Background: Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication following solid organ transplantation, and is the second most common malignancy in this patient population. Many posttransplant lymphomas develop from the uncontrolled proliferation of Epstein-Barr-virus (EBV)-infected B-cells, whereas EBV-negative PTLDs have increasingly been recognized within the past decade. Case: We report on a 47-year-old EBV-seronegative male who developed biopsy-proven EBV positive post-transplantation lymphoproliferative disorder (PTLD) one year after successful cardiac transplantation secondary to ischemic cardiomyopathy while being treated with immunosuppressive agents. He was on maintenance immunosuppression of cyclosporine (85mg bid), everolimus (1.25mg bid), and prednisolone (5mg per day). During routine follow-up elevated markers suggestive of an infection (CRP, Leucocytosis) were found and chest x-ray showed bi - pulmonary masses. Antibiotic treatment was instantly initiated based on the assumed diagnosis of bacterial pneumonia. Since clinical condition did not improve, CT-guided puncture of the susceptive nodules was indicated yielding material for histologic evaluation. A high-malignant diffuse large B-cell-lymphoma was diagnosed and tested positive for EBV with in-situ hybridization. Anti-infectious medication was terminated and therapy with monoclonal antibody (rituximab) was initiated, followed by seven cycles of chemotherapy (cyclophosphamide, caelyx, vincristine, dexamethasone) and low-dose immunosuppressive maintainance therapy (cyclosporine, everolimus). Over the next 6 months, the pulmonary masses gradually decreased in size. One year after the initial diagnosis, routine follow-up in our outpatient heart failure clinic demonstrated complete remission by serial CT-scans. At present, the clinical condition of this patient is stable with satisfactory organ function. Conclusion: Development of PTLD is frequent in solid organ transplant candidates and is associated with high morbidity and mortality. The diagnosis may be challenging and differentiation from an infectious process is important. Higher intensity of immunosuppression and exposure to EBV seem to be relevant risk factors justifying close posttransplant surveillance. We report a case under maintainance therapy with cyclosporine and everolimus. Monoclonal antibody therapy (rituximab) and adjunctive chemotherapy was successful in inducing complete remission so far.
Lung transplantation and related medications are associated with pathobiological changes that can induce frailty, a state of decreased physiological reserve. Causes of persistent or emergent frailty after lung transplantation, and whether such transplant-related frailty is associated with key outcomes, are unknown.Frailty and health-related quality of life (HRQL) were prospectively measured repeatedly for up to 3 years after lung transplantation. Frailty, quantified by the Short Physical Performance Battery (SPPB), was tested as a time-dependent binary and continuous predictor. The association of transplant-related frailty with HRQL and mortality was evaluated using mixed effects and Cox regression models, respectively, adjusting for age, sex, ethnicity, diagnosis, and for body mass index and lung function as time-dependent covariates. We tested the association between measures of body composition, malnutrition, renal dysfunction and immunosuppressants on the development of frailty using mixed effects models with time-dependent predictors and lagged frailty outcomes.Among 259 adults (56% male; mean age 55.9±12.3 years), transplant-related frailty was associated with lower HRQL. Frailty was also associated with a 2.5-fold higher mortality risk (HR 2.51; 95% CI 1.21 to 5.23). Further, each 1-point worsening in SPPB was associated, on average, with a 13% higher mortality risk (HR 1.13; 95% CI 1.04 to 1.23). Secondarily, we found that sarcopenia, underweight and obesity, malnutrition, and renal dysfunction were associated with the development of frailty after transplant.Transplant-related frailty is associated with lower HRQL and higher mortality in lung recipients. Abnormal body composition, malnutrition and renal dysfunction may contribute to the development of frailty after transplant. Confirming the role of these potential contributors and developing interventions to mitigate frailty may improve lung transplant success.
Objectives: Mitral valve regurgitation (MR) of any degree is a common finding in failing hearts and is caused by left ventricular dilatation. However, the impact of MR at time of ventricular assist implantation on outcome is a matter of debate. The aim of this study is to evaluate the influence of pre-implant MR on long-term outcome and to assess changes in MR severity and left ventricular geometry during follow-up.
Although human embryonic stem cells (hESC) have enormous potential for cell replacement therapy of heart failure, immune rejection of hESC derivatives inevitably would occur after transplantation. We therefore aimed to generate a hypoantigeneic hESC line with improved survival characteristics.Using various in vivo, nonischemic, hindlimb xenotransplant models (immunocompetent and defined immunodefective mouse strains) as well as human in vitro T-cell and natural killer (NK)-cell assays, we revealed a central role for T cells in mediating hESC rejection. The NK-cell susceptibility of hESC in vivo was found to be low, and the NK response to hESC challenge in vitro was negligible. To reduce the antigenicity of hESC, we successfully generated human leukocyte antigen (HLA) I knockdown cells (hESC(siRNA+IB)) using both HLA I RNA interference (siRNA) and intrabody (IB) technology. HLA I expression was ≈99% reduced after 7 days and remained low for weeks. Cellular immune recognition of these hESC(siRNA+IB) was strongly reduced in both xenogeneic and allogeneic settings. Immune rejection was profoundly mitigated after hESC(siRNA+IB) transplantation into immunocompetent mice, and even long-term graft survival was achieved in one third of the animals without any immunosuppression. The survival benefit of hESC(siRNA+IB) was further confirmed under ischemic conditions in a left anterior descending coronary artery ligation model.HLA I knockdown hESC(siRNA+IB) provoke T-cell ignorance and experience largely mitigated xenogeneic rejection. By generating hypoantigeneic hESC lines, the generation of acceptable hESC derivatives may become a practical concept and push cell replacement strategies forward.
Current hormone therapy in postmenopausal women is associated with uterotrophic activity and cancer-promoting effects. In this experimental study, we compared the effects of the selective estrogen-receptor (ER) beta agonist biochanin A, and the selective ERalpha agonist ethinylestradiol, on the development of intimal hyperplasia after balloon injury and on uterus morphology.Female F344 rats with or without prior ovariectomy were used for aortic denudations. Animals remained untreated or received oral biochanin A (100 mg/kg) or ethinylestradiol (100 microg/kg). After 14 days, aortas and uteri were harvested for histologic and immunohistochemical analyses. Computerized assessments of aortic adhesion molecule expression, and isometric relaxation experiments, and uteri were analyzed. In vitro studies with smooth muscle cells and endothelial cells were performed to further investigate the effects of hormone treatment on cell proliferation, migration and adhesion molecule expression.Among untreated rats, ovariectomized animals tended to show greater neointimal hyperplasia and increased expression of the adhesion molecules 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). Biochanin A treatment reduced neointima formation, inhibited VCAM-1 up-regulation, and improved the vascular relaxation response. No effect was observed on uterus growth or histology. Ethinylestradiol also reduced aortic neointima formation and inhibited VCAM-1 up-regulation, but failed to improve endothelial function and significantly induced uterus growth. Both agents showed antiproliferative and weak antimigratory effects on smooth muscle cells, and reduced VCAM-1 expression on stimulated endothelial cells in vitro.The ERbeta agonist biochanin A shows vasculoprotective effects without uterotrophic activity. Because hormone therapy may have cancer-promoting side effects, administration of ERbeta-selective agents might be alternatively used to reduce the risk of cardiovascular disease in postmenopausal women.
