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Relaxation-compensated amide proton transfer (APT) MRI signal intensity is associated with survival and progression in high-grade glioma patients

  • Daniel PaechEmail author
  • Constantin Dreher
  • Sebastian Regnery
  • Jan-Eric Meissner
  • Steffen Goerke
  • Johannes Windschuh
  • Johanna Oberhollenzer
  • Miriam Schultheiss
  • Katerina Deike-Hofmann
  • Sebastian Bickelhaupt
  • Alexander Radbruch
  • Moritz Zaiss
  • Andreas Unterberg
  • Wolfgang Wick
  • Martin Bendszus
  • Peter Bachert
  • Mark E. Ladd
  • Heinz-Peter Schlemmer
Neuro

Abstract

Objectives

The purpose of this study was to investigate the association of relaxation-compensated chemical exchange saturation transfer (CEST) MRI with overall survival (OS) and progression-free survival (PFS) in newly diagnosed high-grade glioma (HGG) patients.

Methods

Twenty-six patients with newly diagnosed high-grade glioma (WHO grades III–IV) were included in this prospective IRB-approved study. CEST MRI was performed on a 7.0-T whole-body scanner. Association of patient OS/PFS with relaxation-compensated CEST MRI (amide proton transfer (APT), relayed nuclear Overhauser effect (rNOE)/NOE, downfield-rNOE-suppressed APT (dns-APT)) and diffusion-weighted imaging (apparent diffusion coefficient) were assessed using the univariate Cox proportional hazards regression model. Hazard ratios (HRs) and corresponding 95% confidence intervals were calculated. Furthermore, OS/PFS association with clinical parameters (age, gender, O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation status, and therapy: biopsy + radio-chemotherapy vs. debulking surgery + radio-chemotherapy) were tested accordingly.

Results

Relaxation-compensated APT MRI was significantly correlated with patient OS (HR = 3.15, p = 0.02) and PFS (HR = 1.83, p = 0.009). The strongest association with PFS was found for the dns-APT metric (HR = 2.61, p = 0.002). These results still stand for the relaxation-compensated APT contrasts in a homogenous subcohort of n = 22 glioblastoma patients with isocitrate dehydrogenase (IDH) wild-type status. Among the tested clinical parameters, patient age (HR = 1.1, p = 0.001) and therapy (HR = 3.68, p = 0.026) were significant for OS; age additionally for PFS (HR = 1.04, p = 0.048).

Conclusion

Relaxation-compensated APT MRI signal intensity is associated with overall survival and progression-free survival in newly diagnosed, previously untreated glioma patients and may, therefore, help to customize treatment and response monitoring in the future.

Key Points

• Amide proton transfer (APT) MRI signal intensity is associated with overall survival and progression in glioma patients.

• Relaxation compensation enhances the information value of APT MRI in tumors.

• Chemical exchange saturation transfer (CEST) MRI may serve as a non-invasive biomarker to predict prognosis and customize treatment.

