Including Isocitrate Dehydrogenase Research Articles

Advancing the Management of Skull Base Chondrosarcomas: A Systematic Review of Targeted Therapies.

Chondrosarcomas rank as the second most common primary bone malignancy. Characterized by the production of a cartilaginous matrix, these tumors typically exhibit resistance to both radiotherapy (RT) and chemotherapy (CT), resulting in overall poor outcomes: a high rate of mortality, especially among children and adolescents. Due to the considerable resistance to current conventional therapies such as surgery, CT, and RT, there is an urgent need to identify factors contributing to resistance and discover new strategies for optimal treatment. Over the past decade, researchers have delved into the dysregulation of genes associated with tumor development and therapy resistance to identify potential therapeutic targets for overcoming resistance. Recent studies have suggested several promising biomarkers and therapeutic targets for chondrosarcoma, including isocitrate dehydrogenase (IDH1/2) and COL2A1. Molecule-targeting agents and immunotherapies have demonstrated favorable antitumor activity in clinical studies involving patients with advanced chondrosarcomas. In this systematic review, we delineate the clinical features of chondrosarcoma and provide a summary of gene dysregulation and mutation associated with tumor development, as well as targeted therapies as a promising molecular approach. Finally, we analyze the probable role of the tumor microenvironment in chondrosarcoma drug resistance. A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 10 November 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "chondrosarcomas", "target therapies", "immunotherapies", and "outcomes". The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of target therapies for the treatment of chondrosarcoma in human subjects. Of the initial 279 articles identified, 40 articles were included in the article. The exclusion of 140 articles was due to reasons such as irrelevance, non-reporting of selected results, systematic literature review or meta-analysis, and lack of details on the method/results. Three tables highlighted clinical studies, preclinical studies, and ongoing clinical trials, encompassing 13, 7, and 20 studies, respectively. For the clinical study, a range of molecular targets, such as death receptors 4/5 (DR4 and DR5) (15%), platelet-derived growth factor receptor-alpha or -beta (PDGFR-α, PDGFR-β) (31%), were investigated. Adverse events were mainly constitutional symptoms emphasizing that to improve therapy tolerance, careful observation and tailored management are essential. Preclinical studies analyzed various molecular targets such as DR4/5 (28.6%) and COX-2 (28.6%). The prevalent indicator of antitumoral activity was the apoptotic rate of both a single agent (tumor necrosis factor-related apoptosis-inducing ligand: TRAIL) and double agents (TRAIL-DOX, TRAIL-MG132). Ongoing clinical trials, the majority in Phase II (53.9%), highlighted possible therapeutic strategies such as IDH1 inhibitors and PD-1/PD-L1 inhibitors (30.8%). The present review offers a comprehensive analysis of targeted therapeutics for skull base chondrosarcomas, highlighting a complex landscape characterized by a range of treatment approaches and new opportunities for tailored interventions. The combination of results from molecular research and clinical trials emphasizes the necessity for specialized treatment strategies and the complexity of chondrosarcoma biology.

A custom next-generation sequencing panel for 1p/19q codeletion and mutational analysis in gliomas.

The World Health Organization has updated their classification system for the diagnosis of gliomas, combining histological features with molecular data including isocitrate dehydrogenase 1 and codeletion of chromosomal arms 1p and 19q. 1p/19q codeletion analysis is commonly performed by fluorescence in situ hybridization (FISH). In this study, we developed a 57-gene targeted next-generation sequencing (NGS) panel including 1p/19q codeletion detection mainly to assess diagnosis and potential treatment response in melanoma, gastrointestinal stromal tumor, and glioma patients. Loss of heterozygosity analysis was performed using the NGS method on 37 formalin-fixed paraffin-embedded glioma tissues that showed 1p and/or 19q loss determined by FISH. Conventional methods were applied for the validation of some glioma-related gene mutations. In 81.1% (30 of 37) and 94.6% (35 of 37) of cases, 1p and 19q were found to be in agreement whereas concordance for 1p/19q codeletion and no 1p/19q codeletion was found in 94.7% (18 of 19) and 94.4% (17 of 18) of cases, respectively. Overall, comparing NGS results with those of conventional methods showed high concordance. In conclusion, the NGS panel allows reliable analysis of 1p/19q codeletion and mutation at the same time.

Identification and validation of prognostic genes and immune landscape signatures based on a fatty acid oxidation‑related risk score model in glioma.

