Early-stage detection of hepatocellular carcinoma with hydralazine-augmented contrast ultrasound imaging

Abstract Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths and a significant global health concern. Early detection is crucial, as it significantly improves survival rates; patients diagnosed early can expect a median survival of over 60 months, compared to less than 15 months for those diagnosed at advanced stages. Unfortunately, most HCC cases are diagnosed late, underscoring the urgent need for developing better detection methods. The current sensitivity of ultrasound for early-stage HCC detection is only about 45%, which increases to 63% when alpha-fetoprotein (AFP) testing is added, indicating a pressing need for new imaging techniques to enhance detection capabilities. This research proposes a novel imaging method, hydralazine-augmented contrast ultrasound (HyCUS), which aims to improve HCC visibility by increasing the image contrast between tumors and surrounding tissue by differentially modulating their blood flow. The study will validate HyCUS using an autochthonous rat model of HCC with liver fibrosis, assessing visibility through objective computational metrics and subjective assessments by radiologists. The proposal has three specific aims. Specific Aim 1 will establish HyCUS as a technique for enhancing HCC visibility. The underlying principle of the technique will be validated by measuring the differences in blood flow between HCC and surrounding liver tissue after hydralazine administration. These differences will be correlated to Evans blue dye uptake to assess visibility objectively. Specific Aim 2 will develop an imaging regimen for HyCUS. Understanding the dose-response relationship of hydralazine is essential for clinical applications. These studies will investigate the effect of different hydralazine doses on the visibility of lesions, the timing of contrast enhancement, and the duration of this enhancement across various tumor sizes. Specific Aim 3 will evaluate the performance of HyCUS against existing methods (B-mode ultrasound and contrast-enhanced ultrasound) in detecting early-stage HCC and measuring tumor burden. These studies will track tumor formation and growth of HCC in a rat model, assessing the earliest detection times and overall tumor burden through necropsy analysis post-imaging. In conclusion, the proposed HyCUS technique represents a promising advancement in the early detection of HCC. Enhancing the visibility of tumors through targeted blood flow modulation could significantly improve diagnostic capabilities and ultimately improve patient outcomes in liver cancer management.