International prognostic index, type of transplant and response to rituximab are key parameters to tailor treatment in adults with CD20-positive B cell PTLD: clues from the PTLD-1 trial.

Tailoring treatment by patient strata based on the risk of disease progression and treatment toxicity might improve outcomes of patients with posttransplant lymphoproliferative disorder (PTLD). We analysed the cohort of 70 patients treated in the international, multicenter phase II PTLD-1 trial (NCT01458548) to identify such factors. Of the previously published scoring systems in PTLD, the international prognostic index (IPI), the PTLD prognostic index and the Ghobrial score were predictive for overall survival. None of the scoring systems had a considerable effect on the risk for disease progression. Age and ECOG performance status were the baseline variables with the highest prognostic impact in the different scoring systems. Baseline variables not included in the scoring systems that had an impact on overall survival and disease progression were the type of transplant and the response to rituximab at interim staging. Thoracic organ transplant recipients who did not respond to rituximab monotherapy were at particularly high risk for death from disease progression with subsequent CHOP-based chemotherapy. Patients in complete remission after four courses of rituximab and patients in partial remission with low-risk IPI had a low risk of disease progression. We speculate that chemotherapy might not be necessary in this patient cohort.

A comprehensive analysis of the cellular and EBV-specific microRNAome in primary CNS PTLD identifies different patterns among EBV-associated tumors.

Primary central nervous system (pCNS) posttransplant lymphoproliferative disorder (PTLD) is a complication of solid organ transplantation characterized by poor outcome. In contrast to systemic PTLD, Epstein-Barr virus (EBV)-association of pCNS PTLD is almost universal, yet viral and cellular data are limited. To identify differences in the pattern of EBV-association of pCNS and systemic PTLD, we analyzed the expression of latent and lytic EBV transcripts and the viral and cellular microRNAome in nine pCNS (eight EBV-associated) and in 16 systemic PTLD samples (eight EBV-associated). Notably although 15/16 EBV-associated samples exhibited a viral type III latency pattern, lytic transcripts were also strongly expressed. Members of the ebv-miR-BHRF1 and ebv-miR-BART clusters were expressed in virtually all EBV-associated PTLD samples. There were 28 cellular microRNAs differentially expressed between systemic and pCNS PTLD. pCNS PTLD expressed lower hsa-miR-199a-5p/3p and hsa-miR-143/145 (implicated in nuclear factor kappa beta and c-myc signaling) as compared to systemic PTLD. Unsupervised nonhierarchical clustering of the viral and cellular microRNAome distinguished non-EBV-associated from EBV-associated samples and identified a separate group of EBV-associated pCNS PTLD that displayed reduced levels of B cell lymphoma associated oncomiRs such as hsa-miR-155, -21, -221 and the hsa-miR-17-92 cluster. EBV has a major impact on viral and cellular microRNA expression in EBV-associated pCNS PTLD.

Twenty-year longitudinal follow-up after orthotopic liver transplantation: a single-center experience of 313 consecutive cases.

With excellent short-term survival in liver transplantation (LT), we now focus on long-term outcome and report the first European single-center 20-year survival data. Three hundred thirty-seven LT were performed in 313 patients (09/88-12/92). Impact on long-term outcome was studied and a comparison to life expectancy of matched normal population was performed. A detailed analysis of 20-years follow-up concerning overweight (HBMI), hypertension (HTN), diabetes (HGL), hyperlipidemia (HLIP) and moderately or severely impaired renal function (MIRF, SIRF) is presented. Patient and graft survival at 1, 10, 20 years were 88.4%, 72.7%, 52.5% and 83.7%, 64.7% and 46.6%, respectively. Excluding 1-year mortality, survival in the elderly LT recipients was similar to normal population. Primary indication (p < 0.001), age (p < 0.001), gender (p = 0.017), impaired renal function at 6 months (p < 0.001) and retransplantation (p = 0.034) had significant impact on patient survival. Recurrent disease (21.3%), infection (20.6%) and de novo malignancy (19.9%) were the most common causes of death. Prevalence of HTN (57.3-85.2%, p < 0.001), MIRF (41.8-55.2%, p = 0.01) and HBMI (33.2-45%, p = 0.014) increased throughout follow-up, while prevalence of HLIP (78.0-47.6%, p < 0.001) declined. LT has conquered many barriers to achieve these outstanding long-term results. However, much work is needed to combat recurrent disease and side effects of immunosuppression (IS).

