TY - JOUR
T1 - Tissue Hypoxia and Alterations in Microvascular Architecture Predict Glioblastoma Recurrence in Humans
AU - Stadlbauer, Andreas
AU - Kinfe, Thomas M
AU - Eyüpoglu, Ilker
AU - Zimmermann, Max
AU - Kitzwögerer, Melitta
AU - Podar, Klaus
AU - Buchfelder, Michael
AU - Heinz, Gertraud
AU - Oberndorfer, Stefan
AU - Marhold, Franz
N1 - Funding Information:
The authors acknowledge support by Open Access Publishing Fund of Karl Landsteiner University of Health Sciences, Krems, Austria.
Funding Information:
A. Stadlbauer reports grants from German Research Foundation during the conduct of the study. K. Podar reports personal fees from Celgene, Janssen, and Amgen (consulting and honoraria) and Eutropics, Celgene, and Janssen (advisory board) outside the submitted work. No disclosures were reported by the other authors.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/3/15
Y1 - 2021/3/15
N2 - PURPOSE: Insufficient control of infiltrative glioblastoma (GBM) cells is a major cause of treatment failure and tumor recurrence. Hence, detailed insights into pathophysiologic changes that precede GBM recurrence are needed to develop more precise neuroimaging modalities for tailored diagnostic monitoring and therapeutic approaches.EXPERIMENTAL DESIGN: Overall, 168 physiologic MRI follow-up examinations of 56 patients with GBM who developed recurrence after standard therapy were retrospectively evaluated, that is, two post-standard-therapeutic follow-ups before and one at radiological recurrence. MRI biomarkers for microvascular architecture and perfusion, neovascularization activity, oxygen metabolism, and hypoxia were determined for brain areas that developed in the further course into recurrence and for the recurrent GBM itself. The temporal pattern of biomarker changes was fitted with locally estimated scatterplot smoothing functions and analyzed for pathophysiologic changes preceding radiological GBM recurrence.RESULTS: Our MRI approach demonstrated early pathophysiologic changes prior to radiological GBM recurrence in all patients. Analysis of the time courses revealed a model for the pathophysiology of GBM recurrence: 190 days prior to radiological recurrence, vascular cooption by GBM cells induced vessel regression, detected as decreasing vessel density/perfusion and increasing hypoxia. Seventy days later, neovascularization activity was upregulated, which reincreased vessel density and perfusion. Hypoxia, however, continued to intensify for 30 days and peaked 90 days before radiological recurrence.CONCLUSIONS: Hypoxia may represent an early sign for GBM recurrence. This might become useful in the development of new combined diagnostic-therapeutic approaches for tailored clinical management of recurrent GBM. Further preclinical and in-human studies are required for validation and evaluation.
AB - PURPOSE: Insufficient control of infiltrative glioblastoma (GBM) cells is a major cause of treatment failure and tumor recurrence. Hence, detailed insights into pathophysiologic changes that precede GBM recurrence are needed to develop more precise neuroimaging modalities for tailored diagnostic monitoring and therapeutic approaches.EXPERIMENTAL DESIGN: Overall, 168 physiologic MRI follow-up examinations of 56 patients with GBM who developed recurrence after standard therapy were retrospectively evaluated, that is, two post-standard-therapeutic follow-ups before and one at radiological recurrence. MRI biomarkers for microvascular architecture and perfusion, neovascularization activity, oxygen metabolism, and hypoxia were determined for brain areas that developed in the further course into recurrence and for the recurrent GBM itself. The temporal pattern of biomarker changes was fitted with locally estimated scatterplot smoothing functions and analyzed for pathophysiologic changes preceding radiological GBM recurrence.RESULTS: Our MRI approach demonstrated early pathophysiologic changes prior to radiological GBM recurrence in all patients. Analysis of the time courses revealed a model for the pathophysiology of GBM recurrence: 190 days prior to radiological recurrence, vascular cooption by GBM cells induced vessel regression, detected as decreasing vessel density/perfusion and increasing hypoxia. Seventy days later, neovascularization activity was upregulated, which reincreased vessel density and perfusion. Hypoxia, however, continued to intensify for 30 days and peaked 90 days before radiological recurrence.CONCLUSIONS: Hypoxia may represent an early sign for GBM recurrence. This might become useful in the development of new combined diagnostic-therapeutic approaches for tailored clinical management of recurrent GBM. Further preclinical and in-human studies are required for validation and evaluation.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Austria/epidemiology
KW - Brain Neoplasms/pathology
KW - Combined Modality Therapy
KW - Female
KW - Follow-Up Studies
KW - Glioblastoma/pathology
KW - Humans
KW - Hypoxia/pathology
KW - Magnetic Resonance Imaging/methods
KW - Male
KW - Middle Aged
KW - Neoplasm Recurrence, Local/diagnosis
KW - Neovascularization, Pathologic/pathology
KW - Neuroimaging/methods
KW - Prognosis
KW - Prospective Studies
KW - Retrospective Studies
KW - Survival Rate
UR - http://www.scopus.com/inward/record.url?scp=85103314822&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-3580
DO - 10.1158/1078-0432.CCR-20-3580
M3 - Journal article
C2 - 33293375
SN - 1078-0432
VL - 27
SP - 1641
EP - 1649
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -