High CHAF1A Expression Levels Are Positively-Correlated with PD-L1 Expression and Indicate Poor Prognosis in Gastric Cancer.

Objective: The aim of this study was to analyze the association between the expression of chromatin assembly factor 1 subunit A (CHAF1A) in gastric cancer (GC) and clinicopathological features, disease prognosis, and expression of programmed cell death-ligand 1 (PD-L1). Material and Methods. A total of 140 GC tissue specimens were collected between January 2013 and December 2017. CHAF1A expression in GC and paracancerous tissues was determined. Then, the associations between CHAF1A expression level in the collected tissues and clinicopathological features as well as PD-L1 expression level were investigated. Cox regression analyses were carried out to determine whether CHAF1A is an independent prognostic factor for GC. Finally, the association between CHAF1A expression levels and survival of the GC patients was investigated. Results: A significantly higher level of CHAF1A expression in GC tissues was found compared to that in paracancerous tissues (p=0.042). CHAF1A expression level in GC tissues was found to be strongly associated with family history (p=0.005), smoking history (p=0.016), T stage (p=0.001), tumor marker AFP (p=0.017), tumor marker CEA (p=0.027), and PD-L1 expression (p=0.029). CHAF1A expression was also found to be positively correlated to PD-L1 expression (p=0.012). Moreover, high CHAF1A expression levels were found to lead to poor prognosis (p=0.019). Univariate and multivariate analyses all showed that CHAF1A was an independent poorer prognostic factor for gastric cancer (p=0.021, HR = 1.175, 95% CI: 1.090-2.890 for univariate analyses; p=0.014, HR = 2.191, 95% CI:1.170-4.105 for multivariate analyses). A high level of CHAF1A expression was thus found to be an independent risk factor for GC prognosis. Conclusion: High CHAF1A expression is associated with poor GC prognosis and positively correlated to PD-L1 expression. Thus, CHAF1A expression level may be used as a novel biomarker for GC diagnosis.

Trametes robiniophila Murr Sensitizes Gastric Cancer Cells to 5-Fluorouracil by Modulating Tumor Microenvironment.

Trametes robiniophila Murr (TRM) is a traditional Chinese medicine which has been used in clinics for enhancing immunity and improving the efficacy of chemotherapy. However, the mechanisms of action of TRM are unknown. In the previous study, we found that the Trametes robiniophila Murr n-butanol extract (TRMBE) comprises the major bioactive components of TRM. In the present study, we aimed to assess the combinational effects of TRMBE and 5-fluorouracil (5-FU) on the treatment of gastric cancer (GC) and explore its mechanism of action. It was found that TRMBE significantly potentiated the anticancer activity of 5-FU and prolonged the survival time of mice bearing Mouse Forestomach Carcinoma (MFC) xenograft tumors. We observed that the combination of TRMBE and 5-FU decreased the risk of liver metastasis in vivo. Furthermore, the combination of TRMBE and 5-FU reduced the levels of immune cytokines IL-6, IL-10, and TGF-ß and increased the level of IFN-γ in peripheral blood. This combination therapy also significantly decreased the levels of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and PD-1-positive CD8+ T cells and increased the levels of NK cells in tumor microenvironment (TME). However, TRMBE treatment was unable to enhance the chemosensitivity of GC to 5-FU in vivo after the depletion of CD8+ T and NK cells. Taken together, our results demonstrate that TRMBE can reshape the TME of GC by regulating PMN-MDSCs, CD8+ T cells, and NK cells, therefore improving the therapeutic effects of 5-FU. This study suggests that the combination of TRMBE and 5-FU could enhance immunity and could be a promising approach for GC treatment.

Huaier Inhibits Gastric Cancer Growth and Hepatic Metastasis by Reducing Syntenin Expression and STAT3 Phosphorylation.

Gastric cancer (GC) is a common malignant tumor worldwide and poses a serious threat to human health. As a traditional Chinese medicine, Huaier (Trametes robiniophila Murr.) has been used in the clinical treatment of GC. However, the mechanism underlying the anticancer effect of Huaier remains poorly understood. In this study, we used in vivo imaging technology to determine the anticancer effect of the Huaier n-butanol extract (HBE) on orthotopic and hepatic metastasis of GC mouse models. We found that HBE suppressed tumor growth and metastasis without causing apparent host toxicity. Proteomic analysis of GC cells before and after HBE intervention revealed syntenin to be one of the most significantly downregulated proteins after HBE intervention. We further demonstrated that HBE suppressed the growth and metastasis of GC by reducing the expression of syntenin and the phosphorylation of STAT3 at Y705 and reversing the epithelial-mesenchymal transition (EMT). In addition, we confirmed that syntenin was highly expressed in GC tissue and correlated with metastasis and poor prognosis. In conclusion, our results suggest that Huaier, a clinically used anticancer drug, may inhibit the growth and liver metastasis of GC by inhibiting the syntenin/STAT3 signaling pathway and reversing EMT.

p-MEK expression predicts prognosis of patients with adenocarcinoma of esophagogastric junction (AEG) and plays a role in anti-AEG efficacy of Huaier.

