Clinical Efficacy and Safety of Bevacizumab, Apatinib, and Recombinant Human Endothelial Inhibitor in the Treatment of Advanced Gastric Cancer.

OBJECTIVE: To investigate the clinical efficacy and safety of bevacizumab, apatinib, and recombinant human endothelial inhibitor in the treatment of advanced gastric cancer. METHODS: The medical data of 204 patients with a medium to advanced gastric cancer assessed for eligibility treated in our hospital from February 2019 to April 2020 were retrospectively analyzed. The eligible patients were assigned at a ratio of 1 : 1:1 : 1 to either the control group (chemotherapy), study group I (bevacizumab combined with chemotherapy), study group II (apatinib combined with chemotherapy), or study group III (recombinant human endothelial inhibitor combined with chemotherapy) according to different treatment methods. The treatment efficacy, drug toxicity, quality of life, and serum tumor marker levels before and after treatment were compared among the four groups. RESULTS: Regarding the treatment effects, the effective rate of study group II (68.63%) was significantly higher than that of the control group (33.33%), study group I (58.82%), and study group III (49.02%) (P < 0.05). The four groups showed similar safety and tolerability profiles (P > 0.05). The treatment in study group II led to a significantly higher physiological function score vs. the other three groups, but the scores of other items were not significantly different. Significant reduction was observed in the serum tumor markers after treatment in the four groups (P < 0.05), but treatment in study group II led to a significantly greater reduction than the other three groups (P < 0.05). CONCLUSION: The addition of apatinib, bevacizumab, and recombinant human endothelial inhibitor injection to chemotherapy for the treatment of medium to advanced gastric cancer can significantly improve the clinical treatment efficacy, among which the use of apatinib combined with chemotherapy achieves the best results, which is worthy of clinical promotion.

Knockdown of Serum- and Glucocorticoid-Regulated Kinase 1 Enhances Cisplatin Sensitivity of Gastric Cancer Through Suppressing the Nuclear Factor Kappa-B Signaling Pathway.

BACKGROUND: Previous studies have published the promoting effect of serum and glucocorticoid-regulated kinase 1 (SGK1) in various malignant tumors. However, whether SGK1 promotes gastric cancer remains a mystery. AIMS: To clarify the function of SGK1 in gastric cancer and its potential regulatory mechanism. STUDY DESIGN: Cell culture study. METHODS: The SGK1-silenced model was generated in two gastric cancer cell lines and further evaluated their malignant behavior and susceptibility to cisplatin. The interaction between miR-15a-5p and SGK1 was evaluated by the luciferase reporter assay. The knockdown efficiency of SGK1 was confirmed by RT- qPCR and Western blot assays. Cell proliferation rate was assessed with CCK-8 assay, and flow cytometry was used to determine cell cycle progression and apoptosis. RESULTS: Western blot data displayed an elevated level of SGK1 in gastric cancer cell lines. Functionally, SGK1 deficiency suppressed gastric cancer cell proliferation (P < .01) by acting on cell-cycle progression. Moreover, SGK1 deficiency suppressed cell invasion and migration of gastric cancer cells (P < .01). Further, the silencing of SGK1 obviously suppressed cell proliferation and induced apoptosis of the cells after cisplatin treatment (P < .01), indicating that SGK1 deficiency facilitated the chemosensitivity of these 2 gastric cancer cell lines to cisplatin. Mechanically, downregulation of SGK1 repressed the cytoplasm- to-nucleus translocation of NF-κB p65. Interestingly, we found that miR-15a-5p binds to the 3'UTR of SGK1, which was confirmed using luciferase activity assay (P < .05). Moreover, the data suggested that SGK1 reversed the suppression effect of miR-15a-5p on gastric cancer cell migration (P < .01). CONCLUSION: Loss of SGK1 suppresses the malignant behavior of gastric cancer cells and increases cisplatin sensitivity by restraining the NF-κB signaling pathway. Moreover, SGK1 may exert an inhibitory effect in gastric cancer by being targeted by miR-15a-5p. Therefore, SGK1 may be a prospective target for future gastric cancer therapy.

Nucleoporin 37 promotes the cell proliferation, migration, and invasion of gastric cancer through activating the PI3K/AKT/mTOR signaling pathway.

