PURPOSE: Tumor localization provides crucial information for radiotherapy dose differentiation treatments, such as focal dose escalation and dose painting by numbers, which aim at achieving tumor control with minimal side effects. Multiparametric (mp-)MRI is increasingly used for tumor detection and localization in prostate because of its ability to visualize tissue structure and to reveal tumor characteristics. However, it can be challenging to distinguish cancer, particularly in the transition zone. In this study, we enhance the performance of a mp-MRI-based tumor localization model by incorporating prior knowledge from two sources: a population-based tumor probability atlas and patient-specific biopsy examination results. This information typically would be considered by a physician when carrying out a manual tumor delineation. MATERIALS AND METHODS: Our study involves 40 patients from two centers: 23 patients from the University Hospital Leuven (Leuven), Leuven, Belgium and 17 patients from the Netherlands Cancer Institute (NKI), Amsterdam, the Netherlands. All patients received a mp-MRI exam consisting of a T2-weighted, diffusion-weighted, and dynamic contrast-enhanced MRI before prostatectomy. Thirty-one features were extracted for each voxel in the prostate. Among these, 29 were from the multiparametric-MRI, one was from the population-based tumor probability atlas and one from the biopsy map. T2-weighted images of each patient were registered to whole-mount section pathology slices to obtain the ground truth. The study was validated in two settings: single-center (training and test sets were from the same cohort); and cross-center (training and test sets were from different cohorts). In addition, automatic delineations created by our model were compared with manual tumor delineations done by six different teams on a subset of Leuven cohort including 15 patients. RESULTS: In the single-center setting, mp-MRI-based features yielded area under the ROC curves (AUC) of 0.690 on a pooled set of patients from both cohorts. Including prevalence into mp-MRI-based features increased the AUC to 0.751 and including all features achieved the best performance with AUC of 0.775. Using all features always showed better results when varying the size of the training set. In addition, its performance is comparable with the average performance of six teams delineating the tumors manually. The error rate using all features was 0.22. The two prior knowledge features ranked among the top four most important features out of the 31 features. In the cross-center setting, combining all features also yielded the best performance in terms of the mean AUC of 0.777 on the pooled set of patients from both cohorts. In addition, the difference in performance between the single-center setting and cross-center setting was not significant. CONCLUSIONS: The results showed significant improvements when including prior knowledge features in addition to mp-MRI-based features in both single- and cross-center settings.

Targeting tumor angiogenesis is a potential therapeutic strategy for glioblastoma because of its high vascularization. Tivozanib is an oral pan-VEGF receptor tyrosine kinase inhibitor that hits a central pathway in glioblastoma angiogenesis. We conducted a phase II study to test the effectiveness of tivozanib in patients with recurrent glioblastoma. Ten adult patients were enrolled and treated with tivozanib 1.5 mg daily, 3 weeks on/1 week off in 28-day cycles. Brain MRI and blood biomarkers of angiogenesis were performed at baseline, within 24-72 h of treatment initiation, and monthly thereafter. Dynamic contrast enhanced MRI, dynamic susceptibility contrast MRI, and vessel architecture imaging were used to assess vascular effects. Resting state MRI was used to assess brain connectivity. Best RANO criteria responses were: 1 complete response, 1 partial response, 4 stable diseases, and 4 progressive disease (PD). Two patients were taken off study for toxicity and 8 patients were taken off study for PD. Median progression-free survival was 2.3 months and median overall survival was 8.1 months. Baseline abnormal tumor vascular permeability, blood flow, tissue oxygenation and plasma sVEGFR2 significantly decreased and plasma PlGF and VEGF increased after treatment, suggesting an anti-angiogenic effect of tivozanib. However, there were no clear structural changes in vasculature as vessel caliber and enhancing tumor volume did not significantly change. Despite functional changes in tumor vasculature, tivozanib had limited anti-tumor activity, highlighting the limitations of anti-VEGF monotherapy. Future studies in glioblastoma should leverage the anti-vascular activity of agents targeting VEGF to enhance the activity of other therapies.