The incidence rate of adenocarcinoma of the esophagogastric junction (AEG) is increasing worldwide with poor prognosis and unclear pathogenesis. Trametes robiniophila Murr. (Huaier), a traditional Chinese medicine has been used in the clinical treatment of a variety of solid tumors, including AEG. However, its anticancer components and molecular mechanisms are still unclear. In our previous studies, we have found that Huaier n-butanol extract (HBE) shows the most potent anticancer activity among different extracts. In the present study, we aimed to investigate the clinical relevance of p-MEK expression in AEG patients and the role of the MEK/ERK signaling pathway in the anti-AEG efficacy of HBE in vitro and in vivo. We herein demonstrate that p-MEK expression in AEG tissues was significantly higher than that in paracancerous tissues and correlated with a poor prognosis in AEG patients. We further found that HBE inhibited the colony formation, migration, and invasion in AEG cell lines in a concentration-dependent manner in vitro. HBE also suppressed the growth of AEG xenograft tumors without causing any host toxicity in vivo. Mechanistically, HBE caused the inactivation of the MEK/ERK signaling pathway by dephosphorylating MEK1 at S298, ERK1 at T202, and ERK2 at T185 and modulating the expression of EMT-related proteins. In summary, our results demonstrate that the high expression of p-MEK may be an independent factor of poor prognosis in patients with AEG. The clinically used anticancer drug Huaier may exert its anti-AEG efficacy by inhibiting the MEK/ERK signaling pathway.

A review of capecitabine-based adjuvant therapy for gastric cancer in the Chinese population.

In China, the treatment of locally advanced gastric cancer (AGC) faces unique challenges. Chinese patients may harbor more unfavorable prognostic factors than western populations and, in comparison with other Asian populations such as Japan and South Korea, a higher proportion of Chinese patients are diagnosed with AGC due to inadequate early diagnosis of the malignancy. This review summarizes the use of combination chemotherapy regimens with capecitabine as adjuvant therapy in the Chinese AGC population. Based on the available domestic data in China, the review concludes that capecitabine-based chemotherapy regimens, especially XELOX, offer good efficacy following radical gastrectomy in patients with AGC, with a low incidence of adverse events, acceptable tolerance, greater patient convenience and a lower overall cost than other regimens.

[Correlation of MRI apparent diffusion coeffcient with molecular marker Ki-67 in gastric cancer].

OBJECTIVES: To study the correlation between MRI apparent diffusion coefficient (ADC) and expression of Ki-67 in gastric cancers, and to investigate the application of ADC value in diagnosing the malignance of gastric cancer. METHODS: A retrospective cohort analysis was performed on 87 gastric cancer patients who received MRI examination and radical resection at Zhejiang Provincial Hospital of Traditional Chinese Medicine from November 2014 to August 2015. All the postoperative resected samples were confirmed as gastric cancer. Preoperative MRI examination was performed by using Siemens 3.0-T Verio MRI with following parameters: section thickness 3 mm, gap 1 mm, matrix 182×320, field of view 40 cm. Plain scan was followed by T1-weighted fat suppression technique VIBE 3D(TR3.92/TE1.39,90degree) scans at arterial phase (the 30th second), portal venous phase (the 60th second), lag period (the 90th second), axial planes and coronal planes (the 180th second), and sagittal planes (the 210th second), respectively. ADC value of tumor was measured at b-factor of 800 s/mm2 and ADC map was generated from DWI data on the work station. The expression of Ki-67 in cancer tissue was detected by routine immunohistochemical (SP) staining after surgery. Correlation between ADC value and the expression of Ki-67 in gastric cancer was analyzed. RESULTS: Irregular thickening of the gastric wall and inhomogeneous enhancement of the tumor after injection of the contrast material appeared in gastric cancer. Gastric cancer tissue presented hyperintensity and normal gastric wall presented isointensity in DWI image (b=800 s/mm2). Compared with normal gastric tissue, mean ADC value of gastric cancer tissue was significant lower [(1.114±0.265)×10-3 mm2/s vs. (2.032±0.202)×10-3 mm2/s, t=26.209, P=0.000]. The ADC values of high-middle differentiation group, middle-low differentiation group, low differentiation group and signet ring cell carcinoma/mucinous adenocarcinoma group were (1.347±0.234)×10-3 mm2/s, (1.179±0.257)×10-3 mm2/s, (0.996±0.185)×10-3 mm2/s and (1.082±0.230)×10-3 mm2/s, respectively. The difference of mean ADC value among different tumor stages was significant(F=8.498, P=0.000). Along with the Ki-67 expression up-regulated, the ADC value decreased in cancer tissue. The Ki-67 expressions in cancer tissue was negatively correlated with cancer ADC values (r=-0.570, P=0.000). Furthermore, negative correlations of Ki-67 expressions with ADC values of high-middle differentiation group (r=-0.627, P=0.016), low differentiation group (r=-0.787, P=0.000) and signet ring cell carcinoma/mucinous adenocarcinoma group (r=-0.792, P=0.000) were observed respectively, while Ki-67 expression was not correlated with ADC value of middle-low differentiation group. CONCLUSION: The ADC value of gastric cancer can reflect the level of tumor differentiation, and is negatively correlated with Ki-67 expression in cancer tissues.

