- Diagnostic Radiology
- Abdominal and Pelvic Imaging
- Cancer Imaging
- Molecular Imaging
Member, Molecular Imaging Program at Stanford (MIPS) (2008 - Present)
Member, Center for Biomedical Imaging at Stanford (CBIS) (2008 - Present)
Principal Investigator, Translational Molecular Imaging Laboratory (TMIL) (2008 - Present)
Member, Stanford Cancer Center (2009 - Present)
Associate Chief, Body Imaging, Department of Radiology Stanford University Medical Center, Stanford University Hospital (2012 - 2013)
Member BioX, Stanford University (2012 - Present)
Clinical Division Chief, Body Imaging, Department of Radiology Stanford University Medical Center, Stanford University Hospital (2013 - Present)
Executive Vice Chair of Strategy, Outreach, and Clinical Trials, Department of Radiology, Stanford University Hospital (2017 - Present)
Honors & Awards
Poster award ("cum laude"), German Society of Radiology (2002)
Poster award ("magna cum laude"), Swiss Society of Radiology (2004)
Research Fellowship Award, Swiss Society of Radiology (2006-2007)
Research Fellowship Award, Swiss Foundation For Medical-Biological Grants (SSMBS) (2006-2008)
Editor's Recognition Award - awarded in recognition of outstanding service as a reviewer, European Journal of Radiology (2007)
RSNA Research Award in the category "Molecular Imaging", Radiological Society of North America (2007)
Travel award, Society of Molecular Imaging and Academy of Molecular Imaging (2007)
Editor's Recognition Award - awarded in recognition of outstanding service as a reviewer, European Journal of Radiology (2008)
European Society of Gastrointestinal and Abdominal Radiology Bronze Award, European Radiology (2008)
RSNA Research Award in the category "Molecular Imaging", Radiological Society of North America (2008)
Radiology Editor's Recognition Award with Distinction for reviewing as an outstanding reviewer, Radiological Society of North America (2008)
Molecular Pathogenesis of Digestive Diseases, Pilot Award, Digestive Disease Center Pilot Feasability Program (2009)
The Howard S. Stern Research Award, Society of Gastrointestinal Radiologists (2009)
The Walter Friedrich Award for Outstanding Research in Radiology, German Society of Radiology (2009)
2010 Radiology Editor's Recognition Award with Distinction as an outstanding reviewer, Radiological Society of North America (2010)
2010 Roscoe E. Miller Award of the Society of Gastrointestinal Radiology, USA, Society of Gastrointestinal Radiology (2010)
2011 Roscoe E. Miller Award of the Society of Gastrointestinal Radiology, USA, Society of Gastrointestinal Radiology (2011)
Tenure, Stanford University (2011)
2013 Research Award (co-author), Society of Abdominal Radiology (2013)
Bronze poster award (senior author), Korean Society of Ultrasound in Medicine (2013)
Silver poster award (senior author), Korean Society of Ultrasound in Medicine (2013)
Elected Fellow of the Society of Abdominal Radiology (FSAR), Society of Abdominal Radiology (2014)
Best Basic Translational Research Scientific Paper Award, Society of Abdominal Radiology (2016)
Distinguished Investigator Award 2017, Academy for Radiology & Biomedical Imaging Research (2017)
Election to the College of Fellows, American Institute for Medical and Biological Engineering (AIMBE) (2017)
Boards, Advisory Committees, Professional Organizations
Editorial Board, Journal of Ultrasound (2014 - Present)
Editorial Board, Investigative Radiology (2013 - 2014)
Associate Editor, Quantitative Imaging in Medicine and Surgery (2012 - Present)
Deputy Editor, Academic Radiology (2011 - Present)
Senior Editorial Board, American Journal of Nuclear Medicine and Molecular Imaging (2011 - Present)
Guest Editor, Theranostics (2011 - 2011)
Residency:University Hospital Zurich (2003) Switzerland
Internship:University Hospital Freiburg (1999) Germany
Medical Education:Albert-Ludwigs-University Freiburg (1998) Germany
Current Research and Scholarly Interests
In the United States, cancer continues to be the leading cause of death in patients between 25 and 64 years of age, and the second leading cause of death in patients both above 65 years and between 1 and 14 years. Since prognosis and survival of patients with cancer highly depend on the tumor stage at the time of diagnosis, early cancer detection shows great promise in prolonging survival and improving quality of life in cancer patients. Therefore, novel imaging strategies are highly desirable that allow detection of cancer at early, still curable stages. Furthermore, with the advent of novel therapeutic options for cancer patients there is an increasing demand for non-invasive imaging biomarkers to identify those patients early on that benefit most from a given treatment or to terminate or modify treatment for those patients not responding to a certain treatment.
In my laboratory we focus on the development and clinical translation of novel molecular and functional imaging biomarkers with special focus on imaging abdominal and pelvic cancer including pancreatic, liver, renal, ovarian, and prostate cancer. We further advance clinically available radiological imaging modalities such as ultrasound, magnetic resonance imaging (MRI), and positron emission tomography (PET) as promising imaging tools for early detection and treatment monitoring of abdominal and pelvic cancer. Our mission is to integrate novel molecular and functional imaging strategies into clinical protocols for improved patient care in the near future.
Combined F-18 NaF and F-18 FDG PET/CT for Evaluation of Malignancy
Fluorine-18 Fluorodeoxyglucose (F-18 FDG) PET/CT is established as a powerful imaging tool for cancer detection and monitoring response to therapy. Sodium Fluorine-18 (F-18) was used in the 1970s for bone scanning and can be used as a skeletal tracer in current PET/CT scanners. The combined administration of F-18 and F-18 FDG in a single PET/CT scan for cancer detection was not attempted to date. We hope to learn what is the best approach for detection of cancer and thus to improve cancer treatment.
Feasibility 3D Perfusion Ultrasound for Liver Cancer SABR Planning and Response Evaluation
Primary Objective: The primary objectives of this prospective pilot study is to: 1. determine the feasibility and reproducibility of 3D contrast enhanced ultrasound imaging in liver cancer patients undergoing Stereotactic Ablative Radiotherapy and 2. evaluate whether there are treatment induced early changes in imaging metrics derived from 3D contrast enhanced ultrasound. This study will provide valuable insight as to the potential of baseline and/or early post-treatment 3D ultrasound perfusion characteristics (measurements of blood-flow) of primary and metastatic liver tumors to predict tumor response to Stereotactic Ablative Radiotherapy. The investigators' underlying goal is to assess whether early perfusion changes at 1-7 days after SABR initiation can be used as a non-invasive early biomarker for treatment response assessment. Secondary Objectives: Evaluate the feasibility of contrast-enhanced ultrasound-to-CT fusion by assisting three-dimensional (3D) perfusion ultrasound (US) imaging with optical and electromagnetic tracking of the ultrasound probe on patients with liver cancer that will undergo CT for treatment planning and/or response evaluation.
Pilot 3D Contrast-Enhanced Ultrasound Imaging to Predict Treatment Response in Liver Metastases
Patients are invited to participate in a research study of liver perfusion (how blood flows to the liver over time). Researchers hope to learn whether perfusion characteristics of liver metastases may be predictive of response to treatment and whether liver perfusion characteristics can be used to follow response to treatment. Patients were selected as a possible participant in this study because they are identified as having liver metastases
A Pilot Trial Using BR55 Ultrasound Contrast Agent in the Assessment of Prostate Cancer
Pilot study to evaluate the sensitivity and specificity of BR55 targeting for prostate cancer nodules with Gleason score greater than or equal to 7.
Stanford is currently not accepting patients for this trial. For more information, please contact Phuong Pham, 650-725-9810.
B-mode Ultrasound Imaging in Detecting Early Liver Cancer
This pilot trial studies how well B-mode ultrasound imaging works in detecting liver cancer that is early in its growth and may not have spread to other parts of the body. Diagnostic procedures, such as B-mode ultrasound imaging, may help find and diagnose liver cancer and find out how far the disease has spread.
Stanford is currently not accepting patients for this trial. For more information, please contact Sunitha Bachawal, 650-724-1472.
Perfusion CT as a Predictor of Treatment Response in Patients With Hepatic Malignancies
A research study of liver perfusion (how blood flows to the liver over time). We hope to learn whether perfusion characteristics of liver masses may be predictive of response to treatment and whether liver perfusion characteristics can be used to follow response to treatment.
Stanford is currently not accepting patients for this trial. For more information, please contact Elizabeth Chitouras, 650-498-0623.
Perfusion CT as a Predictor of Treatment Response in Patients With Rectal Cancer
A research study of rectal cancer perfusion (how blood flows to the rectum over time). We hope to learn whether perfusion characteristics of rectal masses may be predictive of response to treatment and whether rectal perfusion characteristics can be used to follow response to treatment.
Stanford is currently not accepting patients for this trial. For more information, please contact Laura Gable, 650-736-0798.
SonoVue®-Enhanced Ultrasound (US) Versus Unenhanced US for Focal Liver Lesion Characterization
The purpose of this study is to demonstrate the Sensitivity and Specificity of SonoVue®-enhanced ultrasound is superior to that of unenhanced ultrasound for the characterization of benign versus malignant FLLs using final diagnosis based on histology or combined imaging (CE-CT and/or CE MRI)/clinical data as truth standard.
Stanford is currently not accepting patients for this trial. For more information, please contact Lindee Burton, (650) 725 - 4712.
Ultrasound Elastography in Diagnosing Patients With Kidney or Liver Solid Focal Lesions
This clinical trial studies ultrasound elastography in diagnosing patients with kidney or liver solid focal lesions. New diagnostic procedures, such as ultrasound elastography, may be a less invasive way to check for kidney or liver solid focal lesions.
Stanford is currently not accepting patients for this trial. For more information, please contact Juergen Willmann, 650-725-1812.
Independent Studies (6)
- Directed Reading in Radiology
RAD 299 (Aut, Win, Spr, Sum)
- Early Clinical Experience in Radiology
RAD 280 (Aut, Win, Spr, Sum)
- Graduate Research
RAD 399 (Aut, Win, Spr, Sum)
- Medical Scholars Research
RAD 370 (Aut, Win, Spr, Sum)
- Readings in Radiology Research
RAD 101 (Aut, Win, Spr, Sum)
- Undergraduate Research
RAD 199 (Aut, Win, Spr, Sum)
- Directed Reading in Radiology
Ultrasound-guided therapeutic modulation of hepatocellular carcinoma using complementary microRNAs.
Journal of controlled release
2016; 238: 272-280
Treatment options for patients with hepatocellular carcinoma (HCC) are limited, in particular in advanced and drug resistant HCC. MicroRNAs (miRNA) are non-coding small RNAs that are emerging as novel drugs for the treatment of cancer. The aim of this study was to assess treatment effects of two complementary miRNAs (sense miRNA-122, and antisense antimiR-21) encapsulated in biodegradable poly (lactic-co-glycolic acid) nanoparticles (PLGA-NP), administered by an ultrasound-guided and microbubble-enhanced delivery approach in doxorubicin-resistant and non-resistant human HCC xenografts. Proliferation and invasiveness of human HCC cells after miRNA-122/antimiR-21 and doxorubicin treatment were assessed in vitro. Confocal microscopy and qRT-PCR were used to visualize and quantitate successful intracellular miRNA-loaded PLGA-NP delivery. Up and down-regulation of miRNA downstream targets and multidrug resistance proteins and extent of apoptosis were assessed in vivo in treated human HCC xenografts in mice. Compared to single miRNA therapy, combination therapy with the two complementary miRNAs resulted in significantly (P<0.05) stronger decrease in cell proliferation, invasion, and migration of HCC cells as well as higher resensitization to doxorubicin. Ultrasound-guided delivery significantly increased in vivo miRNA-loaded PLGA-NP delivery in human HCC xenografts compared to control conditions by 5-9 fold (P<0.001). miRNA-loaded PLGA-NP were internalized in HCC cells and anti-apoptotic proteins were down regulated with apoptosis in ~27% of the tumor volume of doxorubicin-resistant human HCC after a single treatment with complementary miRNAs and doxorubicin. Thus, ultrasound-guided delivery of complementary miRNAs is highly efficient in the treatment of doxorubicin- resistant and non-resistant HCC. Further development of this new treatment approach could aid in better treatment of patients with HCC.
View details for DOI 10.1016/j.jconrel.2016.08.005
View details for PubMedID 27503707
View details for PubMedCentralID PMC5185600
VEGFR2-Targeted Three-Dimensional Ultrasound Imaging Can Predict Responses to Antiangiogenic Therapy in Preclinical Models of Colon Cancer.
2016; 76 (14): 4081-4089
Three-dimensional (3D) imaging capabilities to assess responses to anticancer therapies are needed to minimize sampling errors common to two-dimensional approaches as a result of spatial heterogeneity in tumors. Recently, the feasibility and reproducibility of 3D ultrasound molecular imaging (3D USMI) using contrast agents, which target molecular markers, have greatly improved, due to the development of clinical 3D matrix array transducers. Here we report preclinical proof-of-concept studies showing that 3D USMI of VEGFR2/KDR expression accurately gauges longitudinal treatment responses to antiangiogenesis therapy in responding versus nonresponding mouse models of colon cancer. Tumors in these models exhibited differential patterns of VEGFR2-targeted 3D USMI signals during the course of antiangiogenic treatment with bevacizumab. In responding tumors, the VEGFR2 signal decreased as soon as 24 hours after therapy was started, whereas in nonresponding tumors there was no change in signal at any time point. The early decrease in VEGFR2 signal was highly predictive of treatment outcome at the end of therapy. Our results offer preclinical proof that 3D USMI can predict responses to antiangiogenic therapy, warranting further investigation of its clinical translatability to predicting treatment outcomes in patients. Cancer Res; 76(14); 4081-9. ©2016 AACR.
View details for DOI 10.1158/0008-5472.CAN-15-3271
View details for PubMedID 27206846
Combining in Vitro Diagnostics with in Vivo Imaging for Earlier Detection of Pancreatic Ductal Adenocarcinoma: Challenges and Solutions
2015; 277 (3): 644-661
Pancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer-related death in the United States and is associated with a dismal prognosis, particularly when diagnosed at an advanced stage. Overall survival is significantly improved if PDAC is detected at an early stage prior to the onset of symptoms. At present, there is no suitable screening strategy for the general population. Available diagnostic serum markers are not sensitive or specific enough, and clinically available imaging modalities are inadequate for visualizing early-stage lesions. In this article, the role of currently available blood biomarkers and imaging tests for the early detection of PDAC will be reviewed. Also, the emerging biomarkers and molecularly targeted imaging agents being developed to improve the specificity of current imaging modalities for PDAC will be discussed. A strategy incorporating blood biomarkers and molecularly targeted imaging agents could lead to improved screening and earlier detection of PDAC in the future. (©) RSNA, 2015.
View details for DOI 10.1148/radiol.2015141020
View details for Web of Science ID 000369525100006
View details for PubMedID 26599925
Quantitative Assessment of Inflammation in a Porcine Acute Terminal Ileitis Model: US with a Molecularly Targeted Contrast Agent
2015; 276 (3): 809-817
Purpose To evaluate the feasibility and reproducibility of ultrasonography (US) performed with dual-selectin-targeted contrast agent microbubbles (MBs) for assessment of inflammation in a porcine acute terminal ileitis model, with histologic findings as a reference standard. Materials and Methods The study had institutional Animal Care and Use Committee approval. Acute terminal ileitis was established in 19 pigs; four pigs served as control pigs. The ileum was imaged with clinical-grade dual P- and E-selectin-targeted MBs (MBSelectin) at increasing doses (0.5, 1.0, 2.5, 5.0, 10, and 20 × 10(8) MB per kilogram of body weight) and with control nontargeted MBs (MBControl). For reproducibility testing, examinations were repeated twice after the MBSelectin and MBControl injections. After imaging, scanned ileal segments were analyzed ex vivo both for inflammation grade (by using hematoxylin-eosin staining) and for expression of selectins (by using quantitative immunofluorescence analysis). Statistical analysis was performed by using the t test, intraclass correlation coefficients (ICCs), and Spearman correlation analysis. Results Imaging signal increased linearly (P < .001) between a dose of 0.5 and a dose of 5.0 × 10(8) MB/kg and plateaued between a dose of 10 and a dose of 20 × 10(8) MB/kg. Imaging signals were reproducible (ICC = 0.70), and administration of MBSelectin in acute ileitis resulted in a significantly higher (P < .001) imaging signal compared with that in control ileum and MBControl. Ex vivo histologic grades of inflammation correlated well with in vivo US signal (ρ = 0.79), and expression levels of both P-selectin (37.4% ± 14.7 [standard deviation] of vessels positive; P < .001) and E-selectin (31.2% ± 25.7) in vessels in the bowel wall of segments with ileitis were higher than in control ileum (5.1% ± 3.7 for P-selectin and 4.8% ± 2.3 for E-selectin). Conclusion Quantitative measurements of inflammation obtained by using dual-selectin-targeted US are reproducible and correlate well with the extent of inflammation at histologic examination in a porcine acute ileitis model as a next step toward clinical translation. (©) RSNA, 2015 Online supplemental material is available for this article.
View details for DOI 10.1148/radiol.2015142478
View details for Web of Science ID 000364363500020
View details for PubMedID 25965901
Breast Cancer Detection by B7-H3-Targeted Ultrasound Molecular Imaging.
2015; 75 (12): 2501-2509
Ultrasound complements mammography as an imaging modality for breast cancer detection, especially in patients with dense breast tissue, but its utility is limited by low diagnostic accuracy. One emerging molecular tool to address this limitation involves contrast-enhanced ultrasound using microbubbles targeted to molecular signatures on tumor neovasculature. In this study, we illustrate how tumor vascular expression of B7-H3 (CD276), a member of the B7 family of ligands for T-cell coregulatory receptors, can be incorporated into an ultrasound method that can distinguish normal, benign, precursor, and malignant breast pathologies for diagnostic purposes. Through an IHC analysis of 248 human breast specimens, we found that vascular expression of B7-H3 was selectively and significantly higher in breast cancer tissues. B7-H3 immunostaining on blood vessels distinguished benign/precursors from malignant lesions with high diagnostic accuracy in human specimens. In a transgenic mouse model of cancer, the B7-H3-targeted ultrasound imaging signal was increased significantly in breast cancer tissues and highly correlated with ex vivo expression levels of B7-H3 on quantitative immunofluorescence. Our findings offer a preclinical proof of concept for the use of B7-H3-targeted ultrasound molecular imaging as a tool to improve the diagnostic accuracy of breast cancer detection in patients. Cancer Res; 75(12); 2501-9. ©2015 AACR.
View details for DOI 10.1158/0008-5472.CAN-14-3361
View details for PubMedID 25899053
View details for PubMedCentralID PMC4470725
Ultrasound-guided delivery of microRNA loaded nanoparticles into cancer
JOURNAL OF CONTROLLED RELEASE
2015; 203: 99-108
Ultrasound induced microbubble cavitation can cause enhanced permeability across natural barriers of tumors such as vessel walls or cellular membranes, allowing for enhanced therapeutic delivery into the target tissues. While enhanced delivery of small (<1nm) molecules has been shown at acoustic pressures below 1MPa both in vitro and in vivo, the delivery efficiency of larger (>100nm) therapeutic carriers into cancer remains unclear and may require a higher pressure for sufficient delivery. Enhanced delivery of larger therapeutic carriers such as FDA approved pegylated poly(lactic-co-glycolic acid) nanoparticles (PLGA-PEG-NP) has significant clinical value because these nanoparticles have been shown to protect encapsulated drugs from degradation in the blood circulation and allow for slow and prolonged release of encapsulated drugs at the target location. In this study, various acoustic parameters were investigated to facilitate the successful delivery of two nanocarriers, a fluorescent semiconducting polymer model drug nanoparticle as well as PLGA-PEG-NP into human colon cancer xenografts in mice. We first measured the cavitation dose produced by various acoustic parameters (pressure, pulse length, and pulse repetition frequency) and microbubble concentration in a tissue mimicking phantom. Next, in vivo studies were performed to evaluate the penetration depth of nanocarriers using various acoustic pressures, ranging between 1.7 and 6.9MPa. Finally, a therapeutic microRNA, miR-122, was loaded into PLGA-PEG-NP and the amount of delivered miR-122 was assessed using quantitative RT-PCR. Our results show that acoustic pressures had the strongest effect on cavitation. An increase of the pressure from 0.8 to 6.9MPa resulted in a nearly 50-fold increase in cavitation in phantom experiments. In vivo, as the pressures increased from 1.7 to 6.9MPa, the amount of nanoparticles deposited in cancer xenografts was increased from 4- to 14-fold, and the median penetration depth of extravasated nanoparticles was increased from 1.3-fold to 3-fold, compared to control conditions without ultrasound, as examined on 3D confocal microscopy. When delivering miR-122 loaded PLGA-PEG-NP using optimal acoustic settings with minimum tissue damage, miR-122 delivery into tumors with ultrasound and microbubbles was 7.9-fold higher compared to treatment without ultrasound. This study demonstrates that ultrasound induced microbubble cavitation can be a useful tool for delivery of therapeutic miR loaded nanocarriers into cancer in vivo.
