The patients with colorectal liver metastases used to have a rather disappointing prognosis in the past. At present there is moderate possibility for cure with liver resection. In addition more patients are accessible for liver resection and potential cure when modern chemotherapy combined with biological agents is used. At the time of diagnosis liver metastases of 10–20% of patients are resectable. Potentially unresectable metastases can be converted to resectable in 10–15% of patients with advances in surgery together with improved oncological therapy. Resection rate increases linearly with the response rate to chemotherapy. In this century the 5-year survival rates after resection have improved remarkably being around 50% in many reports. Multidisciplinary management of metastatic colorectal cancer has increased the number of patients with potentially curative treatment and has improved patient survival.
Effective tumor transduction continues to be the limiting step for achieving clinical results with gene therapy agents. The use of oncolytic viruses such as conditionally replicating adenoviruses (CRAds) might prove useful in this regard. These viruses have a cytolytic nature, i.e. the replicative life cycle of the virus results in host cell destruction. Normal tissue is spared due to restriction of replication. The first clinical cancer trial with replicating adenoviruses was published in 1956 with various wild-type strains. More recently, increasing understanding of adenovirus replication and its interactions with cellular proteins and the immune system have allowed us to create more effective recombinant adenoviruses for cancer gene therapy. However, with more effective therapy regimens an increase in side effects is also possible. We hypothesized that we may be able to increase the safety of CRAds by developing means for pharmacological intervention for reduction of replication, which might be useful in the event of severe side effects in trials. Some tumor/tissue specific promoters might be amenable to pharmacological abrogation of CRAd replication. Further, some general steps in the viral replication cycle could be utilized for reduction of replication. We analyzed the effect of anti-inflammatory substances on cyclooxygenase-2 and vascular endothelial growth factor promoter based CRAds. Further, the inhibition of clathrin-dependent endocytosis by cationic amphiphilic drugs (CAD) was evaluated. CADs inhibit the assembly of the clathrin adapter protein AP2 on clathrin-coated pits, and cause the pits to disappear from the cell surface and reappear on endosomal membranes. Finally, a natural bioflavonoid compound was evaluated for its efficacy on tumor growth inhibition, regulation of the cell cycle and apoptosis, and therefore, effect on viral replication. We analyzed the in vitro cell killing efficacy of selected CRAds in the presence and absence of the substances. Further, in vitro replication in cell lines and human liver explants was measured. Moreover, the effect on in vivo efficacy and replication of the CRAds was evaluated. Detailed results will be presented in the meeting. On the basis of our results, we propose that the analyzed substances might reduce the replication of CRAds and of wild-type adenovirus and this could thereby provide a putative safety switch in case of side effects. Importantly, many of the identified substances are already clinically approved and therefore immediately usable in ongoing and forthcoming trials.
Abstract Background: Hepatic lesions constitute a daily challenge to radiology in clinical settings, and non‐invasive methods are valuable in the characterization of these liver tumours. We undertook our investigation to assess the lesion characterization potential of MRI by evaluating several unenhanced MR sequences and the dynamic gadolinium (Gd)‐enhanced technique. Methods: A total of 116 focal liver lesions in 116 patients were included in our retrospective study, and histological verification was available for 107 lesions. Nine haemangiomas had a follow‐up of 2 years. The 1.5‐T MR system was used. T1‐ and T2‐weighted sequences and dynamic Gd‐enhanced studies were evaluated by two individual readers as separate sequences and also collectively. Lesions were classified into benign or malignant, and a specific diagnosis was proposed. The McNemar test was used in statistical analysis, and interobserver variation was measured using kappa statistics. Results: Lesion classification into benign and malignant tumours (by evaluating all images in concert) was assessed in 83% and 89% of cases by readers 1 and 2, respectively. From single sequences, best lesion classification was achieved with Gd‐enhanced T1 by both readers. The difference in classification was statistically significant when all sequences were evaluated in comparison with any single sequence alone (P = 0.02). Specific diagnosis was correctly determined using all sequences together in 60% and 71% of cases by readers 1 and 2, respectively. For individual sequences, correct diagnosis was most frequently proposed with a Gd‐enhanced T1‐weighted sequence by both readers (59% and 65% for readers 1 and 2, respectively). Conclusion: Multisequential MRI using Gd‐enhanced imaging performs extremely well in liver lesion classification, and with moderate ability to determine a specific diagnosis.KeywordsLesion characterization; liverMRI sequences
Cancer after liver transplantation (LT) constitutes a threat also for young recipients, but cancer risk factors are usually absent in children and large studies on the cancer risk profile in young LT recipients are scarce. Data of patients younger than 30 years who underwent LT during the period 1982-2013 in the Nordic countries were linked with respective national cancer registries to calculate standardized incidence ratios (SIRs). A total of 37 cancer cases were observed in 923 patients with 7846 person-years of follow-up. The SIR for all cancer types, compared with the matched general population, was 9.8 (12.4 for males and 7.8 for females). Cumulative incidence of cancer adjusted for the competing risk of death was 2% at 10 years, 6% at 20 years, and 22% at 25 years after LT. Non-Hodgkin lymphoma was the most common cancer type (n = 14) followed by colorectal (n = 4) and hepatocellular cancer (n = 4). Age was a significant risk factor for cancer, and the absolute risk of most cancers (except for lymphoma) increased considerably in young adults older than 20 years. The cancer risk pattern is different in pediatric and young LT patients compared with adult recipients. The striking increase in cancer incidence in young adulthood after the second decade of life deserves further consideration in transition programs.
