Person:

Batchelor, Tracy

Pleomorphic xanthoastrocytoma (PXA) is low-grade glial neoplasm principally affecting children and young adults. Approximately 40% of PXA are reported to recur within 10 years of primary resection. Upon recurrence, patients receive radiation therapy and conventional chemotherapeutics designed for high-grade gliomas. Genetic changes that can be targeted by selective therapeutics have not been extensively evaluated in PXA and ancillary diagnostic tests to help discriminate PXA from other pleomorphic and often more aggressive astrocytic malignancies are limited. In this study, we apply the SNaPshot multiplexed targeted sequencing platform in the analysis of brain tumors to interrogate 60 genetic loci that are frequently mutated in 15 cancer genes. In our analysis we detect BRAF V600E mutations in 12 of 20 (60%) WHO grade II PXA, in 1 of 6 (17%) PXA with anaplasia and in 1 glioblastoma arising in a PXA. Phospho-ERK was detected in all tumors independent of the BRAF mutation status. BRAF duplication was not detected in any of the PXA cases. BRAF V600E mutations were identified in only 2 of 71 (2.8%) glioblastoma (GBM) analyzed, including 1 of 9 (11.1%) giant cell GBM (gcGBM). The finding that BRAF V600E mutations are common in the majority of PXA has important therapeutic implications and may help in differentiating less aggressive PXAs from lethal gcGBMs and GBMs.

Computed tomography (CT) and magnetic resonance (MR) imaging have been widely used for visualizing the inside of the human body. However, in many cases, pathological diagnosis is conducted through a biopsy or resection of an organ to evaluate the condition of tissues as definitive diagnosis. To provide more advanced information onto CT or MR image, it is necessary to reveal the relationship between tissue information and image signals. We propose a registration scheme for a set of PT images of divided specimens and a 3D-MR image by reference to an optical macro image (OM image) captured by an optical camera. We conducted a fundamental study using a resected human brain after the death of a brain cancer patient. We constructed two kinds of registration processes using the OM image as the base for both registrations to make conversion parameters between the PT and MR images. The aligned PT images had shapes similar to the OM image. On the other hand, the extracted cross-sectional MR image was similar to the OM image. From these resultant conversion parameters, the corresponding region on the PT image could be searched and displayed when an arbitrary pixel on the MR image was selected. The relationship between the PT and MR images of the whole brain can be analyzed using the proposed method. We confirmed that same regions between the PT and MR images could be searched and displayed using resultant information obtained by the proposed method. In terms of the accuracy of proposed method, the TREs were 0.56 ± 0.39 mm and 0.87 ± 0.42 mm. We can analyze the relationship between tissue information and MR signals using the proposed method.

OBJECTIVES This study evaluates the repeatability of brain perfusion using dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) with a variety of post-processing methods. METHODS Thirty-two patients with newly diagnosed glioblastoma were recruited. On a 3-T MRI using a dual-echo, gradient-echo spin-echo DSC-MRI protocol, the patients were scanned twice 1 to 5 days apart. Perfusion maps including cerebral blood volume (CBV) and cerebral blood flow (CBF) were generated using two contrast agent leakage correction methods, along with testing normalization to reference tissue, and application of arterial input function (AIF). Repeatability of CBV and CBF within tumor regions and healthy tissues, identified by structural images, was assessed with intra-class correlation coefficients (ICCs) and repeatability coefficients (RCs). Coefficients of variation (CVs) were reported for selected methods. RESULTS CBV and CBF were highly repeatable within tumor with ICC values up to 0.97. However, both CBV and CBF showed lower ICCs for healthy cortical tissues (up to 0.83), healthy gray matter (up to 0.95), and healthy white matter (WM; up to 0.93). The values of CV ranged from 6% to 10% in tumor and 3% to 11% in healthy tissues. The values of RC relative to the mean value of measurement within healthy WM ranged from 22% to 42% in tumor and 7% to 43% in healthy tissues. These percentages show how much variation in perfusion parameter, relative to that in healthy WM, we expect to observe to consider it statistically significant. We also found that normalization improved repeatability, but AIF deconvolution did not. CONCLUSIONS DSC-MRI is highly repeatable in high-grade glioma patients.

