Practice guidelines in acute pancreatitis.

Bile leakage after hepatobiliary and pancreatic surgery: a definition and grading of severity by the International Study Group of Liver Surgery.

Epigenetic enzymes are often dysregulated in human tumors through mutation, altered expression, or inappropriate recruitment to certain loci. The identification of these enzymes and their partner proteins has driven the rapid development of small-molecule inhibitors that target the cancer epigenome. Herein, we discuss the influence of aberrantly regulated histone deacetylases (HDACs) in tumorigenesis. We examine HDAC inhibitors (HDACis) targeting class I, II, and IV HDACs that are currently under development for use as anticancer agents following the FDA approval of two HDACis, vorinostat and romidepsin.

/pdf/new-and-emerging-hdac-inhibitors-for-cancer-treatment-2na2hwuzdv.pdf

New and emerging HDAC inhibitors for cancer treatment.

This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.

/pdf/recent-advances-in-2d-and-3d-in-vitro-systems-using-primary-46n7hrqknx.pdf

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.

Objective To provide a review of the world literature on laparoscopic liver resection. Summary background data Initially described for peripheral, benign tumors resected by nonanatomic wedge resections, minimally invasive liver resections are now being performed more frequently, even for larger, malignant tumors located in challenging locations. Although a few small review articles have been reported, a comprehensive review on laparoscopic liver resection has not been published. Methods We conducted a literature search using Pubmed, screening all English publications on laparoscopic liver resections. All data were analyzed and apparent case duplications in updated series were excluded from the total number of patients. Tumor type, operative characteristics, perioperative morbidity, and oncologic outcomes were tabulated. Results A total of 127 published articles of original series on laparoscopic liver resection were identified, and accounted for 2,804 reported minimally invasive liver resections. Fifty percent were for malignant tumors, 45% were for benign lesions, 1.7% were for live donor hepatectomies, and the rest were indeterminate. Of the resections, 75% were performed totally laparoscopically, 17% were hand-assisted, and 2% were laparoscopic-assisted open hepatic resection (hybrid) technique, with the remainder being other techniques or conversions to open hepatectomies. The most common laparoscopic liver resection was a wedge resection or segmentectomy (45%) followed by anatomic left lateral sectionectomy (20%), right hepatectomy (9%), and left hepatectomy (7%). Conversion from laparoscopy to open laparotomy and from laparoscopy to hand-assisted approach occurred in 4.1% and 0.7% of reported cases, respectively. Overall mortality was 9 of 2,804 patients (0.3%), and morbidity was 10.5%, with no intraoperative deaths reported. The most common cause of postoperative death was liver failure. Postoperative bile leak was observed in 1.5% of cases. For cancer resections, negative surgical margins were achieved in 82% to 100% of reported series. The 5-year overall and disease-free survival rates after laparoscopic liver resection for hepatocellular carcinoma were 50% to 75% and 31% to 38.2%, respectively. The 3-year overall and disease-free survival rates after laparoscopic liver resection for colorectal metastasis to the liver were 80% to 87% and 51%, respectively. Conclusion In experienced hands, laparoscopic liver resections are safe with acceptable morbidity and mortality for both minor and major hepatic resections. Oncologically, 3- and 5-year survival rates reported for hepatocellular carcinoma and colorectal cancer metastases are comparable to open hepatic resection, albeit in a selected group of patients.

World review of laparoscopic liver resection-2,804 patients.

Because of recent advances in liver surgery, hepatic resections are being performed with increasing frequency, and the surgical death rate for such resections is decreasing. 1–7 Bile leakage, of course, is the primary complication occurring after liver surgery, and it can not only debase the quality of the postoperative course of patients, but also can lead to hospital death. Despite a significant decrease in the overall surgical complication rate in hepatic resections, the rate of bile leakage has not changed, with an incidence of 4.8% to 7.6% reported in recent large series. 2–8 The presence of bile, blood, and devitalized tissues in the dead space after hepatectomy may provide the ideal environment for bacterial growth and impair the normal host defense mechanisms. 9, 10 The combination of sudden reduction in the liver volume and development of an intraperitoneal septic complication after hepatectomy (IPSCH) frequently results in liver failure, leading to a grave prognosis. 11

The aims of this study were, therefore, to clarify the perioperative risk factors for postoperative bile leakage after hepatic resection, to evaluate the intraoperative bile leakage test as a preventive measure, and to propose a treatment strategy for postoperative bile leakage according to the outcome of these patients.

