Histotripsy Group
    Biomedical Engineering Department, University of Michigan




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Clinical Applications -> Urology

Urology


Benign prostatic hyperplasia (BPH)
BPH is a common pathological finding in older men that produces difficulty with urination. Treatment for BPH must be tailored for each patient, based on severity of symptoms, tolerance of risks, and anatomical considerations, as no single modality is ideal. The most effective treatment, transurethral resection of the prostate (TURP), is also the most invasive and carries the highest risk of complications. Less invasive alternatives have been developed that destroy prostate tissue by delivery of thermal energy resulting in coagulative necrosis of the prostate tissue. Although complication rates are lower than TURP, these therapies are less effective. Pharmacologic therapy is frequently used as first line management for patients with mild urinary symptoms. However, the cost of medication and progression of BPH drive many patients toward more definitive therapies. Prostatic histotripsy may offer many advantages over the existing treatment modalities for BPH. We believe that non-invasive prostate de-bulking can be achieved with acoustic cavitation to producing mechanical tissue ablation (histotripsy). Preliminary results of histotripsy transcutaneous ablation of normal prostate tissue in a canine model are very promising. Within the target zone, a cavity is produced that contains a liquefied core with smooth walls and sharply demarcated boundaries. Histology demonstrates extensive areas of acellular debris with no remaining cellular structure, surrounded by an almost imperceptibly narrow margin of cellular injury. Additional advantage of histotripsy is its ability to clearly see tissue damage during or after treatment, a goal never attained by thermal therapy.



Prostate Cancer
Widespread prostate cancer screening in the United States has resulted in earlier diagnosis of prostate cancers in men who are younger and healthier than in the past. Many of these men will select treatment in the form of radical prostatectomy with the associated risks of impotence and incontinence. To this end there exists a need for a non-invasive technology capable of precise prostate tissue ablation without injury to adjacent critical structures. Our goal is to develop histotripsy into a non-invasive ultrasound procedure for precise prostate tissue ablation and treatment of early stage prostate cancer. We have developed and tested a novel non-invasive ultrasonic technology that utilizes pulsed, focused ultrasound to generate non-thermal mechanical effects within a targeted tissue volume. We call this technology soft tissue lithotripsy, or "histotripsy". Preliminary results of transcutaneous ablation of normal prostate tissue in a canine model are very promising. Within the target zone, a cavity is produced that contains a liquefied core with smooth walls and sharply demarcated boundaries. Histology demonstrates extensive areas of acellular debris with no remaining cellular structure, surrounded by an almost imperceptibly narrow margin of cellular injury. This extremely sharp transition zone, impossible with thermal therapy, may facilitate complete prostate ablation with preservation of the vital neurovascular bundle and urinary sphincter (damage to which can result in impotence and urinary incontinence). The probability of attaining this goal is also enhanced by the demonstrated ability to clearly see this tissue damage boundary during or after the histotripsy procedure, a goal never attained by thermal therapy.



Renal Tumors
It is estimated that approximately 50,000 patients in the United States are diagnosed with renal cancer annually [1]. As a result of the widespread use of cross-sectional imaging, many of these renal tumors are now being identified when of smaller size and at an earlier stage of disease than in the past. As such, many of these tumors are amenable to newer minimally-invasive ablative therapies which are less morbid alternatives to traditional surgical therapy (radical or partial nephrectomy). Radiofrequency ablation (RFA) and cryoablation are technologies in current clinical use for treatment of small (< 4 cm) renal masses. Ablation is typically performed in a minimally invasive fashion with either a laparoscopic or percutaneous approach.

With RFA, a probe is inserted into the mass within the kidney and multiple tines are advanced from the tip of the probe throughout the targeted volume. Alternating electrical current flows from the tip of each tine to a grounding pad affixed to the patient. Resistive and frictional heating of tissues produces coagulative necrosis in those regions where a sufficient thermal dose is deposited. Electrical current delivery is modulated by either temperature-based feedback from thermocouples or impedance measurement. Because tissue temperatures are notoriously difficult to image, the tines are positioned to incorporate and treat a 5 mm margin of normal tissue around the mass.

Cryoablation is performed by inserting one or several cryoprobes into the targeted volume. Compressed argon gas circulated through channels within the probe produces supercooling of the probe tip to -160 C. A volume of tissue is cooled to below -40 C and then allowed to thaw before a second freeze cycle is applied. During freezing, an ice ball demarcating the 0 C isotherm can be imaged with ultrasound and is typically made to extend up to 1 cm beyond the tumor to ensure adequate treatment of the targeted zone.

There are a number of factors that can contribute to incomplete tumor ablation, such as error in probe positioning, variations in technique, inhomogeneous tissue heating/cooling, variable blood perfusion resulting in heat sink effects, and changing tissue characteristics during treatment [2,3]. An analysis of data from published series in the literature found a 7.9% rate of persistent or recurrent disease at a mean follow up of 10 months for RFA and a 4.6% rate of persistent or recurrent disease with a mean follow up of 30.8 months for cryoablation [4] demonstration the need for accurate post treatment surveillance.

For extirpative surgical procedures, pathologic confirmation of complete tumor resection is possible. However, for minimally invasive procedures, assessment of residual or recurrent tumor in ablated lesions is limited to imaging evaluation and biopsy. Use of biopsy to assess tumor viability is subject to sampling error and identification of viable tumor on surveillance imaging is confounded by a persisting mass of ablated tissue. In a comparative study at the Cleveland Clinic, RFA lesions did not decrease in size up to 2 years after ablation and an average 68% of the volume of cryolesions was still present at 2 years [5]. Radiologic evidence of residual or recurrent disease was found in 11.1% of percutaneous RFA and 1.8% of laparoscopic cryoablation cases [5].

By treating tissues with histotripsy (very intense, short ultrasound pulses at a low duty cycle) we have been able to induce cavitational tissue effects with a negligible thermal component in tissue and in-vivo models. Histotripsy offers the potential advantages of being a non-invasive therapy with real-time imaging feedback to facilitate targeting and assessment of complete treatment.


References

1. A. Jemal, R. Siegel, E. Ward, et al. "Cancer Statistics, 2007". CA Cancer J. Clin., vol. 57, pp. 43-66, 2007.

2. M. Ahmed, Z. Liu, K. S. Afzal, D. Weeks, S. M. Lobo, J. B. Kruskal, et al. "Radiofrequency ablation: effect of surrounding tissue composition on coagulation necrosis in a canine tumor model," Radiology, vol. 230, pp. 761-767, 2004.

3. I. Chang, I Mikityansky, D. Wray-Cahen, W. F. Pritchard, J. W. Karanian, B. J. Wood. "Effects of perfusion on radiofrequency ablation in swine kidneys," Radiology, vol. 231, pp. 500-505, 2004.

4. K. J. Weld and J. Landman. "Comparison of cryoablation, radiofrequency ablation and high-intensity focused ultrasound for treating small renal tumors." BJU International, vol. 96, pp. 1224-1229, 2005.

5. N. J. Hegarty, I. S. Gill, M. M. Desai, E. M. Remer, C. M. O'Malley, J. H. Kaouk. "Probe-Ablative Nephron-Sparing Surgery: Cryablation versus Radiofrequency Ablation," Urology, vol. 68 (suppl. 1A), pp. 7-13, 2006.