Mitochondrial RNA modification-based signature to predict prognosis of lower grade glioma: a multi-omics exploration and verification study.

Mitochondrial RNA modification (MRM) plays a crucial role in regulating the expression of key mitochondrial genes and promoting tumor metastasis. Despite its significance, comprehensive studies on MRM in lower grade gliomas (LGGs) remain unknown. Single-cell RNA-seq data (GSE89567) was used to evaluate the distribution functional status, and correlation of MRM-related genes in different cell types of LGG microenvironment. We developed an MRM scoring system by selecting potential MRM-related genes using LASSO regression analysis and the Random Survival Forest algorithm, based on multiple bulk RNA-seq datasets from TCGA, CGGA, GSE16011, and E-MTAB-3892. Analysis was performed on prognostic and immunological features, signaling pathways, metabolism, somatic mutations and copy number variations (CNVs), treatment responses, and forecasting of potential small-molecule agents. A total of 35 MRM-related genes were selected from the literature. Differential expression analysis of 1120 normal brain tissues and 529 LGGs revealed that 22 and 10 genes were upregulated and downregulated, respectively. Most genes were associated with prognosis of LGG. METLL8, METLL2A, TRMT112, and METTL2B were extensively expressed in all cell types and different cell cycle of each cell type. Almost all cell types had clusters related to mitochondrial RNA processing, ribosome biogenesis, or oxidative phosphorylation. Cell-cell communication and Pearson correlation analyses indicated that MRM may promoting the development of microenvironment beneficial to malignant progression via modulating NCMA signaling pathway and ICP expression. A total of 11 and 9 MRM-related genes were observed by LASSO and the RSF algorithm, respectively, and finally 6 MRM-related genes were used to establish MRM scoring system (TRMT2B, TRMT11, METTL6, METTL8, TRMT6, and TRUB2). The six MRM-related genes were then validated by qPCR in glioma and normal tissues. MRM score can predict the malignant clinical characteristics, abundance of immune infiltration, gene variation, clinical outcome, the enrichment of signaling pathways and metabolism. In vitro experiments demonstrated that silencing METTL8 significantly curbs glioma cell proliferation and enhances apoptosis. Patients with a high MRM score showed a better response to immunotherapies and small-molecule agents such as arachidonyl trifluoromethyl ketone, MS.275, AH.6809, tacrolimus, and TTNPB. These novel insights into the biological impacts of MRM within the glioma microenvironment underscore its potential as a target for developing precise therapies, including immunotherapeutic approaches.

Factors affecting the extent of resection and neurological outcomes following transopercular resection of insular gliomas.

BACKGROUND: Surgical resection of insular gliomas is a challenge. TO resection is considered more versatile and has lower risk of vascular damage. In this study, we aimed to understand the factors that affect resection rates, ischemic changes and neurological outcomes and studied the utility of IONM in patients who underwent TO resection for IGs. METHODS: Retrospective analysis of 66 patients with IG who underwent TO resection was performed. RESULTS: Radical resection was possible in 39% patients. Involvement of zone II and the absence of contrast enhancement predicted lower resection rate. Persistent deficit rate was 10.9%. Although dominant lobe tumors increased immediate deficit and fronto-orbital operculum involvement reduced prolonged deficit rate, no tumor related factor showed significant association with persistent deficits. 45% of patients developed a postoperative infarct, 53% of whom developed deficits. Most affected vascular territory was lenticulostriate (39%). MEP changes were observed in 9/57 patients. 67% of stable TcMEPs and 74.5% of stable strip MEPs did not develop any postoperative motor deficits. Long-term deficits were seen in 3 and 6% patients with stable TcMEP and strip MEPs respectively. In contrast, 25% and 50% of patients with reversible strip MEP and Tc MEP changes respectively had persistent motor deficits. DWI changes were clinically more relevant when accompanied by MEP changes intraoperatively, with persistent deficit rates three times greater when MEP changes occurred than when MEPs were stable. CONCLUSION: Radical resection can be achieved in large, multizone IGs, with reasonable outcomes using TO approach and multimodal intraoperative strategy with IONM.

