to produce cavitation rather than heat to destroy tissue.
Cavitation is produced at the focal point by applying microsecond ultrasound bursts. Heating is avoided by using a low duty cycle less than 1%. Off-target cavitation damage is avoided due to the binary treatment effect which only occurs when a tissue-specific pressure cavitation threshold is exceeded. Cavitation in tissue creates a sonographically visible “bubble cloud” by generating and then collapsing microbubbles which are formed from high negative pressures that pull out endogenous dissolved gas present in all tissues. At the cellular level, the mechanical strain imparted by the rapid expansion and collapse of the microbubbles fractures cells and creates a liquid-appearing acellular slurry that is rapidly absorbed by the body. The treatment effect is highly precise, causes minimal surrounding inflammation and is semiautomated due to advanced planning software and a robotic interface controlled by the treating physician.
Getting involved in histotripsy The Abdominal Image-guided Interventions Laboratory at the University of Wisconsin has a long history of translational research. From percutaneous cryoablation in the early 1990s to multiprobe radiofrequency ablation in the early 2000s, to microwave ablation in the 2010s, we have helped push emerging tumor ablation technologies from concepts and prototypes into routine human clinical use. We had been aware of the pioneering work of Drs. Cain and Xu for several years and thought that our laboratory, in partnership with the University of Michigan and HistoSonics, Inc. (the University of Michigan spin- off company developing histotripsy for human use), may be able to assist in the translation of histotripsy from concept to clinical practice. We began working with histotripsy in 2016, initially performing proof-of-concept liver treatments in human-size pigs with a prototype system to be sure that the concept was translatable. During these initial treatments, multiple lab members remarked that the treatment “looked like the future.”
Our lab then worked with HistoSonics to develop pre-clinical data supporting
regulatory submission for the initial human trial of hepatic histotripsy. We proved that we could safely make precise ablations of a clinically relevant size (3 cm sphere) with minimal effect on overlying tissues.5,6
During these
initial studies, we noted five critically important findings:5–7
1. The achieved ablation zones were within millimeters of what was prescribed.
2. Densely collagenous structures, such as bile ducts and vessels, were patent within treatment zones while there was uniform cellular necrosis.
3. While portal venous clots developed in the vicinity of the ablation zone, they typically resolved within 30 days without specific treatment.
4. There was rapid involution of the ablation zone with a 64% volume reduction at 4 weeks.
5. The transition zone between completely ablated and normal tissue was 4 mm, half that of the best achieved with thermal ablation.
While the translation of an animal model to the clinic is never assured, the first four critical findings were all recapitulated in the initial human trial of hepatic histotripsy. The fifth couldn’t be evaluated, as treatment zones were not resected.
A current limitation of the technology that we are working to overcome is an inability to target tumors that are either isoechoic to liver tissue on ultrasound imaging or where there is an inadequate acoustic window. Advanced multimodal imaging strategies for targeting and guiding histotripsy are in development and will complement the current ultrasound-based approach. A C-arm is an ideal imaging modality for targeting during histotripsy given the dual fluoroscopic and cone-beam CT (CBCT) imaging capabilities. Leveraging the robotic nature of histotripsy, a C-arm can be used to target invisible tumors throughout the body with millimeter-level accuracy.
Additional organs and cancer models It is theoretically possible to use histotripsy in any organ in which enough ultrasound energy can be
applied safely. In addition to liver treatments, our lab has demonstrated the safety and efficacy of treatments in the kidney, spleen, thyroid and subcutaneous fat as potential future treatment targets.8,9
There is ongoing
research at the University of Michigan and Virginia Tech University into treating the heart, prostate, pancreas, brain and musculoskeletal tissue, among others.3
All of the previously
mentioned targetable organs have achieved successful treatments in cancer model studies. Perhaps the most interesting findings noted in these studies are that local tumor control can be achieved with partial treatment of tumors and that the off-target (abscopal) effects of histotripsy equal or exceed that of other local therapies. A study in a rat hepatocellular carcinoma (HCC) model where nine animals underwent complete tumor treatment and six animals had 50–75% of the tumor treated resulted in complete pathologic response in 14/15 animals (5/6 partially treated tumors).10
Another study in a mouse model using both melanoma and HCC cell lines showed that histotripsy caused an intense CD8+ cell infiltration into both the treatment site as well as a second, nontreated tumor. This was compared with both radiofrequency ablation and radiation therapy, with histotripsy being the only modality to demonstrate a significant intratumoral CD8+ cell infiltration at both sites. Histotripsy was also noted to potentiate checkpoint inhibition in these models. Additionally, a melanoma metastasis model was utilized in this study, where histotripsy of a flank tumor resulted in significantly fewer pulmonary metastases following a tail vein injection of a melanoma cell line.11
Human studies Two studies have been completed in humans and two more trials are currently in progress. The first trial treated 25 patients with benign prostatic hyperplasia (NCT01896973) and the second treated eight patients with liver tumors (THERESA: NCT03741088). In the benign prostatic hyperplasia study, the procedure was deemed safe with only a single device-related
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