Surgery is the standard of care for resectable colorectal liver metastases (CRC-LM). Unfortunately, 60 % of patients develop secondary metastatic recurrence (SMR) after R0-resection of CRC-LM. We investigated the impact of surgical re-intervention and chemotherapy (Ctx) on survival in a consecutive series of patients with SMR.

Introduction: Liver transplantation is the standard treatment for end-stage liver cirrhosis as well as for certain primary and secondary tumours. However, the reperfusion technique of the liver graft after transplantation has not been standardized. It is still unclear from the literature which method of revascularization is the best in terms of the development of complications and quality of liver graft function. Aim: To compare the experience of different European transplantation centres concerning the sequence of reperfusion of the liver graft at transplantation. Methods: An online survey was sent to 37 European transplantation centres in order to collect information about the centre-specific technique of liver reperfusion and the reason for the adopted technique. Results: By the end of January 2012, 28 European transplantation centres (75,7%) had responded to our survey, which was sent per e-mail in November 2011. 26 of the 28 responses could be included in this study. 10 centres from 26 (38,5%) perform simultaneous reperfusion; 16 centres (61,5%) perform sequential reperfusion, 13 (81,25%) of which are anterograde and 3 (18,75%) retrograde. 12 of the 13 (92,3%) centres performing the sequential anterograde reperfusion first revascularize the portal vein, one centre (7,7%) first revascularizes first the hepatic artery. One (8,3%) of the centres performing the sequential anterograde reperfusion first using the portal vein does not use this technique on children; in this case simultaneous reperfusion is performed. In 20 of the 26 (77%) centres, the technique and order of reperfusion is standardized. In 19 (95%) of these centres, this standard is based on personal/institutional experience; only in 1 (5%) centre the technique used is based on available literature. In 6 (23%) centres, the technique is not standardized and is left at the discretion of the surgeon performing the procedure. Most of the 26 (73%) centres agree on the need for randomized controlled trials (RCT) in this field and would participate in a multicenter RCT. Conclusion: The most frequently used reperfusion technique (46,1%) in European transplantation centres is the anterograde sequential reperfusion via the portal vein first. In 20 of the 26 centres (77 %), the procedure used is standard. Only 1 (3,8%) centre based the decision of how to reperfuse on available literature. These results confirm a lack of evidence-based data and therefore a lack of consensus on the optimal reperfusion techniques. Almost all European transplantation centres base their decision on personal/institutional experience. These results demonstrate the need for RCTs, which most of the centres would support.

Einleitung: Die prätherapeutische interdisziplinäre Behandlungsplanung gilt als Standard in der Behandlung von Patienten mit kolorektalen Lebermetastasen (KRLM). Notwendig ist dafür, die Möglichkeiten komplementärer Behandlungspartner abschätzen und einen Konsens finden zu können.

Liver transplant recipients are at high risk of developing acute and chronic renal failure. Moreover, introduction of the model for end-stage liver disease (MELD) score for primary allocation of liver grafts favors patients with pretransplant kidney dysfunction, which in turn have a higher risk of posttransplant renal failure. Calcineurin inhibitors (CNI) further increase the risk of renal failure and therefore sparing CNI with the use of mycophenolate mofetil (MMF) may improve renal function. MMF may either be used de novo in the immediate posttransplant period in combination with low-dose CNI (scenario 1) or patients that receive immunosuppression based on CNI may be converted to MMF in combination with minimization or elimination of CNI (scenario 2). Although many retrospective cohort studies and nonrandomized trials have implicated efficacy of this approach the evidence from randomized controlled studies has not been summarized. In the current review we report the results of a systematic review and meta-analysis of randomized controlled trials.

Bilobar colorectal liver metastases (CRLM) are often considered incurable or associated with poor prognosis even after R0 resection. In this single-center study, we evaluate the impact of CRLM spreading on recurrence-free survival (RFS) and cancer-specific overall survival (CSS) after R0 resection of CRLM with respect to multimodal treatment strategies including perioperative chemotherapy and multistep resections. Between January 2001 and December 2010, R0 resection could be achieved in 70 patients with bilobar and 100 with unilobar CRLM. Extent of disease, perioperative chemotherapy, surgical procedures, adjuvant treatment, histopathological workup, RFS, and CSS were compared between both cohorts. Forty-six (66 %) patients with bilobar and 26 (26 %) patients with unilobar CRLM received preoperative chemotherapy (p < 0.001). For bilobar CRLM, more extended and multistep resection including portal vein occlusion were performed (29 % versus 3 %; p < 0.001). Morbidity (39 % versus 28 %, p = 0.183) and mortality (1 % versus 3 %, p = 0.644) rates were comparable in both patients' cohorts. Postoperative therapy was applied in adjuvant intent to 42 (60 %) versus 51 (51 %) patients (p = 0.275). The 5-year RFS and CSS rates were 24 % versus 31 % (p = 0.169) and 42 % versus 55 % (p = 0.131), respectively. To our single-center experience, there is no significant effect of CRLM spreading (bilobar versus unilobar) on RFS and CSS rates. Bilobar CRLM are more likely to require extended multimodal efforts to achieve R0 resection.

Einleitung: Bilobäre kolorektale Lebermetastasen (KRKLM) gelten als oftmals nicht resektabel und prognostisch ungünstig selbst wenn eine R0-Resektion erreicht wird. Die Einführung der präoperativen Chemotherapie sowie aggressiver chirurgischer Konzepte mit Pfortaderokklusion beeinflusst die Patientenselektion und möglicherweise auch deren Prognose.

Patients with bilobular colorectal liver metastases (CRLM) experience poor prognosis, especially when curative resection cannot be achieved. However, resectability in these patients is often limited by low future remnant liver volume (FRLV). The latter can be enhanced by a two-stage liver resection, using portal vein ligation to induce liver hypertrophy. The aim of this prospective pilot study was to evaluate safety, secondary resectability, and time to recurrence of two-stage hepatectomy with portal vein ligation (PVL) and complete surgical clearance of the FRLV in patients with bilobular CRLM.

Background data: Liver transplantation is the best therapeutic option for patients with end- stage liver disease due to its excellent long term survival results. The demand for deceased donor liver transplantation vastly exceeds the supply. In the U.S. the Model for End Stage Liver Disease (MELD) score is now used for allocation in liver transplantation waiting lists, replacing the Child- Turcotte- Pugh (CTP) score. The MELD system is based on the risk of death without transplantation and was originally developed for survival estimation in patients after TIPS. The majority of the European countries still use the CTP score for liver organ allocation. However, there is a debate whether the MELD score is superior CTP to predict mortality in patients with cirrhosis on waiting list and after liver transplantation.

Aims: Prospero-related homeobox 1 (Prox1) transcription factor is a hepatocellular differentiation marker, and is absent from biliary epithelial cells. In this study Prox1-gene-expression was investigated at mRNA and at protein levels in normal human liver tissue, in histologically normal liver surrounding primary liver tumours, in cirrhotic human liver samples, in hepatocellular (HCC) and cholangiocellular carcinomas (CCC), and in HCC- and biliary adenocarcinoma- cell lines.

Lebermetastasen treten bei 40 % der Patienten mit kolorektalen Karzinomen auf. Die Verbesserung der chirurgischen Techniken und des perioperativen Managements haben zu einer deutlichen Senkung der Morbidität und Mortalität der Lebermetastasenresektion (LMR) geführt. Vor dem Hintergrund eines zunehmenden Verständnisses der Tumorbiologie einerseits und deutlich verbesserter Überlebensraten andererseits ist in den letzten Jahren die Indikationsstellung zur LMR in spezialisierten Zentren erweitert worden. Die Therapiestrategie verlagerte sich dabei von einer resektionstechnisch standardisierten Intervention zu einem individualisierten, interdisziplinär geplanten Behandlungskonzept, das sowohl eine präoperative Chemotherapie, mehrzeitige Leberresektionen als auch die ausgedehnte Resektion extrahepatischer Tumormanifestationen umfasst. Ziel dieser Arbeit ist es, den gegenwärtigen Stellenwert der LMR im interdisziplinären Behandlungskonzept darzustellen. Dabei werden insbesondere Grenzsituationen betrachtet, in denen in der Vergangenheit ausschließlich palliative Chemotherapien als einzig sinnvolle onkologische Therapieoption angesehen wurden.