Liver transplant from a donor with occult HEV infection induced chronic hepatitis and cirrhosis in the recipient.

Acute hepatitis E virus (HEV) infection is a self-limiting symptomatic or asymptomatic disease. However, as recently observed, it can manifest itself as chronic hepatitis in patients receiving solid organ transplants as well as in patients with HIV infection or severe hematologic disorders. Here, we describe the clinical course of a 73-year-old male patient in whom HEV transmission occurred after receiving a HEV-infected liver from a donor with occult HEV infection, whereby the patient had tested negative for HEV RNA and anti-HEV antibodies shortly before explantation. Anti-HEV IgG, IgM, and HEV RNA were detected in the first tested serum sample of the liver recipient obtained 150 days after liver transplantation and remained positive (earlier samples after OLT were not available). Liver cirrhosis developed within 15 months and the patient died of septic shock. Based on phylogenetic analyses of the donor and recipient's HEV strains, we were able to prove that the occult HEV infection was transmitted via the graft.

Role of mannose-binding lectin-2 polymorphism in the development of acute cellular rejection after transplantation for hepatitis C virus-induced liver disease.

UNLABELLED: The development of liver and graft disease is suspected to be affected by genetic diversity. Mannose-binding lectin-2 (MBL-2) is an important immunomodulatory factor that is involved in complement activation. The aim of our study was to elucidate the role of MBL-2 genotypes after liver transplantation (LT) for hepatitis C virus (HCV)-induced liver disease regarding the incidence of acute cellular rejection (ACR), graft inflammation, fibrosis development, and antiviral treatment response. METHODS: A group of 149 patients who underwent LT for HCV-induced liver disease were genotyped for MBL-2 (rs7096206; G/C) by TaqMan genotyping assay. We evaluated 518 post-LT protocol biopsies and at least 98 urgent liver biopsies regarding graft fibrosis stages, inflammation grades, and evidence for rejection within MBL-2 genotype groups. RESULT: No association of MBL-2 polymorphisms was observed regarding inflammation, fibrosis, and antiviral treatment outcome. However, the C allele of the MBL-2 gene (P = 0.001) and gender compatibility (P = 0.012) were factors significantly associated with the incidence of ACR. CONCLUSION: MBL-2 polymorphisms and gender are involved in the development of ACR after LT. CC genotype and gender match may be regarded as risk factors for ACR in HCV-positive graft recipients. Further studies are needed to confirm and verify this observation in non-HCV groups as well.

Liver transplantation for alcohol-related cirrhosis: a single centre long-term clinical and histological follow-up.

BACKGROUND: Alcohol-induced liver cirrhosis is one of the leading indications for liver transplantation today. Due to the general organ shortage and continuous deaths on the waiting list there has been some debate on the issue of indication and ethical problems. It was the aim of this study to critically analyse the outcome of patients with alcoholic cirrhosis transplanted at our centre with special emphasis on alcohol-recurrence frequency and long-term histological follow-up. METHODS: Three hundred five patients who received LT for alcoholic cirrhosis at our institution were followed over a period of 3-10 years after transplantation. Biopsies were taken 1, 3, 5, and 10 years after LT. Specimens were analysed and staged concerning inflammation, rejection, fatty involution, and fibrosis/cirrhosis. Clinical characteristics as well as serological parameters, immunosuppressive protocols, rejection episodes, and patient and graft survival were recorded. RESULTS: Recurrence of alcohol abuse occurred in 27% of all patients analysed. Regardless of alcohol consumption, 5-year graft and patient survival were excellent; after 10 years abstinent patients showed significantly better survival (82% vs. 68%; P=0.017). Histological changes were slightly more pronounced among recurrent drinkers, no significant difference regarding inflammation or fibrosis was detected. CONCLUSION: Patients undergoing LT for alcohol-induced cirrhosis show excellent long-term survival rates with stable graft function. Alcohol recurrence impairs long-term prognosis; however, compared to other patient sub-populations (HCC, HCV) results are clearly above average.

