EASL-EORTC clinical practice guidelines : management of hepatocellular carcinoma

Bevacizumab plus Irinotecan,Fluorouracil,and Leucovorin for Metastatic Colorectal Cancer

Posthepatectomy liver failure: A definition and grading by the International Study Group of Liver Surgery (ISGLS)

There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal models of chronic inflammatory diseases. On the other hand, we realize the immunosupportive role of estrogens in trauma/sepsis and the proinflammatory effects in some chronic autoimmune diseases in humans. This review examines possible causes for this paradox. This review delineates how the effects of estrogens are dependent on criteria such as: 1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses (e.g., T cell inhibited by estrogens vs. activation of B cell); 2) the cell types involved during different phases of the disease; 3) the target organ with its specific microenvironment; 4) timing of 17beta-estradiol administration in relation to the disease course (and the reproductive status of a woman); 5) the concentration of estrogens; 6) the variability in expression of estrogen receptor alpha and beta depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens. This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned criteria. It also explains that a uniform concept as to the action of estrogens cannot be found for all inflammatory diseases due to the enormous variable responses of immune and repair systems.

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The complex role of estrogens in inflammation

This review is intended to stimulate interest in the effect of increased expression of heme oxygenase-1 (HO-1) protein and increased levels of HO activity on normal and pathological states. The HO system includes the heme catabolic pathway, comprising HO and biliverdin reductase, and the products of heme degradation, carbon monoxide (CO), iron, and biliverdin/bilirubin. The role of the HO system in diabetes, inflammation, heart disease, hypertension, neurological disorders, transplantation, endotoxemia and other pathologies is a burgeoning area of research. This review focuses on the clinical potential of increased levels of HO-1 protein and HO activity to ameliorate tissue injury. The use of pharmacological and genetic probes to manipulate HO, leading to new insights into the complex relationship of the HO system with biological and pathological phenomena under investigation, is reviewed. This information is critical in both drug development and the implementation of clinical approaches to moderate and to alleviate the numerous chronic disorders in humans affected by perturbations in the HO system.

Pharmacological and Clinical Aspects of Heme Oxygenase

External drainage of pancreatic juice using a pancreatic duct stent following pancreatoduodenectomy is widely performed. We hypothesized that the replacement of externally drained pancreatic juice would help to prevent postoperative complications, including pancreatic fistulas. Sixty-four patients who underwent pancreatoduodenectomy between 2006 and 2008 were randomly assigned to either a pancreatic juice non-replacement (NR) or replacement (R) group. Eighteen patients were excluded from the analysis because they had unresectable tumors (n = 4), low pancreatic juice output ( Grade B) was also significantly higher in the NR group (33.3 vs. 9.1 %, P = 0.046). In cases for whom external pancreatic juice drainage from a stent is applied following pancreaticojejunostomy, enteral replacement of externally drained pancreatic juice may reduce the incidence of postoperative pancreatic fistula formation.

Is the enteral replacement of externally drained pancreatic juice valuable after pancreatoduodenectomy

The aim of this study was to investigate the effects of the preoperative administration of BV on the healing process of intestinal anastomosis in a rabbit model. Twenty male white rabbits were randomly divided into two groups. The control group received saline 1 week before surgery, and the BV group received intravenous BV 1 week before surgery. Each rabbit underwent an enteroenterostomy and a colocolostomy. On postoperative day 7, the bursting pressures of the anastomoses, CD31 and α-smooth muscle actin (α-SMA) staining by immunohistochemistry, the gene expression of α-SMA, and collagen deposition using Picrosirius Red at the site of anastomosis were evaluated. The bursting pressure of small bowel anastomoses was significantly lower in the BV group than in the control group (control 184 ± 10 mmHg vs. BV 140 ± 9 mmHg; p = 0.004). The microvessel counts in the anastomotic tissue were significantly lower in the BV group than in the control group in both the small bowel (p = 0.023) and colon (p = 0.008). The expression of α-SMA, and the degree of collagen deposition decreased in the anastomotic tissue in the BV group compared with the control group. The preoperative use of BV may therefore negatively affect the rigidity of intestinal anastomosis.

