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Meningiomas present as intracranial extra-axial lesions with dural attachment, which are primarily managed surgically. The extent of resection (EOR) may vary depending on patient- and tumor-related factors. The aim of this study is to identify preoperative predictive factors of EOR and to propose an estimation of the predicted gross total resection (GTR) based of patient- and tumor-characteristics. 1469 patients from a retrospectively (1990 to 2002) and prospectively managed (2003 to 2010) databank of Oslo University Hospital, Norway, totalling 11,414 patient-years of follow-up were included. Patients had a mean age at surgery of 64 ± 20.1 years with a female-to-male ratio was 2.4:1 and a mean KPS of 81.2 ± 12.1. Skull-base meningiomas represented 47% of all cases. WHO grades were I in 92.3%, II in 5.2%, and III in 2.2%. Bone infiltration was described in 18.7% of cases. 39.3% of patients had Simpson I resection, 34.3% had Simpson II, 5.4% had Simpson III, 20.6% had Simpson IV, and 0.5% had Simpson V. The risk factors for incomplete resection were: symptomatic presentation (OR 0.56 [0.43–0.72]), skull-base location (OR 0.79 [0.70–0.88]), and bone invasion (OR 0.85 [0.73–0.99]). Using a recursive partitioning analysis, we propose a classification-tree for the prediction of GTR rate based on preoperatively determinable patient- and tumor characteristics. The identification of preoperative predictors of poor GTR rate may aid clinicians managing meningioma patients. In selected cases were the predicted GTR rate is low, staged treatment with surgical debulking followed by adjuvant therapy may be favored in order to minimize postoperative morbidity and mortality.

Glioblastoma remains one of the deadliest brain malignancies. First-line therapy consists of maximal surgical tumor resection, accompanied by chemotherapy and radiotherapy. Malignant cells escape surgical resection by migrating into the surrounding healthy brain tissue, where they give rise to the recurrent tumor. Based on gene expression, tumor cores can be subtyped into mesenchymal, proneural, and classical tumors, each being associated with differences in genetic alterations and cellular composition. In contrast, the adjacent brain parenchyma where infiltrating malignant cells escape surgical resection is less characterized in patients. Using spatial transcriptomics ( n  = 11), we show that malignant cells within proneural or mesenchymal tumor cores display spatially organized differences in gene expression, although such differences decrease within the infiltrated brain tissue. Malignant cells residing in infiltrated brain tissue have increased expression of genes related to neurodevelopmental pathways and glial cell differentiation. Our findings provide an updated view of the spatial landscape of glioblastomas and further our understanding of the malignant cells that infiltrate the healthy brain, providing new avenues for the targeted therapy of these cells after surgical resection. In glioblastoma, malignant cells can escape surgical resection by migrating into the surrounding healthy brain tissue. Here, the authors use spatial transcriptomics to characterise the tumour core and infiltrated brain regions in glioblastoma, and show shifts in malignant cell composition and molecular pathways with potential clinical implications.

AimsIntraductal papillary mucinous neoplasms (IPMNs) may be precursor lesions of pancreatic cancer. The path towards malignancy is associated with mutations in tumour suppressor—and oncogenes that may serve as biomarkers during diagnostic investigation. A novel micro forceps has made it possible to obtain biopsies from the cyst wall for analysis by next generation sequencing (NGS), providing an opportunity for early detection and intervention. However, the impact of spatial tumour heterogeneity on the representability of the biopsies has not been determined. The primary aim is to characterise the impact of molecular heterogeneity of the luminal cyst wall on tissue sampling strategies with small biopsies.MethodsWe performed NGS and immunohistochemical phenotyping on 18 resected IPMNs with varying degrees of dysplasia and for a subset, concomitant carcinoma, using a commercially available NGS-panel of 51 oncogenes. We simulated endoscopic biopsies by performing punch biopsies (PBs) of the cyst wall from resected specimens.ResultsIn total, 127 NGS analyses were performed. Concomitant KRAS and GNAS was a common feature of the IPMNs. Mutations in KRAS and GNAS were associated with low-grade dysplasia whereas alterations in TP53, SMAD4, CDKN2A and PIK3CA were associated with high-grade dysplasia and/or carcinoma. The mutational analysis of the PBs from the cyst wall was compared with the whole lesion. No difference was detected between PBs and whole lesions when the cumulated mutational profile in increasing order of randomly performed PBs was compared.ConclusionsSmall IPMN biopsies from the cyst wall are adequate to yield a molecular diagnosis.

