Dataset Information

Tumor treating fields increases blood-brain barrier permeability and relative cerebral blood volume in patients with glioblastoma.

ABSTRACT:

Background and objective

200 kHz tumor treating fields (TTFields) is clinically approved for newly-diagnosed glioblastoma (nGBM). Because its effects on conventional surveillance MRI brain scans are equivocal, we investigated its effects on perfusion MRI (pMRI) brain scans.

Methods

Each patient underwent institutional standard pMRI: dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) pMRI at three time points: baseline, 2-, and 6-months on-adjuvant therapy. At each timepoint, the difference between T1 pre- versus post-contrast tumor volume (ΔT1) and these pMRI metrics were evaluated: normalized and standardized relative cerebral blood volume (nRCBV, sRCBV); fractional plasma volume (V_p), volume of extravascular extracellular space (EES) per volume of tissue (V_e), blood-brain barrier (BBB) permeability (K^trans), and time constant for gadolinium reflux from EES back into the vascular system (K_ep). Between-group comparisons were performed using rank-sum analysis, and bootstrapping evaluated likely reproducibility of the results.

Results

Among 13 pMRI datasets (11 nGBM, 2 recurrent GBM), therapies included temozolomide-only (n = 9) and temozolomide + TTFields (n = 4). No significant differences were found in patient or tumor characteristics. Compared to temozolomide-only, temozolomide + TTFields did not significantly affect the percent-change in pMRI metrics from baseline to 2 months. But during the 2- to 6-month period, temozolomide + TTFields significantly increased the percent-change in nRCBV (+26.9% [interquartile range 55.1%] vs -39.1% [37.0%], p = 0.049), sRCBV (+9.5% [39.7%] vs -30.5% [39.4%], p = 0.049), K^trans (+54.6% [1768.4%] vs -26.9% [61.2%], p = 0.024), V_e (+111.0% [518.1%] vs -13.0% [22.5%], p = 0.048), and V_p (+98.8% [2172.4%] vs -24.6% [53.3%], p = 0.024) compared to temozolomide-only.

Conclusion

Using pMRI, we provide initial in-human validation of pre-clinical studies regarding the effects of TTFields on tumor blood volume and BBB permeability in GBM.

SUBMITTER: Iv M

PROVIDER: S-EPMC10863570 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Publications

Tumor treating fields increases blood-brain barrier permeability and relative cerebral blood volume in patients with glioblastoma.

Iv Michael M Naya Lewis L Sanan Sajal S Van Buskirk Samuel L SL Nagpal Seema S Thomas Reena P RP Recht Lawrence D LD Patel Chirag B CB

The neuroradiology journal 20231106 1

<h4>Background and objective</h4>200 kHz tumor treating fields (TTFields) is clinically approved for newly-diagnosed glioblastoma (nGBM). Because its effects on conventional surveillance MRI brain scans are equivocal, we investigated its effects on perfusion MRI (pMRI) brain scans.<h4>Methods</h4>Each patient underwent institutional standard pMRI: dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) pMRI at three time points: baseline, 2-, and 6-months on-adjuvant therapy. A ...[more]

PMID: 37931176

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Project description:Glioblastoma is the most common yet most lethal of primary brain cancers with a one-year post-diagnosis survival rate of 65% and a five-year survival rate of barely 5%. Recently the U.S. Food and Drug Administration approved a novel fourth approach (in addition to surgery, radiation therapy, and chemotherapy) to treating glioblastoma; namely, tumor treating fields (TTFields). TTFields involves the delivery of alternating electric fields to the tumor but its mechanisms of action are not fully understood. Current theories involve TTFields disrupting mitosis due to interference with proper mitotic spindle assembly. We show that TTFields also alters cellular membrane structure thus rendering it more permeant to chemotherapeutics. Increased membrane permeability through the imposition of TTFields was shown by several approaches. For example, increased permeability was indicated through increased bioluminescence with TTFields exposure or with the increased binding and ingress of membrane-associating reagents such as Dextran-FITC or ethidium D or with the demonstration by scanning electron microscopy of augmented number and sizes of holes on the cellular membrane. Further investigations showed that increases in bioluminescence and membrane hole production with TTFields exposure disappeared by 24 h after cessation of alternating electric fields thus demonstrating that this phenomenom is reversible. Preliminary investigations showed that TTFields did not induce membrane holes in normal human fibroblasts thus suggesting that the phenomenom was specific to cancer cells. With TTFields, we present evidence showing augmented membrane accessibility by compounds such as 5-aminolevulinic acid, a reagent used intraoperatively to delineate tumor from normal tissue in glioblastoma patients. In addition, this mechanism helps to explain previous reports of additive and synergistic effects between TTFields and other chemotherapies. These findings have implications for the design of combination therapies in glioblastoma and other cancers and may significantly alter standard of care strategies for these diseases.

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Dataset Information

Tumor treating fields increases blood-brain barrier permeability and relative cerebral blood volume in patients with glioblastoma.

Background and objective

Methods

Results

Conclusion

Publications

Tumor treating fields increases blood-brain barrier permeability and relative cerebral blood volume in patients with glioblastoma.

Similar Datasets

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