German Transplant Centers Research Articles

Towards a cardiac allocation score: a retrospective calculation for 73 patients from a German transplant center

BackgroundDue to a growing discrepancy between the transplant waiting list and decreasing numbers of available donor hearts, cardiac transplantation rates in Germany have been declining in the past years. Currently, patients on the waiting list are prioritized by medical urgency and waiting time and therefore a majority of all cardiac transplants is performed in very ill patients. Recently, a different allocation algorithm was proposed that included predicted post-transplant survival as a parameter for organ allocation. So far, little data exists on how such a “Cardiac Allocation Score” (CAS) relates to our current transplant patient population and on how such a change in organ allocation could change clinical practice.MethodsWe calculated a theoretical retrospective Cardiac Allocation Score for 73 patients recruited and transplanted at our medium-volume center in Germany based on a hypothetical scoring algorithm recently published by Eurotransplant.ResultsOverall, 37 patients (50.7%) were transplanted on high urgency status (HU), 27 (37%) were being supported by a VAD at time of transplant. 57 (78.1%) were male. We found a relatively normal distribution of the hypothetical CAS with a median of 32.91 and a mean of 31.95 +/−10.02. Overall, CAS-Scores were lower than previously described for a Eurotransplant patient cohort of high urgency patients, but there was a significant overlap in score values between patients on HU and T status. CAS-values of VAD-supported patients were lower than in patients without mechanical support. The IMPACT-score as part of the CAS was used for prediction of post-transplant survival and seems suitable to predict outcome in our patient population.ConclusionIn a retrospective analysis, the recently proposed Cardiac Allocation Score seems to show a normal distribution of priority values in our patient cohort. The IMPACT-score predicted outcome after transplantation and could serve as part of the CAS-algorithm to predict post-transplant survival in this single center real-world scenario. Implementation of the CAS could significantly change organ allocation practice, including a potential prioritization of current T-status patients over HU-status patients.

Decitabine As Salvage Therapy for Relapse of AML and MDS after Allogeneic Stem Cell Transplantation - a Retrospective Multicenter Analysis on Behalf of the German Cooperative Transplant Study Group

Background:During the last years, based on its efficacy and favourable toxicity profile the hypomethylating agent (HMA) Azacitidine (Aza) has proven to be a valuable treatment option for patients with AML or MDS who relapse after allo-SCT. In contrast to Aza, reports on the use of Decitabine (DAC), the second HMA approved in Europe for the treatment of AML, as salvage therapy for relapse after allo-SCT are scarce covering a total of 9 patients so far. This prompted us to perform a retrospective survey in order to gather more experience on the use of DAC after allo-SCT.Patients and Methods:Retrieving information from the EBMT Med-A form and a study-specific questionnaire we were able to analyze data of 36 patients (median age 56 years, range 21-72 years) from 6 German transplant centers who had received at least one cycle of DAC for the treatment of relapse of AML (n=29) or MDS (n=7) after allo-SCT. Median time to haematological (n=34) or molecular (n=2) relapse was 370 days (range 43-2623 days).Results:Overall, DAC was the first treatment for relapse in 16 pts (44%), whereas 20 pts (56%) had previously received one (n=14), two (n=2) or three (n=4) lines of salvage therapy for relapse after allo-SCT. This included 16 pts treated with Aza, 3 pts with intensive chemotherapy and 2 pts with radiation. Five pts had received a second allo-SCT and 9 pts donor lymphocyte infusions (DLI) before DAC therapy.Patients received a median of 2 DAC cycles (range, 1-10) with 24 pts (67%) treated with the approved dose of 20 mg/m2 for 5 days and 12 pts (33%) treated with 20 mg/m2 for 10 days based on the local policy of the individual transplant center. In addition to DAC, DLI (median number of DLI =1, range: 1-5) were administered to 22 pts (61%).Following treatment with DAC +/- DLI the median survival was 5 months (range 1 - 40 months). Six pts achieved a complete remission (CR, 17%) and 3 pts achieved a partial remission (PR, 8%) leading to an overall response rate of 25%. Median time to documentation of CR was 157 days (range: 47-255 days) and 4 DAC cycles (range: 1-8 cycles). Of 6 patients achieving CR after DAC, 3 had received DAC as first salvage therapy and 3 had previously received Aza, including 2 pts not responding to Aza and 1 patient switched to DAC therapy due to Aza intolerability. With a median follow-up of 12 months (range: 5-40 months), 3 of 6 patients remain in ongoing remission for 4, 23, and 33 months respectively without any further antileukemic therapy, while the other 3 patients died in remission due to infectious complications after second transplant.The 2-year overall survival rate of the entire group as calculated from the start of DAC therapy was 9%. Incidence and severity of acute GvHD (overall: 19%, grade I: 3%, grade II: 8%, grade III: 5%, grade IV: 0%, missing: 3%) and chronic GvHD (overall: 6%, limited 6%, extensive 0%) were low and mild.Conclusion:Our analysis shows, that also the second HMA DAC exerts relevant clinical efficacy in patients with AML or MDS relapsing after allo-SCT and can induce durable remissions in individual pts. Given the heterogeneity of our patient group and the limitations of a retrospective analysis this asks for confirmation in a prospective trial. DisclosuresPlatzbecker:Onconova, Teva, Celgene, Janssen, Novartis, Amgen: Honoraria, Research Funding. Kobbe:Jansen: Honoraria, Other: travel support; Celgene: Honoraria, Other: travel support, Research Funding.

