Image-based personalization of computational models for predicting response of high-grade glioma to chemoradiation.

High-grade gliomas are an aggressive and invasive malignancy which are susceptible to treatment resistance due to heterogeneity in intratumoral properties such as cell proliferation and density and perfusion. Non-invasive imaging approaches can measure these properties, which can then be used to calibrate patient-specific mathematical models of tumor growth and response. We employed multiparametric magnetic resonance imaging (MRI) to identify tumor extent (via contrast-enhanced T1-weighted, and T2-FLAIR) and capture intratumoral heterogeneity in cell density (via diffusion-weighted imaging) to calibrate a family of mathematical models of chemoradiation response in nine patients with unresected or partially resected disease. The calibrated model parameters were used to forecast spatially-mapped individual tumor response at future imaging visits. We then employed the Akaike information criteria to select the most parsimonious member from the family, a novel two-species model describing the enhancing and non-enhancing components of the tumor. Using this model, we achieved low error in predictions of the enhancing volume (median: - 2.5%, interquartile range: 10.0%) and a strong correlation in total cell count (Kendall correlation coefficient 0.79) at 3-months post-treatment. These preliminary results demonstrate the plausibility of using multiparametric MRI data to inform spatially-informative, biologically-based predictive models of tumor response in the setting of clinical high-grade gliomas.

Detection of Glioblastoma Subclinical Recurrence Using Serial Diffusion Tensor Imaging.

Glioblastoma is an aggressive brain tumor with a propensity for intracranial recurrence. We hypothesized that tumors can be visualized with diffusion tensor imaging (DTI) before they are detected on anatomical magnetic resonance (MR) images. We retrospectively analyzed serial MR images from 30 patients, including the DTI and T1-weighted images at recurrence, at 2 months and 4 months before recurrence, and at 1 month after radiation therapy. The diffusion maps and T1 images were deformably registered longitudinally. The recurrent tumor was manually segmented on the T1-weighted image and then applied to the diffusion maps at each time point to collect mean FA, diffusivities, and neurite density index (NDI) values, respectively. Group analysis of variance showed significant changes in FA (p = 0.01) and NDI (p = 0.0015) over time. Pairwise t tests also revealed that FA and NDI at 2 months before recurrence were 11.2% and 6.4% lower than those at 1 month after radiation therapy (p < 0.05), respectively. Changes in FA and NDI were observed 2 months before recurrence, suggesting that progressive microstructural changes and neurite density loss may be detectable before tumor detection in anatomical MR images. FA and NDI may serve as non-contrast MR-based biomarkers for detecting subclinical tumors.

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.

MR temperature imaging of nanoshell mediated laser ablation.

Minimally invasive thermal therapy using high-power diode lasers is an active area of clinical research. Gold nanoshells (AuNS) can be tuned to absorb light in the range used for laser ablation and may facilitate more conformal tumor heating and sparing of normal tissue via enhanced tumor specific heating. This concept was investigated in a xenograft model of prostate cancer (PC-3) using MR temperature imaging (MRTI) in a 1.5T scanner to characterize the spatiotemporal temperature distribution resulting from nanoparticle mediated heating. Tumors with and without intravenously injected AuNS were exposed to an external laser tuned to 808 nm for 180 sec at 4 W/cm(2) under real-time monitoring with proton resonance frequency shift based MRTI. Microscopy indicated that these nanoparticles (140-150 nm) accumulated passively in the tumor and remained close to the tumor microvasculature. MRTI measured a statistically significant (p < 0.001) increase in maximum temperature in the tumor cortex (mean = 21 ± 7°C) in +AuNS tumors versus control tumors. Analysis of the temperature maps helped demonstrate that the overall distribution of temperature within +AuNS tumors was demonstrably higher versus control, and resulted in damage visible on histopathology. This research demonstrates that passive uptake of intravenously injected AuNS in PC-3 xenografts converts the tumor vasculature into a potent heating source for nanoparticle mediated ablation at power levels which do not generate significant damage in normal tissue. When used in conjunction with MRTI, this has implications for development and validation of more conformal delivery of therapy for interstitial laser ablations.

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.

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.

Measurement of temperature dependent changes in bone marrow using a rapid chemical shift imaging technique.

