Harnessing cytokines to optimize chimeric antigen receptor-T cell therapy for gastric cancer: Current advances and innovative strategies.

Enormous patients with gastric cancer (GC) are insensitive to chemotherapy and targeted therapy without the chance of radical surgery, so immunotherapy may supply a novel choice for them. Chimeric antigen receptor (CAR)-T cell therapy has the advantages of higher specificity, stronger lethality, and longer-lasting efficacy, and it has the potential for GC in the future. However, its application still faces numerous obstacles in terms of accuracy, efficacy, and safety. Cytokines can mediate the migration, proliferation, and survival of immune cells, regulate the duration and strength of immune responses, and are involved in the occurrence of severe side effects in CAR-T cell therapy. The expression levels of specific cytokines are associated with the genesis, invasion, metastasis, and prognosis of GC. Applications of cytokines and their receptors in CAR-T cell therapy have emerged, and various cytokines and their receptors have contributed to improving CAR-T cell anti-tumor capabilities. Large amounts of central cytokines in this therapy include chemokines, interleukins (ILs), transforming growth factor-ß (TGF-ß), and colony-stimulating factors (CSFs). Meanwhile, researchers have explored the combination therapy in treating GC, and several approaches applied to other malignancies can also be considered as references. Therefore, our review comprehensively outlines the biological functions and clinical significance of cytokines and summarizes current advances and innovative strategies for harnessing cytokines to optimize CAR-T cell therapy for GC.

Fibroblast growth factor 15, induced by elevated bile acids, mediates the improvement of hepatic glucose metabolism after sleeve gastrectomy.

BACKGROUND: Fibroblast growth factor (FGF) 15/19, which is expressed in and secreted from the distal ileum, can regulate hepatic glucose metabolism in an endocrine manner. The levels of both bile acids (BAs) and FGF15/19 are elevated after bariatric surgery. However, it is unclear whether the increase in FGF15/19 is induced by BAs. Moreover, it remains to be understood whether FGF15/19 elevations contribute to improvements in hepatic glucose metabolism after bariatric surgery. AIM: To investigate the mechanism of improvement of hepatic glucose metabolism by elevated BAs after sleeve gastrectomy (SG). METHODS: By calculating and comparing the changes of body weight after SG with SHAM group, we examined the weight-loss effect of SG. The oral glucose tolerance test (OGTT) test and area under the curve of OGTT curves were used to assess the anti-diabetic effects of SG. By detecting the glycogen content, expression and activity of glycogen synthase as well as the glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (Pepck), we evaluated the hepatic glycogen content and gluconeogenesis activity. We examined the levels of total BA (TBA) together with the farnesoid X receptor (FXR)-agonistic BA subspecies in systemic serum and portal vein at week 12 post-surgery. Then the histological expression of ileal FXR and FGF15 and hepatic FGF receptor 4 (FGFR4) with its corresponding signal pathways involved in glucose metabolism were detected. RESULTS: After surgery, food intake and body weight gain of SG group was decreased compare with the SHAM group. The hepatic glycogen content and glycogen synthase activity was significantly stimulated after SG, while the expression of the key enzyme for hepatic gluconeogenesis: G6Pase and Pepck, were depressed. TBA levels in serum and portal vein were both elevated after SG, the FXR-agonistic BA subspecies: Chenodeoxycholic acid (CDCA), lithocholic acid (LCA) in serum and CDCA, DCA, LCA in portal vein were all higher in SG group than that in SHAM group. Consequently, the ileal expression of FXR and FGF15 were also advanced in SG group. Moreover, the hepatic expression of FGFR4 was stimulated in SG-operated rats. As a result, the activity of its corresponding pathway for glycogen synthesis: FGFR4-Ras-extracellular signal regulated kinase pathway was stimulated, while the corresponding pathway for hepatic gluconeogenesis: FGFR4- cAMP regulatory element-binding protein- peroxisome proliferator-activated receptor γ coactivator-1α pathway was suppressed. CONCLUSION: Elevated BAs after SG induced FGF15 expression in distal ileum by activating their receptor FXR. Furthermore, the promoted FGF15 partly mediated the improving effects on hepatic glucose metabolism of SG.

Efficacy and Safety of Totally Laparoscopic Gastrectomy Compared with Laparoscopic-Assisted Gastrectomy in Gastric Cancer: A Propensity Score-Weighting Analysis.

