Neuro-oncology最新文献

Background: Screening of asymptomatic stage IV breast cancer with brain MRIs is currently not recommended by National Comprehensive Cancer Network (NCCN) Guidelines. The incidence of asymptomatic brain metastasis is not well documented.

Methods: The study is designed as a single arm, phase II trial, with the goal of investigating surveillance brain MRIs in neurologically asymptomatic patients with metastatic breast cancer. Breast cancer patients were classified into triple negative (TN), HER2+, and hormone receptor (HR)+/HER2-. Patients underwent a surveillance brain MRI and a second brain MRI at 6 months if the baseline MRI was negative. Asymptomatic, stage IV breast cancer patients, ECOG ≤2, and life expectancy ≥6 months were eligible. The primary objective was to determine the frequency of asymptomatic brain metastasis in metastatic breast cancer. Clinical trial information: NCT05115474.

Results: A total of 101 patients completed the surveillance brain MRI including 40 HR+/HER2-, 33 HER2+, and 28 TN patients. The overall frequency of brain metastasis on initial surveillance brain MRI was 14% (n=14) with rates of 18%, 15%, and 10% in TN, HER2+, and HR+/HER2- patients, respectively. Following the 6-month MRI, the cumulative rates of brain metastasis increased to 25% in TN, 24% in HER2+, and 23% in HR+/HER2- patients.

Conclusions: The highest frequency of brain metastases at baseline was in TN and HER2+ breast cancer. Following the 6-month MRI, the cumulative frequency was approximately a quarter across all subtypes. These results warrant confirmatory trials to refine brain MRI surveillance recommendations for neurologically asymptomatic stage IV breast cancer.

Background: Our group and others have recently identified four molecular groups of meningioma, with unique underlying biology and outcomes. The relevance of group-specific metabolite profiles (particularly among hypermetabolic tumours), has not been explored.

Methods: We performed untargeted metabolic profiling of meningiomas representing each molecular group and WHO grade. Prognostic biochemicals were identified using Cox regression and their biological importance was explored using RNA and protein-based pathway analyses. Validation was performed using targeted high performance liquid chromatography-mass spectrometry (HPLC-MS/MS).

Results: Global metabolic profiling identified 560 unique biochemicals. We identified a 21-metabolite outcome signatures which is strongly predictive of outcome after adjusting for WHO grade, extent of resection, and receipt of adjuvant radiotherapy (HR 326.49, 95%CI 16.72-6375.48, p < 0.0001). The abundance of N6-trimethyllysine was associated with earlier time to recurrence on our whole cohort (log-rank p = 0.009) and within hypermetabolic and WHO grade 2 tumours specifically; this was validated using targeted HPLC-MS/MS on two cohorts. Consensus RNA and protein expression analysis demonstrated as association between N6-trimethyllysine abundance and activation of oxidative phosphorylation pathways, which portended worse outcomes in the hypermetabolic subgroup but, interestingly, better outcomes in the proliferative subgroup. By contrast, upregulated pyruvate and lactate transporters were associated with worse outcomes in proliferative meningiomas specifically.

Conclusions: This is the first study to demonstrate a subgroup-specific prognostic role of N6-trimethyllysine in hypermetabolic meningiomas, offering increasingly granular outcome predictions using a widely accessible technique (HPLC-MS/MS). We also suggest fundamental differences in preferred energy utilization between and a potential need for subgroup-specific therapies.

Background: Central nervous system (CNS) tumors lead to cancer-related mortality in children. Genetic ancestry-associated cancer prevalence and outcomes have been studied, but is limited.

Methods: We performed genetic ancestry prediction in 1,452 pediatric patients with paired normal and tumor whole genome sequencing from the Open Pediatric Cancer (OpenPedCan) project to evaluate the influence of reported race and ethnicity and ancestry-based genetic superpopulations on tumor histology, molecular subtype, survival, and treatment.

