Optimizing Glioblastoma, IDH-wildtype Treatment Outcomes : A Radiomics and Support Vector Machine -Based Approach to Overall Survival Estimation.

Objective: Glioblastoma multiforme (GBM), particularly the IDH-wildtype type, represents a significant clinical challenge due to its aggressive nature and poor prognosis. Despite advancements in medical imaging and its modalities, survival rates have not improved significantly, demanding innovative treatment planning and outcome prediction approaches. Methods: This study utilizes a Support Vector Machine (SVM) classifier using radiomics features to predict the overall survival (OS) of GBM, IDH-wildtype patients to short (< 12 Months) and long (>=12 Months) survivors. A dataset comprising multi-parametric MRI (mpMRI) scans from 574 patients was analyzed. Radiomic features were extracted from T1, T2, FLAIR, and T1-Gd sequences. Low variance features were removed, and Recursive Feature Elimination (RFE) was used to select the most informative features. The SVM model was trained using a k-fold cross-validation approach. Furthermore, clinical parameters such as age, gender, and MGMT promoter methylation status were integrated to enhance prediction accuracy. Results: The model showed reasonable results in terms of cross-validated AUC of 0.84 (95% CI: 0.80-0.90) with (p-value < 0.001) effectively categorizing patients into short and long survivors. Log-rank test (Chi-square statistics) analysis for the developed model was 0.00029 along with the 1.20 Cohen's d effect size. Most importantly, clinical data integration further refined the survival estimates, providing a more fitted prediction that considers individual patient characteristics by Kaplan-Meier curve with p-value<0.0001. Conclusion: The proposed method significantly enhances the predictive accuracy of OS outcomes in GBM, IDH-wildtype patients. By integrating detailed imaging features with key clinical indicators, this model offers a robust tool for personalized treatment planning, potentially improving OS.

Elevated expression of N-myc downstream regulated gene 1 protein in glioblastomas reflects tumor angiogenesis and poor patient prognosis.

N-myc downstream regulated gene 1 (NDRG1) is a member of the NDRG family, of which four members (NDRG1, NDRG2, NDRG3, and NDRG4) have been identified. NDRG1 is repressed by c-MYC and N-MYC proto-oncogenes. NDRG1 is translated into a 43 kDa protein that is associated with the regulation of cellular stress responses, proliferation, and differentiation. In this study, we aimed to clarify the relationship between progression of glioblastoma (GB) IDH-wildtype and NDRG1 expression in tumor cells. We assessed the expression of NDRG1 in 41 GBs using immunostaining and evaluated its prognostic significance. NDRG1 expression by GBs was evaluated using Histoscore, which showed high and low scores in 23 and 18 cases, respectively. NDRG1-positive cells were strongly expressed in Ki-67 labeled proliferating tumor cells and CD105 positive proliferating microvessels around the area of palisading necrosis. Statistical analyses showed lower survival rates in the high-score group than the low-score group (P < 0.01). This study indicated that overexpression of NDRG1 by GB reflects tumor angiogenesis and poor patient prognosis.

Impact of frailty on survival glioblastoma, IDH-wildtype patients.

