[show abstract][hide abstract] ABSTRACT: Renal function and imaging findings have not been comprehensively and prospectively characterized in a broad age range of patients with molecularly confirmed autosomal recessive polycystic kidney disease (ARPKD).
Ninety potential ARPKD patients were examined at the National Institutes of Health Clinical Center. Seventy-three fulfilled clinical diagnostic criteria, had at least one PKHD1 mutation, and were prospectively evaluated using magnetic resonance imaging (MRI), high-resolution ultrasonography (HR-USG), and measures of glomerular and tubular function.
Among 31 perinatally symptomatic patients, 25% required renal replacement therapy by age 11 years; among 42 patients who became symptomatic beyond 1 month (nonperinatal), 25% required kidney transplantation by age 32 years. Creatinine clearance (CrCl) for nonperinatal patients (103 +/- 54 ml/min/1.73 m(2)) was greater than for perinatal patients (62 +/- 33) (P = 0.002). Corticomedullary involvement on HR-USG was associated with a significantly worse mean CrCl (61 +/- 32) in comparison with medullary involvement only (131 +/- 46) (P < 0.0001). Among children with enlarged kidneys, volume correlated inversely with function, although with wide variability. Severity of PKHD1 mutations did not determine kidney size or function. In 35% of patients with medullary-only abnormalities, standard ultrasound was normal and the pathology was detectable with HR-USG.
In ARPKD, perinatal presentation and corticomedullary involvement are associated with faster progression of kidney disease. Mild ARPKD is best detected by HR-USG. Considerable variability occurs that is not explained by the type of PKHD1 mutation.
Clinical Journal of the American Society of Nephrology 04/2010; 5(6):972-84. · 5.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: Multi-modality imaging probes combine the advantages of individual imaging techniques to yield highly detailed anatomic and molecular information in living organisms. Herein, we report the synthesis and characterization of a dual-modality nanoprobe that couples the magnetic properties of ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) with the near infrared fluorescence of Cy5.5. The fluorophore is encapsulated in a biocompatible shell of silica surrounding the iron oxide core for a final diameter of approximately 17 nm. This silica-coated iron oxide nanoparticle (SCION) has been analyzed by transmission electron microscopy, dynamic light scattering, and superconducting quantum interference device (SQUID). The particle demonstrates a strong negative surface charge and maintains colloidal stability in the physiological pH range. Magnetic hysteresis analysis confirms superparamagnetic properties that could be manipulated for thermotherapy. The viability of primary human monocytes, T cells, and B cells incubated with the particle has been examined in vitro. In vivo analysis of agent leakage into subcutaneous A431 tumors in mice was also conducted. This particle has been designed for diagnostic application with magnetic resonance and fluorescence imaging, and has future potential to serve as a heat-sensitive targeted drug delivery platform.
[show abstract][hide abstract] ABSTRACT: The development of imaging technologies that have sufficient specificity and sensitivity to enable early, accurate detection of cancer and response to therapy has long been a goal in oncology. Various radiological techniques have been used for diagnosis and surveillance of disease recurrence and imaging has revolutionised oncology. However, despite the widespread use of technologies, the ability of currently available imaging methods to facilitate early detection, precise characterisation, and accurate localisation of malignant disease could be improved. The simultaneous use of two or more techniques, contrast reagents, signalling methods, or the coupling of agent and tissue properties to achieve so-called multiplexed imaging is a promising approach. In this review, we provide a broad overview of current and emerging multiplexed, imaging technologies.
The lancet oncology 03/2010; 11(6):589-95. · 14.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: MRI is currently the most promising imaging modality for prostate cancer diagnosis due to its high resolution and multiparametric nature. However, currently there is no standard for integration of diagnostic information from different MRI sequences. We propose a method to increase the diagnostic accuracy of MRI by correlating biopsy specimens with four MRI sequences including T2 weighted MRI, Diffusion Weight Imaging, Dynamic Contrast Enhanced MRI and MRI spectroscopy. This method uses device tracking and image fusion to determine the specimen's position on MRI images. The proposed method is unbiased and cost effective. It does not substantially interfere with the standard biopsy workflow, allowing it to be easily accepted by physicians. A study of 41 patients was carried out to validate the approach. The performance of all four MRI sequences in various combinations is reported. Guidelines are given for multi-parametric imaging and tracked biopsy of prostate cancer.
