Early experiences in establishing a regional quantitative imaging network for PET/CT clinical trials

The Seattle Cancer Care Alliance (SCCA) is a Pacific Northwest regional network that enables patients from community cancer centers to participate in multicenter oncology clinical trials where patients can receive some trial-related procedures at their local center. Results of positron emission tomography (PET) scans performed at community cancer centers are not currently used in SCCA Network trials since clinical trials customarily accept results from only trial-accredited PET imaging centers located at academic and large hospitals. Oncologists would prefer the option of using standard clinical PET scans from Network sites in multicenter clinical trials to increase accrual of patients for whom additional travel requirements for imaging are a barrier to recruitment. In an effort to increase accrual of rural and other underserved populations to Network trials, researchers and clinicians at the University of Washington, SCCA and its Network are assessing the feasibility of using PET scans from all Network sites in their oncology clinical trials. A feasibility study is required because the reproducibility of multicenter PET measurements ranges from approximately 3% to 40% at national academic centers. Early experiences from both national and local PET phantom imaging trials are discussed, and next steps are proposed for including patient PET scans from the emerging regional quantitative imaging network in clinical trials. There are feasible methods to determine and characterize PET quantitation errors and improve data quality by either prospective scanner calibration or retrospective post hoc corrections. These methods should be developed and implemented in multicenter clinical trials employing quantitative PET imaging of patients.     

Sodium and proton diffusion MRI as biomarkers for early therapeutic response in subcutaneous tumors

The ability to quantitate early effects of tumor therapeutic response using noninvasive imaging would have a major impact in clinical oncology. One area of active research interest is the ability to use MR techniques to detect subtle changes in tumor cellular density. In this study, sodium and proton diffusion MRI were compared for their ability to detect early cellular changes in tumors treated with a cytotoxic chemotherapy. Subcutaneous 9L gliosarcomas were treated with a single dose of 1,3-bis(2-chloroethyl)-1-nitrosourea. Both sodium and diffusion imaging modalities were able to detect changes in tumor cellularity as early as 2 days after treatment, which continued to evolve as increased signal intensities reached a maximum approximately 8 days posttreatment. Early changes in tumor sodium and apparent diffusion coefficient values were predictive of subsequent tumor shrinkage, which occurred approximately 10 days later. Overall, therapeutical induced changes in sodium and diffusion values were found to have similar dynamic and spatial changes. These findings suggest that these imaging modalities detected similar early cellular changes after treatment. The results of this study support the continued clinical testing of diffusion MRI for evaluation of early tumor treatment response and demonstrate the complementary insights of sodium MRI for oncology applications.     

Combined imaging biomarkers for therapy evaluation in glioblastoma multiforme: correlating sodium MRI and F-18 FLT PET on a voxel-wise basis

We evaluate novel magnetic resonance imaging (MRI) and positron emission tomography (PET) quantitative imaging biomarkers and associated multimodality, serial-time-point analysis methodologies, with the ultimate aim of providing clinically feasible, predictive measures for early assessment of response to cancer therapy. A focus of this work is method development and an investigation of the relationship between the information content of the two modalities. Imaging studies were conducted on subjects who were enrolled in glioblastoma multiforme (GBM) therapeutic clinical trials. Data were acquired, analyzed and displayed using methods that could be adapted for clinical use. Subjects underwent dynamic [¹⁸F]fluorothymidine (F-18 FLT) PET, sodium (²³Na) MRI and 3-T structural MRI scans at baseline (before initiation of therapy), at an early time point after beginning therapy and at a late follow-up time point after therapy. Sodium MRI and F-18 FLT PET images were registered to the structural MRI. F-18 FLT PET tracer distribution volumes and sodium MRI concentrations were calculated on a voxel-wise basis to address the heterogeneity of tumor physiology. Changes in, and differences between, these quantities as a function of scan timing were tracked.     

Quantifying tissue microvasculature with speckle variance optical coherence tomography

In this Letter, we demonstrate high resolution, three-dimensional optical imaging of in vivo blood vessel networks using speckle variance optical coherence tomography, and the quantification of these images through the development of biologically relevant metrics using image processing and segmentation techniques. Extracted three-dimensional metrics include vascular density, vessel tortuosity, vascular network fractal dimension, and tissue vascularity. We demonstrate the ability of this quantitative imaging approach to characterize normal and tumor vascular networks in a preclinical animal model and the potential for quantitative, longitudinal vascular treatment response monitoring.     