Results: Predicted superpopulations included African (AFR, N=153), Admixed American (AMR, N=222), East Asian (EAS, N=67), European (EUR, N=968), and South Asian (SAS, N=42). Reported race and ethnicity and ancestry-based genetic superpopulations were non-randomly associated (p<0.001). Patients with an atypical teratoid rhabdoid tumor or meningioma were enriched for AFR ancestry (OR=2.6, FDR=0.01; OR=2.9, FDR=0.01, respectively). Among KIAA1549::BRAF fusion-positive low-grade glioma (LGG) diagnoses, EAS and SAS patients disproportionately harbored exon 15:09 breakpoints (FDR<0.05), and AMR patients demonstrated rare breakpoints, which were associated with lesser degree of surgical resection and worse event free survival (EFS) versus other breakpoints (HR=4.6, p=0.03). Non-EUR and AMR patients with germ cell tumors and SHH-activated medulloblastoma, respectively, exhibited worse EFS relative to EUR patients (HR=12.1, p<0.01; HR=5.2, p=0.03) and AFR patients with LGG (HR=16.4, p<0.01) or ependymoma (HR=5.5, p=0.02) had worse overall survival compared to EUR patients. We observed higher frequency of clinical trial enrollment among AMR patients across tumor histologies (OR=2.0, p=<0.01), but increased utilization of photon versus proton radiation relative to other superpopulations (OR=0.55, p=0.04).

Conclusions: Genetic ancestry-associated differences exist across pediatric CNS tumor histological and molecular subtypes from PBTA and PNOC. Further investigation into genetic and socioeconomic factors contributing to these observed inequities is needed.

Background: Peripheral nerve sheath tumors (PNSTs) encompass entities with different cellular differentiation and degrees of malignancy. Spatial heterogeneity complicates diagnosis and grading of PNSTs in some cases. In malignant PNST (MPNST) for example, single cell sequencing data has shown dissimilar differentiation states of tumor cells. Here, we aimed at determining the spatial and biological heterogeneity of PNSTs.

Methods: We performed spatial transcriptomics on formalin-fixed paraffin-embedded diseased peripheral nerve tissue. We used spatial clustering and weighted correlation network analysis to construct niche-similarity networks and gene expression modules. We determined differential expression in primary pathologies, analysed pathways to investigate the biological significance of identified meta-signatures, integrated the transcriptional data with histological features and existing single cell data, and validated expression data by immunohistochemistry.

Results: We identified distinct transcriptional signatures differentiating PNSTs. Immune cell infiltration, APOD and perineurial fibroblast marker expression highlighted the neurofibroma component of hybrid PNSTs (HPNSTs). While APOD was evenly expressed in neurofibromatous tumor tissue in both, HPNST and pure neurofibromas, perineurial fibroblast markers were evenly expressed in HPNST, but restricted to the periphery in plexiform neurofibromas. Furthermore, we provide a spatial cellular differentiation map for MPNST, locating Schwann cell precursors, neural crest-like cells and those with mesenchymal transition.

Conclusions: This pilot study shows that applying spatial transcriptomics to PNSTs provides important insight into their biology. It helps establishing new markers and provides spatial information about cellular composition and distribution of cellular differentiation states. By integrating morphological and high-dimensional molecular data it can improve PNSTs classification in the future.

Background: Diffuse hemispheric glioma, histone 3 (H3) G34-mutant, has been newly defined in the 2021 WHO classification of central nervous system tumors. Here we sought to define the prognostic roles of clinical, neuroimaging, pathological, and molecular features of these tumors.

Methods: We retrospectively assembled a cohort of 114 patients (median age 22 years) with diffuse hemispheric glioma, H3 G34-mutant, CNS WHO grade 4 and profiled the imaging, histological and molecular landscape of their tumors.

Results: Compared with glioblastoma, H3 G34-mutant diffuse hemispheric gliomas exhibited less avid contrast enhancement, necrosis and edema on MRI. Comprehensive analyses of mutational and DNA copy number profiles revealed recurrent mutations in TP53 and ATRX, homozygous deletions of CDKN2A/B, and amplifications of PDGFRA, EGFR, CCND2, and MYCN. MGMT promoter methylation was detected in 79 tumors (75%); 11 tumors (13%) showed DNA copy number profiles suggestive of circumscribed deletions on 10q26.3 involving the MGMT locus. Median survival was 21.5 months. Female sex, gross total resection, and MGMT promoter methylation were positive prognostic factors on univariate analysis. Among radiological, pathological and molecular features, absence of pial invasion, and presence of microvascular proliferation and CDK6 amplification were positive prognostic factors on univariate analyses.