Measurement of vessel caliber by Magnetic Resonance Imaging (MRI) is a valuable technique for in vivo monitoring of hemodynamic status and vascular development, especially in the brain. Here, we introduce a new paradigm in MRI coined as Vessel Architectural Imaging (VAI) that exploits an intriguing and overlooked temporal shift in the MR signal forming the basis for vessel caliber estimation and show how this phenomenon can reveal new information on vessel type and function not assessed by any other non-invasive imaging technique. We also show how this biomarker can provide novel biological insights into the treatment of cancer patients. As an example, we demonstrate using VAI that anti-angiogenic therapy can improve microcirculation and oxygen saturation levels and reduce vessel calibers in patients with recurrent glioblastomas, and more crucially, that patients with these responses have prolonged survival. Thus, VAI has the potential to identify patients who would benefit from therapies.

Recurrent glioblastomas (rGBM) invariably relapse after initial response to anti-VEGF therapy. There are two prevailing hypotheses on how these tumors escape antiangiogenic therapy: switch to VEGF-independent angiogenic pathways and vessel co-option. However, direct evidence in rGBM patients is lacking. Thus, we compared molecular, cellular and vascular parameters in autopsy tissues from five rGBM patients who had been treated with the pan-VEGF receptor tyrosine kinase inhibitor cediranib versus seven patients who received no therapy or chemoradiation but no antiangiogenic agents. After cediranib treatment, endothelial proliferation and glomeruloid vessels were decreased, and vessel diameters and perimeters were reduced to levels comparable to the unaffected contralateral brain hemisphere. In addition, tumor endothelial cells expressed molecular markers specific to the blood-brain barrier, indicative of a lack of revascularization despite the discontinuation of therapy. Surprisingly, in cediranib-treated GBM cellular density in the central area of the tumor was lower than in control cases and gradually decreased towards the infiltrating edge, indicative of a change in growth pattern of rGBMs after cediranib treatment, unlike that after chemo-radiation. Finally, cediranib treated GBMs showed high levels of PDGF-C and c-Met expression and infiltration by myeloid cells, which may potentially contribute to resistance to anti-VEGF therapy. In summary, we show that rGBMs switch their growth pattern after anti-VEGF therapy – characterized by lower tumor cellularity in the central area, decreased pseudopalisading necrosis and blood vessels with normal molecular expression and morphology without a second wave of angiogenesis.

Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171—an oral tyrosine kinase inhibitor of VEGF receptors—has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1α, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.

Purpose

Glioblastoma is an incurable solid tumor characterized by increased expression of vascular endothelial growth factor (VEGF). We performed a phase II study of cediranib in patients with recurrent glioblastoma.

Methods

Cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor, was administered (45 mg/d) until progression or unacceptable toxicity to patients with recurrent glioblastoma. The primary end point was the proportion of patients alive and progression free at 6 months (APF6). We performed magnetic resonance imaging (MRI) and plasma and urinary biomarker evaluations at multiple time points.

Results

Thirty-one patients with recurrent glioblastoma were accrued. APF6 after cediranib was 25.8%. Radiographic partial responses were observed by MRI in 17 (56.7%) of 30 evaluable patients using three-dimensional measurements and in eight (27%) of 30 evaluable patients using two-dimensional measurements. For the 15 patients who entered the study taking corticosteroids, the dose was reduced (n = 10) or discontinued (n = 5). Toxicities were manageable. Grade 3/4 toxicities included hypertension (four of 31; 12.9%); diarrhea (two of 31; 6.4%); and fatigue (six of 31; 19.4%). Fifteen (48.4%) of 31 patients required at least one dose reduction and 15 patients required temporary drug interruptions due to toxicity. Drug interruptions were not associated with outcome. Changes in plasma placental growth factor, basic fibroblast growth factor, matrix metalloproteinase (MMP) -2, soluble VEGF receptor 1, stromal cell–derived factor-1α, and soluble Tek/Tie2 receptor and in urinary MMP-9/neutrophil gelatinase-associated lipocalin activity after cediranib were associated with radiographic response or survival.

