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Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against m IDH glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of d -2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with m IDH1 -R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1–97.6) and 91.1% (95% CrI, 72.0–97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of ‘proneural’ and ‘stemness’ gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with m IDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197. The dual IDH1/IDH2 inhibitor vorasidenib exhibited better brain permeability and target engagement than ivosidenib in a pilot perioperative randomized clinical trial in patients with IDH1-mutant glioma.

Objectives In the latest World Health Organization classification 2021, grade 4 adult diffuse gliomas can be diagnosed with several molecular features even without histological evidence of necrosis or microvascular proliferation. We aimed to explore whole tumor histogram-derived apparent diffusion coefficient (ADC) histogram profiles for differentiating between the presence (Mol-4) and absence (Mol-2/3) of grade 4 molecular features in histologically lower-grade gliomas. Methods Between June 2019 and October 2022, 184 adult patients with diffuse gliomas underwent MRI. After excluding 121 patients, 18 (median age, 64.5 [range, 37–84 years]) Mol-4 and 45 (median 40 [range, 18–73] years) Mol-2/3 patients with histologically lower-grade gliomas were enrolled. Whole tumor volume-of-interest-derived ADC histogram profiles were calculated and compared between the two groups. Stepwise logistic regression analysis with Akaike’s information criterion using the ADC histogram profiles with p values < 0.01 and age at diagnosis was used to identify independent variables for predicting the Mol-4 group. Results The 90th percentile ( p  < 0.001), median ( p  < 0.001), mean ( p  < 0.001), 10th percentile ( p  = 0.014), and entropy ( p  < 0.001) of normalized ADC were lower, and kurtosis ( p  < 0.001) and skewness ( p  = 0.046) were higher in the Mol-4 group than in the Mol-2/3 group. Multivariate logistic regression analysis revealed that the entropy of normalized ADC and age at diagnosis were independent predictive parameters for the Mol-4 group with an area under the curve of 0.92. Conclusion ADC histogram profiles may be promising preoperative imaging biomarkers to predict molecular grade 4 among histologically lower-grade adult diffuse gliomas. Clinical relevance statement This study highlighted the diagnostic usefulness of ADC histogram profiles to differentiate histologically lower grade adult diffuse gliomas with the presence of molecular grade 4 features and those without. Key Points • ADC histogram profiles to predict molecular CNS WHO grade 4 status among histologically lower-grade adult diffuse gliomas were evaluated. • Entropy of ADC and age were independent predictive parameters for molecular grade 4 status. • ADC histogram analysis is useful for predicting molecular grade 4 among histologically lower-grade gliomas.

Immunotherapy is a promising area of therapy in patients with neuro-oncological malignancies. However, early-phase studies show unique challenges associated with the assessment of radiological changes in response to immunotherapy reflecting delayed responses or therapy-induced inflammation. Clinical benefit, including long-term survival and tumour regression, can still occur after initial disease progression or after the appearance of new lesions. Refinement of the response assessment criteria for patients with neuro-oncological malignancies undergoing immunotherapy is therefore warranted. Herein, a multinational and multidisciplinary panel of neuro-oncology immunotherapy experts describe immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria based on guidance for the determination of tumour progression outlined by the immune-related response criteria and the RANO working group. Among patients who demonstrate imaging findings meeting RANO criteria for progressive disease within 6 months of initiating immunotherapy, including the development of new lesions, confirmation of radiographic progression on follow-up imaging is recommended provided that the patient is not significantly worse clinically. The proposed criteria also include guidelines for the use of corticosteroids. We review the role of advanced imaging techniques and the role of measurement of clinical benefit endpoints including neurological and immunological functions. The iRANO guidelines put forth in this Review will evolve successively to improve their usefulness as further experience from immunotherapy trials in neuro-oncology accumulate.

In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684. Autologous tumor lysate (ATL) dendritic cell (DC) vaccination can induce local and systemic anti-tumor immune responses in malignant glioma patients. In this randomized phase II clinical trial, the authors evaluate the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to ATL-DC vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas.