Cerebral X-linked adrenoleukodystrophy is a devastating neurodegenerative disorder caused by mutations in the ABCD1 gene, which lead to a rapidly progressive cerebral inflammatory demyelination in up to 60% of affected males. Selective brain endothelial dysfunction and increased permeability of the blood-brain barrier suggest that white matter microvascular dysfunction contributes to the conversion to cerebral disease. Applying a vascular model to conventional dynamic susceptibility contrast magnetic resonance perfusion imaging, we demonstrate that lack of ABCD1 function causes increased capillary flow heterogeneity in asymptomatic hemizygotes predominantly in the white matter regions and developmental stages with the highest probability for conversion to cerebral disease. In subjects with ongoing inflammatory demyelination we observed a sequence of increased capillary flow heterogeneity followed by blood-brain barrier permeability changes in the perilesional white matter, which predicts lesion progression. These white matter microvascular alterations normalize within 1 year after treatment with haematopoietic stem cell transplantation. For the first time in vivo, our studies unveil a model to assess how ABCD1 alters white matter microvascular function and explores its potential as an earlier biomarker for monitoring disease progression and response to treatment.

Phosphorylation of Pyruvate Kinase M2 (PKM2) on Tyr105 by fibroblast growth factor receptor 1 (FGFR1) has been shown to promote its nuclear localization as well as cell growth in lung cancer. Better understanding the regulation of this process would benefit the clinical treatment for lung cancer. Here, it has been found that the adaptor protein receptor for activated PKC kinase (RACK1) formed a complex with FGFR1 and PKM2, and activated the FGFR1/PKM2 signaling. Knocking down the expression of RACK1 impaired the phosphorylation on Tyr105 of PKM2 and inhibited the growth and migration of lung cancer cells, while over-expression of RACK1 in lung cancer cells led to the resistance to Erdafitinib. Moreover, knocking down the expression of RACK1 impaired the tumorigenesis of lung cancer driven by LKB loss and mutated Ras (KrasG12D). Taken together, our study demonstrated the pivotal roles of RACK1 in FGFR1/PKM2 signaling, suggesting FGFR1/RACK1/PKM2 might be a therapeutic target for lung cancer treatment.

Diffusion imaging is critical for detecting acute brain injury. However, normal apparent diffusion coefficient (ADC) maps change rapidly in early childhood, making abnormality detection difficult. In this article, we explored clinical PACS and electronic healthcare records (EHR) to create age-specific ADC atlases for clinical radiology reference. Using the EHR and three rounds of multiexpert reviews, we found ADC maps from 201 children 0-6 years of age scanned between 2006 and 2013 who had brain MRIs with no reported abnormalities and normal clinical evaluations 2+ years later. These images were grouped in 10 age bins, densely sampling the first 1 year of life (5 bins, including neonates and 4 quarters) and representing the 1-6 year age range (an age bin per year). Unbiased group-wise registration was used to construct ADC atlases for 10 age bins. We used the atlases to quantify (a) cross-sectional normative ADC variations; (b) spatiotemporal heterogeneous ADC changes; and (c) spatiotemporal heterogeneous volumetric changes. The quantified age-specific whole-brain and region-wise ADC values were compared to those from age-matched individual subjects in our study and in multiple existing independent studies. The significance of this study is that we have shown that clinically acquired images can be used to construct normative age-specific atlases. These first of their kind age-specific normative ADC atlases quantitatively characterize changes of myelination-related water diffusion in the first 6 years of life. The quantified voxel-wise spatiotemporal ADC variations provide standard references to assist radiologists toward more objective interpretation of abnormalities in clinical images. Our atlases are available at https://www.nitrc.org/projects/mgh_adcatlases. Hum Brain Mapp 38:3052-3068, 2017. © 2017 Wiley Periodicals, Inc.