Value of long non-coding RNA HAS2-AS1 as a diagnostic and prognostic marker of glioma / El valor de ARNncl HAS2-AS1 como marcador diagnóstico y pronóstico del glioma

Background: Glioma presents high incidence and poor prognosis, and therefore more effective treatments are needed. Studies have confirmed that long non-coding RNAs (lncRNAs) basically regulate various human diseases including glioma. It has been theorized that HAS2-AS1 serves as an lncRNA to exert an oncogenic role in varying cancers. This study aimed to assess the value of lncRNA HAS2-AS1 as a diagnostic and prognostic marker for glioma. Methods: The miRNA expression data and clinical data of glioma were downloaded from the TCGA database for differential analysis and survival analysis. In addition, pathological specimens and specimens of adjacent normal tissue from 80 patients with glioma were used to observe the expression of HAS2-AS1. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic ability and prognostic value of HAS2-AS1 in glioma. Meanwhile, a Kaplan–Meier survival curve was plotted to evaluate the survival of glioma patients with different HAS2-AS1 expression levels. Results: HAS2-AS1 was significantly upregulated in glioma tissues compared with normal tissue. The survival curves showed that overexpression of HAS2-AS1 was associated with poor overall survival (OS) and progression-free survival (PFS). Several clinicopathological factors of glioma patients, including tumor size and WHO grade, were significantly correlated with HAS2-AS1 expression in tissues. The ROC curve showed an area under the curve (AUC) value of 0.863, indicating that HAS2-AS1 had good diagnostic value. The ROC curve for the predicted OS showed an AUC of 0.906, while the ROC curve for predicted PFS showed an AUC of 0.88. Both suggested that overexpression of HAS2-AS1 was associated with poor prognosis.Conclusions: Normal tissues could be clearly distinguished from glioma tissues based on HAS2-AS1 expression. Moreover, overexpression of HAS2-AS1 indicated poor prognosis in glioma patients.(AU)

Introducción: Los gliomas presentan una alta incidencia y un mal pronóstico, por lo que es necesario un tratamiento más efectivo. Algunos estudios han confirmado que los ARN no codificantes de cadena larga (ARNncl) regulan diferentes enfermedades, entre las que se incluyen los gliomas. Se ha postulado que HAS2-AS1 actúa como un ARNncl, con un efecto oncogénico en diferentes tipos de cáncer. Este estudio tiene como objetivo analizar el valor del ARNncl HAS2-AS1 como marcador diagnóstico y pronóstico de glioma. Métodos: Descargamos los datos clínicos y de expresión de micro-ARN de la base de datos del Atlas del Genoma del Cáncer (TCGA) para realizar el análisis diferencial y de supervivencia. También analizamos la expresión de HAS2-AS1 en muestras patológicas y muestras de tejido adyacente normal de 80 pacientes con glioma. Para analizar la capacidad diagnóstica y el valor pronóstico de HAS2-AS1 en el glioma, recurrimos a la curva ROC. También utilizamos curvas de Kaplan-Meier para evaluar la supervivencia de los pacientes con glioma con diferentes niveles de expresión de HAS2-AS1. Resultados: La expresión de HAS2-AS1 era significativamente mayor en las muestras patológicas que en el tejido normal. Las curvas de supervivencia demostraron que la sobreexpresión de HAS2-AS1 estaba relacionada con una menor supervivencia general y supervivencia libre de progresión. Algunos factores clínico-patológicos de los pacientes con glioma, como el tamaño del tumor y su grado, según la clasificación de la OMS, mostraron una correlación significativa con la expresión de HAS2-AS1 en los tejidos afectados. La curva ROC mostró un área bajo la curva de 0,863, lo que indica que la expresión de HAS2-AS1 posee un importante valor diagnóstico. El área bajo la curva de la supervivencia general estimada fue de 0,906; para la supervivencia libre de progresión estimada, de 0,88. Ambos valores muestran que la sobreexpresión de HAS2-AS1 se asocia con un mal pronóstico...(AU)

Rapid P-TEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy.

Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. P-TEFb-mediated pause-release of RNA polymerase II (Pol II) is a conserved regulatory mechanism for synchronous transcriptional induction in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. Using model systems of pediatric high-grade glioma, we show that rapid genome-wide reorganization of active chromatin facilitates P-TEFb-mediated nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of P-TEFb disrupts this chromatin reorganization and blunts transcriptional induction, abrogating key adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival. These studies reveal a central role for P-TEFb underpinning the early adaptive response to radiotherapy, opening avenues for combinatorial treatment in these lethal malignancies.

Molecular Pathology of Gliomas.

Gliomas are the most common adult and pediatric primary brain tumors. Molecular studies have identified features that can enhance diagnosis and provide biomarkers. IDH1/2 mutation with ATRX and TP53 mutations defines diffuse astrocytomas, whereas IDH1/2 mutations with 1p19q loss defines oligodendroglioma. Focal amplifications of receptor tyrosine kinase genes, TERT promoter mutation, and loss of chromosomes 10 and 13 with trisomy of chromosome 7 are characteristic features of glioblastoma and can be used for diagnosis. BRAF gene fusions and mutations in low-grade gliomas and histone H3 mutations in high-grade gliomas also can be used for diagnostics.

MCE: Medical Cognition Embedded in 3D MRI feature extraction for advancing glioma staging.

In recent years, various data-driven algorithms have been applied to the classification and staging of brain glioma MRI detection. However, the restricted availability of brain glioma MRI data in purely data-driven deep learning algorithms has presented challenges in extracting high-quality features and capturing their complex patterns. Moreover, the analysis methods designed for 2D data necessitate the selection of ideal tumor image slices, which does not align with practical clinical scenarios. Our research proposes an novel brain glioma staging model, Medical Cognition Embedded (MCE) model for 3D data. This model embeds knowledge characteristics into data-driven approaches to enhance the quality of feature extraction. Approach includes the following key components: (1) Deep feature extraction, drawing upon the imaging technical characteristics of different MRI sequences, has led to the design of two methods at both the algorithmic and strategic levels to mimic the learning process of real image interpretation by medical professionals during film reading; (2) We conduct an extensive Radiomics feature extraction, capturing relevant features such as texture, morphology, and grayscale distribution; (3) By referencing key points in radiological diagnosis, Radiomics feature experimental results, and the imaging characteristics of various MRI sequences, we manually create diagnostic features (Diag-Features). The efficacy of proposed methodology is rigorously evaluated on the publicly available BraTS2018 and BraTS2020 datasets. Comparing it to most well-known purely data-driven models, our method achieved higher accuracy, recall, and precision, reaching 96.14%, 93.4%, 97.06%, and 97.57%, 92.80%, 95.96%, respectively.

Vasorin promotes endothelial differentiation of glioma stem cells via stimulating the transcription of VEGFR2.

Gliomas are highly vascularized malignancies, but current anti-angiogenic treatments have not demonstrated practical improvements in patient survival. Studies have suggested that glioma-derived endothelial cell (GdEC) formed by glioma stem cell (GSC) differentiation may contribute to the failure of this treatment. However, the molecular mechanisms involved in GSC endothelial differentiation remain poorly understood. We previously reported that vasorin (VASN) is highly expressed in glioma and promotes angiogenesis. Here, we show that VASN expression positively correlates with GdEC signatures in glioma patients. VASN promotes the endothelial differentiation capacity of GSC in vitro and participates in the formation of GSC-derived vessels in vivo. Mechanistically, vascular endothelial growth factor receptor 2 (VEGFR2) is a critical factor that mediates the regulation of VASN on GSC endothelial differentiation. Separation of cell chromatin fractionation and chromatin immunoprecipitation-sequencing analysis show that VASN interacts with Notch1 and co-translocates into the cell nuclei, where VASN binds to the VEGFR2 gene promoter to stimulate its transcription during the progression of GSC differentiation into GdEC. Together, these findings elucidate the role and mechanisms of VASN in promoting the endothelial differentiation of GSC and suggest VASN as a potential target for anti-angiogenic therapy based on intervention in GdEC formation in gliomas.

State of the Art in Low-Grade Glioma Management: Insights From Isocitrate Dehydrogenase and Beyond.

