Malignant glioma represents a diverse set of molecularly heterogeneous diseases. Few therapeutic agents have been approved despite decades of clinical trials research and pre-clinical investigation. Attempts to refine neuroimaging criteria and recent discovery of the genomic profiles linking tumor subsets to survival outcomes have spurred discussion on a variety of new approaches in clinical trial design and relevant endpoints. Here we focus on those endpoints in clinical trial design for patients with primary glioma and related issues still to be resolved.

Local delivery of therapeutic agents into the brain has many advantages; however, the inability to predict, visualize and confirm the infusion into the intended target has been a major hurdle in its clinical development. Here, we describe the current workflow and application of the interventional MRI (iMRI) system for catheter placement and real time visualization of infusion. We have applied real time convection-enhanced delivery (CED) of therapeutic agents with iMRI across a number of different clinical trials settings in neuro-oncology and movement disorders. Ongoing developments and accumulating experience with the technique and technology of drug formulations, CED platforms, and iMRI systems will continue to make local therapeutic delivery into the brain more accurate, efficient, effective and safer.

BACKGROUND: MGMT (O 6 -methylguanine-DNA methyltransferase) promoter methylation is a commonly assessed prognostic marker in glioblastoma (GBM). Epigenetic silencing of the MGMT gene by promoter methylation is associated with greater overall and progression free survival with alkylating agent regimens. To date, there is marked heterogeneity in how MGMT promoter methylation is tested and which CpG sites are interrogated. METHODS: To further elucidate which MGMT promoter CpG sites are of greatest interest, we performed comprehensive searches in PubMed, Web of Science, and Embase and reviewed 2,925 article abstracts. We followed the GRADE scoring system to assess risk of bias and the quality of the studies we included. RESULTS: We included articles on adult glioblastoma that examined significant sites or regions within MGMT promoter for the outcomes: overall survival, progression free survival, and/or MGMT expression. We excluded systemic reviews and articles on lower grade glioma. fifteen articles met inclusion criteria with variable overlap in laboratory and statistical methods employed, as well as CpG sites interrogated. Pyrosequencing or BeadChip arrays were the most popular methods utilized, and CpG sites between CpGs 70-90 were most frequently investigated. Overall, there was moderate concordance between the CpG sites that the studies reported to be highly predictive of prognosis. Combinations or means of sites between CpGs 73-89 were associated with improved OS and PFS. Six studies identified CpG sites associated with prognosis that were closer to the transcription start site: CpGs 8, 19, 22, 25, 27, 32,38, and CpG sites 21-37, as well as low methylation level of the enhancer regions. CONCLUSION: The following systematic review details a comprehensive investigation of the current literature and highlights several potential key CpG sites that demonstrate significant association with OS, PFS, and MGMT expression. However, the relationship between extent of MGMT promoter methylation and survival may be non-linear and could be influenced by potential CpG hotspots, the extent of methylation at each CpG site, and MGMT enhancer methylation status. There were several limitations within the studies such as smaller sample sizes, variance between methylation testing methods, and differences in the various statistical methods to test for association to outcome. Further studies of high impact CpG sites in MGMT methylation is warranted.

Abstract

PURPOSE

7 Tesla (7T) MRI scanners can provide novel information to improve the characterization of gliomas. However, patients who receive 7T scans must undergo separate clinical evaluations at lower field strengths due to a lack of clinical validation of 7T anatomical imaging. The purpose of this study was to develop a robust volumetric anatomical imaging protocol for the clinical evaluation of patients with glioma at 7T and compare lesion definition to standard 3T imaging.

METHODS

3D T2-weighted, T2 FLAIR, and T1-weighted sequences at 7T were optimized to match the contrast, resolution, and scan time of corresponding clinical sequences at 3T. Ten patients with contrast-enhancing glioma (grades II-IV) were scanned with a protocol consisting of pre-contrast anatomical imaging and post-contrast T1-weighted imaging at both field strengths, with the 7T scan occurring in between the pre- and post-contrast 3T imaging. A half-dose of contrast was used at 7T, with an additional half-dose given immediately afterwards at 3T to provide similar lesion contrast given the 2.3-fold difference in field strength. Metrics for comparison between field strengths included volumes of T2 and contrast-enhancing lesions, and Likert-scale ratings (1-5) of lesion definition by a neuro-radiologist.

RESULTS

T2 and contrast-enhancing lesion volumes were not significantly different between field strengths, despite the trend in larger enhancing lesion volumes at 3T, which was expected given the protocol design. 7T T2-weighted and post-contrast T1-weighted images received on average half-point higher Likert-scale ratings than corresponding 3T images, whereas the opposite trend was observed with the T2 FLAIR and pre-contrast T1-weighted images.

