference list searches.. Extrapolation from transplant, rheumatology, skin disease, and inflammatory bowel disease cohorts to the ocular inflammation setting suggest that: 1) alkylating agents increase hematologic malignancy risk and cyclophosphamide increases bladder cancer risk, but less so with < or =18 months' duration of therapy and hydration, respectively; 2) calcineurin inhibitors and azathioprine probably do not increase total cancer risk to a detectable degree, except perhaps some other risk factors (uncommon in ocular inflammation patients) might interact with the former to raise risk; 3) tumor necrosis factor (TNF) inhibitors may accelerate diagnosis of cancer in the first six to 12 months, but probably do not increase long-term cancer risk; and 4) changes in risk with methotrexate, mycophenolate mofetil, and daclizumab appear negligible, although nontransplant data are limited for the latter agents. Immunosuppression in general may increase skin cancer risk in a sun exposure-dependent manner.. Use of alkylating agents for a limited duration seems justifiable for severe, vision-threatening disease, but otherwise cancer risk may be a relevant constraint on use of this approach. Antimetabolites, daclizumab, TNF inhibitors, and calcineurin inhibitors probably do not increase cancer risk to a degree that outweighs the expected benefits of therapy. Monitoring for skin cancer may be useful for highly sun-exposed patients. Data from ocular inflammation patients are needed to confirm the conclusions made in this analysis by extrapolation.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites; Azathioprine; Daclizumab; Databases, Factual; Humans; Immunoglobulin G; Immunosuppressive Agents; Inflammation; Longitudinal Studies; Methotrexate; Mycophenolic Acid; Neoplasms; Risk Factors; Tumor Necrosis Factor-alpha; Uveitis

To rapidly discover clinically useful angiogenesis inhibitors, we created and screened a library of existing drugs for inhibition of endothelial cell proliferation. Mycophenolic acid (MPA), an immunosuppressive drug, was found to potently inhibit endothelial cell proliferation in vitro and block tumor-induced angiogenesis in vivo. Using RNA interference, we found that knockdown of one of the two known isoforms of inosine monophosphate dehydrogenase (IMPDH-1) is sufficient to cause endothelial cell cycle arrest.

Topics: Angiogenesis Inhibitors; Animals; Cell Proliferation; Cells, Cultured; Enzyme Inhibitors; Humans; IMP Dehydrogenase; Mice; Molecular Structure; Mycophenolic Acid; Neoplasms; RNA Interference; Umbilical Cord

Malignancy after organ transplantation has been described as the "price of immunotherapy." Evolving strategies aimed at effective immunosuppression could have differing effects on the likelihood of developing malignancy. We analyzed data from the transplant registry of the International Society for Heart and Lung Transplantation (ISHLT) to ascertain which factors are associated with the development of malignancy after orthotopic heart transplantation (OHT).. Multivariate modeling was performed to determine factors predictive of first post-transplant malignancy in patients taking standard immunosuppressive regimens, defined as cyclosporine or tacrolimus and azathioprine or mycophenolate mofetil (MMF), who underwent OHT between January 1, 1995 and December 31, 1997.. Of the 3,895 transplants described in the cohort, 703 (18%) developed post-transplant malignancy at any time during the follow-up period, and 549 (14%) developed malignancy within the first 5 years post-transplant. The breakdown of malignancy was as follows: skin: 47%; post-transplant lymphoproliferative disease: 10%; other malignancies: 24%; combination of types: 10%; and unreported: 10%. Multivariate modeling revealed that independent predictors of increased risk were prior malignancy and increased age, whereas the use of MMF as part of a standard immunosuppressive regimen was associated with an adjusted relative risk (RR) = 0.73 (95% confidence interval 0.56 to 0.95). Relative to a recipient age of 55 years, the risk of malignancy for 30, 45 and 60 years of age was 0.32, 0.46 and 1.37, respectively. Although the use of tacrolimus appeared protective in the univariate analysis, it was not significant according to multivariate analysis. Female gender appeared to be protective. Neither OKT3 nor anti-thymocyte globulin (ATG) use was associated with a significantly increased risk of malignancy.. The choice of immunosuppressive regimen may affect the likelihood of developing malignancy after OHT. Induction immunosuppression does not appear to increase the risk of subsequent malignancy. The use of MMF in standard immunosuppressive regimens is associated with a significantly lower risk of developing malignancy.

Topics: Aging; Cohort Studies; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Internationality; Lung Transplantation; Male; Medical Records; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Neoplasms; Registries; Risk; Sex Factors; Societies, Medical

Outcomes specifically in mycophenolate mofetil (MMF)-treated diabetic renal transplant patients have not been previously reported. This study compared acute rejection (AR), late acute rejection (LAR), patient survival [and specifically death from cardiovascular (CV), infectious and malignant causes], incidence of post-transplant malignancies, and graft loss in MMF- or azathioprine (AZA)-treated renal transplant patients with pre-transplant diabetes. Outcomes were compared between MMF- (n = 14 144) and AZA- (n = 3001) treated diabetic patients using the Scientific Registry of Transplant Recipients data on all U.S. adult renal transplants performed between 1995 and 2002. Statistical analyses included Kaplan-Meier survival analysis, Cox multivariable regression and chi-square tests. MMF patients had less AR compared with AZA-treated patients (23.5% vs. 28.3%, p < 0.001) and less risk for LAR over 4 yr [hazard ratio (HR): 0.64, 95% CI 0.44, 0.92; p = 0.02]. While time to any-cause death did not differ between the groups, MMF treatment was associated with a 20% decreased risk of CV death (HR: 0.80, 95% CI 0.67, 0.97; p = 0.020) compared with AZA treatment. MMF patients also had a lower incidence of malignancies than AZA patients (2.2% vs. 3.7%, p < 0.001). These results suggest treatment with MMF compared with treatment with AZA in diabetic transplant patients is associated with less AR, less risk of LAR, a decreased risk of CV death, and a lower incidence of malignancies.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azathioprine; Black People; Cause of Death; Diabetes Complications; Female; Graft Rejection; Graft Survival; Heart Diseases; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Infections; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Survival Rate; United States; White People

The most undesirable complication of an effective immunosuppressive therapy is neoplastic tumor recurrence or the development of de novo cancer. Though the immunosuppressive drug, mycophenolate mofetil (MMF), has been introduced into clinical practice, no data dealing with the influence of MMF on tumor cell malignancy are available. We analyzed the adhesion capacity of colon, pancreas and kidney carcinoma cell lines to endothelium, as well as their chemokine profile before and after MMF treatment. Tumor cell adhesion to endothelial cell monolayers was evaluated in the presence of 0.1, 1, and 10 microM MMF and compared to unstimulated controls. Chemokine analysis concentrated on the CXC family, including 6 CXC-receptors (CXCR) and 15 CXC-ligands (CXCL), and was carried out by reverse transcriptase-polymerase chain reaction and flow cytometry. MMF strongly diminished the adhesion capacity of HT-29 colon tumor cells but not of DanG pancreas tumor cells to endothelium. MMF also had a strong impact on the chemokine profile of colon, kidney and pancreas carcinomas, whereby individual changes were observed, depending on the tumor type. Down-regulating effects on chemokines did not correlate with down-regulating effects on tumor cell adhesion. Since several of the chemokines investigated are regulatory elements in the process of cell transformation, dissemination and angiogenesis, we speculate that MMF might prevent post-transplant tumor recurrence and transendothelial migration. However, the efficacy of MMF might differ according to the tumor type.

Topics: Cell Adhesion; Chemokines, CXC; Endothelial Cells; Endothelium, Vascular; Gene Expression; Gene Expression Profiling; Immunosuppressive Agents; Mycophenolic Acid; Neoplasms; Receptors, Chemokine; RNA, Messenger; Tumor Cells, Cultured

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

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

Topics: Adjuvants, Immunologic; Age Factors; Antimalarials; Antiphospholipid Syndrome; Cyclophosphamide; Dehydroepiandrosterone; Female; Heart Diseases; Humans; Immunosuppressive Agents; Kidney Diseases; Lupus Erythematosus, Systemic; Male; Middle Aged; Mycophenolic Acid; Neoplasms

Mycophenolate mofetil (MMF) has been shown to have promise in short-term liver transplantation graft rescue studies. The purpose of this study was to evaluate the long-term efficacy and safety of MMF in liver transplant patients who had failed cyclosporine (CsA)-based conventional immunosuppression.. Nineteen orthotopic liver allograft recipients were converted from azathioprine to MMF in combination with CsA and prednisone in this prospective, open-labeled, single-center, graft rescue, pilot study. Six patients were taken off CsA when MMF was initiated. A 4-year patient follow-up is reported here. Patients were considered to have failed CsA-based immunosuppression either for refractory rejection, chronic rejection, or severe CsA neurologic toxicity.. Twelve patients had complete histologic resolution, two had partial resolution, and three had worsening of their rejection. Thirteen patients had a complete biochemical response; one had a partial response and four had worsening of their rejection. Two patients had no histologic and one no biochemical follow-up. Of the six patients treated with MMF and prednisone alone, four had complete resolution of rejection without recurrence. The majority of adverse reactions were gastrointestinal [nausea and/or vomiting (n=5); diarrhea (n=8); gastritis, duodenitis, or esophagitis (n=4); and ulcers (n=2)] or bone marrow suppressive [leukopenia (n=9), anemia (n=6), and thrombocytopenia (n=5)].. MMF seems to be an effective alternative immunosuppressive in patients failing CsA-based conventional therapy. MMF may be of particular benefit in patients who do not tolerate CsA or tacrolimus. The long-term safety profile is similar to that of other immunosuppressives.

