Terminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system was previously proposed based upon residual contrast-enhancing (CE) tumor. We aimed to (1) explore the prognostic utility of the classification system and (2) define how much removed non-CE tumor translates into a survival benefit. The international RANO resect group retrospectively searched previously compiled databases from 7 neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma per WHO 2021 classification. Clinical and volumetric information from pre- and postoperative MRI were collected. We collected 1,008 patients with newly diagnosed IDHwt glioblastoma. 744 IDHwt glioblastomas were treated with radiochemotherapy per EORTC-26981/22981 (TMZ/RT→TMZ) following surgery. Among these homogenously treated patients, lower absolute residual tumor volumes (in cm³) were favorably associated with outcome: patients with “maximal CE resection” (class 2) had superior outcome compared to patients with “submaximal CE resection” (class 3) or “biopsy” (class 4). Extensive resection of non-CE tumor (≤5 cm³ residual non-CE tumor) was associated with better survival among patients with complete CE resection, thus defining class 1 (“supramaximal CE resection”). The prognostic value of the resection classes was retained on multivariate analysis when adjusting for molecular and clinical markers. The proposed “RANO categories for extent of resection in glioblastoma” are highly prognostic and may serve for stratification within clinical trials. Removal of non-CE tumor beyond the CE tumor borders may translate into additional survival benefit, providing a rationale to explicitly denominate such “supramaximal CE resection.”

The value of re-resection in recurrent glioblastoma remains controversial as a randomized trial that specifies intentional incomplete resection cannot be justified ethically. Here, we aimed to (1) explore the prognostic role of extent of re-resection using the previously proposed Response Assessment in Neuro-Oncology (RANO) classification (based upon residual contrast-enhancing (CE) and non-CE tumor), and to (2) define factors consolidating the surgical effects on outcome. The RANO resect group retrospectively compiled an 8-center cohort of patients with first recurrence from previously resected glioblastomas. The associations of re-resection and other clinical factors with outcome were analyzed. Propensity score-matched analyses were constructed to minimize confounding effects when comparing the different RANO classes. We studied 681 patients with first recurrence of Isocitrate Dehydrogenase (IDH) wild-type glioblastomas, including 310 patients who underwent re-resection. Re-resection was associated with prolonged survival even when stratifying for molecular and clinical confounders on multivariate analysis; ≤1 cm³ residual CE tumor was associated with longer survival than non-surgical management. Accordingly, “maximal resection” (class 2) had superior survival compared to “submaximal resection” (class 3). Administration of (radio-)chemotherapy in the absence of postoperative deficits augmented the survival associations of smaller residual CE tumors. Conversely, “supramaximal resection” of non-CE tumor (class 1) was not associated with prolonged survival but was frequently accompanied by postoperative deficits. The prognostic role of residual CE tumor was confirmed in propensity score analyses. The RANO resect classification serves to stratify patients with re-resection of glioblastoma. Complete resection according to RANO resect classes 1 and 2 is prognostic.

The gut microbiome is fundamental in neurogenesis processes. Alterations in microbial constituents promote inflammation and immunosuppression. Recently, in immune-oncology, specific microbial taxa have been described to enhance the effects of therapeutic modalities. However, the effects of microbial dysbiosis on glioma are still unknown. The aim of this study was to explore the effects of glioma development and Temozolomide (TMZ) on fecal microbiome in mice and humans. C57BL/6 mice were implanted with GL261/Sham and given TMZ/Saline. Fecal samples were collected longitudinally and analyzed by 16S rRNA sequencing. Fecal samples were collected from healthy controls as well as glioma patients at diagnosis, before and after chemoradiation. Compared to healthy controls, mice and glioma patients demonstrated significant differences in beta diversity, Firmicutes/Bacteroides (F/B) ratio, and increase of Verrucomicrobia phylum and Akkermansia genus. These changes were not observed following TMZ in mice. TMZ treatment in the non-tumor bearing mouse-model diminished the F/B ratio, increase Muribaculaceae family and decrease Ruminococcaceae family. Nevertheless, there were no changes in Verrucomicrobia/Akkermansia. Glioma development leads to gut dysbiosis in a mouse-model, which was not observed in the setting of TMZ. These findings seem translational to humans and warrant further study.

A reliable pipeline to identify DNA methylation signatures in CSF ctDNA could serve as potential biomarkers for MB patients.