Alexander Kaltenborn

Incidence and long‐term risk of de novo malignancies after liver transplantation with implications for prevention and detection

The goal of this study was the characterization of long‐term cancer risks after liver transplantation (LT) with implications for prevention and detection. Site‐specific cancer incidence rates and characteristics were compared retrospectively for 2000 LT patients from a single institution (January 1, 1983 to December 31, 2010) and the general German population with standardized incidence ratios (SIRs); the total follow‐up at December 31, 2011 was 14,490 person‐years. The cancer incidence rates for the LT recipients were almost twice as high as those for the age‐ and sex‐matched general population (SIR = 1.94, 95% CI = 1.63‐2.31). Significantly increased SIRs were observed for vulvar carcinoma (SIR = 23.80), posttransplant lymphoproliferative disorder/non‐Hodgkin lymphoma (SIR = 10.95), renal cell carcinoma (SIR = 2.65), lung cancer (SIR = 1.85), and colorectal cancer (SIR = 1.41). The mean time between transplantation and diagnosis was 6.8 years. The mean age at the time of diagnosis was significantly lower for the cohort versus the general population with similar malignancies [50 years (both sexes) versus 69 and 68 years (males and females), P ≤ 0.006]. Tumors were diagnosed at more advanced stages, and there was a trend of higher grading, which suggested more aggressive tumor growth. Tumor treatment was performed according to accepted guidelines. Surprisingly, 5‐year survival was slightly better in the study cohort versus the general population for renal cell carcinoma, lung cancer, colorectal cancer, and thyroid cancer. Long‐term immunosuppression with different protocols did not lead to significantly different SIRs, although patients treated with mycophenolate mofetil had the lowest SIR for de novo cancers (1.65, 95% CI = 1.2‐2.4). Alcoholic liver disease (SIR = 2.30) and primary sclerosing cholangitis (SIR = 3.40) as indications for LT were associated with an increased risk of de novo malignancies. In conclusion, risk‐adapted cancer surveillance is proposed. Tumor treatment performed according to accepted guidelines appears adequate. Mycophenolate may lead to lower long‐term risks for de novo cancers. Liver Transpl 19:1252–1261, 2013.

Risk Factors for Short- and Long-Term Mortality in Liver Transplant Recipients with MELD Score ≥30

BACKGROUND After introduction of MELD-based allocation in Germany, decreased waiting list mortality and increased mortality after transplantation have been reported. MATERIAL AND METHODS This study compares relevant outcome parameters in patients with high MELD ≥30 versus lower MELD scores in a retrospective analysis including 454 consecutively performed liver transplantations in adults (age >16 years) at Hannover Medical School between 01/01/2007 and 31/12/2012 and a follow-up until 31/12/2013. Multivariable risk-adjusted models were applied to identify independent risk factors for 90-day and long-term mortality. RESULTS MELD score ≥30 (n=117; 26.1%) was an independent risk factor for 90-day mortality (p=0.004, odds ratio: 3.045, 95% CI 1.439-6.498) and long-term mortality (p=0.016, hazard ratio: 1.620, 95% CI 1.095-2.396) and was associated with significantly longer hospital and intensive care unit stays (p<0.001), and death occurred in more cases earlier after transplantation (90-day mortality 21.6% vs. 13.0%; p=0.029). Portal vein thrombosis at transplantation was significantly associated with 90-day mortality after transplantation in patients with MELD scores ≥30 (p=0.041), but this was not the case for patients with MELD scores <30, although portal vein thrombosis was equally frequent in individuals of both groups (3.0% vs. 3.4%, p=0.824). CONCLUSIONS Results of this study suggest that liver transplant recipients with portal vein thrombosis at transplantation should be transplanted before reaching a MELD score ≥30.

Mycophenolate mofetil in liver transplantation: a review.

Liver transplantation is the only live-saving, curative treatment for various end-stage liver diseases, and it has excellent survival rates. Mycophenolate mofetil is widely used as co-medication for immunosuppression after liver transplantation, especially to allow a sparing effect on calcineurin-inhibitors, thus reducing their numerous adverse effects. It improves both graft and patient survival. The properties of its active metabolite, mycophenolic acid, are diverse: inhibition of de novo purine synthesis and selective lymphocyte inhibition, anti-tumoral, antiviral, anti-angioneoplastic, and vasculoprotective mechanisms are described and summarized in this review. The most common adverse effects of mycophenolate mofetil are gastrointestinal complaints such as diarrhea, which often lead to dose-reduction or withdrawal of mycophenolate mofetil. A newer, enteric-coated formulation is available, which is meant to reduce the gastrointestinal adverse effects. Mycophenolate mofetil does not relevantly interact with other common drugs. The question of whether therapeutic drug monitoring allows optimized dosing strategies cannot be satisfyingly answered yet. The optimal partner-immunosuppressant seems to be tacrolimus, especially in low doses. This tutorial review provides an overview of recent studies exploring the role of mycophenolate mofetil in liver transplantation with regards to its development, mechanism of action, and actual controversies such as therapeutic drug monitoring or de novo malignancy after transplantation.

