The high sensitivity to motion artifacts is a major limiting factor for applying the dynamic 3D T1-weighted gradient-echo (3D T1w GRE) technique for dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) experiments in small rodents. Dynamic quantification of the relaxation rate R1 (1/T1) presents an alternative approach to reduce these motion artifacts. In this work, an optimized 2D single-shot Look-Locker based T1 mapping technique, named GOLD, applying radial sampling in the golden-angle view order and contrast-enhancing k-space filter was evaluated for its use in free-breathing quantitative DCE-MRI of rat liver on a clinical 1.5 T MRI system.

MATERIALS AND METHODS:

In vitro measurements and initial in vivo experiments in healthy rats were performed to evaluate the accuracy and resilience of the GOLD technique to motion artifacts. Unifocal hepatocellular carcinoma (HCC) was established in 20 male Buffalo rats. Twelve days after tumor cell implantation, animals were screened for intrahepatic tumor nodules by high-resolution T2-weighted MRI. Quantitative DCE-MRI experiments applying bolus injected gadopentetate dimeglumine were performed in 11 HCC-bearing rats using the GOLD technique. For comparison, a standard 3D T1w GRE sequence was applied in 6 additional rats.

RESULTS:

Phantom experiments showed good agreement for T1 values measured by the GOLD method and an inversion recovery spectroscopy measurement. The in vivo experiments in healthy rats confirmed the robustness of the GOLD method in T1 value determination and its resilience to motion artifacts. Gadopentetate dimeglumine concentration (CGd) time curves determined from free-breathing GOLD-based DCE-MRI experiments of HCC-bearing rats allowed reliable and robust pharmacokinetic modeling (K, ve, lag time Td, and slow washout rate rwo) of tumor, liver, and spinal muscle. In comparison to the dynamic 3D T1w GRE, the GOLD method showed less variation and jitter in the CGd time curves and significantly increased accuracy (in terms of the goodness of fit) in the pharmacokinetic modeling. Significant differences were detected for K and ve with the 3D T1w GRE method apparently underestimating those parameters.

CONCLUSIONS:

The GOLD technique allowed dynamic sampling of 2D axial T1 maps of the rat abdomen with 6-second temporal resolution enabling simultaneous and robust pharmacokinetic modeling of HCC, normal liver, and spinal muscle.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor patient outcome often resulting from late diagnosis in advanced stages. To date methods to diagnose early-stage PDAC are limited and in vivo detection of pancreatic intraepithelial neoplasia (PanIN), a pre-invasive precursor of PDAC, is impossible. Using a cathepsin-activatable near-infrared probe in combination with flexible confocal lasermicroscopy (CFL) in a genetically defined mouse model of PDAC we were able to detect and grade murine PanIN lesions in real-time in vivo. Our diagnostic approach is highly sensitive and specific and proved superior to clinically established fluorescein-enhanced imaging. Translation of this endoscopic technique into the clinic should tremendously improve detection of pancreatic neoplasia thus reforming management of patients at risk for PDAC.

Articles:

Nature

Nature reviews cancer

For generation of conditional endogenous PDAC models, Ptfla^+/Cre mice were crossed to Kras^+/LSL-G12D (K)Tgfα(T), K;p53(P)^+/fl, K;P^fl/fl, K;P^+/R172H;T and K;P^+/fl;T GEMMs and subjected to serial T2- weighted (T2w) MRI from 4-6 weeks of age onwards. Upon detection of solid tumor, diffusion- weighted imaging and dynamic contrast enhanced-MRI protocols were implemented. Survival analysis and histopathological characterization of PDAC were performed and correlated with MRI data. Tumor growth kinetics as determined by semi-automated segmentation of TIW data showed good correlation with the animal genotype. In K;P^+/fl animals, tumors were first detected at 12-15 weeks of age while significant tumor burden was observed around weck 20. Tumor appearance was highly heterogeneous, with cystic and solid tumor parts clearly distinguishable. Additional TGFα overexpression led to earlier onset, faster tumor growth and significantly shorter lifespan.

METHODS:

Sixty-six eligible patients were evaluated prospectively with (18)F-FLT PET before R-CHOP. PET was performed 45 min after injection of 300-370 MBq of (18)F-FLT. Mean and maximum standardized uptake values (SUVs) were calculated on a lesion-by-lesion basis. Response was assessed at the end of therapy. International Prognostic Index (IPI) scores and clinical parameters (Ann Arbor stage, lactate dehydrogenase, performance status, extranodal disease) were determined in all patients. Response was assessed according to revised response criteria after the end of therapy. After treatment, patients were followed in intervals from 4 wk to 6 mo (mean follow-up, 23.1 mo [range, 1-63 mo]), and progression-free and overall survival were determined.

RESULTS:

All lymphoma lesions identified by a reference method ((18)F-FDG PET/CT or multislice CT of the trunk) showed increased focal tracer uptake (mean (18)F-FLT SUV, 7.3 ± 2.5). Response assessment revealed progressive disease in 4, partial response in 3, and complete response (CR) in the remaining 55 patients. The IPI score was predictive for achieving CR (P = 0.034). Importantly, initial mean SUV was also significantly higher in patients who showed progressive disease and partial response than in patients who achieved CR (P = 0.049). In addition, we found a significant correlation between IPI score and initial (18)F-FLT uptake.

CONCLUSION:

Taken together, high (18)F-FLT uptake is a negative predictor of response to R-CHOP treatment in aggressive B-cell non-Hodgkin lymphoma and correlates with the IPI score. Thus, (18)F-FLT PET may represent a useful tool for implementing risk-adapted treatment in these patients.

