Proteomic analysis predicts anti-angiogenic resistance in recurred glioblastoma.

BACKGROUND: Recurrence is common in glioblastoma multiforme (GBM) because of the infiltrative, residual cells in the tumor margin. Standard therapy for GBM consists of surgical resection followed by chemotherapy and radiotherapy, but the median survival of GBM patients remains poor (~ 1.5 years). For recurrent GBM, anti-angiogenic treatment is one of the common treatment approaches. However, current anti-angiogenic treatment modalities are not satisfactory because of the resistance to anti-angiogenic agents in some patients. Therefore, we sought to identify novel prognostic biomarkers that can predict the therapeutic response to anti-angiogenic agents in patients with recurrent glioblastoma. METHODS: We selected patients with recurrent GBM who were treated with anti-angiogenic agents and classified them into responders and non-responders to anti-angiogenic therapy. Then, we performed proteomic analysis using liquid-chromatography mass spectrometry (LC-MS) with formalin-fixed paraffin-embedded (FFPE) tissues obtained from surgical specimens. We conducted a gene-ontology (GO) analysis based on protein abundance in the responder and non-responder groups. Based on the LC-MS and GO analysis results, we identified potential predictive biomarkers for anti-angiogenic therapy and validated them in recurrent glioblastoma patients. RESULTS: In the mass spectrometry-based approach, 4957 unique proteins were quantified with high confidence across clinical parameters. Unsupervised clustering analysis highlighted distinct proteomic patterns (n = 269 proteins) between responders and non-responders. The GO term enrichment analysis revealed a cluster of genes related to immune cell-related pathways (e.g., TMEM173, FADD, CD99) in the responder group, whereas the non-responder group had a high expression of genes related to nuclear replisome (POLD) and damaged DNA binding (ERCC2). Immunohistochemistry of these biomarkers showed that the expression levels of TMEM173 and FADD were significantly associated with the overall survival and progression-free survival of patients with recurrent GBM. CONCLUSIONS: The candidate biomarkers identified in our protein analysis may be useful for predicting the clinical response to anti-angiogenic agents in patients with recurred GBM.

Is brain imaging necessary for febrile elderly patients with altered mental status? A retrospective multicenter study.

OBJECTIVE: Altered mental status (AMS) is one of the most common symptoms in the febrile elderly. Brain imaging tests are an important tool for diagnosing AMS patients. However, these may be prescribed unnecessarily in emergency departments, particularly for febrile patients with AMS for whom infection is suspected, leading to excessive radiation risk and cost. In this study, we investigated the factors that can predict clinically significant abnormal brain imaging (ABI) in the febrile elderly with AMS. METHODS: This retrospective multicenter study was conducted from July 2016 to June 2019. Febrile patients over the age of 65 years with AMS who visited the emergency department of two tertiary university hospitals were enrolled. Medical records were reviewed, and laboratory results were obtained. Brain imaging results with a formal reading by a radiologist were obtained. RESULTS: In all, 285 patients were enrolled, and 47 (16.49%) showed ABI. The most common diagnoses in patients admitted to the emergency department were intracranial hemorrhage and ischemic stroke for ABI, and pneumonia and urinary tract infection for non-ABI. In multivariate logistic regression analyses, higher systolic blood pressure (odds ratio [OR], 1.017; 95% confidence interval [CI], 1.006-1.028), lower body temperature (OR, 0.578; 95% CI, 0.375-0.892), the presence of lateralizing sign (OR, 45.676; 95% CI, 5.015-416.025), and lower Glasgow Coma Scale (OR, 0.718; 95% CI, 0.617-0.837) were significantly associated with ABI. CONCLUSION: Lower Glasgow Coma Scale, the presence of lateralizing sign, higher systolic blood pressure, and lower body temperature are significantly associated with ABI in febrile elderly patients with AMS.