Immunization of liver and renal transplant recipients: a seroepidemiological and sociodemographic survey.

Several life-threatening infections, a major risk to adult solid organ transplant (SOT) recipients on immunosuppressive therapy, can be prevented by immunization. We analyzed sociodemographic parameters and the immunization status of adult liver transplant recipients (LTX-R, n=267) and renal transplant recipients (RTX-R, n=197) SOT recipients at the Transplantation Center, Berlin, Germany. Date, number, and provider of recommended vaccines were recorded and seroprotection rates determined. The social status in both groups was similar. Most patients (89%) were not adequately informed about immunizations; and if informed, main sources were physicians (47%) and the media (40%). Vaccinations were predominantly provided by family doctors (LTX-R, 66%; RTX-R, 31%) or hemodialysis centers (RTX-R, 37%). Before transplantation, RTX-R had significantly more often received booster vaccinations against tetanus and diphtheria (P<0.005), and a primary hepatitis B immunization (55%); whereas in LTX-R, post-transplant vaccinations against hepatitis A (16%) and pneumococcal disease (13%) were more frequent. Seroprotection rates against tetanus were fairly high in LTX-R (85.3%) and RTX-R (86.8%), and considerably lower for diphtheria, hepatitis A, and influenza. Immunization rates are too low in SOT recipients. Improvement will depend on a more active role of health care providers.

Immediate recovery of renal function after orthotopic liver transplantation in a patient with hepatorenal syndrome requiring hemodialysis for more than 8 months.

Severe liver dysfunction may lead to impairment of renal function without an underlying renal pathology. This phenomenon is called hepatorenal syndrome (HRS), which is associated with a poor prognosis showing a median survival of less than 2 months if renal replacement therapy is necessary. Liver transplantation is the best therapeutic option to regain renal function, but because of poor survival, these patients often die before transplantation. Herein we report a 37-year-old patient with ethyl-toxic liver cirrhosis who underwent hemodialysis due to HRS type I for more than 8 months. After living donor liver transplantation, diuresis immediately resumed, renal function soon recovered, and intermittent hemodialysis was stopped at 18 days after transplantation. Renal function was stable with a serum creatinine <2 mg/dL during the last 5 years posttransplantation. As far as we know, only a few cases of an anuric patient suffering from HRS have been reported with a survival beyond 8 months and full recovery of renal function after liver transplantation. This underlined that renal replacement therapy in HRS should be considered as a possible bridging method to liver transplantation even for longer periods.

Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo.

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are frequently found in several human cancer types including acute myeloid leukemia (AML) and lead to the production of high levels of the oncometabolite (R)-2-hydroxyglutarate (R-2HG). Here we report the characterization of BAY1436032, a novel pan-mutant IDH1 inhibitor, both in vitro and in vivo. BAY1436032 specifically inhibits R-2HG production and colony growth, and induces myeloid differentiation of AML cells carrying IDH1R132H, IDH1R132C, IDH1R132G, IDH1R132L and IDH1R132S mutations. In addition, the compound impacts on DNA methylation and attenuates histone hypermethylation. Oral administration of BAY1436032 led to leukemic blast clearance, myeloid differentiation, depletion of leukemic stem cells and prolonged survival in two independent patient-derived xenograft IDH1 mutant AML mouse models. Together, BAY1436032 is highly effective against all major types of IDH1 mutant AML.

Acute renal failure after liver transplantation: incidence, etiology, therapy, and outcome.

Acute renal failure (ARF) was a frequent complication after orthotopic liver transplantation (OLT) when ARF was defined by a calculated glomerular filtration rate decrease of >50% or by a doubled serum creatinine above 2.5 mg/dL within the first week after OLT. We analyzed 1352 liver transplant recipients in retrospective fashion with regard to the incidence, etiology, therapy, and outcome of ARF; 162 patients developed ARF within the first week after OLT (12%), among whom 157 patients (97%) were recompensated by postoperative day 28. Altogether 52 patients (32%) received an average of 6 hemodialysis treatments, excluding the 5 patients (3%) who developed end-stage renal failure. Risk factors for this complication included hepatorenal syndrome type II, a glomerular filtration rate of <50 mL/min, and a diagnosis of hepatitis C.

Primary immunosuppression with tacrolimus after liver transplantation: 12-years follow-up.

The early safety and efficacy of tacrolimus after liver transplantation has been shown in two multicenter trials. Herein, we report our single-center long-term follow-up of a randomized controlled trial. As part of a European multicenter trial, 121 patients entered the study at our institution and were randomly assigned to receive either tacrolimus and steroids (n=61) or a quadruple protocol (n=60) using ciclosporin A, steroids, azathioprine, and antithymocyte globulin (ATG). Twelve-year figures of patient survival were 74% in the tacrolimus group and 66% in the cyclosporine-based group. Graft survival after 12 years was 69% in the tacrolimus group compared to 56% in the cyclosporin-based group (not significant, p=0.15). The total rate of graft loss and retransplantation decreased significantly in the tacrolimus arm (p<0.05). De novo malignancies increased significantly in the ciclosporin-based group and dominated as single cause of death beyond 5 years posttransplant. The use of tacrolimus after liver transplantation resulted in a decreased rate of graft loss over the long-term. An increased number of de novo malignancies in the ciclosporin-based group may be attributable to the use of ATG as induction therapy.

Incidence of oral, pharyngeal, and laryngeal squamous cell carcinomas among 1515 patients after liver transplantation.

The purpose of this study was to evaluate the incidence and basic characteristics of oral, pharyngeal, and laryngeal squamous cell carcinomas (OPLC) in a single-centre series of liver transplantations (LT). The medical records of 1515 LT cases with a median follow-up of 6 years were analysed retrospectively for incident cases of OPLC. Incidence rates for the oral cavity and pharynx (ICD-9: 141-149), and larynx (ICD-9: 161) were assessed separately. OPLC cases and non-cases were evaluated with regard to end-stage alcoholic liver disease (ALD) as LT indication, smoking, and immunosuppression. The cumulative incidence of 13 cases with OPLC was 0.86% in total (n=1515). For 11 cases of OPLC in 307 patients with LT for ALD, it was 3.58%. The estimates for the annual incidence of OPLC (ICD-9: 141-149) were 121.79 for females and 111.65 for males (/100.000 patient-years). For OPLC (ICD-9: 161), the estimate was 37.21 for males, respectively (no female cases). ALD (84.6%) and pre-LT smoking (92.3%) were significantly overrepresented in OPLC cases (p<0.001). Age and gender distribution were comparable to non-cases. The 5-year survival rate after OPLC was 41.5%. OPLC were demonstrated as a late-onset complication of LT with poor prognosis. The impact of pre-, post-LT smoking, and, in particular, ALD as a confounder of OPLC deserves further investigation.

Withdrawal of steroids: a randomized prospective study of prednisone and tacrolimus versus mycophenolate mofetil and tacrolimus in liver transplant recipients with autoimmune hepatitis.

The aim of this study was to evaluate the success of steroid (PRED) withdrawal due to replacement by mycophenolate mofetil (MMF) in orthotopic liver transplant (OLT) recipients with autoimmune hepatitis (AIH). Thirty patients with AIH > 12 months after OLT randomized to receive either PRED and tacrolimus (TAC) or MMF and TAC were followed for 24 months. Withdrawal of steroids showed no difference regarding graft and patient survival. Also we demonstrated significantly lower glucose levels with lower HbA1c and a reduced need for insulin as well as a significantly lower serum cholesterol in the MMF group. Patients without steroids showed a lower incidence of osteopenia. Maintenance therapy in OLT patients with AIH may be performed safely using MMF instead of prednisone.

The influence of late acute rejection episodes on long-term graft outcome after liver transplantation.

Acute cellular rejection represents the most important single risk factor for the occurrence of chronic rejection after organ transplantation. We correlated late acute rejections with the occurrence of chronic graft failure after liver transplantation. We followed 1426 liver transplants for late acute rejection episodes defined as occurring >3 months after OLT. The overall incidence of chronic rejection in our patient population was 3.7%. In summary, we observed a predictive increase of transaminase levels prior to routine biopsies among patients with histologic evidence of late acute rejections. In contrast to other organ systems, late acute rejection episodes were not associated with the occurrence of chronic graft deterioration in liver grafts.

