Thymomas and thymic carcinomas: prognostic factors and multimodal management.

BACKGROUND: Thymomas and thymic carcinomas are rare malignant tumors. We report the experience with the resection and multimodal treatment at a single department in Central Europe in the years 2001 to 2010. OBJECTIVE: We sought to determine prognostic factors in this patient population. METHODS: A 10-year retrospective analysis of 84 resections on 72 patients for thymomas/thymic carcinomas or their recurrences was performed. RESULTS: Patients admitted to a single thoracic surgery center presented with Masaoka-Koga stage I (29.2%), II (43.1%), III (13.9%), and IV (13.9%). In approximately 88.9% of cases, a complete resection could be reached. Using overall survival as an outcome measure, the 5-year survival rate was 87%. Of all the cases presented, 9.7% cases showed tumor recurrence and 6.9% cases showed tumor progression. There was decreased survival rate with increasing Masaoka-Koga stage (p = 0.017) and incomplete resection (p < 0.001). CONCLUSION: Completeness of resection and Masaoka-Koga stage were significant prognostic factors. Multidisciplinary treatments of patients with thymoma or thymic carcinoma result in good patient care, and global efforts with larger number of patients are needed to elucidate more about the biology, diagnosis, and treatment of these tumors.

The receptor for advanced glycation endproducts and its ligands in patients with myasthenia gravis.

OBJECTIVE: Myasthenia gravis (MG) is a T- and B-cell mediated autoimmune disorder affecting the neuromuscular junction. The receptor for advanced glycation endproducts (RAGE) plays a role in the amplification of chronic inflammatory disorders and autoimmune diseases. We sought to investigate the role of RAGE and its ligands in the pathophysiology of MG. METHODS: In this cross-sectional study we enrolled 42 patients with MG and 36 volunteers. We employed enzyme-linked immunosorbent assays to determine the concentration of soluble RAGE (sRAGE) and high mobility group box 1 (HMGB1) in serum of patients and volunteers. In a subpopulation of patients we measured the serum levels of endogenous secretory (es) RAGE and various RAGE ligands, such as S100B, S100A8 and advanced glycation endproducts (AGE-CML). Reported are means and standard error mean. RESULTS: We found significantly reduced levels of the soluble receptors sRAGE and esRAGE in patients with MG compared to volunteers without MG (sRAGE [pg/ml] 927.2 ± 80.8 vs. 1400.1 ± 92.4; p<0.001; esRAGE [pg/ml] 273.5±24.6 vs. 449.0 ± 22.4; p<0.001). Further categorization of patients with MG according to the distribution of muscle involvement revealed the following sRAGE concentrations: generalized MG 999.4 ± 90.8 and ocular MG 696.1 ± 161.8 (vs. control; One-way ANOVA: p<0.001; Post hoc analysis: generalized vs. ocular MG: p=0.264, generalized MG vs. control: p=0.008, ocular MG vs. control: p=0.001). In patients with detectable antibodies specific for acetylcholine receptors (Anti-AChR positive) the sRAGE concentration was 970.0 ± 90.2 compared to those without (seronegative) 670.6 ± 133.1 (vs. control; One-way ANOVA: p<0.001; Post hoc analysis: Pos vs. Neg.: p=0.418, Pos vs. control: p=0.003, Neg. vs. control: p=0.008). We next investigated the role of RAGE ligands in MG. The concentrations of RAGE ligands in patients with MG and controls were as follows: (HMGB1 [ng/ml] 1.7 ± 0.1 vs. 2.1 ± 0.2; p=0.058; S100B [pg/ml] 22.5 ± 22.5 vs. 14.4 ± 9.2; p=0.698; S100A8 [pg/ml] 107.0 ± 59.3 vs. 242.5 ± 103.6; p=0.347; and AGE-CML [ng/ml] 1100.8 ± 175.1 vs. 1399.8 ± 132.8; p=0.179). CONCLUSIONS: Our data suggest a role for the RAGE pathway in the pathophysiology of MG. Further studies are warranted to elucidate more about this immunological axis in patients with MG.

Early sST2 Liberation after Implantation of a Left Ventricular Assist Device in Patients with Advanced Heart Failure.

