RESUMO
Although immune checkpoint inhibitors (ICIs) are increasingly used as second-line treatments for urothelial cancer (UC), only a small proportion of patients respond. Therefore, understanding the mechanisms of response to ICIs is critical to improve clinical outcomes for UC patients. The tumor microenvironment (TME) is recognized as a key player in tumor progression and the response to certain anti-cancer treatments. This study aims to investigate the mechanism of response using integrated genomic and transcriptomic profiling of a UC patient who was part of the KEYNOTE-045 trial and showed an exceptional response to pembrolizumab. Diagnosed in 2014 and receiving first-line chemotherapy without success, the patient took part in the KEYNOTE-045 trial for 2 years. She showed dramatic improvement and has now been free of disease for over 6 years. Recently described by Bagaev et al., the Molecular Functional (MF) Portrait was utilized to dissect genomic and transcriptomic features of the patient's tumor and TME. The patient's tumor was characterized as Immune Desert, which is suggestive of a non-inflamed microenvironment. Integrated whole-exome sequencing (WES) and RNA sequencing (RNA-seq) analysis identified an ATM mutation and high TMB level (33.9 mut/mb), which are both positive biomarkers for ICI response. Analysis further revealed the presence of the APOBEC complex, indicating the potential for use of APOBEC signatures as predictive biomarkers for immunotherapy response. Overall, comprehensive characterization of the patient's tumor and TME with the MF Portrait revealed important insights that could potentially be hypothesis generating to identify clinically useful biomarkers and improve treatment for UC patients.
RESUMO
Objective: This study is to analyze fluorescence sensitivity in the diagnosis of brain and spinal cord tumors. Material and methods: The authors conducted a multicenter retrospective analysis of data on 653 cases in 641 patients: 553 of them had brain tumors and 88 spinal cord tumors. Brain tumor resection was performed in 523 patients, of whom 484 were adults and 39 children. The analyzed series was presented by 320 gliomas, 101 meningiomas, and 72 metastases. A stereotactic biopsy was performed in 20 patients and endoscopic surgery in 10 patients. In all cases, 20 mg/kg of 5-Aminolaevulinic acid was administered orally 2-h before surgery. All surgical interventions were performed with a microscope BLUE 400 to visualize fluorescence, while endoscopic surgery-with an endoscope equipped with a fluorescent module. Fluorescence spectroscopy was conducted in 20 cases of stereotactic biopsies and in 88 cases of spinal cord tumors. Results: Among adult brain tumors operated by microsurgical techniques, meningiomas showed the highest 5-ALA fluorescence sensitivity 94% (n = 95/101), brain metastases 84.7% (n = 61/72), low-grade gliomas 46.4% (n = 26/56), and high-grade gliomas 90.2% (n = 238/264). In children the highest 5-ALA visible fluorescence was observed in anaplastic astrocytomas 100% (n = 4/4) and in anaplastic ependymomas 100% (n = 4/4); in low-grade gliomas it made up 31.8% (n = 7/22). As for the spinal cord tumors in adults, the highest sensitivity was demonstrated by glioblastomas 100% (n = 4/4) and by meningiomas 100% (n = 4/4); Fluorescence was not found in gemangioblastomas (n = 0/6) and neurinomas (n = 0/4). Fluorescence intensity reached 60% (n = 6/10) in endoscopic surgery and 90% (n = 18/20) in stereotactic biopsy. Conclusion: 5-ALA fluorescence diagnosis proved to be most sensitive in surgery of HGG and meningioma (90.2 and 94.1%, respectively). Sensitivity in surgery of intracranial metastases and spinal cord tumors was slightly lower (84.7 and 63.6%, correspondingly). The lowest fluorescence sensitivity was marked in pediatric tumors and LGG (50 and 46.4%, correspondingly). Fluorescence diagnosis can also be used in transnasal endoscopic surgery of skull base tumors and in stereotactic biopsy.