Background Methylation of the O 6 -methylguanine-DNA methyltransferase ( MGMT ) gene promoter is a favorable prognostic factor in glioblastoma patients. However, reported methylation frequencies vary significantly partly due to lack of consensus in the choice of analytical method. Method We examined 35 low- and 99 high-grade gliomas using quantitative methylation specific PCR (qMSP) and pyrosequencing. Gene expression level of MGMT was analyzed by RT-PCR. Results When examined by qMSP, 26% of low-grade and 37% of high-grade gliomas were found to be methylated, whereas 97% of low-grade and 55% of high-grade gliomas were found methylated by pyrosequencing. The average MGMT gene expression level was significantly lower in the group of patients with a methylated promoter independent of method used for methylation detection. Primary glioblastoma patients with a methylated MGMT promoter (as evaluated by both methylation detection methods) had approximately 5 months longer median survival compared to patients with an unmethylated promoter (log-rank test; pyrosequencing P = .02, qMSP P = .06). One third of the analyzed samples had conflicting methylation results when comparing the data from the qMSP and pyrosequencing. The overall survival analysis shows that these patients have an intermediate prognosis between the groups with concordant MGMT promoter methylation results when comparing the two methods. Conclusion In our opinion, MGMT promoter methylation analysis gives sufficient prognostic information to merit its inclusion in the standard management of patients with high-grade gliomas, and in this study pyrosequencing came across as the better analytical method.

Abstract BACKGROUND: In order to weigh the risks of surgery against the presumed advantages, it is important to have specific knowledge about complication rates. OBJECTIVE: To study the surgical mortality and rate of reoperations for hematomas and infections after intracranial surgery for brain tumors in a large, contemporary, single-institution consecutive series. METHODS: All adult patients from a well-defined population of 2.7 million inhabitants who underwent craniotomies for intracranial tumors at Oslo University Hospital from 2003 to 2008 were included (n = 2630). The patients were identified from our prospectively collected database and their charts studied retrospectively. Follow-up was 100%. RESULTS: The overall surgical mortality, defined as death within 30 days of surgery, was 2.3% (n = 60). The mortality rates for high- and low-grade gliomas, meningiomas, and metastases were 2.9%, 1.0%, 0.9%, and 4.5%, respectively. Age >60 (odds ratio 1.84, P < 0.05) and biopsy compared with resection (odds ratio 4.67, P < 0.01) were significantly positively associated with increased surgical mortality. Hematomas accounted for 35% of the surgical mortality. Postoperative hematomas needing evacuation occurred in 2.1% (n = 54). Age >60 was significantly correlated to increased risk of postoperative hematomas (odds ratio 2.43, P < 0.001). A total of 39 patients (1.5%) were reoperated for postoperative infection. Meningiomas had an increased risk of infections compared with high-grade gliomas (odds ratio 4.61, P < 0.001). CONCLUSION: The surgical mortality within 30 days of surgery was 2.3%, with age >60 and biopsy vs resection being the 2 factors significantly associated with increased mortality. Postoperative hematomas caused about one third of the surgical mortality.

Intertumoral heterogeneity in glioblastoma—driven by both genomic and transcriptomic variation—complicates our understanding of how different tumor cell populations contribute to disease progression. Infiltrating tumor cells, which invade surrounding brain tissue and evade surgical resection, are thought to play a central role in recurrence. To address this, we aimed to characterize the gene expression profiles and cellular states of infiltrative tumor cells in glioblastoma. We performed high-plex spatial transcriptomics using the CosMx Spatial Molecular Imager (NanoString) on tumor tissue from eight glioblastoma patients. Formalin-fixed paraffin-embedded samples were selected to capture both the tumor core and invasive margin. A targeted panel of 1,000 genes enabled spatially resolved gene expression profiling at single-cell resolution, allowing precise identification and localization of malignant and non-malignant cell states. We show that malignant cells can be distinguished from non-malignant populations by using patient-specific clustering. Based on this annotation, we identified several known malignant states—including AC-, OPC-, NPC-, and MES-like cells—as well as a recently characterized glial-progenitor (GPC)-like state. This population co-expressed genes associated with both astrocytic and oligodendrocyte progenitor lineages and was found to be more proliferative than the traditional AC-like state. The GPC-like state was most enriched in the classical glioblastoma subtype and was strongly associated with EGFR amplification or mutation. Spatial analyses investigating malignant differences between tumor and infiltrated tissue showed heterogeneous infiltration patterns across patients. In the most extreme case, the dominant GPC-like population in the tumor core gave way to increased proportions of AC-like cells in infiltrated regions. Our study highlights diverging infiltration patterns across glioblastoma tumors, with indications of a GPC-like to AC-like transition occurring in classical-subtyped tumors. This shift is associated with a decrease in cell proliferation and may have implications for clinical treatment.

Brain invasion of meningioma is a controversial clinicopathological grading criterion that correlates with prognosis and is a stand-alone criterion for WHO grade 2 meningioma. Molecular correlates of meningioma cells and immune cell infiltration at the brain-meningioma border and its possible role in brain invasion are not known. We hypothesized that brain-invasive meningiomas have distinct gene expression profiles in meningioma cell populations and in tumour-associated microglia and macrophages (TAM) populations, most prominently at the brain-meningioma border. We performed spatial transcriptomics using NanoString GeoMx Digital Spatial Profiling to investigate the gene expression profiles of meningioma cell-enriched populations (Iba1-/CD68-) and TAM-enriched populations (Iba1+/CD68+) across 16 tumours. Regions of interest included core regions of meningiomas, the brain-meningioma border, and brain regions with confirmed invasion. Using an 1800 gene panel, we analysed differential gene expression across regions within each tumour and compared brain-invasive and non-invasive meningiomas. Meningioma cell-enriched populations from brain-invasive meningiomas ( n  = 8) showed significant upregulation of KRT18 , implicated in filament reorganization, as well as genes involved in the cell cycle, glycolysis, and the growth factor receptor PDGFRB compared to non-invasive meningiomas ( n  = 8). Meningioma cell-enriched populations from the brain-meningioma border showed significant upregulation of KRT18 , NDUFA4L2 , and PKM relative to core areas. In TAM-enriched populations in brain tissue, we found upregulation of the chemokine receptor gene CSF1R relative to TAM-enriched populations in meningioma tissue and increased TAM infiltration in brain-invasive cases. In conclusion, our results demonstrate molecular changes in brain-invasive meningiomas compared to non-invasive meningiomas as well as spatial changes along the core-border axis. The expression pattern of TAMs also changed from meningioma to brain tissue. Additional studies are needed to confirm these findings and further reveal how we can target meningioma brain invasion. Graphical abstract