Low-grade gliomas present a formidable challenge in neuro-oncology because of the challenges imposed by the blood-brain barrier, predilection for the young adult population, and propensity for recurrence. In the past two decades, the systematic examination of genomic alterations in adults and children with primary brain tumors has uncovered profound new insights into the pathogenesis of these tumors, resulting in more accurate tumor classification and prognostication. It also identified several common recurrent genomic alterations that now define specific brain tumor subtypes and have provided a new opportunity for molecularly targeted therapeutic intervention. Adult-type diffuse low-grade gliomas are frequently associated with mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), resulting in production of 2-hydroxyglutarate, an oncometabolite important for tumorigenesis. Recent studies of IDH inhibitors have yielded promising results in patients at early stages of disease with prolonged progression-free survival (PFS) and delayed time to radiation and chemotherapy. Pediatric-type gliomas have high rates of alterations in BRAF, including BRAF V600E point mutations or BRAF-KIAA1549 rearrangements. BRAF inhibitors, often combined with MEK inhibitors, have resulted in radiographic response and improved PFS in these patients. This article reviews emerging approaches to the treatment of low-grade gliomas, including a discussion of targeted therapies and how they integrate with the current treatment modalities of surgical resection, chemotherapy, and radiation.

Glioma.

Gliomas are primary brain tumours that are thought to develop from neural stem or progenitor cells that carry tumour-initiating genetic alterations. Based on microscopic appearance and molecular characteristics, they are classified according to the WHO classification of central nervous system (CNS) tumours and graded into CNS WHO grades 1-4 from a low to high grade of malignancy. Diffusely infiltrating gliomas in adults comprise three tumour types with distinct natural course of disease, response to treatment and outcome: isocitrate dehydrogenase (IDH)-mutant and 1p/19q-codeleted oligodendrogliomas with the best prognosis; IDH-mutant astrocytomas with intermediate outcome; and IDH-wild-type glioblastomas with poor prognosis. Pilocytic astrocytoma is the most common glioma in children and is characterized by circumscribed growth, frequent BRAF alterations and favourable prognosis. Diffuse gliomas in children are divided into clinically indolent low-grade tumours and high-grade tumours with aggressive behaviour, with histone 3 K27-altered diffuse midline glioma being the leading cause of glioma-related death in children. Ependymal tumours are subdivided into biologically and prognostically distinct types on the basis of histology, molecular biomarkers and location. Although surgery, radiotherapy and alkylating agent chemotherapy are the mainstay of glioma treatment, individually tailored strategies based on tumour-intrinsic dominant signalling pathways have improved outcome in subsets of patients.

MRI Scoring Systems for Predicting Isocitrate Dehydrogenase Mutation and Chromosome 1p/19q Codeletion in Adult-type Diffuse Glioma Lacking Contrast Enhancement.

Background According to 2021 World Health Organization criteria, adult-type diffuse gliomas include glioblastoma, isocitrate dehydrogenase (IDH)-wildtype; oligodendroglioma, IDH-mutant and 1p/19q-codeleted; and astrocytoma, IDH-mutant, even when contrast enhancement is lacking. Purpose To develop and validate simple scoring systems for predicting IDH and subsequent 1p/19q codeletion status in gliomas without contrast enhancement using standard clinical MRI sequences. Materials and Methods This retrospective study included adult-type diffuse gliomas lacking contrast at contrast-enhanced MRI from two tertiary referral hospitals between January 2012 and April 2022 with diagnoses confirmed at pathology. IDH status was predicted primarily by using T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign, followed by 1p/19q codeletion prediction. A visual rating of MRI features, apparent diffusion coefficient (ADC) ratio, and relative cerebral blood volume was measured. Scoring systems were developed through univariable and multivariable logistic regressions and underwent calibration and discrimination, including internal and external validation. Results For the internal validation cohort, 237 patients were included (mean age, 44.4 years ± 14.4 [SD]; 136 male patients; 193 patients in IDH prediction and 163 patients in 1p/19q prediction). For the external validation cohort, 35 patients were included (46.1 years ± 15.3; 20 male patients; 28 patients in IDH prediction and 24 patients in 1p/19q prediction). The T2-FLAIR mismatch sign demonstrated 100% specificity and 100% positive predictive value for IDH mutation. IDH status prediction scoring system for tumors without mismatch sign included age, ADC ratio, and morphologic characteristics, whereas 1p/19q codeletion prediction for IDH-mutant gliomas included ADC ratio, cortical involvement, and mismatch sign. For IDH status and 1p/19q codeletion prediction, bootstrap-corrected areas under the receiver operating characteristic curve were 0.86 (95% CI: 0.81, 0.90) and 0.73 (95% CI: 0.65, 0.81), respectively, whereas at external validation they were 0.99 (95% CI: 0.98, 1.0) and 0.88 (95% CI: 0.63, 1.0). Conclusion The T2-FLAIR mismatch sign and scoring systems using standard clinical MRI predicted IDH and 1p/19q codeletion status in gliomas lacking contrast enhancement. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Badve and Hodges in this issue.