[show abstract][hide abstract] ABSTRACT: An optical probe, RG-(gal)(28)GSA, was synthesized to improve the detection of peritoneal implants by targeting the beta-d-galactose receptors highly expressed on the cell surface of a wide variety of cancers arising from the ovary, pancreas, colon, and stomach. Evaluation of RG-(gal)(28)GSA, RG-(gal)(20)GSA, glucose-analogue RG-(glu)(28)GSA, and control RG-HSA demonstrates specificity for the galactose, binding to several human adenocarcinoma cell lines, and cellular internalization. Studies using peritoneally disseminated SHIN3 xenografts in mice also confirmed a preference for galactose with the ability to detect submillimeter size lesions. Preliminary toxicity study for RG-(gal)(28)GSA using Balb/c mice reveal no toxic effects up to 100x of the standard imaging dose of 1 mg/kg administered either intraperitoneally or intravenously. These data indicate that RG-(gal)(28)GSA can selectively target a variety of human adenocarcinomas, can improve intraoperative or endoscopic tumor detection and resection, and may have little or no toxic in vivo effects; hence, it may be clinically translatable.
Journal of Medicinal Chemistry 02/2010; 53(4):1579-86. · 5.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: The microdistribution of therapeutic monoclonal antibodies within a tumor is important for determining clinical response. Nonuniform microdistribution predicts therapy failure. Herein, we developed a semiquantitative method for measuring microdistribution of an antibody within a tumor using in situ fluorescence microscopy and sought to modulate the microdistribution by altering the route and timing of antibody dosing. The microdistribution of a fluorescently-labeled antibody, trastuzumab (50-mug and 150-mug intraperitoneal injection (i.p.), and 100-mug intravenous injection (i.v.)) was evaluated in a peritoneal dissemination mouse model of ovarian cancer. In addition, we evaluated the microdistribution of concurrently-injected (30-mug i.p. and 100-mug i.v.) or serial (two doses of 30-mug i.p.) trastuzumab using in situ multicolor fluorescence microscopy. After the administration of 50-mug i.p. and 100-mug i.v. trastuzumab fluorescence imaging showed no significant difference in the central to peripheral signal ratio (C/P ratio) and demonstrated a peripheral-dominant accumulation, whereas administration of 150-mug i.p. trastuzumab showed relatively uniform, central dominant accumulation. With concurrent-i.p.-i.v. injections trastuzumab showed slightly higher C/P ratio than concurrently-injected i.p. trastuzumab. Moreover, in the serial injection study, the second injection of trastuzumab distributed more centrally than the first injection, while no difference was observed in the control group. Our results suggest that injection routes do not affect the microdistribution pattern of antibody in small peritoneal disseminations. However, increasing the dose results in a more uniform antibody distribution within peritoneal nodules. Furthermore, the serial i.p. injection of antibody can modify the microdistribution within tumor nodules. This work has implications for the optimal delivery of antibody based cancer therapies.
[show abstract][hide abstract] ABSTRACT: To evaluate clinical activity and target modulation of vandetanib in women with recurrent ovarian cancer.
A phase II trial of orally administered vandetanib 300 mg daily was designed to include analyses of target inhibition through paired biopsies and dynamic imaging. Core 18-gauge needle biopsies and dynamic contrast-enhanced magnetic resonance imaging were obtained before initiation of therapy and 6 weeks into therapy. Biopsy samples were subjected to reverse-phase protein lysate array endpoint analysis. Cytokine concentrations were measured by enzyme-linked immunosorbent assay in serially collected plasma samples.
Twelve patients entered the study, and accrual was terminated in the first stage because of lack of response or disease stabilization beyond 6 months. Adverse events included rash, diarrhea, and prolonged QT interval corrected for heart rate, but not hypertension. Exploratory analyses showed that epidermal growth factor receptor (EGFR) phosphorylation was reduced in the eight paired biopsy sets obtained; vascular endothelial growth factor (VEGF) receptor-2 phosphorylation was not consistently affected nor were dynamic contrast-enhanced MRI permeability and flow parameters. Serial plasma VEGF concentrations were variable and did not significantly change in the 11 patients assessed.
