Clinical significance of the expression of isoform 165 vascular endothelial growth factor mRNA in noncancerous liver remnants of patients with hepatocellular carcinoma

AIM: To investigate the prognostic role of isoform 165 vascular endothelial growth factor messenger RNA (VEGF165 mRNA)in noncancerous liver tissues from patients with primary hepatocellular carcinoma (HCC).METHODS: Using a reverse-transcription polymerase chain reaction (RT-PCR)-based assay, VEGF mRNA was determined prospectively in noncancerous liver tissues from 60 consecutive patients with HCC undergoing curative resection. We categorized the patients with VEGF165 mRNA over 0.500 in noncancerous liver tissues as group A, and those below 0.500 as group B.RESULTS: Among the isoforms of VEGF mRNA by multivariate analysis, a higher level of VEGF165 mRNA in noncancerous liver tissue correlated significantly with a higher risk of HCC recurrence (P = 0.039) and recurrence-related mortality (P= 0.048), but VEGF121 did not. The other significant predictors of recurrence consisted of vascular permeation (P = 0.022),daughter nodules (P = 0.033), cellular dedifferentiation (P = 0.033), an absent or incomplete capsule (P = 0.037).A significant variable of recurrence-related mortality was Vascular permeation (P= 0.012). As to the clinical manifestations of 16 patients who developed recurrence,the recurrent tumor number over 2, recurrent extent over two-liver segments, and the median survival after recurrence,all significantly correlated with group A patients (P = 0.043,0.043, and 0.048, respectively). However, the presence of extrahepatic metastasis was not (P＞0.05). The difference in recurrence after treatment between the two groups had no statistical significance (P＞0.05).CONCLUSION: The higher expression of isoform VEGF165mRNA in noncancerous liver remnant of patients with HCC may be a significant biological indicator of the invasiveness of postoperative recurrence.

H pylori and gastric cancer: Shifting the global burden

Infection with H pylori leads to a persistent chronic in?ammation of the gastric mucosa, thereby increasing the risk of distal gastric adenocarcinoma. Numerous studies have determined a clear correlation between H pylori infection and the risk of gastric cancer; however, general eradication is not recommended as cancer prophylaxis and time points for treatment remain controversial in different areas of the world. Prevalence rates in Western countries are decreasing, especially in younger people (< 10%); and a decline in distal gastric adenocarcinoma has been observed. Risk groups in Western countries still show considerably higher risk of developing cancer, especially in patients infected with cagA + strains and in persons harboring genetic polymorphism of the IL-1B promoter (-511T/T) and the corresponding IL-1 receptor antagonist (IL-1RN*2). Thus, general eradication of all infected persons in Western countries not recommended and is limited to risk groups in order to achieve a risk reduction. In contrast, infection rates and cancer prevalence are still high in East Asian countries. A prevention strategy to treat infected persons may avoid the development of gastric cancer to a large extent and with enormous clinical importance. However, studies in China and Japan indicate that prevention of gastric cancer is effective only in those patients that do not display severe histological changes such as atrophy and intestinal metaplasia. Thus, prophylactic strategies to prevent gastric cancer in high risk populations such as China should therefore especially aim at individuals now at younger age when the histological alterations caused by the bacterial infection was still reversible. In countries with a low prevalence of gastric cancer, risk groups carrying cagA+ strains and IL-1 genetic polymorphisms should be identi?ed and treated.

Enhanced anti-apoptosis and gut epithelium protection function of acidic fibroblast growth factor after cancelling of its mitogenic activity