The hepatocellular carcinoma (HCC) exhibits varying degrees of vascularization with more poorly differentiated carcinoma commonly exhibiting high amounts of vascularization. Transcatheter arterial embolization (TAE) of HCC tumor nodules results in varying amounts of tumor necrosis. Reliable quantification of necrosis after TAE, would aid in treatment planning and testing of novel combinatorial treatment regimen. The aim of this work was to validate different imaging parameters as individual or combined predictors of tumor necrosis after TAE in an orthotopic rat HCC tumor model.

METHODS:

Unifocal rat HCC was imaged by T(2)-weighted MRI, quantitative dynamic contrast enhanced (DCE) MRI, diffusion weighted MRI (DWI) and [(18)F]-FDG PET imaging before (day-1) and after (days 1 and 3) TAE. Univariate and multivariate regression analyses were carried out to analyze the ability of each imaging parameter to predict the percent residual vital tumor (vtu) and vital tissue (vti) as determined by quantitative histopathology.

RESULTS:

TAE induced a wide range of tumor necrosis. Tumor volume was the only parameter showing a correlation with vti (r(2) = 0.63) before TAE. After TAE, moderate correlations were found for FDG tracer uptake (r(2) = 0.56) and plasma tissue transfer constant (r(2) = 0.55). Correlations were higher for the extravascular extracellular volume fraction (v(e), r(2) = 0.68) and highest for the apparent diffusion coefficient (ADC, r(2) = 0.86). Multivariate analyses confirmed highest correlation of ADC and v(e) with vtu and vti.

CONCLUSIONS:

DWI and DCE-MRI with the respective parameters ADC (day 3) and v(e) (day 1) were identified as the most promising imaging techniques for the prediction of necrosis. This study validates a preclinical platform allowing for the improved tumor stratification after TAE and thus the testing of novel combinatorial therapy approaches in HCC.

In this work, two pharmacokinetic modeling techniques, population arterial input function model, and reference region model, were applied to dynamic contract-enhanced MRI data, to test the influence of a change in heart rate on modeling parameters. A rat population arterial input function was generated by dynamic contrast-enhanced computed tomography measurements using the MR contrast agent gadolinium diethylenetriamine penta-acetic acid. Then, dynamic contract-enhanced MRI was used for treatment monitoring in two groups of hepatocellular carcinoma bearing rats. Whereas group and pre, post checked 1 had the same heart rate as animals analyzed for the population arterial input function (263 6 20 bpm), group 2 had a higher heart rate (369 6 11 bpm) due to a different anesthesia protocol. The pharmacokinetic modeling parameters volume transfer constant Ktrans and relative extravascular extracellular space ve were calculated with both models and statistically compared. For group 1, good correlation and agreement was found between the models showing no difference in Ktrans and ve (DKtrans:4 6 19% and Dve:4 6 12%, P 5 0.2). In contrast, for group 2, abias in parameter values for the population arterial input func- tion model was detected (DKtrans: 245 6 7% and Dve: 231 6 7%, P ! 0.001). The presented work underlines the value of the reference region model in longitudinal treatment monitoring and provides a straightforward approach for the generation of a rat population arterial input function.

_{Magn Reson Med 000:000–000, 2010. V C 2010 Wiley-Liss, Inc.}

Myc oncoproteins promote continuous cell growth, in part by controlling the transcription of key cell cycle regulators. Here, we report that c-Myc regulates the expression of Aurora A and B kinases (Aurka and Aurkb), and that Aurka and Aurkb transcripts and protein levels are highly elevated in Myc-driven B cell lymphomas in both mice and man. The induction of Aurka by Myc is transcriptional and is directly mediated via E-boxes, while Aurkb is regulated indirectly. Blocking Aurka/b kinase activity with a selective Aurora kinase inhibitor triggers transient mitotic arrest, polyploidization and apoptosis of Myc-induced lymphomas. These phenotypes are selectively bypassed by a kinase inhibitor-resistant Aurkb mutant, demonstrating that Aurkb is the primary therapeutic target in the context of Myc. Importantly apoptosis provoked by Aurk inhibition was p53 independent, suggesting that Aurka/Aurkb inhibitors will show efficacy in treating primary or relapsed malignancies having Myc involvement and/or loss of p53 function.

The intrinsic oncolytic specificity of vesicular stomatitis virus (VSV) is currently being exploited to develop alternative therapeutic strategies for hepatocellular carcinoma (HCC). Identifying key regulators in diverse transduction pathways that define VSV oncolysis in cancer cells represents a fundamental prerequisite to engineering more effective oncolytic viral vectors and adjusting combination therapies. After having identified defects in the signalling cascade of type I interferon induction, responsible for attenuated antiviral responses in human HCC cell lines, we have now investigated the role of cell proliferation and translation initiation. Cell cycle progression and translation initiation factors eIF4E and eIF2Bε have been recently identified as key regulators of VSV permissiveness in T-lymphocytes and immortalized mouse embryonic fibroblasts, respectively. Here, we show that in HCC, decrease of cell proliferation by cell cycle inhibitors or siRNA-mediated reduction of G(1) cyclin-dependent kinase activities (CDK4) or cyclin D1 protein expression, do not significantly alter viral growth. Additionally, we demonstrate that translation initiation factors eIF4E and eIF2Bε are negligible in sustaining VSV replication in HCC. Taken together, these results indicate that cellular proliferation and the initiation phase of cellular protein synthesis are not essential for successful VSV oncolysis of HCC. Moreover, our observations indicate the importance of cell-type specificity for VSV oncolysis, an important aspect to be considered in virotherapy applications in the future.

_{Published OnlineFirst on May 11, 2010 as 10.1158/0008-5472.CAN-10-0259}