DESCRIPTION (provided by applicant): Metastatic bone cancer and multiple myeloma affects over 600,000 people every year in the United States and cause progressive bone destruction that results in severe pain, fractures, and the inability to walk. Patients usually present with incapacitating pain secondary to osseous involvement, with or without vertebral collapse, and to spinal cord and/or nerve roots compression, commonly leading to paraplegia and quadriplegia. Conventional therapy consists of bed rest, bracing, anti-inflammatory, or narcotic analgesic medications, and radiation therapy. These conservative options (except radiation therapy) are not dissimilar from the management of osteoporotic compression fractures and are associated with the same type of complications, i.e., atelectasis and pneumonia, deep venous thrombosis and pulmonary embolism. Surgical options are not possible for all patients, but when indicated, they consist of heavy interventions such as corpectomy or cage placement, with significant postprocedural recovery periods and high morbidity and mortality rates in patients who often have limited life expectancies. In addition, multifocal vertebral lesions are common and may contraindicate surgery. Vertebroplasty affects the pain symptom and was not designed to treat cancer. Current options for local treatment of metastatic spine cancer are insufficient. The hypothesis is that thermal ablation with high intensity interstitial ultrasound (HIIU) specifically matched to the tumor size and shape can be safe and efficacious in the management of metastatic spine cancer. We propose to develop a mechanism to perform minimally invasive conformal ultrasound ablation under combined computer tomography (CT) and CT fluoroscopy (CTF) guidance. Our work indicates that this method may provide a consistent, reliable, and safe treatment option in a simple and cost-efficient manner. The unique aspect of our approach is the ability to destruct an asymmetric target volume with a single needle that does not need to be placed in the center of the lesion. Under CT/CTF image guidance, we insert the ablator, localize the ablator with respect to the target zone, and then electronically shape the energy output to conform the target. Thus moderate placement errors can be simply corrected electronically. We also can ablate difficult shapes located nearby sensitive structures. There is a strong clinical need to deliver a means to kill the tumor in a focused and safe way in this sensitive area, protecting the spinal cord, around which the tumor is likely to have caused significant bone destruction already. The ability to conform the energy to the shape of the tumor with a sharply defined fringe field is critical and would add very significant clinical value. This program will develop an integrated instrumentation - ablative treatment delivery system, establish safe and accurate percutaneous HIIU needle placement and tumor ablation under real-time quantitative CT/CTF guidance, develop appropriate clinical workflow, and demonstrate use in clinical application. PUBLIC HEALTH RELEVANCE: Vertebral metastatic disease is the most common malignant disease of the skeletal system and the most common causes of bone destruction in adult patients. Over 600,000 patients per year have progressive bone disease requiring treatment. Progressive bone destruction results in debilitating pain, fractures, and the inability to walk. Traditional techniques have been based on open surgery with potentially substantial surgery-associated morbidity. In addition, many patients may not possess sufficient cardiopulmonary reserve to undergo major spinal procedures. As a result, many of the affected patients are receiving palliative care with only symptomatic treatment of pain and paraparesis or quadriparesis. The first objective in treatment is to alleviate pain and prevent complications such as pathologic fractures, which is especially important in patients with spinal metastasis to avoid instability and neurologic dysfunction. The standard treatments include radiation therapy, surgery, chemotherapy, hormone therapy, and, recently, therapy using systemic radiopharmaceuticals and biphosphonates; radiotherapy remains the treatment of choice. However, the long-term results of these treatments are not satisfying; an effective, minimally invasive local therapy that can be performed at a single outpatient setting would be beneficial. Minimally invasive procedures have been developed to replace standard procedures but most patients still require general and regional anesthesia and the procedures are only moderately minimally invasive. Percutaneous image-guided needle- based surgery is the least invasive mode of intervention practiced today and numerous variations of these techniques have been demonstrated to have high efficacy with low morbidity and low cost across many diseases and organ systems. It is, therefore, a logical imperative to explore percutaneous therapy in the management of metastatic spine cancer. For patients with tumoral spine disease, currently there is no adequate alternative to the immediate pain relief and minimal-invasiveness of percutaneous vertebroplasty. At the same time, however, the mechanism for pain relief in neoplastic lesion is not completely understood, thus vertebroplasty is still debated, and its efficacy has been proven so far on a very limited basis. Besides, the aim of vertebroplasty is pain relief and not eradication of the cancer. Percutaneous vertebroplasty is currently best indicated in patients complaining of a severe, focal, and mechanical back pain related to a neoplastic vertebral collapse without epidural involvement. In our practice, without spinal cord compression or epidural involvement, partial osteolysis of the posterior wall of the vertebral body is not a contraindication [Murphy-2000, Vasconcelos-2002]. Preventive treatment of osteolytic lesions at high risk of vertebral collapse in asymptomatic patients seems to be highly appropriate. Percutaneous vertebroplasty is rarely indicated at the cervical and cervicothoracic junction but may be of value in cases where surgery is contraindicated. These are the patients who would benefit the most from percutaneous US ablation of their bone cancer. Our approach thermal ablation with high intensity interstitial ultrasound (HIIU) specifically matched to the tumor size and shape can be safe and efficacious in the management of metastatic spine cancer. Toward proving this hypothesis, we propose to develop a mechanism to perform minimally invasive conformal ultrasound ablation under combined computer tomography (CT) and CT fluoroscopy (CTF) guidance. In summary, the most unique aspect of HIIU ablation is the ability to destruct an asymmetric target volume with a single needle that does not need to be placed in the center of the lesion. Under intraoperative image guidance, one could insert the ablator to a safe location with respect to the surrounding anatomy, localize the ablator with respect to the target zone, and then electronically shape the energy output to conform the target. This approach will allow for electronic compensation of moderate needle placement errors and for the ablation of difficult shapes located nearby sensitive structures.