Alternative Donor Transplantation Using Intensified Conditioning, T-Cell-Replete HLA-Haploidentical Grafts and Post-Transplantation Cyclophosphamide in the Treatment of High-Risk and Advanced ALL: Feasibility and Outcome

Unmanipulated, T-cell-replete (TCR) HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) using post-transplantation cyclophosphamide (PTCY) for selective in vivo T-cell depletion of allo-reactive T-cells has become a valuable treatment alternative in patients with various hematologic disorders who lack a conventional donor or need timely transplant due to aggressive disease. However, as of yet few data are available for the treatment of ALL with this approach, particularly in relapsed and refractory disease.To evaluate the outcome of TCR haplo-HSCT utilizing PTCY in the context of intensified conditioning in patients with high-risk, relapsed and refractory ALL, we retrospectively analysed 29 patients (B-ALL n=27, T-ALL n=2; 12 male; median age 42 years: range 8-68) transplanted between 2010 and 2015 in five German transplant centers including one pediatric. Disease was active (relapsed/refractory) in 14 patients (48%) while others were in first (35%) or subsequent remission (17%). Eleven patients (38%) had relapsed after a previous allogeneic transplantation. Patients not in CR received cytoreductive chemotherapy prior to the conditioning regimen, according to the "sequential therapy" concept (Schmid C et al., JCO 2005; Tischer J et al, Ann Hematol 2013). Conditioning was TBI-based in 15 adults consisting of fludarabine and +/- cyclophosphamide plus either 12 Gy TBI or 8 Gy TBI applied in patients older than 55 years; children (n=3) received 10-12 Gy TBI plus etoposide. In adults with relapse after a first allogeneic transplantation conditioning was drug-based replacing TBI with treosulfan (3 x 10-12 g/m2) and etoposide. Post-grafting immunosuppression was high-dose cyclophosphamide, tacrolimus or cyclosporine A (n=4) and MMF in all patients. 27/29 patients engrafted, while 2 patients died early in aplasia. No primary graft rejection was observed. Acute GvHD grade II-IV occurred in 7 patients (24%); no patient developed grade IV acute GvHD. Mostly mild to moderate chronic GvHD was observed in 6 patients (21%), and CI of chronic GvHD at 2 years was 25%. No patient died due to GvHD. Severe toxicity (grade III-IV) was observed in 12 patients (41%), most commonly mucositis (n=34%), diarrhoea (31%), hyperbilirubinemia and transient elevation of transaminases (28%) and hemorrhagic cystitis (21%). CMV reactivated in 11/23 patients at risk and EBV in 3 while no patient developed CMV disease or PTLD. Proven invasive aspergillosis was diagnosed in 2, probable invasive aspergillosis in 5 patients. One-year non-relapse mortality (NRM) was 10%. Patients grafted with active disease experienced a one-year NRM of 14%. One-year relapse incidence was 35%. After a median follow up of 31 months (range 7.1-53.6), estimated one-year and three-year overall and relapse-free survival was 72/49% and 55/41%, respectively.In summary, intensification of the preparative regimen is well tolerated in the setting of TCR haplo-HSCT using PTCY as GvHD prophylaxis with low GVHD rates and NRM in patients with high-risk, relapsed and refractory ALL, while providing effective anti-leukemic activity. Results are at least comparable to HLA-matched transplantation. Thus, we suggest that the donor pool can be safely expanded in patients with high-risk and advanced ALL who lack a conventional donor, and that unrelated donor transplantation might be challenged in patients suffering from aggressive disease in the future. DisclosuresAlbert:GSK: Research Funding.

The Glasgow Prognostic Score and its variants predict mortality in living donor but not in deceased donor liver transplantation for hepatocellular carcinoma: A double-center validation study.

This study aimed to evaluate whether the Glasgow Prognostic Score (GPS) and its variants are able to predict mortality in live donor and deceased donor liver transplantation for hepatocellular carcinoma. Data of 29 live donor and 319 deceased donor transplantations from two German transplant centers was analyzed. The GPS, modified GPS, hepatic GPS, and Abe score were investigated. Receiver operating characteristic (ROC) curve analysis was carried out to calculate the sensitivity, specificity, and overall model correctness of the investigated scores as a predictive model. Study end-points were 1-year, 3-year, and long-term mortality. A 1-year mortality of 19.1% (n = 61), 3-year mortality of 26.3% (n = 84), and overall mortality of 37.3% (n = 119) was observed. All investigated scores failed to predict outcome in deceased donor liver transplantation (areas under ROC curves <0.700), whereas GPS, hepatic GPS, modified GPS, and the Abe score reached areas under ROC curves >0.700 for the prediction of 1-year mortality in live donor transplantation. The GPS and Abe score were also able to predict 3-year mortality. None of the investigated scores was a reliable predictor of long-term mortality. Systemic inflammation-based scores have great prognostic potential in live donor transplantation. Abe score could be successfully externally validated in the current study for the first time. In deceased donor transplantation, none of the analyzed scores was able to allow reliable prediction for the investigated study end-points.