Fatty acid oxidation (FAO) plays a crucial role in glioma metabolism and its interaction with the immune microenvironment. The aim of the present study was to investigate the relationship between FAO-related genes and glioma by constructing gene clusters using a glioma cohort. A total of 287 differentially expressed genes related to FAO were identified and the top 50 genes were selected based on their P-values. Subsequently, patients were classified into two distinct gene subtypes (A and B) based on these genes. Scores for each patient were calculated using the 50 genes and the patients were divided into the high and low-score groups accordingly. Patients in subtype B exhibited higher tumor grades and poor prognostic factors such as older age and worse survival rates. The high-score subgroup had unfavorable indicators, including isocitrate dehydrogenase 1 wild-type, high tumor grade and 1p19q non-codeleted, while immune checkpoint expression was generally higher in the high-score subgroup. The constructed scoring model was validated using an external dataset, and the tissue inhibitor of metalloproteinase 1 gene was identified through protein interaction analysis, suggesting its potential involvement in glioma malignancy and promotion of glioblastoma proliferation. In conclusion, FAO-related genes may contribute to tumor development through immune mechanisms and the present study may provide novel insights for potential therapeutic strategies in glioma treatment.

Measurable Residual IDH2 before Allogeneic Transplant for Acute Myeloid Leukemia

Introduction: Detection of measurable residual disease (MRD) in AML patients during remission is associated with adverse clinical outcomes after allogeneic hematopoietic cell transplant (alloHCT), including recent strong evidence from our group regarding residual NPM1 and/or FLT3-ITD variants (PMID: 36881031). Large studies examining the significance of other potential MRD targets, including isocitrate dehydrogenase isoform 2 ( IDH2), are needed. IDH2, which is mutated in approximately 12% of AML patients, is of particular interest due to the possibility of targeted clinical intervention. Methods: Patients over the age of 18 in first complete remission (CR1) with IDH2 mutated AML undergoing alloHCT transplant at a CIBMTR site between 2013-2019 with remission blood samples within 100 days of alloHCT and available clinical data were included in this study. Residual variants in IDH2, NPM1, and FLT3genes were detected by ultrasensitive error-corrected next-generation sequencing (NGS-MRD) on genomic DNA from pre-conditioning blood and validated by digital droplet PCR (ddPCR). The primary outcomes were overall survival (OS) and cumulative incidence of relapse with non-relapse mortality as a competing risk. The day of transplant was considered as time 0, and the median follow-up time was calculated for censored patients. Kaplan-Meier estimation (log-rank tests), Cox proportional hazards models, and Fine-Gray regression models were fitted to examine the clinical outcomes. Results: Among the 257 IDH2-mutated AML patients in this study, 57 (23%) experienced relapse, with 41 events occurring within 12 months after alloHCT. The median follow-up time was 25 months. Among 247 patients with pre-transplant remission flow cytometry results reported, 25% were positive, but no difference in rates of relapse or OS was observed between positive and negative patients. NGS MRD analysis detected residual IDH2 variants in remission samples of 130 patients (51%) with variant allele fraction (VAF) ranging from 0.05-56% (median: 3%), and 100% validation by ddPCR. NGS MRD IDH2 positive patients had increased rates of relapse (p = 0.03; 3yr: +11%, 95% CI: 0.2% to 22%) and decreased OS (p < 0.001; 3yr: -25%, 95% CI: -13% to -38%) compared to those who tested negative (Figure 1A). These OS differences were still observed between NGS MRD IDH2 positive and negative patients, regardless of age stratification (under 60yr p < 0.001, 3yr: -28%, 95% CI: -12% to -43%; over 60yr p = 0.04, 3yr: -19%, 95% CI: -1% to -40%); however, only patients over 60yrs had increased rates of relapse (p = 0.007; 3yr: +21, 95% CI: 6% to 36%). The impact of co-mutation status was examined by subdividing the cohort based on the presence of NPM1 or FLT3-ITD mutations at baseline. Residual IDH2 variants in patients without baseline NPM1 or FLT3-ITD co-mutations (n = 151) were associated with decreased OS and increased relapse ( IDH2+ vs IDH2-; OS p = 0.005, 3yr: -23%, 95% CI: -6% to -40%; Relapse p = 0.01, 3yr: +19, 95% CI: 6% to 32%; Figure 1B). In contrast, residual IDH2 variants were not predictive of relapse in co-mutated patients (n=106, p = 0.5). In these patients, the only prognostic marker for relapse was NPM1 and/or FLT3-ITD MRD, with similar relapse risk between IDH2 only positive and MRD negative groups (p < 0.001; 3yr: 83% vs. 11% vs. 15%; Figure 1B). In multivariable analysis, IDH2 MRD positivity was associated with decreased OS (HR 2.5, 95% CI: 1.5-4.2, p < 0.001) and increased rates of relapse (HR 2.1, 95% CI: 1.4-5.7, p = 0.003) after adjusting for other characteristics. Conclusion: In this study, we demonstrate that adult patients with IDH2-mutated AML who have IDH2 variants detected in CR1 prior to first alloHCT experienced increased relapse rates and decreased overall survival. However, this association is significant only in patients without baseline NPM1 and FLT3-ITD mutations. In co-mutated patients, NPM1 and/or FLT3-ITD MRD serve as superior prognostic markers. Subgroup analyses show the potential influence of factors such as conditioning intensity and age on clinical outcomes. Nevertheless, larger studies with balanced subgroups and more comprehensive baseline mutational information, including IDH2 mutation subtype, are needed to better define the clinical relevance of IDH2 MRD in this context.