Identification of cancer risk groups through multi-omics integration using autoencoder and tensor analysis.

Identifying cancer risk groups by multi-omics has attracted researchers in their quest to find biomarkers from diverse risk-related omics. Stratifying the patients into cancer risk groups using genomics is essential for clinicians for pre-prevention treatment to improve the survival time for patients and identify the appropriate therapy strategies. This study proposes a multi-omics framework that can extract the features from various omics simultaneously. The framework employs autoencoders to learn the non-linear representation of the data and applies tensor analysis for feature learning. Further, the clustering method is used to stratify the patients into multiple cancer risk groups. Several omics were included in the experiments, namely methylation, somatic copy-number variation (SCNV), micro RNA (miRNA) and RNA sequencing (RNAseq) from two cancer types, including Glioma and Breast Invasive Carcinoma from the TCGA dataset. The results of this study are promising, as evidenced by the survival analysis and classification models, which outperformed the state-of-the-art. The patients can be significantly (p-value<0.05) divided into risk groups using extracted latent variables from the fused multi-omics data. The pipeline is open source to help researchers and clinicians identify the patients' risk groups using genomics.

Novel insights into rosacea's role in cancer risk: A Mendelian randomization approach.

BACKGROUND: Chronic inflammation has been shown to promote cancer progression. Rosacea is indeed a long-term inflammatory skin condition and had been reported to link with increased risk for several types of malignancies, but evidence for causality is lacking. OBJECTIVES: To systematically estimate the causal relationship between rosacea and several types of cancer, including cutaneous malignant melanoma (CMM), cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), actinic keratosis (AK), thyroid cancer, breast cancer, glioma and hepatic cancer, as well as explore the potential underlying pathogenesis. METHODS: We conducted a bidirectional two-sample Mendelian randomization study to probe the potential causal relationships between rosacea and several types of cancer. Instrumental variables were established using genome-wide significant single nucleotide polymorphisms associated with rosacea and cancers. The assessment of causality was carried out through multiple methods, and the robustness of the results was evaluated via sensitivity analyses. RESULTS: There was no significant indication of causal effects of rosacea on CMM (pivw = 0.71), cSCC (pivw = 0.45), BCC (pivw = 0.90), AK (pivw = 0.73), thyroid cancer (pivw = 0.59), glioma (pivw = 0.15), and hepatic cancer (pivw = 0.07), but the genetic risk of rosacea was associated with an increased susceptibility to human epidermal growth factor receptor (HER)-negative malignant neoplasm of breast (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.02-1.18; pivw = 0.01). TANK (TRAF family member associated nuclear factor kappa B (NFKB) activator) was identified as a common protective gene for both rosacea (OR, 0.90; 95% CI, 0.82-0.99; pivw = 0.048) and HER-negative malignant neoplasm of the breast (OR, 0.86; 95% CI, 0.75-0.98; pivw = 0.032), which was primarily enriched in the negative regulation of NF-κB signal transduction and may contribute to the genetic links between rosacea and this subtype of breast cancer. CONCLUSIONS: Our findings provide suggestive evidence for causal links between rosacea and HER-negative malignant neoplasm of the breast risk.

The Clinical Utility of a Tiered Approach to Pediatric Glioma Molecular Characterization for Resource-Limited Settings.