Transplant Nurses' Work Environment: A Cross-Sectional Multi-Center Study.

BACKGROUND Numerically, nurses represent the largest healthcare profession, thus setting norms for the quality and safety of direct patient care. Evidence of a global shortage of nurses in all clinical practice settings across different healthcare systems and countries has been documented. The aims of the present study were: (1) to assess work environments in a sample of German transplant nurses, and (2) to compare their statements with a US-based sample. MATERIAL AND METHODS In a cross-sectional study, 181 transplant nurses from 16 German transplant centers provided information on their work environments. The translated version of the Job Design (JD) and Job Satisfaction (JS) survey showed satisfactory internal consistency for the JD (0.78) and JS (0.93) subscales. German nurses' work environments were compared with 331 transplant nurses from the US. RESULTS The majority of transplant nurses were female (81.8%), 55.4% were age 21-40 years, and 78.1% were employed full-time. German (versus US) transplant nurses reported their job design to be best for 'skill varieties' (p≤0.0002), and worst for 'autonomy' (p≤0.01). Job satisfaction was best with 'opportunities for autonomy and growth' (p≤0.0001), and 'pay and benefits' (p≤0.0001) was lowest. A higher professional degree (OR 1.57; p≤0.03; 95% CI 1.19-2.86), and longer time in transplant (OR 1.24; p≤0.001; 95% CI 1.11-1.38) showed a positive impact on German transplant nurses' perceptions of 'job satisfaction'. Nurses with time-dependent working contracts perceived more stress negatively affecting job satisfaction (OR 1.13; p≤0.009; 95% CI 1.02-12.82). CONCLUSIONS German specialty nurses working in the field of solid organ transplantation rate their work environments with respect to job design and job satisfaction as satisfactory. Institutions' investment into satisfactory nurse work environments and specializing nurses might increase the quality of care, thus improving patient outcomes.

Liver transplantation in Germany.

Liver transplantation (LT) is a well-accepted procedure for end-stage liver disease in Germany. In 2015, 1489 patients were admitted to the waiting list (including 1308 new admissions), with the leading etiologies being fibrosis and cirrhosis (n = 349), alcoholic liver disease (n = 302), and hepatobiliary malignancies (n = 220). Organ allocation in Germany is regulated within the Eurotransplant system based on urgency as expressed by the Model for End-Stage Liver Disease score. In 2015, only 894 LTs (n = 48 from living donors) were performed at 23 German transplant centers, reflecting a shortage of organs. Several factors may contribute to the low number of organ donations. The German transplant legislation only accepts donation after brain death (not cardiac death), whereas advances in neurosurgery and a more frequently requested "palliative care" approach render fewer patients suitable as potential donors. The legislation further requires the active consent of the donor or first-degree relatives before donation. Ongoing debates within the German transplant field address the optimal management of patients with alcoholic liver cirrhosis, hepatocellular carcinoma (HCC), and cholangiocarcinoma and measures to increase living donor transplantations. As a result of irregularities at mainly 4 German transplant centers that were exposed in 2012, guiding principles updated by the German authorities have since implemented strict rules (including internal and external auditing, the 8-eyes principle, mandatory repeated testing for alcohol consumption) to prohibit any manipulations in organ allocation. In conclusion, we will summarize important aspects on the management of LT in Germany, discuss legal and organizational aspects, and highlight challenges mainly related to the relative lack of organ donations, increasing numbers of extended criteria donors, and the peculiarities of the recipient patients. Liver Transplantation 22 1136-1142 2016 AASLD.

Organ allocation for liver transplantation: One size does not fill all.