How Antioxidants, Osmoregulation, Genes and Metabolites Regulate the Late Seeding Tolerance of Rapeseeds (Brassica napus L.) during Wintering.

Rapeseed seeding dates are largely delayed under the rice-rape rotation system, but how rapeseeds adapt to the delayed environment remains unclear. Here, five seeding dates (20 October, 30 October, 10 November, 20 November and 30 November, T1 to T5) were set and the dynamic differences between two late-seeding-tolerant (LST) and two late-seeding-sensitive (LSS) rapeseed cultivars were investigated in a field experiment. The growth was significantly repressed and the foldchange (LST/LSS) of yield increased from 1.50-T1 to 2.64-T5 with the delay in seeding. Both LST cultivars showed higher plant coverage than the LSS cultivars according to visible/hyperspectral imaging and the vegetation index acquired from an unmanned aerial vehicle. Fluorescence imaging, DAB and NBT staining showed that the LSS cultivars suffered more stress damage than the LST cultivars. Antioxidant enzymes (SOD, POD, CAT, APX) and osmoregulation substances (proline, soluble sugar, soluble protein) were decreased with the delay in seeding, while the LST cultivar levels were higher than those of the LSS cultivars. A comparative analysis of transcriptomes and metabolomes showed that 55 pathways involving 123 differentially expressed genes (DEGs) and 107 differentially accumulated metabolites (DAMs) participated in late seeding tolerance regulation, while 39 pathways involving 60 DEGs and 68 DAMs were related to sensitivity. Levanbiose, α-isopropylmalate, s-ribosyl-L-homocysteine, lauroyl-CoA and argino-succinate were differentially accumulated in both cultivars, while genes including isocitrate dehydrogenase, pyruvate kinase, phosphoenolpyruvate carboxykinase and newgene_7532 were also largely regulated. This study revealed the dynamic regulation mechanisms of rapeseeds on late seeding conditions, which showed considerable potential for the genetic improvement of rapeseed.

Improving Noninvasive Classification of Molecular Subtypes of Adult Gliomas With Diffusion-Weighted MR Imaging: An Externally Validated Machine Learning Algorithm.