Purpose There remains no consensus normal-appearing white matter (NAWM) normalization method to compute normalized relative cerebral blood volume (nrCBV) and apparent diffusion coefficient (nADC) in brain tumors. This reader study explored nrCBV and nADC differences using different NAWM normalization methods. Methods Thirty-five newly diagnosed glioma patients were studied. For each patient, two readers created four NAWM regions of interests: (1) a single plane in the centrum semiovale (CSOp), (2) 3 spheres in the centrum semiovale (CSOs), (3) a single plane in the slice of the tumor center (TUMp), and (4) 3 spheres in the slice of the tumor center (TUMs). Readers repeated NAWM segmentations 1 month later. Differences in nrCBV and nADC of the FLAIR hyperintense tumor, inter-/intra-reader variability, and time to segment NAWM were assessed. As a validation step, the diagnostic performance of each method for IDH-status prediction was evaluated. Results Both readers obtained significantly different nrCBV ( P < .001), nADC ( P < .001), and time to segment NAWM ( P < .001) between the four normalization methods. nrCBV and nADC were significantly different between CSO and TUM methods, but not between planar and spherical methods in the same NAWM region. Broadly, CSO methods were quicker than TUM methods, and spherical methods were quicker than planar methods. For all normalization techniques, inter-reader reproducibility and intra-reader repeatability were excellent (intraclass correlation coefficient > 0.9), and the IDH-status predictive performance remained similar. Conclusion The selected NAWM region significantly impacts nrCBV and nADC values. CSO methods, particularly CSOs, may be preferred because of time reduction, similar reader variability, and similar diagnostic performance compared to TUM methods.

The value of perfusion and diffusion-weighted MRI in differentiating histological subtypes according to the 2007 WHO glioma classification scheme (i.e. astrocytoma vs. oligodendroglioma) and genetic subtypes according to the 2016 WHO reclassification (e.g. 1p/19q co-deletion and IDH1 mutation status) in WHO grade II and III diffuse gliomas remains controversial. In the current study, we describe unique perfusion and diffusion MR signatures between histological and genetic glioma subtypes. Sixty-five patients with 2007 histological designations (astrocytomas and oligodendrogliomas), 1p/19q status (+ = intact/− = co-deleted), and IDH1 mutation status (MUT/WT) were included in this study. In all patients, median relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) were estimated within T2 hyperintense lesions. Bootstrap hypothesis testing was used to compare subpopulations of gliomas, separated by WHO grade and 2007 or 2016 glioma classification schemes. A multivariable logistic regression model was also used to differentiate between 1p19q + and 1p19q − WHO II–III gliomas. Neither rCBV nor ADC differed significantly between histological subtypes of pure astrocytomas and pure oligodendrogliomas. ADC was significantly different between molecular subtypes (p = 0.0016), particularly between IDH WT and IDH MUT /1p19q + (p = 0.0013). IDH MUT /1p19q + grade III gliomas had higher median ADC; IDH WT grade III gliomas had higher rCBV with lower ADC; and IDH MUT /1p19q − had intermediate rCBV and ADC values, similar to their grade II counterparts. A multivariable logistic regression model was able to differentiate between IDH WT and IDH MUT WHO II and III gliomas with an AUC of 0.84 (p < 0.0001, 74% sensitivity, 79% specificity). Within IDH MUT WHO II–III gliomas, a separate multivariable logistic regression model was able to differentiate between 1p19q + and 1p19q − WHO II–III gliomas with an AUC of 0.80 (p = 0.0015, 64% sensitivity, 82% specificity). ADC better differentiated between genetic subtypes of gliomas according to the 2016 WHO guidelines compared to the classification scheme outlined in the 2007 WHO guidelines based on histological features of the tissue. Results suggest a combination of rCBV, ADC, T2 hyperintense volume, and presence of contrast enhancement together may aid in non-invasively identifying genetic subtypes of diffuse gliomas.