PURPOSE: Frailty increases the risk of mortality among patients. We studied the prognostic significance of frailty using the modified 5-item frailty index (5-mFI) in patients harboring a newly diagnosed supratentorial glioblastoma, IDH-wildtype. METHODS: We retrospectively reviewed records of patients surgical treated at a single neurosurgical institution at the standard radiochemotherapy era (January 2006 - December 2021). Inclusion criteria were: age ≥ 18, newly diagnosed glioblastoma, IDH-wildtype, supratentorial location, available data to assess the 5-mFI index. RESULTS: A total of 694 adult patients were included. The median overall survival was longer in the non-frail subgroup (5-mFI < 2, n = 538 patients; 14.3 months, 95%CI 12.5-16.0) than in the frail subgroup (5-mFI ≥ 2, n = 156 patients; 4.7 months, 95%CI 4.0-6.5 months; p < 0.001). 5-mFI ≥ 2 (adjusted Hazard Ratio (aHR) 1.31; 95%CI 1.07-1.61; p = 0.009) was an independent predictor of a shorter overall survival while age ≤ 60 years (aHR 0.78; 95%CI 0.66-0.93; p = 0.007), KPS score ≥ 70 (aHR 0.71; 95%CI 0.58-0.87; p = 0.001), unilateral location (aHR 0.67; 95%CI 0.52-0.87; p = 0.002), total removal (aHR 0.54; 95%CI 0.44-0.64; p < 0.0001), and standard radiochemotherapy protocol (aHR 0.32; 95%CI 0.26-0.38; p < 0.0001) were independent predictors of a longer overall survival. Frailty remained an independent predictor of overall survival within the subgroup of patients undergoing a first-line oncological treatment after surgery (n = 549) and within the subgroup of patients who benefited from a total removal plus adjuvant standard radiochemotherapy (n = 209). CONCLUSION: In newly diagnosed supratentorial glioblastoma, IDH-wildtype patients treated at the standard combined radiochemotherapy era, frailty, defined using a 5-mFI score ≥ 2 was an independent predictor of overall survival.

Transformation of IDH-wildtype glioblastoma to gliosarcoma with features of osteosarcoma.

Gliosarcoma (GS) is a rare variant of IDH-wildtype glioblastoma. It is classified as grade 4 in the latest WHO CNS classification of both glial and mesenchymal components. Gliosarcoma may arise de novo or secondary from glioblastoma. It occurs in up to 2% of patients diagnosed with glioblastoma. We present a case report of a 51-year-old patient who was initially diagnosed with glioblastoma multiforme, which transformed into secondary gliosarcoma with an osteosarcoma component 16 months after the initial diagnosis. We believe that increasing reporting of secondary gliosarcoma (sGS) will be helpful in understanding, diagnosing and providing more effective treatment for this cancer.

Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile.

BACKGROUND: The term Gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features have not been established yet. METHODS: We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization. RESULTS: Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-years survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2-55.7); grade III: 15.9 months (11.4-26.3); grade IV: 10.4 months (8.8-14.4). By DNA methylation profiling (n=49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wildtype (n=31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n=19), pedHGG_A/B (n=6), and pedHGG_MYCN (n=5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wildtype subgroup, recurrent alterations in EGFR (n=10) and BCOR (n=9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wildtype subgroup TP53 alterations had a significant negative effect on OS. CONCLUSION: Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements).

Proteomics of tumor and serum samples from isocitrate dehydrogenase-wildtype glioblastoma patients: is the detoxification of reactive oxygen species associated with shorter survival?

Proteomics has been little used for the identification of novel prognostic and/or therapeutic markers in isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GB). In this study, we analyzed 50 tumor and 30 serum samples from short- and long-term survivors of IDH-wildtype GB (STS and LTS, respectively) by data-independent acquisition mass spectrometry (DIA-MS)-based proteomics, with the aim of identifying such markers. DIA-MS identified 5422 and 826 normalized proteins in tumor and serum samples, respectively, with only three tumor proteins and 26 serum proteins displaying significant differential expression between the STS and LTS groups. These dysregulated proteins were principally associated with the detoxification of reactive oxygen species (ROS). In particular, GB patients in the STS group had high serum levels of malate dehydrogenase 1 (MDH1) and ribonuclease inhibitor 1 (RNH1) and low tumor levels of fatty acid-binding protein 7 (FABP7), which may have enabled them to maintain low ROS levels, counteracting the effects of the first-line treatment with radiotherapy plus concomitant and adjuvant temozolomide. A blood score built on the levels of MDH1 and RNH1 expression was found to be an independent prognostic factor for survival based on the serum proteome data for a cohort of 96 IDH-wildtype GB patients. This study highlights the utility of circulating MDH1 and RNH1 biomarkers for determining the prognosis of patients with IDH-wildtype GB. Furthermore, the pathways driven by these biomarkers, and the tumor FABP7 pathway, may constitute promising therapeutic targets for blocking ROS detoxification to overcome resistance to chemoradiotherapy in potential GB STS.