Genetic testing for molecular markers of gliomas sometimes is unavailable because of time-consuming and expensive, even limited tumor specimens or nonsurgery cases. To train a three-class radiomic model classifying three molecular subtypes including isocitrate dehydrogenase (IDH) mutations and 1p/19q-noncodeleted (IDHmut-noncodel), IDH wild-type (IDHwt), IDH-mutant and 1p/19q-codeleted (IDHmut-codel) of adult gliomas and investigate whether radiomic features from diffusion-weighted imaging (DWI) could bring additive value. Retrospective. A total of 755 patients including 111 IDHmut-noncodel, 571 IDHwt, and 73 IDHmut-codel cases were divided into training (n=480) and internal validation set (n=275); 139 patients including 21 IDHmut-noncodel, 104 IDHwt, and 14 IDHmut-codel cases were utilized as external validation set. A 1.5T or 3.0 T/multiparametric MRI, including T1-weighted (T1), T1-weighted gadolinium contrast-enhanced (T1c), T2-weighted (T2), fluid attenuated inversion recovery (FLAIR), and DWI. The performance of multiparametric radiomic model (random-forest model) using 22 selected features from T1, T2, FLAIR, T1c images and apparent diffusion coefficient (ADC) maps, and conventional radiomic model using 20 selected features from T1, T2, FLAIR, and T1c images was assessed in internal and external validation sets by comparing probability values and actual incidence. Mann-Whitney U test, Chi-Squared test, Wilcoxon test, receiver operating curve (ROC), and area under the curve (AUC); DeLong analysis. P < 0.05 was statistically significant. The multiparametric radiomic model achieved AUC values for IDHmut-noncodel, IDHwt, and IDHmut-codel of 0.8181, 0.8524, and 0.8502 in internal validation set and 0.7571, 0.7779, and 0.7491 in external validation set, respectively. Multiparametric radiomic model showed significantly better diagnostic performance after DeLong analysis, especially in classifying IDHwt and IDHmut-noncodel subtypes. Radiomic features from DWI could bring additive value and improve the performance of conventional MRI-based radiomic model for classifying the molecular subtypes especially IDHmut-noncodel and IDHwt of adult gliomas. Stage 2.

Association of human telomerase reverse transcriptase promoter mutation with unfavorable prognosis in glioma: A systematic review and meta-analysis.

Glioma is one of the most malignant and aggressive tumors, with an extremely poor prognosis. Human telomerase reverse transcriptase (hTERT) promoter mutation is regarded as a risk factor in tumor growth. Although the prevalence of hTERT promoter (pTERT) mutation in gliomas has been investigated, the results are inconsistent. This meta-analysis aims to investigate the prognostic value of hTERT in glioma patients and its interaction with other biomarkers. We searched 244 citations from four databases: PubMed (2000-2021), Web of Science (2000-2021), Embase (2010-2021), and Cochrane Library (2000-2021) with 28 articles included. We calculated hazard ratios (HRs) using the random effect model and the pooled result suggested that TERT promoter mutation predicted poorer overall survival (HR: 1.53, 95% confidence interval [CI]: 1.34-1.75, P < 0.001, I2: 49.9%, pheterogeneity:0.002) and progression-free survival (HR: 1.55, 95% CI: 1.27-1.88, P < 0.001, I2: 0.0%, pheterogeneity: 0.473). For subgroup analysis, we analyzed multiple factors including iso-citrate dehydrogenase (IDH) genotype, age, diagnosis, pTERT region, so as to locate the sources of heterogeneity. Interestingly, in IDH mutant subgroup, pTERT mutation became a beneficial prognostic factor (HR: 0.73, 95% CI: 0.57-0.93, I2: 22.3%, pheterogeneity: 0.277), which is contrary to the results in pooled analysis. In general, pTERT mutation may result in shorter survival time in glioma patients, but longer survival time when glioma patients are combined with IDH mutation.

Effects of bamboo leaf extract on energy metabolism, antioxidant capacity, and biogenesis of small intestine mitochondria in broilers.

The present study was carried out to investigate the effects of bamboo leaf extract (BLE) on energy metabolism, antioxidant capacity, and biogenesis of broilers' small intestine mitochondria. A total of 384 one-day-old male Arbor Acres broiler chicks were randomly divided into four groups with six replicates each for 42 d. The control group was fed a basal diet, whereas the BLE1, BLE2, and BLE3 groups consumed basal diets with 1.0, 2.0, and 4.0 g/kg of BLE, respectively. Some markers of mitochondrial energy metabolism including isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase and some markers of redox system including total superoxide dismutase, malondialdehyde, and glutathione were measured by commercial colorimetric kits. Mitochondrial and cellular antioxidant genes, mitochondrial biogenesis-related genes, and mitochondrial DNA copy number were measured by quantitative real-time-polymerase chain reaction (qRT-PCR). Data were analyzed using the SPSS 19.0, and differences were considered as significant at P < 0.05. BLE supplementation linearly increased jejunal mitochondrial isocitrate dehydrogenase (P < 0.05) and total superoxide dismutase (P < 0.05) activity. The ileal manganese superoxide dismutase mRNA expression was linearly affected by increased dietary BLE supplementation (P < 0.05). Increasing BLE supplementation linearly increased jejunal sirtuin 1 (P < 0.05) and nuclear respiratory factor 1 (P < 0.05) mRNA expression. Linear (P < 0.05) and quadratic (P < 0.05) responses of the ileal nuclear respiratory factor 2 mRNA expression occurred with increased dietary BLE levels. In conclusion, BLE supplementation was beneficial to the energy metabolism, antioxidant capacity, and biogenesis of small intestine mitochondria in broilers. The dose of 4.0 g/kg BLE demonstrated the best effects.

