German Transplant Research Articles

Orthotopic liver transplantation in human-immunodeficiency-virus-positive patients in Germany.

Objectives. This summary evaluates the outcomes of orthotopic liver transplantation (OLT) of HIV-positive patients in Germany. Methods. Retrospective chart analysis of HIV-positive patients, who had been liver-transplanted in Germany between July 1997 and July 2011. Results. 38 transplantations were performed in 32 patients at 9 German transplant centres. The reasons for OLT were end-stage liver disease (ESLD) and/or liver failure due to hepatitis C (HCV) (n = 19), hepatitis B (HBV) (n = 10), multiple viral infections of the liver (n = 2) and Budd-Chiari-Syndrome. In July 2011 19/32 (60%) of the transplanted patients were still alive with a median survival of 61 months (IQR (interquartile range): 41–86 months). 6 patients had died in the early post-transplantation period from septicaemia (n = 4), primary graft dysfunction (n = 1), and intrathoracal hemorrhage (n = 1). Later on 7 patients had died from septicaemia (n = 2), delayed graft failure (n = 2), recurrent HCC (n = 2), and renal failure (n = 1). Recurrent HBV infection was efficiently prevented in 11/12 patients; HCV reinfection occurred in all patients and contributed considerably to the overall mortality. Conclusions. Overall OLT is a feasible approach in HIV-infected patients with acceptable survival rates in Germany. Reinfection with HCV still remains a major clinical challenge in HIV/HCV coinfection after OLT.

Value of the preoperative SOFT-score, P-SOFT-score, SALT-score and labMELD-score for the prediction of short-term patient and graft survival of high-risk liver transplant recipients with a pre-transplant labMELD-score ≥30

The SOFT-score, P-SOFT-score, SALT-score and labMELD-score have been applied for the prediction of survival of liver transplant recipients after transplantation. We analysed the value of these scores for the prediction of short-term survival in high-risk liver transplant recipients with a labMELD-score ≥30. Retrospective single-centre analysis including 88 consecutive liver transplants in adults between 01.01.2007 and 31.12.2010 with a pretransplant labMELD-score ≥30 and follow-up until the 31.12.2011. Combined and living-related liver transplants were excluded. ROC-curve analysis was used to calculate sensitivity, specificity and overall model correctness of prognostic models. The P-SOFT-score demonstrated a significant influence on 1-year patient survival (p=0.045, Mann-Whitney-U test). Multivariate Cox regression analysis showed a significant influence of the P-SOFT-score on patient (p=0.013; Exp(B)=1.050; 95%CI: 1.010-1.091) and on graft survival (p=0.023; Exp(B)=1.042; 95%CI: 1.006-1.080). ROC-curve analysis showed areas under the curve (AUROCs) <0.5 for the SOFT-score, P-SOFT-score, SALT-score and the labMELD-score ≥30 for the prediction of 3-month patient and graft survival as well as 1-year patient and graft survival. Our results imply that the SOFT-score, P-SOFT-score, SALT-score and labMELD-score ≥30 all have a sensitivity, specificity and overall model correctness that is unable to discriminate short-term survivors from non-survivors in a collective of high-risk liver transplant recipients sufficiently in order to guide clinical decision making in the current German transplant situation with decreasing numbers of deceased liver donors, decreasing donor organ quality and increasingly sick transplant candidates.

Phase II Study of Azacitidine (Vidaza®, Aza) and Donor Lymphocyte Infusions (DLI) As First Salvage Therapy in Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS) Relapsing After Allogeneic Hematopoietic Stem Cell Transplantation (allo-SCT): Final Results From the AZARELA-Trial (NCT-00795548)