Vandetanib 300 mg daily monotherapy had no significant clinical benefit in this disease setting. Proteomic analysis of paired biopsies detected both phosphorylated-EGFR and phosphorylated-VEGF receptor-2 in ovarian tumor tissue, but only phosphorylated-EGFR was measurably inhibited by vandetanib.
Clinical Cancer Research 01/2010; 16(2):664-72. · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: In this paper, a system for fusion of realtime transrectal ultrasound (TRUS) with pre-acquired 3D images of the prostate is
presented with a clinical demonstration on a cohort of 101 patients with suspicion of prostate cancer. Electromagnetically
tracked biopsy guides for endocavity ultrasound transducers were calibrated and used to fuse MRI-based suspicious lesion locations
with ultrasound image coordinates. The prostate shape is segmented from MRI in a semi-automated fashion via a model-based
approach, and intraoperative image registration is performed between MR and ultrasound image space to superimpose target fiducials
markers on the ultrasound image. In order to align both modalities, a surface model is automatically extracted from 2D swept
TRUS images using a partial active shape model, utilizing image features and prior statistics. An automatic prostate motion
compensation algorithm can be triggered as needed. The results were used to display live TRUS images fused with spatially
corresponding realtime multiplanar reconstructions (MPRs) of the MR image volume. In this study, all patients were scanned
with 3T MRI and TRUS for biopsy. Clinical results show significant improvement of target visualization and of positive detection
rates during TRUS-guided biopsies. It also demonstrates the feasibility of realtime MR/TRUS image fusion for out-of-gantry
Prostate Cancer Imaging. Computer-Aided Diagnosis, Prognosis, and Intervention - International Workshop, Held in Conjunction with MICCAI 2010, Beijing, China, September 24, 2010. Proceedings; 01/2010
[show abstract][hide abstract] ABSTRACT: In vivo optical imaging using fluorescently labeled self-quenched monoclonal antibodies, activated through binding and internalization within target cells, results in excellent target-to-background ratios. We hypothesized that these molecular probes could be utilized to accurately report on cellular internalization with fluorescence lifetime imaging (FLI). Two imaging probes were synthesized, consisting of the antibody trastuzumab (targeting HER2/neu) conjugated to Alexa Fluor750 in ratios of either 1:8 or 1:1. Fluorescence intensity and lifetime of each conjugate were initially determined at endosomal pHs. Since the 1:8 conjugate is self-quenched, the fluorescence lifetime of each probe was also determined after exposure to the known dequencher SDS. In vitro imaging experiments were performed using 3T3/HER2(+) and BALB/3T3 (HER2(-)) cell lines. Changes in fluorescence lifetime correlated with temperature- and time-dependent cellular internalization. In vivo imaging studies in mice with dual flank tumors [3T3/HER2(+) and BALB/3T3 (HER2(-))] detected a minimal difference in FLI. In conclusion, fluorescence lifetime imaging monitors the internalization of target-specific activatable antibody-fluorophore conjugates in vitro. Challenges remain in adapting this methodology to in vivo imaging.
[show abstract][hide abstract] ABSTRACT: Prostate cancer continues to represent a major health problem, and yet there is no effective treatment available for advanced metastatic disease. Thus, there is an urgent need for the development of more effective treatment modalities that could improve the outcome. Because prostate specific membrane antigen (PSMA), a transmembrane protein, is expressed by virtually all prostate cancers, and its expression is further increased in poorly differentiated, metastatic, and hormone-refractory carcinomas, it is a very attractive target. Molecules targeting PSMA can be labelled with radionuclides to become both diagnostic and/or therapeutic agents. The use of PSMA binding agents, labelled with diagnostic and therapeutic radio-isotopes, opens up the potential for a new era of personalized management of metastatic prostate cancer.
