Rapid detection of IDH mutations in gliomas by intraoperative mass spectrometry

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(23)

Published: May 28, 2024

The development and performance of two mass spectrometry (MS) workflows for the intraoperative diagnosis isocitrate dehydrogenase (IDH) mutations in glioma is implemented by independent teams at Mayo Clinic, Jacksonville, Huashan Hospital, Shanghai. infiltrative nature gliomas makes rapid necessary to guide extent surgical resection central nervous system (CNS) tumors. combination tissue biopsy MS analysis used here satisfies this requirement. key feature both described methods use tandem measure oncometabolite 2-hydroxyglutarate (2HG) relative endogenous glutamate (Glu) characterize presence mutant tumor. experiments i) provide IDH mutation status individual patients ii) demonstrate a strong correlation 2HG signals with tumor infiltration. measured ratio Glu correlates IDH-mutant (IDH-mut) ( P < 0.0001) core data teams. Despite using different ionization spectrometers, comparable determining from biopsies was achieved sensitivities, specificities, accuracies all 100%. None 31 Clinic or 74 Hospital were misclassified when analyzing biopsies. Robustness methodology evaluated postoperative re-examination samples. Both noted high concentrations margins, supporting future monitor clean margins. power diagnostics shown resolving contradictory clinical features, e.g., distinguishing gliosis IDH-mut glioma.

Language: Английский

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Nanopore-based random genomic sampling for intraoperative molecular diagnosis

Genome Medicine, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 20, 2025

Central nervous system tumors are among the most lethal types of cancer. A critical factor for tailored neurosurgical resection strategies depends on specific tumor types. However, it is uncommon to have a preoperative diagnosis, and intraoperative morphology-based diagnosis remains challenging. Despite recent advances in methylation classifications brain tumors, accuracy may be compromised by low purity. Copy number variations (CNVs), which almost ubiquitous cancer, offer highly sensitive molecular biomarkers diagnosis. These quantitative genomic alterations provide insight into dysregulated oncogenic pathways can reveal potential targets therapies. We develop iSCORED, one-step random DNA reconstruction method that enables efficient, unbiased quantification genome-wide CNVs. By concatenating multiple fragments long reads, leverages low-pass sequencing generate approximately 1–2 million within 1 h. This approach allows ultrafast high-resolution CNV analysis at resolution 50 kb. In addition, concurrent profiling classification identifies promoter amplified oncogenes, providing an integrated diagnostic approach. our retrospective cohort 26 malignant iSCORED demonstrated 100% concordance detection, including chromosomal oncogene amplifications, when compared clinically validated assays such as Next-Generation Sequencing Chromosomal Microarray. Furthermore, we iSCORED's real-time applicability 15 diagnostically challenging primary achieving detecting aberrant gains/losses amplifications (10/10). Of these, 14 out aligned with final pathological diagnoses. streamlined workflow—from tissue arrival automatic generation reports—can completed 105 min. The pipeline represents first capable detection timeframe. combining classification, provides rapid comprehensive tool inform clinical decision. not only enhances but also optimizes surgical planning therapies, all

Language: Английский

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A Multi-center Study on Intraoperative Glioma Grading via Deep Learning on Cryosection Pathology

Modern Pathology, Journal Year: 2025, Volume and Issue: unknown, P. 100749 - 100749

Published: March 1, 2025

Intraoperative glioma grading remains a significant challenge, primarily due to the diminished diagnostic attributable suboptimal quality of cryosectioned slides. Precise intraoperative diagnosis is instrumental in guiding surgical strategy balance resection extent and neurological function preservation, thereby optimizing patient prognoses. This study developed model for via deep learning on images, termed IGGC. The was trained validated Cancer Genome Atlas (TCGA) datasets one cohort (ntrain = 1603, nvalidate 628), tested five cohorts (ntest 213). IGGC achieved an AUC value 0.99 differentiating between high grade (HGG) low (LGG), 0.96 identifying 4 glioma. Integrated into clinical workflow, assisted pathologists varying experience levels reducing inter-observer variability enhancing consistency. integrated possesses potential implementation, offering time-efficient highly accurate method three-grade classification adult-type diffuse gliomas based

Language: Английский

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Artificial Intelligent‐Enhanced Metabolite Profiling for Intraoperative IDH1 Genotyping in Glioma Using an Orthogonally Responsive SERS Probe

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

Intraoperative identification of the isocitrate dehydrogenase type 1 (IDH1) genotype, a key molecular marker in glioma, is essential for optimizing surgical strategies and tailoring post-surgical treatments. However, current clinical practices lack effective methods real-time IDH1 genotype detection during surgery. Here, novel strategy proposed intraoperative by simultaneously measuring two redox-related metabolites. A surface-enhanced Raman scattering (SERS) probe developed to detect glutathione hydrogen peroxide concentrations through orthogonally responsive signals. Additionally, deep learning algorithm implemented, leveraging 2D spectra transformation multi-task enhance measurement speed accuracy. This AI-assisted SERS approach can identify glioma patients within 7 min. In cohort 31 patients, system achieved an area under receiver operating characteristic curve 0.985 accurate differentiation. study holds significant promise refining decision-making personalizing treatments enabling rapid intra-operative biomarker identification.

