Imatinib adherence prediction using machine learning approach in patients with gastrointestinal stromal tumor.

BACKGROUND: Nonadherence to imatinib is common in patients with gastrointestinal stromal tumor (GIST), which is associated with poor prognosis and financial burden. The primary aim of this study was to investigate the adherence rate in patients with GIST and subsequently develop a model based on machine learning (ML) and deep learning (DL) techniques to identify the associated factors and predict the risk of imatinib nonadherence. METHODS: All eligible patients completed four sections of questionnaires. After the data set was preprocessed, statistically significance variables were identified and further processed to modeling. Six ML and four DL algorithms were applied for modeling, including eXtreme gradient boosting, light gradient boosting machine (LGBM), categorical boosting, random forest, support vector machine, artificial neural network, multilayer perceptron, NaiveBayes, TabNet, and Wide&Deep. The optimal ML model was used to identify potential factors for predicting adherence. RESULTS: A total of 397 GIST patients were recruited. Nonadherence was observed in 185 patients (53.4%). LGBM exhibited superior performance, achieving a mean f1_score of 0.65 and standard deviation of 0.12. The predominant indicators for nonadherent prediction of imatinib were cognitive functioning, whether to perform therapeutic drug monitoring (if_TDM), global health status score, social support, and gender. CONCLUSIONS: This study represents the first real-world investigation using ML techniques to predict risk factors associated with imatinib nonadherence in patients with GIST. By highlighting the potential factors and identifying high-risk patients, the multidisciplinary medical team can devise targeted strategies to effectively address the daily challenges of treatment adherence.

Untargeted metabolomics analysis reveals the potential mechanism of imatinib-induced skin rash in patients with gastrointestinal stromal tumor.

Imatinib-induced skin rash poses a significant challenge for patients with gastrointestinal stromal tumor, often resulting in treatment interruption or discontinuation and subsequent treatment failure. However, the underlying mechanism of imatinib-induced skin rashes in gastrointestinal stromal tumor patients remains unclear. A total of 51 patients (27 with rash and 24 without rash) were enrolled in our study. Blood samples were collected concomitantly with the onset of clinical manifestations of rashes, and simultaneously collecting clinical relevant information. The imatinib concentration and untargeted metabolomics were performed by ultra-high-performance liquid chromatography-tandem mass spectrometry. There were no significant differences in age, gender, imatinib concentration and white blood cells count between the rash group and the control group. However, the rash group exhibited a higher eosinophil count (P<0.05) and lower lymphocyte count (P<0.05) compared to the control group. Untargeted metabolomics analysis found that 105 metabolites were significantly differentially abundant. The univariate analysis highlighted erucamide, linoleoylcarnitine, and valine betaine as potential predictive markers (AUC≥0.80). Further enriched pathway analysis revealed primary metabolic pathways, including sphingolipid signaling pathway, sphingolipid metabolism, cysteine and methionine metabolism, biosynthesis of unsaturated fatty acids, arginine and proline metabolism, and biosynthesis of amino acids. These findings suggest that the selected differential metabolites could serve as a foundation for the prediction and management of imatinib-induced skin rash in gastrointestinal stromal tumor patients.

Deciphering chemoresistance in osteosarcoma: Unveiling regulatory mechanisms and function through the lens of noncoding RNA.

Osteosarcoma (OS) is a primary malignant bone tumor and is prevalent in children, adolescents, and elderly individuals. It has the characteristics of high invasion and metastasis. Neoadjuvant chemotherapy combined with surgical resection is the most commonly used treatment for OS. However, the efficacy of OS is considerably diminished by chemotherapy resistance. In recent years, noncoding RNAs (ncRNAs), including microRNAs, long noncoding RNAs, and circular RNAs, are hot topics in the field of chemotherapy resistance research. Several studies have demonstrated that ncRNAs are substantially associated with chemoresistance in OS. Thus, the present study overviews the abnormally expressed ncRNAs in OS and the molecular mechanisms involved in chemoresistance, with an emphasis on their function in promoting or inhibiting chemoresistance. ncRNAs are expected to become potential therapeutic targets for overcoming drug resistance and predictive biomarkers in OS, which are of great significance for enhancing the therapeutic effect and improving the prognosis.

Effects of WuZhi preparations on tacrolimus in pediatric and adult patients carrying the CYP3A5*1 allele of heart transplant during the early period after transplantation.

AIM: Wuzhi preparations (WZP) are commonly administrated with tacrolimus (TAC) in China to improve the liver function and increase the exposure of TAC. This study aims to investigate the effects of WZP on TAC in pediatric heart transplantation (HTx) patients carrying the CYP3A5*1 allele during the early period after transplantation and also make a comparison with these effects in adult recipients. METHODS: A total of 81 recipients with CYP3A5*1 allele were included and divided into the pediatric group (n = 29) and adult group (n = 52). The changes in TAC dose-corrected trough blood concentrations (C0 /D), dose requirement as well as intra-patient variability(IPV) of C0 /D after co-therapy with WZP were evaluated. RESULTS: The TAC C0 /D was significantly increased 1.7 and 1.8 times after co-administration of WZP in the pediatric and adult groups, respectively. We further analyzed the pediatric patients, found that no statistical difference was observed in TAC C0 /D before and after co-therapy with WZP in children <6 years old. The changes of C0 /D increased with the dose of the active ingredient (Schisantherin A) in adult patients, but not in pediatric patients. TAC IPV was reduced by 10.5% in pediatric patients and 4.8% in adult patients when co-administrated with WZP. Furthermore, after taking WZP, the AST and TB were dramatically lowered in pediatric recipients. CONCLUSION: Our study is the first attempt to demonstrate the effects of WZP on TAC in pediatric HTx recipients. By comparing these effects to those observed in adult recipients, valuable insights can be gained regarding the efficacy and potential benefits of WZP in the pediatric population.

Development of a simultaneous quantification method of imatinib and sunitinib and their main metabolites and its application in patients with gastrointestinal stromal tumor.

Correlations between plasma concentrations of imatinib and sunitinib with efficacy and toxicity have been established. It is crucial to develop a sensitive and precise method for determining the plasma concentrations of imatinib and sunitinib, along with their active metabolites, to facilitate therapeutic drug monitoring and individualized therapy. Plasma samples were separated on an Agilent ZORBAX SB-C18 chromatographic column using gradient elution. Quantification was performed using a mass spectrometer equipped with electrospray ionization in multiple reaction monitoring. The analysis time was 18 min per run, with all analytes and internal standards eluting within 8 min. The calibration range was 25-4000 ng/mL for imatinib, 5-800 ng/mL for N-desmethyl imatinib (CGP74588), and 2.5-400 ng/mL for sunitinib and N-desethyl sunitinib (SU12662). Intra- and inter-assay precision were both below 15%, and accuracy ranged between 90.0% and 101.9%. The method was successfully applied to determine blood samples from 120 patients with gastrointestinal stromal tumors who received imatinib (n = 115) and sunitinib (n = 5). It has been validated as linear, accurate, precise, and robust, making it suitable for therapeutic drug monitoring of imatinib and sunitinib in routine clinical practice.