CONCLUSION

Our pilot study suggests that clinical assessment of contrast-enhancing and T2-hyperintense lesions in glioma is feasible at 7T, which would obviate the need for two scans, allowing patients to take advantage of the increased sensitivity in metabolic and physiologic imaging available at 7T and ultimately improve patient care.

Early tumor growth, or increased contrast-enhancing tumor not related to evolving post-surgical injury, in the interval between surgical resection and initiation of radiotherapy has implications for treatment planning and clinical outcomes. In this study we evaluated the incidence of early tumor growth, correlated tumor growth with survival outcome measures, and assessed predictors of early tumor growth in glioblastoma. We reviewed the records of patients with newly-diagnosed glioblastoma who underwent surgical resection and chemoradiotherapy at our institution. Patients with preoperative, immediate postoperative, and preradiotherapy MRI were included. Conventional MRI and DWI features were assessed. The correlation between early tumor growth and extent of resection with survival was assessed with Kaplan-Meier analysis. Logistic regression was carried out to evaluate predictors of early tumor growth. Of 140 included patients, sixty-seven cases (48%) had new or increased contrast enhancement attributed to early tumor growth. Median progression free survival (PFS) and overall survival (OS) were shorter in patients with early tumor growth compared to those without early tumor growth (p < 0.001 for both). Additionally, PFS and OS were longer in patients who underwent gross total resection of enhancing tumor (p = 0.016 and <0.001, respectively). Of the evaluated predictors of early growth, subtotal resection was most likely to result in early growth (p < 0.001). Imaging evidence of early tumor growth is often observed at preradiotherapy MRI and is associated with shorter survival. Gross total resection of contrast enhancing tumor decreases likelihood of early tumor growth.

Background

Radiotherapy (RT) is an integral component in managing patients with glioma, but the damage it may cause to healthy brain tissue and quality of life is of concern. Susceptibility-weighted imaging (SWI) is highly sensitive to the detection of microbleeds that occur years after RT. This study's goals were to characterize the evolution of radiation-induced microbleeds in normal-appearing brain and determine whether the administration of an anti-angiogenic agent altered this process.

Methods

Serial high-resolution SWI was acquired on 17 patients with high-grade glioma between 8 months and 4.5 years posttreatment with RT and adjuvant chemotherapy. Nine of these patients were also treated with the anti-angiogenic agent enzastaurin. Microbleeds were identified as discrete foci of susceptibility not corresponding to vessels, tumor, or postoperative infarct, and counted in normal-appearing brain. Analysis of covariance was performed to compare slopes of regression of individual patients' microbleed counts over time, Wilcoxon rank-sum tests examined significant differences in rates of microbleed formation between groups, and linear and quadratic mixed-effects models were employed.

Results

The number of microbleeds increased with time for all patients, with initial onset occurring at 8-22 months. No microbleeds disappeared once formed. The average rate of microbleed formation significantly increased after 2 years post-RT (P < .001). Patients receiving anti-angiogenic therapy exhibited fewer microbleeds overall (P < .05) and a significant reduction in initial rate of microbleed appearance (P = .01).

Conclusions

We have demonstrated a dramatic increase in microbleed formation after 2 years post-RT that was decelerated by the concomitant administration of anti-angiogenic therapy, which may aid in determining brain regions susceptible to RT.

Abstract Neurocognitive function and quality of life are important clinical outcome measures for patients with lower grade glioma. Here, we performed neurocognitive testing and quality of life assessments in radiologically and clinically stable grade 2 and 3 glioma patients who are not receiving active treatment.

METHODS

Patients completed a computerized battery of standardized neurocognitive tests in the NIH Toolbox and quality of life assessments with the FACT-BR. We acquired patient demographic information, current performance status, current anti-epileptic therapy, treatment history, extent of resection at diagnosis and recurrence, tumor location, and histologic and molecular tumor characteristics. Tumor volumes were measured on T2 FLAIR MRIs.

RESULTS

We have enrolled 15 patients. All patients had previous resection (10 partial, 5 gross total), 11 received chemotherapy, and 6 prior radiation. Median age at testing was 41 years old (range 26 – 65). As a group, patients were impaired on processing speed and fluid cognition. Two patients were impaired on picture vocabulary, 6 on list sorting, 11 on processing speed, 6 on sequence memory, 4 on inhibitory control, 2 on dimensional change, 7 on fluid cognition, and 0 on crystallized cognition. Higher age was significantly associated with poorer age-corrected oral-reading, and sequence memory. Insula and parietal lesions were associated with slower processing speed. Previous chemotherapy treatment was associated with poorer dimensional change. On imaging, larger tumor volumes were associated with poorer list sorting, processing speed, and sequence memory. On the FACT-BR, older patients, patients with prior radiation or those with higher grade were associated with poorer social/family well-being.

