Radiographic endpoints including response and progression are important for the evaluation of new glioblastoma therapies. The current RANO criteria was developed to overcome many of the challenges ...identified with previous guidelines for response assessment, however, significant challenges and limitations remain. The current recommendations build on the strengths of the current RANO criteria, while addressing many of these limitations. Modifications to the current RANO criteria include suggestions for volumetric response evaluation, use contrast enhanced T1 subtraction maps to increase lesion conspicuity, removal of qualitative non-enhancing tumor assessment requirements, use of the post-radiation time point as the baseline for newly diagnosed glioblastoma response assessment, and “treatment-agnostic” response assessment rubrics for identifying pseudoprogression, pseudoresponse, and a confirmed durable response in newly diagnosed and recurrent glioblastoma trials.
Radiogenomics is a provocative new area of research based on decades of previous work examining the association between radiological and histological features. Many generalized associations have been ...established linking anatomical imaging traits with underlying histopathology, including associations between contrast-enhancing tumor and vascular and tumor cell proliferation, hypointensity on pre-contrast T1-weighted images and necrotic tissue, and associations between hyperintensity on T2-weighted images and edema or nonenhancing tumor. Additionally, tumor location, tumor size, composition, and descriptive features tend to show significant associations with molecular and genomic factors, likely related to the cell of origin and growth characteristics. Additionally, physiologic MRI techniques also show interesting correlations with underlying histology and genomic programs, including associations with gene expression signatures and histological subtypes. Future studies extending beyond simple radiology–histology associations are warranted in order to establish radiogenomic analyses as tools for prospectively identifying patient subtypes that may benefit from specific therapies.
Summary 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.
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.
Diffuse gliomas are malignant brain tumors that include lower-grade gliomas (LGGs) and glioblastomas. Transformation of low-grade glioma into a higher tumor grade is typically associated with ...contrast enhancement on magnetic resonance imaging. Mutations in the isocitrate dehydrogenase 1 (
) gene occur in most LGGs (> 70%). Ivosidenib is an inhibitor of mutant IDH1 (mIDH1) under evaluation in patients with solid tumors.
We conducted a multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in patients with m
solid tumors. Ivosidenib was administered orally daily in 28-day cycles.
In 66 patients with advanced gliomas, ivosidenib was well tolerated, with no dose-limiting toxicities reported. The maximum tolerated dose was not reached; 500 mg once per day was selected for the expansion cohort. The grade ≥ 3 adverse event rate was 19.7%; 3% (n = 2) were considered treatment related. In patients with nonenhancing glioma (n = 35), the objective response rate was 2.9%, with 1 partial response. Thirty of 35 patients (85.7%) with nonenhancing glioma achieved stable disease compared with 14 of 31 (45.2%) with enhancing glioma. Median progression-free survival was 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for the nonenhancing and enhancing glioma cohorts, respectively. In an exploratory analysis, ivosidenib reduced the volume and growth rates of nonenhancing tumors.
In patients with m
advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.
Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on ...MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (
). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes.
We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant
(m
) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154.
Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months 95% confidence interval (CI), 11.2-40.8 for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients.
Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing m
LGG.
Purpose
To evaluate the influence of phosphate on amine, amide, and hydroxyl CEST contrast using Bloch‐McConnell simulations applied to physical phantom data.
Methods
Phantom solutions of 4 ...representative metabolites with exchangeable protons—glycine (α‐amine protons), Cr (η‐amine protons), egg white protein (amide protons), and glucose (hydroxyl protons)—were prepared at different pH levels (5.6 to 8.9) and phosphate concentrations (5 to 80 mM). CEST images of the phantom were collected with CEST‐EPI sequence at 3 tesla. The CEST data were then fitted to full Bloch‐McConnell equation simulations to estimate the exchange rate constants. With the fitted parameters, simulations were performed to evaluate the intracellular and extracellular contributions of CEST signals in normal brain tissue and brain tumors, as well as in dynamic glucose‐enhanced experiments.
Results
The exchange rates of α‐amine and hydroxyl protons were found to be highly dependent on both pH and phosphate concentrations, whereas the exchange rates of η‐amine and amide protons were pH‐dependent, albeit not catalyzed by phosphate. With phosphate being predominantly intracellular, CEST contrast of α‐amine exhibited a higher sensitivity to changes in the extracellular microenvironment. Simulations of dynamic glucose‐enhanced signals demonstrated that the contrast between normal and tumor tissue was mostly due to the extracellular CEST effect.
Conclusion
The proton exchange rates in some metabolites can be greatly catalyzed by the presence of phosphate at physiological concentrations, which substantially alters the CEST contrast. Catalytic agents should be considered as confounding factors in future CEST‐MRI research. This new dimension may also benefit the development of novel phosphate‐sensitive imaging methods.
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.
Abstract
A recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to ...discuss challenges and potential solutions for increasing development of therapeutics for central nervous system metastases. A key issue identified at this meeting was the need for consistent tumor measurement for reliable tumor response assessment, including the first step of standardized image acquisition with an MRI protocol that could be implemented in multicenter studies aimed at testing new therapeutics. This document builds upon previous consensus recommendations for a standardized brain tumor imaging protocol (BTIP) in high-grade gliomas and defines a protocol for brain metastases (BTIP-BM) that addresses unique challenges associated with assessment of CNS metastases. The “minimum standard” recommended pulse sequences include: (i) parameter matched pre- and post-contrast inversion recovery (IR)–prepared, isotropic 3D T1-weighted gradient echo (IR-GRE); (ii) axial 2D T2-weighted turbo spin echo acquired after injection of gadolinium-based contrast agent and before post-contrast 3D T1-weighted images; (iii) axial 2D or 3D T2-weighted fluid attenuated inversion recovery; (iv) axial 2D, 3-directional diffusion-weighted images; and (v) post-contrast 2D T1-weighted spin echo images for increased lesion conspicuity. Recommended sequence parameters are provided for both 1.5T and 3T MR systems. An “ideal” protocol is also provided, which replaces IR-GRE with 3D TSE T1-weighted imaging pre- and post-gadolinium, and is best performed at 3T, for which dynamic susceptibility contrast perfusion is included. Recommended perfusion parameters are given.
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