AIM: Mitogenic and non-mitogenic activities of fibroblast growth factor (FGF) are coupled to a range of biological functions, from cell proliferation and differentiation to the onset of many diseases. Recent reports have shown that acidic fibroblast growth factor (aFGF) has a powerful antiapoptosis function, which may have potentially therapeutical effect on gut ischemia and reperfusion injuries. However,whether this function depends on its mitogenic or nonmitogenic activity remains unclear. In this study, we identified the source of its anti-apoptosis function with a mutant,aFGF28-154 and observed its effect on reducing gut ischemia and reperfusion injury.METHODS: aFGF28-154 was generated by amplification of appropriate DNA fragments followed by subcloning the products into pET-3c vectors, then they were expressed in BL21 (DE3) cells and purified on an M2 agarose affinity column.This mutant aFGF28-154 maintained its non-mitogenic activity and lost its mitogenic activity. With a dexamethasone (DEX)-induced mouse thymocyte apoptosis model in vitro and in vivo, we studied the anti-apoptotic function of aFGF28-154. Also, in vivo study was performed to further confirm whether aFGF28-154 could significantly reduce apoptosis in gut epithelium after gut ischemia-reperfusion injury in rats. Based on these studies, the possible signal transduction pathways involved were studied.RESULTS: With a dexamethasone (DEX)-induced mouse thymocyte apoptosis model in vitro and in vivo, we found that the anti-apoptotic function of aFGF28-154 was significantly enhanced when compared with the wild type aFGF. In vivo study further confirmed that aFGF28-154 significantly reduced apoptosis in gut epithelium after gut ischemiareperfusion injury in rats. The mechanisms of anti-apoptosis function of aFGF28-154 did not depend on its mitogenic activity and were mainly associated with its non-mitogenic activities, including the intracellular calcium ion balance protection, ERK1/2 activation sustaining and cell o/de balance.CONCLUSION: These findings emphasize the importance of non-mitogenic effects of aFGF, and have implications for its therapeutic use in preventing apoptosis and other injuries in tissues and internal organs triggered by ischemia-reperfusion injury.

Inhibition of p38 mitogen-activated protein kinase may decrease intestinal epithelial cell apoptosis and improve intestinal epithelial barrier function after ischemia- reperf usion injury

AIM: To investigate the role of p38 mitogen-activated protein kinase in rat small intestine after ischemia-reperfusion (I/R)insult and the relationship between activation of p38 MAPK and apoptotic cell death of intestine.METHODS: Ninety Wistar rats were divided randomly into three groups, namely sham-operated group (C), I/R vehicle group (R) and SB203580 pre-treated group(S).In groups R and S, the superior mesenteric artery(SMA)was separated and occluded for 45 min, then released for reperfusion for0.25, 0.5, 1, 2, 6, 12 and 24 h. In group C, SMA was separated without occlusion. Plasma D-lactate levels were examined and histological changes were observed under a light microscope. The activity of p38 MAPK was determined by Western immunoblotting and apoptotic cells were detected by the terminal deoxynucleotidyl transferase (TdT)-mediated dUDP-biotin nick end labeling (TUNEL).RESULTS: Intestinal ischemia followed by reperfusion activated p38 MAPK, and the maximal level of activation (7.3-fold vs sham-operated group) was reached 30 min after I/R. Treatment with SB 203580, a p38 MAPK inhibitor,reduced intestinal apoptosis (26.72±3.39% vs62.50±3.08%in I/R vehicle, P＜0.01) and decreased plasma D-lactate level (0.78±0.15 mmol/L in I/R vehicle vs0.42±0.17 mmol/L in SB-treated group) and improved post-ischemic intestinal histological damage.CONCLUSION: p38 MAPK plays a crucial role in the signal transduction pathway mediating post-ischemic intestinal apoptosis, and inhibition of p38 MAPK may attenuate ischemia-reperfusion injury.

Clinical Research on Use of Oxaliplcrtin in Combination with HCPT, LV and 5FU in a Regimen for Advanced Gastric Cancer

OBJECTIVE To observe the effects and adverse reactions of a OXA-HCPT LV/5FU 3 regimen for patients with advanced gastric cancer.METHODS OHLF3 regimen: OXA 130 mg/m^2iv d 1, HCPT6 mg/m^2, iv d 1-5, LV 200 mg/m2iv 2 h followed by a 5FU 400 mg/m2 iv bolus and 5FU 600mg/m2 iv d 1-3, were given, every 21 days as 1 cycle. Assessment of the tumor was conducted after 3 cycles and the effective cases were confirmed after 4 weeks.RESULTS Among 39 patients, 36 were actually evaluable. Overall response rates (CR + PR} were 50%' the major adverse reactions were mild hematological toxicity, nausea and vomiting and peripheral nerve abnormalities.CONCLUSION The OHLF 3 regimen using OXA and HCPT is effective and results in mild toxicity when used in combined chemotherapy for advanced gastric cancer.