Technical feasibility of liver transplantation without cold storage.

PURPOSE: The success of liver transplantation (LT) is accompanied by an increased need for organs. The wider use of older donors and marginal organs with risk factors such as steatosis has lead to a new interest to improve the outcome with marginal organs. We herewith report a novel technique for LT with in situ preparation and immediate warm-ischemia liver transplantation (WI-LT). The aim of our study was to demonstrate the technical feasibility and report the transplant course. METHODS: Six patients underwent WI-LT at our institution. Hepatectomies during procurement and LT were both performed in parallel by different surgical teams. Technical factors and postoperative allograft function were analyzed. RESULTS: All six WI-LTs were performed without intraoperative complications with a mean warm-ischemia time (WIT) of 29.0 min. No patient developed primary non-function or required retransplantation. Mean alanine aminotransferase (194.0 ± 170.4 U/l) and aspartate aminotransferase (316.3 ± 222.1 U/l) values on the first postoperative day were low, indicating a low ischemia/reperfusion injury and an excellent liver function. CONCLUSIONS: These results demonstrate that WI-LT is a safe and technically feasible approach for LT with possibly reduced IRI and an excellent postoperative allograft quality. WI-LT may therefore be considered in individual patients especially with extended criteria donors to eventually improve postoperative allograft quality.

[Impact of time of occurrence of liver metastases (synchronous vs. metachronous) on early postoperative outcome and long-term survival of colorectal cancer patients]. / Einfluss des Metastasierungszeitpunkts (synchron vs. metachron) im Hinblick auf das frühpostoperative Outcome sowie das Langzeitüberleben von Patienten nach Resektion kolorektaler Lebermetastasen.

BACKGROUND: Today, liver resection represents the only curative treatment option for patients with resectable colorectal liver metastases. Large studies could show that liver surgery can be performed safely in specialised centres, but most of those studies did not differentiate between resection of synchronous and metachronous metastases. The aim of this study was to evaluate the impact of the time of the occurrence of colorectal liver metastases on the early postoperative course as well as the long-term survival. PATIENTS AND METHODS: Two groups of 30 patients each who underwent liver surgery due to synchronous or metachronous colorectal liver metastases at our centre between 2000 and 2010 were included in a matched-pairs analysis. Early postoperative course as well as long-term survival were assessed and compared between both groups. Matching criteria included: age, sex, number of metastases and size of largest metastasis. RESULTS: Postoperative morbidity for the entire study cohort was 23.3 % with a mortality of 0 %. No significant difference could be shown between synchronous and metachronous metastases with regard to incidence and severity of postoperative complications (20 vs. 26.7 %, p = 0.54). The median survival of the synchronous group was 38.9 months (95 % CI 26.4-51.6) compared to 47.9 months (95 % CI 21.4-74.4 %) in the metachronous group, but no significant difference could be detected in the univariate analysis (p = 0.425). CONCLUSION: According to the present results, liver surgery can be performed safely in a specialised centre. The time of occurrence of the metastases (synchronous vs. metachronous) does not seem to have any impact on the early postoperative course as well as on the long-term survival in patients undergoing curative resection of colorectal liver metastases. However, larger studies appear necessary to confirm the results of the present study.

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).

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.

[Perioperative anesthesia management of extended partial liver resection. Pathophysiology of hepatic diseases and functional signs of hepatic failure]. / Perioperatives anästhesiologisches Management bei ausgedehnten Leberteilresektionen. Pathophysiologie der Lebererkrankungen und funktionelle Zeichen des Leberversagens.

The importance of partial liver resection as a therapeutic option to cure hepatic tumors has increased over the last decades. This has been influenced on the one hand by advances in surgical and anesthetic management resulting in a reduced mortality after surgery and on the other hand by an increased incidence of hepatocellular carcinoma. Nowadays, partial resection of the liver is performed safely and as a routine operation in specialized centers. This article describes the pathophysiological changes secondary to liver failure and assesses the perioperative management of patients undergoing partial or extended liver resection. It looks in detail at the preoperative assessment, the intraoperative anesthetic management including fluid management and techniques to reduce blood loss as well as postoperative analgesia and intensive care therapy.

In vivo visualization of early microcirculatory changes following ischemia/reperfusion injury in human kidney transplantation.

To determine whether microcirculatory changes following ischemia/reperfusion (I/R) may serve as predictors for subsequent graft dysfunction, we used noninvasive orthogonal polarization spectral (OPS) imaging to directly visualize and quantify cortical kidney microcirculation. In a total of 13 combined kidney/pancreas recipients, following reperfusion (5/30 min) microcirculatory parameters such as capillary diameter, functional capillary density (FCD) and red-blood-cell velocity (V(RBC)) of the renal graft were analyzed. From these parameters, a heterogeneity index (HI) and volumetric capillary blood flow (vCBF) were calculated. In addition, the extent of graft injury was determined by daily analysis of serum creatinine, blood urea nitrogen, C-reactive protein and systemic leukocyte count for 7 days post-transplant. At early reperfusion, a heterogeneous perfusion pattern with oscillating flow and scattered microvascular thrombosis of peritubular capillaries, resembling a 'no reflow', was observed. FCD was constant throughout the entire reperfusion period, whereas HI, capillary diameters, V(RBC) and vCBF increased. The latter showed a significant positive correlation with creatinine changes between days 1 and 3. So far our finding of a positive correlation of early microvascular changes (vCBF) and clinical parameters (creatinine) indicate a possible therapeutic implication of OPS imaging to predict early I/R-induced renal graft dysfunction.

A method to assess biochemical activity of liver cells during clinical application of extracorporeal hybrid liver support.

Biochemical activity of a hybrid liver support system based on porcine liver cells was investigated in patients suffering from acute liver failure, coma stage III-IV Patient plasma was drawn systemically and after circulation through the bioreactor at four hour intervals. A method is used that takes into account the rate of plasma flow and the differences in plasma concentration systemically and after circulation through the liver support system to determine the net release or uptake of metabolites such as ammonia, urea and glucose. Urea release (mean 2.28+/-0.37 micromol/h/g cells) and ammonia uptake (mean 0.17+/-0.11 micromol/h/g cells) was seen during treatment, an active role of the system in glucose metabolism was observed. All patients were bridged successfully to liver transplantation.

Experimental evaluation of a cell module for hybrid liver support.

Aim of the study was to evaluate a hybrid liver support system in a porcine model of acute liver failure, after hepatectomy. Pigs with a body weight of 70+/-18 kg underwent total hepatectomy and porto-cavo-caval shunting as well as ligation of the bile duct and the hepatic artery. Control animals were connected to the system (including capillary membrane plasma separation) containing a four compartment bioreactor with integral oxygenation and decentralized mass exchange but without liver cells. The treatment group received hybrid liver support with the same system including 370+/-42 g primary isolated porcine parenchymal liver cells in co-culture with hepatocyte nursing cells, tissue engineered to liver- like structures at high density. Treatment started after complete recovery from anesthesia and was performed continuously. A positive influence on peripheral vascular resistance and a reduced need of catecholamine dosage was observed in the treatment group. Hybrid liver support with a cell module upscaled for clinical application significantly prolonged survival time in animals after hepatectomy with the longest survival being 26 hours in the control group an 57 hours in the treatment group.

Unresectable colorectal liver metastases: percutaneous ablation using CT-guided high-dose-rate brachytherapy (CT-HDBRT).

