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Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death, and most patients with HCC are diagnosed at an advanced stage. Before 2017, tyrosine kinase inhibitors were the main drugs for the treatment of advanced hepatocellular carcinoma. With the emergence of immune checkpoint inhibitors (ICIs), immunotherapy has gradually brought new hope to such patients. At present, the combination of ICIs and other systemic or local treatments has become a potential strategy for the treatment of advanced hepatocellular carcinoma, and some of these combinations have been included in large-scale clinical trials. The main challenges of immunotherapy for advanced hepatocellular carcinoma include the exploration of predictive biomarkers, management of immune-related adverse events, and exploration of effective combination regimens. This article provides the latest research progress on the single or combined use of ICIs and other immunotherapy for hepatocellular carcinoma and discusses the limitations of current research and clinical application and the future development direction.
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Objective To investigate the function of sorafenib on the growth of hepatocellular carcinoma by establishing subcutaneous transplantation tumor model with nude mice.To explore the effect of sorafenib on circadian clock gene expression in hepatoma cells.Methods Mouse tumor model was established by implanting hepatocarcinoma cell (HepG2) subcutaneously in Balb/C nude mice.Sixteen experimental mice were randomly divided into two groups:sorafenib treatment group (n =8) and solvent control group (n =8).The nude mice were treated with sorafenib (100 mg/kg) and DMSO daily by intragastric administration,respectively.The volume of tumors was recorded every 3 days.The expressions level of circadian clock genes (Per1,Per2,Per3,CLOCK,Cry1,Cry2,BMAL1 and CKIε) were detected by real-time polymerase chain reaction (Real-time PCR).The correlations between the size of the xenografts and the expressions of the circadian clock genes were further analyzed.Results Compared with the control group,the tumor size in the sorafenib treatment group were significantly smaller comparing with the control group.Results of Real-time PCR showed that the expression level of Per1,Cry1 and BMAL1 mRNA was remarkably decreased in the treatment group (Per1,P =0.02;Cry1,P =0.002;BMAL1,P =0.035),the differences were statistically significant.Correlation analysis showed that the size of subcutaneous transplantation tumorsin nude mice was negatively correlated with the expressions of Per1,Per2,Cry1 and Cry2 mRNA in control group.While,the size of subcutaneous transplantation tumors was negatively correlated with the expressions of Per2,Per3 and BMAL1 levels in the sorafenib treatment group.Conclusions There is a negative correlation between the expression levels of some biological clock genes and the size of transplantation tumor in nude mice.Sorafenib treatment significantly inhibited the growth of hepatocellular carcinoma in nude mice and down-regulation the expressions of Per1,Cry1 and BMAL1 mRNA in hepatoma cells.
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Objective To investigate the effect of Bmal1 on proliferation in gastric cancer cells and the molecular mechanism, and to provide theoretical and experimental basis for further research targeting circadian therapy for gastric cancer. Methods Applying RNAi technique to silence Bmal1 gene in BGC823 was regarded as experimental group. The normal BGC823 was as control group. The inhibitory effect of the cell line was measured by MTT assay. The mRNA expression of p53, c-Jun and c-Fos was evaluated by real-time RT-PCR. Results Comparing with the data of control group,the inhibitive rates of cell growth in experimental group after 6 h,12 h,24 h were 5.78%(P=0.001),9.20%(P=0.00)and 83.08%(P=0.00)respectively. Down-regulation of Bmal1 decreased p53 (P 0.05). Conclusion RNAi targeting Bmal1 has effects on gastric cancer proliferation by down-regulating p53 mRNA.
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Objective To study the value of combined parenteral and enteral nutrition support with chemotherapy for advanced gastrointestinal cancer in elder patients.Methods Totally 79 patients admitted from 2006 to 2011 were randomly divided into two groups using random number table:the treatment group (n=42) was provided with combined parenteral and enteral nutrition support and chemotherapy,the control group(n =37) was treated with chemotherapy only.Nutritional risks were screened at admission.After two cycles of chemotherapy,the nutritional status,Karnofsky performance score,toxic reaction,and nosocomial infection rate were compared betweeen these two groups.Results After 2 cycles of chemotherapy,the body mass index[(19.00±3.31) kg/m2 vs.(18.24±1.98) kg/m2,P=0.04],albumin [(33.90±1.50) g/Lvs.(29.90±2.38) g/L,P=0.02],prealbumin [(28.19±1.50) g/Lvs.(25.51 ±8.38) g/L,P=0.01],hemoglobin [(107.0 ± 6.90) g/L vs.(104.20 ± 9.70) g/L,P =0.02],and lymphocyte levels [(2.99 ±0.55) × 109/L vs.(2.63 ±0.20) × 109/L,P =0.03] were all significantly higher in the treatment group.The incidence of myelosuppression in the treatment group was 28.57％,significantly lower than that in the control group (83.78％,P =0.00) ; such difference was also detected in patients with nutritional risk in the 2groups (31.03％ vs.95.45％,P =0.00).The incidences of nosocomial infection in the treatment group were significantly lower than in the control group after both the first and the second cycle of chemotherapy (0 vs.10.81％,P=0.03; 2.38％ vs.27.03％,P=0.02).Conclusions Combined enteral and parenteral nutrition support with chemotherapy in elderly patients with advanced gastrointestinal caner could improve nutritional status,reduce toxic reaction,and prevent nosocomial infection.Therefore combined nutrition support is a safe and effective approach for elderly patients with advanced gastrointestinal cancer.
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Objective To investigate the relationship between the cell cycle blocked by hyperthermia and the expression of rhythm gene Bmall in gastric cancer MKN28 cells so as to provide the academic evidence in hyperthermia therapy for gastric cancer.MethodsThe MKN28 cells were resuscitated and cultured in vitro.In control group MKN28 cells were cultivated at 37 ℃.In experimental groups MKN28 cells were heated at 43 ℃ for different durations.The cell morphology was observed by microscopy.Methylthiazdyl tetrazolium (MTT) assay was adopted to evaluate the inhibitory effect of the cell line.The flow-cytometry was adopted to observe the influence on the cell cycle.The Bmall mRNA expression was investigated by real-time quantitative reverse transcription-polymerase chain reaction ( RT-PCR).ResultsThe remarkable changes of cell morphology were observed by microscopy after exposure to heating.According to the data of MTT assay,37 ℃ heating could not inhibit the proliferation of MKN28.The inhibitive rates of cell growth after 0.5 h,1 h,l.5 h at 43 ℃ was (21.76±5.46)％,(25.30 ±4.36)％ and (27.62 ± 3.78 )％,respectively.Results from flow-cytometry showed that G0/G1 phase cells in lh at 43 ℃ were remarkably less than those in the control group.However G2/M cells were significantly more than those in the control group.The mRNA expression of Bmall was the lowest when heating lh at 43 ℃ as compared to the control group.ConclusionsHyperthermia could induced the cell cycle changes and the expression of Bma11 in gastric cancer MKN28 cells.
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Objective To investigate the expression of extracellular matrix metalloproteinase inducer (CD147), nuclear factor kappa B (NF-κB) in esophageal squamous cell carcinoma tissue and probe their relationship to invasion and metastasis of esophageal carcinoma. Methods Immunochemical staining was performed to detect the expression of CD147 and NF-κB protein in 40 cases of esophageal carcinoma tissues and 40 cases of normal control. Results The positive rate of CD147 and NF-κB in esophageal carcinoma tissues and in adjacent noncancerous tissues were 77.5%/87.5% Vs 25%/42. 5%, P＜0.05.The positive rate of their prophase and metaphase-advanced stage esophageal carcinoma tissues were 33.3%/90.3% Vs 55.6%/96.8%, P＜0.05..The positive rate of non-metastatic and metastatic esophageal carcinoma tissues were 28.6%/87.9% Vs 42.9%/97%, P＜0.05.Conclusions Our results suggested that the increased expression of CD147 and NF-κB contributed to tumor angiogenesis in esophageal squamous cell carcinoma, which might be through the common pathway.
