Predictors of Local Control of Brain Metastasis Treated With Laser Interstitial Thermal Therapy.

BACKGROUND: Laser Interstitial Thermal Therapy (LITT) has been used to treat recurrent brain metastasis after stereotactic radiosurgery (SRS). Little is known about how best to assess the efficacy of treatment, specifically the ability of LITT to control local tumor progression post-SRS. OBJECTIVE: To evaluate the predictive factors associated with local recurrence after LITT. METHODS: Retrospective study with consecutive patients with brain metastases treated with LITT. Based on radiological aspects, lesions were divided into progressive disease after SRS (recurrence or radiation necrosis) and new lesions. Primary endpoint was time to local recurrence. RESULTS: A total of 61 consecutive patients with 82 lesions (5 newly diagnosed, 46 recurrence, and 31 radiation necrosis). Freedom from local recurrence at 6 mo was 69.6%, 59.4% at 12, and 54.7% at 18 and 24 mo. Incompletely ablated lesions had a shorter median time for local recurrence (P < .001). Larger lesions (>6 cc) had shorter time for local recurrence (P = .03). Dural-based lesions showed a shorter time to local recurrence (P = .01). Tumor recurrence/newly diagnosed had shorter time to local recurrence when compared to RN lesions (P = .01). Patients receiving systemic therapy after LITT had longer time to local recurrence (P = .01). In multivariate Cox-regression model, the HR for incomplete ablated lesions was 4.88 (P < .001), 3.12 (P = .03) for recurrent tumors, and 2.56 (P = .02) for patients not receiving systemic therapy after LITT. Complication rate was 26.2%. CONCLUSION: Incompletely ablated and recurrent tumoral lesions were associated with higher risk of treatment failure and were the major predicting factors for local recurrence. Systemic therapy after LITT was a protective factor regarding local recurrence.

Image guidance based on MRI for spinal interstitial laser thermotherapy: technical aspects and accuracy.

OBJECTIVE Image guidance for spinal procedures is based on 3D-fluoroscopy or CT, which provide poor visualization of soft tissues, including the spinal cord. To overcome this limitation, the authors developed a method to register intraoperative MRI (iMRI) of the spine into a neuronavigation system, allowing excellent visualization of the spinal cord. This novel technique improved the accuracy in the deployment of laser interstitial thermal therapy probes for the treatment of metastatic spinal cord compression. METHODS Patients were positioned prone on the MRI table under general anesthesia. Fiducial markers were applied on the skin of the back, and a plastic cradle was used to support the MRI coil. T2-weighted MRI sequences of the region of interest were exported to a standard navigation system. A reference array was sutured to the skin, and surface matching of the fiducial markers was performed. A navigated Jamshidi needle was advanced until contact was made with the dorsal elements; its position was confirmed with intraoperative fluoroscopy prior to advancement into a target in the epidural space. A screenshot of its final position was saved, and then the Jamshidi needle was exchanged for an MRI-compatible access cannula. MRI of the exact axial plane of each access cannula was obtained and compared with the corresponding screenshot saved during positioning. The discrepancy in millimeters between the trajectories was measured to evaluate accuracy of the image guidance RESULTS Thirteen individuals underwent implantation of 47 laser probes. The median absolute value of the discrepancy between the location predicted by the navigation system and the actual position of the access cannulas was 0.7 mm (range 0-3.2 mm). No injury or adverse event occurred during the procedures. CONCLUSIONS This study demonstrates the feasibility of image guidance based on MRI to perform laser interstitial thermotherapy of spinal metastasis. The authors' method permits excellent visualization of the spinal cord, improving safety and workflow during laser ablations in the epidural space. The results can be extrapolated to other indications, including biopsies or drainage of fluid collections near the spinal cord.

Laser Interstitial Thermal Therapy Technology, Physics of Magnetic Resonance Imaging Thermometry, and Technical Considerations for Proper Catheter Placement During Magnetic Resonance Imaging-Guided Laser Interstitial Thermal Therapy.

