bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–11–10
six papers selected by
Oltea Sampetrean, Keio University
  1. Pilot Trial of Perampanel on Peritumoral Hyperexcitability in Newly Diagnosed High-grade Glioma.
  2. Degradation fragments of Tau and type IV collagen as serum biomarkers in patients with recurrent glioblastoma treated with nivolumab and bevacizumab.
  3. Development and validation of a clinical risk model for postoperative outcome in newly diagnosed glioblastoma: a report of the RANO resect group.
  4. Detection of IDH mutation in glioma by desorption electrospray ionization (DESI) tandem mass spectrometry.
  5. Potential of ex vivo organotypic slice cultures in neuro-oncology.
  6. Effect of antibiotic drug use on outcome and therapy-related toxicity in patients with glioblastoma-A retrospective cohort study.
  1. Clin Cancer Res. 2024 Nov 05. OF1-OF9
    Pilot Trial of Perampanel on Peritumoral Hyperexcitability in Newly Diagnosed High-grade Glioma.
    Steven Tobochnik, Michael S Regan, Maria K C Dorotan, Dustine Reich, Emily Lapinskas, Md Amin Hossain, Sylwia Stopka, David M Meredith, Sandro Santagata, Melissa M Murphy, Omar Arnaout, Wenya Linda Bi, E Antonio Chiocca, Alexandra J Golby, Michael A Mooney, Timothy R Smith, Keith L Ligon, Patrick Y Wen, Nathalie Y R Agar, Jong Woo Lee.
       PURPOSE: Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the targeted AMPA receptor antagonist perampanel on peritumoral hyperexcitability.
    EXPERIMENTAL DESIGN: An open-label trial was performed comparing perampanel with standard of care (SOC) in patients undergoing resection of newly diagnosed radiologic high-grade glioma. Perampanel was administered as a preoperative loading dose followed by maintenance therapy until progressive disease or up to 12 months. SOC treatment involved levetiracetam for 7 days or as clinically indicated. The primary outcome of hyperexcitability was defined by intraoperative electrocorticography high-frequency oscillation (HFO) rates. Seizure freedom and overall survival were estimated by the Kaplan-Meier method. Tissue concentrations of perampanel, levetiracetam, and correlative biomarkers were measured by mass spectrometry.
    RESULTS: HFO rates were similar between patients treated with perampanel and levetiracetam. The trial was terminated early after a planned interim analysis, and outcomes assessed in 11 patients (seven perampanel treated; four treated with SOC). Over a median 281 days of postenrollment follow-up, 27% of patients had seizures, including 14% maintained on perampanel and 50% treated with SOC. Overall survival in perampanel-treated patients was similar to that in a glioblastoma reference cohort. Glutamate concentrations in surface biopsies were positively correlated with HFO rates in adjacent electrode contacts and were not significantly associated with treatment assignment or drug concentrations.
    CONCLUSIONS: Glioma peritumoral glutamate concentrations correlated with high-gamma oscillation rates. Targeting glutamatergic activity with perampanel achieved similar electrocorticographic hyperexcitability levels as in levetiracetam-treated patients.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-1849
  2. Clin Transl Oncol. 2024 Nov 05.
    Degradation fragments of Tau and type IV collagen as serum biomarkers in patients with recurrent glioblastoma treated with nivolumab and bevacizumab.
    Christina Jensen, Simone Maarup, Hans Skovgaard Poulsen, Benedikte Hasselbalch, Morten Karsdal, Inge Marie Svane, Ulrik Lassen, Nicholas Willumsen.
       PURPOSE: There is an unmet need for new treatment options and biomarkers for patients with glioblastoma (GBM). Here we investigated three non-invasive biomarkers: type VI collagen degraded by granzyme B (C4G) and matrix metalloproteases (C4M), respectively, and ADAM10-degraded Tau (Tau-A).
    METHODS: Biomarker levels in pre- and on-treatment serum samples from patients with recurrent GBM (n = 39) treated with nivolumab and bevacizumab (NCT03890952) were compared to healthy levels (n = 22) and associated with overall survival (OS) outcome (median cutpoint). Longitudinal changes in biomarkers were investigated by a Mixed-effects analysis.