Quantitative assessment of dynamic PET imaging data in cancer imaging

Clinical imaging in positron emission tomography (PET) is often performed using single-time-point estimates of tracer uptake or static imaging that provides a spatial map of regional tracer concentration. However, dynamic tracer imaging can provide considerably more information about in vivo biology by delineating both the temporal and spatial pattern of tracer uptake. In addition, several potential sources of error that occur in static imaging can be mitigated. This review focuses on the application of dynamic PET imaging to measuring regional cancer biologic features and especially in using dynamic PET imaging for quantitative therapeutic response monitoring for cancer clinical trials. Dynamic PET imaging output parameters, particularly transport (flow) and overall metabolic rate, have provided imaging end points for clinical trials at single-center institutions for years. However, dynamic imaging poses many challenges for multicenter clinical trial implementations from cross-center calibration to the inadequacy of a common informatics infrastructure. Underlying principles and methodology of PET dynamic imaging are first reviewed, followed by an examination of current approaches to dynamic PET image analysis with a specific case example of dynamic fluorothymidine imaging to illustrate the approach.     

Optical coherence Doppler tomography quantifies laser speckle contrast imaging for blood flow imaging in the rat cerebral cortex

A dual-imaging modality is demonstrated for high-resolution quantitative imaging of local cerebral blood flow in the rat cortex by combining simultaneous spectral-domain Doppler optical coherence tomography (SDOCT) and full-field laser speckle contrast imaging (LSCI). Preliminary studies in tissue flow phantom and cocaine-induced cerebral blood flow changes indicated that by correlating coregistered cortical arterial blood flow, the relative measurement of flow changes by LSCI could be accurately calibrated by the absolute flow imaging provided by SDOCT (least square fit, r(2) approximately 0.96). Quantitative LSCI of cerebral blood flow is crucial to the quantitative analyses of the spatiotemporal hemodynamics of functional brain activations and thus improved understanding of neural process.     

Image-guided optical spectroscopy provides molecular-specific information in vivo: MRI-guided spectroscopy of breast cancer hemoglobin, water, and scatterer size

A multimodality instrument that integrated optical or near-infrared spectroscopy into a magnetic resonance imaging (MRI) breast coil was used to perform a pilot study of image-guided spectroscopy on cancerous breast tissue. These results are believed to be the first multiwavelength spectroscopic images of breast cancer using MRI-guided constraints, and they show the cancer tumor to have high hemoglobin and water values, decreased oxygen saturation, and increased subcellular granularity. The use of frequency-domain diffuse tomography methods at many wavelengths provides the spectroscopy required for recovering maps of absorbers and scattering spectra, but the integration with MRI allows these data to be recovered on an image field that preserves high resolution and fuses the two data sets together. Integration of molecular spectroscopy into standard clinical MRI can be achieved with this approach to spectral tomography.     

Quantitative ultrasound brain imaging with multiscale deconvolutional waveform inversion

High-resolution images of human brain are critical for monitoring the neurological conditions in a portable and safe manner. Sound speed mapping of brain tissues provides unique information for such a purpose. In addition, it is particularly important for building digital human acoustic models, which form a reference for future ultrasound research. Conventional ultrasound modalities can hardly image the human brain at high spatial resolution inside the skull due to the strong impedance contrast between hard tissue and soft tissue. We carry out numerical experiments to demonstrate that the time-domain waveform inversion technique, originating from the geophysics community, is promising to deliver quantitative images of human brains within the skull at a sub-millimeter level by using ultra-sound signals. The successful implementation of such an approach to brain imaging requires the following items: signals of sub-megahertz frequencies transmitting across the inside of skull, an accurate numerical wave equation solver simulating the wave propagation, and well-designed inversion schemes to reconstruct the physical parameters of targeted model based on the optimization theory. Here we propose an innovative modality of multiscale deconvolutional waveform inversion that improves ultrasound imaging resolution, by evaluating the similarity between synthetic data and observed data through using limited length Wiener filter. We implement the proposed approach to iteratively update the parametric models of the human brain. The quantitative imaging method paves the way for building the accurate acoustic brain model to diagnose associated diseases, in a potentially more portable, more dynamic and safer way than magnetic resonance imaging and x-ray computed tomography.     

