Vascular biomarkers derived from dynamic contrast-enhanced MRI predict response of vestibular schwannoma to antiangiogenic therapy in type 2 neurofibromatosis

Abstract

BackgroundAntiangiogenic therapy of vestibular schwannoma (VS) in type 2 neurofibromatosis can produce tumor shrinkage with response rates of 40%–60%. This study examines the predictive value of parameter-derived MRI in this setting.MethodsTwelve patients with 20 VSs were recruited. Each had at least one rapidly growing tumor. Patients were treated with bevacizumab, 5 mg/kg every 2 weeks. Patients with stable or reduced VS volume were maintained at 2.5–5 mg every 4 weeks after 6 months. Those who failed treatment had their bevacizumab discontinued. Dynamic contrast-enhanced (DCE) MRI performed prior to treatment using a high temporal resolution technique, and data were analyzed to allow measurement of contrast transfer coefficient (Ktrans), vascular fraction (vp), extravascular-extracellular fraction (ve). Relaxation rate (R1N) was measured using a variable flip angle technique. Apparent diffusional coefficient (ADC) was calculated from diffusion-weighted imaging. The predictive power of microvascular parameters and ADC were examined using logistic regression modeling.ResultsResponding tumors were larger (P < .001), had lower R1N (P < .001), and higher Ktrans (P < .05) and ADC (P < .01). They showed increases in R1N (P < .01) and reduction of Ktrans (P < .01) and ADC (P < .01). Modeling to predict response demonstrated significant independent predictive power for R1N (Β = − 0.327, P < .001), and Ktrans (Β = 0.156, P < .05). Modeling to predict percentage change in tumor volume at 90 days identified baseline tumor volume (Β = 5.503, P < .05), R1N (Β = − 5.844, P < .05), and Ktrans (Β = 5.622, P < .05) as independent significant predictors.ConclusionsIn patients with type 2 neurofibromatosis, biomarkers from DCE-MRI are predictive of VS volume response to inhibition of vascular endothelial growth factor inhibition.

Low‐dose T1W DCE‐MRI for early time points perfusion measurement in patients with intracranial tumors: A pilot study applying the microsphere model to measure absolute cerebral blood flow

“…The CBF increases demonstrated using the ACcomb and ACrPK method in normal appearing WM (NAWM) at 90 days post bevacizumab treatment were statistically significant, and exceeded our demonstrated reproducibility threshold for WM CBF measurements. This suggests that these changes are genuine rather than due to reproducibility variation, and, whilst this is a preliminary study of only 12 patients, these findings are biologically plausible, as the therapeutic effect of bevacizumab in this group is believed to result from alleviation of intracranial pressure due to reduction in intratumoral edema . Larger studies will, however, be needed, to further investigate bevacizumab treatment related changes in microcirculatory parameters of normal‐appearing brain tissues.…”

Blood-brain barrier permeability of normal-appearing white matter in patients with vestibular schwannoma: A new hybrid approach for analysis of T 1 -W DCE-MRI

“…Taheri et al used a quarter of the standard Gd-DTPA dose and found that R1 in the vicinity of this reduced dose changed much more rapidly with changes in CA concentration than at higher concentrations. 6 A lower dose of Gd-DTPA entails less possibility of introducing a T Ã 2 effect or truncation of the bolus peak of the arterial input function, 2,30 and also less risk of potential side effects of Gd-DTPA in patients with impairment of renal function. 6,31 Our study supported that a dose as low as only 1/5-1/4 of the standard Gd-DTPA dose was still adequate for performing the measurement of BBB permeability in WM.…”

“…The 4D LDHT DCE-MRI data were spatially aligned with and resliced to the high spatial resolution series of the ICR-DICE, 11,30 using SPM2. 13 The voxel size of the spatially aligned and resliced HT images is much smaller, ie, 1 3 1 3 2 mm 3 (after reslicing) vs. 2.5 3 2.5 3 6.35 mm 3 (before reslicing).…”

“…A mean SI(t) curve was calculated from N (~50) voxels, which had the highest AUC 30 . The averaged mean SI(t) was then converted to the plasma CA concentration time course curve (C p (t)).…”

The role of the immune system in neurofibromatosis type 1-associated nervous system tumors

“…In addition, VEGF contributes to recruitment of macrophages to tumors, is secreted by mast cells to inhibit differentiation of dendritic cells [130,131], thereby downregulating the antitumor immune response, and is a proliferation, survival and chemotactic factor for Schwann cells in the peripheral nervous system [132,133]. Bevacizumab has shown to delay tumor growth for a variety of tumors, including glioblastoma [134][135][136] and is showing promise for vestibular schwannomas associated with neurofibromatosis type 2 [137][138][139]. A trial of bevacizumab in combination with the mTOR inhibitor everolimus in MPNST is ongoing (NCT01661283).…”