Bile Leakage After Hepatic Resection

S. Maehara Background: No reports exist on the role of laparoscopic hepatectomy in the short- and long-term outcomes of patients with hepatocellular carcinoma (HCC). We present our results from using laparoscopic hepatectomy for HCC and discuss the importance of this procedure. Methods: To investigate the role of laparoscopic hepatectomy in the short- and long-term outcomes, 17 patients with HCC who underwent laparoscopic hepatectomy (laparoscopic hepatectomy group) were compared with 38 patients who underwent conventional open hepatectomy (open hepatectomy group) during the same period. Results: No differences in operation time, blood loss, rate of blood transfusion, or incidence of postoperative complications were found between the two groups. The postoperative hospital stay for the laparoscopic hepatectomy group was significantly shorter than for the open hepatectomy group. With long-term prognosis, no difference was found in survival rate and disease-free survival rate between the two groups. No recurrence was found in the stump of the remaining liver after laparoscopic hepatectomy. Conclusions: Laparoscopic hepatectomy has resulted in a better short-term outcome after surgery than conventional open hepatectomy. The long-term prognosis in the laparoscopic hepatectomy group was similar to that in the open hepatectomy group. Therefore, laparoscopic hepatectomy can be a new alternative for treatment of cirrhotic patients with HCC when patients are strictly selected.

Laparoscopic hepatectomy for hepatocellular carcinoma

Objective: Histone deacetylases (HDACs) play an important role in chromatin remodeling, gene repression and regulating cell cycle progression and differentiation. This study was des

Clinical Significance of Histone Deacetylase 1 Expression in Patients with Hepatocellular Carcinoma

Remodeling of the chromatin template by inhibition of HDAC activities represents a potential transcriptional therapy for neoplastic disease. A number of HDAC inhibitors that modulate in vitro cell growth and differentiation have been developed. We analyzed the effects of TSA, a specific and potent HDAC inhibitor, on the human hepatoma cell lines HepG2 and Huh-7. TSA increased levels of acetylated histones H3 and H4 in both HepG2 and Huh-7. It inhibited cell proliferation in vitro and induced G(0)/G(1) arrest in HepG2 and apoptosis in Huh-7. Gene expression of liver-specific functions and liver-enriched transcription factors was upregulated by TSA. TSA upregulated the ammonia removal rate and the albumin synthesis rate of HepG2 and Huh-7. Our results indicate that TSA can induce cell-cycle arrest/apoptosis and hepatocyte differentiation in human liver cancer cell lines.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.10699

Histone deacetylase inhibitor trichostatin A induces cell-cycle arrest/apoptosis and hepatocyte differentiation in human hepatoma cells.

Applications of nonviral vectors for gene transfer into tumors in
vivo have been limited by the relatively low expression levels
of the transferred gene The aim of this study is to evaluate the
efficacy of electroporation-mediated interleukin-12 ( IL-12 ) gene therapy for hepatocellular
carcinoma (HCC) First, we investigated the optimal conditions of
electric pulses (voltage, pulsing duration, numbers of shocks) of
 in vivo electroporation for gene transfer into HCC
established by sc implantation of MH134 cells to C3H mice This
process made use of plasmid DNA that express the luciferase 
gene We concluded that the optimal conditions for the electric pulses
are as follows: voltage at 150 V; pulsing duration at 50 ms; nonpulsing
duration at 950 ms; and the number of shocks at 10 Second, we tried to
treat sc HCC by electroporation using plasmid DNA that expresses the
 murine interleukin-12 ( mIL-12 ) gene
Intratumoral administration of the mIL-12 vector elevated
serum IL-12 and IFN-γ and significantly inhibited the growth not only
of HCC into which the mIL-12 vector had been directly
transferred, but also of the distant HCC In addition, intratumoral
administration of the mIL-12 vector inhibited spontaneous
lung metastasis and delayed establishment of HCC injected 3 days after
 mIL-12 gene therapy The IL-12 gene therapy
induced more lymphocyte infiltration by NK cells, CD3 + 
cells, and Mac-1 positive cells into the tumor and reduced the number
of microvessels Therefore, more terminal deoxynucleotidyl
transferase-mediated dUTP nick end labeling-positive tumor cells were
found These results demonstrate that gene therapy for HCC by
electroporation in vivo using IL-12 is very
efficient and is thus promising for further clinical trial

https://cancerres.aacrjournals.org/content/canres/61/3/1005.full.pdf

Tatsuya Rikimaru

Papers

Bile Leakage After Hepatic Resection

Laparoscopic hepatectomy for hepatocellular carcinoma

Clinical Significance of Histone Deacetylase 1 Expression in Patients with Hepatocellular Carcinoma

Histone deacetylase inhibitor trichostatin A induces cell-cycle arrest/apoptosis and hepatocyte differentiation in human hepatoma cells.

Electroporation-mediated Interleukin-12 Gene Therapy for Hepatocellular Carcinoma in the Mice Model