Background: The use of left ventricular assist device (LVAD) has increased considerably over the past decade; however, there is limited literature to assist in patient selection and monitoring. The frequency of adverse events remains high. We examined the early expression of circulating soluble ST2 (sST2), a biomarker with immunosuppressive and profibrotic activity, and assessed the risk of death at 1 year in patients receiving LVAD implant. Methods: We prospectively enrolled 20 heart failure patients and measured sST2, IL-33, and IL-6 serum concentrations over three weeks after LVAD implantation. We compared the kinetics of IL-6, sST2, and IL-33 release in survivors with those of nonsurvivors using mixed model two-way analysis of variance for repeated measures. We also collected data on hemodynamic parameters (i.e., cardiac output) and frequency of infections during the hospital stay. Results: LVAD therapy led to an immediate and significant improvement of the hemodynamic parameters in 1-year survivors and nonsurvivors alike. The 1-year survival rate was 65%. IL-6 concentrations showed a significant (p = 0.03) peak at admission to the intensive care unit following LVAD implantation, whereas sST2 levels were massively increased (p < 0.0003) on day 1. While 1-year survivors had persistently lower sST2 values compared to nonsurvivors during the first 3 weeks after LVAD implantation (p = 0.012), no differences were observed in the temporal pattern of IL-6 or IL-33. The odds of detecting Candida species in the bronchoalveolar lavage fluid were 14 times higher in nonsurvivors than in survivors (OR 13.7, CI 1.4-127, p = 0.02). Conclusion: In patients implanted with LVAD, circulating sST2 levels and frequency of Candida colonisation were associated with higher mortality. Awareness of this early immune response can guide physicians in risk-benefit analysis.

Comparison of combined prophylaxis of cytomegalovirus hyperimmune globulin plus ganciclovir versus cytomegalovirus hyperimmune globulin alone in high-risk heart transplant recipients.

BACKGROUND: Seronegative heart transplant recipients who receive an allograft from seropositive donors have a higher risk of developing cytomegalovirus (CMV) disease and cardiac allograft vasculopathy (CAV) and dysfunction. Neither CMV-specific hyperimmune globulin nor ganciclovir as sole CMV prophylaxis is sufficient to prevent CMV disease in high-risk patients. We retrospectively evaluated the efficacy of CMV-hyperimmune globulin with and without ganciclovir in 207 D+/R- heart transplant recipients. METHODS: The study population was divided into two groups: Group A was composed of 96 patients who received CMV hyperimmune globulin as sole CMV prophylaxis, and group B was composed of 111 patients who received combined CMV prophylaxis. All recipients were subjected to quadruple cytolytic immunosuppression. Primary and secondary end points included prevention of CMV-associated death, CMV disease and productive infection, CAV, and overall infection. RESULTS: There was no difference in overall survival between the two groups. Four patients in the group A died of CMV sepsis, whereas no CMV-associated death was observed in group B (P =0.0326). The actuarial incidence of CMV disease was significantly lower in patients who received double CMV prophylaxis (32.29 vs. 11.71, P =0.0003). Although no difference was observed with regard to productive CMV infection (53.12 vs. 65.77, P =not significant), CAV and overall infection rates were significantly higher in the first group (7.29 vs. 0.9, P =0.0157 and 70.83 vs. 62.16, P =0.03, respectively). CONCLUSIONS: Double CMV prophylaxis consisting of CMV hyperimmune globulin and ganciclovir is able to abolish CMV death and prevent CMV disease in high-risk heart transplant recipients. Therefore, the use of a combination regimen is recommended for seronegative recipients with seropositive donors.

B-cell activation and allosensitization after left ventricular assist device implantation is due to T-cell activation and CD40 ligand expression.

Left ventricular assist device (LVAD) implantation is frequently complicated by B-cell activation and allosensitization, posing a significant risk to successful transplant outcome. This study investigated whether B-cell hyperreactivity and alloantibody production in LVAD recipients involves T-cell dependent pathways. T-cell calcium flux and nuclear translocation of NFATc were used to determine states of T-cell activation. Flow cytometry was used to assess human T- and B-cell activation after culture with LVAD-derived biomaterial particles. Sera from LVAD recipients and controls were tested for the presence of anti-HLA antibodies, and for soluble CD40 ligand. LVAD-derived biomaterial induced rapid and sustained calcium flux into normal T cells, resulting in calcineurin-dependent nuclear translocation of NFATc. This resulted in increased T-cell expression of CD40 ligand and subsequent B-cell activation, which was reduced by inhibitors of T-cell activation (CsA or anti-CD25 mAb) or by anti-CD40 ligand mAb. LVAD recipients demonstrated higher frequencies of anti-HLA antibodies and serum levels of soluble CD40 ligand compared with heart failure controls. The results indicate that exposure of human mononuclear cells to LVAD-derived biomaterial leads to T-cell dependent B-cell activation via CD40--CD40 ligand interaction, and suggest that treatment with calcineurin inhibitors or monoclonal antibodies against either CD25 or CD40 ligand could be effective at preventing B-cell hyperreactivity and allosensitization after LVAD implantation.

