Role of connective tissue growth factor in oval cell response during liver regeneration after 2-AAF/PHx in rats

BACKGROUND & AIMS: Recruitment and proliferation of Thy-1+ oval cells is a hallmark of liver regeneration after 2-acetylaminofluorene (2-AAF)/partial hepatectomy (PHx) in rats. To understand the molecular mechanism underlying this process, we investigated the role of connective tissue growth factor (CTGF), one of the candidate genes differentially expressed in Thy-1+ oval cells, in this liver injury model. METHODS: Northern and Western analyses were performed to examine the induction of CTGF in total liver homogenate. Quantitative real-time polymerase chain reaction (PCR), immunofluorescent staining, and in situ hybridization were performed to confirm the expression and localization of CTGF in Thy-1+ oval cells. Finally, a known inhibitor of CTGF synthesis, Iloprost, was administered to 2-AAF/PHx treated rats to investigate the effect of Iloprost on oval cell response. RESULTS: CTGF was found to be up-regulated at both the RNA and protein levels and occurred concurrently with an up-regulation of transforming growth factor beta1 (TGF-beta1). Sorted Thy-1+ oval cells expressed a high level of CTGF gene in a quantitative PCR assay. Colocalization of Thy-1 antigen and ctgf signals by in situ hybridization further confirmed that Thy-1+ oval cells were a source of CTGF. Iloprost administration blocked CTGF induction in treated animals but did not affect TGF-beta1 expression. The inhibition of CTGF induction by Iloprost was associated with a significant decrease in oval cell proliferation and a lower level of alpha-fetoprotein expression as compared with control animals. CONCLUSIONS: These results show that CTGF induction is important for robust oval cell response after 2-AAF/PHx treatment in rats.     

Hypertrophy of the non-embolized liver after chemotherapy

Background:

Neoadjuvant chemotherapy (NC⁺) and portal vein embolization (PVE) enables curative resection in more patients with colorectal-liver metastases (CRLM). However, after NC⁺, structural alterations have been reported with the risk of post-operative hepatic failure. We undertook to determine if NC⁺ toxicity limits future remnant liver (FRL) hypertrophy after PVE.

Methods:

PVE was performed in 20 patients, 13 (65%) of whom previously received a mean FOLFIRI (5-fluorouracil + leucovorin + irinotecan) regimen (NC⁺) of 6.6 cycles. The seven remaining patients served as the control group without NC (NC⁻).

Results:

CRLM were bilateral in 69% (NC⁺) and 57% (NC⁻), and synchronous in 84% (NC⁺) and 14% (NC⁻). The FRL hypertrophy rate was 54.1% (NC⁺) and 43.7% (NC⁻) (P= 0.3). CRLM were unresectable in four of our 20 patients, i.e. group NC⁺: one insufficient FRL hypertrophy and one severe steatosis; and group NC⁻: two tumoral progressions. In both groups, the operative parameters were comparable except for pedicular clamping: 8 (NC⁺) and 36 min (NC⁻), respectively (P < 0.05). Also, the surgical outcome rate and hospital stay were comparable. No significant pathological difference was observed between the two groups. No mortality occurred in either group.

Conclusion:

In view of our limited experience, we conclude that hypertrophy of the non-embolized liver (FRL) is not altered after FOLFIRI-based NC.     

Minimally invasive laparoscopic liver resection: 3D MDCT simulation for preoperative planning

Background/purpose

Laparoscopic liver resection has not gained wide acceptance compared with other laparoscopic procedures. We evaluated the impact of simulated surgery using data from multidetector CT scanning on planning for laparoscopic hepatectomy.

Methods

The hepatectomy simulation system was programmed to perform three-dimensional reconstruction of the vasculature and to calculate the liver resection volume and surgical margin. In 35 patients undergoing laparoscopic hepatectomy or laparoscopy-assisted hepatectomy, the liver resection volume and margin were estimated by simulation preoperatively. Then, the estimated values were compared with the actual resected liver weight and margin.