Laser-induced thermal therapy has become a powerful tool in the neurosurgical armamentarium. The physics of laser therapy are complex, but a sound understanding of this topic is clinically relevant, as many centers have incorporated it into their treatment algorithm, and educated patients are demanding consideration of its use for their disease. Laser ablation has been used for a wide array of intracranial lesions. Laser catheter placement is guided by stereotactic planning; however, as the procedure has popularized, the number of ways in which the catheter can be inserted has also increased. There are many technical nuances for laser placement, and, to date, there is not a clear understanding of whether any one technique is better than the other. In this review, we describe the basic physics of magnetic resonance-guided laser-induced thermal therapy and describe the several common techniques for accurate Visualase laser catheter placement in a stepwise fashion. ABBREVIATIONS: MRg-LITT, magnetic resonance-guided laser-induced thermal therapyPAD, precision aiming device.

Spinal Laser Interstitial Thermal Therapy: A Novel Alternative to Surgery for Metastatic Epidural Spinal Cord Compression.

BACKGROUND: Although surgery followed by radiation effectively treats metastatic epidural compression, the ideal surgical approach should enable fast recovery and rapid institution of radiation and systemic therapy directed at the primary tumor. OBJECTIVE: To assess spinal laser interstitial thermotherapy (SLITT) as an alternative to surgery monitored in real time by thermal magnetic resonance (MR) images. METHODS: Patients referred for spinal metastasis without motor deficits underwent MR-guided SLITT, followed by stereotactic radiosurgery. Clinical and radiological data were gathered prospectively, according to routine practice. RESULTS: MR imaging-guided SLITT was performed on 19 patients with metastatic epidural compression. No procedures were discontinued because of technical difficulties, and no permanent neurological injuries occurred. The median follow-up duration was 28 weeks (range 10-64 weeks). Systemic therapy was not interrupted to perform the procedures. The mean preoperative visual analog scale scores of 4.72 (SD ± 0.67) decreased to 2.56 (SD ± 0.71, P = .043) at 1 month and remained improved from baseline at 3.25 (SD ± 0.75, P = .021) 3 months after the procedure. The preoperative mean EQ-5D index for quality of life was 0.67 (SD ± 0.07) and remained without significant change at 1 month 0.79 (SD ± 0.06, P = .317) and improved at 3 months 0.83 (SD ± 0.06, P = .04) after SLITT. Follow-up MR imaging after 2 months revealed significant decompression of the neural component in 16 patients. However, 3 patients showed progression at follow-up, 1 was treated with surgical decompression and stabilization and 2 were treated with repeated SLITT. CONCLUSION: MR-guided SLITT can be both a feasible and safe alternative to separation surgery in carefully selected cases of spinal metastatic tumor epidural compression. ABBREVIATIONS: cEBRT, conventional external beam radiation therapyESCC, epidural spinal cord compressionSLITT, spinal laser interstitial thermotherapySSRS, stereotactic spinal radiosurgeryVAS, visual analog scale.

Precision Nanomedicine Using Dual PET and MR Temperature Imaging-Guided Photothermal Therapy.

Imaging-based techniques have enabled the direct integration of noninvasive imaging with minimally invasive interventions such as photothermal therapy (PTT) to improve the precision of treatment. METHODS: We investigated the feasibility of PTT for ovarian cancer under the guidance of PET and MR temperature imaging using copper sulfide nanoparticles (CuS NPs). The tumor distribution of the CuS NPs after systemic administration was assessed using highly sensitive, quantifiable PET imaging. Two wavelengths of near-infrared (NIR) lasers-808 and 980 nm-were tested for PTT using noninvasive MR temperature imaging real-time monitoring. RESULTS: The in vivo studies revealed that the 980-nm NIR laser had better photothermal effects than the 808-nm NIR laser. These results were in accord with the histologic findings. In vivo PTT using CuS NPs combined with 980-nm laser irradiation achieved significant tumor ablation compared with no treatment control in both subcutaneous (P = 0.007) and orthotopic (P < 0.001) models of ovarian cancer with regard to the percentage of necrotic damage. CONCLUSION: Our results indicate that real-time monitoring of the accuracy of PTT is a promising approach for future clinical translation of this emerging thermal ablation technique.