Immunobiologic consequences of assist devices.

The aberrant state of monocyte and T-cell activation resulting from these host-device interaction is accompanied by two parallel processes: (1) selective loss of Th1 cytokine-producing CD4 T cells through activation-induced cell death, and (2) unopposed activation of Th2 cytokine-producing CD4 T cells resulting in B-cell hyperreactivity and dysregulated immunoglobulin synthesis via Th2 cytokines and heightened CD40 ligand-CD40 interactions. The net result of these events is that on one hand the VAD recipient develops progressive defects in cellular immunity and is at increased risk of serious infection, and on the other hand the VAD recipient is more likely to develop allosensitization, posing a significant risk to successful transplant outcome.

Long-term survival (>10 years) of patients >60 years with induction therapy after cardiac transplantation.

OBJECTIVE: Cardiac transplantation has become an established method for end-stage heart disease. Short- and mid-term outcome has been known to be similar between younger and older (>60 years) recipients. So far, nothing is known about long-term outcome of old patients and the potential long-term effects of antibody induction therapy in these patients. The purpose of this study was to analyse long-term outcome of old cardiac transplant recipients who underwent antibody induction therapy. METHODS: Since 1989, 203 patients (total n = 882) above 60 years have been transplanted at our center. On these patients n = 66 were above 65 years. Survival, incidences of rejection, infection, cancer, graft arteriosclerosis and the amount of renal insufficiency were compared with patients <60 years (n = 679), transplanted during the same period of time. Freedom from specific event was computed by Kaplan-Meier analysis and compared by log-rank test. RESULTS: Ten year survival was similar in all groups (<60 years: 53.7%; 60-64 years: 53.1% and >65 years: 60.2%; P = NS). Causes of death were similar in all patient groups. There were significant fewer rejection episodes in the older patient group (freedom from rejection: 74.9 vs. 83.5 vs. 90.6; P = 0.03). Yet significantly more number of patients >65 years were without steroid maintenance therapy (43.1%) compared to other patient groups (8.2 vs. 9.3%; P < 0.05). There was no difference in overall freedom from severe infection (74.1 vs. 67.7 vs. 85.3%; P = NS), whereas there was a trend towards more CMV disease in the oldest patient group (82.7 vs. 88.6 vs. 70.8%; P=0.06). The incidence of cancer was similar in all groups (freedom from cancer: 82.2 vs. 84.7 vs. 79.1%; P = NS), as well as there was no difference in severe graftsclerosis between all patients (79.2 vs. 93.7 vs. 93.3%; P = NS). There was no difference in development of chronic renal dysfunction (creatinine > 2.0 mg/dl) between the three groups (10 vs. 14 vs. 16%; P = NS). CONCLUSIONS: Old recipients of cardiac transplants have a similar long-term outcome than younger recipients. They were less prone to rejections, had a similar incidence of severe infections and showed a trend towards more CMV disease. All patients had a very low rate of graft arteriosclerosis that was similar amongst the groups. Age-related decline of the immune system further enhanced by immunomodulation of antibody induction therapy might be accounted for the results as well as steroid-free immunosuppression.

Non-melanoma skin cancer and its risk factors in an Austrian population of heart transplant recipients receiving induction therapy.