Abstract 656 Background:Relapse after allo-SCT is a major cause of treatment failure in patients (pts) with myeloid malignancies and is associated with a poor prognosis. As therapeutic options are limited, treatment of these pts is challenging. Indeed, there is a need for novel strategies which ideally target the leukemic clone and direct the immune system towards an enhanced GvL effect without aggravating GvHD. The hypomethylating agent Aza might provide these properties, and results from retrospective studies investigating Aza+/−DLI in pts with AML/MDS relapsing after allo-SCT were encouraging. Design/Methods:We here report the final results from a prospective single-arm EBMT multicenter phase II trial which aimed to investigate the efficacy and safety of a combination of Aza and DLI as 1st salvage therapy in pts with AML or MDS with hematological relapse after allo-SCT. Treatment schedule contained up to 8 cycles Aza (100 mg/m2/d d1-5, every 28 d) followed by DLI with increasing dosages (1-5×106–1-5×108cells/kg) after every 2ndAza cycle. Results:A total of 30 pts (19 f/11 m, median age 56 years, range 29–71) from 6 German transplant centres were included between January 2009 and May 2010. The majority of pts (n=28, 93%) suffered from AML, while 2 pts (8%) had MDS or MDS/MPN, respectively. At transplant, 16 pts (53%) had active disease (6 induction failure, 7 relapse I/II, 3 untreated) and 14 pts (47%) were in remission (12 CR1, 2 CR2). Following standard-dose (n=4, 13%) or dose-reduced conditioning (n=26, 87%), 10 pts (33%) received a graft from MSD and 20 pts (67%) from MUD. PBSC were used in 29 pts (97%), while 1 pt (3%) received BM. Acute GvHD occurred in 13 pts (46%) and 4 pts (13%) had chronic GvHD prior inclusion. None of the pts had active GvHD at the time of relapse, but 6 pts were still on immunosuppressive therapy. All pts had hematological relapse (median BM blasts: 34%, median chimerism: 67%) at a median time of 160 days (range 19–1699) following allo-SCT. A median of 3 courses Aza (range 1–8) were administered, and 22 of 30 pts (73%) received DLI (median: 1, range: 1–4, median CD3 dose 5×106/kg/DLI, range: 1–100×106). Overall response rate was 47%. Seven pts (23%) achieved CR or CRi, 2 pts (7%) PR, and 5 pts (17%) had stable disease (SD). Median time and median number of Aza cycles to best response were 79 days (range 28–299) and 3 cycles (range 1–8) respectively. Of the 7 pts who achieved a CR, 5 pts continue in CR for a median of 605 days (range 307–763) without any additional treatment, while 1 pt relapsed after 490 days and 1 pt died from GvHD. By July 2011 median follow-up of surviving pts is 645 days (range 564–857) and 5 of 30 pts (17%) are currently alive. Twelve pts have died due to progressive disease (PD), while 7 pts died during (n=3, 2 infection, 1 bleeding) or after the end of therapy (n= 4, 1 GvHD, 2 infection, 1 bleeding). All 5 pts who underwent 2nd allo-SCT died. Median overall survival (OS) of all pts is 117 days (95% CI 66–168 days). Patients with CR/CRi had a significant longer OS than pts not reaching CR/CRi (not reached vs. 83 days, p<.001). Eleven pts (37%) developed aGvHD, while cGvHD was observed in 5 pts (17%). Any type of GvHD was seen in 78% of pts with CR/PR as opposed to 33% in pts with SD/PD (p=.03). Cytopenias grade III/IV occurred in all pts, but were considered to be drug-related in only 11 pts (37%). The most common drug-related grade III/IV non-hematological toxicities were infection and bleeding. Conclusion:Aza and DLI as first salvage therapy is a safe and active approach for pts with AML or MDS who relapse after allo-SCT, and induces durable remissions in a subgroup of pts. Further research to better define target patient groups and combination partners for AZA+DLI is needed. Disclosures:Schroeder:Celgene: Financial travel support. Bug:Celgene: Lecture fees, Membership on an entity's Board of Directors or advisory committees. Luft:Celgene: Research Funding. Kobbe:Celgene: Financial travel support, Research Funding.

A Multicenter Retrospective Analysis on Pentostatin As Salvage Therapy of Severe Steroid Refractory Intestinal Acute Graft Versus Host Disease

Abstract 3048Acute graft-versus-host disease (aGvHD) of the gastrointestinal (GI) tract is still a major clinical challenge after allogeneic stem cell transplantation. Patients with steroid-refractory disease have a poor prognosis. Pentostatin, an inhibitor of adenosine deaminase, has shown efficacy as salvage therapy in steroid-refractory aGvHD of the GI tract in small single center studies. Here we report on the experience with pentostatin in severe steroid-refractory aGvHD of the GI tract at seven German transplant centers. PATIENTS:A total number of 123 patients who had been treated with pentostatin due to intestinal steroid-refractory aGvHD between 2000 and 2011 were retrospectively analyzed. Steroid-refractory aGvHD was defined as progression or no improvement of diarrhea despite treatment with prednisolone (≥ 2mg/kg/d) for ≥ 3 days. Pentostatin was infused at a dose of 1mg/m2 for 3 consecutive days. In patients with impaired renal function the dose of pentostatin was reduced. Patients received 1–4 cycles. Steroids and calcineurin inhibitors (CNI) were continued. Response after therapy with pentostatin was classified as complete (CR, no ongoing symptoms of GvHD), very good partial (VGPR, residual symptoms only) or no response (NR). 50 females and 73 males with a median age of 50 (range: 19–70) years were included. The underlying diseases were AML (n=71), ALL (n=15), CML/MPS (n=6), lymphoma (n=12), MDS (n=10), and multiple myeloma (n=9). 85 patients received reduced intensity and 38 myeloablative conditioning. Patients had been transplanted from matched related (n=38), matched unrelated (n=53) or mismatched donors (n=32). All patients suffered from severe steroid-refractory intestinal aGvHD overall grade III (n=59) or IV (n=64). Patients received pentostatin as first line salvage (n=109) or beyond first line salvage therapy (n=14). Results:52 patients (43%) responded after salvage therapy with pentostatin. 39 patients (32%) achieved CR, 13 patients (11%) VGPR. Median survival was 104 days; 2-year and long term survival rates were 26 and 19% with a median follow up of 45 months. Among 109 patients who received pentostatin as first line salvage therapy 49 (45%) responded (37 × CR [34%] and 12 × VGPR [11%]). Median survival, 2-year and long term survival were essentially the same as in the total cohort of patients. After the first infusion of pentostatin clinical improvement occurred within a median of 14 (range: 1–58) days. 71 patients (57%) did not respond. Responding patients had a significantly (p<0.0001) higher probability of survival in comparison with non-responders (2 year survival 44 vs. 14%, long term survival 41 vs. 0%). 94 patients (76%) died (66% therapy related, 10% due to relapse of the malignant disease). Patients who had been transplanted from a matched related donor had a significantly (p=0.04) higher probability of survival in comparison with patients with other donors (2-year survival: 38 vs. 21%, long term survival 35 vs. 8%). 53% (n=20) of these patients responded. Out of the 109 patients who were treated with pentostatin as first line salvage therapy 15 received simultaneously additional immunsuppressive salvage therapies (infliximab, mesenchymal stem cells [MSC] or extracorporeal photopheresis [ECP]). None of these patients survived. 46 patients without CR after one cycle of pentostatin received further immunosuppressive salvage treatment: 28 of these patients were treated with 1–3 further cycles of pentostatin. 18 of the 46 patients received pentostatin plus simultaneous or subsequent additional immunsuppressive therapies (infliximab, alemtuzumab, basiliximab, MSC or ECP). In both groups the probability of survival was identical (2-year survival: 17%). Conclusions:The outcome after salvage therapy of III/IV° steroid-refractory intestinal aGvHD with pentostatin is at least within the range as reported for other salvage approaches. In this critical clinical situation pentostatin has some superior characteristics: a sustainable effect, moderate toxicity, easy application and cost-effectiveness. Moreover, this analysis suggests that the outcome of steroid-refractory aGvHD cannot be improved by the application of more than one immunosuppressive salvage drug in addition to steroids and CNI or by second line salvage approaches. Disclosures:Klein:Hospira: Honoraria, Research Funding. Off Label Use: pentostatin is not licensed for use in acute GvHD.

