Spectroscopic MRI-Based Biomarkers Predict Survival for Newly Diagnosed Glioblastoma in a Clinical Trial.

Despite aggressive treatment, glioblastoma has a poor prognosis due to its infiltrative nature. Spectroscopic MRI-measured brain metabolites, particularly the choline to N-acetylaspartate ratio (Cho/NAA), better characterizes the extent of tumor infiltration. In a previous pilot trial (NCT03137888), brain regions with Cho/NAA ≥ 2x normal were treated with high-dose radiation for newly diagnosed glioblastoma patients. This report is a secondary analysis of that trial where spectroscopic MRI-based biomarkers are evaluated for how they correlate with progression-free and overall survival (PFS/OS). Subgroups were created within the cohort based on pre-radiation treatment (pre-RT) median cutoff volumes of residual enhancement (2.1 cc) and metabolically abnormal volumes used for treatment (19.2 cc). We generated Kaplan-Meier PFS/OS curves and compared these curves via the log-rank test between subgroups. For the subgroups stratified by metabolic abnormality, statistically significant differences were observed for PFS (p = 0.019) and OS (p = 0.020). Stratification by residual enhancement did not lead to observable differences in the OS (p = 0.373) or PFS (p = 0.286) curves. This retrospective analysis shows that patients with lower post-surgical Cho/NAA volumes had significantly superior survival outcomes, while residual enhancement, which guides high-dose radiation in standard treatment, had little significance in PFS/OS. This suggests that the infiltrating, non-enhancing component of glioblastoma is an important factor in patient outcomes and should be treated accordingly.

Applying a Radiation Therapy Volume Analysis Pipeline to Determine the Utility of Spectroscopic MRI-Guided Adaptive Radiation Therapy for Glioblastoma.

Accurate radiation therapy (RT) targeting is crucial for glioblastoma treatment but may be challenging using clinical imaging alone due to the infiltrative nature of glioblastomas. Precise targeting by whole-brain spectroscopic MRI, which maps tumor metabolites including choline (Cho) and N-acetylaspartate (NAA), can quantify early treatment-induced molecular changes that other traditional modalities cannot measure. We developed a pipeline to determine how spectroscopic MRI changes during early RT are associated with patient outcomes to provide insight into the utility of adaptive RT planning. Data were obtained from a study (NCT03137888) where glioblastoma patients received high-dose RT guided by the pre-RT Cho/NAA twice normal (Cho/NAA ≥ 2x) volume, and received spectroscopic MRI scans pre- and mid-RT. Overlap statistics between pre- and mid-RT scans were used to quantify metabolic activity changes after two weeks of RT. Log-rank tests were used to quantify the relationship between imaging metrics and patient overall and progression-free survival (OS/PFS). Patients with lower Jaccard/Dice coefficients had longer PFS (p = 0.045 for both), and patients with lower Jaccard/Dice coefficients had higher OS trending towards significance (p = 0.060 for both). Cho/NAA ≥ 2x volumes changed significantly during early RT, putting healthy tissue at risk of irradiation, and warranting further study into using adaptive RT planning.

Dynamics of MRI-Guided thermal ablation of VX2 tumor in paraspinal muscle of rabbits.

This study combines fast magnetic resonance imaging (MRI) and model simulation of tissue thermal ablation for monitoring and predicting the dynamics of lesion size for tumor destruction. In vivo experiments were conducted using radiofrequency (RF) thermal ablation in paraspinal muscle of rabbit with a VX2 tumor. Before ablation, turbo-spin echo (TSE) images visualized the 3-D tumor (necrotic core and tumor periphery) and surrounding normal tissue. MR gradient-recalled echo (GRE) phase and magnitude images were acquired repeatedly in 3.3 s at 30-s intervals during and after thermal ablation to follow tissue temperature distribution dynamics and lesion development in tumor and surrounding normal tissue. Final lesion sizes estimated from GRE magnitude, post-ablation TSE, and stained histologic images were compared. Model simulations of temperature distribution and lesion development dynamics closely corresponded to the experimental data from MR images in tumor and normal tissue. The combined use of MR image monitoring and model simulation has the potential for improving pretreatment planning and real-time prediction of lesion-size dynamics for guidance of thermal ablation of tumors.

Combination of sensitizing pretreatment and radiofrequency tumor ablation: evaluation in rat model.

