Thomas Lorf

Presence of melatonin in the human hepatobiliary-gastrointestinal tract

A variety of speculations about the possible origin and physiological role of the neurohormone melatonin in the gastrointestinal tract exist. However, the experimental evidence supporting any of these theories is not substantial and are missing for humans. We studied the distribution of melatonin which was measured with radioimmunoassay in the following compartments and organs of the human hepatobiliary-gastrointestinal tract: bile (obtained by endoscopic retrograde cholangiopancreaticography), peripheral venous and portal venous blood (obtained from patients undergoing liver transplantation), endoscopically derived biopsies (mainly consisting of mucosa and submucosa) of stomach, duodenum, large intestine as well as in resected liver tissue. Melatonin concentrations in gastrointestinal mucosa were between 136 +/- 27 pg/100 mg (stomach) and 243 +/- 37 pg/100 mg (descending colon, each n = 5). Biliary melatonin concentrations (85 +/- 45 pg/ml) correlated well with plasma concentrations (55 +/- 38 pg/ml, each n = 14) and a considerable amount of melatonin (about 51 ng/24 hours) appears to be excreted into the gut via the bile duct. Melatonin concentrations were slightly higher in portal than in peripheral venous blood and also the liver contained higher concentrations of melatonin than the blood. In conclusion the presence and distribution of melatonin in human gut, bile, liver and portal blood and the various reports on modulatory actions of melatonin on gut and liver functions suggest that melatonin may act as a mediator of inter-organ communication between gut and liver.

Treatment of Hepatic Metastases from Gastroenteropancreatic Neuroendocrine Tumors: Role of Liver Transplantation

Abstract. The role of liver transplantation in malignancy has been discussed, but controversially, over the past two decades. This is particularly true for hepatic metastases from neuroendocrine tumors, which have a wide variety of primary tumor localizations, morphologic types, functional activities, and clinical presentations. Despite generally slow tumor progression, the prognosis is often unpredictable. Total hepatectomy and liver replacement has been offered primarily to patients with nonresectable metastases and symptomatic disease. The results from retrospective single and multicentric analyses show that most liver recipients experience significant palliation despite tumor recurrence, and in some patients long-term cure can be achieved. The existing data emphasize the importance of proper selection and timing for this approach.

Altered regulation of Prox1-gene-expression in liver tumors

BackgroundProspero-related homeobox 1 (Prox1) transcription factor was described as a tumor-suppressor gene in liver tumors. In contrast, Prox1 knock out in murine embryos drastically reduces proliferation of hepatoblasts.MethodsWe have studied the expression of Prox1 in normal liver, liver cirrhosis and peritumoral liver samples in comparison to hepatocellular (HCC) and cholangiocellular carcinoma (CCC) at mRNA, protein and functional levels.ResultsProx1 was found in hepatocytes of normal liver, while normal bile duct epithelial cells were negative. However, Prox1+ cells, which co-expressed biliary epithelial makers and showed ductular morphology, could be detected within fibrotic septa of cirrhotic livers, and in both HCC and CCC. Two Prox1 mRNA isoforms (2.9 kb and 7.9 kb) were identified with a prevalence of the longer isoform in several HCC samples and the shorter in most CCC samples. Evidence was provided that Myc-associated zinc finger protein (MAZ) might significantly contribute to the gene expression of Prox1 in HCC, while neo-expression of Prox1 in CCC remains to be resolved. A point mutation in the prospero domain of Prox1 was found in one HCC sample.ConclusionOur study shows dysregulation of Prox1 in liver cirrhosis, HCC and CCC, such as neo-expression in cells with biliary epithelial phenotype in liver cirrhosis, and in CCC. Altered Prox1 mRNA expression is partly regulated by MAZ, and mutation of the prospero domain in HCC indicates an involvement for Prox1 during tumor progression.

