This study tested the efficacy of ultra-high-field (7T) magnetic resonance spectroscopy (MRS) for predicting molecular characteristics of glioma tumors by visual inspection of MRS spectra. Participants in a workshop correctly identified the IDH mutation status in 11 out of 13 glioma patients by visually inspecting 7T MRS spectra, demonstrating the potential of 7T MRS for non-invasive glioma diagnosis and precision medicine strategies. While 2-HG detection is challenging at lower field strengths, 7T MRS provides improved detection and resolution of metabolic biomarkers like 2-HG that can help classify glioma molecular subtypes.

1. Diagnostic Efficacy of Ultra-High-Field MRS in Glioma Patients
Uzay E Emir, Jannie Wijnen, Olaf Ansorge, Evita Wiegers, Anja van der Kolk, Alexander Lin, and Clark Chen
School of Health Sciences, Purdue University, West Lafayette, IN, United States, Weldon School of Biomedical Engineering, Purdue University, West
Lafayette, IN, United States, Radiology, University Medical Centre Utrecht,Utrecht, Netherlands, University of Oxford, Oxford, United Kingdom, Antoni van
Leeuwenhoek Hospital, Netherlands Cancer Center, Amsterdam, Netherlands, Brigham and Women’s Hospital / Dana Farber Cancer Institute,Harvard
Medical School, Boston, MA, United States, Department of Neurosurgery, University of Minnesota, Minneapolis, MN, United States
Synopsis:
We have recently initiated a 7T MRS glioma consortium, intending to bring together experts in
the field to discuss pitfalls, promises, and potential research avenues of MRS in gliomas. During
the "GlioMaRS-NET Workshop" in 2020, we tested the efficacy of UHF MRS for predicting the
molecular characteristics by visual inspection by conducting a survey with a set of previously
acquired UHF spectra from glioma patients.
In the post-genomics era, the World Health Organization (WHO) classification of gliomas has
become even more tightly integrated with molecular parameters in addition to histology. Integrated
diagnoses offer prospects for precision medicine strategies tailoring therapies for each individual.
The International Society of Neuropathology‐Haarlem Consensus has proposed the personalized
layered diagnosis for gliomas that merge all of the distinct but related information. For the final
diagnosis, the concept of integrated diagnosis (Layer 1) relies on all available data, which include
the histological classification (Layer 2, e.g., astrocytoma vs. oligodendroglioma), the grading
(Layer 3, e.g., WHO grade II vs. III), and molecular characteristics (Layer 4, e.g., isocitrate
dehydrogenase (IDH)-mutant, 1p/19q-codeletion) (1). Thus, the personalized layered diagnosis
approach has emphasized to tailor the diagnostic imaging to contribute to the integrated diagnosis
by discovering reliable imaging biomarkers and tools capable of differential diagnosis according
to genetic subtypes.
It has recently been shown that definitional features of glioma, such as IDH mutation and 1p/19q
codeletion (Layer 4), can be identified with non-invasive MRS at 3T, opening up exciting new
opportunities for diagnostics, clinical trials, and assessment of treatments (2,3). Ultra-high-field
(UHF, >=7T) MRI scanners offer enhanced detection relative to routine 3T MRI of 2-HG peaks
in the MRS spectra of IDH mutated patients (4,5). This is due to increased SNR at the higher field
strength and increased spectral dispersion, which can improve the delineation of 2HG from
neighboring metabolites such as glutamate and glutamine. Furthermore, at 7T, the 2-HG peak is
not only to contribute to layer 4 of the integrated diagnosis by identifying molecular features but
also to detect subtle changes due to the reprogramming of cellular metabolism during the disease
progression or treatment.
With the recent successes of 2-HG and increased use of UHF MRI in clinical settings as a basis,
we have recently initiated a 7T MRS glioma consortium, intending to bring together experts in the
field to discuss pitfalls, promises, and potential research avenues of MRS in gliomas. During the
"Multi-center 7T Glioma Consortium (GlioMaRS-NET) Workshop" held on 16-20 November

2. 2020 (https://www.ndcn.ox.ac.uk/study-with-us/continuing-professional-development/gliomars ),
we tested the efficacy of UHF MRS for predicting the molecular characteristics by visual
inspection by conducting a survey with a set of previously acquired UHF spectra from glioma
patients.
Method
For this purpose, we asked the attendees of the first GlioMaRS-NET workshop to complete a
survey in which participants predicted the patients' IDH status by inspecting the UHF MRS spectra
visually. A total of 13 glioma patients' 7T MRS single-voxel MRS spectra were used for the
survey. Assessed by immunohistochemical and DNA sequencing from a surgical tissue biopsy,
nine patients were identified carrying IDH mutations. In the survey, MRS voxel placements on
each patient's T1-weighted anatomical MPRAGE were provided. The 2-HG sensitive semi-
localization by adiabatic selective refocusing (semi-LASER, TE=110 ms) pulse sequence spectra
acquired at 7T were illustrated for voxel of interest in the tumor tissue and if available in the
healthy tissue (5). Only preprocessed spectra (frequency and phase-corrected) were shown,
without any information on metabolite fits or quantification. Figure 1 illustrates the
information provided to participants at the beginning of the survey. Figure 2 shows the
representative question asked for the participants to predict the IDH status by visual
inspection of the spectra.
Results
A total of 12 participants consisting of neurooncologists, neurosurgeons, biochemists,
pathologists, and MR physicists answered the questionnaire during the GlioMaRS-NET workshop
(https://purdue.ca1.qualtrics.com/jfe/form/SV_3t0rhgTgMqzxAuV ). Descriptive measures of the
predicted IDH status from the visual inspection are shown in Figure 3. All participants identified
11 glioma patient IDH statuses agreed with clinical molecular statuses by visual inspection with
an accuracy range between 83.3-100 %. In other words, all participants identified the IDH statuses
of 10 patients successfully. Only two glioma patients' IDH statuses were identified falsely with a
range of between 83.3 (10 participants (False) vs. 2 participants) and 75 % (9 participants (False)
vs. 3 participants).
Discussion and Conclusion
Several studies have demonstrated in vivo detection of 2-HG in IDH-mutant tumors at 3T,
commonly used in the clinical setting (2,6)(7)(8). However, the assignment of 2-HG resonances at
3T is a technical challenge not only because of the complex spin-coupling features of overlapping
resonances but also due to the lack of SNR and spectral resolution. As we demonstrate, the IDH
status could be detected by simple visual inspection without using any prior information at 7T.
The collection of more UHF MRS of glioma patients could lead to a prognostic precision medicine
biomarker detection system for identifying, stratifying, and monitoring IDH1 and IDH2 mutant
glioma patients.
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