CONCLUSION

The NIH Toolbox and FACT-BR are effective, accessible tools to assess neurocognitive function and quality of life in glioma patients. By correlating these assessments with patient and tumor characteristics, it may be possible to identify patients at risk for specific deficits and provide opportunity for intervention.

Abstract

INTRODUCTION

While radiation therapy (RT) remains a standard practice in the upfront treatment of high-grade gliomas and low-grade gliomas at the time of recurrence, it is often associated with long-term effects including vascular injury and cognitive decline. The former typically manifests as size-varying hemosiderin deposits in the brain called cerebral microbleeds (CMBs), and can be accompanied by changes in the surrounding white-matter (WM) microstructure. As the median survival of lower grade gliomas can be 10 years or longer with current treatment strategies, minimizing the deficits incurred through treatment becomes especially important. Prior studies have shown increases in CMB formation over time that were dependent on RT dose and were not observed in patients treated only with chemotherapy. The goal of this study was to characterize the evolution of CMBs in a much larger cohort with serial scans and relate their changes over time to alterations in WM structure.

METHODS

125 patients (age:46 ± 12) were scanned on a 7-Tesla GE scanner either once or serially for 2-8 scans. The cohort included patients treated with RT for a glioma 2 months to 27 years prior, and a subset of nonirradiated control patients. Susceptibility-weighted vascular imaging and multi-directional, multi-shell diffusion-tensor imaging were acquired. Characteristics of RT-induced CMBs were evaluated within- and across patients, correlated with clinical and treatment parameters, and related to global and local WM changes.

RESULTS

Total CMB burden increased over time and was more severe for larger irradiated volumes and frontal lobe tumors. WM fractional anisotropy and diffusivity changes initially decreased as a function of CMB burden before improving approximately 6 years post-treatment.

CONCLUSIONS

Although there was initially a direct relationship between RT-induced vasculature injury and degradation of WM microstructure, changes in WM structure appeared to be reversible over time, whereas CMBs, potential markers of vascular injury, persisted.

Background

Although radiation therapy (RT) contributes to survival benefit in many brain tumor patients, it has also been associated with long-term brain injury. Cerebral microbleeds (CMBs) represent an important manifestation of radiation-related injury.

Purpose

To characterize the change in size and number of CMBs over time and to evaluate their relationship to white matter structural integrity as measured using diffusion MRI indices.

Study type

Longitudinal, retrospective, human cohort.

Population

In all, 113 brain tumor patients including patients treated with focal RT (n = 91, 80.5%) and a subset of nonirradiated controls (n = 22, 19.5%).

Field strength/sequence

Single and multiecho susceptibility-weighted imaging (SWI) and multiband, shell, and direction diffusion tensor imaging (DTI) at 7 T.

Assessment

Patients were scanned either once or serially. CMBs were detected and quantified on SWI images using a semiautomated approach. Local and global fractional anisotropy (FA) were measured from DTI data for a subset of 35 patients.

Statistical tests

Potential risk factors for CMB development were determined by multivariate linear regression and using linear mixed-effect models. Longitudinal FA was quantitatively and qualitatively evaluated for trends.

Results

All patients scanned at 1 or more years post-RT had CMBs. A history of multiple surgical resections was a risk factor for development of CMBs. The total number and volume of CMBs increased by 18% and 11% per year, respectively, although individual CMBs decreased in volume over time. Simultaneous to these microvascular changes, FA decreased by a median of 6.5% per year. While the majority of nonirradiated controls had no CMBs, four control patients presented with fewer than five CMBs.

Data conclusion

Identifying patients who are at the greatest risk for CMB development, with its likely associated long-term cognitive impairment, is an important step towards developing and piloting preventative and/or rehabilitative measures for patients undergoing RT.

Level of evidence

3 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2019;50:868-877.

Glioblastoma (GBM) is an incurable brain tumor with a median survival of approximately 15 months despite an aggressive standard of care that includes surgery, chemotherapy, and ionizing radiation. Mouse models have advanced our understanding of GBM biology and the development of novel therapeutic strategies for GBM patients. However, model selection is crucial when testing developmental therapeutics, and each mouse model of GBM has unique advantages and disadvantages that can influence the validity and translatability of experimental results. To shed light on this process, we discuss the strengths and limitations of 3 types of mouse GBM models in this review: syngeneic models, genetically engineered mouse models, and xenograft models, including traditional xenograft cell lines and patient-derived xenograft models.