Dental care and oral health in solid organ transplant recipients: a single center cross-sectional study and survey of German transplant centers

Aim of this study was to collect information about oral health of patients before and after SOT as well as information about center-based recommendations for dental care. In a single center cross-sectional study, the oral situation of 20 patients before and 20 after SOT were examined including dental (DMF-T), periodontal (PSR(®)/PSI), and oral hygiene findings (modified QHI). In a second project, a survey among 50 transplant centers in Germany was questioned regarding their recommendations for dental care of SOT recipients. Patients before and after SOT showed similar quality of dental findings (DMF-T), but worse compared to the general population. In addition, most patients in both groups showed pronounced periodontal treatment need (PSR(®)/PSI score 3 or 4). Oral hygiene findings (modified QHI) after SOT were significantly worse than in patients on the waiting list (P = 0.032). In a second project, the questionnaire was returned by 28 of 50 centers. Interpretation of data showed that 89% carry out a dental examination before SOT and 67% contacted the patients' dentists. After SOT, 83% of the transplant centers recommend antibiotic cover before dental measures. The results of our study revealed lacks in the dental care of SOT recipients. Consistent recommendations regarding the dental care of patients before and after SOT should be determined.

Monosomal Karyotype Predicts Survival In Patients with High Risk AML Undergoing Allogeneic Stem Cell Transplantation

AbstractAbstract 2748 Purpose:Prediction of treatment outcome in the context of specific therapies is a major goal of clinical research. Monosomal karyotype has been established as an independent prognostic marker in patients with AML treated with chemotherapy. Our goal was to investigate the prognostic value of a monosomal karyotype (MK) in patients with acute myeloid leukemia (AML) treated with allogeneic hematopoietic cell transplantation (HCT). Patients and Methods:We performed a retrospective cohort analysis in patients with high risk AML who received a first allogeneic HCT from an HLA-compatible donor in one out of six major German transplant centers between 01/2005 and 12/2008. Chromosomal aberrations were classified according to ELN criteria. Monosomal karyotype was defined as two or more distinct autosomal monosomies or one single autosomal monosomy in the presence of structural abnormalities. Survival endpoints were analysed in a complete case analysis with Cox regression modelling. Age, Karnofsky performance status, HCT comorbidity index, remission status at HCT, donor type, sex and CMV match were selected as potential confounders a priori for the model while stepwise backward selection was applied to a set of additional covariates including karyotype information. Model selection was based on the likelihood ratio test. We checked the proportional hazard assumption by generating a time-dependent covariate and testing the interaction term with the predictors of the model. Results:Data from 236 patients with complete karyotype information were analysed. The median age at HCT was 55 years (range, 21 to 77 years). The HCT-comorbidity index was low, intermediate and high in 22%, 27% and 49% of patients. According to ELN criteria chromosomal aberration were classified as intermediate risk in 33% and as high risk in 67% of the patients. The karyotype of 26% of patients met the criteria for a monosomal karyotype. At HCT 60% of patients had less than 5% marrow blasts, 18% had 5 to 20% marrow blasts and 21% had more than 20% marrow blasts. The median interval from diagnosis to HCT was 107 days. Donors were matched siblings in 27%, matched unrelated donors in 49% and partially matched unrelated donors with one to two mismatches in 25% of the patients. Only 16% of the patients were treated with myeloablative conditioning regimens while the remaining patients received reduced intensity conditioning. At the time of analysis, 110 patients were alive with a median follow up of 28 months (range, 8 months to 61 months). Overall survival at 3 years was 51% (95% CI, 42% to 60%) for MK-negative patients and 16% (95% CI, 5% to 27%) for MK-positive patients (log rank test, p<0.0001) (see overall survival by MK-karyotype in high risk patients only in Figure 1). Cox regression modelling was performed as a complete case analysis with data from 221 patients. The cytogenetic classification according to ELN (HR 1.8, p=0.014) and MK karyotype (HR 2.1, p=0.001) together improved the predictive power of the Cox regression model. When MK karyotype was removed from the final model including cytogenetic risk according to ELN the model significantly lost predictive power (likelihood ratio test, p=0.001). Conclusion:The presence of a monosomal karyotyp is an independent prognostic factor in patients being treated with allogeneic stem cell transplantation and predicts for inferior survival. [Display omitted] Disclosure:Bug:Celgene: Honoraria.

