Arnold Radtke

The impact of 68Ga-DOTATOC positron emission tomography/computed tomography on the multimodal management of patients with neuroendocrine tumors.

Objective:To evaluate the impact of 68Ga-DOTATOC positron emission tomography (PET)/computed tomography (CT) on the multimodal management of neuroendocrine tumors (NET). Background:Establishment of the extent and progression of NET are necessary to decide which treatment option to choose. However, morphological imaging with CT or magnetic resonance imaging (MRI) is often inadequate in identifying the primary tumor and/or in detecting small metastatic lesions. Methods:In total, 52 patients (27 women and 25 men) with histologically proven NET could be included in the protocol of comparison between 68Ga-DOTATOC PET/CT and CT and/or MRI. The examinations were performed in terms of tumor staging and, in some instances, also of primary tumor site identification to evaluate the patients eligibility for treatment. Each patient presented with either CT and/or MRI performed elsewhere and consecutively underwent 68Ga-DOTATOC PET/CT in our institution. Results:In all 52 patients, 68Ga-DOTATOC PET/CT demonstrated pathologically increased uptake for at least 1 tumor site, yielding a sensitivity of 100% on a patient basis. In 3 of 4 patients with unknown primary tumor site, 68Ga-DOTATOC PET/CT visualized the primary tumor region (jejunum, ileum, and pancreas, respectively) not identified on CT and/or MRI. 68Ga-DOTATOC PET/CT detected additional hepatic and/or extrahepatic metastases in 22 of the 33 patients diagnosed with hepatic metastases on CT and/or MRI. Of the 15 patients evaluated for liver transplantation, we omitted 7 (46.6%) from further screening because of evidence of metastatic deposits not seen by conventional imaging. Overall, 68Ga-DOTATOC PET/CT altered our treatment decision based on CT and/or MRI alone, in 31 (59.6%) of the 52 patients. Conclusions:In this study, 68Ga-DOTATOC PET/CT proved clearly superior to CT and/or MRI for detection and staging of NET. More important, 68Ga-DOTATOC PET/CT impacted our treatment decision in more than every second patient.

Role of microRNA-199a-5p and discoidin domain receptor 1 in human hepatocellular carcinoma invasion

BackgroundMicro-ribonucleic acid (miRNA)-199a-5p has been reported to be decreased in hepatocellular carcinoma (HCC) compared to normal tissue. Discoidin domain receptor-1 (DDR1) tyrosine kinase, involved in cell invasion-related signaling pathway, was predicted to be a potential target of miR-199a-5p by the use of miRNA target prediction algorithms. The aim of this study was to investigate the role of miR-199a-5p and DDR1 in HCC invasion.MethodsMature miR-199a-5p and DDR1 expression were evaluated in tumor and adjacent non-tumor liver tissues from 23 patients with HCC undergoing liver resection and five hepatoma cell lines by the use of real-time quantitative RT-PCR (qRT-PCR) analysis. The effect of aberrant miR-199a-5p expression on cell invasion was assessed in vitro using HepG2 and SNU-182 hepatoma cell lines. Luciferase reporter assay was employed to validate DDR1 as a putative miR-199a-5p target gene. Regulation of DDR1 expression by miR-199a-5p was assessed by the use qRT-PCR and western blotting analysis.ResultsA significant down-regulation of miR-199a-5p was observed in 65.2% of HCC tissues and in four of five cell lines. In contrast, DDR1 expression was significantly increased in 52.2% of HCC samples and in two of five cell lines. Increased DDR1 expression in HCC was associated with advanced tumor stage. DDR1 was shown to be a direct target of miR-199a-5p by luciferase reporter assay. Transfection of miR-199a-5p inhibited invasion of HepG2 but not SNU-182 hepatoma cells.ConclusionsDecreased expression of miR-199a-5p contributes to increased cell invasion by functional deregulation of DDR1 activity in HCC. However, the effect of miR-199a-5p on DDR1 varies among individuals and hepatoma cell lines. These findings may have significant translational relevance for development of new targeted therapies as well as prognostic prediction for patients with HCC.

Current trends in live liver donation

The introduction of living donor liver transplantation (LDLT) has been one of the most remarkable steps in the field of liver transplantation (LT), able to significantly expand the scarce donor pool in countries in which the growing demands of organs are not met by the shortage of available cadaveric grafts. Although the benefits of this procedure are enormous, the physical and psychological sacrifice of the donors is immense, and the expectations for a good outcome for themselves, as well as for the recipients, are high. We report a current overview of the latest trends in live liver donation in its different aspects (i.e. donors selection, evaluation, operation, morbidity, mortality, ethics and psychology). This review is based on our centers personal experience with almost 200 LDLTs and a detailed analysis of the international literature of the last 7 years about this topic. Knowing in detail how to approach to the different aspects of living liver donation may be helpful in further improve donors safety and even recipients outcome.

MicroRNA-101 inhibits human hepatocellular carcinoma progression through EZH2 downregulation and increased cytostatic drug sensitivity

BACKGROUND & AIMS Oncogene polycomb group protein enhancer of zeste homolog 2 (EZH2) has been proposed to be a target gene of putative tumor suppressor microRNA-101 (miR-101). The aim of our study was to investigate the functional role of both miR-101 and EZH2 in human hepatocellular carcinoma (HCC). METHODS MiR-101 and EZH2 expressions were evaluated in tumor tissues of 99 HCC patients and 7 liver cancer cell lines by real-time PCR. Luciferase reporter assay was employed to validate whether EZH2 represents a target gene of miR-101. The effect of miR-101 on HCC growth as well as programmed cell death was studied in vitro and in vivo. RESULTS MiR-101 expression was significantly downregulated in most of HCC tissues and all cell lines, whereas EZH2 was significantly overexpressed in most of HCC tissues and all cell lines. There was a negative correlation between expression levels of miR-101 and EZH2. Luciferase assay results confirmed EZH2 as a direct target gene of miR-101, which negatively regulates EZH2 expression in HCC. Ectopic overexpression of miR-101 dramatically repressed proliferation, invasion, colony formation as well as cell cycle progression in vitro and suppressed tumorigenicity in vivo. Furthermore, miR-101 inhibited autophagy and synergized with either doxorubicin or fluorouracil to induce apoptosis in tumor cells. CONCLUSION Tumor suppressor miR-101 represses HCC progression through directly targeting EZH2 oncogene and sensitizes liver cancer cells to chemotherapeutic treatment. Our findings provide significant insights into molecular mechanisms of hepatocarcinogenesis and may have clinical relevance for the development of novel targeted therapies for HCC.

Corticosteroid-free immunosuppression in liver transplantation: a meta-analysis and meta-regression of outcomes.

To examine the impact of steroid withdrawal from the immunosuppression protocols in liver transplantation. The electronic databases Medline, Embase, Pubmed and the Cochrane Library were searched. Meta‐analysis pooled the effects of outcomes of a total of 2590 patients enrolled into 21 randomized controlled trials (RCTs), using classic and modern meta‐analytic methods. Meta‐analysis of RCTs addressing patients transplanted for any indication showed no differences between corticosteroid‐free immunosuppression and steroid‐based protocols in most of the analyzed outcomes. More importantly, steroid‐free cohorts appeared to benefit in terms of de novo diabetes mellitus development [R.R = 1.86 (1.43, 2.41)], Cytomegalovirus (CMV) infection [R.R = 1.47 (0.99, 2.17)], cholesterol levels [WMD = 19.71 (13.7, 25.7)], the number of patients that received the allocated treatment [O.R = 1.55 (1.17, 2.05)], severe acute rejection [R.R = 1.71 (1.14, 2.54)] and overall acute rejection [R.R = 1.31 (1.09, 1.58)] (when steroids were replaced in the steroid‐free arm). Taking RCTs into account independently when steroids were not replaced, overall acute rejection was favoring the steroid‐based arm [R.R = 0.75 (0.58, 0.98)]. Studies addressing exclusively transplanted HCV patients demonstrated a significant advantage of steroid‐free protocols considering HCV recurrence [R.R = 1.15 (1.01, 1.13)], acute graft hepatitis [O.R = 3.15 (1.18, 8.40)], and treatment failure [O.R = 1.87 (1.33, 2.63)]. No unfavorable effects were observed after steroid withdrawal during short‐term follow‐up. On the contrary, significant advantages were documented.

Pulmonary and Blood Stream Infections in Adult Living Donor and Cadaveric Liver Transplant Patients

Background. Infectious complications occur in approximately 50% of cadaveric liver transplant (CDLT) recipients. Living-donor liver transplantation (LDLT) is an established alternative to shorten the waiting time. Currently, the incidence of pulmonary infections after LDLT and the microbiologic causes are unknown. In the present cohort study, we compared the incidence and profiles of pulmonary and blood stream infections (BSI) between LDLT and CDLT recipients. We hypothesized a lower incidence in LDLT recipients. Methods. The clinical course of 55 LDLT recipients consecutively transplanted between January 2003 and December 2006 was analyzed. The 173 CDLT recipients who were transplanted in the same period served as a control group. Patients were treated in a single Intensive Care Unit, applying standardized postoperative care. Results. Mean model for end-stage liver disease score did not differ between LDLT and CDLT recipients (14.2 vs. 13.3). The overall incidence of pulmonary and BSI for both groups was 8% and 24%, respectively. Pulmonary infections were experienced by 18% of LDLT versus 5% of CDLT recipients (P=0.005) and BSI occurred in 33% of LDLT versus 21% of CDLT recipients (P=0.1). Conclusions. In contrast to our hypothesis, LDLT recipients experienced significantly more pulmonary infections and a trend toward increased higher incidence of BSI. These findings emphasize the need for future research on the causative agents and prevention of infection in LDLT recipients. The observation that patients with pulmonary infection had a significantly reduced 1-year survival rate underscores the importance of our observations.

Neurological complications after cadaveric and living donor liver transplantation.

AbstractProblems related to the central nervous system have a major impact on survival and quality of life. The aim of this retrospective study was to evaluate the incidence of neurological complications after liver transplantation (LT), including both cadaveric and living donor liver transplantation. Between April 2001 and March 2004 174 patients (120 cadaveric liver transplantations, 54 living donor transplantations) were admitted to our intensive care after liver transplantation. Of the transplanted patients 24.7% developed neurological complications. These patients’ stay in the intensive care (14.2 ± 17.2 days) was much longer than that of all admitted patients (8.4 ± 10.5 days, p < 0.05). The most common neurological complications were encephalopathy (72.1%) and seizures (11.6 %). The incidence of neurological complications in living donor liver transplanted patients was significantly lower than in cadaveric transplantation patients (20.4% vs 26.7 %). The cold ischemia time in living donor transplanted patients was significantly shorter in comparison with cadaveric transplanted patients (215 ± 119.3 vs. 383.7 ± 214.7). The survival rate after liver transplantation of patients with neurological complications was lower than that of patients without, but not significantly different (79.1 % vs. 82.4%, p > 0.05). The incidence of neurological symptoms was found to be similar between the patients treated with cyclosporine (25%) and tacrolimus (23.8 %) in this study. In conclusion, there was a high incidence of neurological complications after LT, prolonging the patients’ stay in intensive care significantly. The major neurological manifestation in our patients was encephalopathy followed by seizures. Living donor liver transplantation was associated with a significantly lower incidence of neurological complications compared with patients who had received a cadaveric graft. This might be due to the good quality of the organ and the much shorter cold ischemia time of the graft when the donor was alive.

Computer-assisted surgery planning for complex liver resections: when is it helpful? A single-center experience over an 8-year period.