Photoacoustic- and Magnetic Resonance-Guided Photothermal Therapy and Tumor Vasculature Visualization Using Theranostic Magnetic Gold Nanoshells.

Nanoparticle based image-guided therapy is an emerging technology for cancer in recent years. Here, we report simultaneous photoacoustic (PA)- and magnetic resonance (MR)-guided photothermal ablation (PTA) therapy using multifunctional superparamagnetic iron oxide-containing gold nanoshells (SPIO@AuNS). Based on the intrinsic high near-infrared optical absorbance and strong magnetic property of SPIO@AuNS, we carried out in vivo dual-modality PA-MR imaging of mouse tumors. PA- and MR-guided imaging can monitor therapeutic effect after photothermal therapy mediated by our multifunctional nanomaterial. In addition, using our pulsed laser PA technique, we also observe a clearer structure of the tumor vasculature after intravenously administration SPIO@AuNS. The novel dual PA-MRI image-guided PTA therapy provides a promising new platform for cancer diagnosis and treatment simultaneously.

Utilization of laser interstitial thermotherapy guided by real-time thermal MRI as an alternative to separation surgery in the management of spinal metastasis.

OBJECT: High-grade malignant spinal cord compression is commonly managed with a combination of surgery aimed at removing the epidural tumor, followed by spinal stereotactic radiosurgery (SSRS) aimed at local tumor control. The authors here introduce the use of spinal laser interstitial thermotherapy (SLITT) as an alternative to surgery prior to SSRS. METHODS: Patients with a high degree of epidural malignant compression due to radioresistant tumors were selected for study. Visual analog scale (VAS) scores for pain and quality of life were obtained before and within 30 and 60 days after treatment. A laser probe was percutaneously placed in the epidural space. Real-time thermal MRI was used to monitor tissue damage in the region of interest. All patients received postoperative SSRS. The maximum thickness of the epidural tumor was measured, and the degree of epidural spinal cord compression (ESCC) was scored in pre- and postprocedure MRI. RESULTS: In the 11 patients eligible for study, the mean VAS score for pain decreased from 6.18 in the preoperative period to 4.27 within 30 days and 2.8 within 60 days after the procedure. A similar VAS interrogating the percentage of quality of life demonstrated improvement from 60% preoperatively to 70% within both 30 and 60 days after treatment. Imaging follow-up 2 months after the procedure demonstrated a significant reduction in the mean thickness of the epidural tumor from 8.82 mm (95% CI 7.38-10.25) before treatment to 6.36 mm (95% CI 4.65-8.07) after SLITT and SSRS (p = 0.0001). The median preoperative ESCC Grade 2 was scored as 4, which was significantly higher than the score of 2 for Grade 1b (p = 0.04) on imaging follow-up 2 months after the procedure. CONCLUTIONS: The authors present the first report on an innovative minimally invasive alternative to surgery in the management of spinal metastasis. In their early experience, SLITT has provided local control with low morbidity and improvement in both pain and the quality of life of patients.

Estimating nanoparticle optical absorption with magnetic resonance temperature imaging and bioheat transfer simulation.