Subsurface imaging by dual-medium quantitative phase measurement

Quantitative phase imaging by itself allows for direct surface imaging of the transparent homogeneous sample, but it is very difficult or impossible for the inhomogeneous sample by itself due to the surface morphology and subsurface information are coupled. We hereby propose a simple method which obtains quantitative phase data and the physical thickness of sample by dual-medium quantitative phase measurement (DMQ) to extract subsurface sample information without the need of any exogenous dyes and any scan process. By using simulation technology, the feasibility of this method is demonstrated with subsurface imaging of a two-sphere model and a simulated monocyte.     

Recent advances in bioluminescence tomography: methodology and system as well as application

Optical molecular imaging has been rapidly developed to noninvasively visualize in vivo physiological and pathological processes involved in normal and suffering organisms at the cellular and molecular levels, in which advanced optical imaging technology and modern molecular biology are being combined to provide a state‐of‐the‐art tool for preclinical biomedical research. Among optical molecular imaging modalities, bioluminescence tomography (BLT) has experienced considerable growth and attracted much attention in recent years for its excellent performance, unique advantages, and high cost‐effectiveness. This article focuses on the genesis and development of BLT, especially for its computational methodology, imaging system, and biomedical application. An overview of the advantages and challenges of the conventional planar bioluminescence imaging technique is first described in comparison with currently available molecular imaging modalities. The imaging algorithms for inverse source reconstruction are classified and summarized according to different a priori knowledge, followed by a simple depiction of the uniqueness theorems of BLT solution. Diverse imaging systems for obtaining three‐dimensional quantitative information of internal bioluminescent sources are then reviewed. The latest application examples of BLT in tumor study and drug discovery are introduced and compared with other mature imaging technologies. Finally, the paper is concluded and an attractive prospect for BLT is predicted.     

The multi-functional aspect of scanning holographic microscopy: a review(Invited Paper)

Recent developments in scanning holographic microscopy that offer the prospects of new quantitative tools and imaging modalities in bio, micro, and nano sciences are reviewed. The versatility of the method is emphasized. Scanning holography can operate in an incoherent mode for fluorescence imaging, in a coherent mode for quantitative phase imaging, or in a tomographic mode for axial sectioning and rejection of the out-of-focus haze. Possible applications are illustrated with examples, and future prospects ...     

Prognostic and therapeutic evaluation of nasopharyngeal carcinoma by dynamic contrast-enhanced (DCE), diffusion-weighted (DW) magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS)

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck malignancy, and radiotherapy (with or without chemotherapy) is the primary treatment modality. Reliable tumour assessment during the treatment phase, which can portend the efficacy of radiotherapy and early identification of potential treatment failure in radioresistant disease, has been implicit for better cancer management. Technological advancement in the last decade has fostered the development of functional magnetic resonance imaging (fMRI) techniques into a promising tool for diagnostic and therapeutic assessments in head and neck cancer. Apart from conventional morphological assessment, early detection of the physiological environment by fMRI allows a more thorough investigation in monitoring tumour response. This article discusses the relevant fMRI utilities in NPC as an early prognostic and monitoring tool for treatment. Challenges and future developments of fMRI in radiation oncology are also discussed.     

Emulated super-resolution using quantitative phase microscopy

In the case of coherent illumination, knowledge of the phase and the amplitude of a light wave constitutes complete information. Phase and amplitude information can now be simply acquired using the technique of quantitative phase microscopy. It has been shown that this information allows other imaging modalities to be emulated. In this paper we consider how this information may be used to perform a form of super-resolution by emulating the effect of an annular pupil.     

Carr-Purcell-Meiboom-Gill imaging of prostate cancer: quantitative T2 values for cancer discrimination

Quantitative, apparent T(2) values of suspected prostate cancer and healthy peripheral zone tissue in men with prostate cancer were measured using a Carr-Purcell-Meiboom-Gill (CPMG) imaging sequence in order to assess the cancer discrimination potential of tissue T(2) values. The CPMG imaging sequence was used to image the prostates of 18 men with biopsy-proven prostate cancer. Whole gland coverage with nominal voxel volumes of 0.54 x 1.1 x 4 mm(3) was obtained in 10.7 min, resulting in data sets suitable for generating high-quality images with variable T(2)-weighting and for evaluating quantitative T(2) values on a pixel-by-pixel basis. Region-of-interest analysis of suspected healthy peripheral zone tissue and suspected cancer, identified on the basis of both T(1)- and T(2)-weighted signal intensities and available histopathology reports, yielded significantly (P<.0001) longer apparent T(2) values in suspected healthy tissue (193+/-49 ms) vs. suspected cancer (100+/-26 ms), suggesting potential utility of this method as a tissue specific discrimination index for prostate cancer. We conclude that CPMG imaging of the prostate can be performed in reasonable scan times and can provide advantages over T(2)-weighted fast spin echo (FSE) imaging alone, including quantitative T(2) values for cancer discrimination as well as proton density maps without the point spread function degradation associated with short effective echo time FSE sequences.     