See Article on Page 743 In response to a donor pool that is persistently insufficient for demand and broadening of indications for liver transplantation, European countries have developed different approaches to organ allocation, taking into account local legislation, organ donation rates, and indications for liver transplantation.1 In their article in Liver Transplantation, Schrem et al.2 reported on the development and validation of a new prognostic model for the prediction of 90‐day mortality after liver transplantation. Developed in a German transplant center, it was validated in Germany and the United Kingdom. The model performed well in the German cohort, with strong predictive ability, but it failed validation in the English cohort. The results of this study confirm the common disappointment within the transplant community on the impossibility of applying the same prognostic model for liver transplantation in different countries, with different health care systems and allocation policies. Therefore, it is not surprising that the model developed in Germany was not able to predict the mortality rate in the United Kingdom. The liver allocation system is radically different in Germany from that in the United Kingdom: Germany is part of Eurotransplant, where allocation is governed by the Eurotransplant Liver Allocation System. This international collaboration is based on medical and logistical criteria with modifications according to the different national laws.3 In Germany, as well as in the other 3 countries of Eurotransplant (Belgium, the Netherlands, and Luxembourg), allocation is patient‐oriented and based on urgency, using the Model for End‐Stage Liver Disease score to prioritize patients on the waiting list. Conversely, in the United Kingdom, liver allocation is center‐based with a national allocation scheme and with donor areas allocated to each center based on the number of new registrations of prospective candidates; and within each center, the priority is based on United Kingdom Model for End‐Stage Liver Disease4 scores and on the decision of the transplant professionals involved.5 The development of the new German prognostic model would have decreased the 90‐day survival benefit if applied to the United Kingdom, whereas it would have had a beneficial effect in German transplant centers. When developing allocation algorithms, a crucial step should be matching donor and recipient risk factors in order to maximize the benefit and to avoid matching with negative impact on posttransplant outcomes. Therefore, if profound differences exist between 2 countries in terms of donor characteristics and candidate clinical severity, it is clear that a model created in one setting will not fit when applied to another one. The importance of uniformity of clinical variables when applying allocation scores to other countries is reflected2 in that only 2 out of the 10 clinical variables used for the new liver allocation score had a significant influence on 90‐day mortality in the United Kingdom cohort, whereas all 10 variables had independent significant influences on 90‐day mortality in the 2 German cohorts. The impracticality of adopting the same allocation scheme for different countries should reinforce the concept that each country or region may need to develop their own predictive model for organ allocation. This is the case in Italy where a critical revision of the current liver allocation policy was recently prepared after a national consensus conference process that involved transplant surgeons and transplant hepatologists. A new national model that blends together the principles of urgency, utility, and transplant benefit has been developed based on current scientific evidence.6 Again, this system of allocation would be hard to translate to other countries, due to different population characteristics, disease burden, and geography that each country or consortium has.7 Lastly, despite some acknowledged limitations of the study by Schrem et al.,2 such as the retrospective design and the lack of information on potentially relevant prognostic variables (ie, graft steatosis), the authors properly pointed out that because allocation schemes offer clinicians schemes, and not rules, there is no obligation for the transplant professional to accept a liver offered for a specific patient. However, in an urgency‐based allocation system, the competition between transplant centers is increased due to the pressure to accept the organ offered for a patient even if the matching between donor and recipient is not optimal. A strong effort should be made by the transplant community to define national prognostic models able to properly optimize the use of a scarce resource, by using balanced principles of urgency and equity, and integrating them with transplant benefit, which is easily made into a mathematical model but difficult to realize in the daily clinical practice when up to 20% of patients still die on the waiting list.

Biliary strictures and recurrence after liver transplantation for primary sclerosing cholangitis: A retrospective multicenter analysis.

Liver transplantation (LT) is the only definitive treatment for patients with end-stage liver disease due to primary sclerosing cholangitis (PSC), but a high rate of biliary strictures (BSs) and of recurrent primary sclerosing cholangitis (recPSC) has been reported. In this multicenter study, we analyzed a large patient cohort with a long follow-up in order to evaluate the incidence of BS and recPSC, to assess the impact on survival after LT, and to identify risk factors. We collected clinical, surgical, and laboratory data and records on inflammatory bowel disease (IBD), immunosuppression, recipient and graft outcome, and biliary complications (based on cholangiography and histology) of all patients who underwent LT for PSC in 10 German transplant centers between January 1990 and December 2006; 335 patients (68.4% men; mean age, 38.9 years; 73.5% with IBD) underwent transplantation 8.8 years after PSC diagnosis with follow-up for 98.8 months. The 1-, 5-, and 10-year recipient and graft survival was 90.7%, 84.8%, 79.4% and 79.1%, 69.0%, 62.4%, respectively. BS was diagnosed in 36.1% after a mean time of 3.9 years, and recPSC was diagnosed in 20.3% after 4.6 years. Both entities had a significant impact on longterm graft and recipient survival. Independent risk factors for BS were donor age, ulcerative colitis, chronic ductopenic rejection, bilirubin, and international normalized ratio (INR) at LT. Independent risk factors for recPSC were donor age, IBD, and INR at LT. These variables were able to categorize patients into risk groups for BS and recPSC. In conclusion, BS and recPSC affect longterm graft and patient survival after LT for PSC. Donor age, IBD, and INR at LT are independent risk factors for BS and recPSC and allow for risk estimation depending on the recipient-donor constellation.

A German survey of the abdominal transplantation surgical work force.

This manuscript reports the results of a nationwide survey of transplant surgeons in Germany, including the demographics, training, position, individual case loads, center volumes, program structure, professional practice, grade of specialization, workload, work hours, salary, and career expectations. We contacted all 32 German transplant centers that perform liver, kidney, and pancreas transplantation. Surgeons engaged in transplantation were asked to reply to the survey. Eighty-five surgeons responded, with a mean age of 44 ± 8 years, 13% of whom were female. The median transplant frequency per active transplant surgeon was relatively low, with 16 liver transplants, 15 kidney transplants, and three pancreas transplants. The median reported center volumes were 45 liver transplants, 90 kidney transplants, and five pancreas transplants per year. Most of the surgeons reported a primary focus on hepato-pancreato-biliary surgery, and only 10% of effective work time was actually dedicated to perform transplant surgeries. The majority of respondents estimated their weekly work hours to be between 55 and 66 h. When asked about their career satisfaction and expectations, most respondents characterized their salaries as inappropriately low and their career prospects as inadequate. This survey provides a first impression of the transplant surgery work force in Germany.

A New Liver Allocation Score (LivAS) to Facilitate the Weighing of Urgency Against Utility in Liver Transplantation.