140P Retrospective review of actionable IDH mutations and MGMT promoter methylation among CNS tumors

In the revised World Health Organization (WHO) Classification of Tumors of the Central Nervous System, molecular genetic alterations have been incorporated to the classic histology of primary brain tumors (PBT), including isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations and methylation of the O6 -methylguanine-DNA methyltransferase promoter (MGMT). The IDH mutation is associated with a better prognosis in patients with glioma, independently of histological parameters and tumor grade. MGMT methylation silences the MGMT gene and reduces the ability of tumor cells to repair damage caused by temozolomide and other alkylating agents.

Cholangiocarcinoma: a review of the literature and future directions in therapy.

Cholangiocarcinomas (CCA) are a group of rare cancers with an incidence of about 1.26 per 100,000 people. The disease reflects one of three different subtypes: intrahepatic, perihilar or hilar and distal cholangiocarcinoma. The preferred modality of definitive therapy is surgical resection with or without adjuvant therapy, however the majority of patients with this disease do not present at an early stage. Some efforts to improve survival rates have come in the form of offering neoadjuvant therapy prior to surgical resection or liver transplantation. Some new protocols are in the process of development for neoadjuvant therapy. Despite advancements in locally advanced or borderline resectable lesions, most patient present at an advanced stage. The mainstay of treatment for advanced stage disease is chemotherapy regardless of location. The mainstay of treatment in fit patients is the combination of gemcitabine and cisplatin. The addition of nab-paclitaxel to this backbone is currently being evaluated in phase III trial. In addition, the role of targeted therapy is currently being studied extensively through multiple different mutational pathways including isocitrate dehydrogenase-1 (IDH1), fibroblast growth factor receptor (FGFR), epidermal growth factor receptor (EGFR) and ERBB2 (HER2/neu). CCA remains a significant challenge in medicine, however recent studies have shown that there is significant interest in advancing therapy in the form of neoadjuvant, adjuvant and palliative intent treatment.

Precision Medicine of Hepatobiliary and Pancreatic Cancers: Focusing on Clinical Trial Outcomes.

Simple SummaryRecently, tumor-agnostic precision medicine employing comprehensive genome profiling (CGP) and using next-generation sequencing (NGS) has been progressing. This review focuses on the recent progress in precision medicine for advanced unresectable hepatobiliary and pancreatic cancers. We highlight therapies that target several regulators of cancer cell growth and tumor-agnostic therapies that effectively treat biliary and pancreatic cancers. We also discuss our current understanding of precision medicine methods developed using NGS of circulating tumor DNA (ctDNA) as a liquid biopsy technique.Tumor-agnostic precision medicine employing comprehensive genome profiling (CGP) and using next-generation sequencing (NGS) has been progressing recently. This review focuses on precision medicine for advanced unresectable hepatobiliary and pancreatic cancers. In this paper, for biliary tract cancer (BTC), therapies that target several regulators of cancer cell growth, including isocitrate dehydrogenase 1 (IDH1), fibroblast growth factor receptor 2 (FGFR2) fusion, proto-oncogene B-Raf (BRAF), and human epidermal growth factor receptor 2 (HER2) alterations, are reviewed. For pancreatic ductal adenocarcinoma (PDAC), therapies for Kirsten rat sarcoma virus (KRAS) gene mutation G12C, neuregulin (NRG)1, and breast cancer type 1 and 2 susceptibility (BRCA1/2), gene alterations are summarized. On the other hand, precision medicine targets were not established for hepatocellular carcinoma (HCC), although telomerase reverse transcriptase (TERT), tumor protein P53 (TP53), and Wnt/β catenin signaling alterations have been recognized as HCC driver oncogenes. Tumor-agnostic therapies for microsatellite instability-high (MSI-H) and neurotropic tyrosine receptor kinase (NTRK) fusion cancers effectively treat biliary and pancreatic cancers. Precision medicine methods developed using NGS of circulating tumor DNA (ctDNA) and utilizing a liquid biopsy technique are discussed.

Diagnostic and Prognostic Value of pH- and Oxygen-Sensitive Magnetic Resonance Imaging in Glioma: A Retrospective Study.