Conclusions: This study refines the clinical and molecular landscape of H3 G34-mutant diffuse hemispheric gliomas. Dedicated trials for this novel tumor type are urgently needed.

Background: Neuroblastoma is a heterogeneous disease with adrenergic (ADRN)- and therapy resistant mesenchymal (MES)-like cells driven by distinct transcription factor networks. Here, we investigate the expression of immunotherapeutic targets in each neuroblastoma subtype and propose pan-neuroblastoma and cell state specific targetable cell-surface proteins.

Methods: We characterized cell lines, patient-derived xenografts, and patient samples as ADRN-dominant or MES-dominant to define subtype-specific and pan-neuroblastoma gene sets. Targets were validated with ChIP-sequencing, immunoblotting, and flow cytometry in neuroblastoma cell lines and isogenic ADRN-to-MES transition cell line models. Finally, we evaluated the activity of MES-specific agents in vivo and in vitro.

Results: Most immunotherapeutic targets being developed for neuroblastoma showed significantly higher expression in the ADRN subtype with limited expression in MES-like tumor cells. In contrast, CD276 (B7-H3) and L1CAM maintained expression across both ADRN and MES states. We identified several receptor tyrosine kinases (RTKs) enriched in MES-dominant samples and showed that AXL targeting with ADCT-601 was potently cytotoxic in MES-dominant cell lines and showed specific anti-tumor activity in a MES cell line-derived xenograft.

Conclusions: Immunotherapeutic strategies for neuroblastoma must address the potential of epigenetic downregulation of antigen density as a mechanism for immune evasion. We identified several RTKs as candidate MES-specific immunotherapeutic target proteins for the elimination of therapy-resistant cells. We hypothesize that the phenomena of immune escape will be less likely when targeting pan-neuroblastoma cell surface proteins such as B7-H3 and L1CAM, and/or dual targeting strategies that consider both the ADRN- and MES-cell states.

Background: Non-malignant tumors of the CNS contribute substantially to the morbidity and mortality from CNS tumors. It is critical to understand the epidemiology of non-malignant CNS tumors separately from CNS malignancies to inform resource allocation and policy since treatment and prognosis can differ. High quality international data on non-malignant CNS tumor burden are needed to accomplish this goal.

Methods: We assessed cancer registry and vital registration data available to the Global Burden of Disease study by its inclusion of non-malignant CNS tumors, reporting on the availability of data over time and by World Bank income group. We analyzed preliminary age-standardized incidence rates (ASIRs), age-standardized mortality rates (ASMRs), and proportions of CNS tumors by behavior for adults, children, and all ages.

Results: Non-malignant CNS tumors were reported separately in 17·2% (N=66) of registry reports and in aggregate with malignant CNS tumors in 18·0% (N=69) of reports. Only seven low- and middle-income countries (LMICs) had data reporting CNS tumors separately by behavior. Across all ages combined, the median ASIR of non-malignant CNS tumor data was 0·31 (interquartile range: 0·15-0·50) and ASMR was 0·24 (0·10-0·44) per 100,000 in LMICs compared to median ASIR of 3·62 (2·62-4·97) and ASMR of 0·32 (0·16-0·65) in high-income countries (HICs). A larger proportion of incident CNS tumors across were reported as non-malignant in HIC data than LMIC data (p<0.0001).

Conclusions: Our study alludes to current challenges in understanding global non-malignant CNS tumor burden and a need for increased international data collection. Further research is needed to comprehensively investigate opportunities for future data inclusion.

Background: Despite advances in our understanding of the molecular underpinnings of meningioma progression and innovations in systemic and local treatments, recurrent meningiomas remain a substantial therapeutic challenge. The objective of this systematic review and meta-analysis is to provide a historical baseline, contemporary analysis, and propose a "rate of probable interest" to inform future clinical trial design and development on behalf of the RANO meningioma group.