Gastric cancer is a kind of malignant tumor in the world. Emerging studies have proved the regulatory role of nucleoporin 37 in the development of several malignant tumors. However, the potential effect of NUP37 in gastric cancer is still unclear. In this study, we searched for the Cancer Genome Atlas analysis to explore the potential correlation between NUP37 and gastric cancer. Then, we analyzed NUP37 expression in gastric cancer tissues and cell lines. After constructing a NUP37-silenced model in NCI-N87 cells and a NUP37-overexpressed model in MKN45 cells, we evaluated the role of NUP37 in cell proliferation, migration, and invasion as well as its underlying mechanism. TCGA analysis showed that NUP37 expression was highly expressed in stomach adenocarcinoma, which showed a lower survival rate than normal samples. Moreover, NUP37 was found to be highly expressed in gastric cancer tissues and cell lines. Functionally, NUP37 deficiency promoted gastric cancer cell apoptosis and inhibited cell proliferation, migration, and invasion, whereas NUP37 overexpression exhibited the opposite results. Mechanically, upregulation of NUP37 activated the PI3K/AKT/mTOR signaling pathway. Furthermore, the rescue assay exhibited that the mTOR inhibitor rapamycin significantly reversed the promoting effect of NUP37 in cell proliferation, migration, and invasion. In conclusion, our study identified that NUP37 promoted malignant behavior of gastric cancer cells including invasion, proliferation, and migration through activating the PI3K and its downregulated signaling pathway, indicating that NUP37 might become a novel prognostic target for further gastric cancer therapy.

Study on the clinical effects of targeted therapy on elderly patients with gastric cancer.

To explore the clinical effects of targeted drug therapy on elderly patients with gastric cancer. Totally 200 metastatic gastric cancer patients who came to our hospital from January 2017 to January 2020 were selected and randomized into four groups, with 50 patients in each group. Bevacizumab (Group I), apatinib (Group II), and recombinant human endostatin (Group III) adopted respectively. While the control group received no targeted drug. Clinical data and clinical effect was collected and compared. After the therapy, the vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor-2 (sVEGFR2) and human epithelial growth factor receptor-2 (HER2) positive detection of Group I, Group II, and Group III were better than the control group (P<0.05). In addition, the therapeutic effects of Group I, Group II, and Group III were higher and the incidence of adverse reactions was lower than the control group (P<0.05). Targeted drugs have obvious clinical effects in gastric cancer. It can effectively inhibit tumor growth and reduce the occurrence of complications, which is worthy of extensive clinical application and promotion.

Inhibition of MIR4435-2HG on Invasion, Migration, and EMT of Gastric Carcinoma Cells by Mediating MiR-138-5p/Sox4 Axis.

BACKGROUND: The previous investigations have identified that long non-coding RNA (lncRNAs) act as crucial regulators in gastric carcinoma. However, the function of lncRNA MIR4435-2HG in the modulation of gastric carcinoma remains elusive. Here, we aimed to explore the role of MIR4435-2HG in gastric carcinoma. METHOD: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were applied to select the differently expressed lncRNAs in gastric carcinoma. The qRT-PCR was applied to analyze MIR4435-2HG expression in carcinoma tissues and cell lines. The effect of MIR4435-2HG on proliferation, invasion, migration, and apoptosis of gastric carcinoma cells was detected by Cell Counting Kit-8 (CCK-8) assays, transwell assays, and flow cytometry in vitro. A subcutaneous tumor model was constructed to examine the tumor growth of gastric carcinoma cells after knocking out MIR4435-2HG. RNA immunoprecipitation and luciferase reporting assays were applied to evaluate the interaction of MIR4435-2HG, miR-138-5p, and Sox4. RESULTS: The bioinformatics analysis based on TCGA and GEO databases indicated that MIR4435-2HG was obviously elevated in gastric carcinoma samples. The qRT-PCR analysis revealed that MIR4435-2HG was upregulated in clinical gastric carcinoma tissues and cells. The high expression of MIR4435-2HG is associated with the poor survival rate of patients. The knockout of MIR4435-2HG could repress the proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) and accelerate the apoptosis of gastric carcinoma cells. Moreover, the deletion of MIR4435-2HG was able to attenuate the tumor growth in vivo. Mechanically, we identified that MIR4435-2HG enhanced Sox4 expression by directly interacting with miR-138-5p as a competitive endogenous RNA (ceRNA) in gastric carcinoma cells, in which Sox4 was targeted by miR-138-5p. CONCLUSION: MIR4435-2HG is elevated in gastric carcinoma cells and contributes to the growth, metastasis, and EMT of gastric carcinoma cells by targeting miR-138-5p/Sox4 axis. MIR4435-2HG may be applied as a potential therapeutic target in gastric carcinoma.

Clinical study on the safety, efficacy, and prognosis of molecular targeted drug therapy for advanced gastric cancer.

