Short summary

Amide Proton Transfer (APT) weighted imaging is emerging as a new technique that holds the promise of improving the capabilities of MRI with respect to tumor grading, distinguishing between areas of tumor infiltration and vasogenic edema and differentiating tumor recurrence from treatment effects. By detecting the signal from amide protons of endogenous mobile proteins and peptides in tissue - present in higher concentrations in malignant gliomas - APT may provide added value to conventional MRI techniques without the use of contrast agents

Rationale

According to data from the latest Danish Cancer Registry Report and the Danish Neuro-Oncology Registry, 1644 new cases of primary brain and central nervous system (CNS) tumors were diagnosed in Denmark in 2016. Moreover, primary brain and CNS tumors had a prevalence of 18.388 in the Danish population. Roughly 400 (ca. 24%) of the newly diagnosed tumors were gliomas. Of these, 338 (ca. 84%) were high-grade gliomas (WHO grade III and IV).

Odense University Hospital (OUH) plays a significant role in the diagnosis and treatment of patients with primary brain tumors in the Region of Southern Denmark. As one of the largest university hospitals in Denmark, OUH is at the forefront of cancer research and continuously strives to improve patient outcome through the use of advanced diagnosis and treatment options. According to the latest data published in the Danish Neuro-Oncology Registry's Annual Report, a total of 249 patients with newly diagnosed gliomas underwent diagnostic procedures and subsequent oncologic treatment at OUH in 2016. This adds to the patients already receiving treatment and undergoing follow-up examinations.

MRI is the imaging modality of choice used in the diagnosis and grading of gliomas, as well as for assessing treatment response and to distinguish between tumor recurrence/progression and treatment-induced changes. Glioma examinations performed in our Radiology Department include both conventional sequences, i.e. FLAIR, T2 W, contrast-enhanced T1W, but also dynamic susceptibility contrast (DSC) perfusion, diffusion tensor imaging (DTI) and MR spectroscopy.

However, there are situations where the complexity of tumor morphology and the effect of new treatment methods prevent MRI from providing a conclusive answer regarding tumor grade or confirming/infirming the suspicion of tumor progression.

Another important issue regarding contrast administration is the potential accumulation of gadolinium in the brain tissue of patients with normal renal function. Glioma patients undergo repeated contrast-enhanced MRI examinations, which increases their risk of brain tissue gadolinium deposition. 

The challenges posed by glioma complexity and by treatment advances, as well as the potential contrast side-effects, create a need for new imaging techniques that offer diagnostic sensitivity and specificity without the use of contrast agents.

Amide Proton Transfer (APT) weighted imaging is emerging as a new technique that holds the promise of improving the capabilities of MRI with respect to tumor grading, distinguishing between areas of tumor infiltration and vasogenic edema and differentiating tumor recurrence from treatment effects. By detecting the signal from amide protons of endogenous mobile proteins and peptides in tissue - present in higher concentrations in malignant gliomas - APT may provide added value to conventional MRI techniques without the use of contrast agents.

Although APT weighted imaging is currently mostly implemented in the brain, it is also beginning to make its way into body applications such as the histological grading of endometrioid endometrial adenocarcinoma.

The feasibility of APT in glioma imaging has been demonstrated by a number of phantom and animal studies, as well as clinical studies based on small cohorts of patients and healthy volunteers. 

In addition to the topics mentioned above, one of the most interesting clinical applications investigated is the ability to predict isocitrate dehydrogenase (IDH) mutation/ O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status on the basis of APT weighted MRI. According to previous studies, APT signal has been found to be significantly higher in both IDH-wildtype and MGMT unmethylated tumors, compared to IDH mutant and MGMT methylated lesions (6) (7). This could be very relevant in clinical practice, given the fact that the most recent 2016 World Health Organization (WHO) classification of central nervous system (CNS) tumors is now based on molecular parameters, as well as histology. Tumor molecular characteristics are used as grading/ prognostic factors and also play a role in choosing the optimal treatment strateg.

Despite the significant number of studies dedicated to APT imaging, the great majority of these are either phantom/ animal studies or are based on limited cohorts. To overcome this limitation, it is advisable to test the clinical robustness of the APT technique on a larger number of individuals. Given the considerable number of glioma patients who undergo MRI examinations in our Radiology Department, it should be possible to collect sufficient data for a clinical validation study.

It is also worth noting that the great majority of the above-mentioned studies focus on comparing APT-weighted imaging with conventional T2 W, FLAIR and contrast-enhanced T1 W sequences. The inclusion of advanced sequences, such as MR perfusion, in our glioma imaging protocol provides an additional term of comparison for the APT weighted sequence. At the same time, APT data can be validated by comparing it to histopathological results.

Purpose

The present study sets out to prospectively investigate:

1. The clinical utility of APT weighted imaging in grading newly diagnosed brain gliomas compared to DSC perfusion and MR spectroscopy.
2. The clinical utility of APT weighted MRI in detecting glioma recurrence compared to DSC perfusion.
3. To assess the agreement between APT weighted MRI and histopathology as the golden standard. 
4. To perform an intra- and interobserver agreement analysis of quantitative signal intensities based on APT data.

Description of the cohort

50 adult patients (i.e. >18 years) referred for MRI on suspicion of glioma, as well as patients with known gliomas undergoing MRI follow-up and patients with suspected recurrence 

Collaborating researchers and departments

Department of Radiology, Odense University Hospital

• Research Radiographer, Bo Mussmann, Phd.
• MRI radiographer, Ancuta Ioana Friismose, BSc.
• MD, Ljubo Markovic
• MD, Nina Nguyen
• MD, Frederik Harbo

Department of Neurosurgery, Odense University Hospital

• MD, Mette Schultz, Phd

Department of Nuclear Medicine, Odense University Hospital

• Biostatistician, Oke Gerke, Phd,