The effects of bevacizumab on intestinal anastomotic healing in rabbits

We determined whether there is a protective effect of branched-chain amino acid (BCAA) on hepatic ischemia-reperfusion (I/R)-induced acute liver injury. Wister rats were divided into the following four groups: simple laparotomy with vehicle; simple laparotomy with BCAA (1 g/kg body wt orally); I/R (30 min clamp) with vehicle; and I/R with BCAA. Serum liver function tests and the gene expression of adhesion molecules (intercellular adhesion molecule and vascular cell adhesion molecule) and vasoconstrictor-related genes (endothelin-1) in the liver were examined. In the in vivo study, portal venous pressure, leukocyte adhesion, and hepatic microcirculation were evaluated. Furthermore, Kupffer cells were isolated and cultured with various concentrations of BCAA in the presence or absence of lipopolysaccharide (LPS). Increased levels of liver function tests following I/R were significantly attenuated by BCAA treatment. The increased expression of adhesion molecules and endothelin-1 was also significantly attenuated by BCAA treatment. Moreover, increased portal venous pressure, enhanced leukocyte adhesion, and deteriorated hepatic microcirculation following I/R were all improved by BCAA treatment. In the experiment using isolated Kupffer cells, the expression of interleukin-6, interleukin-1β, and endothelin-1 in response to LPS stimulation was attenuated by BCAA in a dose-dependent fashion. These results indicate that perioperative oral administration of BCAA has excellent therapeutic potential to reduce I/R-induced liver injury. These beneficial effects may result from the direct attenuation of Kupffer cell activation under stressful conditions.

liver injury in rats: a direct attenuation of Kupffer cell activation.

Background Differentiation between perihilar cholangiocarcinoma (PHCC) and benign strictures is frequently difficult. The aim of this study was to investigate the incidence and long-term outcome of patients with tumours resected because of suspicion of PHCC, which ultimately turned out to be benign (malignancy masquerade). Methods Patients who underwent surgical resection with a diagnosis of PHCC between 2001 and 2016 were reviewed retrospectively. Results Among 707 consecutive patients, 685 had PHCC and the remaining 22 (3·1 per cent) had benign biliary stricture. All patients with benign disease underwent major hepatectomy, with no deaths. Preoperative histological assessment using bile duct biopsy or aspiration cytology had a high specificity (90 per cent), low sensitivity (62 per cent) and unsatisfactory accuracy (63 per cent). Despite the increasing use of histological assessment, the incidence of benign strictures resected did not decrease over time, being 0·9 per cent in 2001-2004, 4·0 per cent in 2005-2008, 3·8 per cent in 2009-2012 and 2·9 per cent in 2013-2016. The final pathology of benign strictures included IgG4-related sclerosing cholangitis (9 patients), hepatolithiasis (4), granulomatous cholangitis (3), non-specific chronic cholangitis (3), benign strictures after cholecystectomy (2), and a benign stricture possibly caused by parasitic infection (1). The 10-year overall survival rate for the 22 patients with benign stricture was 87 per cent, without recurrence of biliary stricture. Conclusion The incidence of benign strictures resected as PHCC as a proportion of all resections was relatively low, at 3·1 per cent. Currently, unnecessary surgery for suspected PHCC is unavoidable.

Benign hilar bile duct strictures resected as perihilar cholangiocarcinoma.

Background
Inflammation-based prognostic scores are useful prognostic indicators for several types of cancer. The aim of this study was to evaluate whether the scores predict survival impact in unresectable perihilar cholangiocarcinoma.

Methods
The modified Glasgow Prognostic Score (mGPS), Neutrophil Lymphocyte Ratio (NLR), Platelet Lymphocyte Ratio, and Prognostic Nutritional Index, were retrospectively assessed in 219 patients with unresectable perihilar cholangiocarcinoma.

Results
Of the four scores evaluated, mGPS and NLR demonstrated prognostic value, whereas the remaining two systems did not. The median survival time (MST) of patients with a mGPS of 0 and NLR of 0 or 1 were significantly better than that of patients with a mGPS of 1 or 2 and NLR of 2 (12.3 vs. 4.8 months, P < 0.001, and 10.5 vs. 4.4 months, P = 0.001). Multivariate analysis revealed that both mGPS and NLR were independent prognostic factors. The combination of mGPS and NLR stratified survival well: the MST was 12.8 months in patients with a mGPS of 0 and NLR of 1 or 2, while only 3.0 months in patients with a mGPS of 1 or 2 and NLR of 2.

Conclusions
Both mGPS and NLR are independent prognostic factors and pivotal in refining patient stratification in unresectable perihilar cholangiocarcinoma.

Yukihiro Yokoyama

Papers

Is the enteral replacement of externally drained pancreatic juice valuable after pancreatoduodenectomy

The effects of bevacizumab on intestinal anastomotic healing in rabbits

liver injury in rats: a direct attenuation of Kupffer cell activation.

Benign hilar bile duct strictures resected as perihilar cholangiocarcinoma.

Appraisal of inflammation-based prognostic scores in patients with unresectable perihilar cholangiocarcinoma.