Ahmad Abuaisheh

Introduction: Biogenic amines play important roles throughout cellular metabolism. This study explores a role of biogenic amines in glioblastoma pathogenesis. Here, we characterize the plasma levels of biogenic amines in glioblastoma patients undergoing standard-of-care treatment. Methods: We examined 138 plasma samples from 36 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma at multiple stages of treatment. Untargeted gas chromatography–time of flight mass spectrometry (GC-TOF MS) was used to measure metabolite levels. Machine learning approaches were then used to develop a predictive tool based on these datasets. Results: Surgery was associated with increased levels of 12 metabolites and decreased levels of 11 metabolites. Chemoradiation was associated with increased levels of three metabolites and decreased levels of three other metabolites. Ensemble learning models, specifically random forest (RF) and AdaBoost (AB), accurately classified treatment phases with high accuracy (RF: 0.81 ± 0.04, AB: 0.78 ± 0.05). The metabolites sorbitol and N-methylisoleucine were identified as important predictive features and confirmed via SHAP. Conclusion: To our knowledge, this is the first study to describe plasma biogenic amine signatures throughout the treatment of patients with glioblastoma. A larger study is needed to confirm these results with hopes of developing a diagnostic algorithm.

Introduction: This study aims to characterize changes in biogenic amines patterns in glioblasto-ma patients undergoing surgery and concurrent chemoradiation to illustrate how this class of metabolites changes during different stages of standard care treatment protocol. Methods: We examined 138 plasma specimens (before surgery, 2 days after surgical resection, before starting concurrent chemoradiation, immediately after chemoradiation, and after adju-vant chemotherapy treatment) from 36 patients with isocitrate dehydrogenase (IDH) wildtype glioblastoma. Untargeted GC-TOF mass spectrometry-based metabolomics of biogenic amines was used given its superiority for identifying and quantitating small metabolites; this yielded 340 structurally identified metabolites. Results: Comparing post-surgery to pre-surgery showed increased level of 12 metabolites: Gly-codeoxycholic acid (P=7.79E-05), Betonicine (P=9.23E-05), Glycocholic acid (P=3.18E-03), 3-Cysteinylaectaminophen (P=4.95E-03), S-Methyl-3-thioacetaminophen (P=5.77E-03), Tau-rocholic acid (P=9.97E-03), N-glycine (P=0.0013), p-acetamidophenyl.beta.-D-glucuronide (P=0.0048), 2-Hydroxy-5-sulfopyridine-3-carboxylic acid (P=0.0074), Acetaminophen sulfate (P=0.0095), 2-Amino-3-methoxybenzoic acid (P=0.02), and Dehydrofelodipine (P=0.024). There were 11 compounds that were downregulated, which included Mannitol (P=1.96E-19), Sorbitol (P=2.75E-019), Linoleic acid (P=1.51E-10), 1-Methylnicotinamide (P=1.78E-09), Nudifloramide (P=2.81E-08), Hexadecanedioic acid (P=5.49E-05), 3-Hydroxybutyric acid (P=0.0002), Riluzole (0.0036), Bupivacaine (P=0.0041), Lactitol (P=0.008), and 1-hydroxymidazolam.beta.-D-glucuronide (P=0.0414). After chemoradiation, significant de-crease was uncovered in Famotidine (P=0.0074), N-Isovalerylglycine (P=0.012), and 3-Methylcrotonylglycine (P=0.0131). While significant increase was detected in N-Methylisoleucine (P=0.0011), 4-Methyl-5-thiazoleethanol (P=0.042), and 6-Hydroxycaproic acid (P=0.049). Ensemble learning models, specifically random forest (RF) and AdaBoost (AB), accurately classified treatment phases with high accuracy (RF: 0.81 ± 0.04, AB: 0.78 ± 0.05). One significant insight gleamed from these models were that the metabolites Sorbitol and N-methylisoleucine were identified as important predictive features and confirmed by SHAP analysis. Conclusion: To our knowledge, this is the first study to describe plasma biogenic amines signa-tures during different treatment phases in patients with glioblastoma. A larger study is needed to confirm the results and the potential application of this algorithm for classification of treatment responses.