R. Jason Stafford

ELASTOGRAPHIC CHARACTERIZATION OF HIFU-INDUCED LESIONS IN CANINE LIVERS

The elastographic visualization and evaluation of high-intensity focused ultrasound (HIFU)-induced lesions were investigated. The lesions were induced in vitro in freshly excised canine livers. The use of different treatment intensity levels and exposure times resulted in lesions of different sizes. Each lesion was clearly depicted by the corresponding elastogram as being an area harder than the background. The strain contrast of the lesion/background was found to be dependent on the level of energy deposition. A lesion/background strain contrast between -2.5 dB and -3.5 dB was found to completely define the entire zone of tissue damage. The area of tissue damage was automatically estimated from the elastograms by evaluating the number of pixels enclosed inside the isointensity contour lines corresponding to a strain contrast of -2.5, -3 and -3.5 dB. The area of the lesion was measured from a tissue photograph obtained at approximately the same plane where elastographic data were collected. The estimated lesion areas ranged between approximately 10 mm2 and 110 mm2. A high correlation between the damaged areas as depicted by the elastograms and the corresponding areas as measured from the gross pathology photographs was found (r2 = 0.93, p value < 0.0004, n = 16). This statistically significant high correlation demonstrates that elastography has the potential to become a reliable and accurate modality for HIFU therapy monitoring.

Real-time magnetic resonance-guided laser thermal therapy for focal metastatic brain tumors.

OBJECTIVE We report the initial results of a pilot clinical trial exploring the safety and feasibility of the first real-time magnetic resonance-guided laser-induced thermal therapy of treatment-resistant focal metastatic intracranial tumors. METHODS Patients with resistant metastatic intracranial tumors who had previously undergone chemotherapy, whole-brain radiation therapy, and radiosurgery and who were recused from surgery were eligible for this trial. Under local anesthesia, a Leksell stereotactic head frame was used to insert a water-cooled interstitial fiberoptic laser applicator inside the cranium. In the bore of a magnetic resonance imaging (MRI) scanner, laser energy was delivered to heat the tumor while continuous MRI was performed. A computer workstation extracted temperature-sensitive information to display images of laser heating and computed estimates of the thermal damage zone. Posttreatment MRI scans were used to confirm the zone of thermal necrosis, and follow-up was performed at 7, 15, 30, and 90 days after treatment. RESULTS In all cases, the procedure was well tolerated without secondary effect, and patients were discharged to home within 14 hours after the procedure. Follow-up imaging showed an acute increase in apparent lesion volume followed by a gradual and steady decrease. No tumor recurrence within thermal ablation zones was noted. CONCLUSION In this ongoing trial, a total of four patients have had six metastatic tumors treated with laser thermal ablations. Magnetic resonance-guided laser-induced thermal therapy appears to provide a new, efficient treatment for recurrent focal metastatic brain disease. This therapy is a prelude to the future development of closed-head interventional MRI techniques in neurosurgery.

Feasibility Study of Particle-Assisted Laser Ablation of Brain Tumors in Orthotopic Canine Model

We report on a pilot study showing a proof of concept for the passive delivery of nanoshells to an orthotopic tumor where they induce a local, confined therapeutic response distinct from that of normal brain resulting in the photothermal ablation of canine transmissible venereal tumor (cTVT) in a canine brain model. cTVT fragments grown in severe combined immunodeficient mice were successfully inoculated in the parietal lobe of immunosuppressed, mixed-breed hound dogs. A single dose of near-IR (NIR)-absorbing, 150-nm nanoshells was infused i.v. and allowed time to passively accumulate in the intracranial tumors, which served as a proxy for an orthotopic brain metastasis. The nanoshells accumulated within the intracranial cTVT, suggesting that its neovasculature represented an interruption of the normal blood-brain barrier. Tumors were thermally ablated by percutaneous, optical fiber-delivered, NIR radiation using a 3.5-W average, 3-minute laser dose at 808 nm that selectively elevated the temperature of tumor tissue to 65.8 +/- 4.1 degrees C. Identical laser doses applied to normal white and gray matter on the contralateral side of the brain yielded sublethal temperatures of 48.6 +/- 1.1 degrees C. The laser dose was designed to minimize thermal damage to normal brain tissue in the absence of nanoshells and compensate for variability in the accumulation of nanoshells in tumor. Postmortem histopathology of treated brain sections showed the effectiveness and selectivity of the nanoshell-assisted thermal ablation.

Effects of photoacoustic imaging and photothermal ablation therapy mediated by targeted hollow gold nanospheres in an orthotopic mouse xenograft model of glioma

Advancements in nanotechnology have made it possible to create multifunctional nanostructures that can be used simultaneously to image and treat cancers. For example, hollow gold nanospheres (HAuNS) have been shown to generate intense photoacoustic signals and induce efficient photothermal ablation (PTA) therapy. In this study, we used photoacoustic tomography, a hybrid imaging modality, to assess the intravenous delivery of HAuNS targeted to integrins that are overexpressed in both glioma and angiogenic blood vessels in a mouse model of glioma. Mice were then treated with near-infrared laser, which elevated tumor temperature by 20.7°C. We found that PTA treatment significantly prolonged the survival of tumor-bearing mice. Taken together, these results show the feasibility of using a single nanostructure for image-guided local tumor PTA therapy with photoacoustic molecular imaging.