Pattern of chromosomal aberrations in primary liver cancers identified by comparative genomic hybridization

Little is known about the molecular cytogenetic changes in cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma, and on the prognostic significance of chromosomal imbalances in hepatocellular carcinoma. Seventy-eight cases of primary liver cancer with available median follow-up of 16.5 months, including 49 hepatocellular carcinomas, 22 cholangiocarcinomas, and 7 combined hepatocellular-cholangiocarcinomas, were examined by comparative genomic hybridization. In hepatocellular carcinoma, the most frequent changes were +8q (54%), -8p (54%), and +1q (42%), followed by -6q (35%), -4q (33%), -13q (29%), -14q (25%), -16q (19%), -17p (19%), +17q (17%), and +20q (15%). In comparison, cholangiocarcinoma had more gains, losses, and breakpoints than hepatocellular carcinoma or combined hepatocellular-cholangiocarcinoma, specifically more frequently -6q (91%), -3p (68%), -9p (55%), -14q (55%), -13q (45%), +1q (41%), +7q (36%), +7p (32%), and +8q (32%). Combined losses at 6q and 3p appeared to be highly characteristic for cholangiocarcinoma. In contrast, combined hepatocellular-cholangiocarcinoma shared frequent +1q (71%), +8q (57%), and -8p (57%) with hepatocellular carcinoma, but a tendency for higher numbers of imbalances with cholangiocarcinoma. Overall, higher numbers of changes, breakpoints, or gains appeared to carry unfavorable prognostic value among hepatocellular carcinomas, with higher numbers of gains retaining prognostic value among R0-resected hepatocellular carcinomas. Cholangiocarcinoma is characterized by combined losses at 6q and 3p and a tendency for chromosomal instability. On the other hand, combined hepatocellular-cholangiocarcinoma may share similar chromosomal changes with both hepatocellular carcinoma and cholangiocarcinoma, as reflected by common hepatocellular carcinoma-like +8q, +1q, and -8p and a tendency for cholangiocarcinoma-like chromosomal instability. In hepatocellular carcinoma, higher number of gains may prove an adverse prognostic parameter.

Pantoprazole does not affect cyclosporin A blood concentration in kidney-transplant patients

AbstractObjective: Renal-transplant patients who are immunosuppressed with cyclosporin A (CyA) are often treated with proton-pump inhibitors to prevent ulcer disease. No data are available on the effect of the novel proton-pump inhibitor pantoprazole on CyA levels. Methods: In a controlled treatment, we investigated the effect of pantoprazole, which was administered in a pragmatic schedule for acid suppression (40 mg as single oral dose at 2200 hours) in six renal-transplant patients who received CyA (Sandimmun optoral, 50–175 mg twice daily) and prednisolone (5–7.5 mg/24 h). CyA trough levels (0730–0800 hours) were measured by immunoassay. Results: In the absence of pantoprazole, mean CyA trough levels measured on three consecutive days were between 164 ng/ml and 173 ng/ml (therapeutic range 120–200 ng/ml). Pantoprazole did not affect CyA trough levels during an observation period up to 3 months long. Conclusions: Pantoprazole seems to be a safe drug in combination with CyA.

Pitfalls in monitoring Tacrolimus (FK 506)

Tacrolimus (FK 506) is a new, potent immunosuppressive drug for primary and rescue therapy in liver and kidney transplantation. Therapeutic drug monitoring is essential for this drug because of its narrow therapeutic window. Blood levels are monitored routinely by enzyme linked immunoassay (ELISA) or by microparticle enzyme immunoassay (MEIA). In a 13-year-old recipient of a liver transplant who had poor hepatic function during the first postoperative week, the authors observed unusually high tacrolimus blood concentrations using either the ELISA (26.6 to 49.0 microg/l) or MEIA (58.5 to 64.5 microg/l). Parent drug levels measured in the same blood samples by high-performance liquid chromatography/mass spectrometry (HPLC/MS) were up to 10-fold lower (5.1 to 9.0 microg/l). The discrepancies between the immunoassay and HPLC/MS results could not be attributed to any of the known metabolites of tacrolimus.