View details for DOI 10.1016/j.jconrel.2015.02.018
View details for Web of Science ID 000351696600011
View details for PubMedID 25687306
Vascular Endothelial Growth Factor Receptor Type 2-targeted Contrast-enhanced US of Pancreatic Cancer Neovasculature in a Genetically Engineered Mouse Model: Potential for Earlier Detection.
2015; 274 (3): 790-799
Purpose To test ultrasonographic (US) imaging with vascular endothelial growth factor receptor type 2 ( VEGFR2 vascular endothelial growth factor receptor type 2 )-targeted microbubble contrast material for the detection of pancreatic ductal adenocarcinoma ( PDAC pancreatic ductal adenocarcinoma ) in a transgenic mouse model of pancreatic cancer development. Materials and Methods Experiments involving animals were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. Transgenic mice (n = 44; Pdx1-Cre, KRas(G12D), Ink4a(-/-)) that spontaneously develop PDAC pancreatic ductal adenocarcinoma starting at 4 weeks of age were imaged by using a dedicated small-animal US system after intravenous injection of 5 × 10(7) clinical-grade VEGFR2 vascular endothelial growth factor receptor type 2 -targeted microbubble contrast material. The pancreata in wild-type ( WT wild type ) mice (n = 64) were scanned as controls. Pancreatic tissue was analyzed ex vivo by means of histologic examination (with hematoxylin-eosin staining) and immunostaining of vascular endothelial cell marker CD31 and VEGFR2 vascular endothelial growth factor receptor type 2 . The Wilcoxon rank sum test and linear mixed-effects model were used for statistical analysis. Results VEGFR2 vascular endothelial growth factor receptor type 2 -targeted US of PDAC pancreatic ductal adenocarcinoma showed significantly higher signal intensities (26.8-fold higher; mean intensity ± standard deviation, 6.7 linear arbitrary units [ lau linear arbitrary units ] ± 8.5; P < .001) in transgenic mice compared with normal, control pancreata of WT wild type mice (mean intensity, 0.25 lau linear arbitrary units ± 0.25). The highest VEGFR2 vascular endothelial growth factor receptor type 2 -targeted US signal intensities were observed in smaller tumors, less than 3 mm in diameter (30.8-fold higher than control tissue with mean intensity of 7.7 lau linear arbitrary units ± 9.3 [P < .001]; and 1.7-fold higher than lesions larger than 3 mm in diameter with mean intensity of 4.6 lau linear arbitrary units ± 5.8 [P < .024]). Ex vivo quantitative VEGFR2 vascular endothelial growth factor receptor type 2 immunofluorescence demonstrated that VEGFR2 vascular endothelial growth factor receptor type 2 expression was significantly higher in pancreatic tumors (P < .001; mean fluorescent intensity, 499.4 arbitrary units [au] ± 179.1) compared with normal pancreas (mean fluorescent intensity, 232.9 au ± 83.7). Conclusion US with clinical-grade VEGFR2 vascular endothelial growth factor receptor type 2 -targeted microbubbles allows detection of small foci of PDAC pancreatic ductal adenocarcinoma in transgenic mice. © RSNA, 2014 Online supplemental material is available for this article.
View details for DOI 10.1148/radiol.14140568
View details for PubMedID 25322341
- CT Perfusion of the Liver: Principles and Applications in Oncology RADIOLOGY 2014; 272 (2): 321-343
Acoustic and photoacoustic molecular imaging of cancer.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
2013; 54 (11): 1851-1854
Ultrasound and combined optical and ultrasonic (photoacoustic) molecular imaging have shown great promise in the visualization and monitoring of cancer through imaging of vascular and extravascular molecular targets. Contrast-enhanced ultrasound with molecularly targeted microbubbles can detect early-stage cancer through the visualization of targets expressed on the angiogenic vasculature of tumors. Ultrasonic molecular imaging can be extended to the imaging of extravascular targets through use of nanoscale, phase-change droplets and photoacoustic imaging, which provides further molecular information on cancer given by the chemical composition of tissues and by targeted nanoparticles that can interact with extravascular tissues at the receptor level. A new generation of targeted contrast agents goes beyond merely increasing imaging signal at the site of target expression but shows activatable and differential contrast depending on their interactions with the tumor microenvironment. These innovations may further improve our ability to detect and characterize tumors. In this review, recent developments in acoustic and photoacoustic molecular imaging of cancer are discussed.
View details for DOI 10.2967/jnumed.112.115568
View details for PubMedID 24187042
Detection of pancreatic ductal adenocarcinoma in mice by ultrasound imaging of thymocyte differentiation antigen 1.
2013; 145 (4): 885-894 e3
Early detection of pancreatic ductal adenocarcinoma (PDAC) allows for surgical resection and increases patient survival times. Imaging agents that bind and amplify the signal of neovascular proteins in neoplasms can be detected by ultrasound, enabling accurate detection of small lesions. We searched for new markers of neovasculature in PDAC and assessed their potential for tumor detection by ultrasound molecular imaging.Thymocyte Differentiation Antigen 1 (Thy1) was identified as a specific biomarker of PDAC neovasculature by proteomic analysis. Upregulation in PDAC was validated by immunohistochemical analysis of pancreatic tissue samples from 28 healthy individuals, 15 with primary chronic pancreatitis tissues, and 196 with PDAC. Binding of Thy1-targeted contrast microbubbles was assessed in cultured cells, in mice with orthotopic PDAC xenograft tumors expressing human Thy1 on the neovasculature, and on the neovasculature of a genetic mouse model of PDAC.Based on immunohistochemical analyses, levels of Thy1 were significantly higher in the vascular of human PDAC than chronic pancreatitis (P=.007) or normal tissue samples (P<.0001). In mice, ultrasound imaging accurately detected human Thy1-positive PDAC xenografts, as well as PDACs that express endogenous Thy1 in genetic mouse models of PDAC.We have identified and validated Thy1 as a marker of PDAC that can be detected by ultrasound molecular imaging in mice. The development of a specific imaging agent and identification of Thy1 as a new biomarker could aid in the diagnosis of this cancer and management of patients.
View details for DOI 10.1053/j.gastro.2013.06.011
View details for PubMedID 23791701
Earlier Detection of Breast Cancer with Ultrasound Molecular Imaging in a Transgenic Mouse Model
2013; 73 (6): 1689-1698
While there is an increasing role of ultrasound for breast cancer screening in patients with dense breast, conventional anatomical ultrasound lacks sensitivity and specificity for early breast cancer detection. In this study, we assessed the potential of ultrasound molecular imaging using clinically translatable vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted microbubbles (MB(VEGFR2)) to improve the diagnostic accuracy of ultrasound in earlier detection of breast cancer and ductal carcinoma in situ (DCIS) in a transgenic mouse model [FVB/N-Tg(MMTV-PyMT)634Mul]. In vivo binding specificity studies (n = 26 tumors) showed that ultrasound imaging signal was significantly higher (P < 0.001) using MB(VEGFR2) than nontargeted microbubbles and imaging signal significantly decreased (P < 0.001) by blocking antibodies. Ultrasound molecular imaging signal significantly increased (P < 0.001) when breast tissue (n = 315 glands) progressed from normal [1.65 ± 0.17 arbitrary units (a.u.)] to hyperplasia (4.21 ± 1.16), DCIS (15.95 ± 1.31), and invasive cancer (78.1 ± 6.31) and highly correlated with ex vivo VEGFR2 expression [R(2) = 0.84; 95% confidence interval (CI), 0.72-0.91; P < 0.001]. At an imaging signal threshold of 4.6 a.u., ultrasound molecular imaging differentiated benign from malignant entities with a sensitivity of 84% (95% CI, 78-88) and specificity of 89% (95% CI, 81-94). In a prospective screening trail (n = 63 glands), diagnostic performance of detecting DCIS and breast cancer was assessed and two independent readers correctly diagnosed malignant disease in more than 95% of cases and highly agreed between each other [intraclass correlation coefficient (ICC) = 0.98; 95% CI, 97-99]. These results suggest that VEGFR2-targeted ultrasound molecular imaging allows highly accurate detection of DCIS and breast cancer in transgenic mice and may be a promising approach for early breast cancer detection in women.
View details for DOI 10.1158/0008-5472.CAN-12-3391
View details for Web of Science ID 000316187500006
View details for PubMedID 23328585
Cationic versus Neutral Microbubbles for Ultrasound-mediated Gene Delivery in Cancer
2012; 264 (3): 721-732
To test whether plasmid-binding cationic microbubbles (MBs) enhance ultrasound-mediated gene delivery efficiency relative to control neutral MBs in cell culture and in vivo tumors in mice.Animal studies were approved by the institutional animal care committee. Cationic and neutral MBs were characterized in terms of size, charge, circulation time, and DNA binding. Click beetle luciferase (CBLuc) reporter plasmids were mixed with cationic or neutral MBs. The ability of cationic MBs to protect bound plasmids from nuclease degradation was tested by means of a deoxyribonuclease (DNase) protection assay. Relative efficiencies of ultrasound-mediated transfection (ultrasound parameters: 1 MHz, 1 W/cm(2), 20% duty cycle, 1 minute) of CBLuc to endothelial cells by using cationic, neutral, or no MBs were compared in cell culture. Ultrasound-mediated gene delivery to mouse hind limb tumors was performed in vivo (n = 24) with insonation (1 MHz, 2 W/cm(2), 50% duty cycle, 5 minutes) after intravenous administration of CBLuc with cationic, neutral, or no MBs. Tumor luciferase activity was assessed by means of serial in vivo bioluminescence imaging and ex vivo analysis. Results were compared by using analysis of variance.Cationic MBs (+15.8 mV; DNA binding capacity, 0.03 pg per MB) partially protected bound DNA from DNase degradation. Mean CBLuc expression of treated endothelial cells in culture was 20-fold higher with cationic than with neutral MBs (219.0 relative light units [RLUs]/µg protein ± 92.5 [standard deviation] vs 10.9 RLUs/µg protein ± 2.7, P = .001) and was significantly higher (P < .001) than that in the no MB and no ultrasound control groups. Serial in vivo bioluminescence of mouse tumors was significantly higher with cationic than with neutral MBs ([5.9 ± 2.2] to [9.3 ± 5.2] vs [2.4 ± 0.8] to [2.9 ± 1.1] × 10(4) photons/sec/cm(2)/steradian, P < .0001) and versus no MB and no ultrasound controls (P < .0001). Results of ex vivo analysis confirmed these results (ρ = 0.88, P < .0001).Plasmid-binding cationic MBs enhance ultrasound-mediated gene delivery efficiency relative to neutral MBs in both cell culture and mouse hind limb tumors.
View details for DOI 10.1148/radiol.12112368
View details for Web of Science ID 000308645500013
View details for PubMedID 22723497
View details for PubMedCentralID PMC3426857
Molecular Body Imaging: MR Imaging, CT, and US. Part II. Applications
2012; 264 (2): 349-368
Molecular imaging is expected to have a major impact on the early diagnosis of diseases and disease monitoring in the next decade. Traditionally, nuclear imaging techniques have been the mainstay of molecular imaging in the clinical arena. However, with continued development of molecularly targeted contrast agents for nonnuclear imaging techniques such as magnetic resonance (MR), computed tomography (CT), and ultrasonography (US), the spectrum of clinical molecular imaging applications is expanding. In the second part of this review series, an overview of applications of molecular MR imaging-, CT-, and US-based imaging strategies that show promise for clinical translation is presented, and key challenges that need to be addressed to successfully translate these promising techniques in the future are discussed. © RSNA, 2012.
View details for DOI 10.1148/radiol.12111703
View details for Web of Science ID 000306660000007
View details for PubMedID 22821695
Molecular Body Imaging: MR Imaging, CT, and US. Part I. Principles
2012; 263 (3): 633-643
Molecular imaging, generally defined as noninvasive imaging of cellular and subcellular events, has gained tremendous depth and breadth as a research and clinical discipline in recent years. The coalescence of major advances in engineering, molecular biology, chemistry, immunology, and genetics has fueled multi- and interdisciplinary innovations with the goal of driving clinical noninvasive imaging strategies that will ultimately allow disease identification, risk stratification, and monitoring of therapy effects with unparalleled sensitivity and specificity. Techniques that allow imaging of molecular and cellular events facilitate and go hand in hand with the development of molecular therapies, offering promise for successfully combining imaging with therapy. While traditionally nuclear medicine imaging techniques, in particular positron emission tomography (PET), PET combined with computed tomography (CT), and single photon emission computed tomography, have been the molecular imaging methods most familiar to clinicians, great advances have recently been made in developing imaging techniques that utilize magnetic resonance (MR), optical, CT, and ultrasonographic (US) imaging. In the first part of this review series, we present an overview of the principles of MR imaging-, CT-, and US-based molecular imaging strategies.
View details for DOI 10.1148/radiol.12102394
View details for Web of Science ID 000304416900004
View details for PubMedID 22623690
Quantification and Monitoring of Inflammation in Murine Inflammatory Bowel Disease with Targeted Contrast-enhanced US
2012; 262 (1): 172-180
To evaluate ultrasonography (US) by using contrast agent microbubbles (MBs) targeted to P-selectin (MB(P-selectin)) to quantify P-selectin expression levels in inflamed tissue and to monitor response to therapy in a murine model of chemically induced inflammatory bowel disease (IBD).All procedures in which laboratory animals were used were approved by the institutional administrative panel on laboratory animal care. Binding affinity and specificity of MB(P-selectin) were tested in cell culture experiments under flow shear stress conditions and compared with control MBs (MB(Control)). In vivo binding specificity of MB(P-selectin) to P-selectin was tested in mice with trinitrobenzenesulfonic acid-induced colitis (n = 22) and control mice (n = 10). Monitoring of anti-tumor necrosis factor α antibody therapy was performed over 5 days in an additional 30 mice with colitis by using P-selectin-targeted US imaging, by measuring bowel wall thickness and perfusion, and by using a clinical disease activity index score. In vivo targeted contrast material-enhanced US signal was quantitatively correlated with ex vivo expression levels of P-selectin as assessed by quantitative immunofluorescence.Attachment of MB(P-selectin) to endothelial cells was significantly (P = .0001) higher than attachment of MB(Control) and significantly (ρ = 0.83, P = .04) correlated with expression levels of P-selectin on endothelial cells. In vivo US signal in mice with colitis was significantly higher (P = .0001) with MB(P-selectin) than with MB(Control). In treated mice, in vivo US signal decreased significantly (P = .0001) compared with that in nontreated mice and correlated well with ex vivo P-selectin expression levels (ρ = 0.69; P = .04). Colonic wall thickness (P ≥ .06), bowel wall perfusion (P ≥ .85), and clinical disease activity scoring (P ≥ .06) were not significantly different between treated and nontreated mice at any time.Targeted contrast-enhanced US imaging enables noninvasive in vivo quantification and monitoring of P-selectin expression in inflammation in murine IBD.
View details for DOI 10.1148/radiol.11110323
View details for Web of Science ID 000298611500021
View details for PubMedID 22056689
- Targeted Contrast-Enhanced Ultrasound: An Emerging Technology in Abdominal and Pelvic Imaging. Gastroenterology 2011
Reduced dose CT with model-based iterative reconstruction compared to standard dose CT of the chest, abdomen, and pelvis in oncology patients: intra-individual comparison study on image quality and lesion conspicuity.
To compare image quality and lesion conspicuity of reduced dose (RD) CT with model-based iterative reconstruction (MBIR) compared to standard dose (SD) CT in patients undergoing oncological follow-up imaging.Forty-four cancer patients who had a staging SD CT within 12 months were prospectively included to undergo a weight-based RD CT with MBIR. Radiation dose was recorded and tissue attenuation and image noise of four tissue types were measured. Reproducibility of target lesion size measurements of up to 5 target lesions per patient were analyzed. Subjective image quality was evaluated for three readers independently utilizing 4- or 5-point Likert scales.Median radiation dose reduction was 46% using RD CT (P < 0.01). Median image noise across all measured tissue types was lower (P < 0.01) in RD CT. Subjective image quality for RD CT was higher (P < 0.01) in regard to image noise and overall image quality; however, there was no statistically significant difference regarding image sharpness (P = 0.59). There were subjectively more artifacts on RD CT (P < 0.01). Lesion conspicuity was subjectively better in RD CT (P < 0.01). Repeated target lesion size measurements were highly reproducible both on SD CT (ICC = 0.987) and RD CT (ICC = 0.97).RD CT imaging with MBIR provides diagnostic imaging quality and comparable lesion conspicuity on follow-up exams while allowing dose reduction by a median of 46% compared to SD CT imaging.
View details for DOI 10.1007/s00261-017-1140-5
View details for PubMedID 28417170
Molecular Contrast-Enhanced Ultrasound Imaging of Radiation-Induced P-Selectin Expression in Healthy Mice Colon.
International journal of radiation oncology, biology, physics
2017; 97 (3): 581-585
To evaluate the feasibility of using molecular contrast-enhanced ultrasound (mCEUS) to image radiation (XRT)-induced expression of cell adhesion molecules that mediate inflammatory response to XRT in healthy mouse colon tissue.The colons of male BALB/c mice (aged 6-8 weeks, n=9) were irradiated with 14 Gy using a Kimtron IC-225 x-ray irradiator operating at 225 kV/13.0 mA at a dose rate of 0.985 Gy/min. The head and thorax regions were shielded during irradiation. A second control cohort of mice was left untreated (n=6). Molecular CEUS was carried out before and 24 hours after irradiation using a VEVO2100 system and MS250 21-MHz center frequency transducer. Each imaging session comprised mCEUS imaging with P-selectin targeted microbubbles and control microbubbles targeted with an isotype control IgG. Quantification of mCEUS was carried out by measuring the differential targeted enhancement (dTE) parameter. The perfusion parameters peak enhancement and area under the curve were also extracted from the initial injection bolus. Animals were sacrificed at 24 hours and the colon was resected for immunohistochemistry analysis (P-selectin/CD31-stained vessel).For P-selectin targeted microbubble, a significant increase (40 a.u.; P=.013) in dTE (P-dTE) was observed in irradiated mice over 24 hours. In contrast, a nonsignificant change in P-selectin dTE was observed in control mice. For control microbubbles, no significant difference in the IgG dTE parameter was noted in treated and control animals over 24 hours. A nonsignificant increase in the peak enhancement and area under the curve perfusion parameters associated with blood volume was noted in animals treated with radiation. Quantitative histology indicated significantly elevated P-selectin expression per blood vessel (36% in treated; 14% in control).Our results confirm the feasibility of using mCEUS for imaging of XRT-induced expression of P-selectin as a potential approach to monitoring healthy tissue inflammatory damage during radiation therapy.
View details for DOI 10.1016/j.ijrobp.2016.10.037
View details for PubMedID 28126307
Intra-Animal Comparison between Three-dimensional Molecularly Targeted US and Three-dimensional Dynamic Contrast-enhanced US for Early Antiangiogenic Treatment Assessment in Colon Cancer.
2017; 282 (2): 443-452
Purpose To perform an intra-animal comparison between (a) three-dimensional (3D) molecularly targeted ultrasonography (US) by using clinical-grade vascular endothelial growth factor receptor 2 (VEGFR2)-targeted microbubbles and (b) 3D dynamic contrast material-enhanced (DCE) US by using nontargeted microbubbles for assessment of antiangiogenic treatment effects in a murine model of human colon cancer. Materials and Methods Twenty-three mice with human colon cancer xenografts were randomized to receive either single-dose antiangiogenic treatment (bevacizumab, n = 14) or control treatment (saline, n = 9). At baseline and 24 hours after treatment, animals were imaged with a clinical US system equipped with a clinical matrix array transducer by using the following techniques: (a) molecularly targeted US with VEGFR2-targeted microbubbles, (b) bolus DCE US with nontargeted microbubbles, and (c) destruction-replenishment DCE US with nontargeted microbubbles. VEGFR2-targeted US signal, peak enhancement, area under the time-intensity curve, time to peak, relative blood volume (rBV), relative blood flow, and blood flow velocity were quantified. VEGFR2 expression and percentage area of blood vessels were assessed ex vivo with quantitative immunofluorescence and correlated with corresponding in vivo US parameters. Statistical analysis was performed with Wilcoxon signed rank tests and rank sum tests, as well as Pearson correlation analysis. Results Molecularly targeted US signal with VEGFR2-targeted microbubbles, peak enhancement, and rBV significantly decreased (P ≤ .03) after a single antiangiogenic treatment compared with those in the control group; similarly, ex vivo VEGFR2 expression (P = .03) and percentage area of blood vessels (P = .03) significantly decreased after antiangiogenic treatment. Three-dimensional molecularly targeted US signal correlated well with VEGFR2 expression (r = 0.86, P = .001), and rBV (r = 0.71, P = .01) and relative blood flow (r = 0.78, P = .005) correlated well with percentage area of blood vessels, while other US perfusion parameters did not. Conclusion Three-dimensional molecularly targeted US and destruction-replenishment 3D DCE US provide complementary molecular and functional in vivo imaging information on antiangiogenic treatment effects in human colon cancer xenografts compared with ex vivo reference standards. (©) RSNA, 2016 Online supplemental material is available for this article.
View details for DOI 10.1148/radiol.2016160032
View details for PubMedID 27490690
View details for PubMedCentralID PMC5283869
Spectroscopic Photoacoustic Molecular Imaging of Breast Cancer using a B7-H3-targeted ICG Contrast Agent
2017; 7 (6): 1463-1476
Purpose: Breast cancer imaging methods lack diagnostic accuracy, in particular for patients with dense breast tissue, and improved techniques are critically needed. The purpose of this study was to evaluate antibody-indocyanine green (ICG) conjugates, which undergo dynamic absorption spectrum shifts after cellular endocytosis and degradation, and spectroscopic photoacoustic (sPA) imaging to differentiate normal breast tissue from breast cancer by imaging B7-H3, a novel breast cancer associated molecular target. Methods: Quantitative immunohistochemical staining of endothelial and epithelial B7-H3 expression was assessed in 279 human breast tissue samples, including normal (n=53), benign lesions (11 subtypes, n=129), and breast cancers (4 subtypes, n=97). After absorption spectra of intracellular and degraded B7-H3-ICG and Isotype control-ICG (Iso-ICG) were characterized, sPA imaging in a transgenic murine breast cancer model (FVB/N-Tg(MMTVPyMT)634Mul) was performed and compared to imaging of control conditions [B7-H3-ICG in tumor negative animals (n=60), Iso-ICG (n=30), blocking B7-H3+B7-H3-ICG (n=20), and free ICG (n=20)] and validated with ex vivo histological analysis. Results: Immunostaining showed differential B7-H3 expression on both the endothelium and tumor epithelium in human breast cancer with an area under the ROC curve of 0.93 to differentiate breast cancer vs non-cancer. Combined in vitro/in vivo imaging showed that sPA allowed specific B7-H3-ICG detection down to the 13 nM concentration and differentiation from Iso-ICG. sPA molecular imaging of B7-H3-ICG showed a 3.01-fold (P<0.01) increase in molecular B7-H3-ICG signal in tumors compared to control conditions. Conclusions: B7-H3 is a promising target for both vascular and epithelial sPA imaging of breast cancer. Leveraging antibody-ICG contrast agents and their dynamic optical absorption spectra allows for highly specific sPA imaging of breast cancer.
View details for DOI 10.7150/thno.18217
View details for Web of Science ID 000398783200005
View details for PubMedID 28529630
Ultrasound Elastography: Review of Techniques and Clinical Applications
2017; 7 (5): 1303-1329
Elastography-based imaging techniques have received substantial attention in recent years for non-invasive assessment of tissue mechanical properties. These techniques take advantage of changed soft tissue elasticity in various pathologies to yield qualitative and quantitative information that can be used for diagnostic purposes. Measurements are acquired in specialized imaging modes that can detect tissue stiffness in response to an applied mechanical force (compression or shear wave). Ultrasound-based methods are of particular interest due to its many inherent advantages, such as wide availability including at the bedside and relatively low cost. Several ultrasound elastography techniques using different excitation methods have been developed. In general, these can be classified into strain imaging methods that use internal or external compression stimuli, and shear wave imaging that use ultrasound-generated traveling shear wave stimuli. While ultrasound elastography has shown promising results for non-invasive assessment of liver fibrosis, new applications in breast, thyroid, prostate, kidney and lymph node imaging are emerging. Here, we review the basic principles, foundation physics, and limitations of ultrasound elastography and summarize its current clinical use and ongoing developments in various clinical applications.
View details for DOI 10.7150/thno.18650
View details for Web of Science ID 000396574200021
View details for PubMedID 28435467
Gemcitabine and Antisense-microRNA Co-encapsulated PLGA-PEG Polymer Nanoparticles for Hepatocellular Carcinoma Therapy
ACS APPLIED MATERIALS & INTERFACES
2016; 8 (49): 33412-33422
Hepatocellular carcinoma (HCC) is highly prevalent, and the third most common cause of cancer-associated deaths worldwide. HCC tumors respond poorly to chemotherapeutic anticancer agents due to inherent and acquired drug resistance, and low drug permeability. Targeted drug delivery systems with significant improvement in therapeutic efficiency are needed for successful HCC therapy. Here, we report the results of a technique optimized for the synthesis and formulation of antisense-miRNA-21 and gemcitabine (GEM) co-encapsulated PEGylated-PLGA nanoparticles (NPs) and their in vitro therapeutic efficacy in human HCC (Hep3B and HepG2) cells. Water-in-oil-in-water (w/o/w) double emulsion method was used to coload antisense-miRNA-21 and GEM in PEGylated-PLGA-NPs. The cellular uptake of NPs displayed time dependent increase of NPs concentration inside the cells. Cell viability analyses in HCC (Hep3B and HepG2) cells treated with antisense-miRNA-21 and GEM co-encapsulated NPs demonstrated a nanoparticle concentration dependent decrease in cell proliferation, and the maximum therapeutic efficiency was attained in cells treated with nanoparticles co-encapsulated with antisense-miRNA-21 and GEM. Flow cytometry analysis showed that control NPs and antisense-miRNA-21-loaded NPs are not cytotoxic to both HCC cell lines, whereas treatment with free GEM and GEM-loaded NPs resulted in ∼9% and ∼15% apoptosis, respectively. Cell cycle status analysis of both cell lines treated with free GEM or NPs loaded with GEM or antisense-miRNA-21 displayed a significant cell cycle arrest at the S-phase. Cellular pathway analysis indicated that Bcl2 expression was significantly upregulated in GEM treated cells, and as expected, PTEN expression was noticeably upregulated in cells treated with antisense-miRNA-21. In summary, we successfully synthesized PEGylated-PLGA nanoparticles co- encapsulated with antisense-miRNA-21 and GEM. These co-encapsulated nanoparticles revealed increased treatment efficacy in HCC cells, compared to cells treated with either antisense-miRNA-21- or GEM-loaded NPs at equal concentration, indicating that down-regulation of endogenous miRNA-21 function can reduce HCC cell viability and proliferation in response to GEM treatment.
View details for DOI 10.1021/acsami.6b08153
View details for Web of Science ID 000389963300008
View details for PubMedID 27960411
Preoperative Multidetector CT Diagnosis of Extrapancreatic Perineural or Duodenal Invasion Is Associated with Reduced Postoperative Survival after Pancreaticoduodenectomy for Pancreatic Adenocarcinoma: Preliminary Experience and Implications for Patient Care
2016; 281 (3): 816-825
Purpose To test the hypothesis that patients with pancreatic adenocarcinoma who otherwise are viewed to have resectable disease but have preoperative findings of extrapancreatic perineural invasion (EPNI) and/or duodenal invasion at multidetector computed tomography (CT) have reduced postoperative survival after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma (PDAC). Materials and Methods This study was approved by the institutional review board and complied with HIPAA. The authors retrospectively evaluated 76 consecutive patients with PDAC who underwent preoperative multidetector CT and subsequent pancreaticoduodenectomy. Two radiologists blinded to surgical pathology results and clinical outcome evaluated multidetector CT images for evidence of EPNI and duodenal invasion; discrepancies were resolved by consensus. Also determined for each patient were resected lymph node status, tumor size, surgical margin status, time to progression, and time to death. Data were assessed with the Goodman-Kruskal gamma for correlations among indicators and the log-rank test, Kaplan-Meier estimates, and multivariate Cox proportional hazards regression for survival analysis. Results In univariate analysis, duodenal invasion and/or EPNI on preoperativemultidetector CT images was associated with significantly decreased progression-free survival (P < .0001) and overall survival (P = .0013), and the clinical indicators (lymph node status, tumor size, and surgical margin status) as well as duodenal invasion and/or EPNI showed correlation with each other. In multivariate regression that included multidetector CT findings as well as the three traditional clinical indicators, only duodenal invasion and/or EPNI showed significant independent association with reduction in both modes of survival (P < .0001 and P = .014, respectively). Interobserver agreement was substantial with respect to EPNI and duodenal invasion (κ = 0.691 and 0.682, respectively). Conclusion Patients with evidence of EPNI and/or duodenal invasion on preoperative multidetector CT images have significantly reduced survival after pancreaticoduodenectomy for PDAC. (©) RSNA, 2016.
View details for DOI 10.1148/radiol.2016152790
View details for Web of Science ID 000393201500015
View details for PubMedID 27438167
Visualization of Small-Diameter Vessels by Reduction of Incoherent Reverberation With Coherent Flow Power Doppler.
IEEE transactions on ultrasonics, ferroelectrics, and frequency control
2016; 63 (11): 1878-1889
Power Doppler (PD) imaging is a widely used technique for flow detection. Despite the wide use of Doppler ultrasound, limitations exist in the ability of Doppler ultrasound to assess slow flow in the small-diameter vasculature, such as the maternal spiral arteries and fetal villous arteries of the placenta and focal liver lesions. The sensitivity of PD in small vessel detection is limited by the low signal produced by slow flow and the noise associated with small vessels. The noise sources include electronic noise, stationary or slowly moving tissue clutter, reverberation clutter, and off-axis scattering from tissue, among others. In order to provide more sensitive detection of slow flow in small diameter vessels, a coherent flow imaging technique, termed coherent flow PD (CFPD), is characterized and evaluated with simulation, flow phantom experiment studies, and an in vivo animal small vessel detection study. CFPD imaging was introduced as a technique to detect slow blood flow. It has been demonstrated to detect slow flow below the detection threshold of conventional PD imaging using identical pulse sequences and filter parameters. In this paper, we compare CFPD with PD in the detection of blood flow in small-diameter vessels. The results from the study suggest that CFPD is able to provide a 7.5-12.5-dB increase in the signal-to-noise ratio (SNR) over PD images for the same physiological conditions and is less susceptible to reverberation clutter and thermal noise. Due to the increase in SNR, CFPD is able to detect small vessels in high channel noise cases, for which PD was unable to generate enough contrast to observe the vessel.
View details for PubMedID 27824565
View details for PubMedCentralID PMC5154731
Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part II. In Vivo Imaging of Bone Marrow Stromal Cells in Swine with PET/CT and MR Imaging.
2016; 280 (3): 826-836
Purpose To quantitatively determine the limit of detection of marrow stromal cells (MSC) after cardiac cell therapy (CCT) in swine by using clinical positron emission tomography (PET) reporter gene imaging and magnetic resonance (MR) imaging with cell prelabeling. Materials and Methods Animal studies were approved by the institutional administrative panel on laboratory animal care. Seven swine received 23 intracardiac cell injections that contained control MSC and cell mixtures of MSC expressing a multimodality triple fusion (TF) reporter gene (MSC-TF) and bearing superparamagnetic iron oxide nanoparticles (NP) (MSC-TF-NP) or NP alone. Clinical MR imaging and PET reporter gene molecular imaging were performed after intravenous injection of the radiotracer fluorine 18-radiolabeled 9-[4-fluoro-3-(hydroxyl methyl) butyl] guanine ((18)F-FHBG). Linear regression analysis of both MR imaging and PET data and nonlinear regression analysis of PET data were performed, accounting for multiple injections per animal. Results MR imaging showed a positive correlation between MSC-TF-NP cell number and dephasing (dark) signal (R(2) = 0.72, P = .0001) and a lower detection limit of at least approximately 1.5 × 10(7) cells. PET reporter gene imaging demonstrated a significant positive correlation between MSC-TF and target-to-background ratio with the linear model (R(2) = 0.88, P = .0001, root mean square error = 0.523) and the nonlinear model (R(2) = 0.99, P = .0001, root mean square error = 0.273) and a lower detection limit of 2.5 × 10(8) cells. Conclusion The authors quantitatively determined the limit of detection of MSC after CCT in swine by using clinical PET reporter gene imaging and clinical MR imaging with cell prelabeling. (©) RSNA, 2016 Online supplemental material is available for this article.
View details for DOI 10.1148/radiol.2016151150
View details for PubMedID 27332865
View details for PubMedCentralID PMC5006717
Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part I. Reporter Gene Design, Characterization, and Optical in Vivo Imaging of Bone Marrow Stromal Cells after Myocardial Infarction.
2016; 280 (3): 815-825
Purpose To use multimodality reporter-gene imaging to assess the serial survival of marrow stromal cells (MSC) after therapy for myocardial infarction (MI) and to determine if the requisite preclinical imaging end point was met prior to a follow-up large-animal MSC imaging study. Materials and Methods Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mice (n = 19) that had experienced MI were injected with bone marrow-derived MSC that expressed a multimodality triple fusion (TF) reporter gene. The TF reporter gene (fluc2-egfp-sr39ttk) consisted of a human promoter, ubiquitin, driving firefly luciferase 2 (fluc2), enhanced green fluorescent protein (egfp), and the sr39tk positron emission tomography reporter gene. Serial bioluminescence imaging of MSC-TF and ex vivo luciferase assays were performed. Correlations were analyzed with the Pearson product-moment correlation, and serial imaging results were analyzed with a mixed-effects regression model. Results Analysis of the MSC-TF after cardiac cell therapy showed significantly lower signal on days 8 and 14 than on day 2 (P = .011 and P = .001, respectively). MSC-TF with MI demonstrated significantly higher signal than MSC-TF without MI at days 4, 8, and 14 (P = .016). Ex vivo luciferase activity assay confirmed the presence of MSC-TF on days 8 and 14 after MI. Conclusion Multimodality reporter-gene imaging was successfully used to assess serial MSC survival after therapy for MI, and it was determined that the requisite preclinical imaging end point, 14 days of MSC survival, was met prior to a follow-up large-animal MSC study. (©) RSNA, 2016 Online supplemental material is available for this article.
View details for DOI 10.1148/radiol.2016140049
View details for PubMedID 27308957
View details for PubMedCentralID PMC5006716
Photoacoustic Imaging in Oncology: Translational Preclinical and Early Clinical Experience.
2016; 280 (2): 332-349
Photoacoustic imaging has evolved into a clinically translatable platform with the potential to complement existing imaging techniques for the management of cancer, including detection, characterization, prognosis, and treatment monitoring. In photoacoustic imaging, tissue is optically excited to produce ultrasonographic images that represent a spatial map of optical absorption of endogenous constituents such as hemoglobin, fat, melanin, and water or exogenous contrast agents such as dyes and nanoparticles. It can therefore provide functional and molecular information that allows noninvasive soft-tissue characterization. Photoacoustic imaging has matured over the years and is currently being translated into the clinic with various clinical studies underway. In this review, the current state of photoacoustic imaging is presented, including techniques and instrumentation, followed by a discussion of potential clinical applications of this technique for the detection and management of cancer. (©) RSNA, 2016.
View details for DOI 10.1148/radiol.16151414
View details for PubMedID 27429141
Secondary sclerosing cholangitis in a critically ill patient.
Quantitative imaging in medicine and surgery
2016; 6 (2): 224-228
Critically ill patients are commonly imaged for liver dysfunction. An often fatal condition, secondary sclerosing cholangitis, is an important and likely under-recognized hepatic condition in these patients. In presenting this case report, we hope to raise awareness of this condition amongst radiologists as well as other physicians caring for the critically ill.
View details for DOI 10.21037/qims.2016.04.04
View details for PubMedID 27190777
Sonoporation: Applications for Cancer Therapy.
Advances in experimental medicine and biology
2016; 880: 263-291
Therapeutic efficacy of both traditional chemotherapy and gene therapy in cancer is highly dependent on the ability to deliver drugs across natural barriers, such as the vessel wall or tumor cell membranes. In this regard, sonoporation induced by ultrasound-guided microbubble (USMB) destruction has been widely investigated in the enhancement of therapeutic drug delivery given it can help overcome these natural barriers, thereby increasing drug delivery into cancer. In this chapter we discuss challenges in current cancer therapy and how some of these challenges could be overcome using USMB-mediated drug delivery. We particularly focus on recent advances in delivery approaches that have been developed to further improve therapeutic efficiency and specificity of various cancer treatments. An example of clinical translation of USMB-mediated drug delivery is also shown.
View details for DOI 10.1007/978-3-319-22536-4_15
View details for PubMedID 26486343
Ultrasound Molecular Imaging of the Breast Cancer Neovasculature using Engineered Fibronectin Scaffold Ligands: A Novel Class of Targeted Contrast Ultrasound Agent.
2016; 6 (11): 1740-1752
Molecularly-targeted microbubbles (MBs) are increasingly being recognized as promising contrast agents for oncological molecular imaging with ultrasound. With the detection and validation of new molecular imaging targets, novel binding ligands are needed that bind to molecular imaging targets with high affinity and specificity. In this study we assessed a novel class of potentially clinically translatable MBs using an engineered 10(th) type III domain of human-fibronectin (MB-FN3VEGFR2) scaffold-ligand to image VEGFR2 on the neovasculature of cancer. The in vitro binding of MB-FN3VEGFR2 to a soluble VEGFR2 was assessed by flow-cytometry (FACS) and binding to VEGFR2-expressing cells was assessed by flow-chamber cell attachment studies under flow shear stress conditions. In vivo binding of MB-FN3VEGFR2 was tested in a transgenic mouse model (FVB/N Tg(MMTV/PyMT634Mul) of breast cancer and control litter mates with normal mammary glands. In vitro FACS and flow-chamber cell attachment studies showed significantly (P<0.01) higher binding to VEGFR2 using MB-FN3VEGFR2 than control agents. In vivo ultrasound molecular imaging (USMI) studies using MB-FN3VEGFR2 demonstrated specific binding to VEGFR2 and was significantly higher (P<0.01) in breast cancer compared to normal breast tissue. Ex vivo immunofluorescence-analysis showed significantly (P<0.01) increased VEGFR2-expression in breast cancer compared to normal mammary tissue. Our results suggest that MBs coupled to FN3-scaffolds can be designed and used for USMI of breast cancer neoangiogenesis. Due to their small size, stability, solubility, the lack of glycosylation and disulfide bonds, FN3-scaffolds can be recombinantly produced with the advantage of generating small, high affinity ligands in a cost efficient way for USMI.
View details for DOI 10.7150/thno.15169
View details for PubMedID 27570547
View details for PubMedCentralID PMC4997233
Sonographic Detection of Extracapsular Extension in Papillary Thyroid Cancer.
Journal of ultrasound in medicine
2015; 34 (12): 2225-2230
To identify and evaluate sonographic features suggestive of extracapsular extension in papillary thyroid cancer.Three board-certified radiologists blinded to the final pathologic tumor stage reviewed sonograms of pathologically proven cases of papillary thyroid cancer for the presence of extracapsular extension. The radiologists evaluated the following features: capsular abutment, bulging of the normal thyroid contour, loss of the echogenic capsule, and vascularity extending beyond the capsule.A total of 129 cases of pathologically proven thyroid cancer were identified. Of these, 51 were excluded because of lack of preoperative sonography, and 16 were excluded because of pathologic findings showing anaplastic carcinoma, follicular carcinoma, or microcarcinoma (<10 mm). The final analysis group consisted of 62 patients with papillary thyroid carcinoma, 16 of whom had pathologically proven extracapsular extension. The presence of capsular abutment had 100% sensitivity for detection of extracapsular extension. Conversely, lack of capsular abutment had a 100% negative predictive value (NPV) for excluding extracapsular extension. Contour bulging had 88% sensitivity for detection of extracapsular extension and when absent had an 87% NPV. Loss of the echogenic capsule was the best predictor of the presence of extracapsular extension, with an odds ratio of 10.23 (P= .034). This sonographic finding had 75% sensitivity, 65% specificity, and an 88% NPV. Vascularity beyond the capsule had 89% specificity but sensitivity of only 25%.Sonographic features of capsular abutment, contour bulging, and loss of the echogenic thyroid capsule have excellent predictive value for excluding or detecting extracapsular extension and may help in biopsy selection, surgical planning, and treatment of patients with papillary thyroid cancer.
View details for DOI 10.7863/ultra.15.02006
View details for PubMedID 26518279
MDCT Diagnosis of Perineural Invasion Involving the Celiac Plexus in Intrahepatic Cholangiocarcinoma: Preliminary Observations and Clinical Implications.
AJR. American journal of roentgenology
2015; 205 (6): W578-84
The purpose of this study was to test the hypothesis that soft-tissue infiltration along the celiac plexus and delayed enhancement exceeding two-thirds of the tumor area on preoperative MDCT correlate with histologic evidence of perineural invasion in resected intrahepatic cholangiocarcinomas.Two experienced abdominal radiologists retrospectively reviewed preoperative multiphasic MDCT scans of 20 patients who underwent resection of intrahepatic cholangiocarcinoma, identifying soft-tissue infiltration along the celiac plexus, delayed enhancement exceeding two-thirds of the tumor area, and maximum tumor diameter. Consensus findings were compared with intratumoral perineural invasion in resected intrahepatic cholangiocarcinomas using the Fisher exact test.Six patients had histologic intratumoral perineural invasion, five of whom had soft-tissue infiltration along the celiac plexus on preoperative MDCT, with corresponding 83.3% sensitivity and 92.9% specificity for perineural invasion and significant association between these MDCT and histologic findings (p = 0.002). No patients with histologic perineural invasion had enhancement exceeding two-thirds of the tumor area on MDCT; sensitivity was 0.0% for this finding. Tumor diameter on MDCT was not significantly associated with perineural invasion at histopathology (p = 0.530).Soft-tissue infiltration along the celiac plexus on MDCT is an indicator of perineural invasion in patients with intrahepatic cholangiocarcinoma. The data did not confirm an association between delayed enhancement exceeding two-thirds of the tumor area and perineural invasion. Because perineural invasion from intrahepatic cholangiocarcinoma is associated with a very poor prognosis and is generally a contraindication to surgery, the MDCT diagnosis of celiac plexus perineural invasion in patients with intrahepatic cholangiocarcinoma may have important implications for prognosis and treatment planning.