SPIO–RGD nanoparticles as a molecular targeting probe for imaging tumor angiogenesis using synchrotron radiation

Angiogenesis, new blood vessels sprouting from pre‐existing vessels, is essential to tumor growth, invasion and metastasis. It can be used as a biomarker for early stage tumor diagnosis and targeted therapy. To visualize angiogenesis many molecular imaging modalities have been used. In this study a novel X‐ray molecular targeting probe using superparamagnetic iron oxide (SPIO) conjugated with arginine–glycine–aspartic acid (SPIO–RGD) has been developed. Based on the extremely high sensitivity to the iron element of synchrotron radiation X‐ray fluorescence and the superior spatial resolution of third‐generation synchrotron radiation, the feasibility of SPIO–RGD as a promising molecular probe for imaging tumor angiogenesis has been demonstrated.     

Spectral-domain optical coherence phase microscopy for quantitative phase-contrast imaging

We describe a novel microscopy technique for quantitative phase-contrast imaging of a transparent specimen. The technique is based on depth-resolved phase information provided by common path spectral-domain optical coherence tomography and can measure minute phase variations caused by changes in refractive index and thickness inside the specimen. We demonstrate subnanometer level path-length sensitivity and present images obtained on reflection from a known phase object and human epithelial cheek cells.     

High-intensity focused ultrasound for the treatment of liver tumours

High-intensity focused ultrasound (HIFU) has been investigated as a tool for the treatment of cancer for many decades, but is only now beginning to emerge as a potential alternative to conventional therapies. In recent years, clinical trials have evaluated the clinical efficacy of a number of devices worldwide. In Oxford, UK, we have been using the JC HIFU system (HAIFU Technology Company, Chongqing, PR China) in clinical trials since November 2002. This is the first report of its clinical use outside mainland China. The device is non-invasive, and employs an extracorporeal transducer operating at 0.8-1.6 MHz (aperture 12-15 cm, focal length 9-15 cm), operating clinically at Isp (free field) of 5-15 KWcm(-2). The aims of the trials are to evaluate the safety and performance of the device. Performance is being evaluated through two parallel protocols. One employs radiological assessment of response with the use of follow-up magnetic resonance imaging and microbubble-contrast ultrasound. In the other, histological assessment will be made following elective surgical resection of the HIFU treated tumours. Eleven patients with liver tumours have been treated with HIFU to date. Adverse events include transient pain and minor skin burns. Observed response from the various assessment modalities is discussed.     

Tracking extended mucociliary transport activity of individual deposited particles: longitudinal synchrotron X‐ray imaging in live mice

To assess potential therapies for respiratory diseases in which mucociliary transit (MCT) is impaired, such as cystic fibrosis and primary ciliary dyskinesia, a novel and non‐invasive MCT quantification method has been developed in which the transit rate and behaviour of individual micrometre‐sized deposited particles are measured in live mice using synchrotron phase‐contrast X‐ray imaging. Particle clearance by MCT is known to be a two‐phase process that occurs over a period of minutes to days. Previous studies have assessed MCT in the fast‐clearance phase, ～20 min after marker particle dosing. The aim of this study was to non‐invasively image changes in particle presence and MCT during the slow‐clearance phase, and simultaneously determine whether repeat synchrotron X‐ray imaging of mice was feasible over periods of 3, 9 and 25 h. All mice tolerated the repeat imaging procedure with no adverse effects. Quantitative image analysis revealed that the particle MCT rate and the number of particles present in the airway both decreased with time. This study successfully demonstrated for the first time that longitudinal synchrotron X‐ray imaging studies are possible in live small animals, provided appropriate animal handling techniques are used and care is taken to reduce the delivered radiation dose.