PURPOSE: Optically activated nanoparticle-mediated heating for thermal therapy applications is an area of intense research. The ability to characterise the spatio-temporal heating potential of these particles for use in modelling under various exposure conditions can aid in the exploration of new approaches for therapy as well as more quantitative prospective approaches to treatment planning. The purpose of this research was to investigate an inverse solution to the heat equation using magnetic resonance temperature imaging (MRTI) feedback, for providing optical characterisation of two types of nanoparticles (gold-silica nanoshells and gold nanorods). METHODS: The optical absorption of homogeneous nanoparticle-agar mixtures was measured during exposure to an 808 nm laser using real-time MRTI. A coupled finite element solution of heat transfer was registered with the data and used to solve the inverse problem. The L2 norm of the difference between the temperature increase in the model and MRTI was minimised using a pattern search algorithm by varying the absorption coefficient of the mixture. RESULTS: Absorption fractions were within 10% of literature values for similar nanoparticles. Comparison of temporal and spatial profiles demonstrated good qualitative agreement between the model and the MRTI. The weighted root mean square error was <1.5 σMRTI and the average Dice similarity coefficient for ΔT = 5 °C isotherms was >0.9 over the measured time interval. CONCLUSION: This research demonstrates the feasibility of using an indirect method for making minimally invasive estimates of nanoparticle absorption that might be expanded to analyse a variety of geometries and particles of interest.

Multiparametric fat-water separation method for fast chemical-shift imaging guidance of thermal therapies.

PURPOSE: A k-means-based classification algorithm is investigated to assess suitability for rapidly separating and classifying fat/water spectral peaks from a fast chemical shift imaging technique for magnetic resonance temperature imaging. Algorithm testing is performed in simulated mathematical phantoms and agar gel phantoms containing mixed fat/water regions. METHODS: Proton resonance frequencies (PRFs), apparent spin-spin relaxation (T2*) times, and T1-weighted (T1-W) amplitude values were calculated for each voxel using a single-peak autoregressive moving average (ARMA) signal model. These parameters were then used as criteria for k-means sorting, with the results used to determine PRF ranges of each chemical species cluster for further classification. To detect the presence of secondary chemical species, spectral parameters were recalculated when needed using a two-peak ARMA signal model during the subsequent classification steps. Mathematical phantom simulations involved the modulation of signal-to-noise ratios (SNR), maximum PRF shift (MPS) values, analysis window sizes, and frequency expansion factor sizes in order to characterize the algorithm performance across a variety of conditions. In agar, images were collected on a 1.5T clinical MR scanner using acquisition parameters close to simulation, and algorithm performance was assessed by comparing classification results to manually segmented maps of the fat/water regions. RESULTS: Performance was characterized quantitatively using the Dice Similarity Coefficient (DSC), sensitivity, and specificity. The simulated mathematical phantom experiments demonstrated good fat/water separation depending on conditions, specifically high SNR, moderate MPS value, small analysis window size, and low but nonzero frequency expansion factor size. Physical phantom results demonstrated good identification for both water (0.997 ± 0.001, 0.999 ± 0.001, and 0.986 ± 0.001 for DSC, sensitivity, and specificity, respectively) and fat (0.763 ± 0.006, 0.980 ± 0.004, and 0.941 ± 0.002 for DSC, sensitivity, and specificity, respectively). Temperature uncertainties, based on PRF uncertainties from a 5 × 5-voxel ROI, were 0.342 and 0.351°C for pure and mixed fat/water regions, respectively. Algorithm speed was tested using 25 × 25-voxel and whole image ROIs containing both fat and water, resulting in average processing times per acquisition of 2.00 ± 0.07 s and 146 ± 1 s, respectively, using uncompiled MATLAB scripts running on a shared CPU server with eight Intel Xeon(TM) E5640 quad-core processors (2.66 GHz, 12 MB cache) and 12 GB RAM. CONCLUSIONS: Results from both the mathematical and physical phantom suggest the k-means-based classification algorithm could be useful for rapid, dynamic imaging in an ROI for thermal interventions. Successful separation of fat/water information would aid in reducing errors from the nontemperature sensitive fat PRF, as well as potentially facilitate using fat as an internal reference for PRF shift thermometry when appropriate. Additionally, the T1-W or R2* signals may be used for monitoring temperature in surrounding adipose tissue.

Generalised polynomial chaos-based uncertainty quantification for planning MRgLITT procedures.