Quality of life of liver transplant recipients. A pilot study.

In a cross-sectional survey of the quality of life of 45 liver transplant recipients, physical and psychological status, physical complaints, capability to participate in daily life, social support, and global quality of life were assessed. The average time of follow-up was 9 months after transplantation. Nine patients had moderate liver damage, 12 suffered from drug side effects, and 10 had extrahepatic diseases. Physical complaints, especially rheumatism, exhaustion, and gastric complaints, were higher than in the general population. Most patients were able to participate in daily life (do housework, take part in family life, etc.). Apart from the complex "health" (use of body), they did not differ in this respect from healthy individuals. Eighty percent of the patients reported having very good social support. The psychological status was generally good, with only 5% complaining of anxiety and nervousness. Sixty percent regarded their quality of life to be very high, 31% reported medium quality of life, and 9% felt very bad. No relationship was found between low quality of life and transplant malfunction; patients with extrahepatic diseases had the lowest quality of life. Among all subgroups, the individuals who were actively working again felt best. Psychological qualities necessary for coping with daily life (self-assurance, self-realization, satisfaction, and happiness) correlated most with the global quality of life (r = 0.80), whereas no relationship was found between quality of life and complaints in total (r = -0.32). This survey shows that during the first year after transplantation, transplant recipients report a high quality of life in important areas of living, despite many physical complaints, and even display an almost euphoric mood.

Intravenous or intramuscular anti-HBs immunoglobulin for the prevention of hepatitis B reinfection after orthotopic liver transplantation.

To prevent reinfection with hepatitis B virus after orthotopic liver transplantation, patients receive long-term intravenous anti-HBs immunoprophylaxis. We compared the pharmacokinetics of intravenously and intramuscularly administered commercially available hepatitis B virus immunoglobulins. The study group consisted of 12 patients on immunoprophylaxis after orthotopic liver transplantation, who were Hbs antigen negative; 11 were anti-HBe positive and one was HBe positive. The patients first received intravenous immunoglobulin, and six of them were then transferred to intramuscular immunoglobulin. Our findings show that with fortnightly intramuscular application of 1000 IU of anti-HBs, reproducible and stable antibody titers above 100 IU of anti-HBs can be achieved. Side effects of intramuscular immunoprophylaxis are minimal and the method is safe. The switch from intravenous (1500 IU of anti-HBs) to intramuscular (1000 IU of anti-HBs) reduced the cost of immunoprophylaxis by more than 50%.

Long-term changes of markers of alcoholism after orthotopic liver transplantation (OLT).

Both physical rehabilitation and the course of the alcoholism improve after orthotopic liver transplantation (OLT) in patients with end-stage alcoholic liver cirrhosis. In the present study including 17 alcoholics and 14 nonalcoholics, after OLT, three of the alcoholic patients resumed their pre-OLT alcohol drinking habits, 4 consumed alcohol occasionally, 10 remained abstinent over the observation period of 13 to 36 months. The laboratory parameters before OLT did not discriminate alcoholics from nonalcoholic patients. Furthermore, the blood levels of two so-called alcogens (harman and norharman) were determined to investigate whether they discriminate between the two groups. Alcogens are natural compounds that are presumed to induce alcohol abuse in predisposed individuals. Both alcogens measured were elevated in plasma from nonalcoholics and alcoholics before OLT, suggesting a disturbance in inactivation in end-stage liver disease. Following OLT, the alcogens normalized but in the alcoholics this process was slower with respect to harman. The present exploratory study suggests that the normalized metabolic capacity of the liver after OLT causes a normalization of the levels of alcogens, for which harman and norharman are representative. These changes could contribute to the observed benefit to the outcome in alcoholics with respect to the alcohol dependence.

Rapid decline of antibodies after hepatitis A immunization in liver and renal transplant recipients.