Results

Three-dimensional reconstruction allowed stereoscopic identification of the tumor-bearing portal vein and draining vein. The predicted liver resection volume and margin both showed a significant correlation with the actual values: the mean difference was 21 mL (P < 0.0001) and 1.3 mm (P < 0.01), respectively. Preoperative planning based on simulated resection facilitated laparoscopic mobilization of the liver and mini-laparotomy resection of a large tumor located in the upper right lobe.

Conclusions

Three-dimensional simulation of hepatectomy facilitated intraoperative identification of the vascular anatomy, and accurately predicted the resected liver volume and surgical margin. This simulation method should contribute to preoperative planning for safe and curative laparoscopic hepatectomy.     

Perioperative change in white blood cell count predicts outcome of hepatic resection for hepatocellular carcinoma

Background

In spite of improvements in surgical management, hepatocellular carcinoma (HCC) still recurs after operation in 60–70% of patients. Therefore, we investigated the relation between perioperative change in white blood cell count (WBC) and tumor recurrence as well as survival in patients with HCC after hepatic resection.

Methods

Subjects were 53 patients who underwent elective hepatic resection for HCC. We retrospectively examined the relation between perioperative change in WBC and recurrence of HCC as well as overall survival.

Results

Advanced tumor stage and increasing of WBC on postoperative day (POD) 1 were positively associated with worse disease-free survival rate on both univariate and multivariate analysis (P < 0.05). Advanced tumor stage, increasing of WBC on POD 1, and blood transfusion were positively associated with worse overall survival rate on univariate analysis (P < 0.05), while change in WBC was the only independent factor on multivariate analysis (P < 0.05).

Conclusions

Perioperative change in WBC after elective hepatic resection for HCC is positively associated with recurrence and worse survival.     

Pathomorphological study of HCV antibody-positive liver cirrhosis

A morphological investigation was carried out to study the pathological features of liver cirrhosis caused by hepatitis C virus (HCV) infection. The materials consisted of liver specimens taken from 47 cases of anti-HCV antibody-positive liver cirrhosis (37 by surgery for hepatocellular carcinoma and 10 by autopsy), and from 21 cases of hepatitis B surface antigen-positive liver cirrhosis as the control. Liver specimens containing more than 10 regenerative nodules were examined. In addition, a histometric study was conducted to determine the degree of fibrosis and the size of regenerative nodule using a computer image-analysis system. The results showed that the histological characteristics of HCV antibody-positive liver cirrhosis are: (i) broadly expanded fibrous septa and small regenerative nodules; (ii) relatively strong inflammatory reaction and prominent lymphoid aggretation in the fibrous septum; and (iii) mild regenerative activity of the liver parenchyma, and infrequent liver cell dysplasia. These findings may facilitate better understanding of the pathology of HCV antibody-positive liver cirrhosis and more accurate pathological diagnosis by needle biopsy.     

Evaluation of metabolic factors on the prognosis of patients undergoing resection of hepatocellular carcinoma

Background and Aim: The metabolic factors including obesity, diabetes, and hypertension have been implicated as risk factors of hepatocellular carcinoma (HCC) in patients with chronic hepatitis. The effects of metabolic factors were investigated on the prognosis of patients undergoing resection of HCC. Methods: A total of 469 HCC patients were classified into three groups; hepatitis B virus (HBV)‐, hepatitis C virus (HCV)‐, and non‐HBV/HCV (NBC)‐related HCC. Further, the patients with HCV‐related HCC were sub‐classified into three groups; the patients who did not have documented hypertension, hypertensive patients who received angiotensin II‐blocking agents (ABA), and hypertensive patients who received no ABA. Results: There were no significant difference of survival in the HBV‐HCC and NBC‐HCC patients with or without obesity, diabetes, and hypertension. In the patients with HCV‐related HCC, however, hypertensive patients were significantly worse on both disease‐free and overall survivals than non‐hypertensive patients. Among the HCV‐HCC patients with chronic hepatitis, hypertensive patients with ABA had significantly better preoperative liver function, and hypertensive patients without ABA were significantly worse on both disease‐free and overall survivals than those of hypertensive patients with ABA and non‐hypertensive patients. Conclusions: Results suggest that hypertension is a risk factor for a poor prognosis after resection of HCV‐related HCC. Angiotensin II blockade may improve the prognosis of hypertensive patients with early hepatic fibrosis after resection in HCV‐related HCC.     