Introduction: A valid prognostic model with donor and recipient data for the prediction of 3-month mortality after transplantation would be useful to improve donor organ allocation by preoperative weighing of the predicted outcome after transplantation against the urgency of transplantation as predicted by the MELD-score. Methods: This is a multicentre analysis with data from two German transplant centres within the Eurotransplant community. Included were all consecutive liver transplants performed inadult recipients (minimum age 18 years) in Hannover from 01.09.2001-31.12.2010(n=770) and in Kiel from 01.01.2006-08.02.2013 (n=234). Excluded were all combined transplants and living-related transplants. The cohort from Hannover was randomised retrospectively into an internal training group for model development with multivariate binary logit link regression and an internal validation group. The cohort from Kiel was used as an external validation group. Results: Recipient score component: Recipient y = -1.60 + (0.023 x age at transplant in years) + (-0.129 x haemoglobin in g/dl) + (-0.001 x thrombocytes in tsd/μl) + (-0.003 x factor II in %) + (0.003 x creatinine in μmol/l) + (0.474 x artificial ventilation, if yes=1, if no=0) + (0.195 x preTX portal vein thrombosis, if yes=1, if no=0) + (0.894 * risk indication re-TX for primary non-function, if yes=1, if no=0). Donor score component: Donor y = -2.281 + (0.071 x donor liver with macrovesicular steatosis in %, if no biopsy = 0) + (0.544 x ICU stay >11.5 days) + (1.266 x donor sodium >160mmol/l). LivAS = 1,342 + (1,162 x Recipient y) + (0,616 x Donor y). The area under the receiver operating curve for the prediction of 3-month mortality after transplantation was >0.700 in the in the training cohort and the internal and external validation cohorts. The influence of the LivAs above versus below cut-off was significant in all three cohorts (p<0.001). The Goodness-of-Fit test results demonstrated good model fit for all cohorts. Conclusion: The proposed LivAS is a validated prognostic model that could improve organ allocation rules significantly.

Quality of Life for Female Transplant Surgeon or Those in Training in a Developed European Country.

This study was initiated to analyze quality of life of young female surgeons working in a transplant Department with respect to their personal goals within their career and their social life including the possibility of having children. This is of particular interest in Germany as for now there are approximately 90% female medical students due to study entrance requirements that male students ton't meet. Methods: We developed a specialized questionnaire to evaluate our objectives. we analyzed quality of life of male and female surgeons or those in surgical training of all 24 german transplant centers. Results Female transplant surgeons or those in training differ strongly in their expectations and goals then male candidates who answered our questionnaire. The female surgeons could be mainly divided into two groups. Career driven and family orientated. The career driven candidates did not wish to have children at all and even had little expectations about being in a long term relationship. The family orientated candidates planned to leave the surgical department after their basic training and planned to have a family with children working in medical filed. Conclusions: Due to many conditions in Germany female surgeons still find a combination of a full time job as a surgeon and raising a family as to difficult or impossible and therefore choose one or the other option when it comes to career planning. The german system should look at other countries to successful females a chance to combine family and career.

Attitudes of medical staff potentially participating in the organ donation process towards organ donation and transplantation in Bavaria

Organ donation rates in Germany are lower than in other countries and have declined further after manipulations of the waiting lists in some German transplant centers became public. Attitudes and commitment of medical personnel are crucial for successful organ donation. Therefore, we studied the attitudes of hospital staff towards organ donation and transplantation. In 50 Bavarian hospitals, medical professionals working in units relevant to organ donation were asked to respond to an anonymous questionnaire. 2983 questionnaires could be evaluated. The majority of all respondents had a positive attitude towards organ donation; 71 % were willing to donate their organs after brain death and 57 % were willing to accept a transplant in case of organ failure. Rates of positive attitude were lower among nurses than among physicians. 28 % indicated that recent developments had a negative impact on their attitude and of those approximately half evaluated the work of transplant centers negatively. Overall only 23 % considered organ allocation as fair. The majority of nurses and a large proportion of physicians considered themselves as not well informed. The current loss of confidence into organ donation and transplantation also affects the attitude of medical personnel. Intensified measures of information and full transparency of all procedures are urgently needed.

