Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation.

Antiangiogenic therapy has shown clear activity and improved survival benefit for certain tumor types. However, an incomplete understanding of the mechanisms of action of antiangiogenic agents has hindered optimization and broader application of this new therapeutic modality. In particular, the impact of antiangiogenic therapy on tumor blood flow and oxygenation status (i.e., the role of vessel pruning versus normalization) remains controversial. This controversy has become critical as multiple phase III trials of anti-VEGF agents combined with cytotoxics failed to show overall survival benefit in newly diagnosed glioblastoma (nGBM) patients and several other cancers. Here, we shed light on mechanisms of nGBM response to cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, using MRI techniques and blood biomarkers in prospective phase II clinical trials of cediranib with chemoradiation vs. chemoradiation alone in nGBM patients. We demonstrate that improved perfusion occurs only in a subset of patients in cediranib-containing regimens, and is associated with improved overall survival in these nGBM patients. Moreover, an increase in perfusion is associated with improved tumor oxygenation status as well as with pharmacodynamic biomarkers, such as changes in plasma placenta growth factor and sVEGFR2. Finally, treatment resistance was associated with elevated plasma IL-8 and sVEGFR1 posttherapy. In conclusion, tumor perfusion changes after antiangiogenic therapy may distinguish responders vs. nonresponders early in the course of this expensive and potentially toxic form of therapy, and these results may provide new insight into the selection of glioblastoma patients most likely to benefit from anti-VEGF treatments.

Low incidence of pseudoprogression by imaging in newly diagnosed glioblastoma patients treated with cediranib in combination with chemoradiation.

BACKGROUND: Chemoradiation (CRT) can significantly modify the radiographic appearance of malignant gliomas, especially within the immediate post-CRT period. Pseudoprogression (PsP) is an increasingly recognized phenomenon in this setting, and is thought to be secondary to increased permeability as a byproduct of the complex process of radiation-induced tissue injury, possibly enhanced by temozolomide. We sought to determine whether the addition of a vascular endothelial growth factor (VEGF) signaling inhibitor (cediranib) to conventional CRT had an impact on the frequency of PsP, by comparing two groups of patients with newly diagnosed glioblastoma before, during, and after CRT. METHODS: All patients underwent serial magnetic resonance imaging as part of institutional review board-approved clinical studies. Eleven patients in the control group received only chemoradiation, whereas 29 patients in the study group received chemoradiation and cediranib until disease progression or toxicity. Response assessment was defined according to Response Assessment in Neuro-Oncology criteria, and patients with enlarging lesions were classified into true tumor progressions (TTP) or PsP, based on serial radiographic follow-up. RESULTS: Two patients in the study group (7%) showed signs of apparent early tumor progression, and both were subsequently classified as TTP. Six patients in the control group (54%) showed signs of apparent early tumor progression, and three were subsequently classified as TTP and three as PsP. The frequency of PsP was significantly higher in the control group. CONCLUSION: Administration of a VEGF inhibitor during and after CRT modifies the expression of PsP by imaging.

Slice accelerated gradient-echo spin-echo dynamic susceptibility contrast imaging with blipped CAIPI for increased slice coverage.

PURPOSE: To improve slice coverage of gradient echo spin echo (GESE) sequences for dynamic susceptibility contrast (DSC) MRI using a simultaneous-multiple-slice (SMS) method. METHODS: Data were acquired on 3 Tesla (T) MR scanners with a 32-channel head coil. To evaluate use of SMS for DSC, an SMS GESE sequence with two-fold slice coverage and same temporal sampling was compared with a standard GESE sequence, both with 2× in-plane acceleration. A signal to noise ratio (SNR) comparison was performed on one healthy subject. Additionally, data with Gadolinium injection were collected on three patients with glioblastoma using both sequences, and perfusion analysis was performed on healthy tissues as well as on tumor. RESULTS: Retained SNR of SMS DSC is 90% for a gradient echo (GE) and 99% for a spin echo (SE) acquisition, compared with a standard acquisition without slice acceleration. Comparing cerebral blood volume maps, it was observed that the results of standard and SMS acquisitions are comparable for both GE and SE images. CONCLUSION: Two-fold slice accelerated DSC MRI achieves similar SNR and perfusion metrics as a standard acquisition, while allowing a significant increase in slice coverage of the brain. The results also point to a possibility to improve temporal sampling rate, while retaining the same slice coverage.

Leveraging Deep Learning Decision-Support System in Specialized Oncology Center: A Multi-Reader Retrospective Study on Detection of Pulmonary Lesions in Chest X-ray Images.

