Combination of the Deacetylase Inhibitor Panobinostat and the Multi-Kinase Inhibitor Sorafenib for the Treatment of Metastatic Hepatocellular Carcinoma - Review of the Underlying Molecular Mechanisms and First Case Report

Advanced hepatocellular carcinoma still represents an unmet medical need that has only a limited overall survival despite the introduction of the multi-kinase inhibitor sorafenib. Recently, inhibitors of histone and other protein deacetylases have been established as novel therapeutic approaches to cancer diseases. We here review the molecular rationale for combining these two novel targeted therapies and report a patient with metastasized hepatocellular carcinoma who showed a partial remission of primary and metastatic lesions for five months after a combination therapy with sorafenib and the orally available pan-deacetylase inhibitor panobinostat

Inhibition of DNA methyltransferase activity and expression by treatment with the pan-deacetylase inhibitor panobinostat in hepatocellular carcinoma cell lines

Background Hepatocellular carcinoma (HCC) still represents an unmet medical need. Epigenetic inactivation of tumor suppressor genes like RASSF1A or APC by overexpression of DNA methyltransferases (DNMTs) has been shown to be common in HCC and to be linked to the overall prognosis of patients. Inhibitors of protein and histone deacetylases (DACi) have been demonstrated to possess strong anti-tumor effects in HCC models. Methods We therefore investigated whether DACi also has any influence on the expression and activity of DNMTs and methylated target genes in HepG2 and Hep3B cell culture systems and in a xenograft model by immunohistochemistry, westernblotting, RT-qPCR and methylation-specific PCR. Results Our findings demonstrate a rapid inhibition of DNMT activity 6 h after treatment with 0.1 μM of the pan-DACi panobinostat. A downregulation of DNMT mRNAs and protein were also observed at later points in time. This loss of DNMT activity and expression was paralleled by a diminished methylation of the target genes RASSF1A and APC and a concomitant re-expression of APC mRNA and protein. Analysis of HepG2 xenograft specimens confirmed these results in vivo. Conclusion We suggest a dual mode of action of DACi on DNA methylation status: a rapid inhibition of enzyme activity due to interference with posttranslational acetylation and a delayed effect on transcriptional control of DNMT genes by HDAC or miRNA mechanisms

I-scan optical enhancement for the in vivo prediction of diminutive colorectal polyp histology:results from a prospective three-phased multicentre trial

BACKGROUND AND AIMS:Dye-less chromoendoscopy is an emerging technology for colorectal polyp characterization. Herein, we investigated whether the newly introduced I-scan optical enhancement (OE) can accurately predict polyp histology in vivo in real-time. METHODS:In this prospective three-phased study, 84 patients with 230 diminutive colorectal polyps were included. During the first two study phases, five endoscopists assessed whether analysis of polyp colour, surface and vascular pattern under i-scan OE can differentiate in vivo between adenomatous and hyperplastic polyps. Finally, junior and experienced endoscopists (JE, EE, each n = 4) not involved in the prior study phases made a post hoc diagnosis of polyp histology using a static i-scan OE image database. Histopathology was used as a gold-standard in all study phases. RESULTS:The overall accuracy of i-scan OE for histology prediction was 90% with a sensitivity, specificity, positive (PPV) and negative prediction value (NPV) of 91%, 90%, 86% and 94%, respectively. In high confidence predictions, the diagnostic accuracy increased to 93% with sensitivity, specificity, PPV and NPV of 94%, 91%, 89% and 96%. Colonoscopy surveillance intervals were predicted correctly in ≥ 90% of patients. In the post hoc analysis EE predicted polyp histology under i-scan OE with an overall accuracy of 91%. After a single training session, JE achieved a comparable diagnostic performance for predicting polyp histology with i-scan OE. CONCLUSION:The histology of diminutive colorectal polyps can be accurately predicted with i-scan OE in vivo in real-time. Furthermore, polyp differentiation with i-scan OE appears to require only a short learning curve

High-definition endoscopy with digital chromoendoscopy for histologic prediction of distal colorectal polyps

Background Distal diminutive colorectal polyps are common and accurate endoscopic prediction of hyperplastic or adenomatous polyp histology could reduce procedural time, costs and potential risks associated with the resection. Within this study we assessed whether digital chromoendoscopy can accurately predict the histology of distal diminutive colorectal polyps according to the ASGE PIVI statement. Methods In this prospective cohort study, 224 consecutive patients undergoing screening or surveillance colonoscopy were included. Real time histology of 121 diminutive distal colorectal polyps was evaluated using high-definition endoscopy with digital chromoendoscopy and the accuracy of predicting histology with digital chromoendoscopy was assessed. Results The overall accuracy of digital chromoendoscopy for prediction of adenomatous polyp histology was 90.1 %. Sensitivity, specificity, positive and negative predictive values were 93.3, 88.7, 88.7, and 93.2 %, respectively. In high-confidence predictions, the accuracy increased to 96.3 % while sensitivity, specificity, positive and negative predictive values were calculated as 98.1, 94.4, 94.5, and 98.1 %, respectively. Surveillance intervals with digital chromoendoscopy were correctly predicted with >90 % accuracy. Conclusions High-definition endoscopy in combination with digital chromoendoscopy allowed real-time in vivo prediction of distal colorectal polyp histology and is accurate enough to leave distal colorectal polyps in place without resection or to resect and discard them without pathologic assessment. This approach has the potential to reduce costs and risks associated with the redundant removal of diminutive colorectal polyps

Combining regenerative medicine strategies to provide durable reconstructive options: auricular cartilage tissue engineering

Recent advances in regenerative medicine place us in a unique position to improve the quality of engineered tissue. We use auricular cartilage as an exemplar to illustrate how the use of tissue-specific adult stem cells, assembly through additive manufacturing and improved understanding of postnatal tissue maturation will allow us to more accurately replicate native tissue anisotropy. This review highlights the limitations of autologous auricular reconstruction, including donor site morbidity, technical considerations and long-term complications. Current tissue-engineered auricular constructs implanted into immune-competent animal models have been observed to undergo inflammation, fibrosis, foreign body reaction, calcification and degradation. Combining biomimetic regenerative medicine strategies will allow us to improve tissue-engineered auricular cartilage with respect to biochemical composition and functionality, as well as microstructural organization and overall shape. Creating functional and durable tissue has the potential to shift the paradigm in reconstructive surgery by obviating the need for donor sites

Combined inhibitors of angiogenesis and histone deacetylase: Efficacy in rat hepatoma

AIM: To evaluate the antitumoral effect of combined inhibitors of angiogenesis and histone deacetylases in an experimental rat hepatoma model