View details for DOI 10.2214/AJR.15.14607
View details for PubMedID 26587947
- MDCT Diagnosis of Perineural Invasion Involving the Celiac Plexus in Intrahepatic Cholangiocarcinoma: Preliminary Observations and Clinical Implications. AJR. American journal of roentgenology 2015; 205 (6): W578-84
- Three-dimensional Dynamic Contrast-enhanced US Imaging for Early Antiangiogenic Treatment Assessment in a Mouse Colon Cancer Model RADIOLOGY 2015; 277 (2): 424-434
- Ultrasound molecular imaging: Moving toward clinical translation EUROPEAN JOURNAL OF RADIOLOGY 2015; 84 (9): 1685-1693
Ultrasound molecular imaging: Moving toward clinical translation.
European journal of radiology
2015; 84 (9): 1685-1693
Ultrasound is a widely available, cost-effective, real-time, non-invasive and safe imaging modality widely used in the clinic for anatomical and functional imaging. With the introduction of novel molecularly-targeted ultrasound contrast agents, another dimension of ultrasound has become a reality: diagnosing and monitoring pathological processes at the molecular level. Most commonly used ultrasound molecular imaging contrast agents are micron sized, gas-containing microbubbles functionalized to recognize and attach to molecules expressed on inflamed or angiogenic vascular endothelial cells. There are several potential clinical applications currently being explored including earlier detection, molecular profiling, and monitoring of cancer, as well as visualization of ischemic memory in transient myocardial ischemia, monitoring of disease activity in inflammatory bowel disease, and assessment of arteriosclerosis. Recently, a first clinical grade ultrasound contrast agent (BR55), targeted at a molecule expressed in neoangiogenesis (vascular endothelial growth factor receptor type 2; VEGFR2) has been introduced and safety and feasibility of VEGFR2-targeted ultrasound imaging is being explored in first inhuman clinical trials in various cancer types. This review describes the design of ultrasound molecular imaging contrast agents, imaging techniques, and potential future clinical applications of ultrasound molecular imaging.
View details for DOI 10.1016/j.ejrad.2015.03.016
View details for PubMedID 25851932
Development of a High-Throughput Molecular Imaging-Based Orthotopic Hepatocellular Carcinoma Model.
2015; 7 (6)
We have developed a novel orthotopic rat hepatocellular (HCC) model and have assessed the ability to use bioluminescence imaging (BLI), positron emission tomography (PET), and ultrasound for early tumor detection and monitoring of disease progression. Briefly, rat HCC cells were stably transfected with click beetle red as a reporter gene for BLI. Tumor cells were injected under direct visualization into the left or middle lobe of the liver in 37 rats. In six animals, serial PET, BLI, and ultrasound imaging were performed at 10-time points in 28 days. The remainder of the animals underwent PET imaging at 14 days. Tumor implantation was successful in 34 of 37 animals (91.9%). In the six animals that underwent serial imaging, tumor formation was first detected with BLI on Day 4 with continued increase through Day 21, and hypermetabolic activity on PET was first noted on Days 14-15 with continued increase through Day 28. PET activity was seen on Day 14 in the 28 other animals that demonstrated tumor development. Anatomic tumor formation was detected with ultrasound at Days 10-12 with continued growth through Day 28. The first metastases were detected by PET after Day 24. We have successfully developed and validated a novel orthotopic HCC small animal model that permits longitudinal assessment of change in tumor size using molecular imaging techniques. BLI is the most sensitive imaging method for detection of early tumor formation and growth. This model permits high-throughput in vivo evaluation of image-guided therapies.
View details for DOI 10.7759/cureus.281
View details for PubMedID 26180705
Three-dimensional ultrasound molecular imaging of angiogenesis in colon cancer using a clinical matrix array ultrasound transducer.
2015; 50 (5): 322-329
We sought to assess the feasibility and reproducibility of 3-dimensional ultrasound molecular imaging (USMI) of vascular endothelial growth factor receptor 2 (VEGFR2) expression in tumor angiogenesis using a clinical matrix array transducer and a clinical grade VEGFR2-targeted contrast agent in a murine model of human colon cancer.Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mice with human colon cancer xenografts (n = 33) were imaged with a clinical ultrasound system and transducer (Philips iU22; X6-1) after intravenous injection of either clinical grade VEGFR2-targeted microbubbles or nontargeted control microbubbles. Nineteen mice were scanned twice to assess imaging reproducibility. Fourteen mice were scanned both before and 24 hours after treatment with either bevacizumab (n = 7) or saline only (n = 7). Three-dimensional USMI data sets were retrospectively reconstructed into multiple consecutive 1-mm-thick USMI data sets to simulate 2-dimensional imaging. Vascular VEGFR2 expression was assessed ex vivo using immunofluorescence.Three-dimensional USMI was highly reproducible using both VEGFR2-targeted microbubbles and nontargeted control microbubbles (intraclass correlation coefficient, 0.83). The VEGFR2-targeted USMI signal significantly (P = 0.02) decreased by 57% after antiangiogenic treatment compared with the control group, which correlated well with ex vivo VEGFR2 expression on immunofluorescence (ρ = 0.93, P = 0.003). If only central 1-mm tumor planes were analyzed to assess antiangiogenic treatment response, the USMI signal change was significantly (P = 0.006) overestimated by an average of 27% (range, 2%-73%) compared with 3-dimensional USMI.Three-dimensional USMI is feasible and highly reproducible and allows accurate assessment and monitoring of VEGFR2 expression in tumor angiogenesis in a murine model of human colon cancer.
View details for DOI 10.1097/RLI.0000000000000128
View details for PubMedID 25575176
Polymer Nanoparticles Mediated Codelivery of AntimiR-10b and AntimiR-21 for Achieving Triple Negative Breast Cancer Therapy
2015; 9 (3): 2290-2302
The current study shows the therapeutic outcome achieved in triple negative breast cancer (TNBC) by simultaneously antagonizing miR-21-induced antiapoptosis and miR-10b-induced metastasis, using antisense-miR-21-PS and antisense-miR-10b-PS delivered by polymer nanoparticles (NPs). We synthesized the antisense-miR-21 and antisense-miR-10b loaded PLGA-b-PEG polymer NPs and evaluated their cellular uptake, serum stability, release profile, and the subsequent synchronous blocking of endogenous miR-21 and miR-10b function in TNBC cells in culture, and tumor xenografts in living animals using molecular imaging. Results show that multitarget antagonization of endogenous miRNAs could be an efficient strategy for targeting metastasis and antiapoptosis in the treatment of metastatic cancer. Targeted delivery of antisense-miR-21 and antisense-miR-10b coloaded urokinase plasminogen activator receptor (uPAR) targeted polymer NPs treated mice showed substantial reduction in tumor growth at very low dose of 0.15 mg/kg, compared to the control NPs treated mice and 40% reduction in tumor growth compared to scramble peptide conjugated NPs treated mice, thus demonstrating a potential new therapeutic option for TNBC.
View details for DOI 10.1021/nn507465d
View details for Web of Science ID 000351791800007
View details for PubMedID 25652012
- Detection of Osseous Metastasis by 18F-NaF/18F-FDG PET/CT Versus CT Alone. Clinical nuclear medicine 2015; 40 (3): e173-7
Detection of osseous metastasis by 18F-NaF/18F-FDG PET/CT versus CT alone.
Clinical nuclear medicine
2015; 40 (3): e173-7
Sodium fluoride PET (F-NaF) has recently reemerged as a valuable method for detection of osseous metastasis, with recent work highlighting the potential of coadministered F-NaF and F-FDG PET/CT in a single combined imaging examination. We further examined the potential of such combined examinations by comparing dual tracer F-NaF/F-FDG PET/CT with CT alone for detection of osseous metastasis.Seventy-five participants with biopsy-proven malignancy were consecutively enrolled from a single center and underwent combined F-NaF/F-FDG PET/CT and diagnostic CT scans. PET/CT as well as CT only images were reviewed in blinded fashion and compared with the results of clinical, imaging, or histological follow-up as a truth standard.Sensitivity of the combined F-NaF/F-FDG PET/CT was higher than that of CT alone (97.4% vs 66.7%). CT and F-NaF/F-FDG PET/CT were concordant in 73% of studies. Of 20 discordant cases, F-NaF/F-FDG PET/CT was correct in 19 (95%). Three cases were interpreted concordantly but incorrectly, and all 3 were false positives. A single case of osseous metastasis was detected by CT alone, but not by F-NaF/F-FDG PET/CT.Combined F-NaF/F-FDG PET/CT outperforms CT alone and is highly sensitive and specific for detection of osseous metastases. The concordantly interpreted false-positive cases demonstrate the difficulty of distinguishing degenerative from malignant disease, whereas the single case of metastasis seen on CT but not PET highlights the need for careful review of CT images in multimodality studies.
View details for DOI 10.1097/RLU.0000000000000560
View details for PubMedID 25140557
- Assessment of Inflammation in an Acute on Chronic Model of Inflammatory Bowel Disease with Ultrasound Molecular Imaging THERANOSTICS 2015; 5 (11): 1175-1186
Assessment of Inflammation in an Acute on Chronic Model of Inflammatory Bowel Disease with Ultrasound Molecular Imaging.
2015; 5 (11): 1175-1186
Ultrasound (US) molecular imaging has shown promise in assessing inflammation in preclinical, murine models of inflammatory bowel disease. These models, however, initiated acute inflammation on previously normal colons, in contrast to patients where acute exacerbations are often in chronically inflamed regions. In this study, we explored the potential of dual P- and E-selectin targeted US imaging for assessing acute inflammation on a murine quiescent chronic inflammatory background.Chronic colitis was induced using three cycles of 4% DSS in male FVB mice. Acute inflammation was initiated 2 weeks after the final DSS cycle through rectal administration of 1% TNBS. Mice at different stages of inflammation were imaged using a small animal ultrasound system following i.v. injection of microbubbles targeted to P- and E-selectin. In vivo imaging results were correlated with ex vivo immunofluorescence and histology.Induction of acute inflammation resulted in an increase in the targeted US signal from 5.5 ± 5.1 arbitrary units (a.u.) at day 0 to 61.0 ± 45.2 a.u. (P < 0.0001) at day 1, 36.3 ± 33.1 a.u. at day 3, returning to levels similar to control at day 5. Immunofluorescence showed significant increase in the percentage of P- and E-selectin positive vessels at day 1 (P-selectin: 21.0 ± 7.1% of vessels; P < 0.05; E-selectin: 16.4 ±3.7%; P < 0.05) compared to day 0 (P-selectin: 10.3 ± 5.7%; E-selectin: 7.3 ± 7.0%).Acute inflammation can be accurately measured in a clinically relevant murine model of chronic IBD using ultrasound molecular imaging with a dual P- and E- selectin-targeted contrast agent.
View details for DOI 10.7150/thno.13048
View details for PubMedID 26379784
Ultrasound and microbubble guided drug delivery: mechanistic understanding and clinical implications.
Current pharmaceutical biotechnology
2014; 14 (8): 743-752
Ultrasound mediated drug delivery using microbubbles is a safe and noninvasive approach for spatially localized drug administration. This approach can create temporary and reversible openings on cellular membranes and vessel walls (a process called "sonoporation"), allowing for enhanced transport of therapeutic agents across these natural barriers. It is generally believed that the sonoporation process is highly associated with the energetic cavitation activities (volumetric expansion, contraction, fragmentation, and collapse) of the microbubble. However, a thorough understanding of the process was unavailable until recently. Important progress on the mechanistic understanding of sonoporation and the corresponding physiological responses in vitro and in vivo has been made. Specifically, recent research shed light on the cavitation process of microbubbles and fluid motion during insonation of ultrasound, on the spatio-temporal interactions between microbubbles and cells or vessel walls, as well as on the temporal course of the subsequent biological effects. These findings have significant clinical implications on the development of optimal treatment strategies for effective drug delivery. In this article, current progress in the mechanistic understanding of ultrasound and microbubble mediated drug delivery and its implications for clinical translation is discussed.
View details for PubMedID 24372231
CT Perfusion of the Liver: Principles and Applications in Oncology.
2014; 272 (2): 322-344
With the introduction of molecularly targeted chemotherapeutics, there is an increasing need for defining new response criteria for therapeutic success because use of morphologic imaging alone may not fully assess tumor response. Computed tomographic (CT) perfusion imaging of the liver provides functional information about the microcirculation of normal parenchyma and focal liver lesions and is a promising technique for assessing the efficacy of various anticancer treatments. CT perfusion also shows promising results for diagnosing primary or metastatic tumors, for predicting early response to anticancer treatments, and for monitoring tumor recurrence after therapy. Many of the limitations of early CT perfusion studies performed in the liver, such as limited coverage, motion artifacts, and high radiation dose of CT, are being addressed by recent technical advances. These include a wide area detector with or without volumetric spiral or shuttle modes, motion correction algorithms, and new CT reconstruction technologies such as iterative algorithms. Although several issues related to perfusion imaging-such as paucity of large multicenter trials, limited accessibility of perfusion software, and lack of standardization in methods-remain unsolved, CT perfusion has now reached technical maturity, allowing for its use in assessing tumor vascularity in larger-scale prospective clinical trials. In this review, basic principles, current acquisition protocols, and pharmacokinetic models used for CT perfusion imaging of the liver are described. Various oncologic applications of CT perfusion of the liver are discussed and current challenges, as well as possible solutions, for CT perfusion are presented. © RSNA, 2014 Online supplemental material is available for this article.
View details for DOI 10.1148/radiol.14130091
View details for PubMedID 25058132
Stromal response to Hedgehog signaling restrains pancreatic cancer progression.
Proceedings of the National Academy of Sciences of the United States of America
2014; 111 (30): E3091-100
Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention.
View details for DOI 10.1073/pnas.1411679111
View details for PubMedID 25024225
View details for PubMedCentralID PMC4121834
- Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proceedings of the National Academy of Sciences of the United States of America 2014; 111 (30): E3091-100
Ultrasound Molecular Imaging in a Human CD276 Expression-Modulated Murine Ovarian Cancer Model.
Clinical cancer research
2014; 20 (5): 1313-1322
To develop a mouse ovarian cancer model that allows modulating the expression levels of human vascular targets in mouse xenograft tumors and to test whether expression of CD276 during tumor angiogenesis can be visualized by molecularly targeted ultrasound in vivo.CD276-expressing MILE SVEN 1 (MS1) mouse endothelial cells were engineered and used for coinjection with 2008 human ovarian cancer cells for subcutaneous xenograft tumor induction in 15 nude mice. Fourteen control mice were injected with 2008 cells only. After confirming their binding specificity in flow chamber cell attachment studies, anti-CD276 antibody-functionalized contrast microbubbles were used for in vivo CD276-targeted contrast-enhanced ultrasound imaging.CD276-targeted ultrasound imaging signal was significantly higher (P = 0.006) in mixed MS1/2008 tumors than in control tumors. Compared with control microbubbles, the ultrasound signal using CD276-targeted microbubbles was significantly higher (P = 0.002), and blocking with purified anti-CD276 antibody significantly decreased (P = 0.0096) the signal in mixed MS1/2008 tumors. Immunofluorescence analysis of the tumor tissue confirmed higher quantitative immunofluorescence signal in mixed MS1/2008 tumors than in control 2008 only tumors, but showed not significantly different (P = 0.54) microvessel density.Our novel small animal model allows for modulating the expression of human tumor-associated vascular endothelial imaging targets in a mouse host and these expression differences can be visualized noninvasively by ultrasound molecular imaging. The animal model can be applied to other human vascular targets and may facilitate the preclinical development of new imaging probes such as microbubbles targeted at human vascular markers not expressed in mice. Clin Cancer Res; 20(5); 1313-22. ©2014 AACR.
View details for DOI 10.1158/1078-0432.CCR-13-1642
View details for PubMedID 24389327
- Multiparametric Spectroscopic Photoacoustic Imaging of Breast Cancer Development in a Transgenic Mouse Model THERANOSTICS 2014; 4 (11): 1062-1071
Ultrasound and microbubble-mediated gene delivery in cancer: progress and perspectives.
2013; 48 (11): 755-769
Ultrasound-mediated gene delivery with microbubbles has emerged as an attractive nonviral vector system for site-specific and noninvasive gene therapy. Ultrasound promotes intracellular uptake of therapeutic agents, particularly in the presence of microbubbles, by increasing vascular and cell membrane permeability. Several preclinical studies have reported successful gene delivery into solid tumors with significant therapeutic effects using this novel approach. This review provides background information on gene therapy and ultrasound bioeffects and discusses the current progress and overall perspectives on the application of ultrasound and microbubble-mediated gene delivery in cancer.
View details for DOI 10.1097/RLI.0b013e3182982cc1
View details for PubMedID 23697924
Ultrasound and microbubble-mediated gene delivery in cancer: progress and perspectives.
2013; 48 (11): 755-769
Ultrasound-mediated gene delivery with microbubbles has emerged as an attractive nonviral vector system for site-specific and noninvasive gene therapy. Ultrasound promotes intracellular uptake of therapeutic agents, particularly in the presence of microbubbles, by increasing vascular and cell membrane permeability. Several preclinical studies have reported successful gene delivery into solid tumors with significant therapeutic effects using this novel approach. This review provides background information on gene therapy and ultrasound bioeffects and discusses the current progress and overall perspectives on the application of ultrasound and microbubble-mediated gene delivery in cancer.
View details for DOI 10.1097/RLI.0b013e3182982cc1
View details for PubMedID 23697924
Noninvasive imaging of hypoxia-inducible factor-1a gene therapy for myocardial ischemia.
Human gene therapy methods
2013; 24 (5): 279-288
Abstract Hypoxia-inducible factor-1 alpha (HIF-1α) gene therapy holds great promise for the treatment of myocardial ischemia. Both preclinical and clinical evaluations of this therapy are underway and can benefit from a vector strategy that allows noninvasive assessment of HIF-1α expression as an objective measure of gene delivery. We have developed a novel bidirectional plasmid vector (pcTnT-HIF-1α-VP2-TSTA-fluc), which employs the cardiac troponin T (cTnT) promoter in conjunction with a two-step transcriptional amplification (TSTA) system to drive the linked expression of a recombinant HIF-1α gene (HIF-1α-VP2) and the firefly luciferase gene (fluc). The firefly luciferase (FLuc) activity serves as a surrogate for HIF-1α-VP2 expression, and can be noninvasively assessed in mice using bioluminescence imaging after vector delivery. Transfection of cultured HL-1 cardiomyocytes with pcTnT-HIF-1α-VP2-TSTA-fluc led to a strong correlation between FLuc and HIF-1α-dependent vascular endothelial growth factor expression (r(2)=0.88). Intramyocardial delivery of pcTnT-HIF-1α-VP2-TSTA-fluc into infarcted mouse myocardium led to persistent HIF-1α-VP2 expression for 4 weeks, even though it improved neither CD31+ microvessel density nor echocardiographically determined left ventricular systolic function. These results lend support to recent findings of suboptimal efficacy associated with plasmid-mediated HIF-1α therapy. The imaging techniques developed herein should be useful for further optimizing HIF-1α-VP2 therapy in preclinical models of myocardial ischemia.
View details for DOI 10.1089/hgtb.2013.028
View details for PubMedID 23937265
- Detection of pancreatic ductal adenocarcinoma in mice by ultrasound imaging of thymocyte differentiation antigen 1. Gastroenterology 2013; 145 (4): 885-894 e3
Ultrasound and Microbubble Guided Drug Delivery: Mechanistic Understanding and Clinical Implications
CURRENT PHARMACEUTICAL BIOTECHNOLOGY
2013; 14 (8): 743-752
View details for Web of Science ID 000331178900005
- Noninvasive imaging of hypoxia-inducible factor-1a gene therapy for myocardial ischemia. Human gene therapy methods 2013; 24 (5): 279-288
- New technologies in clinical ultrasound. Seminars in roentgenology 2013; 48 (3): 214-223
- New Technologies in Clinical Ultrasound SEMINARS IN ROENTGENOLOGY 2013; 48 (3): 214-223
Molecular Imaging of Inflammation in Inflammatory Bowel Disease with a Clinically Translatable Dual-Selectin-targeted US Contrast Agent: Comparison with FDG PET/CT in a Mouse Model.