Immunohistochemical quantification of H3K27me3 was reported to distinguish meningioma patients with an unfavorable prognosis but is not yet established as a prognostic biomarker within WHO grade 3 meningiomas. We studied H3K27me3 loss in a series of biopsies from primary and secondary malignant meningioma to validate its prognostic performance and describe if loss of H3K27me3 occurs during malignant transformation. Two observers quantified H3K27me3 status as “complete loss”, < 50% and > 50% stained cells in 110 tumor samples from a population-based consecutive cohort of 40 WHO grade 3 meningioma patients. We found no difference in overall survival (OS) in patients with > 50% H3K27me3 retention compared to < 50% in the cohort of patients with WHO grade 3 meningioma (Wald test p  = 0.5). H3K27me3 staining showed heterogeneity in full section tumor slides while staining of the Barr body and peri-necrotic cells complicated quantification further. H3K27me3 expression differed without a discernible pattern between biopsies from repeated surgeries of meningioma recurrences. In conclusion, our results were not compatible with a systematic pattern of immunohistochemical H3K27me3 loss being associated with OS or malignant transformation of meningiomas and did not support H3K27me3 loss as a useful immunohistochemical biomarker within grade 3 meningiomas due to staining-specific challenges in quantification.

Glioblastoma (GBM), the most aggressive form of brain cancer, is characterized by a high level of molecular heterogeneity, and infiltration by various immune and stromal cell populations. Important advances have been made in deciphering the microenvironment of GBMs, but its association with existing molecular subtypes and its potential prognostic role remain elusive. We have investigated the abundance of infiltrating immune and stromal cells in silico, from gene expression profiles. Two cohorts, including in‐house normal brain and glioma samples (n = 70) and a large sample set from TCGA (n = 393), were combined into a single exploratory dataset. A third independent cohort (n = 124) was used for validation. Tumors were clustered based on their microenvironment infiltration profiles, and associations with known GBM molecular subtypes and patient outcome were tested a posteriori in a multivariable setting. We identified a subset of GBM samples with significantly higher abundances of most immune and stromal cell populations. This subset showed increased expression of both immune suppressor and immune effector genes compared to other GBMs and was enriched for the mesenchymal molecular subtype. Survival analyses suggested that tumor microenvironment infiltration pattern was an independent prognostic factor for GBM patients. Among all, patients with the mesenchymal subtype with low immune and stromal infiltration had the poorest survival. By combining molecular subtyping with gene expression measures of tumor infiltration, the present work contributes with improving prognostic models in GBM. This work combined molecular subtyping of glioblastomas (GBMs) with gene expression measures of tumor infiltration and identified a subset of GBMs with high abundances of most immune and stromal cell populations. Survival analyses suggested that tumor microenvironment infiltration was an independent prognostic factor for GBM patients. Among all, patients with the mesenchymal subtype and low infiltration had the poorest survival.

Ependymoma is the second most common malignant brain tumor in children. The etiology is largely unknown and germline DNA sequencing studies focusing on childhood ependymoma are limited. We therefore performed germline whole-genome sequencing on a population-based cohort of children diagnosed with ependymoma in Denmark over the past 20 years (n = 43). Single nucleotide and structural germline variants in 457 cancer related genes and 2986 highly evolutionarily constrained genes were assessed in 37 children with normal tissue available for sequencing. Molecular ependymoma classification was performed using DNA methylation profiling for 39 children with available tumor tissue. Pathogenic germline variants in known cancer predisposition genes were detected in 11% (4/37; NF2 , LZTR1 , NF1 & TP53 ). However, DNA methylation profiling resulted in revision of the histopathological ependymoma diagnosis to non-ependymoma tumor types in 8% (3/39). This included the two children with pathogenic germline variants in TP53 and NF1 whose tumors were reclassified to a diffuse midline glioma and a rosette-forming glioneuronal tumor, respectively. Consequently, 50% (2/4) of children with pathogenic germline variants in fact had other tumor types. A meta-analysis combining our findings with pediatric pan-cancer germline sequencing studies showed an overall frequency of pathogenic germline variants of 3.4% (7/207) in children with ependymoma. In summary, less than 4% of childhood ependymoma is explained by genetic predisposition, virtually restricted to pathogenic variants in NF2 and NF1 . For children with other cancer predisposition syndromes, diagnostic reconsideration is recommended for ependymomas without molecular classification. Additionally, LZTR1 is suggested as a novel putative ependymoma predisposition gene.