OBJECTIVE: To investigate the safety, efficacy, and prognosis of advanced gastric cancer patients treated with molecular targeted drug therapy. METHODS: A total of 200 patients with metastatic gastric cancer admitted to our hospital from March 2018 to December 2018 were randomly selected and divided into the control group, group A, group B and group C, with 50 patients in each group. Patients in the control group received surgical treatment combined with conventional chemotherapy. Patients in group A were provided with surgical treatment combined with bevacizumab, patients in group B received surgical treatment combined with apatinib, and patients in group C received surgical treatment combined with recombinant human endostatin (RHE). Clinical efficacy, vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR-2) levels, Response Evaluation Criteria in Solid Tumors (RECIST), sentinel lymph node (SLD) metastasis, and adverse reactions were compared among different groups of patients with metastatic gastric cancer. RESULTS: There were no significant differences in treatment efficiency, VEGF and VEGFR-2 levels, RECIST, SLD metastasis value and adverse reactions among group A, group B and group C, and the results were not statistically significant (P>0.05). The levels of VEGF, VEGFR-2, SLD metastasis, and adverse reactions in group A, B, and C were significantly lower than those in the control group (P<0.05). The effective rate of treatment and RECIST in group A, B and C were significantly higher than those in the control group, and the comparison results were statistically significant (P<0.05). CONCLUSION: Molecular targeted drug therapy is effective and safe in patients with advanced gastric cancer, and the prognosis of patients is satisfactory, without the proliferation and metastasis of cancer cells.

LINC_00355 promotes gastric cancer progression by upregulating PHF19 expression through sponging miR-15a-5p.

BACKGROUND: Long non-coding RNAs exert vital roles in several types of cancer. The objective of this study was to explore the role of LINC_00355 in gastric cancer (GC) progression and its potential mechanism. METHODS: The expression levels of LINC_00355 in GC tissues and cells were detected by quantitative real-time PCR, followed by assessing the effects of LINC_00355 knockdown or overexpression on cell properties. Dual-luciferase reporter assay was utilized to identify the relationship between LINC_00355 and microRNA (miR)-15a-5p and miR-15a-5p and PHD finger protein 19 (PHF19), followed by the rescue experiments. RESULTS: The results showed that LINC_00355 was highly expressed in GC tissues and cells compared with the corresponding control. LINC_00355 knockdown decreased the viability, migration, and invasion and increased the accumulation of GC cells in G1 phase and apoptosis. Meanwhile, LINC_00355 downregulation markedly increased cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase protein levels, whereas decreased cyclin D1, cyclin E, matrix metalloproteinase (MMP) 9, MMP2, and N-cadherin protein levels in GC cells. However, LINC_00355 overexpression had the opposite effects. It was verified that LINC_00355 upregulated the expression of PHF19 through sponging miR-15a-5p. Furthermore, PHF19 overexpression reversed the effect of LINC_00355 knockdown on GC cell properties, including cell viability, migration, invasion, and apoptosis. CONCLUSIONS: Collectively, these results suggest that LINC_00355 promotes GC progression by up-regulating PHF19 through sponging miR-15a-5p. Our findings may provide an important clinical basis for reversing the malignant phenotype of GC.

Treatment-related severe and fatal adverse events with molecular targeted agents in the treatment of advanced gastric cancer: a meta-analysis.

AIM: To perform a systematic review and meta-analysis of Phase III randomized controlled trials (RCTs) to determine the incidence and risk of severe adverse events (AEs) with molecular targeted agents (MTAs) in advanced/metastatic gastric cancer (GC) patients. METHODS: A comprehensive literature search for related trials published up to December 2015 was performed. Eligible studies were Phase III RCTs of advanced/metastatic GC patients assigned to MTAs or control group. Data were extracted by two authors for severe and fatal AEs (FAEs). RESULTS: A total of nine Phase III RCTs involved 4,934 GC patients were ultimately identified. The pooled results demonstrated that the addition of TAs to therapies in advanced GC significantly increased the risk of developing severe AEs (relative risk: 1.12, 95% confidence interval: 1.02-1.24, P=0.02), but not for FAEs (relative risk: 0.97, 95% confidence interval: 0.65-1.45, P=0.88). Additionally, the most common causes of FAEs with MTAs were infections (16.3%), gastrointestinal hemorrhage (8.2%), and arterial thromboembolic events (8.2%), respectively. CONCLUSION: With available evidence, the use of TAs in GC patients was associated with an increased risk of severe AEs, but not for FAE. Clinicians should be aware of the risk of severe AEs with the administration of these drugs in these patients.

Growth differentiation factor 15 promotes cell viability, invasion, migration, and angiogenesis in human liver carcinoma cell line HepG2.

AIM: This study was aimed to explore the role of growth differentiation factor 15 (GDF15) in hepatocellular carcinoma (HCC). METHODS: Human liver carcinoma cell line HepG2 was used and transfected with vector and/or short hairpin RNA (shRNA) against GDF15. Then, the transfection efficiency was ascertained by real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Cell viability was measured by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyltetrazolium bromide (MTT). Cell invasion and migration were measured by Transwell assay and Scratch assay. In addition, human umbilical vein endothelial cell (HUVEC) tube formation assay was performed to analysis the angiogenesis. Further, the protein expressions of epithelial-mesenchymal transition (EMT)-related factors were measured by Western blot. RESULT: We found that GDF15 overexpression significantly facilitated cell viability, cell invasion, migration, and angiogenesis (P<0.05 or P<0.01). The protein expressions of N-Cadherin, Vimentin and Twist1 were up-regulated by GDF15 overexpression, while E-Cadherin was down-regulated. Reciprocally, using a GDF15-shRNA strategy, we observed that GDF15 downregulation inhibited both basal and GDF15-induced cell viability, migration, invasion and angiogenesis in HepG2 cells. CONCLUSION: GDF15 could promote cell viability, invasion, migration, and angiogenesis of HepG2 cells. GDF15 overexpression might be a potential risk factor of HCC.

Malignant Peritoneum Mesothelioma with Hepatic Involvement: A Single Institution Experience in 5 Patients and Review of the Literature.

Malignant peritoneal mesothelioma with invasion of the liver is an invariably fatal disease. We aimed to clarify the characteristics of malignant peritoneal mesothelioma cases with liver involvement. The clinical presentation, computed tomography images, and immunohistochemical and histopathological features of 5 patients with malignant peritoneal mesothelioma and liver involvement were evaluated. The diagnosis was established by imaging and immune profiles of the tumours. A review of 8 cases with primary or invading malignant mesothelioma in liver is presented. All 5 mesothelioma cases were asbestos-related. CT images of malignant peritoneal mesothelioma with the liver involvement typically showed that the lesion grew inside the liver along the capsule and was possibly accompanied by capsule breakthrough and extrahepatic infiltration. The tumours exhibited a common epithelioid appearance in all 5 patients and most cases revealed positive Cal, CK, and MC with negative CEA and HeP. Different from our findings, the review of literature revealed that most malignant mesothelioma of liver was due to primary intrahepatic malignant mesothelioma. Finally, we concluded that the diagnosis of malignant peritoneal mesothelioma cases with liver invasion is reliably achieved by the history of asbestos exposure, the characteristic CT imaging, and immune profiles of the tumours.

[Efficacy and prognosis of different treatments on 63 patients with small intestinal gastrointestinal stromal tumors].

OBJECTIVE: To analyze the efficacy and prognosis of different treatments on small intestinal gastrointestinal stromal tumors(SIGIST). METHODS: Clinical data of 63 patients with SIGIST who were admitted to the Chinese PLA General Hospital from January 2004 to December 2013 were analyzed retrospectively. According to resection procedure and postoperative use of imatinib, patients were divided into R0 resection plus imatinib group (13 cases), R0 resection without imatinib group (42 cases), non-R0 resection plus imatinib group (7 cases), non-R0 resection without imatinib group (1 case). Survival was compared among groups. Result All the patients were followed up with a median length of 24 months(3 to 120 months), and the over survival (OS) rates at 1-year, 3-year, 5-year were 97%, 94% and 80%. In R0 resection plus imatinib group, R0 resection without imatinib group, and non-R0 resection plus imatinib group, the progression free survival(PFS) time was 24, 24 and 23 months; the 1-year PFS were 100%, 97% and 83%; the 3-year PFS were 100%, 45% and 83%; the 5-year PFS were 100%, 28% and 42%. R0 resection plus imatinib group had significantly higher PFS(all P<0.05). The case of non-R0 resection without imatinib died 6 months after operation. Among 55 patients undergoing R0 resection, recurrence was found in 16 patients, whose recurrence rates of 1-year, 3-yeart and 5-year were 2%,43% and 58%. Local recurrence was found in 8 cases, hepatic recurrence in 3 cases and widespread recurrence in 5 cases, who received simple imatinib, operation plus imatinib and imatinib intervention, with median survival time of 66.5 months, 92.5 months and 48 months respectively. One patient initiatively abandoned treatment and died 17 months later. CONCLUSION: The total resection and postoperative imatinib administration can improve the prognosis and raise the progression free survival of patients with small intestinal stromal tumors.