Histotripsy for the Treatment of Cholangiocarcinoma Liver Tumors: In Vivo Feasibility and Ex Vivo Dosimetry Study

Abstract

Histotripsy is a non-invasive, non-ionizing, and nonthermal focused ultrasound ablation method that is currently being developed for the treatment of liver cancer. Promisingly, histotripsy has been shown for ablating primary (hepatocellular carcinoma, HCC) and metastatic (colorectal liver metastasis, CLM) liver tumors in preclinical and early clinical studies. The feasibility of treating cholangiocarcinoma (CC), a less common primary liver tumor that arises from the bile ducts, has not been explored previously. Given that prior work has established that histotripsy susceptibility is based on tissue mechanical properties, there is a need to explore histotripsy as a treatment for CC due to their dense fibrotic stromal components. In this work, we first investigated the feasibility of histotripsy for ablating CC tumors in vivo in a patient-derived xenograft mouse model. The results showed that histotripsy could generate CC tumor ablation using a 1 MHz small animal histotripsy system with treatment doses of 250, 500, and 1000 pulses/point. A second set of experiments compared the histotripsy doses required to ablate CC tumors to HCC and CLM tumors ex vivo. For this, human tumor samples were harvested after surgery and treated ex vivo with a 700 kHz clinical histotripsy transducer. Results demonstrated significantly higher treatment doses were required to ablate CC and CLM tumors compared to HCC, with the highest treatment dose required for CC tumors. Overall, the results of this study suggest that histotripsy has the potential to be used for the ablation of CC tumors while also highlighting the need for tumor-specific treatment strategies.

Mechanical High-Intensity Focused Ultrasound (Histotripsy) in Dogs With Spontaneously Occurring Soft Tissue Sarcomas

“…The robotic micropositioner moved the focus between treatment locations, and each point was treated with ~500 pulses. The transducer frequency and treatment PRF used in this study were chosen to minimize the treatment time required to ablate the large STS tumors [6,37], and the treatment dosage was chosen based on previous histotripsy studies for other soft tissue applications [12,14,38,39]. The bubble cloud and tissue effects were monitored during treatment using real-time ultrasound imaging.…”

“…Histotripsy treatment is typically guided in real-time by ultrasound imaging, allowing the precise, non-invasive targeting of tissues ranging from deep, visceral structures to superficial, subcutaneous tumors. Previous preclinical studies have shown that histotripsy can successfully ablate various tumor types ex vivo and in vivo [4], including prostate [8], kidney [9], bone [10], brain [11], pancreatic [12], and liver tumors [13,14]. Additionally, a recent human clinical trial has shown safe and effective ablation of primary and metastatic liver tumors [15].…”

Mechanical High-Intensity Focused Ultrasound (Histotripsy) in Dogs with Spontaneously Occurring Soft Tissue Sarcomas

“…No significant adverse events associated with histotripsy were reported for any of the patients. Although histotripsy has been previously studied for the ablation of multiple tumor types [8][9][10][12][13][14][15], ablation of superficial tumors, including STS, presents a unique case for histotripsy due to the close proximity of the skin, which has the potential to be damaged by ablative therapies [24,25,45,46]. In this study, skin injury due to histotripsy was noted in the first patient that was treated, with all subsequent treatments showing no change in the VCOG-CTCAE score after treatment.…”

“…The robotic micropositioner moved the focus between treatment locations, and each point was treated with ~500 pulses. The histotripsy treatment parameters employed in this study were chosen based on previous histotripsy studies for other soft tissue applications [12,14,40,41]. The bubble cloud and tissue effects were monitored during treatment using real-time ultrasound imaging.…”

“…Histotripsy treatment is typically guided in real-time by ultrasound imaging, allowing the precise, non-invasive targeting of tissues ranging from deep, visceral structures to superficial, subcutaneous tumors. Previous preclinical studies have shown that histotripsy can successfully ablate various tumor types ex vivo and in vivo, including prostate [8], kidney [9], bone [10], brain [11], pancreatic [12], and liver tumors [13,14]. Additionally, a recent human clinical trial has shown safe and effective ablation of primary and metastatic liver tumors [15].…”