The HCT-Specific Comorbidity Index Fails to Predict Survival After Allogeneic HCT In High Risk AML Patients - A Single Center Experience

AbstractAbstract 1326 Introduction:Assessment of the individual risk of mortality after allogeneic hematopoietic cell transplantation (HCT) is essential for decision-making and patient counseling. For patients with AML several risk factors have been identified, including patient age, comorbidity, unfavorable cytogenetics, prior history of myelodysplasia and the remission status at HCT. The hematopoietic cell transplantation – specific comorbidity index (HCT-CI) has been designed and validated to predict mortality by concurrent disease and organ dysfunction prior to HCT at the Fred Hutchinson Cancer Research Center. Local data-dependence may affect the transportability of a prognostic system. Cross center validation of prognostic systems is therefore essential. In order to check the performance of the HCT-CI for our center, we applied the HCT-CI in a well defined cohort of AML patients. Our unit represents a large German transplant center characterised by referral of a large proportion of elderly patients with advanced myeloid leukemias. Methods:We performed a retrospective cohort analysis in patients with AML according to the WHO definition who were transplanted between January 2000 and December 2008. Second allogeneic HCTs and haploidentical HCTs were excluded. Baseline variables were extracted from the local database by a trained data manager. Supplementary data were collected by comprehensive review of medical records by the investigator. For each patient we assessed the HCT-CI prior to transplant. Overall survival (OS) was estimated using the Kaplan-Meier method. Non-relapse mortality (NRM) was calculated with cumulative incidence statistics. The effect of the HCT-CI on the OS and NRM was analyzed in a multivariate Cox regression model, considering age, Karnofsky score, type of AML, cytogenetic risk (according to the ELN classification), treatment and remission status, sex match, CMV match, donor type, and conditioning intensity. Results:340 patients were eligible for the analysis. The median age of our patients was 53 years (range, 11 to 76 years). Eighty-six patients (26%) were in CR-1 of standard risk AML and 45 patients (14%) were in CR-1 of high risk AML while the remainder had more advanced disease. The median HCT-CI was 4 (range, 0 to 10). Donors were HLA-identical siblings in 116 patients (34%), matched unrelated donors in 130 patients (38%) and partially matched unrelated donors in 94 patients (28%). Overall survival at 2 years was 41±12%, 49±6% and 49±3% in the low, intermediate and high-risk HCT-CI groups (p=0.7), respectively. The corresponding NRM at 2 years was 33±23%, 26±10% and 23±5% (p=0.6). In multivariate analysis the HCT-CI failed to predict OS and NRM. In multivariate regression modeling neither its inclusion as a categorical variable (low, intermediate or high risk) nor as a numerical variable demonstrated adequate discrimination.Comparing our population with the original validation cohort of the index hepatic impairment (51% vs. 20%, p=0.06), infection (47% vs. 4%, p=<0.001) and heart valve disease (44% vs. 2%, p=<0.001) were significantly more frequent in our population. These differences led to a statistically highly different distribution among the three HCT-CI risk categories of our patients (5% low risk, 21% intermediate risk, and 74% high risk patients) compared to the Seattle cohort of AML patients (51% low risk, 29% intermediate risk, and 21% high risk patients) (chi square test, p<0.0001). Referring to heart valve disease, we strictly applied the definitions from the original publication and considered even trace or mild regurgitation as heart valve disease. The fact that the resulting frequency of valvular dysfunction in our cohort is within the expected range for elderly patients (∼35% according to the Framingham Heart Study) leads to the suggestion that different working definitions had been applied. However, even after correction of this potential misclassification the modified HCT-CI did not discriminate OS and NRM. Conclusion:We found no predictive value of the HCT-CI for OS and NRM in our patients. Our results suggest that different working definitions for the assignment of comorbidities had been applied. Refined definitions could therefore help to improve the performance of the index. Until its validity has been shown across different patient populations, its use as decision making tool for transplantation eligibility needs to be reconsidered. Disclosures:Platzbecker:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Azacitidine (Vidaza®, Aza) and Donor Lymphocyte Infusions (DLI) In Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS) Relapsing After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): Interim-Analysis From the AZARELA-Trial (NCT-00795548).