Objectives: To compare the short- and long-term outcomes of totally laparoscopic gastrectomy (TLG) with laparoscopic-assisted gastrectomy (LAG) in gastric cancer (GC) patients and evaluate the efficacy and safety of TLG. Methods: This retrospective study was based on GC patients who underwent laparoscopic radical gastrectomy in the Qilu Hospital from January 2017 to December 2020. The groups' variables were balanced by using the propensity score-based inverse probability of treatment weighting (PS-IPTW). The primary outcomes were 3-year relapse-free survival (RFS) and 3-year overall survival (OS). Postoperative recovery and complications were the secondary outcomes. Results: A total of 250 GC patients were included in the study. There were no significant differences in baseline and pathological features between the TLG and the LAG groups after the PS-IPTW. TLG took around 30 min longer than LAG, while there were more lymph nodes obtained and less blood loss throughout the procedure. TLG patients had less wound discomfort than LAG patients in terms of short-term prognosis. There were no significant differences between groups in the 3-year RFS rate [LAG vs. TLG: 78.86% vs. 78.00%; hazard ratio (HR) = 1.14, 95% confidence interval (CI), 0.55-2.35; p = 0.721] and the 3-year OS rate (LAG vs. TLG: 78.17% vs. 81.48%; HR = 0.98, 95% CI, 0.42-2.27; p = 0.955). The lymph node staging was found to be an independent risk factor for tumor recurrence and mortality in GC patients with laparoscopic surgery. The subgroup analysis revealed similar results of longer operation time, less blood loss, and wound discomfort in totally laparoscopic distal gastrectomy, while the totally laparoscopic total gastrectomy showed benefit only in terms of blood loss. Conclusion: TLG is effective and safe in terms of short- and long-term outcomes, with well-obtained lymph nodes, decreased intraoperative blood loss, and postoperative wound discomfort, which may be utilized as an alternative to LAG.

Ox-LDL-mediated ILF3 overexpression in gastric cancer progression by activating the PI3K/AKT/mTOR signaling pathway.

BACKGROUND: This study aimed to investigate the relationship of dyslipidemia and interleukin-enhancer binding factor 3 (ILF3) in gastric cancer, and provide insights into the potential application of statins as an agent to prevent and treat gastric cancer. METHODS: The expression levels of ILF3 in gastric cancer were examined with publicly available datasets such as TCGA, and western blotting and immunohistochemistry were performed to determine the expression of ILF3 in clinical specimens. The effects of ox-LDL on expression of ILF3 were further verified with western blot analyses. RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Gene Set Enrichment Analysis (GSEA) pathway analyses were performed to reveal the potential downstream signaling pathway targets of ILF3. The effects of statins and ILF3 on PI3K/AKT/mTOR signaling pathway, cell proliferation, cell cycle, migration and invasion of gastric cancer cells were investigated with Edu assay, flow cytometry and transwell assay. RESULTS: Immunohistochemistry and western blot demonstrated that the positive expression rates of ILF3 in gastric cancer tissues were higher than adjacent mucosa tissues. The ox-LDL promoted the expression of ILF3 in a time-concentration-dependent manner. ILF3 promoted the proliferation, cell cycle, migration and invasion by activating the PI3K/AKT/mTOR signaling pathway. Statins inhibited the proliferation, cell cycle, migration and invasion of gastric cancer by inhibiting the expression of ILF3. CONCLUSIONS: These findings demonstrate that ox-LDL promotes ILF3 overexpression to regulate gastric cancer progression by activating the PI3K/AKT/mTOR signaling pathway. Statins inhibits the expression of ILF3, which might be a new targeted therapy for gastric cancer.

Comparison Between Linear Stapler and Circular Stapler After Laparoscopic-Assisted Distal Gastrectomy in Patients With Gastric Cancer.