Simple SummaryGliomas are known to present with an altered metabolic phenotype that contributes to the abnormal tumor microenvironment detectable on MRI. The aim of this study was to quantify metabolic statuses of glioma using pH- and oxygen-sensitive MRI and associate the measurements with genetic mutation and prognosis. Using the data of 159 adult glioma patients, we revealed that isocitrate dehydrogenase mutation, 1p/19q co-deletion, and epidermal growth factor receptor amplification statuses were associated with the MRI measurements revealing tissue acidosis and hypoxia, and these measurements were also associated with progression-free survival and overall survival, independent of patient age, treatment status, and isocitrate dehydrogenase mutation status. In conclusion, the pH- and oxygen-sensitive MRI is clinically feasible and potentially valuable for distinguishing glioma genotypes and provides additional prognostic value to clinical practice.Characterization of hypoxia and tissue acidosis could advance the understanding of glioma biology and improve patient management. In this study, we evaluated the ability of a pH- and oxygen-sensitive magnetic resonance imaging (MRI) technique to differentiate glioma genotypes, including isocitrate dehydrogenase (IDH) mutation, 1p/19q co-deletion, and epidermal growth factor receptor (EGFR) amplification, and investigated its prognostic value. A total of 159 adult glioma patients were scanned with pH- and oxygen-sensitive MRI at 3T. We quantified the pH-sensitive measure of magnetization transfer ratio asymmetry (MTRasym) and oxygen-sensitive measure of R2’ within the tumor region-of-interest. IDH mutant gliomas showed significantly lower MTRasym × R2’ (p < 0.001), which differentiated IDH mutation status with sensitivity and specificity of 90.0% and 71.9%. Within IDH mutants, 1p/19q codeletion was associated with lower tumor acidity (p < 0.0001, sensitivity 76.9%, specificity 91.3%), while IDH wild-type, EGFR-amplified gliomas were more hypoxic (R2’ p = 0.024, sensitivity 66.7%, specificity 76.9%). Both R2’ and MTRasym × R2’ were significantly associated with patient overall survival (R2’: p = 0.045; MTRasym × R2’: p = 0.002) and progression-free survival (R2’: p = 0.010; MTRasym × R2’: p < 0.0001), independent of patient age, treatment status, and IDH status. The pH- and oxygen-sensitive MRI is a clinically feasible and potentially valuable imaging technique for distinguishing glioma subtypes and providing additional prognostic value to clinical practice.

Association of dynamic susceptibility contrast- and dynamic contrast-enhanced magnetic resonance imaging parameters with molecular marker status in lower-grade gliomas: A retrospective study.

Molecular marker status is clinically relevant for treatment planning and predicting the prognosis of gliomas. This study aimed to assess whether quantitative imaging parameters from dynamic susceptibility contrast- (DSC-) and dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) can predict the molecular marker status of lower-grade gliomas (LGGs). Overall, 132 patients with LGGs who underwent DSC- and DCE-MRI were retrospectively enrolled. Statuses of relevant molecular markers including isocitrate dehydrogenase isoenzyme (IDH), 1p19q codeletion, epidermal growth factor receptor (EGFR), O6-methylguanine-DNA methyltransferase (MGMT), and telomerase reverse transcriptase (TERT) were collected. For each molecular marker, age, tumor diameter and location, and DSC- and DCE-MRI parameters, including the normalized cerebral blood volume (nCBV), volume transfer constant (Ktrans), rate transfer coefficient (Kep), extravascular extracellular volume fraction (Ve), and plasma volume fraction (Vp), were compared. Multivariable logistic regression analyses were performed. The nCBV was significantly lower in LGGs with IDH mutation (p = .001) and TERT mutation (p = .027) than those without these mutations. Ktrans (p = .034), Ve (p = .023), and Vp (p = .044) values were significantly lower in MGMT methylated LGGs than in MGMT unmethylated LGGs. Perfusion parameters were not significantly associated with EGFR amplification and 1p19q codeletion. Young age (p < .001) and small diameter (p = .001) were significantly associated with IDH mutation. The nCBV was independently associated with IDH status (AUC, 0.817; 95% CI: 0.739-0.894). DSC- and DCE-MRI parameters demonstrated correlations with molecular markers of LGGs. Especially, the nCBV can be helpful in predicting the IDH mutation status.

Probing individual-level structural atrophy in frontal glioma patients.