Negative regulation of liver regeneration by innate immunity (natural killer cells/interferon-gamma)

BACKGROUND AND AIMS: Hepatic lymphocytes are composed mainly of natural killer (NK) cells and NKT cells, which play key roles in innate immune responses against pathogens and tumors in the liver. This report analyzes the effects of activation of innate immunity by viral infection or the toll-like receptor 3 (TLR3) ligand on liver regeneration. METHODS: The partial hepatectomy (PHx) method was used as a model of liver regeneration. Murine cytomegalovirus (MCMV) infection and the TLR3 ligand polyinosinic-polycytidylic acid [poly(I:C)] were used to activate innate immunity. RESULTS: NK cells are activated after PHx, as evidenced by producing interferon (IFN)-gamma. Infection with MCMV or injection of poly(I:C) further activates NK cells to produce IFN-gamma and attenuates liver regeneration in the PHx model. Depletion of NK cells or disruption of either the IFN-gamma gene or the IFN-gamma receptor gene enhances liver regeneration and partially abolishes the negative effects of MCMV and polyI:C on liver regeneration, whereas NKT cells may only play a minor role in suppression of liver regeneration. Adoptive transfer of IFN-gamma +/+ NK cells, but not IFN-gamma -/- NK cells, restores the ability of polyI:C to attenuate liver regeneration in NK-depleted mice. Finally, administration of polyI:C or IFN-gamma enhances expression of several antiproliferative proteins, including STAT1, IRF-1, and p21cip1/waf1 in the livers of partially hepatectomized mice. CONCLUSIONS: Our findings suggest that viral infection and the TLR3 ligand negatively regulate liver regeneration via activation of innate immunity (NK/IFN-gamma), which may play an important role in the pathogenesis of viral hepatitis.     

Adjuvant chemotherapy for patients with primary hepatocellular carcinoma: A meta‐analysis

Numerous studies have investigated the effects of adjuvant chemotherapy for primary hepatocellular carcinoma (HCC) patients. We conducted this analysis to evaluate the efficacy of adjuvant chemotherapy in HCC patients after hepatectomy. PubMed/MEDLINE, EMBASE, Cochrane, and other databases were searched for eligible studies. The major endpoints were overall survival (OS) and disease‐free survival (DFS). The pooled odds ratio (OR) was calculated using a random‐effects model to summarize the results. In the meta‐analysis of 13 randomized control trials (RCTs) and 35 observational studies with 4747 patients, hepatectomy plus adjuvant chemotherapy showed superiority over hepatectomy alone in 1‐year DFS (OR = 1.86, 1.38–2.51, p < 0.001), 3‐year DFS (OR = 2.37, 1.73–3.24, p < 0.001) and 5‐year DFS (OR = 1.99, 1.55–2.55, p < 0.001), as well as 1‐year OS (OR = 2.16, 95% confidence interval 1.75–2.68, p < 0.001), 3‐year OS (OR = 1.77, 1.48–2.13, p < 0.001) and 5‐year OS (OR = 1.92, 1.44–2.56, p < 0.001). Subgroup and sensitivity analysis revealed that only adjuvant TACE had significant survival benefits. The meta‐analysis of studies involving patients with portal vein tumor thrombus (PVTT), but not other factors related to recurrence risk, revealed favorable outcomes of the Treatment arm over the Control arm. The present study shows that adjuvant chemotherapy can improve outcomes for HCC patients. The benefits of adjuvant TACE have been confirmed whereas the effects of other adjuvant chemotherapy modalities remain uncertain. Adjuvant chemotherapy is likely to be more applicable to certain patient populations for instance those with PVTT, but further research in identifying these patient factors is of importance for tailoring adjuvant therapies to individual patients in the future.