2013; 267 (3): 818-829
Purpose: To develop and test a molecular imaging approach that uses ultrasonography (US) and a clinically translatable dual-targeted (P- and E-selectin) contrast agent (MBSelectin) in the quantification of inflammation at the molecular level and to quantitatively correlate selectin-targeted US with fluorodeoxyglucose (FDG) combined positron emission tomography (PET) and computed tomography (CT) in terms of visualization and quantification of different levels of inflammation in a murine acute colitis model. Materials and Methods: Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. MBSelectin was developed by covalently binding an analog of the naturally occurring binding ligand P-selectin glycoprotein ligand 1 fused to a human fragment crystallizable(or Fc) domain onto the lipid shell of perfluorobutane and nitrogen-containing MBs. Binding specificity of MBSelectin was assessed in vitro with a flow chamber assay and in vivo with a chemically induced acute colitis murine model. US signal was quantitatively correlated with FDG uptake at PET/CT and histologic grade. Statistical analysis was performed with the Student t test, analysis of variance, and Pearson correlation analysis. Results: MBSelectin showed strong attachment to both human and mouse P- and E-selectin compared with MBControl in vitro (P ≤ .002). In vivo, US signal was significantly increased (P < .001) in mice with acute colitis (173.8 arbitrary units [au] ± 134.8 [standard deviation]) compared with control mice (5.0 au ± 4.5). US imaging signal strongly correlated with FDG uptake on PET/CT images (ρ = 0.89, P < .001). Ex vivo analysis enabled confirmation of inflammation in mice with acute colitis and high expression levels of P- and E-selectin in mucosal capillaries (P = .014). Conclusion: US with MBSelectin specifically enables detection and quantification of inflammation in a murine acute colitis model, leveraging the natural pathway of leukocyte recruitment in inflammatory tissue. US imaging with MBSelectin correlates well with FDG uptake at PET/CT imaging. © RSNA, 2013 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122509/-/DC1.
View details for DOI 10.1148/radiol.13122509
View details for PubMedID 23371306
Dual-therapeutic reporter genes fusion for enhanced cancer gene therapy and imaging.
2013; 20 (5): 529-537
Two of the successful gene-directed enzyme prodrug therapies include herpes simplex virus-thymidine kinase (HSV1-TK) enzyme-ganciclovir prodrug and the Escherichia coli nitroreductase (NTR) enzyme-CB1954 prodrug strategies; these enzyme-prodrug combinations produce activated cytotoxic metabolites of the prodrugs capable of tumor cell death by inhibiting DNA synthesis and killing quiescent cells, respectively. Both these strategies also affect significant bystander cell killing of neighboring tumor cells that do not express these enzymes. We have developed a dual-combination gene strategy, where we identified HSV1-TK and NTR fused in a particular orientation can effectively kill tumor cells when the tumor cells are treated with a fusion HSV1-TK-NTR gene- along with a prodrug combination of GCV and CB1954. In order to determine whether the dual-system demonstrate superior therapeutic efficacy than either HSV1-TK or NTR systems alone, we conducted both in vitro and in vivo tumor xenograft studies using triple negative SUM159 breast cancer cells, by evaluating the efficacy of cell death by apoptosis and necrosis upon treatment with the dual HSV1-TK genes-GCV-CB1954 prodrugs system, and compared the efficiency to HSV1-TK-GCV and NTR-CB1954. Our cell-based studies, tumor regression studies in xenograft mice, histological analyses of treated tumors and bystander studies indicate that the dual HSV1-TK-NTR-prodrug system is two times more efficient even with half the doses of both prodrugs than the respective single gene-prodrug system, as evidenced by enhanced apoptosis and necrosis of tumor cells in vitro in culture and xenograft of tumor tissues in animals.
View details for DOI 10.1038/gt.2012.66
View details for PubMedID 22914496
Three-dimensional volume-rendered multidetector CT imaging of the posterior inferior pancreaticoduodenal artery: its anatomy and role in diagnosing extrapancreatic perineural invasion.
2013; 13 (4): 580-590
Extrapancreatic perineural spread in pancreatic adenocarcinoma contributes to poor outcomes, as it is known to be a major contributor to positive surgical margins and disease recurrence. However, current staging classifications have not yet taken extrapancreatic perineural spread into account. Four pathways of extrapancreatic perineural spread have been described that conveniently follow small defined arterial pathways. Small field of view three-dimensional (3D) volume-rendered multidetector computed tomography (MDCT) images allow visualization of small peripancreatic vessels and thus perineural invasion that may be associated with them. One such vessel, the posterior inferior pancreaticoduodenal artery (PIPDA), serves as a surrogate for extrapancreatic perineural spread by pancreatic adenocarcinoma arising in the uncinate process. This pictorial review presents the normal and variant anatomy of the PIPDA with 3D volume-rendered MDCT imaging, and emphasizes its role as a vascular landmark for the diagnosis of extrapancreatic perineural invasion from uncinate adenocarcinomas. Familiarity with the anatomy of PIPDA will allow accurate detection of extrapancreatic perineural spread by pancreatic adenocarcinoma involving the uncinate process, and may potentially have important staging implications as neoadjuvant therapy improves.
View details for DOI 10.1102/1470-7330.2013.0051
View details for PubMedID 24434918
- Three-dimensional volume-rendered multidetector CT imaging of the posterior inferior pancreaticoduodenal artery: its anatomy and role in diagnosing extrapancreatic perineural invasion CANCER IMAGING 2013; 13 (4): 580-590
Intermodality comparison between 3D perfusion CT and 18F-FDG PET/CT imaging for predicting early tumor response in patients with liver metastasis after chemotherapy: Preliminary results of a prospective study
EUROPEAN JOURNAL OF RADIOLOGY
2012; 81 (11): 3542-3550
To evaluate the feasibility of 3D perfusion CT for predicting early treatment response in patients with liver metastasis from colorectal cancer.Seventeen patients with colon cancer and liver metastasis were prospectively enroled to undergo perfusion CT and 18F-FDG-PET/CT before and after one-cycle of chemotherapy. Two radiologists and three nuclear medicine physicians measured various perfusion CT and PET/CT parameters, respectively from the largest hepatic metastasis. Baseline values and reduction rates of the parameters were compared between responders and nonresponders. Spearman correlation test was used to correlate perfusion CT and PET/CT parameters, using RECIST criteria as reference standard.Nine patients responded to treatment, eight patients were nonresponders. Baseline SUVmean30 on PET/CT, reduction rates of 30% metabolic volume and 30% lesion glycolysis (LG30) on PET/CT and blood flow (BF) and flow extraction product (FEP) on perfusion CT after chemotherapy were significantly different between responders and nonresponders (P=0.008-0.046). Reduction rates of BF (correlation coefficient=0.630) and FEP (correlation coefficient=0.578) significantly correlated with that of LG30 on PET/CT (P<0.05).CT perfusion parameters including BF and FEP may be used as early predictors of tumor response in patients with liver metastasis from colorectal cancer.
View details for DOI 10.1016/j.ejrad.2012.02.012
View details for Web of Science ID 000309554400096
View details for PubMedID 22459347
Ultrasound Molecular Imaging Contrast Agent Binding to Both E- and P-Selectin in Different Species
2012; 47 (9): 516-523
Ultrasound molecular imaging is increasingly used in preclinical studies to measure the expression of vascular markers during inflammation process. In this context, a new ultrasound contrast agent functionalized with a recombinant P-selectin glycoprotein ligand-1 analogue (rPSGL-Ig) was developed (MBrPSGL-Ig). This agent was assayed in vitro and in vivo to evaluate its binding performance and potential to image expression of inflammatory markers E- and P-selectin. Performance of this newly developed agent was compared with that of antibody (MBAb) or sialyl Lewis X (MBsLe) containing microbubbles and with control microbubbles (MBC).The targeted ultrasound contrast agents were prepared by coupling biotin-conjugated ligands onto streptavidin-functionalized microbubbles. First, in vitro experiments were performed to measure the adhesion efficiency of these microbubble constructs under static or flow conditions (114 sec), on cell monolayer (human umbilical vein endothelial cells and bEnd.5), or coatings of E- or P-selectin of various animal species, respectively. Second, molecular imaging studies were performed in a rat inflammatory model 24 hours after intramuscular injection of lipopolysaccharide in the hind limb. Finally, immunohistochemistry staining of rat inflamed muscle tissue was performed to assess expression of E- and P-selectin.Microbubbles functionalized with rPSGL-Ig (MBrPSGL-Ig) displayed firm in vitro binding on the coating of both recombinant E- or P-selectin, with an efficiency similar to microbubbles comprising antibody specific for E-selectin (MBE) or P-selectin (MBP). In contrast, lower binding capacity was measured with MBsLe. At the surface of inflamed endothelial cells, MBrPSGL-Ig were able to interact specifically with E- and P-selectin. Binding specificity was demonstrated by performing blocking experiments with target-specific antibodies, resulting in an 80% to 95% decrease in binding. Ten minutes after microbubble injection, echo signal measured with MBrPSGL-Ig in the inflamed muscles was 20-fold higher compared with MBC. Moreover, the in vivo adhesion of MBrPSGL-Ig was 2- and 7-fold higher compared with P-selectin or E-selectin-specific microbubbles, respectively. Immunohistochemistry revealed a temporal coexpression of E- and P-selectin in the vascular bed of inflamed rat muscle 24 hours after lipopolysaccharide injection.The molecular imaging study demonstrates that MBrPSGL-Ig provide imaging signal higher than those measured with antibody or sialyl Lewis X containing microbubbles. These results suggest that MBrPSGL-Ig is a powerful agent to image the expression of both E- and P-selectin in the context of an inflammatory process.
View details for DOI 10.1097/RLI.0b013e31825cc605
View details for Web of Science ID 000307381700004
View details for PubMedID 22814589
Quantitative assessment of tumor angiogenesis using real-time motion-compensated contrast-enhanced ultrasound imaging
2012; 15 (3): 433-442
To develop and test a real-time motion compensation algorithm for contrast-enhanced ultrasound imaging of tumor angiogenesis on a clinical ultrasound system.The Administrative Institutional Panel on Laboratory Animal Care approved all experiments. A new motion correction algorithm measuring the sum of absolute differences in pixel displacements within a designated tracking box was implemented in a clinical ultrasound machine. In vivo angiogenesis measurements (expressed as percent contrast area) with and without motion compensated maximum intensity persistence (MIP) ultrasound imaging were analyzed in human colon cancer xenografts (n = 64) in mice. Differences in MIP ultrasound imaging signal with and without motion compensation were compared and correlated with displacements in x- and y-directions. The algorithm was tested in an additional twelve colon cancer xenograft-bearing mice with (n = 6) and without (n = 6) anti-vascular therapy (ASA-404). In vivo MIP percent contrast area measurements were quantitatively correlated with ex vivo microvessel density (MVD) analysis.MIP percent contrast area was significantly different (P < 0.001) with and without motion compensation. Differences in percent contrast area correlated significantly (P < 0.001) with x- and y-displacements. MIP percent contrast area measurements were more reproducible with motion compensation (ICC = 0.69) than without (ICC = 0.51) on two consecutive ultrasound scans. Following anti-vascular therapy, motion-compensated MIP percent contrast area significantly (P = 0.03) decreased by 39.4 ± 14.6 % compared to non-treated mice and correlated well with ex vivo MVD analysis (Rho = 0.70; P = 0.05).Real-time motion-compensated MIP ultrasound imaging allows reliable and accurate quantification and monitoring of angiogenesis in tumors exposed to breathing-induced motion artifacts.
View details for DOI 10.1007/s10456-012-9271-3
View details for Web of Science ID 000307272200009
View details for PubMedID 22535383
beta-Catenin Regulates Hepatic Mitochondrial Function and Energy Balance in Mice
2012; 143 (3): 754-764
Wnt signaling regulates hepatic function and nutrient homeostasis. However, little is known about the roles of β-catenin in cellular respiration or mitochondria of hepatocytes.We investigated β-catenin's role in the metabolic function of hepatocytes under homeostatic conditions and in response to metabolic stress using mice with hepatocyte-specific deletion of β-catenin and their wild-type littermates, given either saline (sham) or ethanol (as a model of binge drinking and acute ethanol intoxication).Under homeostatic conditions, β-catenin-deficient hepatocytes demonstrated mitochondrial dysfunctions that included impairments to the tricarboxylic acid cycle and oxidative phosphorylation (OXPHOS) and decreased production of adenosine triphosphate (ATP). There was no evidence for redox imbalance or oxidative cellular injury in the absence of metabolic stress. In mice with β-catenin-deficient hepatocytes, ethanol intoxication led to significant redox imbalance in the hepatocytes and further deterioration in mitochondrial function that included reduced OXPHOS, fatty acid oxidation (FAO), and ATP production. Ethanol feeding significantly increased liver steatosis and oxidative damage, compared with wild-type mice, and disrupted the ratio of nicotinamide adenine dinucleotide. β-catenin-deficient hepatocytes also had showed disrupted signaling of Sirt1/peroxisome proliferator-activated receptor-α signaling.β-catenin has an important role in the maintenance of mitochondrial homeostasis, regulating ATP production via the tricarboxylic acid cycle, OXPHOS, and fatty acid oxidation; β-catenin function in these systems is compromised under conditions of nutrient oxidative stress. Reagents that alter Wnt-β-catenin signaling might be developed as a useful new therapeutic strategy for treatment of liver disease.
View details for DOI 10.1053/j.gastro.2012.05.048
View details for Web of Science ID 000308399300039
View details for PubMedID 22684045
Stromal galectin-1 expression is associated with long-term survival in resectable pancreatic ductal adenocarcinoma
CANCER BIOLOGY & THERAPY
2012; 13 (10): 899-907
The overall 5 year survival rate for pancreatic ductal adenocarcinoma (i.e., PDAC) is a dismal 5%, although patients that have undergone surgical resection have a somewhat better survival rate of up to 20%. Very long-term survivors of PDAC (defined as patients with ≥ 10 year survival following apparently curative resection), on the other hand, are considerably less frequent. The molecular characteristics of very long-term survivors (VLTS) are poorly understood, but might provide novel insights into prognostication for this disease. In this study, a panel of five VLTS and stage-matched short-term survivors (STS, defined as disease-specific mortality within 14 months of resection) were identified, and quantitative proteomics was applied to comparatively profile tumor tissues from both cohorts. Differentially expressed proteins were identified in cancers from VLTS vs. STS patients. Specifically, the expression of galectin-1 was 2-fold lower in VLTS compared with STS tumors. Validation studies were performed by immunohistochemistry (IHC) in two additional cohorts of resected PDAC, including: 1) an independent cohort of VLTS and 2) a panel of sporadic PDAC with a considerable range of overall survival following surgery. Immunolabeling analysis confirmed that significantly lower expression of stromal galectin-1 was associated with VLTS (p = 0.02) and also correlated with longer survival in sporadic, surgically-treated PDAC cases (hazard ratio = 4.9, p = 0.002). The results from this study provide new insights to better understand the role of galectin-1 in PDAC survival, and might be useful for rendering prognostic information, and developing more effective therapeutic strategies aimed at improving survival.
View details for DOI 10.4161/cbt.20842
View details for Web of Science ID 000307118100008
View details for PubMedID 22785208
View details for PubMedCentralID PMC3414412
Ultrasound for molecular imaging and therapy in cancer.
Quantitative imaging in medicine and surgery
2012; 2 (2): 87-97
Over the past decade, molecularly-targeted contrast enhanced ultrasound (ultrasound molecular imaging) has attracted significant attention in preclinical research of cancer diagnostic and therapy. Potential applications for ultrasound molecular imaging run the gamut from early detection and characterization of malignancies to monitoring treatment responses and guiding therapies. There may also be a role for ultrasound contrast agents for improved delivery of chemotherapeutic drugs and gene therapies across biological barriers. Currently, a first Phase 0 clinical trial in patients with prostate cancer assesses toxicity and feasibility of ultrasound molecular imaging using contrast agents targeted at the angiogenic marker vascular endothelial growth factor receptor type 2 (VEGFR2). This mini-review highlights recent advances and potential applications of ultrasound molecular imaging and ultrasound-guided therapy in cancer.
View details for PubMedID 23061039
Fast microbubble dwell-time based ultrasonic molecular imaging approach for quantification and monitoring of angiogenesis in cancer.
Quantitative imaging in medicine and surgery
2012; 2 (2): 68-80
PURPOSE: To develop and test a fast ultrasonic molecular imaging technique for quantification and monitoring of angiogenesis in cancer. MATERIALS AND METHODS: A new software algorithm measuring the dwell time of contrast microbubbles in near real-time (henceforth, fast method) was developed and integrated in a clinical ultrasound system. In vivo quantification and monitoring of tumor angiogenesis during anti-VEGF antibody therapy was performed in human colon cancer xenografts in mice (n=20) using the new fast method following administration of vascular endothelial growth factor receptor 2 (VEGFR2)-targeted contrast microbubbles. Imaging results were compared with a traditional destruction/replenishment approach (henceforth, traditional method) in an intra-animal comparison. RESULTS: There was excellent correlation (R(2)=0.93; P<0.001) between the fast method and the traditional method in terms of VEGFR2-targeted in vivo ultrasonic molecular imaging with significantly higher (P=0.002) imaging signal in colon cancer xenografts using VEGFR2-targeted compared to control non-targeted contrast microbubbles. The new fast method was highly reproducible (ICC=0.87). Following anti-angiogenic therapy, ultrasonic molecular imaging signal decreased by an average of 41±10%, whereas imaging signal increased by an average of 54±8% in non-treated tumors over a 72-hour period. Decreased VEGFR2 expression levels following anti-VEGF therapy were confirmed on ex vivo immunofluorescent staining. CONCLUSIONS: Fast ultrasonic molecular imaging based on dwell time microbubble signal measurements correlates well with the traditional measurement method, and allows reliable in vivo monitoring of anti-angiogenic therapy in human colon cancer xenografts. The improved work-flow afforded by the new quantification approach may facilitate clinical translation of ultrasonic molecular imaging.
View details for PubMedID 22943043
Adenocarcinoma of the uncinate process of the pancreas: MDCT patterns of local invasion and clinical features at presentation
2012; 22 (5): 1067-1074
To compare the multidetector CT (MDCT) patterns of local invasion and clinical findings at presentation in patients with adenocarcinoma of the uncinate process of the pancreas to patients with adenocarcinomas in the non-uncinate head of the pancreas.We evaluated the two cohorts for common duct and pancreatic duct dilatation, mesenteric vascular encasement, root of mesentery invasion, perineural invasion and duodenal invasion. In addition, we compared the clinical findings at presentation in both groups.Common duct (P < 0.001) and pancreatic duct dilatation (P = 0.001) were significantly less common in uncinate process adenocarcinomas than in the non-uncinate head of the pancreas. Clinical findings of jaundice (P = 0.01) and pruritis (P = 0.004) were significantly more common in patients with lesions in the non-uncinate head of the pancreas. Superior mesenteric artery encasement (P = 0.02) and perineural invasion (P = 0.001) were significantly more common with uncinate process adenocarcinomas.Owing to its unique anatomic location, adenocarcinomas within the uncinate process of the pancreas have significantly different patterns of both local invasion and clinical presentation compared to patients with carcinomas in the non-uncinate head of the pancreas. Key Points • SMA encasement and perineural invasion were more common with uncinate process adenocarcinomas. • Common bile duct and pancreatic duct dilatation were less common in uncinate process adenocarcinomas • Jaundice and pruritis were more common with lesions elsewhere in the pancreatic head.
View details for DOI 10.1007/s00330-011-2339-4
View details for Web of Science ID 000303875900015
View details for PubMedID 22124777
Incidentally discovered solid pancreatic masses: imaging and clinical observations
2012; 37 (1): 91-97
The purpose of this study was to review the CT findings and clinical outcome in patients with incidentally discovered solid pancreatic masses.Over an 8-year period, from 2001 to 2009, we identified 24 patients with solid pancreatic masses incidentally detected by CT. There were 13 females and 11 males, with a mean age of 67 years. We determined the indication for initial CT, analyzed the CT features, and ascertained the clinical follow-up in all the patients.All of the solid masses were malignant. There were 14 adenocarcinomas and 10 neuroendocrine tumors. The most common indications for the initial CT were surveillance of an extrapancreatic malignancy (n = 10) and evaluation for hematuria (n = 6). On the initial CT, 16 of the patients (67%) had a clearly visible pancreatic mass. In eight patients isoattenuating masses were identified, only recognized by subtle signs including unexplained dilatation of the pancreatic duct (n = 5) or minimal contour deformity or density of the pancreas (n = 3). The mean survival time for the patients with adenocarcinoma was 21.6 months, and 42 months for the patients with neuroendocrine tumors.Although uncommon, incidentally discovered solid pancreatic masses are malignant neoplasms, either ductal adenocarcinomas or neuroendocrine tumors. Unlike incidentally discovered small cystic lesions, solid pancreatic lesions are often biologically aggressive.