Relevance Statement - Project Narrative Vertebral metastatic disease is the most common malignant disease of the skeletal system and the most common causes of bone destruction in adult patients. Over 600,000 patients per year have progressive bone disease requiring treatment. Progressive bone destruction results in debilitating pain, fractures, and the inability to walk. Traditional techniques have been based on open surgery with potentially substantial surgery-associated morbidity. In addition, many patients may not possess sufficient cardiopulmonary reserve to undergo major spinal procedures. As a result, many of the affected patients are receiving palliative care with only symptomatic treatment of pain and paraparesis or quadriparesis. The first objective in treatment is to alleviate pain and prevent complications such as pathologic fractures, which is especially important in patients with spinal metastasis to avoid instability and neurologic dysfunction. The standard treatments include radiation therapy, surgery, chemotherapy, hormone therapy, and, recently, therapy using systemic radiopharmaceuticals and biphosphonates; radiotherapy remains the treatment of choice. However, the long-term results of these treatments are not satisfying; an effective, minimally invasive local therapy that can be performed at a single outpatient setting would be beneficial. Minimally invasive procedures have been developed to replace standard procedures but most patients still require general and regional anesthesia and the procedures are only moderately minimally invasive. Percutaneous image-guided needle- based surgery is the least invasive mode of intervention practiced today and numerous variations of these techniques have been demonstrated to have high efficacy with low morbidity and low cost across many diseases and organ systems. It is, therefore, a logical imperative to explore percutaneous therapy in the management of metastatic spine cancer. For patients with tumoral spine disease, currently there is no adequate alternative to the immediate pain relief and minimal-invasiveness of percutaneous vertebroplasty. At the same time, however, the mechanism for pain relief in neoplastic lesion is not completely understood, thus vertebroplasty is still debated, and its efficacy has been proven so far on a very limited basis. Besides, the aim of vertebroplasty is pain relief and not eradication of the cancer. Percutaneous vertebroplasty is currently best indicated in patients complaining of a severe, focal, and mechanical back pain related to a neoplastic vertebral collapse without epidural involvement. In our practice, without spinal cord compression or epidural involvement, partial osteolysis of the posterior wall of the vertebral body is not a contraindication [Murphy-2000, Vasconcelos-2002]. Preventive treatment of osteolytic lesions at high risk of vertebral collapse in asymptomatic patients seems to be highly appropriate. Percutaneous vertebroplasty is rarely indicated at the cervical and cervicothoracic junction but may be of value in cases where surgery is contraindicated. These are the patients who would benefit the most from percutaneous US ablation of their bone cancer. Our approach thermal ablation with high intensity interstitial ultrasound (HIIU) specifically matched to the tumor size and shape can be safe and efficacious in the management of metastatic spine cancer. Toward proving this hypothesis, we propose to develop a mechanism to perform minimally invasive conformal ultrasound ablation under combined computer tomography (CT) and CT fluoroscopy (CTF) guidance. In summary, the most unique aspect of HIIU ablation is the ability to destruct an asymmetric target volume with a single needle that does not need to be placed in the center of the lesion. Under intraoperative image guidance, one could insert the ablator to a safe location with respect to the surrounding anatomy, localize the ablator with respect to the target zone, and then electronically shape the energy output to conform the target. This approach will allow for electronic compensation of moderate needle placement errors and for the ablation of difficult shapes located nearby sensitive structures.