PURPOSE: Molecular characterization is key to optimally diagnose and manage cancer. The complexity and cost of routine genomic analysis have unfortunately limited its use and denied many patients access to precision medicine. A possible solution is to rationalize use-creating a tiered approach to testing which uses inexpensive techniques for most patients and limits expensive testing to patients with the highest needs. Here, we tested the utility of this approach to molecularly characterize pediatric glioma in a cost- and time-sensitive manner. METHODS: We used a tiered testing pipeline of immunohistochemistry (IHC), customized fusion panels or fluorescence in situ hybridization (FISH), and targeted RNA sequencing in pediatric gliomas. Two distinct diagnostic algorithms were used for low- and high-grade gliomas (LGGs and HGGs). The percentage of driver alterations identified, associated testing costs, and turnaround time (TAT) are reported. RESULTS: The tiered approach successfully characterized 96% (95 of 99) of gliomas. For 82 LGGs, IHC, targeted fusion panel or FISH, and targeted RNA sequencing solved 35% (29 of 82), 29% (24 of 82), and 30% (25 of 82) of cases, respectively. A total of 64% (53 of 82) of samples were characterized without targeted RNA sequencing. Of 17 HGG samples, 13 were characterized by IHC and four were characterized by targeted RNA sequencing. The average cost per sample was more affordable when using the tiered approach as compared with up-front targeted RNA sequencing in LGG ($405 US dollars [USD] v $745 USD) and HGGs ($282 USD v $745 USD). The average TAT per sample was also shorter using the tiered approach (10 days for LGG, 5 days for HGG v 14 days for targeted RNA sequencing). CONCLUSION: Our tiered approach molecularly characterized 96% of samples in a cost- and time-sensitive manner. Such an approach may be feasible in neuro-oncology centers worldwide, particularly in resource-limited settings.

CDCA3 is a potential biomarker for glioma malignancy and targeted therapy.

CDCA3, a cell cycle regulator gene that plays a catalytic role in many tumors, was initially identified as a regulator of cell cycle progression, specifically facilitating the transition from the G2 phase to mitosis. However, its role in glioma remains unknown. In this study, bioinformatics analyses (TCGA, CGGA, Rembrandt) shed light on the upregulation and prognostic value of CDCA3 in gliomas. It can also be included in a column chart as a parameter predicting 3- and 5-year survival risk (C index = 0.86). According to Gene Set Enrichment Analysis and gene ontology analysis, the biological processes of CDCA3 are mainly concentrated in the biological activities related to cell cycle such as DNA replication and nuclear division. CDCA3 is closely associated with many classic glioma biomarkers (CDK4, CDK6), and inhibitors of CDK4 and CDK6 have been shown to be effective in tumor therapy. We have demonstrated that high expression of CDCA3 indicates a higher malignancy and poorer prognosis in gliomas.

Contemporary Management of Pediatric Brainstem Tumors.

Brain tumors are the second most common malignancy in childhood. Around 15-20% of pediatric brain tumors occur in the brainstem. The most common type of brainstem tumor are diffuse tumors in the ventral pons, whereas focal tumors tend to arise from the midbrain, medulla, and dorsal pons. Glioma is the most common pathological entity. Contemporary management consists of surgery, radiotherapy, chemotherapy, and other adjuvant treatment. Surgical options range from biopsy to radical excision. Biopsy can be performed for diagnostic and prognostic purposes, or in the setting of clinical trials, mainly for diffuse intrinsic pontine gliomas. For focal tumors, surgeons need to carefully balance clinical outcomes against possible neurological sequelae in order to achieve maximal safe resection. Radiotherapy is essential for control of high-grade tumors and may be applied to residual or recurrent low-grade tumors. Proton therapy may provide similar efficacy and less neurotoxicity in comparison to conventional photon therapy. Oncological treatment continues to evolve from conventional chemotherapy to targeted therapy, immunotherapy, and other novel treatment methods and holds great potential as adjuvant therapy for pediatric brainstem tumors.

Per- and polyfluoroalkyl substances (PFAS) exposure in plasma and their blood-brain barrier transmission efficiency-A pilot study.