View details for DOI 10.1007/s00261-011-9720-2
View details for Web of Science ID 000299890300011
View details for PubMedID 21394600
Pharmacokinetically Stabilized Cystine Knot Peptides That Bind Alpha-v-Beta-6 Integrin with Single-Digit Nanomolar Affinities for Detection of Pancreatic Cancer
CLINICAL CANCER RESEARCH
2012; 18 (3): 839-849
Detection of pancreatic cancer remains a high priority and effective diagnostic tools are needed for clinical applications. Many cancer cells overexpress integrin α(v)β(6), a cell surface receptor being evaluated as a novel clinical biomarker.To validate this molecular target, several highly stable cystine knot peptides were engineered by directed evolution to bind specifically and with high affinity (3-6 nmol/L) to integrin α(v)β(6). The binders do not cross-react with related integrin α(v)β(5), integrin α(5)β(1), or tumor-angiogenesis-associated integrin, α(v)β(3).Positron emission tomography showed that these disulfide-stabilized peptides rapidly accumulate at tumors expressing integrin α(v)β(6). Clinically relevant tumor-to-muscle ratios of 7.7 ± 2.4 to 11.3 ± 3.0 were achieved within 1 hour after radiotracer injection. Minimization of off-target dosing was achieved by reformatting α(v)β(6)-binding activities across various natural and pharmacokinetically stabilized cystine knot scaffolds with different amino acid content. We show that the primary sequence of a peptide scaffold directs its pharmacokinetics. Scaffolds with high arginine or glutamic acid content suffered high renal retention of more than 75% injected dose per gram (%ID/g). Substitution of these amino acids with renally cleared amino acids, notably serine, led to significant decreases in renal accumulation of less than 20%ID/g 1 hour postinjection (P < 0.05, n = 3).We have engineered highly stable cystine knot peptides with potent and specific integrin α(v)β(6)-binding activities for cancer detection. Pharmacokinetic engineering of scaffold primary sequence led to significant decreases in off-target radiotracer accumulation. Optimization of binding affinity, specificity, stability, and pharmacokinetics will facilitate translation of cystine knots for cancer molecular imaging.
View details for DOI 10.1158/1078-0432.CCR-11-1116
View details for Web of Science ID 000300115000027
View details for PubMedID 22173551
View details for PubMedCentralID PMC3271184
Ultrasound-Mediated Gene Delivery with Cationic Versus Neutral Microbubbles: Effect of DNA and Microbubble Dose on In Vivo Transfection Efficiency
2012; 2 (11): 1078-1091
To assess the effect of varying microbubble (MB) and DNA doses on the overall and comparative efficiencies of ultrasound (US)-mediated gene delivery (UMGD) to murine hindlimb skeletal muscle using cationic versus neutral MBs.Cationic and control neutral MBs were characterized for size, charge, plasmid DNA binding, and ability to protect DNA against endonuclease degradation. UMGD of a codon optimized firefly luciferase (Fluc) reporter plasmid to endothelial cells (1 MHz, 1 W/cm², 20% duty cycle, 1 min) was performed in cell culture using cationic, neutral, or no MBs. In vivo UMGD to mouse hindlimb muscle was performed by insonation (1 MHz, 2 W/cm², 50% duty cycle, 5 min) after intravenous administration of Fluc combined with cationic, neutral, or no MBs. Gene delivery efficiency was assessed by serial in vivo bioluminescence imaging. Efficiency of in vivo UMGD with cationic versus neutral MBs was systematically evaluated by varying plasmid DNA dose (10, 17.5, 25, 37.5, and 50 µg) while maintaining a constant MB dose of 1x10(8) MBs and by changing MB dose (1x10(7), 5x10(7), 1x10(8), or 5x10(8) MBs) while keeping a constant DNA dose of 50 µg.Cationic and size-matched control neutral MBs differed significantly in zeta potential with cationic MBs being able to bind plasmid DNA (binding capacity of 0.03 pg/MB) and partially protect DNA from nuclease degradation while neutral MBs could not. Cationic MBs enhanced UMGD compared to neutral MBs as well as no MB and no US controls both in cell culture (P < 0.001) and in vivo (P < 0.05). Regardless of MB type, in vivo UMGD efficiency increased dose-dependently with DNA dose and showed overall maximum transfection with 50 µg DNA. However, there was an inverse correlation (ρ = -0.90; P = 0.02) between DNA dose and the degree of enhanced UMGD efficiency observed with using cationic MBs instead of neutral MBs. The delivery efficiency advantage associated with cationic MBs was most prominent at the lowest investigated DNA dose (7.5-fold increase with cationic versus neutral MBs at a DNA dose of 10 µg; P = 0.02) compared to only a 1.4-fold increase at a DNA dose of 50 µg (P < 0.01). With increasing MB dose, overall in vivo UMGD efficiency increased dose-dependently with a maximum reached at a dose of 1x10(8) MBs with no further significant increase with 5x10(8) MBs (P = 0.97). However, compared to neutral MBs, cationic MBs enhanced UMGD efficiency the most at low MB doses. Relative enhancement of UMGD efficiency using cationic over neutral MBs decreased from a factor of 27 for 1x10(7) MBs (P = 0.02) to a factor of 1.4 for 1x10(8) MBs (P < 0.01) and no significant difference for 5x10(8) MBs.Cationic MBs enhance UMGD to mouse skeletal muscle relative to neutral MBs but this is dependent on MB and DNA dose. The enhancement effect of cationic MBs on UMGD efficiency is more evident when lower doses of MBs or DNA are used, whereas the advantage of cationic MBs over neutral MBs is substantially reduced in the presence of excess MBs or DNA.
View details for DOI 10.7150/thno.4240
View details for Web of Science ID 000312955800005
View details for PubMedID 23227124
View details for PubMedCentralID PMC3516840
Antiangiogenic and Radiation Therapy Early Effects on In Vivo Computed Tomography Perfusion Parameters in Human Colon Cancer Xenografts in Mice
2012; 47 (1): 25-32
To assess early treatment effects on computed tomography (CT) perfusion parameters after antiangiogenic and radiation therapy in subcutaneously implanted, human colon cancer xenografts in mice and to correlate in vivo CT perfusion parameters with ex vivo assays of tumor vascularity and hypoxia.Dynamic contrast-enhanced CT (perfusion CT, 129 mAs, 80 kV, 12 slices × 2.4 mm; 150 μL iodinated contrast agent injected at a rate of 1 mL/min intravenously) was performed in 100 subcutaneous human colon cancer xenografts on baseline day 0. Mice in group 1 (n=32) received a single dose of the antiangiogenic agent bevacizumab (10 mg/kg body weight), mice in group 2 (n=32) underwent a single radiation treatment (12 Gy), and mice in group 3 (n=32) remained untreated. On days 1, 3, 5, and 7 after treatment, 8 mice from each group underwent a second CT perfusion scan, respectively, after which tumors were excised for ex vivo analysis. Four mice were killed after baseline scanning on day 0 for ex vivo analysis. Blood flow (BF), blood volume (BV), and flow extraction product were calculated using the left ventricle as an arterial input function. Correlation of in vivo CT perfusion parameters with ex vivo microvessel density and extent of tumor hypoxia were assessed by immunofluorescence. Reproducibility of CT perfusion parameter measurements was calculated in an additional 8 tumor-bearing mice scanned twice within 5 hours with the same CT perfusion imaging protocol.The intraclass correlation coefficients for BF, BV, and flow extraction product from repeated CT perfusion scans were 0.93 (95% confidence interval: 0.78, 0.97), 0.88 (0.66, 0.95), and 0.88 (0.56, 0.95), respectively. Changes in perfusion parameters and tumor volumes over time were different between treatments. After bevacizumab treatment, all 3 perfusion parameters significantly decreased from day 1 (P ≤ 0.006) and remained significantly decreased until day 7 (P ≤ 0.008); tumor volume increased significantly only on day 7 (P=0.04). After radiation treatment, all 3 perfusion parameters decreased significantly on day 1 (P < 0.001); BF and flow extraction product increased again on day 3 and 5, although without reaching statistically significant difference; and tumor volumes did not change significantly at all time points (P ≥ 0.3). In the control group, all 3 perfusion parameters did not change significantly, whereas tumor volume increased significantly at all the time points, compared with baseline (P ≤ 0.04). Ex vivo immunofluorescent staining showed good correlation between all 3 perfusion parameters and microvessel density (ρ=0.71, 0.66, and 0.69 for BF, BV, and flow extraction product, respectively; P < 0.001). There was a trend toward negative correlation between extent of hypoxia and all 3 perfusion parameters (ρ=-0.53, -0.47, and -0.40 for BF, BV, and flow extraction product, respectively; P ≥ 0.05).CT perfusion allows a reproducible, noninvasive assessment of tumor vascularity in human colon cancer xenografts in mice. After antiangiogenic and radiation therapy, BF, BV, and flow extraction product significantly decrease and change faster than the tumor volume.
View details for DOI 10.1097/RLI.0b013e31823a82f6
View details for Web of Science ID 000298400100006
View details for PubMedID 22178893
Non-invasive Bioluminescence Imaging of Myoblast-Mediated Hypoxia-Inducible Factor-1 Alpha Gene Transfer
MOLECULAR IMAGING AND BIOLOGY
2011; 13 (6): 1124-1132
We tested a novel imaging strategy, in which both the survival of transplanted myoblasts and their therapeutic transgene expression, a recombinant hypoxia-inducible factor-1α (HIF-1α-VP2), can be monitored using firefly luciferase (fluc) and Renilla luciferase (hrl) bioluminescence reporter genes, respectively.The plasmid pUbi-hrl-pUbi-HIF-1α-VP2, which expresses both hrl and HIF-1α-VP2 using two ubiquitin promoters, was characterized in vitro. C2c12 myoblasts stably expressing fluc and transiently transfected with pUbi-hrl-pUbi-HIF-1α-VP2 were injected into the mouse hindlimb. Both hrl and fluc expression were monitored using bioluminescence imaging (BLI).Strong correlations existed between the expression of hRL and each of HIF-1α-VP2, VEGF, and PlGF (r(2) > 0.83, r(2) > 0.82, and r(2) > 0.97, respectively). In vivo, both transplanted cells and HIF-1α-VP2 transgene expression were successfully imaged using BLI.An objective evaluation of myoblast-mediated gene transfer in living mice can be performed by monitoring both the survival and the transgene expression of transplanted myoblasts using the techniques developed herein.
View details for DOI 10.1007/s11307-011-0471-9
View details for Web of Science ID 000296794400009
View details for PubMedID 21267661
View details for PubMedCentralID PMC4657136
Non-emergency small bowel obstruction: assessment of CT findings that predict need for surgery
2011; 21 (5): 982-986
To identify CT findings predictive of surgical management in non-emergency small bowel obstruction (SBO).Contrast-enhanced abdominal CT of 129 patients with non-emergency SBO were evaluated for small bowel luminal diameter, wall thickness, presence of the small bowel faeces sign (intraluminal particulate matter in a dilated small bowel) and length, transition point, submucosal oedema, mesenteric stranding, ascites and degree of obstruction (low grade partial, high grade partial and complete obstruction). Medical records were reviewed for age, gender, management and history of abdominal surgery, abdominal malignancy, or SBO. Statistical analyses were performed with Stata Release 9.2.Degree of obstruction was the only predictor of need for surgery. Whereas 18.0% of patients with low-grade partial obstruction (n = 50) underwent surgery, 32.5% of patients with high-grade partial obstruction (n = 77) and 100% of patients with complete obstruction (n = 2) required surgery (P = 0.004). The small bowel faeces sign was inversely predictive of surgery (P = 0.018).In non-emergency SBO patients with contrast-enhanced CT imaging, grade of obstruction predicts surgery, while the small bowel faeces sign inversely predicts need for surgery.
View details for DOI 10.1007/s00330-010-1983-4
View details for Web of Science ID 000289291100011
View details for PubMedID 20963444
Early Diagnosis of Ovarian Carcinoma: Is a Solution in Sight?
2011; 259 (2): 329-345
Ovarian cancer is the most lethal of the gynecologic malignancies. Because ovarian cancer symptoms are subtle and nonspecific, the diagnosis is often delayed until the disease is well advanced. Overall 5-year survival is a rather dismal 50% but can be improved to greater than 90% if the disease is confined to the ovary at the time of diagnosis (generally in fewer than 25% of patients). Effective screening tools are currently not available. Owing to the rather low incidence of the disease in the general population, potential screening tests must provide very high specificity to avoid unnecessary interventions in false-positive cases. This article reviews currently available serum biomarkers and imaging tests for the early detection of ovarian cancer and provides an outlook on the potential improvements in these noninvasive diagnostic tools that may lead to successful implementation in a screening program. Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11090563/-/DC1.
View details for DOI 10.1148/radiol.11090563
View details for Web of Science ID 000289667300006
View details for PubMedID 21502390
Tumor Angiogenic Marker Expression Levels during Tumor Growth: Longitudinal Assessment with Molecularly Targeted Microbubbles and US Imaging
2011; 258 (3): 804-811
To evaluate the use of molecularly targeted microbubbles (MBs) and ultrasonography (US) in the noninvasive assessment of the level of expression of three angiogenic markers, α(v)β(3) integrin, endoglin, and vascular endothelial growth factor receptor (VEGFR) 2, on tumor vascular endothelial cells in vivo during tumor growth.All procedures using laboratory animals were approved by the Institutional Administrative Panel on Laboratory Animal Care. Binding specificity of three types of targeted MBs (MB(Integrin), MB(Endoglin), MB(VEGFR2)) was tested in cell culture under flow shear stress conditions. In vivo targeted contrast material-enhanced US imaging signal using the three MB types was measured at three tumor stages (small, medium, large) in three subcutaneous cancer xenografts (breast, ovarian, pancreatic cancer) in mice (n = 54). In vivo US imaging signal was correlated with ex vivo angiogenic marker expression. Significant differences were evaluated by using the Student t, analysis of variance, Wilcoxon, and Tukey Honest Significant Difference tests.Cell attachment of all three MB types was significantly (P = .016) higher compared with control MBs, and this attachment could be significantly (P = .026) decreased by blocking antibodies. Angiogenic marker-expressing cells bound significantly (P = .003) more targeted MBs than negative control cells, and MB attachment significantly (P < .001) correlated with marker expression levels on cells (ρ = 0.87). In early stage breast and ovarian cancers, in vivo targeted contrast-enhanced US demonstrated significantly (P ≤ .04) higher endoglin expression than both α(v)β(3) integrin and VEGFR2 expression, whereas in early stage pancreatic cancer, marker expressions were not significantly different (P ≥ .07). There was good correlation (ρ ≥ 0.63; P ≤ .05) between in vivo targeted contrast-enhanced US imaging signals using the three MB types and ex vivo immunoblotting results regarding expression levels of the three angiogenic markers. Immunofluorescence confirmed expression of α(v)β(3) integrin, endoglin, and VEGFR2 on tumor vascular endothelial cells.Targeted contrast-enhanced US imaging allows noninvasive in vivo assessment of the expression levels of α(v)β(3) integrin, endoglin, and VEGFR2, which vary during tumor growth in subcutaneous cancer xenografts.
View details for DOI 10.1148/radiol.10101079
View details for Web of Science ID 000287573100017
View details for PubMedID 21339349
- Targeted Contrast-Enhanced Ultrasound: An Emerging Technology in Abdominal and Pelvic Imaging GASTROENTEROLOGY 2011; 140 (3): 785-U161
Assessment and Monitoring Tumor Vascularity With Contrast-Enhanced Ultrasound Maximum Intensity Persistence Imaging
2011; 46 (3): 187-195
Contrast-enhanced ultrasound imaging is increasingly being used in the clinic for assessment of tissue vascularity. The purpose of our study was to evaluate the effect of different contrast administration parameters on the in vivo ultrasound imaging signal in tumor-bearing mice using a maximum intensity persistence (MIP) algorithm and to evaluate the reliability of in vivo MIP imaging in assessing tumor vascularity. The potential of in vivo MIP imaging for monitoring tumor vascularity during antiangiogenic cancer treatment was further evaluated.In intraindividual experiments, varying contrast microbubble concentrations (5 × 10⁵, 5 × 10⁶, 5 × 10⁷, 5 × 10⁸ microbubbles in 100 μL saline) and contrast injection rates (0.6, 1.2, and 2.4 mL/min) in subcutaneous tumor-bearing mice were applied and their effects on in vivo contrast-enhanced ultrasound MIP imaging plateau values were obtained using a dedicated small animal ultrasound imaging system (40 MHz). Reliability of MIP ultrasound imaging was tested following 2 injections of the same microbubble concentration (5 × 10⁷ microbubbles at 1.2 mL/min) in the same tumors. In mice with subcutaneous human colon cancer xenografts, longitudinal contrast-enhanced ultrasound MIP imaging plateau values (baseline and at 48 hours) were compared between mice with and without antiangiogenic treatment (antivascular endothelial growth factor antibody). Ex vivo CD31 immunostaining of tumor tissue was used to correlate in vivo MIP imaging plateau values with microvessel density analysis.In vivo MIP imaging plateau values correlated significantly (P = 0.001) with contrast microbubble doses. At 3 different injection rates of 0.6, 1.2, and 2.4 mL/min, MIP imaging plateau values did not change significantly (P = 0.61). Following 2 injections with the same microbubble dose and injection rate, MIP imaging plateau values were obtained with high reliability with an intraclass correlation coefficient of 0.82 (95% confidence interval: 0.64, 0.94). In addition, in vivo MIP imaging plateau values significantly correlated (P = 0.01; R² = 0.77) with ex vivo microvessel density analysis. Tumor volumes in treated and nontreated mice did not change significantly (P = 0.22) within 48 hours. In contrast, the change of in vivo MIP imaging plateau values from baseline to 48 hours was significantly different (P = 0.01) in treated versus nontreated mice.Contrast-enhanced ultrasound MIP imaging allows reliable assessment of tumor vascularity and monitoring of antiangiogenic cancer therapy in vivo, provided that a constant microbubble dose is administered.
View details for DOI 10.1097/RLI.0b013e3181f9202d
View details for Web of Science ID 000286971700006
View details for PubMedID 21150790
PET Imaging of Tumor Neovascularization in a Transgenic Mouse Model with a Novel Cu-64-DOTA-Knottin Peptide
2010; 70 (22): 9022-9030
Due to the high mortality of lung cancer, there is a critical need to develop diagnostic procedures enabling early detection of the disease while at a curable stage. Targeted molecular imaging builds on the positive attributes of positron emission tomography/computed tomography (PET/CT) to allow for a noninvasive detection and characterization of smaller lung nodules, thus increasing the chances of positive treatment outcome. In this study, we investigate the ability to characterize lung tumors that spontaneously arise in a transgenic mouse model. The tumors are first identified with small animal CT followed by characterization with the use of small animal PET with a novel 64Cu-1,4,7,10-tetra-azacylododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-knottin peptide that targets integrins upregulated during angiogenesis on the tumor associated neovasculature. The imaging results obtained with the knottin peptide are compared with standard 18F-fluorodeoxyglucose (FDG) PET small animal imaging. Lung nodules as small as 3 mm in diameter were successfully identified in the transgenic mice by small animal CT, and both 64Cu-DOTA-knottin 2.5F and FDG were able to differentiate lung nodules from the surrounding tissues. Uptake and retention of the 64Cu-DOTA-knottin 2.5F tracer in the lung tumors combined with a low background in the thorax resulted in a statistically higher tumor to background (normal lung) ratio compared with FDG (6.01±0.61 versus 4.36±0.68; P<0.05). Ex vivo biodistribution showed 64Cu-DOTA-knottin 2.5F to have a fast renal clearance combined with low nonspecific accumulation in the thorax. Collectively, these results show 64Cu-DOTA-knottin 2.5F to be a promising candidate for clinical translation for earlier detection and improved characterization of lung cancer.
View details for DOI 10.1158/0008-5472.CAN-10-1338
View details for Web of Science ID 000284213300008
View details for PubMedID 21062977
Antiangiogenic Cancer Therapy: Monitoring with Molecular US and a Clinically Translatable Contrast Agent (BR55)
2010; 256 (2): 519-527
To develop and test human kinase insert domain receptor (KDR)-targeted microbubbles (MBs) (MB(KDR)) for imaging KDR at the molecular level and for monitoring antiangiogenic therapy in a human colon cancer xenograft tumor model in mice.Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. A heterodimeric peptide that binds to human KDR with low nanomolar affinity (K(D) = 0.5 nmol/L) was coupled onto the surface of perfluorobutane-containing lipid-shelled MBs (MB(KDR)). Binding specificity of MB(KDR) to human KDR and cross-reactivity with murine vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) were tested in cell culture under flow shear stress conditions (at 100 sec(-1)). In vivo binding specificity of MB(KDR) to VEGFR2 was tested in human LS174T colon cancer xenografts in mice with a 40-MHz ultrasonographic (US) transducer. Targeted contrast material-enhanced US imaging signal by using MB(KDR) was longitudinally measured during 6 days in tumors with (n = 6) and without (n = 6) antiangiogenic treatment (anti-VEGF antibody). Ex vivo VEGFR2 staining and microvessel density analysis were performed. Significant differences were evaluated (t, Mann-Whitney, or Wilcoxon test).Cell culture experiments showed four times greater binding specificity of MB(KDR) to human KDR and cross-reactivity to murine VEGFR2 (P < or = .01). In vivo imaging signal was more than three times higher (P = .01) with MB(KDR) compared with control MBs and decreased significantly (approximately fourfold lower, P = .03) following in vivo receptor blocking with anti-VEGFR2 antibody. One day after initiation of antiangiogenic therapy, imaging signal was significantly decreased (approximately 46% lower, P = .02) in treated versus untreated tumors; it remained significantly lower (range, 46%-84% decreased; P = .038) during the following 5 days. Microvessel density was significantly reduced (P = .04) in treated (mean, 7.3 microvessels per square millimeter +/- 4.7 [standard deviation]) versus untreated tumors (mean, 22.0 microvessels per square millimeter +/- 9.4); VEGFR2 expression was significantly decreased (>50% lower, P = .03) in treated tumors.Human MB(KDR) allow in vivo imaging and longitudinal monitoring of VEGFR2 expression in human colon cancer xenografts.
