title: pH-weighted molecular imaging of gliomas using amine chemical exchange saturation transfer MRI.
abstract: BACKGROUND
  Interstitial tissue acidosis resulting from abnormal perfusion and metabolism is a hallmark of cancer. The current study demonstrates that chemical exchange saturation transfer (CEST) MRI can be used as a noninvasive pH-weighted molecular imaging technique by targeting the chemical exchange between amine protons and protons in extracellular bulk water.
  
  
  METHODS
  First, the sensitivity of amine CEST was validated in phantoms under a variety of conditions, including different magnetic field strengths, amino acid concentrations, and pH values. Amine CEST was compared with histology in both a preclinical GL261 intracranial glioma model at 7T and human patients at 3T. The association between physiologic and pH-weighted MRI was explored, along with the ability to predict time to progression to radiochemotherapy in 20 glioblastoma patients.
  
  
  RESULTS
  z-Spectral asymmetry increased at 3 ppm (amine range) on CEST MRI with decreasing pH within the range observed in tumors for both 3T and 7T scanners. Lesions with acidic signatures showed active tumor and pseudopalisading tumor on histology and showed elevated FDOPA PET uptake, lactate on MR spectroscopy, and perfusion abnormalities. Patients with acidic lesions after surgery or stable/growing acidic lesions had a shorter time to progression following radiochemotherapy compared with patients with lesions demonstrating relatively low acidity (P < .001).
  
