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Objective@#To investigate the significance of monitoring imatinib mesylate (IM) plasma concentrations in patients with gastrointestinal stromal tumor (GIST).@*Methods@#A retrospective descriptive study was carried out. Inclusion criteria: (1) patients with GIST confirmed by postoperative pathology or puncture pathology receiving maintenance therapy of IM; (2) administration of same dose of IM for at least 4 weeks (achieving steady - state plasma concentration). Patients who had severe organ dysfunction, received IM generics, or received IM simultaneously with other drugs significantly affecting IM pharmacokinetic were excluded. A total of 185 patients at the GIST Clinic of Renji Hospital, Shanghai Jiaotong University School of Medicine from August 2018 to May 2019 were enrolled, including 114 males (61.6%) and 71 females (38.4%) with a median age of 60 years old (range, 30-89 years), and 63 advanced cases. Patients receiving preoperative or postoperative adjuvant therapy were given IM 400 mg QD; patients with KIT exon 9 mutation or with disease progression during IM 400 mg QD treatment were given IM 600 mg QD. If the patient had adverse reactions such as myelosuppression during the medication, IM would be reduced or given BID per day. The peripheral venous blood was collected (22 to 24 hours after the last dose for patients who took IM QD and 2 hours before the first dose per day for those who took IM BID). IM plasma concentration was measured through high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). Correlation analysis between IM plasma concentration results and clinical data was performed using linear regression analysis.@*Results@#A total of 241 stable blood samples of IM plasma concentration from 185 patients were finally collected. The IM plasma concentrations were significantly different between the doses of 300 mg/d and 400 mg/d [(942.4±433.5) μg/L vs. (1340.0±500.1) μg/L, t=6.317, P<0.001], and between 400 mg/d and 600 mg/d [(1340.0±500.1) μg/L vs. (2188.0±875.5) μg/L, t=3.557, P=0.004]. Among the blood samples of 57 patients receiving IM 300 mg/d, the IM plasma concentration of the advanced patients was significantly lower than that of the non-advanced patients [(795.6±225.8) μg/L vs. (992.2±484.4) μg/L, t=2.088, P=0.042]. Among the 137 blood samples of patients receiving IM 400 mg/d, the IM plasma concentration was higher in patients aged >60 years than those aged ≤60 years [(1461.0±595.3) μg/L vs. (1240.0±380.9) μg/L, t=2.528, P=0.013] and the IM plasma concentration of cases with diarrhea was significantly lower than that of those without diarrhea [(745.8±249.6) μg/L vs. (1382.0±486.9) μg/L, t=6.794, P<0.001]. Gender, primary location, surgical procedure, mutated gene, mutation type, or time of administration was associated with IM plasma concentration no matter in patients taking IM doses of 400 mg/d or 300 mg/d (all P>0.05). Regression analysis showed that body mass (P=0.004 and P=0.019), body mass index (P=0.016 and P=0.042), and body surface area (P=0.007 and P=0.028) were all negatively correlated with IM plasma concentrations in patients taking IM doses of 300 mg/d and 400 mg/d. Within the 137 patients who received a fixed oral dose of 400 mg/d IM, 17 patients received oral 200 mg BID, whose IM plasma drug concentration was not significantly different compared with that of 120 patients who received 400 mg IM QD [(1488.0±408.3) μg/L vs. (1319.0±509.7) μg/L, t=1.307, P=0.193].@*Conclusions@#Monitoring IM plasma concentration is significant throughout the whole process of management of GIST patients receiving IM treatment. In particular, regular monitoring IM plasma concentration and developing appropriate treatment strategies can bring better therapeutic benefits for patients with low doses, diarrhea, advanced condition and older age.
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Tumor-specific neoantigens have attracted much attention since they can be used as biomarkers to predict therapeutic effects of immune checkpoint blockade therapy and as potential targets for cancer immunotherapy. In this study, we developed a comprehensive tumor-specific neoantigen database (TSNAdb v1.0), based on pan-cancer immunogenomic analyses of somatic mutation data and human leukocyte antigen (HLA) allele information for 16 tumor types with 7748 tumor samples from The Cancer Genome Atlas (TCGA) and The Cancer Immunome Atlas (TCIA). We predicted binding affinities between mutant/wild-type peptides and HLA class I molecules by NetMHCpan v2.8/v4.0, and presented detailed information of 3,707,562/1,146,961 potential neoantigens generated by somatic mutations of all tumor samples. Moreover, we employed recurrent mutations in combination with highly frequent HLA alleles to predict potential shared neoantigens across tumor patients, which would facilitate the discovery of putative targets for neoantigen-based cancer immunotherapy. TSNAdb is freely available at http://biopharm.zju.edu.cn/tsnadb.
Subject(s)
Humans , Antigens, Neoplasm , Metabolism , Data Analysis , Databases, Genetic , Immunotherapy , Mutation , Genetics , Neoplasms , Genetics , Allergy and Immunology , Tumor Suppressor Protein p53 , Genetics , Urinary Bladder Neoplasms , GeneticsABSTRACT
New immunotherapy represented by immune checkpoint inhibitor therapy and chimeric antigen receptor T-Cell immunotherapy (CAR-T) has already become hot trend in the treatment of malignant tumors. In gastrointestinal stromal tumor (GIST), with notable tumor-infiltrating immune cells existing in GIST tissues and immunological effects reported in imatinib mesylate (IM) treatment, the clinicians and researchers started to realize the possibilities of immunotherapy in GIST. Recent studies reported that PD-1/PD-L1 or CTLA-4 blockade may enhance the T-cell activity and anti-tumor effect of targeted therapy, which can be applied in advanced GIST, and anti-KIT CAR T-cells indicated a new immunotherapeutic targeted strategy for GIST patients with TKI resistance. All the immunotherapies in GIST mentioned above are frontline researches but their efficacies still need more evidence from clinical trials to verify.
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<p><b>OBJECTIVE</b>To investigate the clinical characteristics, pathological classification and prognostic factors of gastrointestinal neuroendocrine neoplasms (GI-NENs).</p><p><b>METHODS</b>Clinicopathological data of 119 GI-NENs patients at Shanghai Renji Hospital from November 2007 to December 2016 were analyzed retrospectively. According to the classification and grading criteria of the WHO Neuroendocrine Tumor 2010 edition, patients were classified pathologically to realize the malignant degree of tumors. The overall survival rate was calculated by Kaplan-Meier curve, the prognostic risk factors were analyzed by Cox regression model, and the factors including the platelet/lymphocyte ratio (PLR) and neutrophil/lymphocyte ratio (NLR) were included in the analysis in addition to the routine clinicopathological factors.</p><p><b>RESULTS</b>Of 119 patients with GI-NENs, there were 83 cases (69.7%) of male and 36 cases (30.3%) of female. The age of patients ranged from 24 to 86 (median 61) years. Tumor locations included the stomach(n=70, 58.8%), duodenum(n=10, 8.4%), small intestine(n=2, 1.7%), appendix(n=3, 2.5%), colon(n=12, 10.1%), and rectum(n=22, 18.5%). The tumor diameter was 0.6 to 20 cm, the mean diameter was 5.4 cm, and the median diameter was 4 cm. There were 25 cases of G1 neuroendocrine tumor (NET), 7 cases of G2 NET and 87 cases of G3 neuroendocrine carcinoma (NEC). Among the 119 patients, 113 cases (95%) had complete follow-up, and the median follow-up was 75 (1 to 112) months. The 5-years overall survival rate was 58.4%. The survival rate of G1 NET, G2 NET and G3 NEC were 100%, 71.4%, 44.4%, and the difference was statistically significant (P=0.000). Univariate analysis showed that age ≥61 years (P=0.000), tumor located in the stomach, duodenum and colon (P=0.041), tumor size ≥4 cm (P=0.002), pathology classification of G3 NEC (P=0.000), late TNM staging (P=0.000) and blood PLR ≥133 (P=0.017) were associated with lower 5-year survival rate, but blood NLR level was not(P=0.263). Multivariate analysis showed that the patient age (HR=3.036, 95%CI: 1.548 to 5.956, P=0.001), the pathology classification(HR = 1.852, 95%CI:1.099 to 3.122, P=0.021), lymph node metastasis (HR=2.635, 95%CI:1.198 to 5.797, P=0.016) and distant metastasis (HR=2.685, 95%CI:1.383 to 5.214, P=0.004) were independent risk factors affecting the prognosis of patients, but the blood PLR level was not (HR=1.735, 95%CI: 0.947 to 3.176, P=0.074).</p><p><b>CONCLUSIONS</b>The malignant degree of GI-NEN is quite high, and the prognosis of patients is relatively poor. The age, pathological type and TNM staging are closely related to the prognosis of patients. Preoperative blood PLR may play a role in the prediction of prognosis, but preoperative blood NLR is not related with the prognosis of patients.</p>
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Objective To study the risk factors related to recurrence of gastrointestinal stromal tumor (GIST) after discontinuing postoperative adjuvant imatinib mesylate (IM) treatment.Methods We retrospectively analyzed our clinical database of 138 GIST patients who received radical resection and subsequent IM adjuvant treatment at the Renji Hospital,Shanghai Jiaotong University School of Medicine between January 2006 and January 2014.Results For the entire Multivariate analysis study group,the overall 5-year recurrent free survival (RFS) rate was 54.5％.There were two tumor characteristics which were independent prognostic factors of GIST treated by postoperative IM:Ki67 index (P =0.005),and serosal invasion (P =0.026).The accuracy of comprehensive evaluation based on the two weighted variables was better than NIH staging criteria(AUC:0.714 vs.0.631).Furthermore,two risk groups were created according to the risk model with 5-year RFS of 81.3％ and 31.1％ as low-risk and high-risk groups,respectively (P ＜0.05).Conclusions For patients with intermediate or high risk in NIH classification,if there was tumor serosal invasion,or if there was no local invasion but Ki67 index ＞ 8％,extended continuous IM adjuvant treatment should be recommended after the primary tumor was radically resected.
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Objective To investigate the influence of CO2 pneumoperitoneum on the adhesive and invasive ability of gastric cancer cells based on the expression of adhesive and invasive molecules. Methods With an artificial CO2 pneumoperitoneum model in vitro, human gastric cancer cells MKN-45, SGC-7901 and MKN-28 were exposed to 3 different CO2 gradients: 9 mm Hg, 15 mm Hg and control group (0 mm Hg). The expression of E-cadherin, ICAM-1, MMP-2 and VEGF-A were measured at 2 and 4 hours exposure by using RT-PCR, CytoMatrixTM kit and ECMatrixTM kit. The pretreated gastric cancer cells were injected into abdominal cavity of nude mice(2×106 cells per mouse). Five mice in each group were sacrificed 4 weeks later to record the number of tumor nodules in abdominal cavity. The remaining mice were kept for observation of survival time. Results The expression of E-cadherin (MKN-45: from 2.26 to 2.19, SGC-7901 :from 2.16 to 2.09、MKN-28 :from 2.06 to 1.99), ICAM-1 (MKN-45 : from 2.20 to 2.28、SGC-7901: from 2.10 to 2.18、MKN-28: from 2.00 to 2.08), MMP-2 (MKN-45:from 2.05 to 2.13、SGC-7901: from 1.95 to 2.03、MKN-28: from 1.85 to 1.93) and VEGF-A(MKN-45 : from 2.10 to 2.16、SGC-7901 :from 2.00 to 2.06、MKN-28: from 1.90 to 1.96) didn't change significantly with increasing pressure and time (P>0.05). The expression of adhesive and invasive molecules didn't change significantly between the experimental groups and the control group. There was no statistical significance of tumor metastasis in abdominal cavity of nude mice(MKN-45:from 22 to 23、SGC-7901 :from 20 to 22、MKN-28:from 21 to 22) and survival time(MKN-45 :from 23 to 21、SGC-7901 :from 22 to 21、MKN-28 :from 22 to 21) among all the groups. Conclusion Under low pressure and short time of CO2 exposure, the adhesive and invasive capacity of gastric cancer cells did not change significantly hence did not increase the possibility of neoplasm metastasis.