EGFR/CEP7 high polysomy is separate and distinct from EGFR amplification in glioblastoma as determined by fluorescence in situ hybridization.

EGFR amplification in gliomas is commonly defined by an EGFR/CEP7 ratio of ≥2. In testing performed at a major reference laboratory, a small subset of patients had ≥5 copies of both EGFR and CEP7 yet were not amplified by the EGFR/CEP7 ratio and were designated high polysomy cases. To determine whether these tumors are more closely related to traditionally defined EGFR-amplified or nonamplified gliomas, a retrospective search identified 22 out of 1143 (1.9%) gliomas with an average of ≥5 copies/cell of EGFR and CEP7 with an EGFR/CEP7 ratio of <2 displaying high polysomy. Of these cases, 4 had insufficient clinicopathologic data to include in additional analysis, 15 were glioblastomas, 2 were IDH-mutant astrocytomas, and 1 was a high-grade glial neoplasm, NOS. Next-generation sequencing available on 3 cases demonstrated one with a TERT promoter mutation, TP53 mutations in all cases, and no EGFR mutations or amplifications, which most closely matched the nonamplified cases. The median overall survival times were 42.86, 66.07, and 41.14 weeks for amplified, highly polysomic, and nonamplified, respectively, and were not significantly different (p = 0.3410). High chromosome 7 polysomic gliomas are rare but our data suggest that they may be biologically similar to nonamplified gliomas.

Leptomeningeal Dissemination Complicated With Acute Tetraplegia From a Supratentorial Multicentric Isocitrate Dehydrogenase (IDH)-Wildtype Glioblastoma: A Case Report.

Glioblastoma (GBM) is a major concern for neurosurgeons and oncologists, being a malignant tumor with a high recurrence rate and reduced survival. Leptomeningeal dissemination (LMD) of GBM is rare and difficult to diagnose due to the low rate of cellular detection in the cerebrospinal fluid and clinical and imaging similarities with fungal and tuberculous meningitis. We report the case of a 25-year-old female patient suffering from multicentric GBM who developed hydrocephalus and extensive LMD three months after surgery for a left frontal parafalcine cerebral GBM isocitrate dehydrogenase (IDH)-wildtype.

Isocitrate Dehydrogenase 1/2 Wildtype Adult Astrocytoma with WHO Grade 2/3 Histological Features: Molecular Re-Classification, Prognostic Factors, Clinical Outcomes.

BACKGROUND: Isocitrate Dehydrogenase 1/2 (IDH 1/2)-wildtype (WT) astrocytomas constitute a heterogeneous group of tumors and have undergone a series of diagnostic reclassifications over time. This study aimed to investigate molecular markers, clinical, imaging, and treatment factors predictive of outcomes in WHO grade 2/3 IDH-WT astrocytomas ('early glioblastoma'). METHODOLOGY: Patients with WHO grade 2/3 IDH-WT astrocytomas were identified from the hospital archives. They were cross-referenced with the electronic medical records systems, including neuroimaging. The expert neuro-pathology team retrieved data on molecular markers-MGMT, TERT, IDH, and EGFR. Tumors with a TERT mutation and/or EGFR amplification were reclassified as glioblastoma. RESULTS: Fifty-four patients were identified. Sixty-three percent of the patients could be conclusively reclassified as glioblastoma based on either TERT mutation, EGFR amplification, or both. On imaging, 65% showed gadolinium enhancement on MRI. Thirty-nine patients (72%) received long-course radiotherapy, of whom 64% received concurrent chemotherapy. The median follow-up of the group was 16 months (range: 2-90), and the median overall survival (OS) was 17.3 months. The 2-year OS of the whole cohort was 31%. On univariate analysis, older age, worse performance status (PS), and presence versus absence of contrast enhancement on diagnostic MRI were statistically significant for poorer OS. CONCLUSION: IDH-WT WHO grade 2/3 astrocytomas are a heterogeneous group of tumors with poor clinical outcomes. The majority can be reclassified as glioblastoma, based on current WHO classification criteria, but further understanding of the underlying biology of these tumors and the discovery of novel targeted agents are needed for better outcomes.

The Roles of AGTRAP, ALKBH3, DIVERSIN, NEDD8 and RRM1 in Glioblastoma Pathophysiology and Prognosis.

This study determined the expression of five novel biomarker candidates in IDH wild-type glioblastoma (GBM) tissues compared to non-malign brain parenchyma, as well as their prognostic relevance for the GBM patients' outcomes. The markers were analysed by immunohistochemistry in tumour tissues (n = 186) and healthy brain tissues (n = 54). The association with the patients' overall survival (OS) and progression-free survival (PFS) was assessed by Kaplan-Meier and log-rank test. The prognostic value of the markers was determined using multivariate Cox proportional hazard models. AGTRAP, DIVERSIN, cytoplasmic NEDD8 (NEDD8c) and RRM1 were significantly overexpressed in tumour tissues compared to the healthy brain, while the opposite was observed for ALKBH3. AGTRAP, ALKBH3, NEDD8c and RRM1 were significantly associated with OS in univariate analysis. AGTRAP and RRM1 were also independent prognostic factors for OS in multivariate analysis. For PFS, only AGTRAP and NEDD8c reached significance in univariate analysis. Additionally, AGTRAP was an independent prognostic factor for PFS in multivariate models. Finally, combined analysis of the markers enhanced their prognostic accuracy. The combination AGTRAP/ALKBH3 had the strongest prognostic value for the OS of GBM patients. These findings contribute to a better understanding of the GBM pathophysiology and may help identify novel therapeutic targets in this type of cancer.

ecGBMsub: an integrative stacking ensemble model framework based on eccDNA molecular profiling for improving IDH wild-type glioblastoma molecular subtype classification.

IDH wild-type glioblastoma (GBM) intrinsic subtypes have been linked to different molecular landscapes and outcomes. Accurate prediction of molecular subtypes of GBM is very important to guide clinical diagnosis and treatment. Leveraging machine learning technology to improve the subtype classification was considered a robust strategy. Several single machine learning models have been developed to predict survival or stratify patients. An ensemble learning strategy combines several basic learners to boost model performance. However, it still lacked a robust stacking ensemble learning model with high accuracy in clinical practice. Here, we developed a novel integrative stacking ensemble model framework (ecGBMsub) for improving IDH wild-type GBM molecular subtype classification. In the framework, nine single models with the best hyperparameters were fitted based on extrachromosomal circular DNA (eccDNA) molecular profiling. Then, the top five optimal single models were selected as base models. By randomly combining the five optimal base models, 26 different combinations were finally generated. Nine different meta-models with the best hyperparameters were fitted based on the prediction results of 26 different combinations, resulting in 234 different stacked ensemble models. All models in ecGBMsub were comprehensively evaluated and compared. Finally, the stacking ensemble model named "XGBoost.Enet-stacking-Enet" was chosen as the optimal model in the ecGBMsub framework. A user-friendly web tool was developed to facilitate accessibility to the XGBoost.Enet-stacking-Enet models (https://lizesheng20190820.shinyapps.io/ecGBMsub/).

Pediatric-type high-grade gliomas with PDGFRA amplification in adult patients with Li-Fraumeni syndrome: clinical and molecular characterization of three cases.

Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome caused by heterozygous germline mutations or deletions in the TP53 tumor suppressor gene. Central nervous system tumors, such as choroid plexus tumors, medulloblastomas, and diffuse gliomas, are frequently found in patients with LFS. Although molecular profiles of diffuse gliomas that develop in pediatric patients with LFS have been elucidated, those in adults are limited. Recently, diffuse gliomas have been divided into pediatric- and adult-type gliomas, based on their distinct molecular profiles. In the present study, we investigated the molecular profiles of high-grade gliomas in three adults with LFS. These tumors revealed characteristic histopathological findings of high-grade glioma or glioblastoma and harbored wild-type IDH1/2 according to whole exome sequencing (WES). However, these tumors did not exhibit the key molecular alterations of glioblastoma, IDH-wildtype such as TERT promoter mutation, EGFR amplification, or chromosome 7 gain and 10 loss. Although WES revealed no other characteristic gene mutations or copy number alterations in high-grade gliomas, such as those in histone H3 genes, PDGFRA amplification was found in all three cases together with uniparental disomy of chromosome 17p, where the TP53 gene is located. DNA methylation analyses revealed that all tumors exhibited DNA methylation profiles similar to those of pediatric-type high-grade glioma H3-wildtype and IDH-wildtype (pHGG H3-/IDH-wt), RTK1 subtype. These data suggest that high-grade gliomas developed in adult patients with LFS may be involved in pHGG H3-/IDH-wt. PDGFRA and homozygous alterations in TP53 may play pivotal roles in the development of this type of glioma in adult patients with LFS.

Accuracy of MRI in Detecting 1p/19q Co-deletion Status of Gliomas: A Single-Center Retrospective Study.

Background Oligodendrogliomas, rare brain tumors in the frontal lobe's white matter, are reshaped by molecular markers like isocitrate dehydrogenase mutations and 1p/19q co-deletion, influencing treatment outcomes. Despite the initial indolence, these tumors pose a significant risk, with a median survival of 10-12 years. Non-invasive alternatives, such as magnetic resonance imaging (MRI) for assessing T2-fluid-attenuated inversion recovery (FLAIR) mismatch and calcifications, provide insights into molecular subtypes and aid prognosis. Our study explored these features to predict the oligodendroglioma status and refine patient management to improve outcomes. Methods In this retrospective study, patient data identified patients with suspected central nervous system tumors undergoing MRI, revealing low-grade gliomas. Surgical biopsy and 1p/19q fluorescence in situ hybridization confirmed the co-deletion status. MRI was used to assess various morphological features. Statistical analyses included x2 tests, Fisher's exact tests, Kruskal-Wallis tests, and binary logistic regression models, with significance set at p < 0.05. Results Seventy-three patients (median age, 37 years) were stratified according to 1p/19q co-deletion. Most (61.6%) were 18-40 years old and mostly male (67.1%). Co-deletion cases, primarily frontal lobe lesions (67.6%), were unilateral (88.2%), with 55.9% non-circumscribed margins and 58.8% ill-defined contours. Smooth contrast enhancement and no necrosis were observed in 48.1% of 1p/19q co-deletion cases. Logistic regression analysis showed a significant association between ill-defined/irregular contours and 1p/19q co-deletion. Fisher's exact test confirmed this but raised concerns about the small sample size influencing the conclusions. Conclusions This study established a significant link between glioma tumor contour characteristics, particularly irregular and ill-defined contours, and the likelihood of 1p/19q co-deletion. Our findings underscore the clinical relevance of using tumor contours in treatment decisions and prognosis assessments.

Clinicopathological and Molecular Characteristics of IDH-Wildtype Glioblastoma with FGFR3::TACC3 Fusion.

The World Health Organization Classification of Tumors of the Central Nervous System recently incorporated histological features, immunophenotypes, and molecular characteristics to improve the accuracy of glioblastoma (GBM) diagnosis. FGFR3::TACC3 (F3T3) fusion has been identified as an oncogenic driver in IDH-wildtype GBMs. Recent studies have demonstrated the potential of using FGFR inhibitors in clinical trials and TACC3-targeting agents in preclinical models for GBM treatment. However, there is limited information on the clinicopathological and genetic features of IDH-wildtype GBMs with F3T3 fusion. The aim of this study was to comprehensively investigate the clinical manifestations, histological features, and mutational profiles of F3T3-positive GBMs. Between September 2017 and February 2023, 25 consecutive cases (5.0%) of F3T3-positive GBM were extracted from 504 cases of IDH-wildtype GBM. Clinicopathological information and targeted sequencing results obtained from 25 primary and 4 recurrent F3T3-positive GBMs were evaluated and compared with those from F3T3-negative GBMs. The provisional grades determined by histology only were distributed as follows: 4 (26/29; 89.7%), 3 (2/29; 6.9%), and 2 (1/29; 3.4%). Grade 2-3 tumors were ultimately diagnosed as grade 4 GBMs based on the identification of the TERT promoter mutation and the combined gain of chromosome 7 and loss of chromosome 10 (7+/10-). F3T3-positive GBMs predominantly affected women (2.6 females per male). The mean age of patients with an F3T3-positive GBM at initial diagnosis was 62 years. F3T3-positive GBMs occurred more frequently in the cortical locations compared to F3T3-negative GBMs. Imaging studies revealed that more than one-third (12/29; 41.4%) of F3T3-positive GBMs displayed a circumscribed tumor border. Seven of the seventeen patients (41.2%) whose follow-up periods exceeded 20 months died of the disease. Histologically, F3T3-positive GBMs more frequently showed curvilinear capillary proliferation, palisading nuclei, and calcification compared to F3T3-negative GBMs. Molecularly, the most common alterations observed in F3T3-positive GBMs were TERT promoter mutations and 7+/10-, whereas amplifications of EGFR, PDGFRA, and KIT were not detected at all. Other genetic alterations included CDKN2A/B deletion, PTEN mutation, TP53 mutation, CDK4 amplification, and MDM2 amplification. Our observations suggest that F3T3-positive GBM is a distinct molecular subgroup of the IDH-wildtype GBM. Both clinicians and pathologists should consider this rare entity in the differential diagnosis of diffuse astrocytic glioma to make an accurate diagnosis and to ensure appropriate therapeutic management.

Diagnostic utility of genetic alterations in distinguishing IDH-wildtype glioblastoma from lower-grade gliomas: Insight from next-generation sequencing analysis of 479 cases.

The accurate diagnosis and classification of gliomas are essential for appropriate treatment planning and prognosis prediction. This study aimed to investigate the molecular diagnostics of IDH-wildtype diffuse astrocytic gliomas and identify potential genetic variants that could differentiate glioblastoma (GBM) from lower-grade gliomas when DNA methylation analysis is not feasible. In total, 479 H3-and IDH-wildtype diffuse astrocytic gliomas were included in this study. All the cases were diagnosed according to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors. Panel sequencing data were collected, and clinicopathological information was retrieved from medical records. Genetic alterations and histological findings were analyzed to determine their diagnostic utility and prognostic implications. Out of 479 cases, 439 (91.6%) were diagnosed with GBM, including 28 cases that were molecularly diagnosed as GBM. However, 40 (8.4%) cases could not be classified according to the 2021 WHO classification and were diagnosed as lower-grade diffuse astrocytic glioma, IDH-wildtype, not elsewhere classified (LGNEC). In addition to the three genetic alterations included in the diagnostic criteria of GBM, PTEN and EGFR mutations were found to be enriched in GBM. Patients harboring mTOR pathway mutations demonstrated a more favorable prognosis and often exhibited morphology resembling subependymal giant cell astrocytoma, along with a high tumor mutational burden. Among patients with mTOR pathway mutations, those lacking molecular diagnostic features of GBM exhibited outstanding survival outcomes, even in the presence of grade 4 histology. Integration of molecular features enhanced the diagnostic accuracy of IDH-wildtype gliomas. Some molecular alterations enriched in GBM offer valuable insights for molecular diagnosis and glioma classification. Furthermore, high-grade diffuse astrocytic gliomas featuring mTOR pathway mutations in the absence of molecular diagnostic features of GBM could represent more favorable tumor types distinct from GBM.

The effect of p53 on the activity of NRF2 and NDRG2 genes through apoptotic pathway in IDH-wildtype glioblastoma.