View details for DOI 10.1148/radiol.10091858
View details for Web of Science ID 000280272100023
View details for PubMedID 20515975
Indirect imaging of cardiac-specific transgene expression using a bidirectional two-step transcriptional amplification strategy
2010; 17 (7): 827-838
Transcriptional targeting for cardiac gene therapy is limited by the relatively weak activity of most cardiac-specific promoters. We have developed a bidirectional plasmid vector, which uses a two-step transcriptional amplification (TSTA) strategy to enhance the expression of two optical reporter genes, firefly luciferase (fluc) and Renilla luciferase (hrluc), driven by the cardiac troponin T (cTnT) promoter. The vector was characterized in vitro and in living mice using luminometry and bioluminescence imaging to assess its ability to mediate strong, correlated reporter gene expression in a cardiac cell line and the myocardium, while minimizing expression in non-cardiac cell lines and the liver. In vitro, the TSTA system significantly enhanced cTnT-mediated reporter gene expression with moderate preservation of cardiac specificity. After intramyocardial and hydrodynamic tail vein delivery of an hrluc-enhanced variant of the vector, long-term fluc expression was observed in the heart, but not in the liver. In both the cardiac cell line and the myocardium, fluc expression correlated well with hrluc expression. These results show the vector's ability to effectively amplify and couple transgene expression in a cardiac-specific manner. Further replacement of either reporter gene with a therapeutic gene should allow non-invasive imaging of targeted gene therapy in living subjects.
View details for DOI 10.1038/gt.2010.30
View details for Web of Science ID 000279614600002
View details for PubMedID 20237511
View details for PubMedCentralID PMC2900530
Molecular imaging: current status and emerging strategies
2010; 65 (7): 500-516
In vivo molecular imaging has a great potential to impact medicine by detecting diseases in early stages (screening), identifying extent of disease, selecting disease- and patient-specific treatment (personalized medicine), applying a directed or targeted therapy, and measuring molecular-specific effects of treatment. Current clinical molecular imaging approaches primarily use positron-emission tomography (PET) or single photon-emission computed tomography (SPECT)-based techniques. In ongoing preclinical research, novel molecular targets of different diseases are identified and, sophisticated and multifunctional contrast agents for imaging these molecular targets are developed along with new technologies and instrumentation for multi-modality molecular imaging. Contrast-enhanced molecular ultrasound (US) with molecularly-targeted contrast microbubbles is explored as a clinically translatable molecular imaging strategy for screening, diagnosing, and monitoring diseases at the molecular level. Optical imaging with fluorescent molecular probes and US imaging with molecularly-targeted microbubbles are attractive strategies as they provide real-time imaging, are relatively inexpensive, produce images with high spatial resolution, and do not involve exposure to ionizing irradiation. Raman spectroscopy/microscopy has emerged as a molecular optical imaging strategy for ultrasensitive detection of multiple biomolecules/biochemicals with both in vivo and ex vivo versatility. Photoacoustic imaging is a hybrid of optical and US techniques involving optically-excitable molecularly-targeted contrast agents and quantitative detection of resulting oscillatory contrast agent movement with US. Current preclinical findings and advances in instrumentation, such as endoscopes and microcatheters, suggest that these molecular imaging methods have numerous potential clinical applications and will be translated into clinical use in the near future.
View details for DOI 10.1016/j.crad.2010.03.011
View details for Web of Science ID 000280379900002
View details for PubMedID 20541650
Molecular ultrasound imaging: current status and future directions
2010; 65 (7): 567-581
Targeted contrast-enhanced ultrasound (molecular ultrasound) is an emerging imaging strategy that combines ultrasound technology with novel molecularly-targeted ultrasound contrast agents for assessing biological processes at the molecular level. Molecular ultrasound contrast agents are nano- or micro-sized particles that are targeted to specific molecular markers by adding high-affinity binding ligands onto the surface of the particles. Following intravenous administration, these targeted ultrasound contrast agents accumulate at tissue sites overexpressing specific molecular markers, thereby enhancing the ultrasound imaging signal. High spatial and temporal resolution, real-time imaging, non-invasiveness, relatively low costs, lack of ionising irradiation and wide availability of ultrasound systems are advantages compared to other molecular imaging modalities. In this article we review current concepts and future directions of molecular ultrasound imaging, including different classes of molecular ultrasound contrast agents, ongoing technical developments of pre-clinical and clinical ultrasound systems, the potential of molecular ultrasound for imaging different diseases at the molecular level, and the translation of molecular ultrasound into the clinic.
View details for DOI 10.1016/j.crad.2010.02.013
View details for Web of Science ID 000280379900008
View details for PubMedID 20541656
Antioxidants Improve Early Survival of Cardiomyoblasts After Transplantation to the Myocardium
MOLECULAR IMAGING AND BIOLOGY
2010; 12 (3): 325-334
We tested the hypothesis that modulation of the microenvironment (using antioxidants) will increase stem cell survival in hypoxia and after transplantation to the myocardium.Rat cardiomyoblasts were stably transfected with a reporter gene (firefly luciferase) for bioluminescence imaging (BLI). First, we examined the role of oxidative stress in cells under hypoxic conditions. Subsequently, stem cells were transplanted to the myocardium of rats using high-resolution ultrasound, and their survival was monitored daily using BLI.Under hypoxia, oxidative stress was increased together with decreased cell survival compared to control cells, both of which were preserved by antioxidants. In living subjects, oxidative stress blockade increased early cell survival after transplantation to the myocardium, compared to untreated cells/animals.Modulation of the local microenvironment (with antioxidants) improves stem cell survival. Increased understanding of the interaction between stem cells and their microenvironment will be critical to advance the field of regenerative medicine.
View details for DOI 10.1007/s11307-009-0274-4
View details for Web of Science ID 000277375300011
View details for PubMedID 20013064
Molecular ultrasound assessment of tumor angiogenesis
2010; 13 (2): 175-188
Angiogenesis, the growth of new blood vessels, plays a critical role in progression of tumor growth and metastasis, making it an attractive target for both cancer imaging and therapy. Several molecular markers, including those that are involved in the angiogenesis signaling pathway and those unique to tumor angiogenic vessels, have been identified and can be used as targets for molecular imaging of cancer. With the introduction of ultrasound contrast agents that can be targeted to those molecular markers, targeted contrast-enhanced ultrasound (molecular ultrasound) imaging has become an attractive imaging modality to non-invasively assess tumor angiogenesis at the molecular level. The advantages of molecular ultrasound imaging such as high temporal and spatial resolution, non-invasiveness, real-time imaging, relatively low cost, lack of ionizing irradiation and wide availability among the imaging community will further expand its roles in cancer imaging and drug development both in preclinical research and future clinical applications.
View details for DOI 10.1007/s10456-010-9175-z
View details for Web of Science ID 000280552400010
View details for PubMedID 20549555
Targeted Contrast-Enhanced Ultrasound Imaging of Tumor Angiogenesis with Contrast Microbubbles Conjugated to Integrin-Binding Knottin Peptides
JOURNAL OF NUCLEAR MEDICINE
2010; 51 (3): 433-440
Targeted contrast-enhanced ultrasound imaging is increasingly being recognized as a powerful imaging tool for the detection and quantification of tumor angiogenesis at the molecular level. The purpose of this study was to develop and test a new class of targeting ligands for targeted contrast-enhanced ultrasound imaging of tumor angiogenesis with small, conformationally constrained peptides that can be coupled to the surface of ultrasound contrast agents.Directed evolution was used to engineer a small, disulfide-constrained cystine knot (knottin) peptide that bound to alpha(v)beta(3) integrins with a low nanomolar affinity (Knottin(Integrin)). A targeted contrast-enhanced ultrasound imaging contrast agent was created by attaching Knottin(Integrin) to the shell of perfluorocarbon-filled microbubbles (MB-Knottin(Integrin)). A knottin peptide with a scrambled sequence was used to create control microbubbles (MB-Knottin(Scrambled)). The binding of MB-Knottin(Integrin) and MB-Knottin(Scrambled) to alpha(v)beta(3) integrin-positive cells and control cells was assessed in cell culture binding experiments and compared with that of microbubbles coupled to an anti-alpha(v)beta(3) integrin monoclonal antibody (MB(alphavbeta3)) and microbubbles coupled to the peptidomimetic agent c(RGDfK) (MB(cRGD)). The in vivo imaging signals of contrast-enhanced ultrasound with the different types of microbubbles were quantified in 42 mice bearing human ovarian adenocarcinoma xenograft tumors by use of a high-resolution 40-MHz ultrasound system.MB-Knottin(Integrin) attached significantly more to alpha(v)beta(3) integrin-positive cells (1.76 +/- 0.49 [mean +/- SD] microbubbles per cell) than to control cells (0.07 +/- 0.006). Control MB-Knottin(Scrambled) adhered less to alpha(v)beta(3) integrin-positive cells (0.15 +/- 0.12) than MB-Knottin(Integrin). After blocking of integrins, the attachment of MB-Knottin(Integrin) to alpha(v)beta(3) integrin-positive cells decreased significantly. The in vivo ultrasound imaging signal was significantly higher after the administration of MB-Knottin(Integrin) than after the administration of MB(alphavbeta3) or control MB-Knottin(Scrambled). After in vivo blocking of integrin receptors, the imaging signal after the administration of MB-Knottin(Integrin) decreased significantly (by 64%). The imaging signals after the administration of MB-Knottin(Integrin) were not significantly different in the groups of tumor-bearing mice imaged with MB-Knottin(Integrin) and with MB(cRGD). Ex vivo immunofluorescence confirmed integrin expression on endothelial cells of human ovarian adenocarcinoma xenograft tumors.Integrin-binding knottin peptides can be conjugated to the surface of microbubbles and used for in vivo targeted contrast-enhanced ultrasound imaging of tumor angiogenesis. Our results demonstrate that microbubbles conjugated to small peptide-targeting ligands provide imaging signals higher than those provided by a large antibody molecule.
View details for DOI 10.2967/jnumed.109.068007
View details for Web of Science ID 000275133100026
View details for PubMedID 20150258
Pathways of Extrapancreatic Perineural Invasion by Pancreatic Adenocarcinoma: Evaluation With 3D Volume-Rendered MDCT Imaging
AMERICAN JOURNAL OF ROENTGENOLOGY
2010; 194 (3): 668-674
The purpose of this article is to familiarize radiologists with the common pathways of extrapancreatic perineural invasion of pancreatic adenocarcinoma and to highlight the potential value of 3D volume-rendered MDCT in its diagnosis.The perineural plexuses closely follow peripancreatic vessels, which are well depicted by contrast-enhanced 3D volume-rendered imaging, thus facilitating the diagnosis of extrapancreatic perineural invasion of pancreatic adenocarcinoma.
View details for DOI 10.2214/AJR.09.3285
View details for Web of Science ID 000274741100020
View details for PubMedID 20173143
Focal Liver Lesions: Detection and Characterization at Double-Contrast Liver MR Imaging with Ferucarbotran and Gadobutrol versus Single-Contrast Liver MR Imaging
2009; 253 (3): 724-733
To retrospectively compare, in a multiobserver study, double-contrast-material (sequential administration of ferucarbotran and gadobutrol) magnetic resonance (MR) imaging with single-contrast-material ferucarbotran-enhanced and dynamic postferucarbotran gadobutrol-enhanced MR imaging for the detection and characterization of benign and malignant focal liver lesions.This study was institutional review board approved, and the requirement for informed patient consent was waived. Eighty-nine patients with a total of 128 focal liver lesions underwent double-contrast liver MR imaging (nonenhanced, ferucarbotran-enhanced, and dynamic postferucarbotran gadobutrol-enhanced MR imaging performed during one session). Four readers independently reviewed the data sets during three reading sessions focused on focal liver lesion detection and characterization: In session 1, the nonenhanced and dynamic postferucarbotran gadobutrol-enhanced images obtained at double-contrast MR imaging were analyzed. In session 2, the nonenhanced and ferucarbotran-enhanced images were analyzed. In session 3, all MR images were analyzed together. The diagnostic performance of each MR technique and each reader was evaluated by using receiver operating characteristic (ROC) analysis; differences between postferucarbotran gadobutrol-enhanced, ferucarbotran-enhanced, and double-contrast MR imaging were assessed at Wilcoxon signed rank testing; and interreader agreement was assessed at Cohen kappa analysis. Histopathologic confirmation or an unchanged clinical course or MR finding was the reference standard.The four readers' detection of the benign and malignant lesions was not significantly different (P > or = .11) between the three MR techniques. The benign and malignant focal liver lesions were differentiated with significantly higher confidence (P < or = .01) on the double-contrast (area under ROC curve [A(z)] = 0.988) and ferucarbotran-enhanced (A(z) = 0.985) MR images than on the dynamic gadobutrol-enhanced images (A(z) = 0.963). Accuracy in the diagnosis of hepatocellular carcinoma (HCC) was highest (P = .02) and confidence in the final diagnosis of HCC (P = .001) or metastasis (P = .049) was significantly higher with double-contrast imaging.In select cases, double-contrast MR imaging can improve diagnostic accuracy and increase confidence in characterizing focal liver lesions as HCC or metastasis.
View details for DOI 10.1148/radiol.2533090161
View details for Web of Science ID 000272247300019
View details for PubMedID 19789232
MR angiography with parallel acquisition for assessment of the visceral arteries: comparison with conventional MR angiography and 64-detector-row computed tomography
2009; 19 (11): 2679-2688
The purpose of the study was to retrospectively compare three-dimensional gadolinium-enhanced magnetic resonance angiography (conventional MRA) with MRA accelerated by a parallel acquisition technique (fast MRA) for the assessment of visceral arteries, using 64-detector-row computed tomography angiography (MDCTA) as the reference standard. Eighteen patients underwent fast MRA (imaging time 17 s), conventional MRA (29 s) and MDCTA of the abdomen and pelvis. Two independent readers assessed subjective image quality and the presence of arterial stenosis. Data were analysed on per-patient and per-segment bases. Fast MRA yielded better subjective image quality in all segments compared with conventional MRA (P = 0.012 for reader 1, P = 0.055 for reader 2) because of fewer motion-induced artefacts. Sensitivity and specificity of fast MRA for the detection of arterial stenosis were 100% for both readers. Sensitivity of conventional MRA was 89% for both readers, and specificity was 100% (reader 1) and 99% (reader 2). Differences in sensitivity between the two types of MRA were not significant for either reader. Interobserver agreement for the detection of arterial stenosis was excellent for fast (kappa = 1.00) and good for conventional MRA (kappa = 0.76). Thus, subjective image quality of visceral arteries remains good on fast MRA compared with conventional MRA, and the two techniques do not differ substantially in the grading of arterial stenosis, despite the markedly reduced acquisition time of fast MRA.
View details for DOI 10.1007/s00330-009-1473-8
View details for Web of Science ID 000270838000016
View details for PubMedID 19526242
A Novel Estrogen Receptor Intramolecular Folding-based Titratable Transgene Expression System
2009; 17 (10): 1703-1711
The use of regulated gene expression systems is important for successful gene therapy applications. In this study, ligand-induced structural change in the estrogen receptor (ER) was used to develop a novel ER intramolecular folding-based transcriptional activation system. The system was studied using ER-variants of different lengths, flanked on either side by the GAL4-DNA-binding domain and the VP16-transactivation domain (GAL4(DBD)-ER-VP16). The ER ligands of different types showed efficient ligand-regulated transactivation. We also characterized a bidirectional transactivation system based on the ER and demonstrated its utility in titrating both reporter and therapeutic gene expression. The ligand-regulated transactivation system developed by using a mutant form of the ER (G521T, lacking affinity for the endogenous ligand 17beta-estradiol, whereas maintaining affinity for other ligands) showed efficient activation by the ligand raloxifene in living mice without significant interference from the circulating endogenous ligand. The ligand-regulated transactivation system was used to test the therapeutic efficiency of the tumor suppressor protein p53 in HepG2 (p53(+/+)) and SKBr3 (p53(-/-)/mutant-p53(+/+)) cells in culture and tumor xenografts in living mice. The multifunctional capabilities of this system should be useful for gene therapy applications, to study ER biology, to evaluate gene regulation, ER ligand screening, and ER ligand biocharacterization in cells and living animals.
View details for DOI 10.1038/mt.2009.171
View details for Web of Science ID 000270851900008
View details for PubMedID 19654568
Evaluation of periampullary pathology with CT volumetric oblique coronal reformations.
AJR. American journal of roentgenology
2009; 193 (3): W202-8
The purpose of this article is to show the value of volumetric oblique coronal reformation of CT data sets for assessing the normal anatomy and abnormalities of the ampulla of Vater.Volumetric oblique coronal reformations are a useful noninvasive method to provide diagnostic information about periampullary abnormalities as well as show secondary features important for local staging and management. The technique is also valuable in providing a time-efficient method to review pertinent findings with clinicians.
View details for DOI 10.2214/AJR.08.2069
View details for PubMedID 19696260
Imaging Gene Expression in Human Mesenchymal Stem Cells: From Small to Large Animals
2009; 252 (1): 117-127
To evaluate the feasibility of reporter gene imaging in implanted human mesenchymal stem cells (MSCs) in porcine myocardium by using clinical positron emission tomography (PET)-computed tomography (CT) scanning.Animal protocols were approved by the Institutional Administrative Panel on Laboratory Animal Care. Transduction of human MSCs by using different doses of adenovirus that contained a cytomegalovirus (CMV) promoter driving the mutant herpes simplex virus type 1 thymidine kinase reporter gene (Ad-CMV-HSV1-sr39tk) was characterized in a cell culture. A total of 2.25 x 10(6) transduced (n = 5) and control nontransduced (n = 5) human MSCs were injected into the myocardium of 10 rats, and reporter gene expression in human MSCs was visualized with micro-PET by using the radiotracer 9-(4-[fluorine 18]-fluoro-3-hydroxymethylbutyl)-guanine (FHBG). Different numbers of transduced human MSCs suspended in either phosphate-buffered saline (PBS) (n = 4) or matrigel (n = 5) were injected into the myocardium of nine swine, and gene expression was visualized with a clinical PET-CT. For analysis of cell culture experiments, linear regression analyses combined with a t test were performed. To test differences in radiotracer uptake between injected and remote myocardium in both rats and swine, one-sided paired Wilcoxon tests were performed. In swine experiments, a linear regression of radiotracer uptake ratio on the number of injected transduced human MSCs was performed.In cell culture, there was a viral dose-dependent increase of gene expression and FHBG accumulation in human MSCs. Human MSC viability was 96.7% (multiplicity of infection, 250). Cardiac FHBG uptake in rats was significantly elevated (P < .0001) after human MSC injection (0.0054% injected dose [ID]/g +/- 0.0007 [standard deviation]) compared with that in the remote myocardium (0.0003% ID/g +/- 0.0001). In swine, myocardial radiotracer uptake was not elevated after injection of up to 100 x 10(6) human MSCs (PBS group). In the matrigel group, signal-to-background ratio increased to 1.87 after injection of 100 x 10(6) human MSCs and positively correlated (R(2) = 0.97, P < .001) with the number of administered human MSCs.Reporter gene imaging in human MSCs can be translated to large animals. The study highlights the importance of co-administering a "scaffold" for increasing intramyocardial retention of human MSCs.
View details for DOI 10.1148/radiol.2513081616
View details for Web of Science ID 000268362900015
View details for PubMedID 19366903
View details for PubMedCentralID PMC2702468
Comparison of Optical Bioluminescence Reporter Gene and Superparamagnetic Iron Oxide MR Contrast Agent as Cell Markers for Noninvasive Imaging of Cardiac Cell Transplantation
MOLECULAR IMAGING AND BIOLOGY
2009; 11 (3): 178-187
In this study, we compared firefly luciferase (Fluc) reporter gene and superparamagnetic iron oxide (Feridex) as cell markers for longitudinal monitoring of cardiomyoblast graft survival using optical bioluminescence imaging (BLI) and magnetic resonance imaging (MRI), respectively.Rats (n = 31) underwent an intramyocardial injection of cardiomyoblasts (2 x 10(6)) labeled with Fluc, Feridex, or no marker (control) or an injection of Feridex alone (75 microg). Afterward, rats were serially imaged with BLI or MRI and killed at different time points for histological analysis.BLI revealed a drastically different cell survival kinetics (half-life = 2.65 days over 6 days) than that revealed by MRI (half-life = 16.8 days over 80 days). Injection of Feridex alone led to prolonged tissue retention of Feridex (> or =16 days) and persistent MR signal (> or =42 days).Fluc BLI reporter gene imaging is a more accurate gauge of transplanted cell survival as compared to MRI of Feridex-labeled cells.