AbstractAbstract 1294 Background:Patients with AML or MDS who relapse after allogeneic HSCT have a poor prognosis and therapeutic options are limited. The DNA hypomethylating agent Aza has significant activity in patients (pts) with AML and MDS and retrospective analyses have recently shown encouraging results with the use of Aza +/− DLI in patients with AML and MDS, who relapsed after allogeneic HSCT (Czibere et al., 2010; Luebbert et al., 2010). In line with these clinical observations preclinical data suggest that Aza enhances a Graft-versus-Leukemia (GvL) effect while mitigating Graft-versus-Host Disease (GvHD). Design/Methods:To evaluate the activity and safety of Aza in combination with DLI as first salvage therapy in pts with AML or MDS relapsing after HSCT, we conducted a prospective, multicenter, single-arm phase-II trial. Pts were allowed to receive up to 8 cycles Aza (100 mg/m2/d d1-5, every 28 days) and 3 DLI with increasing dosages (1-5×106 – 1–5×108 cells/kg) after every 2nd Aza treatment cycle. Additional DLI were permitted. Results:Between January 2009 and May 2010, 30 pts from 6 German transplant centres were included into this trial. So far, 25 pts (15 female/10 male) were evaluable and are presented in this analysis:Of these, 23 (92%) suffered from AML (15 de novo/8 secondary following MDS), 1(4%) from a MDS (RAEB-1) and 1 (4%) from a myelodysplastic/myeloproliferative syndrome (MDS/MPS, CMML-1). Median age was 54 years (range 29–71).Conditioning was myeloablative in 24 pts (96%) and non-myeloablative in 1 patient (4%). Eight pts (35%) received a graft from a matched sibling donor, while 15 (65%) were transplanted with a matched unrelated donor (2 pts missing data). Peripheral blood stem cells (PBSC) were used in 24 pts (96%; 1 pt missing data).At the time of transplant 6 pts (24%) had primary induction failure, another 6 (24%) suffered from first or secondary relapse, 10 pts (40%) were in first or second complete remission (CR), while 3 pts (12%) were untreated. With regard to their molecular and genetic characteristics at diagnosis, 21 pts belonged to an adverse (9 pts) or intermediate (12 pts) group, whereas 2 pts were diagnosed with a favourable genetic phenotype (2 pts not performed).Prior to relapse 9 (36%) and 3 (12%) pts had episodes of acute GvHD and/or chronic GvHD, respectively.Relapse occurred in all pts after a median of 160 days (range 19–1199) following HSCT (median BM blasts: 34%, range 5–100%, median chimerism: 63% range-1-100%). At the time of relapse, karyotype was evaluable in 13 of 25 pts (52%). Of these 13 pts, 4 pts had a normal karyotype, while 9 had chromosomal aberrations including 6 pts with a complex karyotype.Patients received a median of 3 courses Aza (range 1–8) and 18 of 25 pts (72%) received DLI (median: 1, range: 1–4, median CD3 dose 5×106/kg/DLI, range: 1–207×106).Following treatment, overall response rate was 64% with 5 pts (20%) achieving a CR or CRi, 3 (12%) a partial remission (PR) and 8 (32%) a stable disease (SD). Median response duration was 266 days. Acute GvHD occurred in 6 pts (24%) (2 skin/6 liver/ 2 gut) after a median of 65 days (range 19–179) following the first DLI, while chronic GvHD was observed in 3 pts (12 %, all limited). Hematotoxicity (grade III-IV) was observed in 64% of all evaluated patients. Common adverse events were gastrointestinal side effects as well as infections.After a median follow-up of 100 days (range 25–485) 15 of 25 pts (60%) are currently alive. Median overall survival of all pts is 184 days (range 87–281). All pts, who achieved a CR/CRi, remained in ongoing remission for a median time of 229 days. Achieving a CR (CR: not reached vs. no CR: 117 days, p .008) or any type of response (CR/CRi, PR or SD) to the combination of Aza and DLI (any response: not reached vs. no response: 79 days, p .0001) were associated with a significantly longer overall survival. Conclusion:The combination of Aza and DLI as salvage treatment for patients with AML or MDS who relapse after allogeneic HSCT seems to be safe and shows significant anti-leukemic activity. Response, including CR rates, so far match those from retrospective analyses. Data presented in this interim-analysis suggest that salvage therapy with Aza and DLI is of substantial therapeutic benefit in these challenging patients. Disclosures:Platzbecker:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bug:Celgene: Honoraria. Luft:Celgene: Research Funding. Fenk:Celgene: Research Funding. Kobbe:Celgene: Research Funding.

Risk factors for Pneumocystis jiroveci pneumonia (PcP) in renal transplant recipients

Pneumocystis jiroveci pneumonia (PcP) is a potentially life-threatening complication in renal transplant recipients with increased reports during the past few years. Individual risk factors for susceptibility to PcP are incompletely understood. We retrospectively analysed 60 cases of confirmed PcP, diagnosed in six German transplant centres between 2004 and 2008, as well as 60 matched controls. Compared with controls, PcP cases revealed the following significant differences: PcP cases had a poorer renal function (eGFR 31 vs. 42mL/min in controls), more biopsy-proven rejections (18 vs. 5 patients), more frequent treatment with mycophenolate mofetil (53 vs. 44 patients) and less frequent treatment with interleukin-2 receptor antagonist (20 vs. 32 patients). According to centre policy, in those years, none of the patients or controls had received PcP prophylaxis after transplantation. Of the 60 patients with PcP, 30% developed the disease after the currently recommended duration of prophylactic treatment, 27% died in the course of the disease and 45% required treatment in the ICU. Our case-control study reveals a novel risk profile for PcP. Renal transplant recipients with more pronounced renal insufficiency following rejection episodes and treated with intensified immunosuppression are at particular risk for PcP.

