High-grade meningiomas are associated with neuro-cognitive morbidity and have limited treatments. High-grade meningiomas harbor an immunosuppressive tumor microenvironment (TME) and programmed ...death-ligand 1 (PD-L1) expression may contribute to their aggressive phenotype. Here, we present the results of a single-arm, open-label phase 2 trial (NCT03279692) evaluating the efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 25 evaluable patients with recurrent and progressive grade 2 and 3 meningiomas. The primary endpoint is the proportion of patients alive and progression-free at 6 months (PFS-6). Secondary endpoints include progression-free and overall survival, best intracranial response, and toxicity. Our study has met its primary endpoint and achieved a PFS-6 rate of 0.48 (90% exact CI: 0.31-0.66) and a median PFS of 7.6 months (90% CI: 3.4-12.9 months). Twenty percent of patients have experienced one (or more) grade-3 or higher treatment-related adverse events. These results suggest that pembrolizumab exerts promising efficacy on a subset of these tumors. Further studies are needed to identify the biological facets within the meningioma TME that may drive response to immune-based therapies.
Accurate classification is essential for understanding the pathophysiology of a disease and can inform therapeutic choices. For hematopoietic malignancies, a classification scheme based on the ...phenotypic similarity between tumor cells and normal cells has been successfully used to define tumor subtypes; however, use of normal cell types as a reference by which to classify solid tumors has not been widely emulated, in part due to more limited understanding of epithelial cell differentiation compared with hematopoiesis. To provide a better definition of the subtypes of epithelial cells comprising the breast epithelium, we performed a systematic analysis of a large set of breast epithelial markers in more than 15,000 normal breast cells, which identified 11 differentiation states for normal luminal cells. We then applied information from this analysis to classify human breast tumors based on normal cell types into 4 major subtypes, HR0-HR3, which were differentiated by vitamin D, androgen, and estrogen hormone receptor (HR) expression. Examination of 3,157 human breast tumors revealed that these HR subtypes were distinct from the current classification scheme, which is based on estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Patient outcomes were best when tumors expressed all 3 hormone receptors (subtype HR3) and worst when they expressed none of the receptors (subtype HR0). Together, these data provide an ontological classification scheme associated with patient survival differences and provides actionable insights for treating breast tumors.
Proliferation is a fundamental trait of cancer cells, but its properties and spatial organization in tumours are poorly characterized. Here we use highly multiplexed tissue imaging to perform ...single-cell quantification of cell cycle regulators and then develop robust, multivariate, proliferation metrics. Across diverse cancers, proliferative architecture is organized at two spatial scales: large domains, and smaller niches enriched for specific immune lineages. Some tumour cells express cell cycle regulators in the (canonical) patterns expected of freely growing cells, a phenomenon we refer to as 'cell cycle coherence'. By contrast, the cell cycles of other tumour cell populations are skewed towards specific phases or exhibit non-canonical (incoherent) marker combinations. Coherence varies across space, with changes in oncogene activity and therapeutic intervention, and is associated with aggressive tumour behaviour. Thus, multivariate measures from high-plex tissue images capture clinically significant features of cancer proliferation, a fundamental step in enabling more precise use of anti-cancer therapies.
Telomeres are nucleoprotein complexes located at the termini of eukaryotic chromosomes that prevent exonucleolytic degradation and end-to-end chromosomal fusions. Cancers often have critically ...shortened, dysfunctional telomeres contributing to genomic instability. Telomere shortening has been reported in a wide range of precancerous lesions and invasive carcinomas. However, the role of telomere alterations, including the presence of alternative lengthening of telomeres (ALT), has not been studied in pituitary adenomas. Telomere length and the presence of ALT were assessed directly at the single cell level using a telomere-specific fluorescence in situ hybridization assay in tissue microarrays. Tumors were characterized as either ALT-positive or having short, normal, or long telomere lengths and then these categories were compared with clinicopathological characteristics. ATRX and DAXX expression was studied through immunohistochemistry. We characterized a discovery set of 106 pituitary adenomas including both functional and nonfunctional subsets (88 primary, 18 recurrent). Telomere lengths were estimated and we observed 64 (59.4%) cases with short, 39 (36.8%) cases with normal, and 0 (0%) cases with long telomeres. We did not observe significant differences in the clinicopathological characteristics of the group with abnormally shortened telomeres compared to the group with normal telomeres. However, three pituitary adenomas were identified as ALT-positive of which two were recurrent tumors. Two of these three ALT-positive cases had alterations in either of the chromatin remodeling proteins, ATRX and DAXX, which are routinely altered in other ALT-positive tumor subtypes. In a second cohort of 32 recurrent pituitary adenomas from 22 patients, we found that the tumors from 36% of patients (n = 8) were ALT-positive. This study demonstrates that short telomere lengths are prevalent in pituitary adenomas and that ALT-positive pituitary adenomas are enriched in recurrent disease.
The presence of two active X chromosomes (XaXa) is a hallmark of the ground state of pluripotency specific to murine embryonic stem cells (ESCs). Human ESCs (hESCs) invariably exhibit signs of X ...chromosome inactivation (XCI) and are considered developmentally more advanced than their murine counterparts. We describe the establishment of XaXa hESCs derived under physiological oxygen concentrations. Using these cell lines, we demonstrate that (1) differentiation of hESCs induces random XCI in a manner similar to murine ESCs, (2) chronic exposure to atmospheric oxygen is sufficient to induce irreversible XCI with minor changes of the transcriptome, (3) the Xa exhibits heavy methylation of the
XIST promoter region, and (4) XCI is associated with demethylation and transcriptional activation of
XIST along with H3K27-me3 deposition across the Xi. These findings indicate that the human blastocyst contains pre-X-inactivation cells and that this state is preserved in vitro through culture under physiological oxygen.
