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Glioblastoma IDH-wildtype presents with a wide histological spectrum. Some features are so distinctive that they are considered as separate histological variants or patterns for the purpose of classification. However, these usually lack defined (epi-)genetic alterations or profiles correlating with this histology. Here, we describe a molecular subtype with overlap to the unique histological pattern of glioblastoma with primitive neuronal component. Our cohort consists of 63 IDH-wildtype glioblastomas that harbor a characteristic DNA methylation profile. Median age at diagnosis was 59.5 years. Copy-number variations and genetic sequencing revealed frequent alterations in TP53, RB1 and PTEN, with fewer gains of chromosome 7 and homozygous CDKN2A/B deletions than usually described for IDH-wildtype glioblastoma. Gains of chromosome 1 were detected in more than half of the cases. A poorly differentiated phenotype with frequent absence of GFAP expression, high proliferation index and strong staining for p53 and TTF1 often caused misleading histological classification as carcinoma metastasis or primitive neuroectodermal tumor. Clinically, many patients presented with leptomeningeal dissemination and spinal metastasis. Outcome was poor with a median overall survival of only 12 months. Overall, we describe a new molecular subtype of IDH-wildtype glioblastoma with a distinct histological appearance and genetic signature.

Simple Summary: Diffuse midline glioma is a rare distinct brain tumor entity introduced by the recent WHO (Lyon, France) brain tumor classification. MR imaging is important for detection as well as characterization of these midline tumors, which are located within the brainstem, since neurosurgical tissue sampling in these locations can be challenging. We therefore searched for possible differences in the MRI pattern between diffuse midline gliomas and midline glioblastomas, both regarded as grade IV entities. We conducted a two-center retrospective survey on standard MRI features including apparent diffusion coefficient mapping (ADC) of diffuse midline gliomas H3 K27M-mutant (DMG) compared to midline glioblastomas H3 K27M-wildtype (midGBM-H3wt). We identified 39 intracranial DMG and 18 midGBM-H3wt tumors. Samples were microscopically re-evaluated for microvascular proliferations and necrosis. Image analysis focused on location, peritumoral edema, degree of contrast enhancement and DWI features. Within DMG, MRI features between tumors with or without histomorphological GBM features were compared. DMG occurred in 15/39 samples from the thalamus (38%), in 23/39 samples from the brainstem (59%) and in 1/39 tumors involving primarily the cerebellum (2%). Edema was present in 3/39 DMG cases (8%) versus 78% in the control (midGBM-H3wt) group (p < 0.001). Contrast enhancement at the tumor rim was detected in 17/39 DMG (44%) versus 67% in control (p = 0.155), and necrosis in 24/39 (62%) versus 89% in control (p = 0.060). Strong contrast enhancement was observed in 15/39 DMG (38%) versus 56% in control (p = 0.262). Apparent diffusion coefficient (ADC) histogram analysis showed significantly higher skewness and kurtosis values in the DMG group compared to the controls (p = 0.0016/p = 0.002). Minimum relative ADC (rADC) values, as well as the 10th and 25th rADC-percentiles, were lower in DMGs with GBM features within the DMG group (p < 0.001/p = 0.012/p = 0.027). In conclusion, DMG cases exhibited markedly less edema than midGBM-H3wt, even if histomorphological malignancy was present. Histologically malignant DMGs and midGBM-H3wt more often displayed strong enhancement, as well as rim enhancement, than DMGs without histomorphological malignancy. DMGs showed higher skewness and kurtosis values on ADC-histogram analysis compared to midGBM-H3wt. Lower minimum rADC values in DMGs indicated malignant histomorphological features, likely representing a more complex tissue microstructure. [ABSTRACT FROM AUTHOR]

Aims: Brain invasion (BI) was firstly defined as a single criterion of atypia in otherwise benign meningiomas in the revised fourth edition of 2016 WHO classification of brain tumours after being previously inconsistently addressed. However, recent studies have raised doubts about the prognostic significance of BI in otherwise benign meningiomas. In our study, we investigate the reproducibility of such a prognostic effect. Methods: We identified two cohorts one consisting of 483 patients with meningioma WHO grade I (M°I) or atypical meningioma WHO grade II (M°II) from Hannover Medical School and the other including atypical meningiomas defined according to the classical WHO criteria (M°IIb) from the University Hospital Heidelberg. Follow‐up data with a median observation time of 38.2 months were available from 308 cases. These included 243 M°I and 65 M°II patients with the latter group consisting of 25 patients with otherwise benign meningiomas with BI (M°IIa) and 40 with M°IIb. Results: A significant difference of progression‐free interval (PFI) was found between patients with M°I and M°II, M°I and M°IIa and those with M°I and M°IIb of both cohorts and each separately. However, PFI of M°IIa and M°IIb patients showed no significant difference. In the multivariate regression analysis adjusted for M°I/M°IIa versus M°IIb, sex, age, extent of resection and tumour location, BI exhibited the strongest risk of relapse (Hazard ratio: 4.95) serving as an independent predictor of PFI (p = 0.002). Conclusions: Our results clearly support the definition of BI as a single criterion of atypia in WHO classification of 2016. [ABSTRACT FROM AUTHOR]