BACKGROUND: Tumor suppressor (p53) acts to integrate multiple stress signals into diverse antiproliferative responses. Its potential to transactivate or downregulate genes through apoptotic pathway in IDH-wildtype glioblastoma has never been explored. METHODS: A group of twenty patients diagnosed with IDH-wildtype glioblastoma, were tested for p53 expression and NDRG2/NRF2 genes activity through protein and gene profiling assays. The connotation between these elements has been explored. RESULTS: The mean patients' age was 64-years. All tumors were IDH-wildtype. p53 was expressed in 12 tumors and absent in 8 tumors. The activity of NDRG2 gene was downregulated in all cases. The activity of NRF2 gene was upregulated in 17 tumors and downregulated in 3 tumors. There was a significant statistical difference in PFS among tumors exhibiting different levels of p53 expression and NDRG2 gene activity [p-value= 0.025], in which 12 tumors with downregulated NDRG2 expression and positive p53 expression had earlier tumor recurrence. This statistical difference in PFS was insignificant when we compared p53 expression with NRF2 gene activity [p-value= 0.079]. CONCLUSIONS: During cell cycle arrest at G2 phase, p53 expression in IDH-wildtype glioblastoma in elderly individuals, coupled with the downregulation of NDRG2 gene activity, led to an aberrant increase in tumor cell proliferation and accelerated tumor recurrence. However, the influence of p53 on NRF2 gene activity was found to be insignificant.

Advances in molecular and imaging biomarkers in lower-grade gliomas.

INTRODUCTION: Lower-grade (grade 2-3) gliomas (LGGs) constitutes a group of primary brain tumors with variable clinical behaviors and treatment responses. Recent advancements in molecular biology have redefined their classification, and novel imaging modalities emerged for the noninvasive diagnosis and follow-up. AREAS COVERED: This review comprehensively analyses the current knowledge on molecular and imaging biomarkers in LGGs. Key molecular alterations, such as IDH mutations and 1p/19q codeletion, are discussed for their prognostic and predictive implications in guiding treatment decisions. Moreover, the authors explore theranostic biomarkers for the potential of tailored therapies. Additionally, they also describe the utility of advanced imaging modalities, including widely available techniques, as dynamic susceptibility contrast perfusion-weighted imaging and less validated, emerging approaches, for the noninvasive LGGs characterization and follow-up. EXPERT OPINION: The integration of molecular markers enhanced the stratification of LGGs, leading to the new concept of integrated histomolecular classification. While the IDH mutation is an established key prognostic and predictive marker, recent results from IDH inhibitors trials showed its potential value as a theranostic marker. In this setting, advanced MRI techniques such as 2-D-hydroxyglutarate spectroscopy are very promising for the noninvasive diagnosis and monitoring of LGGs. This progress offers exciting prospects for personalized medicine and improved treatment outcomes in LGGs.

Biological underpinnings of radiomic magnetic resonance imaging phenotypes for risk stratification in IDH wild-type glioblastoma.

BACKGROUND: To develop and validate a conventional MRI-based radiomic model for predicting prognosis in patients with IDH wild-type glioblastoma (GBM) and reveal the biological underpinning of the radiomic phenotypes. METHODS: A total of 801 adult patients (training set, N = 471; internal validation set, N = 239; external validation set, N = 91) diagnosed with IDH wild-type GBM were included. A 20-feature radiomic risk score (Radscore) was built for overall survival (OS) prediction by univariate prognostic analysis and least absolute shrinkage and selection operator (LASSO) Cox regression in the training set. GSEA and WGCNA were applied to identify the intersectional pathways underlying the prognostic radiomic features in a radiogenomic analysis set with paired MRI and RNA-seq data (N = 132). The biological meaning of the conventional MRI sequences was revealed using a Mantel test. RESULTS: Radscore was demonstrated to be an independent prognostic factor (P < 0.001). Incorporating the Radscore into a clinical model resulted in a radiomic-clinical nomogram predicting survival better than either the Radscore model or the clinical model alone, with better calibration and classification accuracy (a total net reclassification improvement of 0.403, P < 0.001). Three pathway categories (proliferation, DNA damage response, and immune response) were significantly correlated with the prognostic radiomic phenotypes. CONCLUSION: Our findings indicated that the prognostic radiomic phenotypes derived from conventional MRI are driven by distinct pathways involved in proliferation, DNA damage response, and immunity of IDH wild-type GBM.