Situs inversus of donor or recipient in liver transplantation

Abstract Situs inversus is a rare anatomical abnormality that is often associated with multiple, complex malformations. In the past, patients with situs inversus were considered unsuitable candidates for transplantation or organ donation because associated visceral, and especially vascular, anomalies pose special technical difficulties. Recently, several cases of successful liver transplantation in recipients with situs inversus have been published using modified surgical techniques. This report reviews the literature and describes our own experience, including two liver graft recipients with complete and incomplete situs inversus, and one patient who underwent successful transplantation using a liver from a donor with situs inversus.

Calcineurin Inhibitor Sparing With Mycophenolate Mofetil in Liver Transplantion: A Systematic Review of Randomized Controlled Trials

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.

Posterior cavoplasty: a new approach to avoid venous outflow obstruction and symptoms for small-for-size syndrome in right lobe living donor liver transplantation

PurposeA common and serious problem after living donor liver transplantation (LDLT) of small grafts is small-for-size syndrome (SFSS). Although hyperdynamic portal inflow and portal hypertension are cornerstones in the development of SFSS, inadequate outflow may aggravate SFSS. Therefore, enlargement of the portal outflow tract by incision of the anterior rim of the orifice of the right hepatic vein (RHV) has been advocated for right lobe LDLT. But backwards tilt of a small graft into a large abdominal cavity may lead to a choking of the otherwise large anastomosis and thus we propose posterior enlargement of the orifice of the RHV.MethodIn this test-of-concept study, we evaluated portal vein pressure (PVP), clinical parameters, and laboratory measurements in 22 patients that underwent right lobe LDLT and either received standard end-to-end anastomosis of the RHV or posterior cavoplasty.ResultsIn patients that underwent posterior cavoplasty, we observed significantly lower PVP and less hyperbilirubinemia. There was a non-significant trend to lower incidence of SFSS. Other laboratory measurements and clinical parameters were not significantly different.ConclusionWe recommend posterior cavoplasty for enlargement of the hepatic venous outflow tract in right lobe LDLT as a method to avoid portal hypertension, hyperbilirubinemia, and possibly SFSS, especially in patients that receive small grafts.

A therapeutic exploratory study to determine the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation: CILT

BackgroundImmunosuppression with calcineurin inhibitors (CNI) increases the risk of renal dysfunction after orthotopic liver transplantation (OLT). Controlled trials have shown improvement of renal function in patients that received delayed and/or reduced-dose CNI after OLT. Delaying immunosuppression with CNI in combination with induction therapy does not increase the risk of acute rejection but reduces the incidence of acute renal dysfunction. Based on this clinical data this study protocol was designed to assess the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation.Methods/DesignA prospective therapeutic exploratory, non-placebo controlled, two stage monocenter trial in a total of 29 liver transplant patients was designed to assess the safety and efficacy of de-novo CNI-free immunosuppression with basiliximab, mycophenolate sodium, prednisolone and everolimus. The primary endpoint is the rate of steroid resistant rejections. Secondary endpoints are the incidence of acute rejection, kidney function (assessed by incidence and duration of renal replacement therapy, incidence of chronic renal failure, and measurement glomerular filtration rate), liver allograft function (assessed by measurement of AST, ALT, total bilirubin, AP, GGT), treatment failure, (i. e., re-introduction of CNI), incidence of adverse events, and mortality up to one year after OLT.DiscussionThis prospective, two-stage, single-group pilot study represents an intermediate element of the research chain. If the data of the phase II study corroborates safety of de-novo CNI-free immunosuppressive regimen this should be confirmed in a randomized, prospective, controlled double-blinded clinical trial. The exploratory data from this trial may then also facilitate the design (e. g. sample size calculation) of this phase III trial.Trial registration numberNCT00890253 (clinicaltrials.gov)