The feasibility of elastographic visualization of HIFU-induced thermal lesions in soft tissues

The potential for visualizing high-intensity focused ultrasound (HIFU)-induced thermal lesions in biological soft tissues in vitro using elastography was investigated. Thermal lesions were created in rabbit paraspinal skeletal muscle in vivo. The rabbits were sacrificed 60 h following the treatment and lesioned tissues were excised. The tissues were cast in a block of clear gel and elastographic images of the lesions were acquired. Gross pathology of the tissue samples confirmed the characteristics of the lesions.The potential for visualizing high-intensity focused ultrasound (HIFU)-induced thermal lesions in biological soft tissues in vitro using elastography was investigated. Thermal lesions were created in rabbit paraspinal skeletal muscle in vivo. The rabbits were sacrificed 60 h following the treatment and lesioned tissues were excised. The tissues were cast in a block of clear gel and elastographic images of the lesions were acquired. Gross pathology of the tissue samples confirmed the characteristics of the lesions.

Laser thermal therapy: Real‐time MRI‐guided and computer‐controlled procedures for metastatic brain tumors

We report the final results of a pilot clinical trial exploring the safety and feasibility of real‐time magnetic resonance‐guided laser‐induced thermal therapy (MRgLITT) for treatment of resistant focal metastatic intracranial tumors.

Imaging bone metastases in breast cancer: techniques and recommendations for diagnosis

Bone is the most common site of distant metastases from breast carcinoma. The presence of bone metastases affects a patients prognosis, quality of life, and the planning of their treatment. We discuss recent innovations in bone imaging and present algorithms, based on the strengths and weaknesses of each technique, to facilitate the most successful and cost-effective choice of imaging studies for the detection of osseous metastases. Skeletal scintigraphy (bone scan) is very sensitive in the detection of osseous metastases and is recommended as the first imaging study in patients who are asymptomatic. Radiographs are recommended for the assessment of abnormal radionuclide uptake or the risk of pathological fracture and as initial imaging studies in patients with bone pain. MRI or PET-CT can be considered for cases of abnormal radionuclide uptake that are not addressed by radiography. Osseous metastases can lead to emergent situations, such as spinal-cord compression or impending fracture of a weight-bearing bone, and imaging guidelines are essential for early detection and initiation of appropriate therapy. The imaging method used in non-emergent situations, such as assessment of the ribs, sternum, pelvis, hips, and joints, should be guided by the strengths and limitations of each technique.

MRI-guided thermal therapy of transplanted tumors in the canine prostate using a directional transurethral ultrasound applicator

To evaluate MRI‐based techniques for visual guidance, thermal monitoring, and assessment during transurethral ultrasound thermal therapy of implanted tumors in an in vivo canine prostate model.

Magnetic resonance imaging-guided focused ultrasound thermal therapy in experimental animal models: Correlation of ablation volumes with pathology in rabbit muscle and VX2 tumors

To further investigate the use of magnetic resonance‐guided focused ultrasound therapy (MRgFUS) as a noninvasive alternative to surgery in the local control of soft‐tissue tumors by ablating prescribed volumes of VX2 rabbit tumors and comparing with ablation of normal tissue volumes.

Targeted multifunctional gold-based nanoshells for magnetic resonance-guided laser ablation of head and neck cancer

Image-guided thermal ablation of tumors is becoming a more widely accepted minimally invasive alternative to surgery for patients who are not good surgical candidates, such as patients with advanced head and neck cancer. In this study, multifunctional superparamagnetic iron oxide coated with gold nanoshell (SPIO@Au NS) that have both optical and magnetic properties was conjugated with the targeting agent, C225 monoclonal antibody, against epidermal growth factor receptor (EGFR). C225-SPIO@Au NS have an average a diameter of 82 ± 4.4 nm, contain 142 ± 15 antibodies per nanoshell, have an absorption peak in the near infrared (~800 nm), and have transverse relaxivity (r(2)) of 193 and 353 mM(-1) s(-1) versus Feridex™ of 171 and 300 mM(-1) s(-1), using 1.5 T and 7 T MR scanners, respectively. Specific targeting of the synthesized C225-SPIO@Au NS was tested in vitro using A431 cells and oral cancer cells, FaDu, OSC19, and HN5, all of which overexpress EGFR. Selective binding was achieved using C225-SPIO@Au NS but not with the non-targeting PEG-SPIO@Au NS and blocking group (excess of C225 + C225-SPIO@Au NS). In vivo biodistribution on mice bearing A431 tumors also showed selective targeting of C225-SPIO@Au NS compared with the non-targeting and blocking groups. The selective photothermal ablation of the nanoshells shows that without laser treatment there were no cell death and among the groups that were treated with laser at a power of 36 W/cm(2) for 3 min, only the cells treated with C225-SPIO@Au NS had cell killing (p < 0.001). In summary, successful synthesis and characterization of targeted C225-SPIO@Au NS demonstrating both superparamagnetic and optical properties has been achieved. We have shown both in vitro and in vivo that these nanoshells are MR-active and can be selectively heated up for simultaneous imaging and photothermal ablation therapy.