Composite risk scores and depression as predictors of competing waiting-list outcomes: the Waiting for a New Heart Study

We evaluated two composite risk scores, (Heart Failure Survival Score, HFSS; German Transplant Society Score, GTSS), and depression as predictors of mortality and competing waiting-list outcomes [high-urgency transplantation (HU-HTx), elective transplantation, delisting because of clinical improvement] in 318 heart transplant (HTx) candidates (18% women; aged 53 ± 11 years) from 17 hospitals and newly registered with Eurotransplant. Demographic variables and depression (Hospital Anxiety and Depression Scale, HADS) were assessed using questionnaires. Variables to compute HFSS and GTSS, age, medications, and outcomes were provided by Eurotransplant. At 12 months, 33 patients died, 83 received urgent HTx, 30 elective HTx, and 17 were delisted because of improvement. Applying cause-specific Cox regressions, only the HFSS was significantly associated with 1-year mortality [HR = 0.64 (95% CI = 0.43-0.95), P = 0.029]. The GTSS was the strongest predictor of HU-HTx [HR= 1.02 (95% CI = 1.01-1.02), P < 0.001]. Low depression scores contributed significantly to clinical improvement, even after adjusting for age and risk scores [HADS: HR = 0.12 (95% CI = 0.02-0.89), P = 0.039]. These findings confirm the usefulness of composite risk scores for the prediction of mortality and HU-HTx, validating both scores for their intended use. The finding that depression was an independent predictor of the waiting-list outcome clinical improvement suggests that considering patients' psychological attributes in addition to their medical characteristics is advisable.

Multicentric evaluation of model for end-stage liver disease-based allocation and survival after liver transplantation in Germany - limitations of the ‘sickest first’-concept

Since the introduction of model for end-stage liver disease (MELD) in 2006, post-orthotopic liver transplantation (OLT) survival in Germany has declined. The aim of this study was to evaluate risk factors and prognostic scores for outcome. All adult OLT recipients in seven German transplant centers after MELD implementation (December 2006-December 2007) were included. Recipient data were analyzed for their influence on 1-year outcome. A total of 462 patients (mean calculated MELD = 20.5, follow-up: 1 year) were transplanted for alcoholic cirrhosis (33.1%), hepatocellular carcinoma (26.6%), Hepatitis-C (17.1%), Hepatitis-B (9.5%), primary sclerosing cholangitis (5.6%) and late graft-failure after first OLT before December 2006 (8.7%). 1-year patient survival was 75.8% (graft survival 71.2%) correlating with MELD parameters and serum choline esterase. MELD score >30 [odds ratio (OR) = 4.17, confidence interval: 2.57-6.78, 12-month survival = 52.6%, c-statistic = 0.669], hyponatremia (OR = 2.07), and pre-OLT hemodialysis (OR = 2.35) were the main death risk factors. In alcoholic cirrhosis (n = 153, mean MELD = 21.1) and hepatocellular carcinoma (n = 123, mean MELD = 13.5), serum bilirubin and the survival after liver transplantation score were independent outcome parameters, respectively. MELD >30 currently represents a major risk factor for outcome. Risk factors differ in individual patient subgroups. In the current German practice of organ allocation to sicker patients, outcome prediction should be considered to prevent results below acceptable standards.

Diagnosis and Staging of Chronic Graft-versus-Host Disease in the Clinical Practice

Based on expert opinion and retrospective data the National Institutes of Health (NIH) Consensus Development Project proposed criteria for diagnosis and staging of both overall severity as well as organ severity of chronic graft-versus-host disease (cGVHD) for use in clinical trials. In 2008, representatives of German and Austrian allogeneic hematopoietic stem cell transplant (HSCT) centers established a study group on cGVHD during the annual meeting of the German Working Group on Bone Marrow and Blood Stem Cell Transplantation (DAG-KBT) to intensify a dialog among HSCT physicians, pathologists, and medical consultants focusing on the usefulness of the NIH consensus criteria for patient care in clinical practice and to promote collaborations between HSCT centers as well as different medical specialities involved in HSCT. We first conducted a survey of current practices of diagnosis, staging, and overall grading of cGVHD in daily clinical routine by sending an electronic questionnaire to the heads of the HSCT centers. During 3 meetings in 2009, more representatives of allogeneic HSCT centers were included into the discussion process, resulting in 81% participation representing 88% of all allogeneic HSCT activities in Germany, Austria, and Switzerland. During the third consensus meeting held in Regensburg, Germany, from November 6 to November 7, 2009, important agreements were achieved among participant having a strong impact on care of patients with cGVHD. Areas of disagreement such as distinction between classical NIH cGVHD and overlap syndrome or assignment of liver GVHD after day 100 to acute or chronic category will be further assessed in prospective observational studies among participants in the near future.