PURPOSE: A generalised polynomial chaos (gPC) method is used to incorporate constitutive parameter uncertainties within the Pennes representation of bioheat transfer phenomena. The stochastic temperature predictions of the mathematical model are critically evaluated against MR thermometry data for planning MR-guided laser-induced thermal therapies (MRgLITT). METHODS: The Pennes bioheat transfer model coupled with a diffusion theory approximation of laser tissue interaction was implemented as the underlying deterministic kernel. A probabilistic sensitivity study was used to identify parameters that provide the most variance in temperature output. Confidence intervals of the temperature predictions are compared to MR temperature imaging (MRTI) obtained during phantom and in vivo canine (n = 4) MRgLITT experiments. The gPC predictions were quantitatively compared to MRTI data using probabilistic linear and temporal profiles as well as 2-D 60 °C isotherms. RESULTS: Optical parameters provided the highest variance in the model output (peak standard deviation: anisotropy 3.51 °C, absorption 2.94 °C, scattering 1.84 °C, conductivity 1.43 °C, and perfusion 0.94 °C). Further, within the statistical sense considered, a non-linear model of the temperature and damage-dependent perfusion, absorption, and scattering is captured within the confidence intervals of the linear gPC method. Multivariate stochastic model predictions using parameters with the dominant sensitivities show good agreement with experimental MRTI data. CONCLUSIONS: Given parameter uncertainties and mathematical modelling approximations of the Pennes bioheat model, the statistical framework demonstrates conservative estimates of the therapeutic heating and has potential for use as a computational prediction tool for thermal therapy planning.

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.

Near-infrared light modulated photothermal effect increases vascular perfusion and enhances polymeric drug delivery.

Hyperthermia, which is heating of tumors above 43°C for about 30min, has been known to modulate vascular permeability for enhanced chemotherapy. However, it is not clear whether a similar effect exists when temperature at tumor sites is elevated above 43°C, such as temperature achieved in laser-induced photothermal ablation (PTA) therapy. Also, the effect of timing of chemotherapeutic drug administration following heating in the efficiency of drug delivery is not established. In this study, we investigated the impact of near infrared (NIR) laser irradiated anti-EGFR monoclonal antibody C225-conjugated hollow gold nanospheres (C225-HAuNS) on vascular permeability and subsequent tumor uptake of a water-soluble polymer using combined MRI, ultrasound and optical imaging approaches. Magnetic temperature imaging showed a maximum temperature of 65.2±0.10 °C in A431 tumor xenograft of mice treated with C225-HAuNS plus laser and 47.0±0.33 °C in tumors of mice treated with saline plus laser at 4 W/cm² for 3 min (control) at 2 mm from the light incident surface. Dynamic contrast enhanced (DCE) MRI demonstrated greater than 2-fold increase of DTPA-Gd in the initial area under the curve (IAUC90) in mice injected with C225-HAuNS and exposed to NIR laser compared with control mice at 3 min after laser treatment. Similarly, Power Doppler (PD) ultrasound revealed a 4- to 6-fold increase in percentage vascularization in mice treated with C225-HAuNS plus NIR laser compared to control mice and confirmed increased vascular perfusion immediately after laser treatment. Twenty-four hours later, the blood perfusion was shut down. On optical imaging, tumor uptake of PG-Gd-NIR813, which is the model polymeric drug used, was significantly higher (p-value<0.05) in mice injected with PG-Gd-NIR813 at 5 min after laser treatment than in mice injected with PG-Gd-NIR813 at 24h after laser treatment and the saline-treated mice. In conclusion, laser irradiation of tumors after intravenous injection of C255-HAuNS induces a thermally mediated modulation of the vascular perfusion, which enhances the delivery of polymeric drugs to the tumors at the time phototherapy is initiated.

Quantitative comparison of thermal dose models in normal canine brain.

