First-in-Human Phase I Study to Evaluate the Brain-Penetrant PI3K/mTOR Inhibitor GDC-0084 in Patients with Progressive or Recurrent High-Grade Glioma.

PurposeGDC-0084 is an oral, brain-penetrant small-molecule inhibitor of PI3K and mTOR. A first-in-human, phase I study was conducted in patients with recurrent high-grade glioma.Patients and methodsGDC-0084 was administered orally, once daily, to evaluate safety, pharmacokinetics (PK), and activity. Fluorodeoxyglucose-PET (FDG-PET) was performed to measure metabolic responses.ResultsForty-seven heavily pretreated patients enrolled in eight cohorts (2-65 mg). Dose-limiting toxicities included 1 case of grade 2 bradycardia and grade 3 myocardial ischemia (15 mg), grade 3 stomatitis (45 mg), and 2 cases of grade 3 mucosal inflammation (65 mg); the MTD was 45 mg/day. GDC-0084 demonstrated linear and dose-proportional PK, with a half-life (∼19 hours) supportive of once-daily dosing. At 45 mg/day, steady-state concentrations exceeded preclinical target concentrations producing antitumor activity in xenograft models. FDG-PET in 7 of 27 patients (26%) showed metabolic partial response. At doses ≥45 mg/day, a trend toward decreased median standardized uptake value in normal brain was observed, suggesting central nervous system penetration of drug. In two resection specimens, GDC-0084 was detected at similar levels in tumor and brain tissue, with a brain tissue/tumor-to-plasma ratio of >1 and >0.5 for total and free drug, respectively. Best overall response was stable disease in 19 patients (40%) and progressive disease in 26 patients (55%); 2 patients (4%) were nonevaluable.ConclusionsGDC-0084 demonstrated classic PI3K/mTOR-inhibitor related toxicities. FDG-PET and concentration data from brain tumor tissue suggest that GDC-0084 crossed the blood-brain barrier

Validation of vessel size imaging (VSI) in high-grade human gliomas using magnetic resonance imaging, image-guided biopsies, and quantitative immunohistochemistry.

To evaluate the association between a vessel size index (VSIMRI) derived from dynamic susceptibility contrast (DSC) perfusion imaging using a custom spin-and-gradient echo echoplanar imaging (SAGE-EPI) sequence and quantitative estimates of vessel morphometry based on immunohistochemistry from image-guided biopsy samples. The current study evaluated both relative cerebral blood volume (rCBV) and VSIMRI in eleven patients with high-grade glioma (7 WHO grade III and 4 WHO grade IV). Following 26 MRI-guided glioma biopsies in these 11 patients, we evaluated tissue morphometry, including vessel density and average radius, using an automated procedure based on the endothelial cell marker CD31 to highlight tumor vasculature. Measures of rCBV and VSIMRI were then compared to histological measures. We demonstrate good agreement between VSI measured by MRI and histology; VSIMRI = 13.67 μm and VSIHistology = 12.60 μm, with slight overestimation of VSIMRI in grade III patients compared to histology. rCBV showed a moderate but significant correlation with vessel density (r = 0.42, p = 0.03), and a correlation was also observed between VSIMRI and VSIHistology (r = 0.49, p = 0.01). The current study supports the hypothesis that vessel size measures using MRI accurately reflect vessel caliber within high-grade gliomas, while traditional measures of rCBV are correlated with vessel density and not vessel caliber

Diffusion MR Characteristics Following Concurrent Radiochemotherapy Predicts Progression-Free and Overall Survival in Newly Diagnosed Glioblastoma.