Glioblastoma Multiforme in a Patient With Alpha-1-Antitrypsin Deficiency.

Alpha-1 antitrypsin (A1AT) is a common genetic disease caused by a mutation in the SERPINA1 gene, predisposing patients to severe premature lung and liver disease. Higher expression of SERPINA1 has been associated with a poor prognosis in patients with high-grade glioblastoma. We present a woman in her 70s with a history of A1AT deficiency treated with weekly plasma-purified A1AT infusions, who presented with metabolic encephalopathy. A CT scan of the brain obtained during admission revealed a left frontal lobe mass measuring 1.1 cm. A craniotomy and resection of the lesion were performed, and the pathology studies revealed a glioblastoma multiforme, WHO grade IV. She is currently healing and awaiting treatment with temozolomide with concomitant radiation and tolerating treatment well.

Establishment of a Prediction Model Based on Preoperative MRI Radiomics for Diffuse Astrocytic Glioma, IDH-Wildtype, with Molecular Features of Glioblastoma.

PURPOSE: In 2021, the WHO central nervous system (CNS) tumor classification criteria added the diagnosis of diffuse astrocytic glioma, IDH wild-type, with molecular features of glioblastoma, WHO grade 4 (DAG-G). DAG-G may exhibit the aggressiveness and malignancy of glioblastoma (GBM) despite the lower histological grade, and thus a precise preoperative diagnosis can help neurosurgeons develop more refined individualized treatment plans. This study aimed to establish a predictive model for the non-invasive identification of DAG-G based on preoperative MRI radiomics. PATIENTS AND METHODS: Patients with pathologically confirmed glioma in Huashan Hospital, Fudan University, between September 2019 and July 2021 were retrospectively analyzed. Furthermore, two external validation datasets from Wuhan Union Hospital and Xuzhou Cancer Hospital were also utilized to verify the reliability and accuracy of the prediction model. Two regions of interest (ROI) were delineated on the preoperative MRI images of the patients using the semi-automatic tool ITK-SNAP (version 4.0.0), which were named the maximum anomaly region (ROI1) and the tumor region (ROI2), and Pyradiomics 3.0 was applied for feature extraction. Feature selection was performed using a least absolute shrinkage and selection operator (LASSO) filter and a Spearman correlation coefficient. Six classifiers, including Gauss naive Bayes (GNB), K-nearest neighbors (KNN), Random forest (RF), Adaptive boosting (AB), and Support vector machine (SVM) with linear kernel and multilayer perceptron (MLP), were used to build the prediction models, and the prediction performance of the six classifiers was evaluated by fivefold cross-validation. Moreover, the performance of prediction models was evaluated using area under the curve (AUC), precision (PRE), and other metrics. RESULTS: According to the inclusion and exclusion criteria, 172 patients with grade 2-3 astrocytoma were finally included in the study, and a total of 44 patients met the diagnosis of DAG-G. In the prediction task of DAG-G, the average AUC of GNB classifier was 0.74 ± 0.07, that of KNN classifier was 0.89 ± 0.04, that of RF classifier was 0.96 ± 0.03, that of AB classifier was 0.97 ± 0.02, that of SVM classifier was 0.88 ± 0.05, and that of MLP classifier was 0.91 ± 0.03, among which, AB classifier achieved the best prediction performance. In addition, the AB classifier achieved AUCs of 0.91 and 0.89 in two external validation datasets obtained from Wuhan Union Hospital and Xuzhou Cancer Hospital, respectively. CONCLUSIONS: The prediction model constructed based on preoperative MRI radiomics established in this study can basically realize the prospective, non-invasive, and accurate diagnosis of DAG-G, which is of great significance to help further optimize treatment plans for such patients, including expanding the extent of surgery and actively administering radiotherapy, targeted therapy, or other treatments after surgery, to fundamentally maximize the prognosis of patients.