Non-melanoma skin cancer is reduced after switch of immunosuppression to mTOR-inhibitors in organ transplant recipients

Organ transplant recipients are prone to the development of non‐melanoma skin cancer. Organ transplant recipients often develop multiple non‐melanoma skin cancers and the tumors show an aggressive growth pattern, therefore surgical therapy can be difficult. Switch of the immunosuppressive regimen to mTOR‐inhibitors such as everolimus or sirolimus can have an antitumor effect.

Prognostic limitations of the Eurotransplant-donor risk index in liver transplantation

BackgroundLiver transplantation is the only life-saving therapeutic option for end-stage liver disease. Progressive donor organ shortage and declining donor organ quality justify the evaluation of the leverage of the Donor-Risk-Index, which was recently adjusted to the Eurotransplant community’s requirements (ET-DRI). We analysed the prognostic value of the ET-DRI for the prediction of outcome after liver transplantation in our center within the Eurotransplant community.Results291 consecutive adult liver transplants were analysed in a single centre study with ongoing data collection. Determination of the area under the receiver operating characteristic curve (AUROC) was performed to calculate the sensitivity, specificity, and overall correctness of the Eurotransplant-Donor-Risk-Index (ET-DRI) for the prediction of 3-month and 1-year mortality, as well as 3-month and 1-year graft survival. Cut-off values were determined with the best Youden-index. The ET-DRI is unable to predict 3-month mortality (AUROC: 0.477) and 3-month graft survival (AUROC: 0.524) with acceptable sensitivity, specificity and overall correctness (54% and 56.3%, respectively). Logistic regression confirmed this finding (p = 0.573 and p = 0.163, respectively). Determined cut-off values of the ET-DRI for these predictions had no significant influence on long-term patient and graft survival (p = 0.230 and p = 0.083, respectively; Kaplan-Meier analysis with Log-Rank test).ConclusionsThe ET-DRI should not be used for donor organ allocation policies without further evaluation, e.g. in combination with relevant recipient variables. Robust and objective prognostic scores for donor organ allocation purposes are desperately needed to balance equity and utility in donor organ allocation.

Insulin dependence and pancreatic enzyme replacement therapy are independent prognostic factors for long-term survival after operation for chronic pancreatitis.

BACKGROUND This retrospective, single-center, observational study on postoperative long-term results aims to define yet unknown factors for long-term outcome after operation for chronic pancreatitis. PATIENTS AND METHODS We analyzed 147 consecutive patients operated for chronic pancreatitis from 2000 to 2011. Mean follow-up was 5.3 years (range, 1 month to 12.7 years). Complete long-term survival data were provided by the German citizen registration authorities for all patients. A quality-of-life questionnaire was sent to surviving patients after a mean follow-up of 5.7 years. RESULTS Surgical principles were resection (n = 86; 59%), decompression (n = 29; 20%), and hybrid procedures (n = 32; 21%). No significant influences of different surgical principles and operative procedures on survival, long-term quality of life and pain control could be detected. Overall 30-day mortality was 2.7%, 1-year survival 95.9%, and 3-year survival 90.8%. Multivariate Cox regression analysis revealed that only postoperative insulin dependence at the time of hospital discharge (P = .027; Exp(B) = 2.111; 95% confidence interval [CI], 1.089-4.090) and the absence of pancreas enzyme replacement therapy at the time of hospital discharge (P = .039; Exp(B) = 2.102; 95% CI, 1.037-4.262) were significant, independent risk factors for survival with significant hazard ratios for long-term survival. Long-term improvement in quality of life was reported by 55 of 76 long-term survivors (73%). CONCLUSION Pancreatic enzyme replacement should be standard treatment after surgery for chronic pancreatitis at the time of hospital discharge, even when no clinical signs of exocrine pancreatic failure exist. This study underlines the potential importance of early operative intervention in chronic pancreatitis before irreversible endocrine dysfunction is present.

Species-specific regulation of fibrinogen synthesis with implications for porcine hepatocyte xenotransplantation.

Patients with liver failure could potentially be bridged with porcine xenogeneic liver cell transplantation. We examined species‐specific differences between primary human and porcine hepatocytes in the regulation of coagulation protein expression and function.

The new liver allocation score for transplantation is validated and improved transplant survival benefit in Germany but not in the United Kingdom.

Prognostic models for the prediction of 90‐day mortality after transplantation with pretransplant donor and recipient variables are needed to calculate transplant benefit. Transplants in adult recipients in Germany (Hannover, n = 770; Kiel, n = 234) and the United Kingdom (Birmingham, n = 829) were used for prognostic model design and validation in separate training and validation cohorts. The survival benefit of transplantation was estimated by subtracting the observed posttransplant 90‐day mortality from the expected 90‐day mortality without transplantation determined by the Model for End‐Stage Liver Disease (MELD) score. A prognostic model called the liver allocation score (LivAS) was derived using a randomized sample from Hannover using pretransplant donor and recipient variables. This model could be validated in the German training and validation cohorts (area under the receiver operating characteristic curve [AUROC] > 0.70) but not in the English cohort (AUROC, 0.58). Although 90‐day mortality rates after transplantation were 13.7% in Hannover, 12.1% in Kiel, and 8.3% in Birmingham, the calculated 90‐day survival benefits of transplantation were 6.8% in Hannover, 7.8% in Kiel, and 2.8% in Birmingham. Deployment of the LivAS for limiting allocation to donor and recipient combinations with likely 90‐day survival as indicated by pretransplant LivAS values below the cutoff value would have increased the survival benefit to 12.9% in the German cohorts, whereas this would have decreased the benefit in England to 1.3%. The English and German cohorts revealed significant differences in 21 of 28 pretransplant variables. In conclusion, the LivAS could be validated in Germany and may improve German allocation policies leading to greater survival benefits, whereas validation failed in England due to profound differences in the selection criteria for liver transplantation. This study suggests the need for national prognostic models. Even though the German centers had higher rates of 90‐day mortality, estimated survival benefits were greater. Liver Transplantation 22 743–756 2016 AASLD.

Helicobacter hepaticus Induces an Inflammatory Response in Primary Human Hepatocytes

Helicobacter hepaticus can lead to chronic hepatitis and hepatocellular carcinoma in certain strains of mice. Until now the pathogenic role of Helicobacter species on human liver tissue is still not clarified though Helicobacter species identification in human liver cancer was successful in case controlled studies. Therefore we established an in vitro model to investigate the interaction of primary human hepatocytes (PHH) with Helicobacter hepaticus. Successful co-culturing of PHH with Helicobacter hepaticus was confirmed by visualization of motile bacteria by two-photon-microscopy. Isolated human monocytes were stimulated with PHH conditioned media. Changes in mRNA expression of acute phase cytokines and proteins in PHH and stimulated monocytes were determined by Real-time PCR. Furthermore, cytokines and proteins were analyzed in PHH culture supernatants by ELISA. Co-cultivation with Helicobacter hepaticus induced mRNA expression of Interleukin-1 beta (IL-1β), Tumor necrosis factor-alpha, Interleukin-8 (IL-8) and Monocyte chemotactic protein-1 (MCP-1) in PHH (p<0.05) resulting in a corresponding increase of IL-8 and MCP-1 concentrations in PHH supernatants (p<0.05). IL-8 and IL-1β mRNA expression was induced in monocytes stimulated with Helicobacter hepaticus infected PHH conditioned media (p<0.05). An increase of Cyclooxygenase-2 mRNA expression was observed, with a concomitant increase of prostaglandin E2 concentration in PHH supernatants at 24 and 48 h (p<0.05). In contrast, at day 7 of co-culture, no persistent elevation of cytokine mRNA could be detected. High expression of intercellular adhesion molecule-1 on PHH cell membranes after co-culture was shown by two-photon-microscopy and confirmed by flow-cytomety. Finally, expression of Cytochrome P450 3A4 and albumin mRNA were downregulated, indicating an impairment of hepatocyte synthesis function by Helicobacter hepaticus presence. This is the first in vitro model demonstrating a pathogenic effect of a Helicobacter spp. on human liver cells, resulting in an inflammatory response with increased synthesis of inflammatory mediators and consecutive monocyte activation.

Long-term outcome analysis of liver transplantation for severe hepatic trauma.

BACKGROUND Liver transplantation (LTX) for severe hepatic trauma and its sequelae is a rare but potentially lifesaving option at the far end of the operative spectrum. METHODS This study analyzes 12 cases with LTX for hepatic trauma and its consequences from two transplant centers. A total of 2,701 consecutive liver transplants unrelated to trauma served as a control group. &khgr;2 and Mann-Whitney U-tests, Kaplan-Meier analysis with log-rank tests, and Cox regression analysis were applied. Addressed were issues before, during, and after LTX. Major study end points were patient and graft survival. RESULTS The posttrauma transplant recipients are significantly younger (p = 0.014), with a significantly shorter graft survival (p = 0.038), resulting in a significantly higher retransplantation rate (p = 0.043). Of the 12 patients, 11 underwent surgical treatment for hepatic trauma before LTX with 7 of 12 patients experiencing liver necrosis at the time of LTX. Short-term survival and long-term survival are not significantly different between trauma and nontrauma patients. Severity of liver trauma (Moore Score) and concomitant injuries (Injury Severity Score [ISS]) have no significant impact on patient and graft survival. Four patients with hepatic trauma were treated with two-stage LTX with anhepatic phases between 14 hours and 28 hours. Two of those patients reached long-term survival (20–22 years). CONCLUSION LTX for severe liver trauma and its consequences seems justified in extreme cases. The high frequency of liver necrosis at the time of LTX may indicate possible shortcomings in liver packing technique or liver resection for hemorrhage control. Thus, severe hepatic trauma requires treatment by experienced liver surgeons and emergency physicians. LEVEL OF EVIDENCE Therapeutic study, level IV.