Methods: PubMed, ClinicalTrials.gov, and ASCOpubs databases were screened for clinical trials evaluating the activity of systemic therapies for adults with recurrent meningiomas. The pooled progression-free survival at 6-months and 1-year (PFS-6 and PFS-1 year) values were calculated using the random effects technique with I-squared indices.

Results: The pooled PFS-6 and PFS-1 year rates for recurrent WHO grade 1 meningiomas were 43.6% (95% CI: 22.7-67.0%, I2=80%) and 21.7% (95% CI: 6.2-53.9%, I2=76%), and for grade 2-3 meningiomas, the PFS-6 was 38.0% (95% CI: 28.3-48.8%, I2=68%). In targeted therapy group, PFS-6 and PFS-1 year rates stood at 62.0% (I2=58%) and 49.0% (I2=63%) for grade 1, while for grade 2-3 tumors, the PFS-6 rate with targeted therapy and immunotherapy was 42.1% (I²=60%) and 46.0% (I²=0%), respectively. The benchmarks were set at 67% and 54% for PFS-6 and PFS-1 year for grade 1 tumors, and PFS-6 of 49% for grade 2-3 tumors.

Conclusions: Several studies have reported outcomes in patients with recurrent meningiomas testing a variety of agents with modest, but variable and progressively increasing activity. In this context, we recommend new benchmarks for future trials to define efficacy of future investigational therapies.

Background: Treatment of childhood medulloblastoma has evolved to reduce neurotoxicity while improving survival. However, the impact of evolving therapies on late neurocognitive outcomes and adult functional independence remains unknown.

Methods: Adult survivors of childhood medulloblastoma (n = 505; median [minimum-maximum] age, 29 [18-46] years) and sibling controls (n = 727; 32 [18-58] years) from the Childhood Cancer Survivor Study completed surveys assessing neurocognitive problems and chronic health conditions (CHCs). Treatment exposures were categorized as historical (craniospinal irradiation [CSI] ≥ 30 Gy, no chemotherapy), standard-risk (CSI > 0 to <30 Gy + chemotherapy) and high-risk (CSI ≥ 30 Gy + chemotherapy) therapy. Latent class analysis identified patterns of functional independence using employment, independent living, assistance with routine/personal care needs, driver's license, and marital/partner status. Multivariable models estimated the risk of neurocognitive impairment in survivors versus siblings and by treatment exposure group, and associations between neurocognitive impairment, CHCs, and functional independence.

Results: Survivors in each treatment exposure group had a 4- to 5-fold elevated risk of impaired memory and task efficiency compared to siblings. Contemporary risk-based therapies did not confer lower risk compared to historical therapy. Survivors treated in the 1990s had a higher risk of memory impairment (relative risk [RR] 2.24, 95% confidence interval 1.39-3.60) compared to survivors treated in the 1970s. Sensorimotor, hearing problems, and seizures were associated with 33-34%, 25-26%, and 21-42% elevated risk of task efficiency and memory impairment, respectively. Treatment-related CHCs and neurocognitive impairment were associated with nonindependence.

Conclusions: Despite treatment changes, long-term survivors of childhood medulloblastoma remain at risk for neurocognitive impairment, which was associated with CHCs. Neurocognitive surveillance after contemporary regimens is imperative.

The field of immunology has traditionally focused on immune checkpoint modulation of adaptive immune cells. However, many malignancies such as glioblastoma are mostly devoid of T cells and rather are enriched with immunosuppressive myeloid cells of the innate immune system. While some immune checkpoint targets are shared between adaptive and innate immunity, myeloid-specific checkpoints could also serve as potential therapeutics. To better understand the impact of immune checkpoint blockade on myeloid cells, we systematically summarize the current literature focusing on the direct immunological effects of PD-L1/PD-1, CD24/Siglec-10, collagen/LAIR-1, CX3CL1/CX3CR1, and CXCL10/CXCR3. By synthesizing the molecular mechanisms and the translational implications, we aim to prioritize agents in this category of therapeutics for glioblastoma.