In the present study we investigated a combination of diffusion tensor imaging (DTI) and magnetic resonance spectroscopic (MRS) biomarkers in order to predict neurological impairment in patients with cervical spondylosis. Twenty-seven patients with cervical spondylosis were evaluated. DTI and single voxel MRS were performed in the cervical cord. N-acetylaspartate (NAA) and choline (Cho) metabolite concentration ratios with respect to creatine were quantified, as well as the ratio of choline to NAA. The modified mJOA scale was used as a measure of neurologic deficit. Linear regression was performed between DTI and MRS parameters and mJOA scores. Significant predictors from linear regression were used in a multiple linear regression model in order to improve prediction of mJOA. Parameters that did not add value to model performance were removed, then an optimized multiparametric model was established to predict mJOA. Significant correlations were observed between the Torg-Pavlov ratio and FA (R2 = 0.2021, P = 0.019); DTI fiber tract density and FA, MD, Cho/NAA (R2 = 0.3412, P = 0.0014; R2 = 0.2112, P = 0.016; and R2 = 0.2352, P = 0.010 respectively); along with FA and Cho/NAA (R2 = 0.1695, P = 0.033). DTI fiber tract density, MD and FA at the site of compression, along with Cho/NAA at C2, were significantly correlated with mJOA score (R2 = 0.05939, P < 0.0001; R2 = 0.4739, P < 0.0001; R2 = 0.7034, P < 0.0001; R2 = 0.4649, P < 0.0001). A combination biomarker consisting of DTI fiber tract density, MD, and Cho/NAA showed the best prediction of mJOA (R2 = 0.8274, P<0.0001), with post-hoc tests suggesting fiber tract density, MD, and Cho/NAA were all significant contributors to predicting mJOA (P = 0.00053, P = 0.00085, and P = 0.0019, respectively). A linear combination of DTI and MRS measurements within the cervical spinal cord may be useful for accurately predicting neurological deficits in patients with cervical spondylosis. Additional studies may be necessary to validate these observations.

Contrast-enhanced MRI is typically used to follow treatment response and progression in patients with glioblastoma (GBM). However, differentiating tumor progression from pseudoprogression remains a clinical dilemma largely unmitigated by current advances in imaging techniques. Noninvasive imaging techniques capable of distinguishing these two conditions could play an important role in the clinical management of patients with GBM and other brain malignancies. We hypothesized that PET probes for deoxycytidine kinase (dCK) could be used to differentiate immune inflammatory responses from other sources of contrast-enhancement on MRI. Orthotopic malignant gliomas were established in syngeneic immunocompetent mice and then treated with dendritic cell (DC) vaccination and/or PD-1 mAb blockade. Mice were then imaged with [18F]-FAC PET/CT and MRI with i.v. contrast. The ratio of contrast enhancement on MRI to normalized PET probe uptake, which we term the immunotherapeutic response index, delineated specific regions of immune inflammatory activity. On postmortem examination, FACS-based enumeration of intracranial tumor-infiltrating lymphocytes directly correlated with quantitative [18F]-FAC PET probe uptake. Three patients with GBM undergoing treatment with tumor lysate-pulsed DC vaccination and PD-1 mAb blockade were also imaged before and after therapy using MRI and a clinical PET probe for dCK. Unlike in mice, [18F]-FAC is rapidly catabolized in humans; thus, we used another dCK PET probe, [18F]-clofarabine ([18F]-CFA), that may be more clinically relevant. Enhanced [18F]-CFA PET probe accumulation was identified in tumor and secondary lymphoid organs after immunotherapy. Our findings identify a noninvasive modality capable of imaging the host antitumor immune response against intracranial tumors.

Purpose We aimed to evaluate whether the heterogeneity of tuber imaging features, evaluated on the structural imaging and apparent diffusion coefficient (ADC) map, can facilitate detecting epileptogenic tubers before surgery in tuberous sclerosis complex (TSC) patients. Methods Twenty-three consecutive patients, who underwent tuber resection at our institute, were retrospectively selected. A total of 125 tubers (39 epileptogenic, 86 non-epileptogenic) were used for the analysis. Tuber heterogeneity was evaluated, using a 5-point visual scale and standard deviation of ADC values (ADC sd ). A 5-point visual scale reflected the degree of T1/T2 prolongation, presence of internal cystic degeneration, and their spatial distribution within the tuber. These results were statistically compared between epileptogenic and non-epileptogenic groups, and their performance in predicting the epileptogenicity was also evaluated by receiver operating characteristic (ROC) analysis. Results A 5-point visual scale demonstrated that more heterogeneous tubers were significantly more epileptogenic ( p  < 0.001). Multiplicity of internal cystic degeneration moderately correlated with epileptogenicity ( p  < 0.03) based on the comparison between class 4 and class 5 tubers. ADC sd was significantly higher in epileptogenic tubers ( p  < 0.001). ROC curves revealed that a 5-point visual scale demonstrated higher area under the curve (AUC) value than ADC sd (0.75 and 0.72, respectively). Conclusion Tuber heterogeneity may help identify the epileptogenic tubers in presurgical TSC patients. Visual assessment and standard deviation of ADC value, which are easier to implement in clinical use, may be a useful tool predicting epileptogenic tubers, improving presurgical clinical management for TSC patients with intractable epilepsy.

Objective To determine the feasibility and biologic correlations of dynamic susceptibility contrast (DSC), dynamic contrast enhanced (DCE), and quantitative maps derived from contrast leakage effects obtained simultaneously in gliomas using dynamic spin-and-gradient-echo echoplanar imaging (dynamic SAGE-EPI) during a single contrast injection. Materials and methods Thirty-eight patients with enhancing brain gliomas were prospectively imaged with dynamic SAGE-EPI, which was processed to compute traditional DSC metrics (normalized relative cerebral blood flow [nrCBV], percentage of signal recovery [PSR]), DCE metrics (volume transfer constant [ K trans ], extravascular compartment [ v e ]), and leakage effect metrics: Δ R 2,ss * (reflecting T 2 *-leakage effects), Δ R 1,ss (reflecting T 1 -leakage effects), and the transverse relaxivity at tracer equilibrium ( TRATE , reflecting the balance between Δ R 2,ss * and Δ R 1,ss ). These metrics were compared between patient subgroups (treatment-naïve [TN] vs recurrent [R]) and biological features (IDH status, Ki67 expression). Results In IDH wild-type gliomas (IDH wt —i.e., glioblastomas), previous exposure to treatment determined lower TRATE ( p  = 0.002), as well as higher PSR ( p  = 0.006), K trans ( p  = 0.17), Δ R 1,ss ( p  = 0.035), v e ( p  = 0.006), and ADC ( p  = 0.016). In IDH-mutant gliomas (IDH m ), previous treatment determined higher K trans and Δ R 1,ss ( p  = 0.026). In TN-gliomas, dynamic SAGE-EPI metrics tended to be influenced by IDH status ( p ranging 0.09–0.14). TRATE values above 142 mM −1 s −1 were exclusively seen in TN-IDH wt , and, in TN-gliomas, this cutoff had 89% sensitivity and 80% specificity as a predictor of Ki67 > 10%. Conclusions Dynamic SAGE-EPI enables simultaneous quantification of brain tumor perfusion and permeability, as well as mapping of novel metrics related to cytoarchitecture ( TRATE ) and blood–brain barrier disruption (Δ R 1,ss ), with a single contrast injection. Clinical relevance statement Simultaneous DSC and DCE analysis with dynamic SAGE-EPI reduces scanning time and contrast dose, respectively alleviating concerns about imaging protocol length and gadolinium adverse effects and accumulation, while providing novel leakage effect metrics reflecting blood–brain barrier disruption and tumor tissue cytoarchitecture. Key Points • Traditionally, perfusion and permeability imaging for brain tumors requires two separate contrast injections and acquisitions. • Dynamic spin-and-gradient-echo echoplanar imaging enables simultaneous perfusion and permeability imaging. • Dynamic spin-and-gradient-echo echoplanar imaging provides new image contrasts reflecting blood–brain barrier disruption and cytoarchitecture characteristics. Graphical Abstract