PURPOSE: Minimally invasive thermal ablative therapies as alternatives to conventional surgical management of solid tumors and other pathologies is increasing owing to the potential benefits of performing these procedures in an outpatient setting with reduced complications and comorbidity. Magnetic resonance temperature imaging (MRTI) measurement allows existing thermal dose models to use the spatiotemporal temperature history to estimate the thermal damage to tissue. However, the various thermal dose models presented in the literature employ different parameters and thresholds, affecting the reliability of thermal dosimetry. In this study, the authors quantitatively compared three thermal dose models (Arrhenius rate process, CEM43, and threshold temperature) using the dice similarity coefficient (DSC). METHODS: The DSC was used to compare the spatial overlap between the region of thermal damage as predicted by the models for in vivo normal canine brain during thermal therapy to the region of thermal damage as revealed by contrast-enhanced T1-weighted images acquired immediately after therapy (< 20 min). The outer edge of the hyperintense rim of the ablation region was used as the surrogate marker for the limits of thermal coagulation. The DSC was also used to investigate the impact of varying the thresholds on each models' ability to predict the zone of thermal necrosis. RESULTS: At previously reported thresholds, the authors found that all three models showed good agreement (defined as DSC > 0.7) with post-treatment imaging. All three models examined across the range of commonly applied thresholds consistently showed highly accurate spatial overlap, low variability, and little dependence on temperature uncertainty. DSC values corresponding to cited thresholds were not significantly different from peak DSC values. CONCLUSIONS: Thus, the authors conclude that the all three thermal dose models can be used as a reliable surrogate for postcontrast tissue damage verification imaging in rapid ablation procedures and can also be used to enhance the capability of MRTI to control thermal therapy in real time.

Modulation of in vivo tumor radiation response via gold nanoshell-mediated vascular-focused hyperthermia: characterizing an integrated antihypoxic and localized vascular disrupting targeting strategy.

We report noninvasive modulation of in vivo tumor radiation response using gold nanoshells. Mild-temperature hyperthermia generated by near-infrared illumination of gold nanoshell-laden tumors, noninvasively quantified by magnetic resonance temperature imaging, causes an early increase in tumor perfusion that reduces the hypoxic fraction of tumors. A subsequent radiation dose induces vascular disruption with extensive tumor necrosis. Gold nanoshells sequestered in the perivascular space mediate these two tumor vasculature-focused effects to improve radiation response of tumors. This novel integrated antihypoxic and localized vascular disrupting therapy can potentially be combined with other conventional antitumor therapies.

Partially parallel imaging with phase-sensitive data: Increased temporal resolution for magnetic resonance temperature imaging.

Magnetic resonance temperature imaging can be used to monitor the progress of thermal ablation therapies, increasing treatment efficacy and improving patient safety. High temporal resolution is important when therapies rapidly heat tissue, but many approaches to faster image acquisition compromise image resolution, slice coverage, or phase sensitivity. Partially parallel imaging techniques offer the potential for improved temporal resolution without forcing such concessions. Although these techniques perturb image phase, relative phase changes between dynamically acquired phase-sensitive images, such as those acquired for MR temperature imaging, can be reliably measured through partially parallel imaging techniques using reconstruction filters that remain constant across the series. Partially parallel and non-accelerated phase-difference-sensitive data can be obtained through arrays of surface coils using this method. Average phase differences measured through partially parallel and fully Fourier encoded images are virtually identical, while phase noise increases with g(sqrt)L as in standard partially parallel image acquisitions..

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

PURPOSE: 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. MATERIALS AND METHODS: Small, ellipsoidal ablations at shallow depth were created using 5- to 15-second sonication pulses at radio frequency (RF) powers of 50-125 W using a spherical, air-backed transducer operating at 1.463 MHz under MR guidance in a 1.5-T clinical scanner. RESULTS: Excellent correlation was observed between prescribed treatment volumes, MR thermal dosimetry, post-treatment verification MRI, and histopathology. Multifocal ablations of VX2 tumors in rabbits at depths of up to 2.5 cm resulted in complete ablation of the prescribed treatment volume. CONCLUSION: MRgFUS is an effective technique for treating tumors in vivo. Techniques developed for treatments in homogeneous tissue volumes are applicable in the more complicated tumor environment if MR temperature feedback is available to modify treatment delivery parameters.