Imaging beyond the diagnosis: image-guided enzyme/prodrug cancer therapy

The ideal therapy would target cancer cells while sparing normal tissue. However, in most conventional chemotherapies normal cells are damaged together with cancer cells resulting in the unfortunate side effects. The principle underlying enzyme/prodrug therapy is that a prodrug-activating enzyme is delivered or expressed in tumor tissue following which a non-toxic prodrug is administered systemically. Non-invasive imaging modalities can fill an important niche in guiding prodrug administration when the enzyme concentration is detected to be high in the tumor tissue but low in the normal tissue. Therefore, high therapeutic efficacy with minimized toxic effect can be anticipated. This review introduces the latest developments of molecular imaging in enzyme/prodrug cancer therapies. We focus on the application of imaging modalities including magnetic resonance imaging, position emission tomography and optical imaging in monitoring the enzyme delivery/expression, guiding the prodrug administration and evaluating the real-time therapeutic response in vivo.     

Promising techniques for breast cancer detection,diagnosis, and staging using non-ionizing radiation imaging techniques

Traditional imaging for the diagnosis and staging of breast cancer has relied on the tissue morphology of cancers in the background of normal patterns of fibroglandular breast tissue. X-ray mammography and ultrasound have been the primary modalities for the diagnosis and the work-up of breast cancer. New modalities have been validated including magnetic resonance imaging (MRI) and positron emission tomography (PET). New pulse sequences in MRI combined with contrast enhancement kinetic perfusion curves have greatly enhanced detection of mammographically occult cancers. New modalities on the horizon include optical imaging, exploiting again the differential perfusion properties of cancers in a background of normal glandular tissue. Even more specificity can be ach eved with the addition of ductal or intravenous introduction of optical probes specific to tumor associated antigens such as the HER-2/neu receptor in aggressive breast cancers. Quantum dots and other fluorescent dyes coupled to peptides or other probes will greatly enhance our ability to detect cancers earlier and without ionizing radiation.     

In vivo optical molecular imaging and analysis in mice using dorsal window chamber models applied to hypoxia, vasculature and fluorescent reporters

Optical techniques for functional imaging in mice have a number of key advantages over other common imaging modalities such as magnetic resonance imaging, positron emission tomography or computed tomography, including high resolution, low cost and an extensive library of available contrast agents and reporter genes. A major challenge to such work is the limited penetration depth imposed by tissue turbidity. We describe a window chamber technique by which these limitations can be avoided. This facilitates the study of a wide range of processes, with potential endpoints including longitudinal gene expression, vascular remodeling and angiogenesis, and tumor growth and invasion. We further describe several quantitative imaging and analysis techniques for characterizing in vivo fluorescence properties and functional endpoints, including vascular morphology and oxygenation. The procedure takes ～2 h to complete, plus up to several weeks for tumor growth and treatment procedures.     

Application of Numerical Methods to Elasticity Imaging

Elasticity imaging can be understood as the intersection of the study of biomechanical properties, imaging sciences, and physics. It was mainly motivated by the fact that pathological tissue presents an increased stiffness when compared to surrounding normal tissue. In the last two decades, research on elasticity imaging has been an international and interdisciplinary pursuit aiming to map the viscoelastic properties of tissue in order to provide clinically useful information. As a result, several modalities of elasticity imaging, mostly based on ultrasound but also on magnetic resonance imaging and optical coherence tomography, have been proposed and applied to a number of clinical applications: cancer diagnosis (prostate, breast, liver), hepatic cirrhosis, renal disease, thyroiditis, arterial plaque evaluation, wall stiffness in arteries, evaluation of thrombosis in veins, and many others. In this context, numerical methods are applied to solve forward and inverse problems implicit in the algorithms in order to estimate viscoelastic linear and nonlinear parameters, especially for quantitative elasticity imaging modalities. In this work, an introduction to elasticity imaging modalities is presented. The working principle of qualitative modalities (sonoelasticity, strain elastography, acoustic radiation force impulse) and quantitative modalities (Crawling Waves Sonoelastography, Spatially Modulated Ultrasound Radiation Force (SMURF), Supersonic Imaging) will be explained. Subsequently, the areas in which numerical methods can be applied to elasticity imaging are highlighted and discussed. Finally, we present a detailed example of applying total variation and AM-FM techniques to the estimation of elasticity.     

Current imaging paradigms in radiation oncology

The technological revolution in imaging during recent decades has transformed the way image-guided radiation therapy is performed. Anatomical imaging (plain radiography, computed tomography, magnetic resonance imaging) greatly improved the accuracy of delineating target structures and has formed the foundation of 3D-based radiation treatment. However, the treatment planning paradigm in radiation oncology is beginning to shift toward a more biological and molecular approach as advances in biochemistry, molecular biology, and technology have made functional imaging (positron emission tomography, nuclear magnetic resonance spectroscopy, optical imaging) of physiological processes in tumors more feasible and practical. This review provides an overview of the role of current imaging strategies in radiation oncology, with a focus on functional imaging modalities, as it relates to staging and molecular profiling (cellular proliferation, apoptosis, angiogenesis, hypoxia, receptor status) of tumors, defining radiation target volumes, and assessing therapeutic response. In addition, obstacles such as imaging-pathological validation, optimal timing of post-therapy scans, spatial and temporal evolution of tumors, and lack of clinical outcome studies are discussed that must be overcome before a new era of functional imaging-guided therapy becomes a clinical reality.     

Treatment of high-grade glioma with radiolabeled peptides

The management of high-grade glioma (HGG) patients in clinical routine represents a challenging task. HGG has a poor prognosis because of early recurrence or therapy-refractory disease following first-line standard therapy, which includes a multidisciplinary approach involving radical surgical resection followed by external beam radiation therapy in combination with chemotherapy.Glioma cells are known to express specific receptors or glycoproteins on their surface which can be used as biological targets for treatment. The application of radiopharmaceuticals consisting of a targeting and an effector domain has led to the introduction of new treatment approaches, aiming at a tumor-specific treatment sparing normal brain tissue.One of these new modalities is the peptide receptor radionuclide therapy (PRRT). Peptides labeled with radioactive nuclides can bind directly to the tumor cells and deliver high doses of radioactivity directly to the tumor tissue.This article reviews the literature for PRRT in HGG.     

Computed tomography and magnetic resonance imaging in the diagnosis of accessory nasal sinuses, upper jaw and nasal cavity tumors

Radiation studies, including computed tomography (CT) and magnetic resonance imaging (MRI), revealed that these techniques can accurately determine the site of a tumor, the borders of its spread to the adjacent anatomic structures. They also revealed the features of CT in detecting osseous structural destruction and the advantage of MRI in visualizing the soft tissue component of a neoplasm and in distinguishing the degree of contrast of tumor tissue and concurrent secondary inflammation. The accuracy of CT and MRI for small tumors is 45-80 and 29% higher than that of X-ray study and traditional tomography, respectively. The potentialities of all radiation diagnostic techniques for over 3.0-cm tumors are equal.     

