Genetic Polymorphisms and Adverse Events on Unbound Imatinib and Its Active Metabolite Concentration in Patients With Gastrointestinal Stromal Tumors.

Imatinib is a first-line drug for the treatment of gastrointestinal stromal tumors (GIST). This study aims to investigate the influence of different kinds of protein concentrations and genetic polymorphisms of metabolizing enzymes and drug transporters on unbound imatinib and its active metabolite N-desmethyl-imatinib concentration, as well as the relationship between adverse drug reactions (ADRs) and drug concentration. A total of 62 Chinese patients with GIST were genotyped for five single nucleotide polymorphisms (SNPs). Total and unbound 3h and trough concentration of imatinib and N-desmethyl-imatinib in GIST patients were determined by an LC-MS/MS method combined with an equilibrium dialysis. Single-Use Red Plate with inserts was used to separate the unbound drug. When the protein concentration became higher, the unbound imatinib and N-desmethyl-imatinib plasma concentration got higher (p < 0.05). Patients with GA genotype in rs755828176 had significantly higher unbound N-desmethyl-imatinib dose-adjusted trough plasma concentrations (p = 0.012). Patients with CC genotype in rs3814055 had significantly higher unbound imatinib dose-adjusted trough plasma concentrations (p = 0.040). The mean total imatinib C3h of patients with ADRs (3.10 ± 0.96 µg/ml) was significantly higher than that of patients without ADRs (p = 0.023). The mean total N-desmethyl-imatinib C3h of patients (0.64 ± 0.21 µg/ml) with ADRs was significantly higher than that of patients without ADRs (p = 0.004). The mean unbound N-desmethyl-imatinib C3h of patients with ADRs (6.49 ± 2.53 ng/ml) was significantly higher than that of patients without ADRs (p = 0.042). The total and unbound C3h of imatinib and N-desmethyl-imatinib in patients with ADRs was significantly higher than that in patients without ADRs (p < 0.05). Protein concentrations have great influence on the unbound imatinib and N-desmethyl-imatinib concentrations. The genetic polymorphisms of CYP3A4 rs755828176 and NR1I2 rs3814055 were significantly associated with unbound imatinib and N-desmethyl-imatinib dose-adjusted trough plasma levels. The total and unbound imatinib or N-desmethyl-imatinib concentration in patients with GIST was also significantly correlated with ADRs.

Comparison of treatment outcomes between laparoscopic and endoscopic surgeries for relatively small gastric gastrointestinal stromal tumors.

BACKGROUND: Complete surgical resection remains the predominant treatment modality for primary gastrointestinal stromal tumors (GISTs). No therapeutic consensus exists for 2-5 cm gastric GISTs. We compared the efficacy, safety, and prognosis of laparoscopic and endoscopic surgeries in the treatment of relatively small (2-5 cm) intraluminal gastric GISTs. METHODS: We collected 101 patients with relatively small intraluminal gastric GISTs who had integrated clinicopathological data and underwent laparoscopic or endoscopic resection (laparoscopic group n = 66; endoscopic group n = 35). Clinicopathological characteristics, perioperative data, and long-term oncological outcomes were retrospectively analyzed. Comparative analysis of clinicopathological data in the two groups was performed by using a chi-square test, Fisher's exact test, and Student's t-test. Recurrence-free survival (RFS) was analyzed by the log-rank test. RESULTS: All clinicopathological characteristics had no significant difference between the two groups. Patients in the endoscopic group had shorter operation time (P < 0.001), postoperative hospital stay (P < 0.001), time to a liquid diet (P < 0.01), and time to a semi-liquid diet (P < 0.01), and lower hospital charges (P < 0.001), compared to those in the laparoscopic group. Four patients (6.1%) in the laparoscopic group and one patient (2.9%) in the endoscopic group had perioperative complications, but with no significant difference. Recurrence occurred in 6 patients (9.1%) and 2 patients (5.7%) in the laparoscopic and endoscopic groups, respectively. There was no significant difference in RFS between the two groups. CONCLUSION: Endoscopic resection is a feasible and safe treatment modality for patients with relatively small (2-5 cm) intraluminal gastric GISTs. Due to faster recovery and lower cost, endoscopic resection is more suitable for elderly and weak patients, or patients with a poor financial situation.

miR-324-3p promotes gastric cancer development by activating Smad4-mediated Wnt/beta-catenin signaling pathway.

BACKGROUND: Emerging evidence suggested that miRNAs can function as oncogenes or tumor suppressors by regulating downstream target genes. miR-324-3p has been reported to function in several carcinomas, but its role in gastric cancer (GC) is still unknown. This study aims to explore the effects of miR-324-3p on the development of GC. METHODS: Expression of miR-324-3p was examined in GC cells and tissues by qRT-PCR. Effects of miR-324-3p on GC cells were evaluated by cell vitality assay, colony formation assay, cell migration assay, and flow cytometric assay. The dual luciferase assay was used to verify whether miR-324-3p could interact with the potential target genes. Western blot was used to assess the expression level of Smad4 and beta-catenin. Intracellular ATP level was also examined. The tumor xenografts were established using nude mice. A gastric organoid model was made from fresh stomach tissue. RESULTS: miR-324-3p was expressed at higher levels in the tumor tissues compared with adjacent normal tissues. Overexpression of miR-324-3p promoted cell growth, migration, and decreased apoptosis. miR-324-3p repressed the expression of Smad4, and loss of Smad4 activated the Wnt/beta-catenin signaling pathway. Overexpression of Smad4 rescued the effects of miR-324-3p on GC cells. The intracellular ATP level was upregulated with overexpression of miR-324-3p. miR-324-3p facilitated tumor cell colonization and growth in vivo and contributed to the growth of gastric organoids. CONCLUSIONS: The results suggested that miR-324-3p promoted GC through activating the Smad4-mediated Wnt/beta-catenin signaling pathway. The miR-324-3p/Smad4/Wnt signaling axis may be a potential therapeutic target to prevent GC progression.