Search

Objective: To explore the efficacy of adjusting the dose of imatinib dose in the context of therapeutic drug monitoring (TDM) in patients with gastrointestinal stromal tumors (GISTs) who are receiving adjuvant therapy after complete resection of their tumors. Methods: This was a descriptive study. Inclusion criteria were (1) complete surgical resection with a pathological diagnosis of GIST, (2) postoperative adjuvant therapy with imatinib and dosage adjustment, (3) multiple TDM of imatinib, and (4) complete clinical, pathological, and follow-up data. The data of 70 patients with GISTs treated at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology between January 2015 and December 2023 were collected retrospectively. The study cohort comprised 15 (21.4%) men and 55 (78.6%) women of median age 60 years (range: 25-82). Of the eligible patients, 49 (70.0%) were at high-risk, 14 (20.0%) at intermediate-risk, six (8.6%) at low-risk, and one (1.4%) at very low risk. Patients were followed up by the gastrointestinal stromal tumor clinic every 2-3 months and their plasma concentrations of imatinib were checked. The dose was adjusted to 300 mg/d or 200 mg/d depending on whether they had had ≥ grade III adverse reactions, and whether the first plasma concentration of imatinib was ≥ 1,500 μg/L or between the expected range of 760 μg/L-1,100 μg/L. Studied indicators included adverse reactions, quality of life before and after dose adjustment, and overall survival and recurrence-free survival (RFS) after dose adjustment. Results: Before dose adjustment, all 70 patients received 400 mg of imatinib daily, with initial TDM values of 1,900 ± 568 μg/L, for a median duration of 8.3 months. After dose adjustment, 60 patients received 300 mg daily, with a TDM of 1,216 ± 350 μg/L, whereas 10 received 200 mg daily, with a TDM of 1,023 ± 269 μg/L. The median duration of treatment after dose adjustment was 23.4 months. Compared with those whose dosages were not adjusted, the incidence of bone marrow suppression was significantly lower (74.3% [52/70] vs. 51.4% [36/70], χ 2 =9.202, P =0.010); as were the incidences of edema (95.7% [67/70] vs. 50.0% [35/70], χ 2 =40.526, P <0.001); skin reactions (70.0% [49/70] vs. 32.9% [23/70), χ 2 =22.495, P <0.001); and gastrointestinal reactions (38.6% [27/70] vs. 10.0% [7/70], χ 2 =15.899, P <0.001) in those whose dosages were adjusted. The average total scores for physical health before and after dose adjustment were 76 ± 5 and 88 ± 4, respectively; whereas the mental health scores were 75 ± 6 and 89 ± 4, respectively. The median follow-up period was 36 months (range 6-126). During the first 3 years of follow-up, five high-risk patients with non-gastric GISTs developed recurrences. The 3-year overall survival rate was 100%, and the 3-year RFS rate was 92.8%, high-risk patients having a 3-year RFS rate of 89.8%. Conclusion: The adverse reactions and quality of life of GIST patients with severe adverse reactions to adjuvant imatinib therapy after complete resection can be mitigated by appropriately reducing the dosage of imatinib under the guidance of TDM.

Objective: To study the effect of Lugu Ganoderma Lucidum (LGL) on low-density lipoprotein (LDL) oxidation and monocyte adhesion to endothelium (AdM-E) induced by oxydative LDL and advanced glycosylation endproducts (AGE) by using serum pharmacological technique., Methods: LDL oxidation was determined by measuring the thiobarbituric acid reactive substances in the supernatants, and AdM-E was determined by measuring myeloperoxidase activity of adherent monocyte., Results: Serum derived from rats 0.5 hrs, 1 hr, 2 hrs, 3 hrs after LGL administering 0.12 g/kg once and 0.5 hrs, 1 hr after LGL administering twice showed no significant effect on LDL oxidation, but the serum from rats 2 hrs, 3 hrs after LGL 0.12 g/kg administering twice or from rats after 10 successive days LGL administering in dose of 0.12 g/kg, 0.24 g/kg and 0.72 g/kg, all could lower the LDL oxidation (P < 0.05). Besides, the serum from rats with 10 days LGL administering of all dosages also could inhibit AdM-E induced by AGE (P < 0.05), and those of 0.24 g/kg and 0.72 g/kg could inhibit AdM-E induced by oxydative LDL (P < 0.05)., Conclusion: LGL could decrease LDL oxidation and AdM-E induced by AGE or oxydative LDL.

TFAR19 TF-1 cell apoptosis related gene 19 is a novel apoptosis-related gene cloned from human leukemia cell line TF-1 cells undergoing apoptosis in 1999 (accession number AF014955 in GenBank). The human TFAR19 encodes a protein which shares significant homology to the corresponding proteins of species ranging from yeast to mice. TFAR19 exhibits a ubiquitous expression pattern and its expression is upregulated in tumor cells undergoing apoptosis. Overexpression of TFAR19 could enhance apoptosis of some tumor cells induced by growth factor withdrawal or serum deprivation. But the exact mechanism of TFAR19 is unclear. Mitochondria not only provides energy for the cell, but also plays a critical role on cell death or survival. The release of apoptosis promoting factor, such as cytochrome c from mitochondria, resulted by the damage of mitochondrial membrane integrity, is the key factor controlling apoptosis. The permeability transition pore (PTP) of mitochondria is a protein complex located between the mitochondrial membranes, and it plays an important role in regulating the integrity of mitochondrial membrane. In this study, the effect of recombinant TFAR19 on isolated mitochondrial PTP, membrane potential, and release of cytochrome c was investigated in vitro. The results indicated that recombinant TFAR19 facilitated the isolated mitochondrial PTP opening, decreased the membrane potential, and promoted the release of cytochrome c. The effect of TFAR19 on mitochondria is implemented by opening the mitochondrial PTP. Experimental results implicate that TFAR19 may positively feedback apoptosis signal of mitochondria, forming a positive loop to promote apoptosis.