Stereotactic Radiosurgery for Gynecologic Cancer

Stereotactic body radiotherapy (SBRT) distinguishes itself by necessitating more rigid patient immobilization, accounting for respiratory motion, intricate treatment planning, on-board imaging, and reduced number of ablative radiation doses to cancer targets usually refractory to chemotherapy and conventional radiation. Steep SBRT radiation dose drop-off permits narrow ''pencil beam'' treatment fields to be used for ablative radiation treatment condensed into 1 to 3 treatments.Treating physicians must appreciate that SBRT comes at a bigger danger of normal tissue injury and chance of geographic tumor miss. Both must be tackled by immobilization of cancer targets and by high-precision treatment delivery. Cancer target immobilization has been achieved through use of indexed customized Styrofoam casts, evacuated bean bags, or body-fix molds with patient-independent abdominal compression.^1-3 Intrafraction motion of cancer targets due to breathing now can be reduced by patient-responsive breath hold techniques,⁴ patient mouthpiece active breathing coordination,⁵ respiration-correlated computed tomography,⁶ or image-guided tracking of fiducials implanted within and around a moving tumor.^7-9 The Cyberknife system (Accuray [Sunnyvale, CA]) utilizes a radiation linear accelerator mounted on a industrial robotic arm that accurately follows patient respiratory motion by a camera-tracked set of light-emitting diodes (LED) impregnated on a vest fitted to a patient.¹⁰ Substantial reductions in radiation therapy margins can be achieved by motion tracking, ultimately rendering a smaller planning target volumes that are irradiated with submillimeter accuracy.^11-13Cancer targets treated by SBRT are irradiated by converging, tightly collimated beams. Resultant radiation dose to cancer target volume histograms have a more pronounced radiation "shoulder" indicating high percentage target coverage and a small high-dose radiation "tail." Thus, increased target conformality comes at the expense of decreased dose uniformity in the SBRT cancer target. This may have implications for both subsequent tumor control in the SBRT target and normal tissue tolerance of organs at-risk. Due to the sharp dose falloff in SBRT, the possibility of occult disease escaping ablative radiation dose occurs when cancer targets are not fully recognized and inadequate SBRT dose margins are applied. Clinical target volume (CTV) expansion by 0.5 cm, resulting in a larger planning target volume (PTV), is associated with increased target control without undue normal tissue injury.^7,8 Further reduction in the probability of geographic miss may be achieved by incorporation of 2-[¹⁸F]fluoro-2-deoxy-D-glucose (¹⁸F-FDG) positron emission tomography (PET).⁸ Use of ¹⁸F-FDG PET/CT in SBRT treatment planning is only the beginning of attempts to discover new imaging target molecular signatures for gynecologic cancers.     

Micro-CT of rodents: State-of-the-art and future perspectives

Micron-scale computed tomography (micro-CT) is an essential tool for phenotyping and for elucidating diseases and their therapies. This work is focused on preclinical micro-CT imaging, reviewing relevant principles, technologies, and applications. Commonly, micro-CT provides high-resolution anatomic information, either on its own or in conjunction with lower-resolution functional imaging modalities such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). More recently, however, advanced applications of micro-CT produce functional information by translating clinical applications to model systems (e.g. measuring cardiac functional metrics) and by pioneering new ones (e.g. measuring tumor vascular permeability with nanoparticle contrast agents). The primary limitations of micro-CT imaging are the associated radiation dose and relatively poor soft tissue contrast. We review several image reconstruction strategies based on iterative, statistical, and gradient sparsity regularization, demonstrating that high image quality is achievable with low radiation dose given ever more powerful computational resources. We also review two contrast mechanisms under intense development. The first is spectral contrast for quantitative material discrimination in combination with passive or actively targeted nanoparticle contrast agents. The second is phase contrast which measures refraction in biological tissues for improved contrast and potentially reduced radiation dose relative to standard absorption imaging. These technological advancements promise to develop micro-CT into a commonplace, functional and even molecular imaging modality.     

Current views on imaging of adrenal tumors.

Anatomical imaging modalities (such as computed tomography [CT] or magnetic resonance imaging [MRI]) and functional imaging modalities (that is, nuclear medicine) are used in the evaluation of adrenal glands. The use of CT (unenhanced, followed by contrast-enhanced) evaluation is the cornerstone of imaging of adrenal tumors. Attenuation values of less than 10 Hounsfield units at unenhanced CT are practically diagnostic for adenomas, while attenuation values of greater than 10 HU are not diagnostic of metastatic disease since non-metastatic disease is also a possibility. When lesions cannot be characterized adequately with CT, MRI evaluation (with T1 and T2-weighted sequences and chemical shift and fat-suppression refinements) is sought. Functional nuclear medicine imaging can be of utility in the evaluation of adrenal masses, more particularly for lesions not adequately characterized with CT and MRI. Nuclear medicine techniques are based on physiological and pathophysiological processes (cellular metabolism, tissue perfusion and local synthesis, uptake, storage of hormones and their receptors). Functional imaging aids initial preoperative staging, diagnostic evaluation of suspicious lesions, identification of metastatic or recurrent tumors, refining prognosis, and deciding on and predicting responses to therapy. [ (131)I]-6-iodomethyl norcholesterol scintigraphy can differentiate adenomas from carcinomas. Pheochromocytomas appear as areas of abnormal/increased [ (131)I]- and [ (123)I]-meta-iodobenzylguanidine uptake. Our experience has shown that [ (18)F]-fluorodopamine is an excellent agent for localizing adrenal and extra-adrenal pheochromocytomas.     