Language: Английский

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Lactylation in Glioblastoma: A Novel Epigenetic Modifier Bridging Epigenetic Plasticity and Metabolic Reprogramming

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 3368 - 3368

Published: April 4, 2025

Glioblastoma, the most common and aggressive primary malignant brain tumor, is characterized by a high rate of recurrence, disability, lethality. Therefore, there pressing need to develop more effective prognostic biomarkers treatment approaches for glioblastoma. Lactylation, an emerging form protein post-translational modification, has been closely associated with lactate, metabolite glycolysis. Since initial identification lactylation sites in core histones 2019, accumulating evidence shown critical role that plays glioblastoma development, assessment poor clinical prognosis, immunosuppression, which provides fresh angle investigating connection between metabolic reprogramming epigenetic plasticity cells. The objective this paper present overview roles expanding field research explore practical value developing novel plans combining targeted therapy immunotherapy.

Language: Английский

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Detection of IDH mutation in glioma by desorption electrospray ionization (DESI) tandem mass spectrometry

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Nov. 6, 2024

Desorption electrospray ionization (DESI) tandem mass spectrometry (MS) is used to assess mutation status of isocitrate dehydrogenase (IDH) in human gliomas. Due the diffuse nature gliomas, total gross resection not normally achieved during surgery, leading tumor recurrence. The IDH has clinical significance due better prognosis IDH-mutant patients. mutant converts alpha-ketoglutaric acid (α-KG) into 2-hydroxyglutarate (2HG), which accumulates abnormally cells. Immunohistochemical staining (IHC) and genetic testing, gold standards, are incompatible with intraoperative applications but DESI (MS/MS) can be enzyme from tissue intraoperatively. Here, on off-line evaluation made performance two different types spectrometers characterization status. intensity 2HG measured against glutamate (Glu), an intrinsic reference molecule, both MS measurements. In cases using clear separation between (mut) IDH-wildtype (wt) samples (p < 0.0001) observed, despite short analysis time. higher detection sensitivity, multiple reaction monitoring experiments a triple quadrupole show slightly compared product ion MS/MS performed simple linear trap. Both DESI-MS platforms capable providing information status, might future at time surgery support decision-making regions, especially margins.

Language: Английский

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Simultaneous Quantitation of Multiple Biological Thiols Using Reactive Ionization and Derivatization with Charged Mass Tags

Analytical Chemistry, Journal Year: 2024, Volume and Issue: 96(49), P. 19414 - 19421

Published: Nov. 21, 2024

The biologically important thiols (cysteine, homocysteine, N-acetyl cysteine, and glutathione) are key species in redox homeostasis, there is a clinical need to measure them rapidly, accurately, simultaneously at low levels complex biofluids. solution the challenge presented here based on new derivatizing reagent that combines thiol-selective unit optimize chemical transformation precharged pyridinium chosen maximize sensitivity mass spectrometry. Derivatization performed with ionization ("reactive ionization"), spectrometry used record characterize thiol reaction products. method applicable over concentration range from 1 μM 10 mM demonstrated for 25 blood serum, plasma, 3 types of tissue samples. experiment characterized by limited sample preparation (<4 min) short analysis time (<1 min). High precision accuracy (both better than 8%) validated using independent HPLC-MS analysis. Cystine–cysteine homeostasis can be monitored introducing an additional reduction step, these results also HPLC-MS.

Language: Английский

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Patient-derived glioma organoids real time identification of IDH mutation, 1p/19q-codeletion and CDKN2A/B homozygous deletion with differential ion mobility spectrometry

Journal of Neuro-Oncology, Journal Year: 2024, Volume and Issue: 171(3), P. 691 - 703

Published: Nov. 23, 2024

Abstract Purpose Extent of brain tumor resection continues to be one the central decisions taken during standard care in glioma patients. Here, we aimed evaluate most essential molecular factors, such as IDH (isocitrate dehydrogenase) mutation gliomas classification with patient-derived organoids (PGOs) using differential mobility spectrometry (DMS). Methods prospectively recruited 12 patients, 6 IDH-mutated and wild-type tumors, from which PGOs were generated ex-vivo . Altogether, 320 DMS spectra analyzed a classifier algorithm based on linear discriminant analysis (LDA). Results LDA model accuracy (CA) obtained between IDH-mutant was 90% (91% sensitivity 89% specificity). Furthermore, 1p/19q codeletion within mutant reached 98% CA (93% 99% specificity), while CDKN2A/B homozygous loss status had 86% (63% 93% Conclusion suitability differentiate thus validated ex vivo cultured samples, PGOs. Preliminary results regarding codeleted identification endorse testing prospective intraoperative patient cohort. Our reveal sample set-up that is compatible real-time surgery guidance.

Language: Английский

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