PURPOSE: To provide quantitative temperature monitoring for thermal therapies in bone marrow by measuring temperature-dependent signal changes in the bone marrow of ex vivo canine femurs heated with a 980-nm laser at 1.5T and 3.0T. MATERIALS AND METHODS: Using a multi-gradient echo (≤ 16) acquisition and signal modeling with the Stieglitz-McBride algorithm, the temperature sensitivity coefficients (TSC, ppm/°C) of water and multiple lipid components' proton resonance frequency (PRF) values are measured at high spatiotemporal resolutions (1.6 × 1.6 × 4 mm(3) , ≤ 5 seconds). Responses in R(2) * and amplitudes of each peak were also measured as a function of temperature simultaneously. RESULTS: Calibrations demonstrate that lipid signal may be used to compensate for B(0) errors to provide accurate temperature readings (<1.0°C). Over a temperature range of 17.2-57.2°C, the TSCs after correction to a bulk methylene reference are -0.87 × 10(-2) ± 4.7 × 10(-4) ppm/°C and -0.87 × 10(-2) ± 4.0 × 10(-4) ppm/°C for 1.5T and 3.0T, respectively. CONCLUSION: Overall, we demonstrate that accurate and precise temperature measurements can be made in bone marrow. In addition, the relationship of R(2) * and signal amplitudes with respect to temperature are shown to differ significantly where conformal changes are predicted by Arrhenius rate model analysis.

Anisotropy characterization of I-125 seed with attached encapsulated cobalt chloride complex contrast agent markers for MRI-based prostate brachytherapy.

We have developed a novel MRI marker for prostate brachytherapy. The purpose of this study was to evaluate the changes in anisotropy when cobalt chloride complex contrast agent encapsulated contrast agent markers (C4-ECAM) were placed adjacent to an iodine-125 (I-125) titanium seed, and to verify that the C4-ECAMs were visible on magnetic resonance imaging (MRI) after radiation exposure. Two C4-ECAMs were verified to be MRI visible in a phantom before radiation exposure. The C4-ECAMs were then attached to each end of a 12.7-U (10-mCi) I-125 titanium seed in a polymer tube. Anisotropy was measured and analyzed with the seed alone and with attached C4-ECAMs by suspending thermoluminescent dosimeters in a water phantom in 2 circles surrounding the radioactive source with radius of 1 or 2 cm. A T1-weighted MRI evaluation of C4-ECAMs was then performed after exposure to the amount of radiation typically delivered during 1 month of prostate brachytherapy. Measured values of the anisotropy function F(r, θ) for the I-125 seed with and without the C4-ECAMs were mutually statistically indistinguishable (standard error of the mean <4.2%) and agreed well with published TG-43 values for the bare seed. As expected, the anisotropy function ϕ(an)(r) for the 2 datasets (with and without C4-ECAMs) derived from the measured F(r, θ) did not exhibit statistically measurable difference. Both datasets showed agreement with the published TG-43 ϕ(an)(r) for the bare seed. The C4-ECAMs were well visualized by MRI after 1 month of radiation exposure. There were no changes in anisotropy when the C4-ECAMs were placed next to an I-125 radioactive seed, and the C4-ECAMs were visualized after radiation exposure.

Magnetic resonance guided, focal laser induced interstitial thermal therapy in a canine prostate model.

PURPOSE: We evaluated a newly Food and Drug Administration cleared, closed loop, magnetic resonance guided laser induced interstitial thermal therapy system for targeted ablation of prostate tissue to assess the feasibility of targeting, real-time monitoring and predicting lesion generation in the magnetic resonance environment. MATERIALS AND METHODS: Seven mongrel dogs (University of Texas Health Science Center, Houston, Texas) with (2) and without (5) canine transmissible venereal tumors in the prostate were imaged with a 1.5 T magnetic resonance imaging scanner. Real-time 3-dimensional magnetic resonance imaging was used to accurately position water cooled, 980 nm laser applicators to predetermined targets in the canine prostate. Destruction of targeted tissue was guided by real-time magnetic resonance temperature imaging to precisely control thermal ablation. Magnetic resonance predictions of thermal damage were correlated with posttreatment imaging results and compared to histopathology findings. RESULTS: Template based targeting using magnetic resonance guidance allowed the laser applicator to be placed within a mean ± SD of 1.1 ± 0.7 mm of the target site. Mean width and length of the ablation zone on magnetic resonance imaging were 13.7 ± 1.3 and 19.0 ± 4.2 mm, respectively, using single and compound exposures. The damage predicted by magnetic resonance based thermal damage calculations correlated with the damage on posttreatment imaging with a slope near unity and excellent correlation (r(2) = 0.94). CONCLUSIONS: This laser induced interstitial thermal therapy system provided rapid, localized tissue heating under magnetic resonance temperature imaging control. Combined with real-time monitoring and template based planning, magnetic resonance guided, laser induced interstitial thermal therapy is an attractive modality for prostate cancer focal therapy.

Use of gold nanoshells to constrain and enhance laser thermal therapy of metastatic liver tumours.