The standard of care for newly diagnosed glioblastoma (GBM) is surgery, then radiotherapy (RT) with concurrent temozolomide (TMZ), followed by adjuvant TMZ. We hypothesized patients with low diffusivity measured using apparent diffusion coefficient (ADC) histogram analysis evaluated after RT+TMZ, prior to adjuvant TMZ, would have a significantly shorter progression-free (PFS) and overall survival (OS). To test this hypothesis we evaluated 120 patients with newly diagnosed GBM receiving RT+TMZ followed by adjuvant TMZ. MRI was performed after completion of RT+TMZ, prior to initiation of adjuvant TMZ. A double Gaussian mixed model was used to describe the ADC histograms within the enhancing tumor, where ADCL and ADCH were defined as the mean ADC value of the lower and higher Gaussian distribution, respectively. An ADCL value of 1.0 um2/ms and ADCH value of 1.6 um2/ms were used to stratify patients into high and low risk categories. Results suggest patients with low ADCL had significantly shorter PFS (Cox Hazard Ratio = 0.12, P = 0.0006). OS was significantly shorter with low ADCL tumors, showing a median OS of 407 vs. 644 days (Cox Hazard Ratio = 0.31, P = 0.047). ADCH was not predictive of PFS or OS when accounting for age and ADCL. In summary, newly diagnosed glioblastoma patients with low ADCL after completion of RT+TMZ are likely to progress and die earlier than patients with higher ADCL. Results suggest ADC histogram analysis may be useful for patient risk stratification following completion of RT+TMZ

Standardized brain tumor imaging protocols for clinical trials: current recommendations and tips for integration

Standardized MRI acquisition protocols are crucial for reducing the measurement and interpretation variability associated with response assessment in brain tumor clinical trials. The main challenge is that standardized protocols should ensure high image quality while maximizing the number of institutions meeting the acquisition requirements. In recent years, extensive effort has been made by consensus groups to propose different “ideal” and “minimum requirements” brain tumor imaging protocols (BTIPs) for gliomas, brain metastases (BM), and primary central nervous system lymphomas (PCSNL). In clinical practice, BTIPs for clinical trials can be easily integrated with additional MRI sequences that may be desired for clinical patient management at individual sites. In this review, we summarize the general concepts behind the choice and timing of sequences included in the current recommended BTIPs, we provide a comparative overview, and discuss tips and caveats to integrate additional clinical or research sequences while preserving the recommended BTIPs. Finally, we also reflect on potential future directions for brain tumor imaging in clinical trials

The Radio Sky at Meter Wavelengths: m-Mode Analysis Imaging with the Owens Valley Long Wavelength Array

A host of new low-frequency radio telescopes seek to measure the 21-cm transition of neutral hydrogen from the early universe. These telescopes have the potential to directly probe star and galaxy formation at redshifts $20 \gtrsim z \gtrsim 7$, but are limited by the dynamic range they can achieve against foreground sources of low-frequency radio emission. Consequently, there is a growing demand for modern, high-fidelity maps of the sky at frequencies below 200 MHz for use in foreground modeling and removal. We describe a new widefield imaging technique for drift-scanning interferometers, Tikhonov-regularized $m$-mode analysis imaging. This technique constructs images of the entire sky in a single synthesis imaging step with exact treatment of widefield effects. We describe how the CLEAN algorithm can be adapted to deconvolve maps generated by $m$-mode analysis imaging. We demonstrate Tikhonov-regularized $m$-mode analysis imaging using the Owens Valley Long Wavelength Array (OVRO-LWA) by generating 8 new maps of the sky north of $\delta=-30^\circ$ with 15 arcmin angular resolution, at frequencies evenly spaced between 36.528 MHz and 73.152 MHz, and $\sim$800 mJy/beam thermal noise. These maps are a 10-fold improvement in angular resolution over existing full-sky maps at comparable frequencies, which have angular resolutions $\ge 2^\circ$. Each map is constructed exclusively from interferometric observations and does not represent the globally averaged sky brightness. Future improvements will incorporate total power radiometry, improved thermal noise, and improved angular resolution -- due to the planned expansion of the OVRO-LWA to 2.6 km baselines. These maps serve as a first step on the path to the use of more sophisticated foreground filters in 21-cm cosmology incorporating the measured angular and frequency structure of all foreground contaminants.Comment: 27 pages, 18 figure

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor