Michael D. Kuo

Decoding global gene expression programs in liver cancer by noninvasive imaging

Paralleling the diversity of genetic and protein activities, pathologic human tissues also exhibit diverse radiographic features. Here we show that dynamic imaging traits in non-invasive computed tomography (CT) systematically correlate with the global gene expression programs of primary human liver cancer. Combinations of twenty-eight imaging traits can reconstruct 78% of the global gene expression profiles, revealing cell proliferation, liver synthetic function, and patient prognosis. Thus, genomic activity of human liver cancers can be decoded by noninvasive imaging, thereby enabling noninvasive, serial and frequent molecular profiling for personalized medicine.

Identification of noninvasive imaging surrogates for brain tumor gene-expression modules

Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor in adults. We combined neuroimaging and DNA microarray analysis to create a multidimensional map of gene-expression patterns in GBM that provided clinically relevant insights into tumor biology. Tumor contrast enhancement and mass effect predicted activation of specific hypoxia and proliferation gene-expression programs, respectively. Overexpression of EGFR, a receptor tyrosine kinase and potential therapeutic target, was also directly inferred by neuroimaging and was validated in an independent set of tumors by immunohistochemistry. Furthermore, imaging provided insights into the intratumoral distribution of gene-expression patterns within GBM. Most notably, an “infiltrative” imaging phenotype was identified that predicted patient outcome. Patients with this imaging phenotype had a greater tendency toward having multiple tumor foci and demonstrated significantly shorter survival than their counterparts. Our findings provide an in vivo portrait of genome-wide gene expression in GBM and offer a potential strategy for noninvasively selecting patients who may be candidates for individualized therapies.

C-arm Cone-beam CT: General Principles and Technical Considerations for Use in Interventional Radiology

Digital flat-panel detector cone-beam computed tomography (CBCT) has recently been adapted for use with C-arm systems. This configuration provides projection radiography, fluoroscopy, digital subtraction angiography, and volumetric computed tomography (CT) capabilities in a single patient setup, within the interventional suite. Such capabilities allow the interventionalist to perform intraprocedural volumetric imaging without the need for patient transportation. Proper use of this new technology requires an understanding of both its capabilities and limitations. This article provides an overview of C-arm CBCT with particular attention to trade-offs between C-arm CBCT systems and conventional multi-detector CT.

Three-Dimensional C-arm Cone-beam CT: Applications in the Interventional Suite

C-arm cone-beam computed tomography (CT) with a flat-panel detector represents the next generation of imaging technology available in the interventional radiology suite and is predicted to be the platform for many of the three-dimensional (3D) roadmapping and navigational tools that will emerge in parallel with its integration. The combination of current and unappreciated capabilities may be the foundation on which improvements in both safety and effectiveness of complex vascular and nonvascular interventional procedures become possible. These improvements include multiplanar soft tissue imaging, enhanced pretreatment target lesion roadmapping and guidance, and the ability for immediate multiplanar posttreatment assessment. These key features alone may translate to a reduction in the use of iodinated contrast media, a decrease in the radiation dose to the patient and operator, and an increase in the therapeutic index (increase in safety-vs-benefit ratio). In routine practice, imaging information obtained with C-arm cone-beam CT provides a subjective level of confidence factor to the operator that has not yet been thoroughly quantified.

Local Overexpression of Thrombomodulin for In Vivo Prevention of Arterial Thrombosis in a Rabbit Model

-Endothelial thrombomodulin plays a critical role in hemostasis by binding thrombin and subsequently converting protein C to its active form, a powerful anticoagulant. Thrombomodulin thus represents a central mechanism by which patency is maintained in normal vessels. However, thrombomodulin expression decreases in perturbed endothelial cells, predisposing to thrombotic occlusion. An adenoviral construct expressing thrombomodulin (Adv/RSV-THM) was created and functionally characterized in vitro and in vivo. The impact of local overexpression of thrombomodulin on in vivo thrombus formation was subsequently examined in a stasis/injury model of arterial thrombosis. The construct prevented arterial thrombosis formation in all animals, while viral and nonviral controls typically developed occluding thrombi. By histological analysis, nonviral controls exhibited intravascular thrombus occluding a mean of 70.52+/-3.72% of available lumen, while viral controls reached 86. 85+/-2.82% thrombotic occlusion; in contrast, Adv/RSV-THM reduced thrombosis to 28.61+/-3.31% of lumen in cross section. No significant intima-to-media ratio was observed in the thrombomodulin group relative to controls. Local infiltration of granulocytes and macrophages significantly decreased in the Adv/RSV-THM group relative to controls, while neutrophilic infiltration increased in viral controls relative to nonviral controls. This construct thus offers a viable technique for promoting a locally thromboresistant small-caliber artery, without the inflammatory damage that has limited many other adenoviral applications.

Thrombomodulin Overexpression to Limit Neointima Formation

BACKGROUND-These studies were initiated to confirm that high-level thrombomodulin overexpression is sufficient to limit neointima formation after mechanical overdilation injury. METHODS AND RESULTS-An adenoviral construct expressing thrombomodulin (Adv/RSV-THM) was created and functionally characterized in vitro and in vivo. The impact of local overexpression of thrombomodulin on neointima formation 28 days after mechanical overdilation injury was evaluated. New Zealand White rabbit common femoral arteries were treated with buffer, viral control, or Adv/RSV-THM and subjected to mechanical overdilation injury. The treated vessels (n=4 per treatment) were harvested after 28 days and evaluated to determine intima-to-media (I/M) ratios. Additional experiments were performed to determine early (7-day) changes in extracellular elastin and collagen content; local macrophage, T-cell, and neutrophil infiltration; and local thrombus formation as potential contributors to the observed impact on 28-day neointima formation. The construct significantly decreased neointima formation after mechanical dilation injury in this model. By histological analysis, buffer controls exhibited mean I/M ratios of 0.76+/-0.06%, whereas viral controls reached 0.77+/-0.08%; in contrast, Adv/RSV-THM reduced I/M ratios to 0.47+/-0.06%. Local inflammatory infiltrate decreased in the Adv/RSV-THM group relative to controls, whereas matrix remained relatively preserved. Rates of early thrombus formation also decreased in Adv/RSV-THM animals. CONCLUSIONS-This construct thus offers a viable technique for promoting a locally neointima-resistant small-caliber artery via decreased thrombus bulk, normal matrix preservation, and decreased local inflammation without the inflammatory damage that has limited many other adenoviral applications.

Behind the Numbers: Decoding Molecular Phenotypes with Radiogenomics—Guiding Principles and Technical Considerations

As the field of radiogenomics grows, we can expect improved robustness of the measurement technologies, analysis methods, and, ultimately, the predictive capabilities of radiogenomic maps.

Illuminating Radiogenomic Characteristics of Glioblastoma Multiforme through Integration of MR Imaging, Messenger RNA Expression, and DNA Copy Number Variation

PURPOSE To perform a multilevel radiogenomics study to elucidate the glioblastoma multiforme (GBM) magnetic resonance (MR) imaging radiogenomic signatures resulting from changes in messenger RNA (mRNA) expression and DNA copy number variation (CNV). MATERIALS AND METHODS Radiogenomic analysis was performed at MR imaging in 23 patients with GBM in this retrospective institutional review board-approved HIPAA-compliant study. Six MR imaging features-contrast enhancement, necrosis, contrast-to-necrosis ratio, infiltrative versus edematous T2 abnormality, mass effect, and subventricular zone (SVZ) involvement-were independently evaluated and correlated with matched genomic profiles (global mRNA expression and DNA copy number profiles) in a significant manner that also accounted for multiple hypothesis testing by using gene set enrichment analysis (GSEA), resampling statistics, and analysis of variance to gain further insight into the radiogenomic signatures in patients with GBM. RESULTS GSEA was used to identify various oncogenic pathways with MR imaging features. Correlations between 34 gene loci were identified that showed concordant variations in gene dose and mRNA expression, resulting in an MR imaging, mRNA, and CNV radiogenomic association map for GBM. A few of the identified gene-to-trait associations include association of the contrast-to-necrosis ratio with KLK3 and RUNX3; association of SVZ involvement with Ras oncogene family members, such as RAP2A, and the metabolic enzyme TYMS; and association of vasogenic edema with the oncogene FOXP1 and PIK3IP1, which is a member of the PI3K signaling network. CONCLUSION Construction of an MR imaging, mRNA, and CNV radiogenomic association map has led to identification of MR traits that are associated with some known high-grade glioma biomarkers and association with genomic biomarkers that have been identified for other malignancies but not GBM. Thus, the traits and genes identified on this map highlight new candidate radiogenomic biomarkers for further evaluation in future studies.

A computed tomography radiogenomic biomarker predicts microvascular invasion and clinical outcomes in hepatocellular carcinoma

Microvascular invasion (MVI) in hepatocellular carcinoma (HCC) is an independent predictor of poor outcomes subsequent to surgical resection or liver transplantation (LT); however, MVI currently cannot be adequately determined preoperatively. Radiogenomic venous invasion (RVI) is a contrast‐enhanced computed tomography (CECT) biomarker of MVI derived from a 91‐gene HCC “venous invasion” gene expression signature. Preoperative CECTs of 157 HCC patients who underwent surgical resection (N = 72) or LT (N = 85) between 2000 and 2009 at three institutions were evaluated for the presence or absence of RVI. RVI was assessed for its ability to predict MVI and outcomes. Interobserver agreement for scoring RVI was substantial among five radiologists (κ = 0.705; P < 0.001). The diagnostic accuracy, sensitivity, and specificity of RVI in predicting MVI was 89%, 76%, and 94%, respectively. Positive RVI score was associated with lower overall survival (OS) than negative RVI score in the overall cohort (P < 0.001; 48 vs. >147 months), American Joint Committee on Cancer tumor‐node‐metastasis stage II (P < 0.001; 34 vs. >147 months), and in LT patients within Milan criteria (P < 0.001; 69 vs. >147 months). Positive RVI score also portended lower recurrence‐free survival at 3 years versus negative RVI score (P = 0.001; 27% vs. 62%). Conclusion: RVI is a noninvasive radiogenomic biomarker that accurately predicts histological MVI in HCC surgical candidates. Its presence on preoperative CECT is associated with early disease recurrence and poor OS and may be useful for identifying patients less likely to derive a durable benefit from surgical treatment. (Hepatology 2015;62:792–800)

Society of Interventional Radiology position statement: prostate artery embolization for treatment of benign disease of the prostate.

Prostatic artery embolization (PAE) is a promising new treatment for lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). It has therefore garnered much interest in the interventional community. This article will review the scientific background for this therapy, describe the current devices available for treatment, and state the position of the Society of Interventional Radiology (SIR) with regard to the study and potential adoption of this therapy.