Radiation therapy (RT) is used in the management of several cancers; however, tumor radioresistance remains a challenge. Polymorphonuclear neutrophils (PMNs) are recruited to the tumor immune microenvironment (TIME) post-RT and can facilitate tumor progression by forming neutrophil extracellular traps (NETs). Here, we demonstrate a role for NETs as players in tumor radioresistance. Using a syngeneic bladder cancer model, increased NET deposition is observed in the TIME of mice treated with RT and inhibition of NETs improves overall radiation response. In vitro, the protein HMGB1 promotes NET formation through a TLR4-dependent manner and in vivo, inhibition of both HMGB1 and NETs significantly delays tumor growth. Finally, NETs are observed in bladder tumors of patients who did not respond to RT and had persistent disease post-RT, wherein a high tumoral PMN-to-CD8 ratio is associated with worse overall survival. Together, these findings identify NETs as a potential therapeutic target to increase radiation efficacy.
Background: The Vesical Imaging-Reporting and Data System (VI-RADS) score is a novel standardized approach to image and report bladder cancer (BC) with multiparametric MRI (mpMRI). Objectives: To describe and evaluate the performance of the VI-RADS score using mpMRI and assess its potential clinical applications and limitations. Methods: A systematic review was conducted using the MEDLINE and EMBASE electronic bibliographic databases between June 2020 and December 2020. All reports deemed relevant to describe the VI-RADS score and assess its performance and applications were retrieved. Results presentation stands as narrative, purely descriptive synthesis based on aggregate studies data. Results: A total of 20 relevant studies were retrieved: three meta-analyses, five prospective studies, and twelve retrospective studies. The retrospective studies covered 1676 patients, while the prospective studies included a total number of 468 patients. Pooled sensitivity, specificity to differentiate muscle-invasive from non-muscle-invasive bladder cancer, ranged from 74.1% to 97.3%, and 77% to 100%, respectively. The chosen VI-RADS score thresholds for this discrimination varied across studies. The interreader agreement ranged from 0.73 to 0.95. Currently, the potential clinical applications of VI-RADS consist of initial BC risk stratification, assessment of neoadjuvant therapies response, and bladder sparing approaches, although further validation is required. Conclusions: The VI-RADS score helps to discriminate muscle invasive from non-muscle invasive BC with good performance and reproducibility. A simple algorithm based on four basic questions may enhance its popularization. Further studies are required to validate the clinical applications.
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