Physiologically relevant hepatic cell culture models must be based on three-dimensional (3D) culture of human cells. However, liver cells are generally cultured in two-dimensional (2D) format that deviates from the normal in vivo morphology. We generated 3D culture environment for HepaRG liver progenitor cells using wood-derived nanofibrillar cellulose (NFC) and hyaluronan-gelatin (HG) hydrogels. Culture of undifferentiated HepaRG cells in NFC and HG hydrogels induced formation of 3D multicellular spheroids with apicobasal polarity and functional bile canaliculi-like structures, structural hallmarks of the liver tissue. Furthermore, hepatobiliary drug transporters, MRP2 and MDR1, were localized on the canalicular membranes of the spheroids and vectorial transport of fluorescent probes towards the biliary compartment was demonstrated. Cell culture in 3D hydrogel supported the mRNA expression of hepatocyte markers (albumin and CYP3A4), and metabolic activity of CYP3A4 in the HepaRG cell cultures. On the contrary, the 3D hydrogel cultures with pre-differentiated HepaRG cells showed decreasing expression of albumin and CYP3A4 transcripts as well as CYP3A4 activity. It is concluded that NFC and HG hydrogels expedite the hepatic differentiation of HepaRG liver progenitor cells better than the standard 2D culture environment. This was shown as improved cell morphology, expression and localization of hepatic markers, metabolic activity and vectorial transport. The NFC and HG hydrogels are promising materials for hepatic cell culture and tissue engineering.
To investigate markers for high-grade dysplasia for the optimal timing of liver transplantation in patients with primary sclerosing cholangitis (PSC).Earlier data support a dysplasia-carcinoma sequence, even low- to high-grade dysplasia, in PSC-associated cholangiocarcinoma (CCA). Surveillance using endoscopic retrograde cholangiography (ERC) and brush cytology aims to detect cases of biliary dysplasia, and liver transplantation is an option in cases with suspicion of malignancy in brushing. This study investigated markers to identify patients with high-grade biliary dysplasia for optimal timing in early liver transplantation. Patients undergoing surveillance using ERC and brush cytology during 2008-2014 and who were diagnosed with biliary dysplasia in explanted liver or CCA until February 2016 were included in the study. Demographic data, cholangiography findings, laboratory values, cytological morphology and DNA ploidy were analysed.Thirty PSC patients had biliary neoplasia in the explanted liver during the study period. Sixteen of these patients had low-grade dysplasia, 10 patients had high-grade dysplasia, and 4 patients had CCA. Fifteen PSC patients diagnosed with CCA were not transplanted. Patients with low-grade dysplasia were younger. Alkaline phosphatase or carcinoembryonic antigen values did not differ between groups during surveillance, but carbohydrate antigen 19-9 was higher in CCA patients. No difference in PSC duration, ERC scores, suspicious cytology, or ploidy analysis was found between groups. No difference was observed between fibrosis stage in explanted livers. Low- and high-grade dysplasia could not be differentiated before liver transplantation based on liver enzymes, tumour markers, ERC scores, brush cytology or DNA ploidy.Repeated suspicion of neoplasia in brush cytology should be an indication for evaluations of liver transplantation prior to the development of CCA.
Introduction: Chronic calcineurin-inhibitor (CNI) nephrotoxicity is associated with histological kidney lesions, but the contribution of CNIs to the decline over time in glomerular filtration rate (GFR) after liver transplantation (LT) remains unclear. Methods: We studied annual changes in estimated GFR among 105 CNI-treated adult LT patients with a GFR between 60-100 ml/min at 1 year post-LT. Transplantations were between 1982 and 2002. The mean follow-up was 7 years (20 years in 20 patients). At 1 year post-transplant, 81% received cyclosporine, 19% tacrolimus, 68% azathioprine, 96% corticosteroids, whereas no patient received mTOR inhibitors. During follow-up, CNIs were discontinued in 2 (2%) patients and mTOR inhibitors were used for a period less than 1 year in 2 (2%) patients. Results: The annual GFR decline >1 year post-transplant was 0.2 ml/min/year (SD 3.8; Figure). This decline rate was unaffected by the decade of LT, follow-up period, GFR at 1 year, and showed no correlation with cyclosporine or tacrolimus trough levels at various post-transplant time points (all correlation coefficients < 0.34). Also, no significant impact on the annual GFR change emerged from indication (chronic liver disease versus acute liver failure versus liver tumor) or whether or not the patient was alive or dead at the end of follow-up. Thirteen (12%) patients had a GFR decline rate >3 ml/min/year, and of these, 77% presented with hypertension, diabetes, and/or dyslipidemia.[Figure]Conclusions: The decline in GFR among the LT patients did not exceed the decline of 0.5-0.8 ml/min/year reported by various studies in the general population. Declines faster than 3 ml/min/year, which occurred no more frequently among patients than in the general population, seemed attributable to co-existent vascular risk factors. Our findings challenge the clinical impact of chronic progressive CNI nephrotoxicity and highlight the importance of a tight control of blood pressures, glucose and lipid levels, and other modifiable risk factors in order to preserve kidney function long-term post-transplant.