PURPOSE: To evaluate the clinical outcome of CT-guided high-dose-rate brachytherapy (CT-HDRBT) of unresectable colorectal liver metastases (CRLMs). MATERIALS AND METHODS: Retrospective analysis of all consecutive patients with unresectable CRLMs treated with CT-HDRBT between January 2008 and November 2012. Treatment was performed by CT-guided catheter placement and high-dose-rate brachytherapy with an iridium-192 source. MRI follow-up was performed after 6 weeks and then every 3 months post-intervention. The primary endpoint was local tumor control (LTC); secondary endpoints included time to progression (TTP) and overall survival (OS). RESULTS: 80 heavily pretreated patients with 179 metastases were available for MRI evaluation for a mean follow-up time of 16.9 months. The mean tumor diameter was 28.5 mm (range: 8 - 107 mm). No major complications were observed. A total of 23 (12.9 %) local tumor progressions were observed. Lesions ≥ 4 cm in diameter showed significantly more local progression than smaller lesions (< 4 cm). 50 patients (62.5 %) experienced systemic tumor progression. The median TTP was 6 months. 28 (43 %) patients died during the follow-up period. The median OS after ablation was 18 months. CONCLUSION: CT-HDRBT is an effective technique for the treatment of unresectable CRLMs and warrants promising LTC rates compared to thermal ablative techniques. A combination with other local and systemic therapies should be evaluated in patients with lesions > 4 cm in diameter, in which higher progression rates are expected. KEY POINTS: • CT-HDRBT enables a highly cytotoxic irradiation of colorectal liver metastases with simultaneous conservation of important neighboring structures (eg liver parenchyma, bile ducts and bowel)• The local tumor control rates obtained by CT-HDRBT in patients with colorectal liver metastases are promising, also compared to the local tumor control rates after RFA• Metastases with a diameter of 4 cm or abow, display a higher local progression rate after CT-HDRBT, therefor a combination therapy with other locoregional or systemic treatments should be investigated in prospective studies.

APACHE III score is superior to King's College Hospital criteria, MELD score and APACHE II score to predict outcomes after liver transplantation for acute liver failure.

OBJECTIVES: The Model for End-Stage Liver Disease score and King's College Hospital (KCH) criteria are accepted prognostic models acute liver failure (ALF), while the use of (APACHE) scores predict to outcomes of emergency liver transplantation is rare. MATERIALS AND METHODS: The present study included 87 patients with ALF who underwent liver transplantation. We calculated (KCH) criteria, as well as MELD, APACHE II, and APACHE III scores at the listing date for comparison with 3-month outcomes. RESULTS: According to the Youden-Index, the best cut-off value for the APACHE II score was 8.5 with 100% sensitivity, 49% specificity, 24% positive predictive value (PPV), and 100% negative predictive value (NPV). Patients with <8.5 points had a significantly higher survival rate (P < .05). The proposed APACHE III cut-off was 80. The APACHE III score demonstrated the highest specificity and PPV (90% specificity, 50% PPV). The NPV was 92%. With a 90-point threshold the specificity increased to 98% with 75% PPV and 89% NPV. Only 1 of 4 patients with a score >90 survived transplantation (P = .001). MELD score and KCH criteria were not significant (P > .05). According to the Hosmer-Lemeshow test, only the APACHE III score adequately describe the data. CONCLUSIONS: The APACHE III score was superior to KCH criteria, MELD score, and APACHE II score to predict outcomes after transplantation for ALF. It is a valuable parameter for pretransplantation patient selection.

The impact of simultaneous liver resection for occult liver metastases of pancreatic adenocarcinoma.

Backround. Pancreas resection is the only curative treatment for pancreatic adenocarcinoma. In the event of unexpected incidental liver metastases during operative exploration patients were traditionally referred to palliative treatment arms. With continuous progress in the surgical expertise simultaneous pancreas and liver resections seem technically feasible nowadays. The aim of this study therefore was to analyze the impact of synchronous liver-directed therapy on operative outcome and overall survival in patients with hepatic metastasized pancreatic adenocarcinoma (HMPA). Methods. 22 patients who underwent simultaneous pancreas resection and liver-directed therapy for HMPA between January 1, 2004 and January 1, 2009 were compared to 22 patients who underwent classic pancreas resection for nonmetastasized pancreatic adenocarcinoma (NMPA) in a matched pair study design. Postoperative morbidity, preoperative, and operative data and overall survival were analyzed. Results. Overall survival was significantly decreased in the HMPA group. Postoperative morbidity and mortality and median operation time did not significantly differ between the groups. Conclusion. The results of our study showed that simultaneous pancreas resection and liver-directed therapy may safely be performed and may therefore be applied in individual patients with HMPA. However, a potential benefit of this radical surgical approach with regard to overall survival and/or quality of life remains to be proven.

[Portosystemic shunt surgery between TIPS and liver transplantation]. / Portosystemische Shuntchirurgie zwischen TIPSS und Lebertransplantation.