Background and Aim: To evaluate the safety and efficacy of laparoscopy distal gastrectomy using a linear stapler compared with a circular stapler in patients with gastric cancer. Methods: We retrospectively reviewed 173 patients who underwent laparoscopic distal gastrectomy for gastric cancer at a single center from January 2018 to December 2020. Patients were categorized into the linear stapler group and the circular stapler group. General data, intraoperative and postoperative outcomes, postoperative pathological results, postoperative complications, and postoperative follow-up in the two groups were compared and analyzed. Results: The operation time (208.76 ± 32.92 vs. 226.69 ± 26.92 min, p < 0.05), anastomosis time (71.87 ± 9.50 vs. 90.56 ± 3.18 min, p < 0.05), time to first flatus (68.60 ± 25.96 vs. 76.16 ± 21.05 h, p < 0.05), time to the first sip of water (3.66 ± 0.61 vs. 4.07 ± 0.77 days, p < 0.05), and time to the first liquid diet (4.43 ± 1.02 vs. 5.03 ± 1.70 days, p < 0.05) were significantly shorter in the linear stapler group. In addition, the highest postoperative body temperature within 3 days (37.4 ± 0.61 vs. 37.7 ± 0.61, p < 0.05) after the operation, white blood cell count (WBC) on the 3rd day (9.07 ± 2.52 vs. 10.01 ± 2.98 × 10∧9/L, p < 0.05), and average gastric tube drainage within 3 days (36.65 ± 24.57 vs. 52.61 ± 37 ml, p < 0.05) were also significantly lower in the linear stapler group. Conclusions: Both circular and linear staplers are safe and feasible for gastrointestinal reconstruction in laparoscopic distal gastrectomy. In contrast, a linear stapler has advantages over a circular stapler in shortening operation time and accelerating the postoperative recovery of patients.

Study on the application of preoperative three-dimensional CT angiography of perigastric arteries in laparoscopic radical gastrectomy.

To investigate the clinical value and significance of preoperative three-dimensional computerized tomography angiography (CTA) in laparoscopic radical gastrectomy for gastric cancer. The clinical data were analyzed retrospectively from 214 gastric cancer patients. We grouped according to whether to perform CTA, and we compared and analyzed the difference of the data between the two groups. The perigastric arteries were classified according to CTA images of patients in the CTA group. The celiac trunk was classified according to Adachi classification: Type I (118/125, 94.4%), Type II (3/125, 2.4%), Type III (0/125, 0%), Type IV (1/125, 0.8%), Type V (2/125, 1.6%), Type VI (1/125, 0.8%). Hepatic artery classification was performed according to Hiatt classification: Type I (102/125, 81.6%), Type II (9/125, 7.2%), Type III (6/125, 4.8%), Type IV (2/125, 1.6%), Type V (3/125, 2.4%), Type VI (0, 0%), Others (3/125, 2.4%). And this study combined vascular anatomy and surgical risk to establish a new splenic artery classification model. In comparison, the operation time, first exhaust time, and estimated blood loss in the CTA group were significantly lower than those in the non-CTA group. In addition, the blood loss in the CTA group combined with ICG (Indocyanine Green) labeled fluorescence laparoscopy was significantly less than that in the group without ICG labeled. Preoperative CTA could objectively evaluate patients' vascular route and variation and then help us avoid or decrease the risk of vascular injury and bleeding. When combined with ICG labeled fluorescence laparoscopy, it could further reduce the risk of iatrogenic injury during the operation and improve postoperative recovery.

Clinical Application of Indocyanine Green Fluorescence Technology in Laparoscopic Radical Gastrectomy.

Background: This study aimed to observe the application and evaluate the feasibility and safety of indocyanine green (ICG) fluorescence technology in laparoscopic radical gastrectomy (LRG). Methods: Patients who underwent LRG & D2 lymphadenectomy at Qilu Hospital of Shandong University were included between January 2018 and August 2019. According to whether endoscopic injection of ICG was performed, patients were assigned to the ICG group (n=107) and the control group (n=88). The clinicopathologic features, retrieved lymph nodes, postoperative recovery, and follow-up data were compared between the two groups. Results: Baseline characteristics are comparable. The ICG group had a significantly larger number of lymph nodes retrieved (49.55 ± 12.72 vs. 44.44 ± 10.20, P<0.05), shorter total operation time (min) (198.22 ± 13.14 vs. 202.50 ± 9.91, P<0.05), shorter dissection time (min) (90.90 ± 5.34 vs. 93.74 ± 5.35, P<0.05) and less blood loss (ml) (27.51 ± 12.83 vs. 32.02 ± 17.99, P<0.05). The median follow-up time was 29.0 months (range 1.5-43.8 months), and there was no significant difference between the ICG group and the control group in 2-year OS (87.8% vs. 82.9%, P>0.05) or DFS (86.0% vs. 80.7%, P>0.05). Conclusions: ICG fluorescence technology in laparoscopic radical gastrectomy has advantages in LN dissection, operation time, and intraoperative blood loss. The 2-year OS and 2-year DFS rates between the two groups were comparable. In conclusion, ICG fluorescence technology is feasible and safe.