Chest X-ray (CXR) is considered to be the most widely used modality for detecting and monitoring various thoracic findings, including lung carcinoma and other pulmonary lesions. However, X-ray imaging shows particular limitations when detecting primary and secondary tumors and is prone to reading errors due to limited resolution and disagreement between radiologists. To address these issues, we developed a deep-learning-based automatic detection algorithm (DLAD) to automatically detect and localize suspicious lesions on CXRs. Five radiologists were invited to retrospectively evaluate 300 CXR images from a specialized oncology center, and the performance of individual radiologists was subsequently compared with that of DLAD. The proposed DLAD achieved significantly higher sensitivity (0.910 (0.854-0.966)) than that of all assessed radiologists (RAD 10.290 (0.201-0.379), p < 0.001, RAD 20.450 (0.352-0.548), p < 0.001, RAD 30.670 (0.578-0.762), p < 0.001, RAD 40.810 (0.733-0.887), p = 0.025, RAD 50.700 (0.610-0.790), p < 0.001). The DLAD specificity (0.775 (0.717-0.833)) was significantly lower than for all assessed radiologists (RAD 11.000 (0.984-1.000), p < 0.001, RAD 20.970 (0.946-1.000), p < 0.001, RAD 30.980 (0.961-1.000), p < 0.001, RAD 40.975 (0.953-0.997), p < 0.001, RAD 50.995 (0.985-1.000), p < 0.001). The study results demonstrate that the proposed DLAD could be utilized as a decision-support system to reduce radiologists' false negative rate.

Standard chemoradiation for glioblastoma results in progressive brain volume loss.

OBJECTIVE: To investigate the effects of chemotherapy and cranial irradiation on normal brain tissue using in vivo neuroimaging in patients with glioblastoma. METHODS: We used longitudinal MRI to monitor structural brain changes during standard treatment in patients newly diagnosed with glioblastoma. We assessed volumetric and diffusion tensor imaging measures in 14 patients receiving 6 weeks of chemoradiation, followed by up to 6 months of temozolomide chemotherapy alone. We examined changes in whole brain, gray matter (GM), white matter (WM), anterior lateral ventricle, and hippocampal volumes. Normal-appearing GM, WM, and hippocampal analyses were conducted within the hemisphere of lowest/absent tumor burden. We examined diffusion tensor imaging measures within the subventricular zone. RESULTS: Whole brain (F = 2.41; p = 0.016) and GM (F = 2.13; p = 0.036) volume decreased during treatment, without significant WM volume change. Anterior lateral ventricle volume increased significantly (F = 65.51; p < 0.001). In participants analyzed beyond 23 weeks, mean ventricular volume increased by 42.2% (SE: 8.8%; t = 4.94; p < 0.005). Apparent diffusion coefficient increased within the subventricular zone (F = 7.028; p < 0.001). No significant changes were identified in hippocampal volume. CONCLUSIONS: We present evidence of significant and progressive treatment-associated structural brain changes in patients with glioblastoma treated with standard chemoradiation. Future studies using longitudinal neuropsychological evaluation are needed to characterize the functional consequences of these structural changes.

Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion.

The abnormal vasculature of the tumor microenvironment supports progression and resistance to treatment. Judicious application of antiangiogenic therapy may normalize the structure and function of the tumor vasculature, promoting improved blood perfusion. However, direct clinical evidence is lacking for improvements in blood perfusion after antiangiogenic therapy. In this study, we used MRI to assess tumor blood perfusion in 30 recurrent glioblastoma patients who were undergoing treatment with cediranib, a pan-VEGF receptor tyrosine kinase inhibitor. Tumor blood perfusion increased durably for more than 1 month in 7 of 30 patients, in whom it was associated with longer survival. Together, our findings offer direct clinical evidence in support of the hypothesis that vascular normalization can increase tumor perfusion and help improve patient survival.

Apoptosis and inhibition of gap-junctional intercellular communication induced by LA-12, a novel hydrophobic platinum(IV) complex.

A new hydrophobic platinum(IV) complex, LA-12, a very efficient anticancer drug lacking cross-resistance with cisplatin (CDDP), is now being tested in clinical trials. Here we investigated the apoptogenic activity of LA-12 and its effect on gap-junctional intercellular communication (GJIC) in the rat liver epithelial cell line WB-F344. LA-12 induced apoptosis much more efficiently than did CDDP due to a combination of rapid penetration into the cell and attack on DNA, leading to fast activation of p53 and caspase-3. Exposure of WB-F344 cells to LA-12 led to rapid induction of the time- and dose-dependent decrease in GJIC. On the molecular level, loss of GJIC induced by LA-12 was mediated by activation of extracellular signal-regulated kinase (ERK)-1 and ERK-2, as demonstrated by the use of inhibitors of ERK activation. Inhibition of GJIC was linked to rapid hyperphosphorylation of connexin-43 and disappearance of connexon clusters from membranes, which was not observed in the case of CDDP.