PURPOSE: To prospectively determine, in an animal tumor model, if the block copolymer Pluronic P85 (BASF, Shreveport, La) sensitizes cancer cells to hyperthermia and if intratumorally or intravenously administered copolymer improves the therapeutic outcome of radiofrequency (RF) ablation tumor treatment. MATERIALS AND METHODS: The effects of Pluronic P85 and mild hyperthermia in vitro were tested in DHD/K12/TRb rat colorectal carcinoma cells. Cells were incubated at 37 degrees C or 43 degrees C for 15-60 minutes with 0%, 7%, or 10% wt/wt Pluronic P85, and cell viability was assessed by using a mitochondrial enzyme assay. In vivo experiments were performed as approved by the Institutional Animal Care and Use Committee at Case Western Reserve University and according to all applicable guidelines on animal use. Bilateral subcutaneous tumors in rats were treated with either intratumoral (13 tumors) or intravenous (15 tumors) Pluronic P85 followed by ablation or with ablation alone (14 tumors) and were monitored for 14 days by using volumes estimated from caliper measurements of tumor diameter. Acute effects of Pluronic P85 on the size of ablation-induced coagulation were measured after 24 hours in additional tumors (six tumors each treated according to the protocol for the ablation-only, intratumoral injection, and intravenous injection groups). Statistical testing was performed by using linear regression analysis and two-sided t tests with a significance level of .05. RESULTS: At 43 degrees C, 7% and 10% Pluronic P85 reduced in vitro cell viability by 22% +/- 5 (standard error of the mean) (P < .001) and 28% +/- 5 (P < .001), respectively, compared with the viability of control cells. At day 14, the volume of tumors ablated after local and systemic Pluronic P85 pretreatment changed by -55% +/- 14 (P = .03) and -59% +/- 14 (P = .02), respectively, compared with an increase of 16% +/- 28 for tumors treated with ablation alone. Coagulation area at 24 hours was reduced by 44% relative to that in control tumors (P = .03) after intratumoral Pluronic P85 but was unchanged after systemic Pluronic P85. CONCLUSION: Tumor pretreatment with Pluronic P85 improved the outcome of RF ablation by decreasing the tumor volume and residual tumor in an experimental carcinoma model.

Effect of intratumoral injection of carboplatin combined with pluronic P85 or L61 on experimental colorectal carcinoma in rats.

Pluronic, a poly(ethylene oxide)-poly(propylene oxide)-poly (ethylene oxide) block copolymer, has been shown to enhance the cytotoxic activity of anticancer drugs in various cell lines. In the current study the effect of Pluronic P85 (P85) and Pluronic L61 (L61) on the intratumoral chemotherapy of an experimental adenocarcinoma in rats was examined. A total of 120 subcutaneous tumors (4 per rat) were inoculated in 30 BDIX rats and were treated weekly for 4 weeks with intratumoral injection of carboplatin (CPt) alone or with either P85 or L61. Tumors were monitored weekly and were excised at the endpoint for histologic evaluation. The effect of Pluronic on levels of intracellular ATP was explored as a possible mechanism of sensitization. Results showed that tumors treated with low-dose CPt (2.8 mg/kg) and P85 or L61 exhibited significant reductions in tumor volume after 28 days relative to Day 0 (112.7% +/- 34.4%, n = 15; 131.3% +/- 55.6%, n = 8) compared with tumors treated with free drug (339.4% +/- 75.0%, n = 16). Control tumors treated with either P85 or L61 alone or with saline showed volume increases of 1079.4% +/- 143.6% (n = 16), 729.4% +/- 202.2% (n = 7), and 1119.2% +/- 6.1% (n = 16), respectively. Treatment with high-dose CPt (20.7 mg/kg) led to a 79.3% +/- 4.2% reduction in tumor volume, and no differences were noted with addition of P85 or L61. In vitro ATP measurements showed that 28.0 mg/kg of P85 significantly reduced levels of intracellular ATP to 44.7% +/- 1.5% of controls, whereas L61 at this concentration depleted ATP levels completely. Results confirm that Pluronic P85 and L61 act as potent sensitizers to carboplatin chemotherapy of the experimental colorectal carcinoma, leading to a significant reduction of tumor growth compared to carboplatin alone. ATP depletion is a possible mechanism for these observed differences.

Three-dimensional model of lesion geometry for evaluation of MR-guided thermal ablation therapy.

RATIONALE AND OBJECTIVES: High-radiofrequency energy is used clinically to ablate pathologic tissue with interventional magnetic resonance (MR) imaging. For many tissues, resulting lesions have a characteristic appearance on contrast-enhanced T1- and T2-weighted MR images, with two boundaries enclosing an inner hypointense region and an outer hyperintense margin. Geometric modeling of three-dimensional thermal lesions in animal experiments and patient treatments would improve analyses and visualization. MATERIALS AND METHODS: The authors created a model with two quadric surfaces and 12 parameters to describe both lesion surfaces. Parameters were estimated with iterative optimization to minimize the sum of the squared shortest distances from segmented points to the model surface. The authors validated the estimation process with digital lesion phantoms that simulated varying levels of segmentation error and missing surface information. They also applied their method to in vivo images of lesions in a rabbit model. RESULTS: For simulated phantom lesions, the lesion geometry was accurate despite manual segmentation error and incomplete surface data. Even when 50% of the surface was missing, the median error was less than 0.5 mm. For all in vivo lesions, the median distance from the model surface to data was no more than 0.58 mm for both inner and outer surfaces, less than a voxel width (0.7 mm). The interquartile range was 0.89 mm or less for all data. CONCLUSION: The authors' model provides a good approximation of actual lesion geometry and is highly resistant to missing segmentation information. It should prove useful for three-dimensional lesion visualization, volume estimation, automated segmentation, and volume registration.