40 % of patients suffering from colorectal cancer will develop liver metastases during the course of their disease. Advances in both surgical technique and perioperative management lead to a decrease in postoperative morbidity and mortality. Against the background of an increasing understanding of tumor biology as well as excellent survival data following hepatic resection, the indication for liver resection has been extended in specialized surgical centers. Similarly the intention to treat changed from a standardized resection towards an individual and interdisciplinary therapy including preoperative chemotherapy, staged liver resection and resection of extrahepatic disease. The aim of this study is to investigate the current value of hepatic resection for colorectal liver metastases in the interdisciplinary oncological concept. It specially addresses these challenging situations where palliative chemotherapy seemed to be the only reasonable way of therapy in past.

14507 Background: As shown recently (JCO 2005; 23:6763–70), a single application of RAIT improved both, median overall survival (OS), and 5-year survival rates of colorectal cancer (CRC) patients (pts) post salvage resection of liver metastases (LM) compared to controls without RAIT (P=0.004). In an ongoing phase II trial we are evaluating the safety and efficacy of repeated RAIT at doses of 2x 40–50 mCi/m2 (3 mos apart) post salvage resection of LM. Methods: To date, 26 pts (8x f, 18x m; age: 63 ± 9 ys) who underwent surgery for CRC-LM have received the first dose of 131I-labetuzumab (Immunomedics, In., NJ, USA), a humanized monoclonal antibody against CEA, within 2 months of LM surgery. Three months after the first RAIT, a second infusion of 40–50 mCi/m2 has been applied to all pts after completion of standardized re-staging procedures. Results: The primary tumor sites were 17 colonic and 9 rectal cancers; primary tumor stages were 5x UICC-II, 7x UICC-III, 14x UICC-IV. 13 pts received adjuvant therapy. In 11 pts preoperative chemotherapy (FOLFOX or FOLFIRI) was given to achieve resectability of bilobular LM. After resection of LM (y)mTNM tumor stages were 1x mTNM-I, 6x mTNM-II, 6x mTNM-III and 4x mTNM-IV, respectively. After first RAIT, hematologic Grade 3 and 4, toxicity (WBC/platelet count) occurred in 8/14 and 5/3 pts, respectively. No cumulative toxicity was seen after repeated RAIT, with complete bone marrow recovery observed in all cases so far. To date, all pts are alive. Of the total, 17 pts received RAIT with adjuvant intention (as classified by FDG-PET and CT scans at pre-RAIT re-staging). In these, DFS was 70% post salvage resection of LM during ongoing follow-up of 15 months (median; range: 4–23 mos). As of Dec. 20, 2006, cancer recurrence was detected in 5/17 pts (3x pulmonary, 1x intrahepatic, 1x both) and in 4 pts R0-resection of distant metastases was done. 1 patient with pulmonary and intrahepatic relapses receives polychemotherapy with palliative intention. The pts‘ compliance to repeated RAIT has been 100%. Conclusion: RAIT re-treatment to date appears to be safe, feasible, and well accepted. Extended follow-up of the encouraging survival data will be presented. No significant financial relationships to disclose.

13572 Background: Complete resection of liver metastases (LM) remains the treatment of choice for colorectal cancer (CRC). As shown recently (Liersch et al., JCO 2005; 23:6763–70), RAIT with a single application of the humanized monoclonal anti-CEA antibody, 131I-labetuzumab, improved both the median overall survival (OS) and 5-yr survival rates significantly in patients post salvage resection of LM. The major adverse side effects (≤ grade 3 CTC) were transient myelosuppression and/or thrombocytopenia in patients receiving 40 to 60 mCi/m2 of 131I-labetuzumab. These encouraging results stimulated the current ongoing Phase-II trial to evaluate the safety of repeated RAIT at doses of 2 × 50 mCi/m2 (3 mos apart), post salvage resection of LM. Methods: At present, 13 patients (primary CRC: 8x UICC stage IV, 1× UICC stage III and 4× UICC stage II) who underwent surgery for LM of CRC (postsalvage mTMN stages: 4× mT4, 2× mT3, 6× mT2, 1× mT1) have received the first dose of 50 mCi/m2 131I-labetuzumab within 2 mos of LM surgery. Three months later, a second infusion of 50 mCi/m2 has already been given to 5 pts. In two, a dose reduction to 40 mCi/m2 was performed. At re-staging CT and PET scans) for the 2nd RAIT, in one patient pulmonary metastases were diagnosed and in another patient a re-resection of hepatic relapse was performed. Results: In the previous trial, at a median follow-up of 67 mos, the median OS from the first liver resection for 19 pts treated with single-dose RAIT was 68.0 mos and median DFS was 18.0 mos. Also, 5-year survival was achieved by 51.3% of RAIT pts independently of bilobar involvement, size and number of LM, or resection margins. In the current study with repeated RAIT, transient grade-4 myelosuppression (2 cases in combination with a myelotoxic thiamazol medication) occurred in 4/13 pts after the first dose (1× grade 4 thrombocytopenia). No cumulative toxicity was seen in 6 of 7 RAIT-re-treated patients. Complete bone marrow recovery was observed in all 6 cases within 5–12 weeks; in one pt severe neutropenia persisted to about week 16 post 2nd RAIT. As of January, 2006, patient compliance was 100%. Conclusion: RAIT re-treatment to-date appears to be safe, feasible, and well accepted. Extended follow-up data are being collected. [Table: see text]

Endokrine Pankreastumoren sind seltene Tumoren, histologisch heterogen und verursachen ganz unterschiedliche klinische Symptome. Diese Tumorentitäten werden vornehmlich in erfahrenen Chirurgischen Zentren behandelt. In einem Zeitraum von 20 Jahren wurden alle Patienten mit endokrinen Pankreastumoren, die einer chirurgischen Therapie zugeführt worden waren, erfasst und retrospektiv ausgewertet. Insgesamt kamen 49 Patienten zur Auswertung. Die Geschlechterverteilung war mit 29 Frauen und 20 Männern in etwa ausgeglichen. Die Mehrzahl der Tumoren waren Insulinome (21 Tumore bei 20 Patienten) und mit absteigender Frequenz nicht funktionelle neuroendokrine Tumoren (n=12), Karzinoide (n=5, histologisch nicht weiter klassifiziert), Vipome (n=4), Glukagonome (n=3), Gastrinome (n=2) und Somatostatinome (n=1). Die häufigste unilokuläre Lokalisation war der Pankreaskopf mit 21 von 49 Tumoren, der Pankreasschwanz mit 15 und der Korpus mit 6 Tumoren. In 7 Fällen fanden sich multilokuläre Tumoren, am häufigsten im Pankreaskorpus/schwanz Bereich (n=5). Die präoperative Diagnostik beinhaltete in 45 von 49 Fällen ein CT sowie bei 32 Patienten eine Sonographie. Bei 9 der 20 Patienten mit einem Insulinom war eine intraoperative Sonographie zur Detektion des Tumors notwendig. Bei dieser Vorgehensweise war nur in einem Fall die Operation ohne den Nachweis eines Insulinoms erfolgt. Die chirurgischen Verfahren für das Gesamtkollektiv umfassten in 17 Fällen Enukleationen, 16 Pankreaslinksresektionen, 4 Operationen nach Kausch/Whipple und in den letzten 10 Jahren die Pyloruserhaltende Pankreaskopfresektion nach Longmire/Traverso bei 5 Patienten. In den verbliebenden Patienten wurden in aller Regel palliative Eingriffe durchgeführt. Bei 20 von 49 Patienten traten keinerlei postoperative Komplikationen auf. Es verstarb kein Patient postoperativ. Die schlechteste Prognose hatten Patienten mit einem malignen endokrinen Karzinom, die besten Patienten mit einem Insulinom. Patienten mit endokrinen Pankreastumoren stellen ein heterogenes Patientengut dar, welches diagnostisch und insbesondere chirurgisch sehr anspruchsvoll ist. Patienten mit einem vermuteteten endokrinen Pankreastumor sollten daher in Zentren mit entsprechender Erfahrung behandelt werden.

We report on a 59-year-old woman and a 31-year-old man with no previous medical history of liver disease presenting with acute liver failure probably caused by drug toxicity. High urgency liver transplantation was performed 30 and 51 days after the onset of symptoms, respectively. Histomorphological evaluation of the explanted livers revealed incidental dysplastic nodules and hepatocellular carcinoma of up to 8 mm in diameter. Up to now only a few cases of metastatic liver disease and even fewer cases of primary liver cancer presenting as acute liver failure have been described. Our cases indicate hepatic tumorigenesis not as a cause of hepatic failure but either as an event taking place in parallel or as a process being induced by progressive liver failure.

Bei Patienten mit terminaler Leberzirrhose wurde die Prognose quoad vitam mittels Child-Pugh-Score ermittelt. In der letzten Zeit wird die Dringlichkeitsstufe zur Lebertransplantation bei solchen Patienten mit Hilfe des MELD-Scores festgestellt. Wir haben die Aussagefähigkeit beider Methoden an unserem Patientenkollektiv überprüft.