    RESULTS: Tau-A (p < 0.0001) and C4G (p = 0.005), but not C4M (p = 0.106), were increased in patients. High Tau-A and C4G associated with improved OS (Tau-A: HR = 0.41, 95%CI = 0.20-0.86, C4G: HR = 0.47, 95%CI = 0.24-0.94). Only C4G increased with treatment (p = 0.024-0.005).
    CONCLUSIONS: Tau-A and C4G are elevated in serum from patients with recurrent GBM and prognostic for OS. If validated, these biomarkers could be applied to clinical trials.
    Keywords:  Biomarkers; Collagen; Glioblastoma; Tau; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12094-024-03775-z
  3. Neuro Oncol. 2024 Nov 04. pii: noae231. [Epub ahead of print]
    Development and validation of a clinical risk model for postoperative outcome in newly diagnosed glioblastoma: a report of the RANO resect group.
    RANO resect group
       BACKGROUND: Following surgery, patients with newly diagnosed glioblastoma frequently enter clinical trials. Nuanced risk assessment is warranted to reduce imbalances between study arms. Here, we aimed (I) to analyze the interactive effects of residual tumor with clinical and molecular factors on outcome and (II) to define a postoperative risk assessment tool.
    METHODS: The RANO resect group retrospectively compiled an international, seven-center training cohort of patients with newly diagnosed glioblastoma. The combined associations of residual tumor with molecular or clinical factors and survival were analyzed, and recursive partitioning analysis was performed for risk modeling. The resulting model was prognostically verified in a separate external validation cohort.
    RESULTS: Our training cohort compromised 1003 patients with newly diagnosed isocitrate dehydrogenase-wildtype glioblastoma. Residual tumor, O6-methylguanine DNA methyltransferase (MGMT) promotor methylation status, age, and postoperative KPS were prognostic for survival and incorporated into regression tree analysis. By individually weighting the prognostic factors, an additive score (range, 0-9 points) integrating these four variables distinguished patients with low (0-2 points), intermediate (3-5 points), and high risk (6-9 points) for inferior survival. The prognostic value of our risk model was retained in treatment-based subgroups and confirmed in an external validation cohort of 258 patients with glioblastoma. Compared to previously postulated models, goodness-of-fit measurements were superior for our model.
    CONCLUSIONS: The novel RANO risk model serves as an easy-to-use, yet highly prognostic tool for postoperative patient stratification prior to further therapy. The model may serve to guide patient management and reduce imbalances between study arms in prospective trials.
    Keywords:  extent of resection; glioblastoma; patient stratification; postoperative risk modeling; risk assessment
    DOI:  https://doi.org/10.1093/neuonc/noae231
  4. Sci Rep. 2024 11 06. 14(1): 26865
    Detection of IDH mutation in glioma by desorption electrospray ionization (DESI) tandem mass spectrometry.
    Mahdiyeh Shahi, Steven Pringle, Michael Morris, Diogo Moniz Garcia, Alfredo Quiñones-Hinojosa, R Graham Cooks.
      Desorption electrospray ionization (DESI) tandem mass spectrometry (MS) is used to assess mutation status of isocitrate dehydrogenase (IDH) in human gliomas. Due to the diffuse nature of gliomas, total gross resection is not normally achieved during surgery, leading to tumor recurrence. The mutation status of IDH has clinical significance due to better prognosis in IDH-mutant patients. The mutant IDH converts alpha-ketoglutaric acid (α-KG) into 2-hydroxyglutarate (2HG), which accumulates abnormally in cells. Immunohistochemical staining (IHC) and genetic testing, the gold standards, are incompatible with intraoperative applications but DESI tandem mass spectrometry (MS/MS) can be used to assess the mutation status of IDH enzyme from tissue intraoperatively. Here, on off-line evaluation is made of the performance of two different types of mass spectrometers in characterization of IDH mutation status. The intensity of 2HG is measured against glutamate (Glu), an intrinsic reference molecule, in both tandem MS measurements. In both cases using DESI clear separation between IDH-mutant (mut) and IDH-wildtype (wt) samples (p < 0.0001) is observed, despite the short analysis time. Due to the higher detection sensitivity, multiple reaction monitoring experiments using a triple quadrupole show slightly better performance compared to product ion MS/MS performed on a simple linear ion trap. Both DESI-MS platforms are capable of providing information on IDH mutation status, which might in future be used at the time of surgery to support decision-making on resection regions, especially at tumor margins.