Per- and polyfluoroalkyl substances (PFAS) have been shown to penetrate the blood-brain barrier (BBB) and accumulate in human brain. The BBB transmission and accumulation efficiency of PFAS, as well as the potential health risks from human co-exposure to legacy and emerging PFAS due to differences in transport efficiency, need to be further elucidated. In the present pilot study, 23 plasma samples from glioma patients were analyzed for 17 PFAS. The concentrations of PFAS in six paired brain tissue and plasma samples were used to calculate the BBB transmission efficiency of PFAS (RPFAS). This RPFAS analysis was conducted with utmost care and consideration amid the limited availability of valuable paired samples. The results indicated that low molecular weight PFAS, including short-chain and emerging PFAS, may have a greater potential for accumulation in brain tissue than long-chain PFAS. As an alternative to perfluorooctane sulfonic acid (PFOS), 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA) exhibited brain accumulation potential similar to that of PFOS, suggesting it may not be a suitable substitute concerning health risk in brain. The BBB transmission efficiencies of perfluorooctanoic acid, PFOS, and 6:2 Cl-PFESA showed similar trends with age, which may be an important factor influencing the entry of exogenous compounds into the brain. A favorable link between perfluorooctane sulfonamide (FOSA) and the development and/or progression of glioma may be implicated by a strong positive correlation (r2 = 0.94; p < 0.01) between RFOSA and Ki-67 (a molecular marker of glioma). However, a causal relationship between RFOSA and glioma incidence were not established in the present study. The present pilot study conducted the first examination of BBB transmission efficiency of PFAS from plasma to brain tissue and highlighted the importance of reducing and/or controlling exposure to PFAS.

Anatomical analysis of white fiber tracts in SMA and its implications related to en-masse tumor resection technique.

OBJECTIVE: Anatomy and connections of the supplementary motor area (SMA) are studied essentially to analyze the SMA syndrome. Experience with surgical treatment of 19 tumors located in SMA is analyzed. MATERIAL AND METHODS: The cortical anatomy and subcortical connectivity of the SMA was studied on ten previously frozen and formalin fixed human cadaveric brain specimens. The white fiber dissection was performed using Klingler's method. Nineteen patients with low grade gliomas in the region of the SMA treated surgically were clinically analyzed. RESULTS: The white fiber connections of the SMA include short arcuate connections with the pre-central, middle and inferior frontal gyri, the medial part of the SLF, the cingulum, the frontal aslant tract (FAT), the claustro-cortical fibers, the fronto-striatal tract and the crossed frontal aslant tract. All tumors were operated using en-masse surgical technique described by us and its subsequent modifications that focused on attempts towards preservation of related critical fiber tracts namely FAT, cingulum and corpus callosum presumed to be responsible for postoperative SMA syndrome. Eight patients developed an SMA syndrome in the immediate post-operative period. Eleven patients did not develop any post-operative neurological deficits. In all these 11 patients it was apparent that the cingulum, FAT and the corpus callosal fibers were preserved during surgery by modifying the tumor resection technique. CONCLUSIONS: SMA syndrome is a frequent occurrence following surgery in patients with tumors in the region of the SMA complex. Surgical strategy that preserves the cingulum and the FAT can prevent the occurrence of the SMA syndrome.

A multicenter proof-of-concept study on deep learning-based intraoperative discrimination of primary central nervous system lymphoma.

Accurate intraoperative differentiation of primary central nervous system lymphoma (PCNSL) remains pivotal in guiding neurosurgical decisions. However, distinguishing PCNSL from other lesions, notably glioma, through frozen sections challenges pathologists. Here we sought to develop and validate a deep learning model capable of precisely distinguishing PCNSL from non-PCNSL lesions, especially glioma, using hematoxylin and eosin (H&E)-stained frozen whole-slide images. Also, we compared its performance against pathologists of varying expertise. Additionally, a human-machine fusion approach integrated both model and pathologic diagnostics. In external cohorts, LGNet achieved AUROCs of 0.965 and 0.972 in distinguishing PCNSL from glioma and AUROCs of 0.981 and 0.993 in differentiating PCNSL from non-PCNSL lesions. Outperforming several pathologists, LGNet significantly improved diagnostic performance, further augmented to some extent by fusion approach. LGNet's proficiency in frozen section analysis and its synergy with pathologists indicate its valuable role in intraoperative diagnosis, particularly in discriminating PCNSL from glioma, alongside other lesions.