Discovery medicine 01/2010; 9(44):55-61. · 2.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: Accurate imaging of the lymphatic system can aid in cancer staging, optimize surgical procedures to reduce lymphedema, and may one day be a means of delivering intralymphatic therapy. The Sentinel Lymph Node (SLN) concept has been pivotal in driving new imaging techniques. Metastasis to a SLN is a critical indicator of advanced disease. However, presently, few tools are available for imaging the lymphatics, and even fewer are available for locating the SLN for biopsy. Recently, new macromolecular agents, including gadolinium-labeled dendrimers, fluorescent quantum dots, and fluorescently-labeled immunoglobins, have been used to image the lymphatics and SLN with MRI and optical techniques, and new fluorescent nanoparticles such as upconverting nanocrystals are potential future agents. Additionally, multi-modality probes combining two modalities such as optical/MR dendrimers have been designed to provide both preoperative imaging, and intraoperative guidance during lymph node resections. These probes can map the lymphatic system for maximal therapeutic benefit while minimizing complications such as lymphedema. Advances in the understanding of the molecular mechanisms of lymphangiogenesis and lymphatic spread of tumors offer the opportunity for more targeted imaging of the lymphatic system. Additionally, these imaging agents could be used as powerful research tools for tracking immunological cells and monitoring the immune response as well as providing the means to deliver lymphatic-targeted therapies. The future holds great promise for the translation of these methods to the clinic.
Lymphatic Research and Biology 12/2009; 7(4):205-14. · 2.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: Fluorophores are potentially useful for in vivo cancer diagnosis. Using relatively inexpensive and portable equipment, optical imaging with fluorophores permits real-time detection of cancer. However, fluorophores can be toxic and must be investigated before they can be administered safely to patients. A review of published literature on the toxicity of 19 widely used fluorophores was conducted by searching 26 comprehensive biomedical and chemical literature databases and analyzing the retrieved material. These fluorophores included Alexa Fluor 488 and 514, BODIPY FL, BODIPY R6G, Cy 5.5, Cy 7, cypate, fluorescein, indocyanine green, Oregon green, 8-phenyl BODIPY, rhodamine 110, rhodamine 6G, rhodamine X, rhodol, TAMRA, Texas red, and Tokyo green. Information regarding cytotoxicity, tissue toxicity, in vivo toxicity, and mutagenicity was included. Considerable toxicity-related information was available for the Food and Drug Administration (FDA)-approved compounds indocyanine green and fluorescein, but published information on many of the non-FDA-approved fluorophores was limited. The information located was encouraging because the amounts of fluorophore used in molecular imaging probes are typically much lower than the toxic doses described in the literature. Ultimately, the most effective and appropriate probes for use in patients will be determined by their fluorescent characteristics and the safety of the conjugates.
[show abstract][hide abstract] ABSTRACT: Angiogenesis is a key step in the pathophysiology of tumor growth and metastatic spread. Recently, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has emerged as a method for assessing angiogenesis both during the initial diagnosis and for follow up of anti-angiogenic therapies. In this review, we discuss the technical aspects of implementing DCE-MRI in clinical practice with emphasis on acquisition methods and analytic techniques.
[show abstract][hide abstract] ABSTRACT: Near-infrared (NIR) fluorescence cancer imaging is a growing field for both preclinical and clinical application to the clinical management for cancer patients due to its advantageous features, including a high spatial resolution, portability, real-time display and detailed molecular profiling with the multiplexed use of fluorescent probes. In this review, we present a basic concept of NIR fluorescence imaging and overview its potential clinical applications for in vivo cancer imaging, including cancer detection/characterization, lymphatic imaging (sentinel lymph node detection) and surgical/endoscopic guidance. NIR fluorescence imaging can compensate some limitations of conventional imaging modalities, and thus it could play an important role for cancer imaging combined with other modalities in clinical practice.
[show abstract][hide abstract] ABSTRACT: Advancements in medical imaging have brought about unprecedented changes in the in vivo assessment of cancer. Positron emission tomography, single photon emission computed tomography, optical imaging, and magnetic resonance imaging are the primary tools being developed for oncologic imaging. These techniques may still be in their infancy, as recently developed chemical molecular probes for each modality have improved in vivo characterization of physiologic and molecular characteristics. Herein, we discuss advances in these imaging techniques, and focus on the major design strategies with which molecular probes are being developed.