Imaging dose from cone beam computed tomography in radiation therapy

Imaging dose in radiation therapy has traditionally been ignored due to its low magnitude and frequency in comparison to therapeutic dose used to treat patients. The advent of modern, volumetric, imaging modalities, often as an integral part of linear accelerators, has facilitated the implementation of image-guided radiation therapy (IGRT), which is often accomplished by daily imaging of patients. Daily imaging results in additional dose delivered to patient that warrants new attention be given to imaging dose. This review summarizes the imaging dose delivered to patients as the result of cone beam computed tomography (CBCT) imaging performed in radiation therapy using current methods and equipment. This review also summarizes methods to calculate the imaging dose, including the use of Monte Carlo (MC) and treatment planning systems (TPS). Peripheral dose from CBCT imaging, dose reduction methods, the use of effective dose in describing imaging dose, and the measurement of CT dose index (CTDI) in CBCT systems are also reviewed.     

Dynamic Lung Tumor Tracking for Stereotactic Ablative Body Radiation Therapy

Physicians considering stereotactic ablative body radiation therapy (SBRT) for the treatment of extracranial cancer targets must be aware of the sizeable risks for normal tissue injury and the hazards of physical tumor miss. A first-of-its-kind SBRT platform achieves high-precision ablative radiation treatment through a combination of versatile real-time imaging solutions and sophisticated tumor tracking capabilities. It uses dual-diagnostic kV x-ray units for stereoscopic open-loop feedback of cancer target intrafraction movement occurring as a consequence of respiratory motions and heartbeat. Image-guided feedback drives a gimbaled radiation accelerator (maximum 15 x 15 cm field size) capable of real-time ±4 cm pan-and-tilt action. Robot-driven ±60° pivots of an integrated ±185° rotational gantry allow for coplanar and non-coplanar accelerator beam set-up angles, ultimately permitting unique treatment degrees of freedom. State-of-the-art software aids real-time six dimensional positioning, ensuring irradiation of cancer targets with sub-millimeter accuracy (0.4 mm at isocenter). Use of these features enables treating physicians to steer radiation dose to cancer tumor targets while simultaneously reducing radiation dose to normal tissues. By adding respiration correlated computed tomography (CT) and 2-[¹⁸F] fluoro-2-deoxy-ᴅ-glucose (¹⁸F-FDG) positron emission tomography (PET) images into the planning system for enhanced tumor target contouring, the likelihood of physical tumor miss becomes substantially less¹. In this article, we describe new radiation plans for the treatment of moving lung tumors.     

Molecular imaging in prostate cancer

Prostate cancer (PCa) is the most common non-cutaneous malignancy in men. New ways to diagnose this cancer in its early stages are needed. Unique genetic and biochemical changes in the cell pave the way for tumors to grow and metastasize. Novel imaging approaches attempt to detect pathological processes in cancer cells at the molecular level. This has led to the establishment and development of the field of molecular imaging. Positron emission tomography (PET), magnetic resonance spectroscopic imaging (MRSI), magnetic resonance imaging (MRI), and radiolabeled antibodies are a few of the modalities that can detect abnormal tumor metabolic processes in the clinical setting. Other imaging techniques are still in their early phase of development but hold promise for the future, including bioluminescence imaging (BLI), measurement of tumor oxygenation, and measurement of uptake of iodine by tumors. These techniques are non-invasive and can spare the patient undue morbidity, while potentially providing early diagnosis, accurate follow-up and, finally, valuable prognostic information.     

PET-MRI in oncology

Hybrid positron emission tomography (PET)-MRI imaging enable the acquisition of functional information by PET, and structural as well as functional information by MRI. The two modalities are complementary: PET offers unparalleled sensitivity to molecular events, e.g. occupation of receptors, activity of glucose metabolism, during tumor or inflammation; while MRI offers high soft tissue contrast (including in highly mobile structures such as the heart) and other information (diffusion, blood flow, spectroscopy). Simultaneous acquisition is crucial for understanding brain function, the pathophysiology of cancer, mechanic cardiovascular dysfunction, and disorders of nutrition and metabolism.     

Imaging in gout - What can we learn from MRI,CT, DECT and US?

There are many exciting new applications for advanced imaging in gout. These modalities employ multiplanar imaging and allow computerized three-dimensional rendering of bone and joints (including tophi) and have the advantage of electronic data storage for later retrieval. High-resolution computed tomography has been particularly helpful in exploring the pathology of gout by investigating the relationship between bone erosions and tophi. Magnetic resonance imaging and ultrasonography can image the inflammatory nature of gouty arthropathy, revealing synovial and soft tissue inflammation, and can provide information about the composition and vascularity of tophi. Dual-energy computerized tomography is a new modality that is able to identify tophi by their chemical composition and reveal even small occult tophaceous deposits. All modalities are being investigated for their potential roles in diagnosis and could have important clinical applications in the patient for whom aspiration of monosodium urate crystals from the joint is not possible. Imaging can also provide outcome measures, such as change in tophus volume, for monitoring the response to urate-lowering therapy and this is an important application in the clinical trial setting.     

Imaging in cardiac resynchronisation therapy

A substantial number of heart failure (HF) patients do not respond after cardiac resynchronisation therapy (CRT). Recent studies observed that assessment of intraventricular (LV) dyssynchrony may allow identification of potential responders to CRT. In addition, presence of scar tissue and venous anatomy may play a role in the selection of candidates. In this review, an extensive overview of the available LV dyssynchrony measurements is provided using different echocardiographic modalities. In addition, the value of other noninvasive techniques such as magnetic resonance imaging, nuclear imaging and computed tomography for the selection of potential candidates for CRT will be discussed. (Neth Heart J 2008;16(suppl 1):S36-S40.)     

Recent advances in intravital microscopy for preclinical research

Intravital microscopy (IVM) has revolutionized our understanding of single-cell behavior in complex tissues by enabling real-time observation of molecular and cellular processes in their natural environment. In preclinical research, IVM has emerged as a standard tool for mechanistic studies of therapy response and the rational design of new treatment strategies. Technological developments keep expanding the imaging depth and quality that can be achieved in living tissue, and the maturation of imaging modalities such as fluorescence and phosphorescence lifetime imaging facilitates co-registration of individual cell dynamics with metabolic tissue states. Correlation of IVM with mesoscopic and macroscopic imaging modalities further promotes the translation of mechanistic insights gained by IVM into clinically relevant information. This review highlights some of the recent advances in IVM that have made the transition from experimental optical techniques to practical applications in basic and preclinical research.     

Imaging and therapy of malignant pleural mesothelioma using replication-competent herpes simplex viruses

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive cancer that is refractory to current treatment modalities. Oncolytic herpes simplex viruses (HSV) used for gene therapy are genetically engineered, replication-competent viruses that selectively target tumor cells while sparing normal host tissue. The localized nature, the potential accessibility and the relative lack of distant metastasis make MPM a particularly suitable disease for oncolytic viral therapy. METHODS: The infectivity, selective replication, vector spread and cytotoxic ability of three oncolytic HSV: G207, NV1020 and NV1066, were tested against eleven pathological types of MPM cell lines including those that are resistant to radiation therapy, gemcitabine or cisplatin. The therapeutic efficacy and the effect on survival of NV1066 were confirmed in a murine MPM model. RESULTS: All three oncolytic HSV were highly effective against all the MPM cell lines tested. Even at very low concentrations of MOI 0.01 (MOI: multiplicity of viral infection, ratio of viral particles per cancer cell), HSV were highly effective against MPM cells that are resistant to radiation, gemcitabine and cisplatin. NV1066, an oncolytic HSV that expresses green fluorescent protein (GFP), was able to delineate the extent of the disease in a murine model of MPM due to selective infection and expression of GFP in tumor cells. Furthermore, NV1066 was able to reduce the tumor burden and prolong survival even when treatment was at an advanced stage of the disease. CONCLUSION: These findings support the continued investigation of oncolytic HSV as potential therapy for patients with therapy-resistant MPM.