Although every glioma patient varies in tumor size, location, histological grade and molecular biomarkers, non-tumoral morphological abnormalities are commonly detected by a statistical comparison among patient groups, missing the information of individual morphological alterations. In this study, we introduced an individual-level structural abnormality detection method for glioma patients and proposed several abnormality indexes to depict individual atrophy patterns. Forty-five patients with a glioma in the frontal lobe and fifty-one age-matched healthy controls participated in the study. Individual structural abnormality maps (SAM) were generated using patients' preoperative T1 images, by calculating the degree of deviation of voxel volume in each patient with the normative model built from healthy controls. Based on SAM, a series of individual abnormality indexes were computed, and their relationship with glioma characteristics was explored. The results demonstrated that glioma patients showed unique non-tumoral atrophy patterns with overlapping atrophy regions mainly located at hippocampus, parahippocampus, amygdala, insula, middle temporal gyrus and inferior temporal gyrus, which are closely related to the human cognitive functions. The abnormality indexes were associated with several molecular biomarkers including isocitrate dehydrogenase (IDH) mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutation. Our study provides an effective way to access the individual-level non-tumoral structural abnormalities in glioma patients, which has the potential to significantly improve individualized precision medicine.

Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1) expression in glioblastoma is driven by ETS1- and MYBL2-dependent transcriptional activation

Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1) encodes the 4EBP1 protein, a negative regulator of mRNA translation and a substrate of the mechanistic target of rapamycin (mTOR), whose function and relevance in cancer is still under debate. Here, we analyzed EIF4EBP1 expression in different glioma patient cohorts and investigated its mode of transcriptional regulation in glioblastoma cells. We verified that EIF4EBP1 mRNA is overexpressed in malignant gliomas, including isocitrate dehydrogenase (IDH)-wildtype glioblastomas, relative to non-neoplastic brain tissue in multiple publically available datasets. Our analyses revealed that EIF4EBP1 overexpression in malignant gliomas is neither due to gene amplification nor to altered DNA methylation, but rather results from aberrant transcriptional activation by distinct transcription factors. We found seven transcription factor candidates co-expressed with EIF4EBP1 in gliomas and bound to the EIF4EBP1 promoter, as revealed by chromatin immunoprecipitation (ChIP)-sequencing data. We investigated the ability of these candidates to activate the EIF4EBP1 promoter using luciferase reporter assays, which supported four transcription factors as candidate EIF4EBP1 regulators, namely MYBL2, ETS1, HIF-1A, and E2F6. Finally, by employing transient knock-down experiments to repress either of these transcription factors, we identified MYBL2 and ETS1 as the relevant transcriptional drivers of enhanced EIF4EBP1 expression in malignant glioma cells. Taken together, our findings confirm enhanced expression of EIF4EBP1 in malignant gliomas relative to non-neoplastic brain tissue and characterize the underlying molecular pathomechanisms.

Prognostic risk stratification of gliomas using deep learning in digital pathology images.

BackgroundEvaluation of tumor-tissue images stained with hematoxylin and eosin (H&E) is pivotal in diagnosis, yet only a fraction of the rich phenotypic information is considered for clinical care. Here, we propose a survival deep learning (SDL) framework to extract this information to predict glioma survival.MethodsDigitized whole slide images were downloaded from The Cancer Genome Atlas (TCGA) for 766 diffuse glioma patients, including isocitrate dehydrogenase (IDH)-mutant/1p19q-codeleted oligodendroglioma, IDH-mutant/1p19q-intact astrocytoma, and IDH-wildtype astrocytoma/glioblastoma. Our SDL framework employs a residual convolutional neural network with a survival model to predict patient risk from H&E-stained whole-slide images. We used statistical sampling techniques and randomized the transformation of images to address challenges in learning from histology images. The SDL risk score was evaluated in traditional and recursive partitioning (RPA) survival models.ResultsThe SDL risk score demonstrated substantial univariate prognostic power (median concordance index of 0.79 [se: 0.01]). After adjusting for age and World Health Organization 2016 subtype, the SDL risk score was significantly associated with overall survival (OS; hazard ratio = 2.45; 95% CI: 2.01 to 3.00). Four distinct survival risk groups were characterized by RPA based on SDL risk score, IDH status, and age with markedly different median OS ranging from 1.03 years to 14.14 years.ConclusionsThe present study highlights the independent prognostic power of the SDL risk score for objective and accurate prediction of glioma outcomes. Further, we show that the RPA delineation of patient-specific risk scores and clinical prognostic factors can successfully demarcate the OS of glioma patients.

