[18F]-FMISO PET study of hypoxia in gliomas before surgery: correlation with molecular markers of hypoxia and angiogenesis.
OBJECTIVE
Hypoxia in gliomas is associated with tumor resistance to radio- and chemotherapy. However, positron emission tomography (PET) imaging of hypoxia remains challenging, and the validation of biological markers is, therefore, of great importance. We investigated the relationship between uptake of the PET hypoxia tracer [18F]-FMISO and other markers of hypoxia and angiogenesis and with patient survival.


METHODS
In this prospective single center clinical study, 33 glioma patients (grade IV: n = 24, III: n = 3, and II: n = 6) underwent [18F]-FMISO PET and MRI including relative cerebral blood volume (rCBV) maps before surgery. Maximum standardized uptake values (SUVmax) and hypoxic volume were calculated, defining two groups of patients based on the presence or absence of [18F]-FMISO uptake. After surgery, molecular quantification of CAIX, VEGF, Ang2 (rt-qPCR), and HIF-1α (immunohistochemistry) were performed on tumor specimens.


RESULTS
[18F]-FMISO PET uptake was closely linked to tumor grade, with high uptake in glioblastomas (GB, grade IV). Expression of biomarkers of hypoxia (CAIX, HIF-1α), and angiogenesis markers (VEGF, Ang2, rCBV) were significantly higher in the [18F]-FMISO uptake group. We found correlations between the degree of hypoxia (hypoxic volume and SUVmax) and expression of HIF-1α, CAIX, VEGF, Ang2, and rCBV (p < 0.01). Patients without [18F]-FMISO uptake had a longer survival time than uptake positive patients (log-rank, p < 0.005).


CONCLUSIONS
Tumor hypoxia as evaluated by [18F]-FMISO PET is associated with the expression of hypoxia markers on a molecular level and is related to angiogenesis. [18F]-FMISO uptake is a mark of an aggressive tumor, almost always a glioblastoma. Our results underline that [18F]-FMISO PET could be useful to guide glioma treatment, and in particular radiotherapy, since hypoxia is a well-known factor of resistance.
Department of Neurology, CHU de Caen, Caen, France. lien.bekaert@gmail.com.|Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, 14000, Caen, France. lien.bekaert@gmail.com.|Department of Neurosurgery, CHU de Caen, Caen, France. lien.bekaert@gmail.com.|Service de Neurochirurgie, CHU de Caen, Avenue de la Côte de Nacre, 14000, Caen, France. lien.bekaert@gmail.com.
Lien
L
Bekaert
Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, 14000, Caen, France.
Samuel
S
Valable
Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, 14000, Caen, France.|Department of Pathology, CHU de Caen, Caen, France.
Emmanuèle
E
Lechapt-Zalcman
Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, 14000, Caen, France.|Department of Neurosurgery, CHU de Caen, Caen, France.
Keven
K
Ponte
Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, 14000, Caen, France.
Solène
S
Collet
Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, 14000, Caen, France.|Department of Neuroradiology, CHU de Caen, Caen, France.
Jean-Marc
JM
Constans
Department of Pathology, CHU de Caen, Caen, France.
Guénaëlle
G
Levallet
Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, 14000, Caen, France.
Karim
K
Bordji
Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, 14000, Caen, France.
Edwige
E
Petit
Department of Neurology, CHU de Caen, Caen, France.
Pierre
P
Branger
Department of Neurosurgery, CHU de Caen, Caen, France.
Evelyne
E
Emery
Department of Nuclear Medicine, CHU de Caen, Caen, France.
Alain
A
Manrique
Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/LDM-TEP group, 14000, Caen, France.
Louisa
L
Barré
Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, 14000, Caen, France.
Myriam
M
Bernaudin
Department of Neurology, CHU de Caen, Caen, France. jeansebastien.GUILLAMO@chu-nimes.fr.|Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, 14000, Caen, France. jeansebastien.GUILLAMO@chu-nimes.fr.|Department of Neurology, CHU de Nimes, Place du Professeur Robert Debre, 30029, Nimes cedex 9, France. jeansebastien.GUILLAMO@chu-nimes.fr.
Jean-Sébastien
JS
Guillamo
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001692:Biological Transport; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D000071937:Cerebral Blood Volume; D018572:Disease-Free Survival; D005260:Female; D005910:Glioma / Q000000981:diagnostic imaging* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography; D016634:Radiosurgery; D000072258:Tumor Hypoxia
D014408:Biomarkers, Tumor; C031843:fluoromisonidazole; D008920:Misonidazole
Angiogenesis; Glioblastoma; Glioma; Hypoxia; [18F]-FMISO PET