Conclusion

Cediranib monotherapy for recurrent glioblastoma is associated with encouraging proportions of radiographic response, 6-month progression-free survival, and a steroid-sparing effect with manageable toxicity. We identified early changes in circulating molecules as potential biomarkers of response to cediranib. The efficacy of cediranib and the predictive value of these candidate biomarkers will be explored in prospective trials.

In vitro treatment of Nf2-deficient cells with epidermal growth factor receptor (EGFR) inhibitors can inhibit cellular proliferation. We retrospectively assessed the effect of erlotinib (150 mg daily) on eleven consecutive NF2 patients with progressive VS who were poor candidates for standard therapy. A radiographic response was defined as ≥ 20% decrease in tumor volume compared to baseline. A hearing response was defined as a statistically significant increase in word recognition score (WRS) compared to baseline; a minor hearing response was defined as a 10 dB improvement in pure-tone average with stable WRS. Before treatment, the median and mean annual volumetric growth rate for eleven index VS were 26% and 46%, respectively. Among 10 evaluable patients, the median time-to-tumor progression was 9.2 months. Three patients with stable disease experienced maximum tumor shrinkage of 4%, 13%, and 14%. Nine patients underwent audiologic evaluations. One experienced a transient hearing response, two experienced minor hearing responses, three remained stable, and two developed progressive hearing loss. The median time-to-progressive hearing loss was 9.2 months and to either tumor growth or progressive hearing loss was 7.1 months. Adverse treatment effects included mild-to-moderate rash, diarrhea, and hair thinning, with 2 episodes of grade 3 toxicity. Erlotinib treatment was not associated with radiographic or hearing responses in NF2 patients with progressive VS. Because a subset of patients experienced prolonged stable disease, time-to-progression may be more appropriate than radiographic or hearing response for anti-EGFR agents in NF2-associated VS.

Targeting angiogenesis in glioblastoma (GBM) may improve patient outcome by normalizing tumor vasculature and improving delivery of chemotherapeutics and oxygen. Consequently, concomitant administration of small molecule inhibitors of the VEGF pathway will likely have a positive impact on chemoradiation treatment outcome. We conducted a Phase I study of vatalanib, a small molecule inhibitor of VEGFR, PDGFR, and c-kit in patients with newly diagnosed GBM receiving radiation, temozolomide, and an enzyme-inducing anti-epileptic drug in order to determine the MTD of vatalanib in this patient population. We incorporated circulating biomarker and SNP analyses and pharmacokinetic studies. Nineteen patients were enrolled and the MTD was not reached at the time of study termination. Vatalanib was well tolerated with only 2 DLTs (thrombocytopenia and elevated transaminases). Other grade 3/4 toxicities included leukopenia, lymphopenia, neutropenia, and hand-foot syndrome. There were no wound-healing complications. Of the 13 patients evaluable for a radiographic response, 2 had a partial response and 9 had stable disease. Vatalanib significantly increased PlGF and sVEGFR1 in plasma circulation and decreased sVEGFR2 and sTie2. Plasma collagen IV increased significantly by day 50 of treatment. Vatalanib was well tolerated and this study demonstrates the safety of oral small molecule inhibitors in newly diagnosed GBM patients. Blood biomarkers may be useful as pharmacodynamic markers of response to anti-angiogenic therapies.

Opinion statement Therapeutic options are limited in primary central nervous system lymphoma (PCNSL) with no uniform consensus on optimal management and few published, randomized trials. High-dose methotrexate in combination with other chemotherapeutic agents forms the mainstay of treatment. There hasn’t been much progress beyond high-dose methotrexate in this disease, and although results from trials using high-dose chemotherapy and autologous stem-cell transplant seem promising, these need to be further validated. Moreover, the role of whole brain radiation in the upfront setting remains to be determined. However, international efforts in this direction are underway, with ongoing randomized trials in newly diagnosed PCNSL, more research on the molecular pathogenesis and biomarkers, and the use of novel agents in salvage therapy. There also is emphasis on quality of life parameters and neurocognitive status. Future treatment options should optimize high-efficacy rates while minimizing the risk of neurotoxicity.