PURPOSE: To investigate the impact of intravenously injected gold nanoparticles on interstitially delivered laser induced thermal therapy (LITT) in the liver. METHODS: 3D finite element modelling, ex vivo canine liver tissue containing gold nanoparticles absorbing at 800 nm, and agar gel phantoms were used to simulate the presence of nanoparticles in the liver during LITT. Real-time magnetic resonance temperature imaging (MRTI) based on the temperature sensitivity of the proton resonance frequency shift (PRFS) was used to map the spatiotemporal distribution of heating in the experiments and validate the predictions of 3D finite element simulations of heating. RESULTS: Experimental results show good agreement with both the simulation and the ex vivo experiments. Average discrepancy between simulation and experiment was shown to be 1.6 degrees C or less with the maximum difference being 3.8 degrees C due to a small offset in laser positioning. CONCLUSION: A high nanoshell concentration in the surrounding liver parenchyma, such as that which would be expected from an intravenous injection of gold nanoshells ( approximately 120 nm) acts as both a beam stop for the laser and secondary heat source for the treatment, helping to better heat the lesions and confine the treatment to the lesion. This indicates a potential to use nanoparticles to enhance both the safety and efficacy of LITT procedures in the liver.

Quantitative comparison of delta P1 versus optical diffusion approximations for modeling near-infrared gold nanoshell heating.

Laser induced thermal therapy combined with the wavelength dependent optical absorption and heating power of gold-coated silica nanoshells can achieve therapeutic heating localized to a tumor volume. Accurate modeling of the spatiotemperal thermal distribution associated with this heating is essential for accurate thermal therapy treatment planning. The optical diffusion approximation (ODA), used in numerous applications of laser fluence in biology, is compared to the delta P1 optical approximation in phantoms containing different concentrations of nanoshells for several laser powers. Results are compared with temperature maps generated by magnetic resonance temperature imaging techniques and show that the delta P1 approximation is more effective than ODA at modeling the thermal distribution. The discrepancy between the two is especially prominent in phantoms with higher nanoshell concentrations where ODA was shown to give unsatisfactory results.

Dynamic chemical shift imaging for image-guided thermal therapy: analysis of feasibility and potential.

A fast chemical shift imaging (CSI) technique based on a multiple gradient-recalled acquisition using a small number of echoes with intentional aliasing of the reference lipid peak is studied to determine its feasibility for temperature monitoring. Simulations were implemented to find parameters where the lipid and water peaks can be measured using a Fourier-based peak fitting approach as well as using an innovative autoregressive moving average technique. A phantom consisting of 50% mayonnaise/50% lemon juice was calibrated to temperature and compared to literature values. A porcine kidney was treated ex vivo with an external laser and imaged with the CSI technique with comparisons to temperature readings from a fluoroptic monitoring system and complex phase difference (CPD) calculations. To demonstrate the technique in vivo, a Balb/c mouse with a CT26 xenograft in the subcutaneous lower back was treated using gold-coated, silica-core nanoshells heated with an 808 nm interstitial laser. Compared to standard CPD techniques using a two-dimensional fast spoiled gradient recalled echo, this technique maintains spatiotemporal resolution, has high signal-to-noise ratio and accuracy over a wide range of T2* tissue values, can separate water and lipid signals, and additionally can use the lipid peak, when present, as an internal reference.

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.

Magnetic resonance imaging assessment of a convective therapy delivery paradigm in a canine prostate model.

PURPOSE: To quantitatively investigate the feasibility of MRI as a tool for assessing the spatial distribution of a convectively delivered agent using a canine prostate model. MATERIALS AND METHODS: Canine prostates (ex vivo, n = 3; in vivo, n = 12) were injected under several injection paradigms with a solution of gadolinium-DTPA for MR contrast and methylene blue as a grossly visible surrogate drug marker. Ex vivo and in vivo distributions were assessed at 1.5T and quantitatively compared. RESULTS: Measured distributions using MRI and methylene blue pathology photographs were analyzed using a Bland-Altman method. The fractional percentage volume covered (V frac) compared the measurements grossly: Pearson's correlation coefficients were R = 0.99 for ex vivo and R = 0.77 for in vivo (P < 0.05). The fractional percentage of area covered (A frac) demonstrated the high degree of spatial correlation between individual slices: R = 0.93 for ex vivo and R = 0.98 for in vivo (P < 0.05). There was no statistically observable bias in scale or offset between the measurements. CONCLUSION: Measured distributions using MRI and pathology were highly correlated and unbiased, indicating the potential of MRI as a tool for quantitative assessment of interstitial delivery of injected therapies in vivo.

Laser-induced thermal response and characterization of nanoparticles for cancer treatment using magnetic resonance thermal imaging.

Spherical nanoparticles with a gold outer shell and silica core can be tuned to absorb near-infrared light of a specific wavelength. These nanoparticles have the potential to enhance the treatment efficacy of laser-induced thermal therapy (LITT). In order to enhance both the potential efficacy and safety of such procedures, accurate methods of treatment planning are needed to predict the temperature distribution associated with treatment application. In this work, the standard diffusion approximation was used to model the laser fluence in phantoms containing different concentrations of nanoparticles, and the temperature distribution within the phantom was simulated in three-dimensions using the finite element technique. Magnetic resonance temperature imaging was used to visualize the spatiotemporal distribution of the temperature in the phantoms. In most cases, excellent correlation is demonstrated between the simulations and the experiment (<3.0% mean error observed). This has significant implications for the treatment planning of LITT treatments using gold-silica nanoshells.

Nonlinear averaging reconstruction method for phase-cycle SSFP.

The ability to obtain high-quality images of small structures, such as the nerves of the inner ear, is important for the early diagnosis of numerous conditions. Balanced steady-state free precession (SSFP; e.g., true fast imaging with steady-state precession) is a fast acquisition method, but its use has been limited by the presence of off-resonance banding artifacts. To reduce these artifacts multiacquisition balanced SSFP with phase cycling is used, yielding multiple data sets in which the banding artifacts are spatially shifted with respect to each other (e.g., as in CISS). We present a new method, called nonlinear averaging (NLA), for combining these data sets to reduce banding artifacts. The NLA method arithmetically averages the three highest magnitude signals from four-phase-cycle SSFP data on a pixel-by-pixel basis. Simulations indicate that NLA offers improved signal-to-noise ratio (SNR) over the more standard maximum intensity projection (MIP) reconstruction. NLA is compared to MIP in simulations and volunteer tests. Simulations suggest that NLA provides substantially improved SNR compared to MIP. In a randomized blinded comparison of 10 volunteer studies, two radiologists found that NLA, compared to MIP, gave improved results. NLA also provided superior noise reduction and enhanced edge sharpness compared to MIP. We demonstrate that NLA, similar to MIP, improves SNR and image quality. It does so consistently in all situations to which it is applied.

Bifunctional Gold Nanoshells with a Superparamagnetic Iron Oxide-Silica Core Suitable for Both MR Imaging and Photothermal Therapy.

We describe the synthesis, characterization, and use of hybrid nanoparticles with a superparamagnetic iron oxide (SPIO) core and a gold nanoshell. These multifunctional nanoparticles, designated SPIO-Au nanoshells, displayed superparamagnetic characteristics and a significant absorbance in the near-infrared (NIR) region of the electromagnetic spectrum. In addition, they exhibited high transverse relaxivity, r2 , and a large r2/r1 ratio and therefore could be imaged by MRI to obtain T2-weighted images. Moreover, SPIO-Au nanoshells showed efficient photo-thermal effect when exposed to NIR light. The use of SPIO-Au nanoshells, with their combination of unique magnetic and optical properties, should enhance the efficacy of nanoshell-mediated photo-thermal therapy by making it possible to direct more nanoparticles to tumors through the application of external magnetic field and by permitting real-time in vivo MRI imaging of the distribution of the nanoparticles before, during, and after photo-thermal therapy.

Motion correction properties of the shells k-space trajectory.

The feasibility of a k-space trajectory that samples data on a set of 3D shells is demonstrated with phantom and volunteer experiments. Details of an interleaved multi-shot, helical spiral pulse sequence and a gridding reconstruction algorithm that uses Voronoi diagrams are provided. The motion-correction properties of the shells k-space trajectory are described. It is shown that when used in conjunction with three point markers, k-space data acquired with the shells trajectory provide a generalization of the RINGLET method, allowing for correction of arbitrary rigid-body motion with six degrees of freedom. Use of dedicated navigator echoes or redundant acquisitions of k-space data are not required. Retrospective motion correction is demonstrated with controlled phantom experiments and with seven healthy human volunteers. The motion correction is shown to improve the images, both qualitatively and quantitatively with a metric calculated from image entropy. Advantages and challenges of the shells trajectory are discussed, with particular attention to acquisition efficiency.

RINGLET motion correction for 3D MRI acquired with the elliptical centric view order.

A new rigid-body motion correction algorithm is described that is compatible with 3D image sets acquired with the elliptical centric (EC) view order. With this view order, an annular ring of k-space data is acquired in the ky-kz plane during any short time interval. Images for tracking motion can be reconstructed in the yz-plane from any ring of the acquisition data. In these tracking images, a point source (such as an external marker) shows a characteristic bull's-eye pattern that permits motion monitoring and correction. The true position of the point object is located at the center of the bull's-eye pattern. Cross correlation can be performed to automatically track the positions of markers reconstructed from adjacent rings of k-space. To increase the marker signal, the markers are encased in inductively coupled RF coils. Rigid-body motion in the yz-plane is calculated directly with the Euclidean group for rotation and translation, and corrected by rotating and applying phase shifts to any corrupted rings of data. In the current work we present a theoretical analysis of this method, as well as results of volunteer and controlled phantom experiments that demonstrate its initial feasibility. Although the EC view order has mainly been used for MR angiography (MRA), it can also be used for most 3D acquisitions.