BACKGROUND: Hepatitis A vaccine is safe and achieves good seroconversion rates in liver (LTX) and renal (RTX) transplant recipients. METHODS: A study was performed to determine the anti-hepatitis A virus (HAV) antibody decline in LTX and RTX patients, and in healthy controls who have been immunized with two doses of hepatitis A vaccine. RESULTS: LTX and RTX patients had a satisfactory seroconversion rate after complete immunisation. However, 2 years later they had experienced a much more rapid antibody decline than controls, and only 59% of LTX and 26% of RTX seroconverters showed titres above the cut-off level defined as protective. CONCLUSIONS: Patients on immunosuppressive therapy may not be adequately protected against hepatitis A a few years after vaccination and alternative vaccination schemes may have to be considered.

Comparison of famciclovir and lamivudine in the long-term treatment of hepatitis B infection after liver transplantation.

BACKGROUND: Preliminary results of short-term famciclovir and lamivudine therapy in patients with hepatitis B virus (HBV) infection after liver transplantation revealed promising results. In a retrospective study the efficacy of long-term treatment with these substances was compared. METHODS: A total of 53 HBV-infected adults (48 reinfections and 7 de novo infections) received antiviral treatment. A total of 32 of these patients were treated with famciclovir 3x500 mg, 20 of them were later switched to lamivudine. Fourteen patients received lamivudine, 150 mg/day orally, as first line therapy and 7 patients after failure of famciclovir-prophylaxis. Follow-up time was 8 to 62 months (mean 35 months). Response to therapy (HBV-DNA negative) was compared using Kaplan-Meier estimates. Potential influence factors (HBV-DNA and HBeAg pretransplant, HDV coinfection, pretreatment with famciclovir and immunosuppression) on treatment response were analyzed by log. Rank test (univariate); then a multivariate analysis (Cox multiple stepwise regression model) was applied. RESULTS: A total of 19 and 76% of the patients treated with famciclovir and lamivudine resp. became HBV-DNA negative; 0 and 24% HBsAg negative. Lamivudine was also effective as second line therapy. In a multivariate analysis of all 73 treatment courses, lamivudine treatment and HDV-coinfection were significant factors for better treatment response; regarding only the lamivudine group, negative HBeAg pretransplant was significant. Viral breakthrough after prolonged treatment occurred in 55% (lamivudine) to 80% (famciclovir) of treatment courses but was only accompanied by mild hepatitis. CONCLUSIONS: Lamivudine and famciclovir are potent drugs for the treatment of HBV-infection after liver transplantation. The antiviral capacity of lamivudine is superior even after pretreatment with famciclovir but after prolonged treatment viral breakthrough is often observed.

Long-term follow-up of hepatitis B virus-infected recipients after orthotopic liver transplantation.

The outcome after OLT was studied in 53 patients with chronic hepatitis B virus (HBV)* infection, 15 of whom had, in addition, evidence of hepatitis delta virus (HDV) superinfection. Nine of 53 patients received short-term immunoprophylaxis with anti-hepatitis B surface (HBs) hyperimmunoglobulin up to 1 week after OLT and 44 of 53 patients received long-term unlimited immunoprophylaxis. Eight of 9 (89%) patients with short-term immunoprophylaxis showed reactivation of replication with HBV DNA in serum > 10 pg/ml independently of the preoperative HBV DNA level and HBsAg reappeared in all cases. Four (44%) patients in this group lost their graft because of fulminant hepatitis or cirrhosis and required retransplantation, and 2 patients (22%) died after reinfection in the second graft. Nineteen of 44 (43%) patients with long-term immunoprophylaxis developed HBV values > 10 pg/ml after transplant and 12 of 44 (27%) became HBsAg+ again. Most of them had quantifiable HBV DNA levels before OLT. Retransplantation was required in 5 of 44 (11%) patients and 4 of them died after HBV recurrence. The frequency of HBV reactivation and the development of viral hepatitis after OLT were associated with the preoperative presence of HBV, as determined by the molecular hybridization assay. With nested polymerase chain reaction, all 53 patients were HBV-DNA+ in the serum before and after OLT. with just one exception, none of the patients with HDV superinfection died, in spite of increased HDV replication after OLT. The data indicate that long-term immunoprophylaxis with anti-HBs hyperimmunoglobulin after OLT improves the prognosis in HBV-infected patients. The preoperative detection of HBV DNA in serum by molecular hybridization assay is correlated with graft infection and represents a prognostic parameter. The presence of HDV may have a protective effect after OLT.