Background. Ischemia-reperfusion injury (IRI) can result in severe organ dys- or nonfunction. Interaction of leukocytes and endothelial cells mediated by E-selectin appears to be a key step for disturbed microcirculation. Therefore we studied gene and protein expression as well as localization of E-selectin during intestinal IRI.Methods. Intestinal tissue samples were obtained from extracorporeal perfused intestines (cold ischemia time [CIT] 2 or 20 hours, each n = 5) and additionally in intestinal transplanted pigs (CIT 2 or 20 hours, each n = 1). Mucosal damage was graded according to the Chin classification. E-selectin mRNA was determined by PCR and quantitative RT-PCR. Localization of E-selectin mRNA was performed by in situ hybridization and of the protein by immunohistochemistry.Results. Histologically, mucosal damage occurred during reperfusion and was earlier and more severe after 20 hours of CIT. E-selectin mRNA expression was detected by PCR already after laparotomy and was elevated after reperfusion. Interestingly, mRNA expression was already increased after 20 hours of CIT. E-selectin mRNA was localized to the luminal surface of muscular, submucosal, and mucosal endothelial cells and the protein was detected on submucosal arterial endothelium as early as 2 hours after reperfusion.Conclusion. Prolongation of CIT results in more severe mucosal damage during reperfusion, which is associated with protein expression of E-selection that might be used as a marker for activated endothelial cells. Increased E-selectin mRNA at end of 20 hours of CIT might indicate a preactivated state of endothelial cells potentially triggered by bacterial translocation or products.

[Einleitung] Gastrointestinale Stromatumoren (GISTs) bezeichnen mesenchymale Tumoren des Magen-Darm-Traktes, denen die Mutation einer Tyrosin-Rezeptor-Kinase gemeinsam ist. Einen therapeutischen Ansatz bildet die Gabe des Tyrosin-Kinase Inhibitors Imatinib. Bei insgesamt gutem Erfolg wird in 11% der betroffenen Patienten jedoch ein Tumorprogreß beschrieben (1). Wir möchten hier zwei Fälle aus der Ära vor Imatinib anführen, in denen nach Resektion des Primärtumors eine erfolgreiche Lebertransplantation durchgeführt wurde. [Fallberichte] Bei Patient 1 wurde im Alter von 39 Jahren ein GIST des Magens diagnostiziert. 4 Jahre nach Tumorresektion zeigten sich Lebermetastasen in beiden Leberlappen. Eine Leberbiopsie bestätigte das Vorliegen von Metastasen des initialen GISTs. Nach erfolglos durchgeführter Chemotherapie und Chemoembolisation wurde im Alter von 43 Jahren die Lebertransplantation durch eine Leberlebendspende möglich. Nach bisher 32 Monaten ist der Patient frei von einem Tumorrezidiv. Der GIST von Patientin 2 war Teil einer Carney Triade. Dieses Tumorsyndrom umfasst GISTs, pulmonale Hamartochondrome, extraadrenale Paragangliome und Tumoren der Nebenniere. Im Alter von 29 Jahren wurde ein GIST des Magens diagnostiziert und eine Billroth-II-Operation durchgeführt. Im Alter von 38 Jahren wurde das Vollbild der Carney Triade manifest. Zunächst wurde eine Leberteilresektion durchgeführt. Ein halbes Jahr später wurde bei multifokalen Lebermetastasen transplantiert. In den vergangenen 55 Monaten ist kein weiterer Tumor diagnostiziert worden. [Zusammenfassung] Die Lebertransplantation ist eine Option für Tumore der Leber, wenn die erwarteten Langzeitergebnisse denen benigner Lebererkrankungen entsprechen. Für Lebermetastasen wird die Lebertransplantation kontrovers diskutiert und bisher nur für Lebermetastasen neuroendokriner Tumoren in Erwägung gezogen. Unsere vor der Imatinib-Ära erhobenen Daten zeigen, dass die Lebertransplantation auch für Metastasen mesenchymaler Tumoren eine Therapieoption darstellt. Bei Therapieresistenz der Metastasen auf Imatinib oder bei GIST-Rezidiv verbleibt mit der Lebertransplantation eine Therapiemöglichkeit, die bei den langen Wartezeiten rechtzeitig erwogen werden sollte.