Key Points
- A Foundation-funded preclinical study tested how different histotripsy doses affected liver tumors.
- The highest dose did not work best, suggesting that treatment may need to be tailored to each tumor.
Since its development at the University of Michigan more than two decades ago, histotripsy has progressed from an experimental method for mechanically destroying tissue to a US Food and Drug Administration (FDA)–cleared treatment for liver tumors. The noninvasive technique uses short, high-pressure ultrasound pulses to generate microscopic bubble clouds that break apart targeted tissue without heat. Now that histotripsy has reached clinical use, researchers are turning to a more precise question: What treatment parameters achieve the best results? Current clinical protocols use a fixed number of ultrasound pulses selected to ensure tumor destruction, but tumors vary in size, stiffness, and composition. Identifying optimal treatment parameters will help clinicians destroy tumors more effectively while also supporting favorable immune responses and avoiding overtreatment.
Source: https://www.nature.com/articles/s41598-026-48331-7
Dose Comparison Studies
In a preclinical study published in Scientific Reports, research led by Tejaswi Worlikar, PhD, tested several histotripsy doses in a rat model of hepatocellular carcinoma (a common form of liver cancer). The team treated smaller, intermediate-stage tumors and larger, late-stage tumors with doses ranging from undertreatment to overtreatment. Although increasing the number of pulses produced greater cellular destruction, the highest dose (overtreatment) did not actually produce the best results. Smaller tumors had the highest rate of complete regression with a lower dose, while larger tumors responded best to an intermediate dose, likely because smaller tumors can be less stiff compared to larger tumors. Softer tissues generally require lower doses for ablation compared to stiffer tissues The intermediate dose also produced the strongest immune response in the late-stage tumors: the infiltration of T cells and natural killer cells into untreated portions of partially treated tumors.
Abscopal Effect Studies
In another experiment, the researchers created tumors in two separate liver lobes but treated only one. At the more effective intermediate dose, both tumors completely regressed in 90% of the animals, compared with 54.5% at the lower dose. These findings suggest an abscopal effect, in which treating one tumor stimulates a response against cancer elsewhere in the body. Overall survival was higher in animals treated with the intermediate dose, although the immune response between the two dose groups was not statistically significant.
“Our results suggest that the most effective histotripsy dose may depend on the mechanical characteristics and stage of each tumor,” said Dr. Worlikar. “Delivering additional pulses after the target tissue has been completely disrupted may increase treatment time and tissue damage without improving tumor control or immune activation.”
Although the doses used in this study cannot be directly translated to patients, it supports further research into personalized histotripsy treatment planning.
Next Steps
The researchers are now investigating feedback methods that could help determine when an individual tumor has received enough treatment. Ultimately, this work could support a shift from fixed dosing toward treatments tailored to the physical and biological characteristics of each tumor.
Dr. Worlikar also recently launched a new Foundation-funded project titled, “Histotripsy-Induced Local and Abscopal Responses in Hepatocellular Carcinoma: Molecular Mechanisms and Synergistic Potential with Immunotherapy.”
The published study was supported in part by the Focused Ultrasound Foundation. Additional funding was provided by the University of Michigan Rogel Cancer Center, a Li Ka Shing Foundation grant, and the National Institutes of Health.
Read “Histotripsy Dose Impacts Tumor Cellular Damage and Treatment Outcomes in a Preclinical Model of Hepatocellular Carcinoma” in Scientific Reports