Portosystemic shunt surgery in addition to transjugular intrahepatic portosystemic shunt (TIPS) insertion must still be regarded as a current treatment option for portomesenteric decompression in patients with pharmacological and endoscopic treatment failure, where liver transplantation is not imminent. This applies to secondary prophylaxis of rebleeding from varices in patients with well preserved liver function, e.g. liver cirrhosis CHILD A or extrahepatic portal vein thrombosis. Even if emergency endoscopy represents the treatment of choice in the acute bleeding situation, latest data from San Diego on emergency portacaval shunt surgery are encouraging. Likewise, portacaval shunt procedures can be an attractive alternative to TIPS or liver transplantation for acute Budd-Chiari syndrome or veno-occlusive disease.This article is an update on the systematics and methodology of portacaval shunt surgery, emphasizing the significance of this treatment option based on latest studies.

Donor age does not influence 12-month outcome after orthotopic liver transplantation.

OBJECTIVE: Orthotopic liver transplantation (OLT) is the most effective treatment for patients with end-stage liver disease to date. The discrepancy between the numbers of donor livers and recipients has become a significant problem, resulting in a high patient mortality on the waiting list. Due to this, an expansion of the donor pool is necessary, for example, by accepting donor grafts from elderly donors. The aim of this study was to investigate the outcome after OLT depending on donor age. METHODS: We retrospectively evaluated the outcome of 272 full-size cadaveric initial single OLTs within 12 months after OLT. The outcome was analyzed by dividing the collective into four donor age categories: donor age under 50, between 50 and 59, between 60 and 69, and 70 years or above. The outcome after OLT in these patients was retrospectively reviewed by using a prospective database. Patients positive for hepatitis C were excluded from the analysis. RESULTS: No increase of initial nonfunction was observed. Furthermore, no significant differences with regard to surgical complications and serum liver parameter were observed between the groups. Neither patient mortality rates nor rejection rates were different between the groups. However, ischemic-type biliary lesion rates increased significantly with donor age over 70 years (P<.05). CONCLUSIONS: The acceptance of liver grafts from older donors is a possible alternative to narrow the gap between donated and required organs. Safe use under optimal protocols is necessary to avoid a deterioration of post-OLT results.

Association of TLR7 single nucleotide polymorphisms with chronic HCV-infection and response to interferon-a-based therapy.

An efficient immune response against hepatitis C virus (HCV) is necessary to clear infection. As HCV is a single-stranded RNA virus, a role for TLR7 in the immune response against HCV is possible, and early clinical studies have demonstrated an antiviral effect of TLR7 stimulation. We tested the hypothesis that genetic variations of TLR7 are associated with chronic HCV-infection and outcome of therapy. The prevalence of three TLR7 variations was analysed in 978 patients with chronic HCV-infection, 898 patients with chronic liver disease of other aetiologies, and in 203 healthy controls. The prevalence of TLR7 variations was correlated with the response to interferon-alpha-based treatment in 544 patients with chronic HCV-infection. We analysed TLR7 polymorphisms by melting curve analysis and reconstructed haplotypes. The c.32A>T variation was over-represented in female patients with chronic HCV-infection compared to patients with other chronic liver diseases and to healthy controls (P < 0.05). In contrast, c.2403 G>A was less prevalent in male patients with chronic HCV-infection (P < 0.05). No association was observed for the third variant, c.1-120T>G. Haplotype analysis confirmed the differential distribution of TLR7 variants between the groups. Within the group of female patients with chronic HCV-infection, c.32T was predictive of an unfavourable outcome of interferon-alpha therapy (P < 0.05). This study reports the association of TLR7 variants with chronic HCV-infection and with the response to interferon-alpha therapy in patients with chronic HCV-infection. Our results suggest that variations of TLR7 impair the immune response to HCV and imply a gender-specific effect of this X-chromosomal variation.

[Hepatorenal syndrome]. / Hepatorenales Syndrom.

Hepatorenal syndrome (HRS) is defined as the development of renal insufficiency in chronic liver disease with portal hypertension when other causes of functional renal failure are excluded. Incidence in patients with refractory ascites is 8%, with an overall incidence of renal failure in end stage liver disease being 75%. HRS is predictive for the prognosis of end stage liver failure but its pathogenesis is complex and currently not fully understood.