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Objective To study the effects of different enteric-coated aspirin tablets on upper gastrointestinal tract in the elderly. Methods 404 inpatients aged more than 65 years in last three years who took enteric-coated aspirin tablets (100mg/d) for more than three months were analyzed.They were divided into two groups: bayaspirin-treated group (232 cases) and control group with ordinary enteric-coated aspirin tablet treatment (172 cases). The clinical data and the results of gastroseopy were compared between two groups, and the effects of two kinds of enteric-coated aspirin tablets on upper gastrointestinal tract in the elderly were analyzed by Chi-square test. Results The upper gastrointestinal bleeding rates were 20.3% in Bayaspirin-treated group (47/232) and 32.0% in control group (55/172), and there was significant difference between two groups(χ2=7.19,P<0.01)Gastroscopy indicated that gastroduodenal inflammation occurred in 16 patients (6.9% and peptic ulcer occurred in 8 patients (3.5%) in bayaspirin-treated group, while gastroduodenal inflammation occurred in 12 patients (7.0%) and peptic ulcer occurred in 36 patients(20.9%)in control group. The difference of the incidence of peptic ulcer between two groups had statistical significance(χ2= 31.10,P<0.01). The incidences of gastrointestinal adverse reactions were 8.6% (20/232) in bayaspirin-treated group and 23.3% (40/172) in control group, and there was a statistical difference between two groups. Conclusions Compared with ordinary enteric-coated aspirin tablet, bayaspirin has less adverse effects on upper gastrointestinal tract in the elderly and is more safe for treatment.
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Objective To study the changes of serum and tissue soluble intercellular adhesion molecule(sICAM)-1 in colorectal cancer patients and their clinical significance. Methods Serum level of sICAM-1 was detected by the double antibody sandwich enzyme-linked immunosorbent assay method in 44 patients with colorectal cancer before and after operation, 28 patients with intestinal polyps and 30 controls.Simultaneously, tissue level of sICAM-1 was measured in the patients of colorectal cancer and intestinal polyps. Results The serum sICAM-1 level in colorectal cancer patients[ (693.22±276.25) mg/L]was significantly higher than that in the intestinal polyps patients [(61.99±27.39) mg/L]and healthy controls[(59.28±27.55) mg/L]. The tissue sICAM-1 level in the colorectal cancer [(706.92±286.09)mg/L ]was significantly higher than that in the intestinal polyps patients[ (63.06±27.06) mg/L,P<0.01 ]. The serum and tissue levels of sICAM-1 in Dukes C-D stages of the colorectal cancer showed significantly higher than those in Dukes A-B stages (P<0.01 ). The level of sICAM-1 declined remarkably after one month of radical operation. Conversely, it decreased illegibly after palliative operation. Conclusion Dynamic alterations of serum and tissue sICAM-1 level may be used as indicators of diagnosis, choice of operative method and judgment of prognosis in patients with colorectal cancer.
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Objective To investigate the serum levels of CD147 and MMP-2 and the relationship between these proteins and colorectal tumor differentiation, Dukes stage. Methods Serum levels of CD147 and MMP-2 in 44 patients with colorectal carcinoma,28 polyp intestinal patients and 36 normal subjects were measured by ELISA. Results Serum levels of CD147(103.59±40.74pg/ml)and MMP-2(14.92±2.02ng/ml)in the cancer patients were significantly higher than those of the polyp intestinal(66.27±16.91;10:96±1.71)and normal control(63.84±18.71;10.49±1.61)(P＜0.05).The levels were associated with tumor differentiation and Dukes stage. Patients with poor differentiation had significantly higher levels of MMP-2 than those of patients with well differentiation. And Dukes C and D stage tumors had significantly higher levels of CD147 than Dukes A and B stage tumors(P＜0.05).The levels of CD147 and MMP-2 declined remarkably after one month of radical operation. Conversely, it decreased illegibly after palliative operation. The serum levels of CD147were positively correlated with MMP-2 in patients with colorectal cancer. Conclusion Elevated CD147 and MMP-2 serum levels are associated with tumor differentiation, invasion, metastasis. Dynamic alterations of serum CD147 and MMP-2 may be used as the indicators of diagnosis, the choice of operative method and the judgment of prognosis in patients with colorectal cancer.