Depression and disease severity as correlates of everyday physical activity in heart transplant candidates

It is unclear to what extent patients awaiting heart transplantation (HTx) engage in physical activities. We examined the everyday physical activity and its associations with depressive symptoms and disease severity in 318 patients newly registered for HTx in the multi-site study 'Waiting for a New Heart' (aged 53.5 +/- 11.4 years, 18% female patients). Participants completed questionnaires assessing depressive symptomatology and physical activity (number of physical activities, caloric expenditure associated with each activity), and estimated the distance they were able to walk without a break. Medical parameters at the time of listing [e.g. peak oxygen consumption (peakVO(2)); the German Transplant Society Score (GTSS)] were provided by Eurotransplant. Almost 50% of patients engaged in activities of daily living (housework, walking), but <10% engaged in regular exercise. All physical activity measures correlated significantly with peakVO(2) (Ps < 0.01). Elevated depression scores were present in 39% of patients. Controlling for confounding variables (e.g. peakVO(2), diastolic blood pressure, GTSS, age), depressive symptomatology accounted for additional variance in all physical activity measures (Ps < 0.05). The association of depressive symptoms with reduced physical activity suggests two important perspectives: attempts to increase physical activity (especially in the area of daily living) might benefit from targeting depression, and increased physical activity might also help to reduce depressive symptoms.

Practical experience in post-mortem tissue donation in consideration of the European tissue law

In consequence of the European guidelines of safety and quality standards for the donation, retrieval, storing and distribution of human tissues and cells the purpose of tissue transplantation was implemented into German legislation in May 2007. The law came into effect on August 1st 2007 considering of the European rules. The Institutes for Legal Medicine of the University of Frankfurt/Main and the University Medical Center Hamburg-Eppendorf developed a model for tissue retrieval. The Institute of Legal Medicine (I.f.R.) at the University Medical Center Hamburg cooperates with the German Institute of Cell and Tissue Replacement (Deutsches Institut für Zell--und Gewebeersatz DIZG). Potential post-mortem tissue donors (PMTD) among the deceased are selected by standardized sets of defined criteria. The procedure is guided by the intended exclusion criteria of the tissue regulation draft (German Transplant Law TPG GewV) in accordance with the European Guideline (2006/17/EC). Following the identification of the donor and subsequent removal of tissue, the retrieved samples were sent to the DIZG, a non-profit tissue bank according to the tissue regulation. Here the final processing into transplantable tissue grafts takes place, which then results in the allocation of tissue to hospitals in Germany and other European countries. The Center of Legal Medicine at the Johann Wolfgang Goethe-University Medical Center Frankfurt/Main cooperates since 2000 with Tutogen, a pharmaceutical company. Harvesting of musculoskeletal tissues follows corresponding regulations. To verify the outcome of PMTD at the I.f.R. Hamburg, two-statistic analysis over 12 and 4 months have been implemented. Our results have shown an increasing number of potential appropriate PMTD within the second inquiry interval but a relatively small and unvaryingly rate of successful post-mortem tissue retrievals similar to the first examination period. Thus, the aim of the model developed by the I.f.R. is to increase the number of PMTD retrievals and, furthermore, to avoid any conflict of interest between organ and tissue donation.

Erweiterung des Donorpools in der Nierentransplantation

The number of patients on the renal transplant waiting list has remained constantly high. In this article we highlight two strategies to extend the donor pool and focus on AB0 incompatible and cross-over renal transplantation. Increased immunologic knowledge and improved therapeutic management have facilitated successful AB0 incompatible renal transplantation with very good long-term results. However, this method has only been applied in very few German transplant centers and should be explored further. The term cross-over transplantation implies the exchange of organs between two otherwise incompatible couples enabling compatible transplantation in both couples. The German transplantation law allows only living transplantation in emotionally related couples. However, in specific cases of close interpersonal relationships cross-over transplantation between two couples is acceptable.

Prediction of duration and success rate of unrelated hematopoietic stem cell donor searches based on the patient's HLA-DRB1 allele and DRB1-DQB1 haplotype frequencies

Rapid identification of a matched unrelated donor is essential for patients in need of hematopoietic SCT. We carried out a retrospective evaluation of 549 unrelated donor searches (UDSs), which were completed in 2005 for 23 German transplant centers. On the basis of the patient's HLA-DRB1 allele and DRB1-DQB1 haplotype frequencies, UDSs were divided into four groups with different search success probability predictions. For 90.5% of the patients, an acceptable HLA-matched, and for 61.6% an HLA-A-B-Cw-DRB1-DQB1-identical (10/10 matched) unrelated donor was found. The median search duration was 22 days. In the groups with high (n = 318), medium (n = 157), low (n = 56) and very low (n = 18) UDS success probability, an acceptable donor was found for 99.1, 86.6, 75.0 and 22.2% of the patients, and a 10/10-matched donor was found for 78.3, 49.7, 17.9 and 4.5% of the patients, respectively. The median search duration was 20, 27, 45 and 477 days in the groups with high, medium, low and very low probability, respectively. The search success rate and duration can be predicted on the basis of the patient's HLA-DRB1 allele and HLA-DRB1-DQB1 haplotype frequencies. An unrelated donor can be found for most of the patients, even if the indication for transplantation is urgent.