Adverse Prognostic Role of IDH2 Mutations at Diagnosis and during Follow-up in Patients with Acute Myeloid Leukemia and Normal Karyotype

Adverse Prognostic Role of IDH2 Mutations at Diagnosis and during Follow-up in Patients with Acute Myeloid Leukemia and Normal Karyotype

Longitudinal Next Generation Sequencing Reveals the Clonal Hierarchy of IDH Mutated Clones and Impact on Survival in NPM1 Mutated AML

Longitudinal Next Generation Sequencing Reveals the Clonal Hierarchy of IDH Mutated Clones and Impact on Survival in NPM1 Mutated AML

P04.11 10-Year Institutional Retrospective Case Series of WHO Grade II Gliomas and Correlation of Seizures, Lobar Location, Histopathological Subtype and IDH-1 Mutation (2010–2020)

Abstract BACKGROUND A 10-year retrospective case series was undertaken of all patients who had a tissue diagnosis of a World Health Organisation (WHO) Grade II glioma, i.e. low grade glioma (LGGM), at the Institute of Neurological Sciences (INS) between January 2010 and January 2020 (NB: pre-2016 World Health Organisation classification). The objective was to assess the correlation of World Health Organisation (WHO) Grade II gliomas to seizure symptomology, intracerebral tumour location, histopathological glioma sub-type and molecular markers including isocitrate dehydrogenase-1 (IDH-1) mutation. MATERIAL AND METHODS We extracted data regarding clinical, radiological, histological, molecular discriminators and functional outcomes in patients. The pre-operative symptomology was restricted to seizures, headache and focal neurological deficits. RESULTS 84 patients underwent resection and had a mean age of 42rs (range: 21-77yrs]). Seizures (NB: pre-2017 International League against Epilepsy classification [ILAE]) occurred in 71% and of these 52% were generalised, 37% partial and 11% mixed. 31% had ongoing seizures postoperatively. Headache occurred in 38% (of these 50% had headache and seizures). Focal neurological deficits (FNDs) occurred in 21% (of these 61% had FNDs and seizures). Seizure, as an isolated pre-operative symptom occurred in 48% patients compared to isolated headache in 10% and isolated FNDs in 4%. Anatomically, 58% of lesions were frontal. The seizure spatial frequency was 60% frontal. Histologically, 60% were diffuse astrocytomas and 40% oligodendrogliomas. Furthermore, 71% of oligodendrogliomas and 49% of diffuse astrocytomas had a frontal location. IDH-1 mutation occurred in 80% patients (75% of these had seizures) and of these 66% were frontal. CONCLUSIONS Our analysis confirms a correlation between incidence of seizures, frontal lobar location, histopathological subtype and IDH-1 mutations (p = &amp;lt;0.05

Protective effects of vitexin on cadmium-induced renal toxicity in rats.

Cadmium (Cd) is an industrial contaminant that poses severe threats to human and animal health. Vitexin (VIT) is a polyphenolic flavonoid of characteristic pharmacological properties. We explored the curative role of vitexin on Cd-induced mitochondrial-dysfunction in rat renal tissues. Twenty-four rats were equally divided into four groups and designated as control, Cd, Cd + vitexin and vitexin treated groups. The results showed that Cd exposure increased urea and creatinine levels while decreased creatinine clearance. Cd reduced the activities of antioxidant enzymes, i.e., catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione content in the Cd exposed group. Cd exposure significantly (p < 0.05) elevated the reactive oxygen species (ROS) and Thiobarbituric acid reactive substances (TBARS) levels in rat kidney. Cd also caused a significant (p < 0.05) reduction in the mitochondrial TCA-cycle enzymes, including isocitrate dehydrogenase, succinate dehydrogenase, alpha-ketoglutarate dehydrogenase, and malate-dehydrogenase activities. Besides, mitochondrial respiratory chain enzymes, including NADH-dehydrogenase, coenzyme Q-cytochrome reductase, succinic-coenzyme Q, and cytochrome c-oxidase activities were also decreased under Cd exposure. Cd exposure also damaged the mitochondrial membrane potential (MMP). However, VIT treatment potentially reduced the detrimental effects of Cd in the kidney of rats. In conclusion, our study indicated that the VIT could attenuate the Cd-induced renal toxicity in rats.