Purpose: The entity 'diffuse midline glioma, H3 K27M-mutant (DMG)' was introduced in the revised 4th edition of the 2016 WHO classification of brain tumors. However, there are only a few reports on magnetic resonance imaging (MRI) of these tumors. Thus, we conducted a retrospective survey focused on MRI features of DMG compared to midline glioblastomas H3 K27M-wildtype (mGBM-H3wt). Methods: We identified 24 DMG cases and 19 mGBM-H3wt patients as controls. After being retrospectively evaluated for microscopic evidence of microvascular proliferations (MVP) and tumor necrosis by two experienced neuropathologists to identify the defining histological criteria of mGBM-H3wt, the samples were further analyzed by two experienced readers regarding imaging features such as shape, peritumoral edema and contrast enhancement. Results: The DMG were found in the thalamus in 37.5% of cases (controls 63%), in the brainstem in 50% (vs. 32%) and spinal cord in 12.5% (vs. 5%). In MRI and considering MVP, DMG were found to be by far less likely to develop peritumoral edema (OR: 0.13; 95%-CL: 0.02–0.62) (p = 0.010). They, similarly, were associated with a significantly lower probability of developing strong contrast enhancement compared to mGBM-H3wt (OR: 0.10; 95%-CL: 0.02–0.47) (P = 0.003). Conclusion: Despite having highly variable imaging features, DMG exhibited markedly less edema and lower contrast enhancement in MRI compared to mGBM-H3wt. Of these features, the enhancement level was associated with evidence of MVP. [ABSTRACT FROM AUTHOR]

Purpose: To propose a novel recursive partitioning analysis (RPA) classification model in patients with IDH-wildtype glioblastomas that incorporates the recently expanded conception of the extent of resection (EOR) in terms of both supramaximal and total resections., Experimental Design: This multicenter cohort study included a developmental cohort of 622 patients with IDH-wildtype glioblastomas from a single institution (Severance Hospital) and validation cohorts of 536 patients from three institutions (Seoul National University Hospital, Asan Medical Center, and Heidelberg University Hospital). All patients completed standard treatment including concurrent chemoradiotherapy and underwent testing to determine their IDH mutation and MGMTp methylation status. EORs were categorized into either supramaximal, total, or non-total resections. A novel RPA model was then developed and compared to a previous RTOG RPA model., Results: In the developmental cohort, the RPA model included age, MGMTp methylation status, KPS, and EOR. Younger patients with MGMTp methylation and supramaximal resections showed a more favorable prognosis (class I: median overall survival [OS] 57.3 months), while low-performing patients with non-total resections and without MGMTp methylation showed the worst prognosis (class IV: median OS 14.3 months). The prognostic significance of the RPA was subsequently confirmed in the validation cohorts, which revealed a greater separation between prognostic classes for all cohorts compared to the previous RTOG RPA model., Conclusions: The proposed RPA model highlights the impact of supramaximal versus total resections and incorporates clinical and molecular factors into survival stratification. The RPA model may improve the accuracy of assessing prognostic groups.

Purpose: Interactions with tumor-associated microglia and macrophages (TAM) are critical for glioblastoma progression. Polysialic acid (polySia) is a tumor-associated glycan, but its frequency of occurrence and its prognostic value in glioblastoma are disputed. Through interactions with the opposing immune receptors Siglec-11 and Siglec-16, polySia is implicated in the regulation of microglia and macrophage activity. However, due to a nonfunctional SIGLEC16P allele, SIGLEC16 penetrance is less than 40%. Here, we explored possible consequences of SIGLEC16 status and tumor cell-associated polySia on glioblastoma outcome., Experimental Design: Formalin-fixed paraffin-embedded specimens of two independent cohorts with 70 and 100 patients with newly diagnosed glioblastoma were retrospectively analyzed for SIGLEC16 and polySia status in relation to overall survival. Inflammatory TAM activation was assessed in tumors, in heterotypic tumor spheroids consisting of polySia-positive glioblastoma cells and Siglec-16-positive or Siglec-16-negative macrophages, and by exposing Siglec-16-positive or Siglec-16-negative macrophages to glioblastoma cell-derived membrane fractions., Results: Overall survival of SIGLEC16 carriers with polySia-positive tumors was increased. Consistent with proinflammatory Siglec-16 signaling, levels of TAM positive for the M2 marker CD163 were reduced, whereas the M1 marker CD74 and TNF expression were increased, and CD8+ T cells enhanced in SIGLEC16/polySia double-positive tumors. Correspondingly, TNF production was elevated in heterotypic spheroid cultures with Siglec-16-expressing macrophages. Furthermore, a higher, mainly M1-like cytokine release and activating immune signaling was observed in SIGLEC16-positive as compared with SIGLEC16-negative macrophages confronted with glioblastoma cell-derived membranes., Conclusions: Collectively, these results strongly suggest that proinflammatory TAM activation causes the better outcome in patients with glioblastoma with a functional polySia-Siglec-16 axis., (©2023 American Association for Cancer Research.)