    Keywords:  2-hydroxyglutarate; Ambient ionization; Brain cancer; Molecular diagnostics; Multiple reaction monitoring (MRM); Oncometabolite
    DOI:  https://doi.org/10.1038/s41598-024-77044-y
  5. Neuro Oncol. 2024 Nov 06. pii: noae195. [Epub ahead of print]
    Potential of ex vivo organotypic slice cultures in neuro-oncology.
    Ariane Steindl, Manuel Valiente.
      Over recent decades, in vitro and in vivo models have significantly advanced brain cancer research; however, each presents distinct challenges for accurately mimicking in situ conditions. In response, organotypic slice cultures have emerged as a promising model recapitulating precisely specific in vivo phenotypes through an ex vivo approach. Ex vivo organotypic brain slice models can integrate biological relevance and patient-specific variability early in drug discovery, thereby aiming for more precise treatment stratification. However, the challenges of obtaining representative fresh brain tissue, ensuring reproducibility, and maintaining essential central nervous system (CNS)-specific conditions reflecting the in situ situation over time have limited the direct application of ex vivo organotypic slice cultures in robust clinical trials. In this review, we explore the benefits and possible limitations of ex vivo organotypic brain slice cultures in neuro-oncological research. Additionally, we share insights from clinical experts in neuro-oncology on how to overcome these current limitations and improve the practical application of organotypic brain slice cultures beyond academic research.
    Keywords:  brain metastases; ex vivo models; glioblastoma; organotypic brain cultures; organotypic slice cultures
    DOI:  https://doi.org/10.1093/neuonc/noae195
  6. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae170
    Effect of antibiotic drug use on outcome and therapy-related toxicity in patients with glioblastoma-A retrospective cohort study.
    Linda Götz, Tananeh Ansafi, Michael Gerken, Monika Klinkhammer-Schalke, Anna Fischl, Markus J Riemenschneider, Martin Proescholdt, Elisabeth Bumes, Oliver Kölbl, Nils Ole Schmidt, Ralf Linker, Peter Hau, Tareq M Haedenkamp.
       Background: Glioblastoma (GB) is the most frequent malignant brain tumor and has a dismal prognosis. In other cancers, antibiotic use has been associated with severity of chemotherapy-induced toxicity and outcome. We investigated if these mechanisms are also involved in GB.
    Methods: We selected a cohort of 78 GB patients who received combined radiochemotherapy. We investigated if exposure to prediagnostic antibiotic use is associated with clinical side effects and laboratory changes during adjuvant therapy as well as overall survival (OS) and progression-free survival (PFS) using chi-square test, binary logistic regression, Kaplan-Meyer analysis, and multivariable Cox regression.
    Results: Seventeen patients (21.8%) received at least one course of prediagnostic antibiotics and 61 (78.2%) received no antibiotics. We found a higher incidence of loss of appetite (23.5% vs. 4.9%; P = .018) and myelosuppression (41.2% vs. 18.0%; P = .045) in the antibiotic group. Multivariable logistic regression analysis revealed antibiotics to be a predictor for nausea (OR = 6.94, 95% CI: 1.09-44.30; P = .041) and myelosuppression (OR = 9.75, 95% CI: 1.55-61.18; P = .015). Furthermore, lymphocytopenia was more frequent in the antibiotic group (90.0% vs. 56.1%, P = .033). There were no significant differences in OS (P = .404) and PFS (P = .844). Multivariable Cox regression showed a trend toward shorter survival time (P = .089) in the antibiotic group.
    Conclusions: Our study suggests that antibiotic use affects symptoms and lab values in GB patients. Larger prospective studies are required to investigate if prediagnostic antibiotic use could be a prognostic factor in GB patients.
    Keywords:  antibiotics; glioblastoma; intestinal microbiome; survival; therapy-related toxicity
    DOI:  https://doi.org/10.1093/noajnl/vdae170
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