Objective:The purpose of this study was (1) to compare 2-dimensional computed tomographic (2D-CT) and 3D-CT computer-assisted preoperative surgical planning, and (2) to define the indications for the latter method. Background:The determination of functional residual liver volumes and the imaging of intrahepatic anatomy are critical when planning complex liver resections. Patients and Methods:Prospective study of 202 consecutive patients who underwent high-risk procedures (extended right/left hepatectomies, central resections, polysegmentectomies, large atypical resections, repeated resections, and hepatectomies in the setting of abnormal liver parenchyma). Preoperative evaluation included 3D-CT computer-assisted surgical planning (3D-CASP) and conventional 2D-CT imaging. Endpoints of the study were (1) determination of resectability and (2) changes in operative strategy (resection modifications/extensions/intrahepatic vascular reconstructions). Results:Thirty-four of 202 cases were considered nonresectable on the basis of both 2D and 3D imaging results. In 56 (33%) instances, 3D-CASP either changed the 2D strategy (expansion of resection, n = 40; intrahepatic vascular reconstructions, n = 13) or provided an entirely different approach (n = 3). Eleven (5.4%) cases were considered unresectable at laparotomy on the basis of poor liver quality (n = 8) or unfeasible vascular reconstructions resulting in remnants too small to sustain physiologic function (n = 3). Significant differences between resectional 2D and functional 3D remnant liver volumes were observed in extended left hepatectomies and left trisectionectomies. Conclusions:3D-CASP was particularly helpful in patients with unconventional resection planes and in those with central left tumors. Its main advantages were the individualized inflow/outflow virtual analyses and the accurate determination of safely perfused/drained retained liver volumes.

Orthotopic Liver Transplantation: T-tube or Not T-tube? Systematic Review and Meta-analysis of Results

Background. The purpose of this study was to compare outcomes after duct-to-duct anastomoses with or without biliary T-tube in orthotopic liver transplantation. Methods. We pooled the outcomes of 1027 patients undergoing choledocho-choledochostomy with or without T-tube in 9 of 46 screened trials by means of fixed or random effects models. Results. The “without T-tube” and “with T-tube” groups had equivalent outcomes for: anastomotic bile leaks or fistulas, choledocho-jejunostomy revisions, dilatation and stenting, hepatic artery thromboses, retransplantation, and mortality due to biliary complications. The “without T-tube” group had better outcomes when considering “fewer episodes of cholangitis,” “fewer episodes of peritonitis,” and showed a favorable trend for “overall biliary complications.” Although the “with T-tube” group showed superior result for “anastomotic and nonanastomotic strictures,” the incidence of interventions was not diminished. Conclusions. Our systematic review and meta analysis favor the abandonment of T-tubes in orthotopic liver transplantation.

Preoperative volume prediction in adult living donor liver transplantation: how much can we rely on it?

Accurate preoperative prediction of functional donor and remnant hemiliver volumes in live donor liver transplantation is essential in preventing postoperative liver failure and optimizing safety. Our aim was (1) to evaluate volume variability associated with multiphasic CT imaging and (2) to determine over‐ or under‐estimations of 3‐D CT graft‐volume assessments based on ‘largest’ versus ‘smallest’ CT phases with respect to intraoperative findings. Native, arterial and venous phase CT images from 83 potential live liver donors were subject to 3‐D CT liver volume calculations and virtual 3‐D liver partitioning. Estimates were compared to intraoperative volumes obtained in 43 cases. Calculated (preoperative) graft‐volume‐body‐weight‐ratios (GVBWR) versus measured (intraoperative) graft‐weight‐body‐weight‐ratios (GWBWR) were analyzed. Significant differences in total liver volume‐ and in graft‐liver volume calculations were found among the largest (venous) and smallest (native) CT phases. High significant overestimations were observed in graft‐volume determinations and in GVBWR‐calculations based on the ‘largest’ CT phase when compared to intraoperatively obtained graft‐weight and ‐GWBWR values. In contrast, differences among intraoperative measurements and preoperative calculations based on the ‘smallest’ CT phase yielded less significant overestimations. While 3‐D CT volumetry based on the ‘largest’ (venous) CT phase is associated with considerable overestimation, 3‐D volumetry based on the ‘smallest’ (native) CT phase accurately matches the intraoperative findings.