  
  CONCLUSIONS
  Results suggest pH-weighted MRI may provide new insight into brain tumor physiology beyond traditional imaging technologies.
authors.affiliation: Department of Radiological Sciences (R.J.H., W.B.P., B.M.E.), Department of Biomedical Physics (R.J.H., B.M.E.), Department of Neurology (T.F.C., A.L., P.L.N.), Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (L.M.L., R.M.P., J.P.A.); Department of Biomedical Sciences and Imaging, Cedars-Sinai Medical Center, Los Angeles, California (D.L.); Department of Bioengineering (D.L., B.M.E.), Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.).
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Harris
authors.affiliation: Department of Radiological Sciences (R.J.H., W.B.P., B.M.E.), Department of Biomedical Physics (R.J.H., B.M.E.), Department of Neurology (T.F.C., A.L., P.L.N.), Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (L.M.L., R.M.P., J.P.A.); Department of Biomedical Sciences and Imaging, Cedars-Sinai Medical Center, Los Angeles, California (D.L.); Department of Bioengineering (D.L., B.M.E.), Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.).
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.affiliation: Department of Radiological Sciences (R.J.H., W.B.P., B.M.E.), Department of Biomedical Physics (R.J.H., B.M.E.), Department of Neurology (T.F.C., A.L., P.L.N.), Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (L.M.L., R.M.P., J.P.A.); Department of Biomedical Sciences and Imaging, Cedars-Sinai Medical Center, Los Angeles, California (D.L.); Department of Bioengineering (D.L., B.M.E.), Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.).
authors.forename: Linda M
authors.initials: LM
authors.lastname: Liau
authors.affiliation: Department of Radiological Sciences (R.J.H., W.B.P., B.M.E.), Department of Biomedical Physics (R.J.H., B.M.E.), Department of Neurology (T.F.C., A.L., P.L.N.), Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (L.M.L., R.M.P., J.P.A.); Department of Biomedical Sciences and Imaging, Cedars-Sinai Medical Center, Los Angeles, California (D.L.); Department of Bioengineering (D.L., B.M.E.), Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.).
authors.forename: Robert M
authors.initials: RM
authors.lastname: Prins
authors.affiliation: Department of Radiological Sciences (R.J.H., W.B.P., B.M.E.), Department of Biomedical Physics (R.J.H., B.M.E.), Department of Neurology (T.F.C., A.L., P.L.N.), Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (L.M.L., R.M.P., J.P.A.); Department of Biomedical Sciences and Imaging, Cedars-Sinai Medical Center, Los Angeles, California (D.L.); Department of Bioengineering (D.L., B.M.E.), Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.).
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Antonios
authors.affiliation: Department of Radiological Sciences (R.J.H., W.B.P., B.M.E.), Department of Biomedical Physics (R.J.H., B.M.E.), Department of Neurology (T.F.C., A.L., P.L.N.), Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (L.M.L., R.M.P., J.P.A.); Department of Biomedical Sciences and Imaging, Cedars-Sinai Medical Center, Los Angeles, California (D.L.); Department of Bioengineering (D.L., B.M.E.), Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.).
authors.forename: Debiao
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Radiological Sciences (R.J.H., W.B.P., B.M.E.), Department of Biomedical Physics (R.J.H., B.M.E.), Department of Neurology (T.F.C., A.L., P.L.N.), Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (L.M.L., R.M.P., J.P.A.); Department of Biomedical Sciences and Imaging, Cedars-Sinai Medical Center, Los Angeles, California (D.L.); Department of Bioengineering (D.L., B.M.E.), Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.).
authors.forename: William H
authors.initials: WH
authors.lastname: Yong
authors.affiliation: Department of Radiological Sciences (R.J.H., W.B.P., B.M.E.), Department of Biomedical Physics (R.J.H., B.M.E.), Department of Neurology (T.F.C., A.L., P.L.N.), Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (L.M.L., R.M.P., J.P.A.); Department of Biomedical Sciences and Imaging, Cedars-Sinai Medical Center, Los Angeles, California (D.L.); Department of Bioengineering (D.L., B.M.E.), Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.).
authors.forename: Whitney B
authors.initials: WB
authors.lastname: Pope
authors.affiliation: Department of Radiological Sciences (R.J.H., W.B.P., B.M.E.), Department of Biomedical Physics (R.J.H., B.M.E.), Department of Neurology (T.F.C., A.L., P.L.N.), Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (L.M.L., R.M.P., J.P.A.); Department of Biomedical Sciences and Imaging, Cedars-Sinai Medical Center, Los Angeles, California (D.L.); Department of Bioengineering (D.L., B.M.E.), Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.).
authors.forename: Albert
authors.initials: A
authors.lastname: Lai
authors.affiliation: Department of Radiological Sciences (R.J.H., W.B.P., B.M.E.), Department of Biomedical Physics (R.J.H., B.M.E.), Department of Neurology (T.F.C., A.L., P.L.N.), Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (L.M.L., R.M.P., J.P.A.); Department of Biomedical Sciences and Imaging, Cedars-Sinai Medical Center, Los Angeles, California (D.L.); Department of Bioengineering (D.L., B.M.E.), Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.).
authors.forename: Phioanh L
authors.initials: PL
authors.lastname: Nghiemphu
authors.affiliation: Department of Radiological Sciences (R.J.H., W.B.P., B.M.E.), Department of Biomedical Physics (R.J.H., B.M.E.), Department of Neurology (T.F.C., A.L., P.L.N.), Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (L.M.L., R.M.P., J.P.A.); Department of Biomedical Sciences and Imaging, Cedars-Sinai Medical Center, Los Angeles, California (D.L.); Department of Bioengineering (D.L., B.M.E.), Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California (W.H.Y.).
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Ellingson
mesh_terms: D000588:Amines; D000818:Animals; D001932:Brain Neoplasms / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D059248:Chemoradiotherapy; D018572:Disease-Free Survival; D005260:Female; D005910:Glioma / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007090:Image Interpretation, Computer-Assisted / Q000379:methods; D053208:Kaplan-Meier Estimate; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D008875:Middle Aged; D057054:Molecular Imaging / Q000379:methods*; D059906:Neuroimaging / Q000379:methods*; D019047:Phantoms, Imaging; D011522:Protons
chemical_list: D000588:Amines; D011522:Protons
keywords: CEST; chemical exchange saturation transfer; glioma; pH; pH-weighted MRI