Keywords

Magnetic resonance imaging Glioma Glioblastoma Survival Biomarkers, cancer 

Abbreviations

APT

Amide proton transfer

APTAREX

APT contrast calculated with the AREX metric

APTLD

APT contrast calculated with the LD metric

AREX

Apparent exchange-dependent relaxation

CEST

Chemical exchange saturation transfer

dns-APT

Downfield relayed nuclear Overhauser effect suppressed APT

FLAIR

Fluid-attenuated inversion recovery

FoV

Field of view

GBCA

Gadolinium-based contrast agents

GBM

Glioblastoma multiforme

gdce-T1

T1-weighted gadolinium contrast-enhanced MRI

GRE

Gradient echo

HGG

High-grade glioma

IDH

Isocitrate dehydrogenase

IQR

Interquartile range

KPS

Karnofsky performance scale

LD

Lorentzian difference

MGMT

O6-Methylguanine-DNA methyltransferase

MITK

Medical Imaging Interaction Toolkit

MPRAGE

Magnetization-prepared rapid gradient echo

MTRasym

Magnetization transfer ratio asymmetry

MTRLD

Magnetization transfer Lorentzian difference

NOE

Nuclear Overhauser effect

NOEAREX

NOE contrast calculated with the AREX metric

NOELD

NOE contrast calculated with the LD metric

OS

Overall survival

PFS

Progression-free survival

RANO

Response assessment in neuro-oncology

rCBV

Relative cerebral blood volume

RCT

Radio-chemotherapy

rNOE

Relayed nuclear Overhauser effect

T1-w

T1-weighted

T2-w

T2-weighted

TE

Echo time

TR

Repetition time

TSE

Turbo spin echo

WASABI

Simultaneous mapping of water shift and B1

WHO

World Health Organization

Zlab

Label Z-spectrum

Zref

Reference Z-spectrum

Notes

Acknowledgements

The authors would like to thank Prof. Dr. Annette Kopp-Schneider for her invaluable help with the statistical analyses and Joseph Weygand, M.S., for carefully proof reading and reviewing of the manuscript.

Funding

The authors state that this work has not received any funding.

Compliance with ethical standards

Guarantor

The scientific guarantor of this publication is Dr. Daniel Paech.

Conflict of interest

The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article.

Statistics and biometry

Prof. Dr. Annette Kopp-Schneider (Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany) kindly provided statistical advice for this manuscript.

Informed consent

Written informed consent was obtained from all subjects (patients) in this study.

Ethical approval

Institutional Review Board approval was obtained.

Study subjects or cohorts overlap

The study cohort has previously been reported (Paech et al. Neuro Oncol, 2018, noy073 and Regnery et al. Oncotarget, 2018, 9:28772–28783) and a subcohort of eleven patients has been included in methodical publications (Zaiss et al. Neuroimage, 2015, 112:180–188 and Zaiss et al. MRM, 2017, 77(1):196–208). However, no investigations of overall survival and progression-free survival have previously been performed.

Methodology

• prospective

• diagnostic or prognostic

• performed at one institution

Supplementary material

330_2019_6066_MOESM1_ESM.docx (2.7 mb)
ESM 1 (DOCX 2813 kb)

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Copyright information

© European Society of Radiology 2019

Authors and Affiliations

  • Daniel Paech
    • 1
    Email author
  • Constantin Dreher
    • 1
  • Sebastian Regnery
    • 1
    • 2
  • Jan-Eric Meissner
    • 3
  • Steffen Goerke
    • 3
  • Johannes Windschuh
    • 3
  • Johanna Oberhollenzer
    • 1
  • Miriam Schultheiss
    • 1
  • Katerina Deike-Hofmann
    • 1
  • Sebastian Bickelhaupt
    • 1
  • Alexander Radbruch
    • 1
    • 4
  • Moritz Zaiss
    • 5
  • Andreas Unterberg
    • 6
  • Wolfgang Wick
    • 7
  • Martin Bendszus
    • 8
  • Peter Bachert
    • 3
  • Mark E. Ladd
    • 3
    • 9
    • 10
  • Heinz-Peter Schlemmer
    • 1
  1. 1.Division of RadiologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  2. 2.Department of Radiation OncologyUniversity Hospital HeidelbergHeidelbergGermany
  3. 3.Division of Medical Physics in RadiologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  4. 4.Department of RadiologyUniversity Hospital EssenEssenGermany
  5. 5.Magnetic Resonance CenterMax-Planck-Institute for Biological CyberneticsTuebingenGermany
  6. 6.Department of NeurosurgeryUniversity Hospital HeidelbergHeidelbergGermany
  7. 7.Department of NeurologyUniversity Hospital HeidelbergHeidelbergGermany
  8. 8.Department of NeuroradiologyUniversity Hospital HeidelbergHeidelbergGermany
  9. 9.Faculty of Physics and AstronomyUniversity of HeidelbergHeidelbergGermany
  10. 10.Faculty of MedicineUniversity of HeidelbergHeidelbergGermany

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