BACKGROUND: Solid organ transplant recipients have a high risk of developing nonmelanoma skin cancers (NMSC). We describe the characteristics and incidence of skin tumors in an Austrian population of heart transplant recipients (HTR). METHODS: Three hundred and twenty-two HTR out of 970 who had received their organ between December 1984 and July 2003 were analyzed for NMSC. Factors associated with tumor development including the different immunosuppressive (IS) modalities were evaluated. Besides triple combination immunosuppressive therapy, all allograft recipients had received induction therapy either with antithymocyte globulin, OKT3 or monoclonal anti-IL-2 receptor antibodies. RESULTS: Median post-transplant follow-up for all patients was 74.18 months (minimum: 2.6, maximum: 224.8). The median time from transplantation until the excision of the first NMSC was 79.57 months (minimum: 2.69, maximum: 192.8). A total of 263 NMSC were excised in 73 patients. The cumulative incidence of developing a skin tumor increased from 7.3% after 5 years to 26.9% after 10 years and to 56.5% after 15 years. Older age at transplantation (P < 0.0001) and the presence of pre-cancerous skin conditions (P < 0.0001) were associated with an increased occurrence of NMSC. No significant difference in NMSC incidence was found when the different IS therapies were compared. CONCLUSIONS: The cumulative incidence of NMSC in our cohort of HTR is comparable to published data on HTR adjusted according to the geographic location. Transplant patients with clinical evidence of pre-cancerous skin conditions have a higher degree of susceptibility for the development of NMSC and require particular dermatologic care.

Is the transpulmonary pressure gradient a predictor for mortality after orthotopic cardiac transplantation?

Elevated pulmonary vascular resistance (PVR) is a well-known risk factor for right ventricular failure after orthotopic cardiac transplantation. The influence of preoperative transpulmonary pressure gradient (TPG) and PVR on post-transplant 30 days mortality was evaluated. To analyze the response of PVR and TPG to cardiac transplantation, we analyzed 718 adult patients undergoing primary cardiac transplantation. Indications for operation were: 35.2% ischemic cardiomyopathy (ICM), 61.2% idiopathic dilated cardiomyopathy (DCM), and 3.3% other diagnosis (e.g. hypertrophic cardiomyopathy). The mean age (51.9) and the mean ischemic time (169.7 min) were comparable between 30 days survivors and nonsurvivors. Student's t-tests and chi-square analysis were used to compare data from 30-day survivors and nonsurvivors. Statistical significance was defined as P < 0.05. Fisher's exact test and multiple logistic regression analysis was performed to evaluate the relationship between hemodynamic parameters and outcome after transplantation. Primary end-point was 30 days mortality and secondary end-point long-term survival of patient groups with different TPG and PVR values. In survivors the mean TPG was 10.3 +/- 5.1 (mean +/- SD) vs. 13 +/- 6.6 in patients who died after transplantation (P = 0.0012). The PVR was 2.6 +/- 1.4 vs. 3.5 +/- 2.2 (P = 0.0012). In multivariate logistic regression, the parameters TPG and PVR exhibit a significant influence between survivors and nonsurvivors after cardiac transplantation within 30 days (TPG: P = 0.0012; PVR: P = 0.0012). The mortality rates in patients with TPG > 11 mmHg and PVR < 2.8 Wood units or TPG < 11 mmHg and PVR > 2.8 Wood units were comparable to those with TPG < 11 mmHg and PVR < 2.8 mmHg. The TPG is an important predictor in nonrejection-related early mortality after orthotopic cardiac transplantation. The determination of TPG in combination with PVR is a more reliable predictor of early post-transplant survival than PVR alone.

Extracorporeal membrane oxygenation is superior to right ventricular assist device for acute right ventricular failure after heart transplantation.

BACKGROUND: Acute right ventricular failure after heart transplantation is a life-threatening condition, and sometimes the use of mechanical circulatory support is inevitable. The aim of this retrospective study was to investigate the effectiveness of two different mechanical circulatory support systems for this indication. METHODS: From 1984 to 2003, 28 heart transplant recipients exhibited right ventricular failure resistant to drug therapy. Right ventricular assist device (n = 15) or extracorporeal membrane oxygenation (n = 13) was implanted to support the failing heart. RESULTS: Overall in-hospital survival was 43%. In the right ventricular assist device group, only 2 patients (13%) could be weaned from mechanical circulatory support compared with 10 patients (77%) in the extracorporeal membrane oxygenation group (p = 0.001). Retransplantation was necessary in 6 patients in the right ventricular assist device group and in 1 patient in the extracorporeal membrane oxygenation group (p = 0.049). There was no difference in patient survival between groups, but graft survival was significantly better in the extracorporeal membrane oxygenation group (p = 0.005). CONCLUSIONS: In view of these results, extracorporeal membrane oxygenation seems to be the better option as mechanical circulatory support for right ventricular failure in heart transplantation.