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► Conventional human ESCs (hESCs) have undergone X chromosome inactivation (XiXa) ► hESCs with two active X chromosomes (XaXa) can be isolated in 5% oxygen ► Oxidative and cellular stress induces irreversible epigenetic changes in hESCs ► Human blastocysts likely contain cells with two active X chromosomes (XaXa)
Patients with meningiomas have widely divergent clinical courses. Some entirely recover following surgery alone, while others have relentless tumor recurrences. This clinical conundrum is exemplified ...by rhabdoid meningiomas, which are designated in the World Health Organization Classification of Tumours as high grade, despite only a subset following an aggressive clinical course. Patient management decisions are further exacerbated by high rates of interobserver variability, biased against missing possibly aggressive tumors. Objective molecular determinants are needed to guide classification and clinical decision making.
To define genomic aberrations of rhabdoid meningiomas, we performed sequencing of cancer-related genes in 27 meningiomas from 18 patients with rhabdoid features and evaluated breast cancer BRCA1-associated protein 1 (BAP1) expression by immunohistochemistry in 336 meningiomas. We assessed outcomes, germline status, and family history in patients with BAP1-negative rhabdoid meningiomas.
The tumor suppressor gene BAP1, a ubiquitin carboxy-terminal hydrolase, is inactivated in a subset of high-grade rhabdoid meningiomas. Patients with BAP1-negative rhabdoid meningiomas had reduced time to recurrence compared with patients with BAP1-retained rhabdoid meningiomas (Kaplan-Meier analysis, 26 mo vs 116 mo, P < .001; hazard ratio 12.89). A subset of patients with BAP1-deficient rhabdoid meningiomas harbored germline BAP1 mutations, indicating that rhabdoid meningiomas can be a harbinger of the BAP1 cancer predisposition syndrome.
We define a subset of aggressive rhabdoid meningiomas that can be recognized using routine laboratory tests. We implicate ubiquitin deregulation in the pathogenesis of these high-grade malignancies. In addition, we show that familial and sporadic BAP1-mutated rhabdoid meningiomas are clinically aggressive, requiring intensive clinical management.
The clinical management of meningioma is guided by tumor grade and biological behavior. Currently, the assessment of tumor grade follows surgical resection and histopathologic review. Reliable ...techniques for pre-operative determination of tumor grade may enhance clinical decision-making.
A total of 175 meningioma patients (103 low-grade and 72 high-grade) with pre-operative contrast-enhanced T1-MRI were included. Fifteen radiomic (quantitative) and 10 semantic (qualitative) features were applied to quantify the imaging phenotype. Area under the curve (AUC) and odd ratios (OR) were computed with multiple-hypothesis correction. Random-forest classifiers were developed and validated on an independent dataset (n = 44).
Twelve radiographic features (eight radiomic and four semantic) were significantly associated with meningioma grade. High-grade tumors exhibited necrosis/hemorrhage (ORsem = 6.6, AUCrad = 0.62-0.68), intratumoral heterogeneity (ORsem = 7.9, AUCrad = 0.65), non-spherical shape (AUCrad = 0.61), and larger volumes (AUCrad = 0.69) compared to low-grade tumors. Radiomic and sematic classifiers could significantly predict meningioma grade (AUCsem = 0.76 and AUCrad = 0.78). Furthermore, combining them increased the classification power (AUCradio = 0.86). Clinical variables alone did not effectively predict tumor grade (AUCclin = 0.65) or show complementary value with imaging data (AUCcomb = 0.84).
We found a strong association between imaging features of meningioma and histopathologic grade, with ready application to clinical management. Combining qualitative and quantitative radiographic features significantly improved classification power.
How the glioma immune microenvironment fosters tumorigenesis remains incompletely defined. Here, we use single-cell RNA-sequencing and multiplexed tissue-imaging to characterize the composition, ...spatial organization, and clinical significance of extracellular purinergic signaling in glioma. We show that microglia are the predominant source of CD39, while tumor cells principally express CD73. In glioblastoma, CD73 is associated with EGFR amplification, astrocyte-like differentiation, and increased adenosine, and is linked to hypoxia. Glioblastomas enriched for CD73 exhibit inflammatory microenvironments, suggesting that purinergic signaling regulates immune adaptation. Spatially-resolved single-cell analyses demonstrate a strong spatial correlation between tumor-CD73 and microglial-CD39, with proximity associated with poor outcomes. Similar spatial organization is present in pediatric high-grade gliomas including H3K27M-mutant diffuse midline glioma. These data reveal that purinergic signaling in gliomas is shaped by genotype, lineage, and functional state, and that core enzymes expressed by tumor and myeloid cells are organized to promote adenosine-rich microenvironments potentially amenable to therapeutic targeting.
Matrix assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) is an emerging analytical technique, which generates spatially resolved proteomic and metabolomic images from tissue ...specimens. Conventional MALDI MSI processing and data acquisition can take over 30 min, limiting its clinical utility for intraoperative diagnostics. We present a rapid MALDI MSI method, completed under 5 min, including sample preparation and analysis, providing a workflow compatible with the clinical frozen section procedure.
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