Liver Transplantation for Hilar Cholangiocarcinoma: A German Survey

Background The present study reports a German survey addressing outcomes in nonselected historical series of liver transplantation (OLT) for hilar cholangiocarcinoma (HL). Patients and Methods We sent to all 25 German transplant centers performing OLT a survey that addressed (1) the number of OLTs for HL and the period during which they were performed; (2) the incidence of HL diagnosed prior to OLT/rate of incidental HL (for example, in primary sclerosing cholangitis); (3) tumor stages according to Union Internationale Centre le Cancer; (4) patient survival; and (5) tumor recurrence rate. Results Eighty percent of centers responded, reporting 47 patients who were transplanted for HL. Tumors were classified as pT2 (25%), pT3 (73%), or pT4 (2%). HL was diagnosed incidentally in 10% of cases. A primary diagnosis of PSC was observed in 16% of patients. Overall median survival was 35.5 months. When in-hospital mortality (n = 12) was excluded, the median survival was 45.4 months, corresponding to 3- and 5-year survival rates of 42% and 31%, versus 31% and 22% when in-hospital mortality was included. HL recurred in 34% of cases. Three- and 5-year survivals for the 15 patients transplanted since 1998 was 57% and 48%, respectively. Median survival ranged from 20 to 42 months based on the time period ( P = .014). Conclusions The acceptable overall survival, the improved results after careful patient selection since 1998, and the encouraging outcomes from recent studies all suggest that OLT may be a potential treatment for selected cases of HL. Prospective multicenter randomized studies with strict selection criteria and multimodal treatments seem necessary.

Matched Unrelated or Matched Sibling Donors Result in Comparable Survival After Allogeneic Stem-Cell Transplantation in Elderly Patients With Acute Myeloid Leukemia: A Report From the Cooperative German Transplant Study Group

In patients with acute myeloid leukemia (AML), differential indications for matched sibling and unrelated hematopoietic stem-cell transplantation (HCT) are considered, and arbitrary age limits for HCT exist. We sought to determine whether donor type is a prognostic factor in elderly patients in the era of high-resolution DNA-based HLA typing. We performed univariate and multivariate analyses of event-free survival (EFS) and overall survival (OS) in patients older than 50 years with standard- or high-risk AML who had received an allogeneic HCT between 1995 and 2005. Available DNA from donors and recipients of unrelated HCT was retyped so that the HLA-A, -B, -C, and -DRB1 alleles could be characterized in detail. Unrelated donors (UDs) were classified as matched (8/8), possibly matched (matched, but incomplete information), partially matched (one mismatch), or poorly matched (two or more mismatches) according to the final typing results. Data from 368 patients with a median age of 57 years (range, 50 to 73 years) were included. Multivariate Cox regression analysis revealed that patients' disease status at HCT (P < .001) and the cytogenetic risk (P < .001) highly significantly predicted EFS and OS. Compared with patients with matched sibling donors, the adjusted relative risk of EFS was 0.7 (95% CI, 0.4 to 1.1) for patients with matched UDs and 1.0 (95% CI, 0.7 to 1.6) for patients with partially matched UDs. Donor type is not a major prognostic factor for HCT in elderly patients with standard- or high-risk AML.

Der Weg zur Etablierung der laparoskopischen Spendernephrektomie zum Standardverfahren bei der Nierenlebendspende - eine unizentrische Erfahrung

In contrast to the USA, laparoscopic donor nephrectomy is rarely practised in German transplant centres. Safety concerns and difficulties with the learning curve of this advanced laparoscopic procedure are the main obstacles to the establishment of this operation. From 1998-2005, we performed laparoscopic kidney procurement in 50 live kidney donors on an intention to treat basis harvesting a total of 29 left and 21 right kidneys for transplantation. Negative adverse effects on the donor side were temporary nerve irritation (2 patients) and postoperative retroperitoneal hematoma. Reasons to convert to open nephrectomy were bleeding (2 patients) and adhesions (1 patient). On the recipient side, one kidney was lost due to renal vein thrombosis. Three patients required short-time dialysis after transplantation. All other kidney transplants worked without any problems. Laparoscopic donor nephrectomy is a safe procedure and has been established as the method of choice for live kidney donation in our hospital.

Herztransplantation heute - ein Update

On the third of december 1967 the first human heart transplantation was performed. During the last decades the evolution of clinical heart transplantation went from a hazardous adventure towards a safe and very successful treatment for end-stage heart failure patients. The major limiting factor is the shortage of donor organs. Patients with end-stage heart failure without any treatment options for conventional heart surgery or medical treatment are suitable candidates for heart transplantation. The major contraindication is a refractory pulmonary hypertension with a high risk for postoperative right heart failure. Due to the lack of donor organs, there is an age limitation above 65 years for the acceptance of patients in the majority of transplant centers. The distribution of donor organs is regulated by the german transplant law with eurotransplant as the executive organization. Within an acceptable cold ischemic time of 4 hours, harvesting of the donor organ, transportation and implantation of the heart has to be done. The implantation technique was developed by R. Lower and N. Shumway. In some centers, the more advanced total orthotopic heart transplantation is the technique of choice with a reduced risk of AV-valve incompetence. Postoperative treatment is very similar to standard heart surgery patients. The major difference is the immunosuppressive treatment. A balance between the risk of rejection and the risk of infection due to over immunosuppression requires an individual monitoring and tailoring of the medication. Despite the risk of heart transplantation, long term survival with one year survival greater 80 percent and 5 year survival greater than 60 percent in this particular patient group is excellent. Besides survival, quality of live and exercise capability is well restored after heart transplantation.