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A pragmatic adaptation of the RANO clinical risk score for IDH-Wildtype glioblastoma in the absence of MGMT promoter methylation testing.

BACKGROUND: The novel RANO risk score provides prognostic stratification for patients with IDH-wildtype glioblastoma(GBM) and includes age, Karnofsky Performance Scale(KPS), RANO resection class(RRC), and MGMT promoter methylation(MGMTm). However, MGMTm testing is unavailable in many countries. We aimed to explore the prognostic performance of a RANO-adapted clinical score excluding MGMTm. METHODS: We applied the same scoring system established by original RANO score, excluding MGMTm. Three risk classes were defined as numerical scores derived through tertiles. The primary endpoint was overall survival(OS), and the secondary exploratory endpoint was progression-free survival(PFS). RESULTS: One-hundred twenty patients were included. Three risk classes were identified:low-risk(0-1 points,n:47, 39.2%), intermediate-risk(2-3 points,n:27, 22.5%), and high-risk(&#x2265;4 points,n:46, 38.3%). The median OS was 35.5&#x2009;months(95% CI:21.1-49.9) for the low-risk group, 16&#x2009;months(95% CI:9.9-22.1) for the intermediate-risk group, and 5&#x2009;months(95% CI:3.6-6.3) for the high-risk group(p&#x2009;<&#x2009;0.001). Similarly, the median PFS was 16.3&#x2009;months(95% CI:12.3-20.3) for the low-risk group, 9.9&#x2009;months(95% CI:7.2-12.6) for the intermediate-risk group, and 4.1&#x2009;months(95% CI:3.5-4.7) for the high-risk group(p&#x2009;<&#x2009;0.001). CONCLUSION: This simplified RANO-adapted score demonstrated promising prognostic stratification using basic clinical parameters. As a pragmatic adaptation study, external validation is required before clinical application, particularly in settings where MGMTm testing is unavailable.

Humans

A Phase I and Biodistribution Study of Ifabotuzumab, a Humanized Agonistic EphA3-Targeted Antibody, in Patients with Recurrent Glioblastoma.

PURPOSE: To conduct a phase I and biodistribution study of the EphA3 antibody ifabotuzumab and zirconium-89-labeled ifabotuzumab (89Zr-ifabotuzumab) in patients with glioblastoma (GBM). PATIENTS AND METHODS: This multisite study was conducted in adults with recurrent GBM whose tumors were measurable according to Response Assessment in Neuro-Oncology (RANO) criteria and whose Eastern Cooperative Oncology Group performance status was 0 to 1. Patients underwent a biodistribution study with PET scans with 89Zr-ifabotuzumab, followed by three infusions of ifabotuzumab at either 3.5 or 5.25 mg/kg before undergoing a second study with 89Zr-ifabotuzumab PET scans. Resected patient diagnostic tumor samples were collected for multiplex immunofluorescence and spatial transcriptomics analyses. RESULTS: Twelve patients were recruited, of which six were treated with 3.5 mg/kg and six with 5.25 mg/kg of ifabotuzumab. 89Zr-ifabotuzumab and associated PET scanning were well tolerated, as was ifabotuzumab. There were no objective responses, but one patient had prolonged stable disease. In addition, two patients showed changes in peritumor edema that were suggestive of modulation of tumor vasculature. 89Zr-ifabotuzumab scans showed highly specific tumor uptake in all patients concordant with disease sites on MRI and PET imaging, without evidence of nonspecific binding. Spatial transcriptomics and immunofluorescence analyses of the patient's archival tissue specimens showed that EphA3 was expressed in the tumor microenvironment in all patients and tumor cells with different transcriptional states. CONCLUSIONS: Targeting EphA3 with ifabotuzumab in patients with GBM is safe and attractive, showing chronologic stable expression across both tumor compartments (particularly in cells with a mesenchymal phenotype) and nontumor compartments (particularly the vascular compartment) with evidence of target modulation.

Humans