Expression of multidrug resistance-associated proteins and their relation to postoperative individualized chemotherapy in gastric cancer.

BACKGROUND: Adjuvant chemotherapy could reduce residual tumor cells and prevent relapse, however, not all patients are suitable for adjuvant chemotherapy. Screening appropriate patients based on molecular markers for individualized adjuvant chemotherapy is necessary. METHODS: Between June 2002 and June 2004, 119 patients who underwent radical gastrectomy were retrospectively analyzed. Some patients had adjuvant chemotherapy based on platinum and 5-FU for four to six cycles. Topoisomerase II (ToPo II) negative, multidrug resistance protein (MRP) positive and glutathione S-transferase π (GST-π) positive were regarded as three risk factors that may be associated with chemotherapy resistance and poor prognosis. Patients were divided into two groups: a high-risk group (≥2 risk factors) and a low-risk group (<2 risk factors), and tumor recurrence and patient survival time of the two groups were analyzed. RESULTS: The average recurrence time of the low-risk group was significantly longer than that of the high-risk group (21.29 ± 11.10 versus 15.16 ± 8.05 months, P < 0.01). The 3-year and 5-year survival rates of the high-risk group were 57.4% and 42.6%, however, it had no significant difference compared to 66.2% and 58.5% of the low-risk group (P >0.05). In the high-risk group, the 3-year survival rates of patients with/without chemotherapy were 62.1% and 52.0% and the 5-year survival rates were 44.8% and 40.0%, respectively, but the difference was not statistically significant (P > 0.05). In the low-risk group, the 3-year survival rates of patients with/without chemotherapy were 81.2% and 51.5%, and the 5-year survival rates were 71.9% and 45.5%, respectively, these differences were statistically significant (P < 0.05). CONCLUSIONS: Combined detection of the multidrug resistance (MDR)-related proteins ToPo II, MRP and GST-π may be prospectively valuable for postoperative individualized chemotherapy and in further predicting the outcomes of gastric cancer patients.

PCF Chemotherapy Combined with Surgical Treatment of Late Gastric Cancer.

BACKGROUND/AIMS: To investigate the efficacy and safety of PCF chemotherapy combined with surgery in the treatment of late-stage gastric cancer. METHODOLOGY: From July 2008 to February 2011, 72 cases of late-stage gastric cancer that could not be treated with R0 resection were treated prospectively. Patients received 2-4 cycles of paclitaxel plus cisplatin and 5-fluorouracil (PCF regimen) chemotherapy followed by cytoreductive surgery for the primary and metastatic tumors and another 2-4 cycles of PCF chemotherapy post-operatively. The treatment completion rate, patient tolerance and overall survival time were analyzed. RESULTS: There was one perioperative death. The overall response rate (complete and partial response) was 72.2%. Fifty patients (69.4%) completed chemotherapy and surgical resection as planned and 42 (58.3%) cases had R0 resection. The median survival time was 23.5 months (95% CI: 15.8-31.2 months). One-year and 2-year survival rates were 67.0% and 47.0%. The survival time of patients with surgical resection was much longer than that of the non-surgery group (30.2 vs. 8.9 months) (P < 0.01). The survival time of local advanced group was 30.3 months, and was significantly longer than 17.6 months of the distant metastasis group (P < 0.01); however, it had no significant difference compared to 28.2 months of the distant metastasis group with R0 resection. CONCLUSIONS: PCF chemotherapy combined with surgical resection were safe and effective, and can make survival benefits for some late-stage gastric cancer patients.