Topics: Adult; Cytomegalovirus Infections; Female; Follow-Up Studies; Gastrointestinal Diseases; Graft vs Host Disease; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Treatment Outcome

Cultured tumor cell lines, tumor xenografts grown in athymic nude mice, and a murine experimental metastasis model were used to assess the in vitro and in vivo anti-tumor activity of the potent IMP dehydrogenase (IMPDH) inhibitor, mycophenolic acid (MPA), and its morpholinoethyl ester pro-drug, mycophenolate mofetil (MM). The growth of all the cell lines tested was inhibited by MPA in vitro, with EC50 values ranging from less than 0.1 microM to 3.9 microM. Mice were monitored for s.c. tumor outgrowth in the case of human tumor xenograft models or survival time for the murine experimental metastasis model. Treatment with MM p.o. was started 24 hr after tumor challenge or after tumors became palpable. Treatment of athymic nude mice bearing A3.01 (T-lymphoblast), Molt-4 (T-cell leukemia), CaPan-2 (pancreatic adenocarcinoma), CaLu-3 (non-small-cell lung adenocarcinoma), LS174T and T84 (colon adenocarcinoma), and Daudi (B-cell lymphoma) human tumor xenografts with MM significantly inhibited s.c. tumor growth. Treatment of BALB/c mice with MM after i.v. injection of murine RAW117-H10 lymphoma cells in an experimental metastasis assay resulted in increased survival time for treated animals. No significant inhibitory effect on s.c. tumor outgrowth was seen with MM treatment of SK-Hep-1, a human hepatic endothelioma, or Hep-3B, a liver adenocarcinoma, at any of the doses tested.

Topics: Animals; Antineoplastic Agents; Cell Division; Disease Models, Animal; Drug Screening Assays, Antitumor; Female; Humans; IMP Dehydrogenase; Leukemia; Lymphoma; Mice; Mice, Inbred BALB C; Mice, Nude; Mycophenolic Acid; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Transplantation, Heterologous

In previous studies of up to 2 years' duration, mycophenolic acid has been shown to be an effective psoriasis suppressant. As the result of questions raised regarding the possible immunosuppressive and carcinogenic potentials of the drug, in addition to its apparent acute gastrointestinal side effects, widespread clinical trials were discontinued in 1977. We were given the unique opportunity of continuing to administer the drug on a compassionate-use basis to 85 patients for up to 13 years. In this review we report continued efficacy without dose escalation. Gastrointestinal side effects, prominent in the early years of the study, became infrequent. Although 11.6% of the patients developed uncomplicated zoster, no clinical evidence of immunosuppression was noted. The seven malignant neoplasms that arose in six of the patients were not unusual considering the age of the study population. Six patients died of conditions believed to be unrelated to drug therapy. We continue to believe that mycophenolic acid is an effective drug for the treatment of moderate to severe psoriasis and that the risks of its long-term administration are acceptable. With appropriate clinical and laboratory monitoring it can be given safely to patients who cannot take methotrexate and who may not be candidates for PUVA, retinoids, or other systemic chemotherapy.

Topics: Adult; Aged; Arthritis; Capsules; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Psoriasis

Topics: Animals; Cell Communication; Cell Fusion; Cell Line; Cell Transformation, Neoplastic; Drug Resistance; Genetic Vectors; Mice; Mice, Nude; Mycophenolic Acid; Neoplasms; Plasmids

CAM is a derivative compound of mycophenolic acid produced by Penicillium brevicompactum, and is a new oral Purine antagonistic anticancer agent. The Phase I study was carried out cooperatively in ten hospitals. The results are as follows: The administration method was single administration and the starting dose was 200 mg/m2 (1n). The dose level was escalated according to varied Fibonacci formula. The number of total cases was thirty-one: three cases at 1n level, four at 2n, six at 3.3n, six at 7n and seven at 9n. Side effects were observed in five of thirteen cases over 7n dose levels, such as nausea, vomiting, anorexia and diarrhea. Leukopenia was developed in only one case at 7n dose level. Other side effects such as anemia, thrombocytopenia, and disturbances of liver function and renal function were not observed. It was estimated from above results that a dose limiting factor of CAM is nausea and vomiting. A subtoxic dose was 7n (1,400 mg/m2) and a maximum tolerated dose was 9n (1,800 mg/m2) which corresponded to 2,200-3,000 mg as a single administration.

Topics: Animals; Antineoplastic Agents; Dogs; Drug Evaluation; Female; Humans; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Rats