Intraprocedural Transcatheter Intraarterial Perfusion (TRIP)-MRI for Evaluation of Irreversible Electroporation Therapy Response in a Rabbit Liver Tumor Model.

PURPOSE: Irreversible electroporation (IRE) is a promising new ablation method for hepatocellular carcinoma (HCC) treatment with few side-effects; however, tissue perfusion and differentiation between treatment zones have not been sufficiently studied. In this project, we analyzed HCC tumor perfusion changes immediately after IRE treatment using transcatheter intraarterial perfusion (TRIP)-MRI to monitor treatment zone margins. MATERIALS AND METHODS: All protocols were approved by the institutional animal care and use committee. A total of 34 rabbits were used for this prospective study: tumor liver group (n=17), normal liver group (n=14), and 3 for growing VX2 tumors. All procedures and imaging were performed under anesthesia. VX2 tumors were grown by injection of VX2 cells into rabbit hindlimbs. Liver tumors were induced by percutaneous US-guided injection of VX2 tumor fragments into liver. For digital subtraction angiography (DSA), a 2F catheter was advanced through left hepatic artery via femoral artery access, followed by contrast injection. All rabbits underwent baseline anatomic MRI, then IRE procedure or IRE probe placement only, and lastly post-procedure anatomic and TRIP-MRI. Liver tissues were dissected immediately after imaging for histology. All statistical analyses were performed on GraphPad Prism, with P<0.05 considered significant. RESULTS: IRE generated central IRE zone and peripheral reversible electroporation (RE) zone on anatomic MRI for both normal liver and liver tumor tissues. The semiquantitative analysis showed that IRE zone had the lowest AUC, PE, WIS, Ktrans, ve , and vp as well as the highest TTP, followed by RE zone, then untreated tissues. Receiver operating characteristic analysis showed that WIS and AUC60 had the highest AUCROC. Histologic analysis showed a positive correlation in viable area fraction between MRI and histologic measurements. IRE zone had the highest %apoptosis and lowest CD31+ staining. CONCLUSION: Our results demonstrated that intraprocedural TRIP-MRI can effectively differentiate IRE and RE zones after IRE ablation in normal liver and liver tumor tissues.

DWI and DCE-MRI approaches for differentiating reversibly electroporated penumbra from irreversibly electroporated ablation zones in a rabbit liver model.

The purpose of our study was to investigate the hypothesis that DWI-MRI and DCE-MRI cab be used to distinguish between IRE and RE zones of IRE treatment in a rabbit liver model. 6 rabbits underwent baseline and post-procedure MR imaging with DWI and DCE-MRI as well as IRE (10 pulses, 2000 V, 10 µs/pulse, 10 ms between pulses). Rabbits were euthanized immediately after post-procedure MRI to acquire liver tissue for histology. Liver tissues were fixed and then stained with HE and TUNEL. T1w and T2w intensities in different treatment zones were calculated and normalized to paraspinal muscle signal. ADC maps were generated from DWI. AUC, PE, TTP, WIS, Ktrans, Kep, and VE were calculated from DCE-MRI. Apoptosis index was calculated from TUNEL stained tissues. P<0.05 was considered statistically significant. Entire IRE treated region was hyperintense compared with untreated tissues on T1w, with the RE zone having a higher signal intensity. On DWI, IRE treated tissue had decreased ΔADC. The IRE zone has a lower ΔADC than the RE zone within the treated region. On DCE-MRI, IRE zone demonstrated the highest TTP and the lowest PE, WIS, Ktrans, Kep, and VE, followed by the RE zone then the untreated tissue. TUNEL staining of liver tissues showed that the IRE zone had the highest apoptosis index, followed by the RE zone and then untreated tissue. In conclusion, DCE-MRI and DWI parameters allow differentiation between RE and IRE zones in a rabbit liver model.

Early growth response 3 (Egr-3) is induced by transforming growth factor-ß and regulates fibrogenic responses.

Members of the early growth response (Egr) gene family of transcription factors have nonredundant biological functions. Although Egr-3 is implicated primarily in neuromuscular development and immunity, its regulation and role in tissue repair and fibrosis has not been studied. We now show that in normal skin fibroblasts, Egr-3 was potently induced by transforming growth factor-ß via canonical Smad3. Moreover, transient Egr-3 overexpression was sufficient to stimulate fibrotic gene expression, whereas deletion of Egr-3 resulted in substantially attenuated transforming growth factor-ß responses. Genome-wide expression profiling in fibroblasts showed that genes associated with tissue remodeling and wound healing were prominently up-regulated by Egr-3. Notably, <5% of fibroblast genes regulated by Egr-1 or Egr-2 were found to be coregulated by Egr-3, revealing substantial functional divergence among these Egr family members. In a mouse model of scleroderma, development of dermal fibrosis was accompanied by accumulation of Egr-3-positive myofibroblasts in the lesional tissue. Moreover, skin biopsy samples from patients with scleroderma showed elevated Egr-3 levels in the dermis, and Egr-3 mRNA levels correlated with the extent of skin involvement. These results provide the first evidence that Egr-3, a functionally distinct member of the Egr family with potent effects on inflammation and immunity, is up-regulated in scleroderma and is necessary and sufficient for profibrotic responses, suggesting important and distinct roles in the pathogenesis of fibrosis.