Center volume, competition, and outcome in German liver transplant centers

In recent years, a growing body of literature has suggestedthat patients who undergo surgery at high-volume centersfare better than those treated in low-volume hospitals.In the study by Nijboer et al. (unpublished work) in thismonth’s Transplant Research issue, liver transplantationoutcomes were investigated in relation to center case vol-ume in 24 German transplant centers. High-volume centershad higher 1-year survival rates, but no difference in in-hospital mortality. The overall outcomes of all Germantransplant centers were poor with in hospital mortality rateof 18% and a 1-year patient survival of 73%. The ROC ana-lysis did not reveal a clinical meaningful cutoff value forlow- versus high-volume center. Looking at the center datain Nijboer’s study, one gets the impression that the volumeoutcome relationship is not linear but a bell-shaped curvewith inferior outcomes in small centers ( 80-100). Centers with a volumebelow 20 cases per year show very heterogeneous results,suggesting that some centers in that group may not havethe personal and infrastructural resources to run the pro-gram. On the other hand, very high-volume centers may bepressured to keep their high market share by acceptingmarginal transplant candidates and a poor donor organ/re-cipient match. A recently published article by Macomberet al. has analyzed for the same purpose the UHC databasewhich included 63 US liver transplant centers [1]. Whatthey found was that high-volume centers, defined as thoseperforming more than 75 liver transplants per year hadlower morbidity and mortality rates than lower-volumecenters and were also more cost-efficient. To provide easyadequate access for patients in some German regions theestablishment of small-volume centers may be necessary,but in those where such issues are not so pressing it maybecome difficult to justify having higher-cost and worse-performing small centers, as a high-performing lower-costcenter. In Germany such decisions usually lie in the handsof the federal states, but in close-by centers patients maywell vote with their feet if the data are made public. Besidesvolume another important factor, hospital competition,may negatively interfere with outcome. Although more hos-pital competition is associated with improved access tocare, it also can be linked to poorer outcomes, according toa recent study by Halldorson et al. [2]. The authors foundthat low, mid, and high levels of competition significantlyincreased the risk of graft failure and patient death. Withincreased competition among medical centers that per-form liver transplants, higher-risk patients received lower-quality donor organs. Transplantation for sicker patientsand the use of higher-risk organs also meant higher costs.The findings question whether competition for the sameorgans decreased the ability to match donor and recipientcharacteristics. Competition may incentivize medical cen-ters to perform enough transplants to meet fixed costs,boost profits, and maintain market share, which can in-hibit them from best matching organs with recipients.Competition has been advocated as important for better-ing market performance, but there may be limits to thevalue of competition in the healthcare setting. The debateabout volume, competition, and transparent outcomereporting continues. Liver transplantation is often lookedon as a ‘prestige programme’ and healthcare providers arereluctant to give up their (small and not cost-effective)liver transplant program. In the light of unacceptable pooroutcomes in liver transplantation in Germany, the studyby Nijboer et al. will contribute to an ongoing discussionon the size and organization of transplant centers.

Azacitidine and Donor Lymphocyte Infusions As Treatment For Relapse After Allogeneic Stem Cell Transplantation - a Retrospective Multicenter Analysis In 115 Patients On Behalf Of The German Cooperative Transplant Study Group

Background Two prospective studies and small retrospective series have demonstrated feasibility and clinical efficacy of Azacitidine (Aza) as salvage therapy for relapse of AML or MDS after allo-HSCT. As a consequence, Aza has become a clinically relevant treatment alternative in this setting. Still, due to the heterogeneity and limited number of patients reported so far predictive factors for response and long-term survival are unknown. Patients and Methods We analyzed data of 115 pts (median age 50 years, range 21-72 years) with AML (n=90), MDS (n=23) or myeloproliferative syndrome (MPS n=2), who had experienced relapse (hematological n=101; molecular n=14) after a median of 181 days (range: 19-3349 days) after allo-HSCT. Patients were treated with Aza ± DLI at 11 German transplant centers and in 109 of them (95%) Aza was the first treatment of relapse. Patients received a median of 3 courses Aza (range 1-14) and 78 patients (68%) received DLI (median number of DLI = 2, range: 1-6). Thirty patients were treated within a prospective phase-II trial (NCT-00795548). Their results have been published previously but were updated for this analysis. Results Following this treatment, 34 pts achieved CR (29%) and 8 patients achieved PR (7%) resulting in an overall response rate of 36%. Median time to CR was 84 days (range: 26-430 days) corresponding to 3 Aza cycles (range: 1-8 cycles). Of 6 patients with an extramedullary relapse, 3 patients achieved CR. The 2-year OS rate was 34%. With a median follow-up of 17 months (range 1-82) for survivors, 22 pts (65%) are in ongoing CR for a median of 16 months (range 2-48) without further treatment, while 12 pts relapsed again after a median of 11 months (range 2-48). Bone marrow blast count (&lt; 20% vs. ≥20%, CR rate 47% vs. 12% p=0.0001) and type of relapse (molecular vs. hematological, CR rate 71% vs. 24%, p=0.0007) were identified as predictive factors for the achievement of CR. No correlation was found for any karyotype abnormalities, time interval from allo-HSCT to relapse, the presence of blasts in the peripheral blood and the diagnosis of MDS vs de-novo AML. Incidence and severity of acute GvHD (overall: 25%, grade I: 10%, grad II: 6%, grade III: 7%, grade IV: 2%) and chronic GvHD (overall 23%, limited 19%, extensive 4%) were low and mild. Conclusion This analysis shows that the combination Aza and DLI is a valuable treatment option in the challenging situation of relapse after allo-HSCT. The association of disease burden with the likelihood to respond emphasizes the need for stringent disease monitoring and early intervention. Disclosures: Schroeder: Celgene: Financial travel support Other, Honoraria. Bug:Celgene: Honoraria, Travel grants Other. Platzbecker:Celgene: Honoraria. Kobbe:Celgene: Research Funding.

High-resolution HLA matching in hematopoietic stem cell transplantation: a retrospective collaborative analysis

AbstractTo validate current donor selection strategies based on previous international studies, we retrospectively analyzed 2646 transplantations performed for hematologic malignancies in 28 German transplant centers. Donors and recipients were high resolution typed for HLA-A, -B, -C, -DRB1, and -DQB1. The highest mortality in overall survival analysis was seen for HLA-A, -B, and DRB1 mismatches. HLA-DQB1 mismatched cases showed a trend toward higher mortality, mostly due to HLA-DQB1 antigen disparities. HLA incompatibilities at >1 locus showed additive detrimental effects. HLA mismatching had no significant effect on relapse incidence and primary graft failure. Graft source had no impact on survival end points, neither in univariate nor in multivariate analysis. Higher patient age, advanced disease, transplantations before 2004, patient C2C2 killer cell immunoglobulin-like receptor (KIR)-ligand phenotype, and unavailability of a national donor adversely influenced outcomes in multivariate analysis. Our study confirms the association of HLA-A, -B, -C, and -DRB1 incompatibilities with adverse outcome in hematopoietic stem cell transplantation (HSCT). The relevance of HLA-DQB1 disparities in single mismatched transplantations remains unclear. Similar hazard ratios for allele and antigen mismatches (possibly with an exception for HLA-DQB1) highlight the importance of allele level typing and matching in HSCT. The number of incompatibilities and their type significantly impact survival.

Accept or refuse? Factors influencing the decision-making of transplant surgeons who are offered a pancreas: results of a qualitative study

BackgroundMost offered pancreases are not transplanted. This study investigates the factors that inform and influence the transplant surgeon’s decision to select an offered pancreas.MethodsSemi-standardized interviews were conducted with 14 highly qualified transplant surgeons from all 14 German transplant centers performing > 5 pancreas transplantations per year. The interviews focused on medical and non-medical criteria on which the individual accept/refuse decision depends. Interviews were recorded, transcribed and underwent content analysis.ResultsThe interviewees agreed upon certain main selection criteria, e.g. donor age, lab results, ICU stay. However, there was no consistency in judging these parameters, and clear cut-offs did not exist. The pancreas macroscopy is a pivotal factor, as well as knowing (and trusting) the donor surgeon. 3/14 surgeons reported that they had occasionally refused a pancreas because of staff shortage. Some interviewees followed a restrictive acceptance policy, whereas others preferred to accept almost any pancreas and inspect it personally before deciding.ConclusionThe assessment of medical donor characteristics is highly inconsistent. Both very cautious as well as very permissive acceptance policies may render the allocation process less efficient. A more standardized policy should be discussed. Finally, better training for donor surgeons seems advisable, in order to increase trust and thus pancreas utilization.

Protocol TOP-Study (tacrolimus organ perfusion): a prospective randomized multicenter trial to reduce ischemia reperfusion injury in transplantation of marginal liver grafts with an ex vivotacrolimus perfusion

BackgroundCritical organ shortage results in the utilization of extended donor criteria (EDC) liver grafts. These marginal liver grafts are prone to increased ischemia reperfusion injury (IRI) which may contribute to deteriorated graft function and survival. Experimental data have shown that the calcineurin inhibitor tacrolimus exerts protective effects on hepatic IRI when applied intravenously or directly as a hepatic rinse. Therefore, the aim of the present study is to examine the effects of an ex vivo tacrolimus perfusion on IRI in transplantation of EDC liver grafts.Methods/DesignThe TOP-Study (tacrolimus organ perfusion) is a randomized multicenter trial comparing the ex vivo tacrolimus perfusion of marginal liver grafts with placebo. We hypothesize that a tacrolimus rinse reduces IRI, potentially improving organ survival following transplantation of EDC livers. The study includes livers with two or more EDC, according to Eurotransplant International Foundation’s definition of EDC livers. Prior to implantation, livers randomized to the treatment group are rinsed with tacrolimus at a concentration of 20 ng/ml in 1000 ml Custodiol solution and in the placebo group with Custodiol alone. The primary endpoint is the maximum serum alanine transamninase (ALT) level within the first 48 hours after surgery; however, the study design also includes a 1-year observation period following transplantation. The TOP-Study is an investigator-initiated trial sponsored by the University of Munich Hospital. Seven other German transplant centers are participating (Berlin, Frankfurt, Heidelberg, Mainz, Münster, Regensburg, Tübingen) and aim to include a total of 86 patients.DiscussionTacrolimus organ perfusion represents a promising strategy to reduce hepatic IRI following the transplantation of marginal liver grafts. This treatment may help to improve the function of EDC grafts and therefore safely expand the donor pool in light of critical organ shortage.Trial registerEudraCT number: 2010-021333-31, ClinicalTrials.gov identifier: NCT01564095

Current Practice in Diagnosis and Treatment of Acute Graft-versus-Host Disease: Results from a Survey among German-Austrian-Swiss Hematopoietic Stem Cell Transplant Centers

To assess current clinical practice in diagnosis and treatment of acute graft-versus-host disease (aGVHD), we performed a survey among German, Austrian, and Swiss allogeneic hematopoietic stem cell transplantation (allo-HSCT) centers. Thirty-four of 72 contacted centers (47%) completed both the diagnostic and therapeutic sections of the survey, representing 65% of allo-HSCT activity within the participating countries in 2011. Three pediatric centers answered as requested only the diagnostic part of the survey. In the presence of diarrhea and decreased oral intake after engraftment, only 4 centers (12%) do not perform any endoscopy before the start of immunosuppressive treatment. In case of a skin rash with the differential diagnosis of drug reaction, only 12 centers (35%) perform a skin biopsy up front, whereas 19 do so after failure of systemic steroids. In the presence of rapidly increasing cholestasis occurring without any other signs of aGVHD, 11 centers (32%) perform a liver biopsy up front and 14 only after failure of steroid treatment, whereas 9 centers do not perform a liver biopsy at all. Twenty centers (59%) use a percutaneous approach, 12 a transvenous approach, and 1 mini-laparoscopy for liver biopsies. First-line treatment of cutaneous aGVHD stage 1 consists of topical treatment alone in 17 of 31 responding centers (61%), whereas isolated cutaneous aGVHD stage III is treated with systemic steroids (prednisolone below 0.5 mg/kg/day n = 2, 0.5 to 1.0 mg/kg/day n = 10, above 1.0 to 2.5 mg/kg/day n = 19) without or with topical agents (steroids n = 10; calcineurin inhibitors n = 3). In gastrointestinal manifestations of aGVHD, 9 centers (29%) add topical to systemic steroids, and 3 consider topical steroids as the only treatment for mild gastrointestinal and cutaneous aGVHD. The choice of agent for second-line treatment as well as the sequence of administration are extremely heterogeneous, most likely due to a lack of convincing data published. Most frequently used are mycophenolate mofetil (n = 14) and extracorporeal photopheresis (n = 10). Our survey also demonstrates that clinicians chose salvage therapies for steroid-refractory aGVHD based on their centers' own clinical experience.

Outcome after Orthotopic Liver Transplantation in 33 Human Immunodeficiency Virus (HIV)-Positive Patients in Germany: Recurrence of Chronic Hepatitis-C Infection after Transplantation

Background: The introduction of HAART has led to a dramatic reduction in HIV-associated morbidity and mortality. As a consequence liver disease associated complications have become an increasing clinical challenge. With one third of European HIV-patients having hepatitis C co-infection and 6-9 % hepatits B co-infection a rising need for liver organ transplantation (OLTX) has emerged. The current study evaluates the outcome of OLTX in HIV-patients in Germany. Methods: Retrospective chart analysis of 33 HIV-positive patients who were liver transplanted in 9 German transplant centers (Bonn n=11, Essen n=8, Heidelberg n=4, Hamburg n=3, Frankfurt n=2, Mainz n=1, Tübingen n=1, Regensburg n=2, Hannover n=1) between 1997-2010. Results: Reasons for OLTX were end-stage liver disease (ESLD) due to hepatitis C (n =15, with 4 having additionally HCC) ESLD due to HBV (n =9, one with additional alcoholic cirrhosis and one with HCC), one with Budd-Chiari syndrome (n=1) and HBV/HCV/HDV-coinfection (n=1). The median CD4 T-cell count before transplantation was 223/μl (IQR,158-372). Of all transplanted patients 17/26 are still alive in 2010 with a median survival of 30 months (IQR,1-153). 9/33 patients died, 5 in the early post-transplantation period within 3 months, one due to organ rejection and acute renal failure, the other because of intrathoracal hemorrhage and 3 of septicemia. 4 patients died after 8, 10, 31 and 56 months respectively, 1 due to anastamotic leak with massive bleeding, 2 because of secondary graft failure and 1 after re-re-transplantation of septicaemia. Recurrent hepatitis B infection was efficiently prevented in 8/9 patients, whereas hepatitis C reinfection occurred in all patients. Conclusion: OLTX is a feasible approach in HIV-infected patients with ESLD in Germany with overall acceptable survival rates. Reinfection with HCV remains one of the biggest clinical challenges after OLTX in HIV/HCV coinfection.

Mutations in podocyte genes are a rare cause of primary FSGS associated with ESRD in adult patients

Several genes have been identified to be causative for the disease in a subset of patients with focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome (NS). Mutations in genes with autosomal dominant inheritance mostly affect adolescent or adult patients. In rare cases recessive mutations in NPHS2 are associated with late-onset FSGS. Hereditary FSGS is associated with poor renal survival and low rates of disease recurrence after renal transplantation. Aim of the study was to evaluate the incidence of gene mutations within a cohort of adult patients with primary FSGS and/or NS and progression to end-stage renal disease (ESRD). Genotyping for TRPC6, ACTN4, CD2AP, WT1, INF2, NPHS2 and NPHS1 was performed in all patients with primary FSGS and ESRD registered on the waiting list for kidney transplantation of a large German transplant center (n = 26 out of 478 registered patients). Mean age at onset was 31.7 years; a positive family history for renal disease was documented in 11 (42%) patients, of these one with familiar history of FSGS. A missense mutation (p.R360H) was identified in TRPC6, 2 missense mutations in compound heterozygous state in NPHS1 (p.P368L; p.G412C), a sequence variation of unknown significance (p.R310Q) in ACTN4 and the non-neutral NPHS2 polymorphism p.R229Q in two additional patients. No mutations were detected in INF2, CD2AP and WT1. The observed mutation rate was 8% in this single-center cohort of adult patients with primary FSGS. Mutations in podocyte genes seem to be a rare cause of FSGS and renal failure in adult patients. However, they should be considered as the underlying cause in a subset of patient as the impact on family counseling and patients' life perspectives are significant.