View details for DOI 10.1007/s11307-008-0182-z
View details for Web of Science ID 000265686900005
View details for PubMedID 19034584
View details for PubMedCentralID PMC4155941
Targeted microbubbles for imaging tumor angiogenesis: Assessment of whole-body biodistribution with dynamic micro-PET in mice
2008; 249 (1): 212-219
To evaluate in vivo whole-body biodistribution of microbubbles (MBs) targeted to tumor angiogenesis-related vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by using dynamic micro-positron emission tomography (PET) in living mice.Animal protocols were approved by the Institutional Administrative Panel on Laboratory Animal Care. Lipid-shell perfluorocarbon-filled MBs, targeted to VEGFR2 via anti-VEGFR2 antibodies, were radiolabeled by conjugating the radiofluorination agent N-succinimidyl-4-[(18)F]fluorobenzoate (SFB) to the anti-VEGFR2 antibodies. These MBs were then injected intravenously into nude mice (n = 4) bearing angiosarcomas, and the whole-body biodistribution of these probes was assessed for 60 minutes by using dynamic micro-PET. Results were compared with ex vivo gamma counting (n = 6) and immunofluorescence staining (n = 6). Control studies in angiosarcoma-bearing mice were performed with injection of the radiolabeled antibodies alone (n = 3) or free SFB (n = 3). A mixed-effects regression of MB accumulation on fixed effects of time and tissue type (tumor or muscle) and random effect of animal was performed.VEGFR2-targeted MBs rapidly cleared from the blood circulation (50% blood clearance after approximately 3.5 minutes) and accumulated in the liver (mean, 33.4% injected dose [ID]/g +/- 13.7 [standard deviation] at 60 minutes) and spleen (mean, 9.3% ID/g +/- 6.5 at 60 minutes) on the basis of micro-PET imaging. These findings were confirmed with ex vivo gamma counting. Uptake of targeted MBs was significantly higher (P < .0001) in tumor than in adjacent skeletal muscle tissue. Immunofluorescence staining demonstrated accumulation of the targeted MBs within hepatic Kupffer cells and splenic macrophages. Biodistribution of the radiolabeled antibodies and free SFB differed from the distribution of the targeted MBs.Dynamic micro-PET allows assessment of in vivo biodistribution of VEGFR2-targeted MBs.
View details for DOI 10.1148/radiol.2491072050
View details for Web of Science ID 000259505200025
View details for PubMedID 18695212
Dual-targeted contrast agent for US assessment of tumor angiogenesis in vivo
2008; 248 (3): 936-944
To develop and validate a dual-targeted ultrasonographic (US) imaging agent with microbubbles (MBs) that attaches to both vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and alpha(v)beta(3) integrin and to compare the US imaging signal obtained from dual-targeted MBs (MB(D)) with that from single-targeted MBs (MB(S)) in a murine model of tumor angiogenesis.Animal protocols were approved by the institutional Administrative Panel on Laboratory Animal Care. Single- and dual-targeted US imaging agents were prepared by attaching anti-VEGFR2, anti-alpha(v)beta(3) integrin, or both antibodies to the shell of perfluorocarbon-filled MBs. Binding specificities of targeted MBs compared with isotype-matched immunoglobulin G-labeled control MBs (MB(C)) and nontargeted nonlabeled MBs (MB(N)) were tested with VEGFR2-positive and alpha(v)beta(3) integrin-positive cells (mouse SVR cells) and control cells (mouse 4T1 cells). In vivo imaging signals of contrast material-enhanced US by using anti-VEGFR2-targeted MBs (MB(V)), anti-alpha(v)beta(3) integrin-targeted MBs (MB(I)), MB(D), and MB(C) were quantified in 49 mice bearing SK-OV-3 tumors (human ovarian cancer). Tumor tissue was stained for VEGFR2, alpha(v)beta(3) integrin, and CD31.Attachment of MB(D) to SVR cells (mean, 0.74 MBs per cell +/- 0.05 [standard deviation]) was significantly higher than attachment to 4T1 cells (mean, 0.04 +/- 0.03), and attachment to SVR cells was higher for MB(D) than for MB(V) (mean, 0.58 +/- 0.09), MB(I) (mean, 0.42 +/- 0.21), MB(C) (mean, 0.11 +/- 0.13), and MB(N) (mean, 0.01 +/- 0.01) (P < .05). Imaging signal in the murine tumor angiogenesis model was significantly higher (P < .001) for MB(D) (mean, 16.7 +/- 7.2) than for MB(V) (mean, 11.3 +/- 5.7), MB(I) (mean, 7.8 +/- 5.3), MB(C) (mean, 2.8 +/- 0.9), and MB(N) (mean, 1.1 +/- 0.4). Immunofluorescence confirmed expression of VEGFR2 and alpha(v)beta(3) integrin on tumor vasculature.Dual-targeted contrast-enhanced US directed at both VEGFR2 and alpha(v)beta(3) integrin improves in vivo visualization of tumor angiogenesis in a human ovarian cancer xenograft tumor model in mice.http://radiology.rsnajnls.org/cgi/content/full/248/3/936/DC1.
View details for DOI 10.1148/radiol.2483072231
View details for Web of Science ID 000258541500031
View details for PubMedID 18710985
Cancer screening: A mathematical model relating secreted blood biomarker levels to tumor sizes
2008; 5 (8): 1287-1297
Increasing efforts and financial resources are being invested in early cancer detection research. Blood assays detecting tumor biomarkers promise noninvasive and financially reasonable screening for early cancer with high potential of positive impact on patients' survival and quality of life. For novel tumor biomarkers, the actual tumor detection limits are usually unknown and there have been no studies exploring the tumor burden detection limits of blood tumor biomarkers using mathematical models. Therefore, the purpose of this study was to develop a mathematical model relating blood biomarker levels to tumor burden.Using a linear one-compartment model, the steady state between tumor biomarker secretion into and removal out of the intravascular space was calculated. Two conditions were assumed: (1) the compartment (plasma) is well-mixed and kinetically homogenous; (2) the tumor biomarker consists of a protein that is secreted by tumor cells into the extracellular fluid compartment, and a certain percentage of the secreted protein enters the intravascular space at a continuous rate. The model was applied to two pathophysiologic conditions: tumor biomarker is secreted (1) exclusively by the tumor cells or (2) by both tumor cells and healthy normal cells. To test the model, a sensitivity analysis was performed assuming variable conditions of the model parameters. The model parameters were primed on the basis of literature data for two established and well-studied tumor biomarkers (CA125 and prostate-specific antigen [PSA]). Assuming biomarker secretion by tumor cells only and 10% of the secreted tumor biomarker reaching the plasma, the calculated minimally detectable tumor sizes ranged between 0.11 mm(3) and 3,610.14 mm(3) for CA125 and between 0.21 mm(3) and 131.51 mm(3) for PSA. When biomarker secretion by healthy cells and tumor cells was assumed, the calculated tumor sizes leading to positive test results ranged between 116.7 mm(3) and 1.52 x 10(6) mm(3) for CA125 and between 27 mm(3) and 3.45 x 10(5) mm(3) for PSA. One of the limitations of the study is the absence of quantitative data available in the literature on the secreted tumor biomarker amount per cancer cell in intact whole body animal tumor models or in cancer patients. Additionally, the fraction of secreted tumor biomarkers actually reaching the plasma is unknown. Therefore, we used data from published cell culture experiments to estimate tumor cell biomarker secretion rates and assumed a wide range of secretion rates to account for their potential changes due to field effects of the tumor environment.This study introduced a linear one-compartment mathematical model that allows estimation of minimal detectable tumor sizes based on blood tumor biomarker assays. Assuming physiological data on CA125 and PSA from the literature, the model predicted detection limits of tumors that were in qualitative agreement with the actual clinical performance of both biomarkers. The model may be helpful in future estimation of minimal detectable tumor sizes for novel proteomic biomarker assays if sufficient physiologic data for the biomarker are available. The model may address the potential and limitations of tumor biomarkers, help prioritize biomarkers, and guide investments into early cancer detection research efforts.
View details for DOI 10.1371/journal.pmed.0050170
View details for Web of Science ID 000258739200018
View details for PubMedID 18715113
Molecular imaging in drug development
NATURE REVIEWS DRUG DISCOVERY
2008; 7 (7): 591-607
Molecular imaging can allow the non-invasive assessment of biological and biochemical processes in living subjects. Such technologies therefore have the potential to enhance our understanding of disease and drug activity during preclinical and clinical drug development, which could aid decisions to select candidates that seem most likely to be successful or to halt the development of drugs that seem likely to ultimately fail. Here, with an emphasis on oncology, we review the applications of molecular imaging in drug development, highlighting successes and identifying key challenges that need to be addressed for successful integration of molecular imaging into the drug development process.
View details for DOI 10.1038/nrd2290
View details for Web of Science ID 000257268200014
View details for PubMedID 18591980
Recurrent lower-limb varicose veins: Effect of direct contrast-enhanced three-dimensional MR venographic findings on diagnostic thinking and therapeutic decisions
2008; 247 (3): 887-895
To assess the effect of direct three-dimensional (3D) magnetic resonance (MR) venographic findings on diagnostic thinking and therapeutic decisions in patients with complex recurrent varicose vein anatomy who were being evaluated for surgical treatment.The study was approved by the Institutional Review Board; informed consent was obtained from patients. MR venography was performed before surgery in 22 legs of 14 patients (seven women: mean age, 53 years; seven men: mean age, 59 years) thought to have recurrent varicose veins. Two radiologists assessed image quality and evaluated sites and sources of varicose veins on MR venograms. One vascular surgeon completed a questionnaire before and after MR venography and noted diagnosis and therapeutic decisions. Diagnoses at MR venography were compared with surgical results in 19 legs that underwent surgery. Differences between diagnosed and treated varicose veins per leg before and after MR venography were analyzed with logistic regression for survey data. kappa Values were calculated to illustrate interobserver agreement for grading image quality of venous segments and for diagnosing recurrent varicose veins.Mean graded image quality of the deep venous system and the recurrent varicose veins was good or excellent in 89% of segments. There was good agreement between readers regarding grading of image quality of venous segments (kappa = 0.80). After MR venography, diagnosis of the sites and sources of recurrent varicose veins changed in 17 of 22 legs of nine of 14 patients. In one of 14 patients, the preoperative diagnosis of recurrent varicose veins was withdrawn. A change in treatment plan occurred in 17 of 22 legs after MR venography. The number of diagnosed and treated sources of reflux increased significantly after MR venography. MR venographic diagnoses were confirmed at surgery in all 19 legs.MR venographic results have a substantial effect on diagnostic thinking and therapeutic decisions when recurrent lower-limb varicose veins are suspected.
View details for DOI 10.1148/radiol.2473070987
View details for Web of Science ID 000256079700037
View details for PubMedID 18403627
Dynamic MRI of the liver with parallel acquisition technique: characterization of focal liver lesions and analysis of the hepatic vasculature in a single MRI session
ROFO-FORTSCHRITTE AUF DEM GEBIET DER RONTGENSTRAHLEN UND DER BILDGEBENDEN VERFAHREN
2008; 180 (5): 440-448
To retrospectively evaluate the performance of breath-hold contrast-enhanced 3D dynamic parallel gradient echo MRI (pMRT) for the characterization of focal liver lesions (standard of reference: histology) and for the analysis of hepatic vasculature (standard of reference: contrast-enhanced 64-detector row computed tomography; MSCT) in a single MRI session.Two blinded readers independently analyzed preoperative pMRT data sets (1.5T-MRT) of 45 patients (23 men, 22 women; 28 - 77 years, average age, 48 years) with a total of 68 focal liver lesions with regard to image quality of hepatic arteries, portal and hepatic veins, presence of variant anatomy of the hepatic vasculature, as well as presence of portal vein thrombosis and hemodynamically significant arterial stenosis. In addition, both readers were asked to identify and characterize focal liver lesions. Imaging parameters of pMRT were: TR/TE/matrix/slice thickness/acquisition time: 3.1 ms/ 1.4 ms/ 384 x 224 / 4 mm/ 15 - 17 s. MSCT was performed with a pitch of 1.2, an effective slice thickness of 1 mm and a matrix of 512 x 512.Based on histology, the 68 liver lesions were found to be 42 hepatocellular carcinomas (HCC), 20 metastases, 3 cholangiocellular carcinomas (CCC) as well as 1 dysplastic nodule, 1 focal nodular hyperplasia (FNH) and 1 atypical hemangioma. Overall, the diagnostic accuracy was high for both readers (91 - 100 %) in the characterization of these focal liver lesions with an excellent interobserver agreement (kappa-values of 0.89 [metastases], 0.97 [HCC] and 1 [CCC]). On average, the image quality of all vessels under consideration was rated good or excellent in 89 % (reader 1) and 90 % (reader 2). Anatomical variants of the hepatic arteries, hepatic veins and portal vein as well as thrombosis of the portal vein were reliably detected by pMRT. Significant arterial stenosis was found with a sensitivity between 86 % and 100 % and an excellent interobserver agreement (kappa = 0.85).Diagnostic image quality remains good or excellent in most cases when the data acquisition time is accelerated by means of parallel imaging in dynamic MRI. It allows reliable detection and characterization of focal liver lesions as well as the depiction of hepatic vascular variants, portal vein thrombosis, and arterial stenosis. Introducing pMRT in routine liver MRI may be another step towards a simplified diagnostic work-up prior to liver surgery.
View details for DOI 10.1055/s-2008-1027279
View details for Web of Science ID 000256025800009
View details for PubMedID 18438745
Imaging of VEGF receptor in a rat myocardial infarction model using PET
JOURNAL OF NUCLEAR MEDICINE
2008; 49 (4): 667-673
Myocardial infarction (MI) leads to left ventricular (LV) remodeling, which leads to the activation of growth factors such as vascular endothelial growth factor (VEGF). However, the kinetics of a growth factor's receptor expression, such as VEGF, in the living subject has not yet been described. We have developed a PET tracer (64Cu-DOTA-VEGF121 [DOTA is 1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraacetic acid]) to image VEGF receptor (VEGFR) expression after MI in the living subject.In Sprague-Dawley rats, MI was induced by ligation of the left coronary artery and confirmed by ultrasound (n = 8). To image and study the kinetics of VEGFRs, 64Cu-DOTA-VEGF121 PET scans were performed before MI induction (baseline) and on days 3, 10, 17, and 24 after MI. Sham-operated animals served as controls (n = 3).Myocardial origin of the 64Cu-DOTA-VEGF121 signal was confirmed by CT coregistration and autoradiography. VEGFR specificity of the 64Cu-DOTA-VEGF121 probe was confirmed by in vivo use of a 64Cu-DOTA-VEGFmutant. Baseline myocardial uptake of 64Cu-DOTA-VEGF121 was minimal (0.30 +/- 0.07 %ID/g [percentage injected dose per gram of tissue]); it increased significantly after MI (day 3, 0.97 +/- 0.05 %ID/g; P < 0.05 vs. baseline) and remained elevated for 2 wk (up to day 17 after MI), after which time it returned to baseline levels.We demonstrate the feasibility of imaging VEGFRs in the myocardium. In summary, we imaged and described the kinetics of 64Cu-DOTA-VEGF121 uptake in a rat model of MI. Studies such as the one presented here will likely play a major role when studying pathophysiology and assessing therapies in different animal models of disease and, potentially, in patients.
View details for DOI 10.2967/jnumed.107.040576
View details for Web of Science ID 000254813600028
View details for PubMedID 18375924
View details for PubMedCentralID PMC2853914
Monitoring of the biological response to murine Hindlimb ischemia with Cu-64-labeled vascular endothelial growth factor-121 positron emission tomography
2008; 117 (7): 915-922
Vascular endothelial growth factor-121 (VEGF121), an angiogenic protein secreted in response to hypoxic stress, binds to VEGF receptors (VEGFRs) overexpressed on vessels of ischemic tissue. The purpose of this study was to evaluate 64Cu-VEGF121 positron emission tomography for noninvasive spatial, temporal, and quantitative monitoring of VEGFR2 expression in a murine model of hindlimb ischemia with and without treadmill exercise training.64Cu-labeled VEGF121 and a VEGF mutant were tested for VEGFR2 binding specificity in cell culture. Mice (n=58) underwent unilateral ligation of the femoral artery, and postoperative tissue ischemia was assessed with laser Doppler imaging. Longitudinal VEGFR2 expression in exercised and nonexercised mice was quantified with 64Cu-VEGF121 positron emission tomography at postoperative day 8, 15, 22, and 29 and correlated with postmortem gamma-counting. Hindlimbs were excised for immunohistochemistry, Western blotting, and microvessel density measurements. Compared with the VEGF mutant, VEGF121 showed specific binding to VEGFR2. Perfusion in ischemic hindlimbs fell to 9% of contralateral hindlimb on postoperative day 1 and recovered to 82% on day 29. 64Cu-VEGF121 uptake in ischemic hindlimbs increased significantly (P < 0.001) from a control level of 0.61+/-0.17% ID/g (percentage of injected dose per gram) to 1.62+/-0.35% ID/g at postoperative day 8, gradually decreased over the following 3 weeks (0.59+/-0.14% ID/g at day 29), and correlated with gamma-counting (R2 = 0.99). Compared with nonexercised mice, 64Cu-VEGF121 uptake was increased significantly (P < or = 0.0001) in exercised mice (at day 15, 22, and 29) and correlated with VEGFR2 levels as obtained by Western blotting (R2 = 0.76). Ischemic hindlimb tissue stained positively for VEGFR2. In exercised mice, microvessel density was increased significantly (P<0.001) compared with nonexercised mice.64Cu-VEGF121 positron emission tomography allows longitudinal spatial and quantitative monitoring of VEGFR2 expression in murine hindlimb ischemia and indirectly visualizes enhanced angiogenesis stimulated by treadmill exercise training.
View details for DOI 10.1161/CIRCULATIONAHA.107.733220
View details for Web of Science ID 000253428100008
View details for PubMedID 18250264
View details for PubMedCentralID PMC4157592
- Reporter gene imaging following percutaneous delivery in swine - Moving toward clinical applications JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2008; 51 (5): 595-597
US imaging of tumor angiogenesis with microbubbles targeted to vascular endothelial growth factor receptor type 2 in mice
2008; 246 (2): 508-518
To prospectively evaluate contrast material-enhanced ultrasonography (US) with microbubbles targeted to vascular endothelial growth factor receptor type 2 (VEGFR2) for imaging tumor angiogenesis in two murine tumor models.Animal protocols were approved by the Institutional Administrative Panel on Laboratory Animal Care. A US contrast agent, consisting of encapsulated gaseous microbubbles, was developed specifically to bind to VEGFR2 (by using anti-VEGFR2 antibodies and biotin-streptavidin interaction) which is up-regulated on endothelial cells of tumor blood vessels. VEGFR2-targeted microbubbles (MB(V)), control microbubbles (MB(C)), and nonlabeled microbubbles (MB(N)) were tested for binding specificity on cells expressing VEGFR2 (mouse angiosarcoma SVR cells) and control cells (mouse skeletal myoblast C2C12 cells). Expression of mouse VEGFR2 in culture cells was tested with immunocytochemical and Western blot analysis. Contrast-enhanced US imaging with MB(V) and MB(C) was performed in 28 tumor-bearing nude mice (mouse angiosarcoma, n = 18; rat malignant glioma, n = 10). Differences were calculated by using analysis of variance.In cell culture, adherence of MB(V) on SVR cells (2.1 microbubbles per SVR cell) was significantly higher than adherence of control microbubbles (0.01-0.10 microbubble per SVR cell; P < .001) and significantly more MB(V) attached to SVR cells than to C2C12 cells (0.15 microbubble per C2C12 cell; P < .001). In vivo, contrast-enhanced US imaging showed significantly higher average video intensity when using MB(V) compared with MB(C) for angiosarcoma and malignant glioma tumors (P < .001). Results of immunohistochemical analysis confirmed VEGFR2 expression on vascular endothelial cells of both tumor types.US imaging with contrast microbubbles targeted to VEGFR2 allows noninvasive visualization of VEGFR2 expression in tumor vessels in mice.
View details for DOI 10.1148/radio1.2462070536
View details for Web of Science ID 000252796300021
View details for PubMedID 18180339
Mapping of hepatic vascular anatomy: Dynamic contrast-enhanced parallel MR Imaging compared with 64-detector row CT
2007; 245 (3): 872-880
The study was approved by the institutional review board, and informed consent was obtained from all patients. The purpose of this study was to retrospectively evaluate the feasibility, reliability, and accuracy of breath-hold dynamic contrast material-enhanced parallel gradient-echo (GRE) magnetic resonance (MR) imaging for mapping the hepatic vascular anatomy, with contrast-enhanced 64-detector row computed tomography (CT) as the reference standard. The parallel GRE MR data sets of 100 patients acquired at 1.5 T were evaluated independently by two blinded readers with respect to (a) image quality for depiction of the hepatic arteries and the portal and hepatic veins and (b) presence of arterial stenosis and variant hepatic vasculature. The readers rated image quality to be good or excellent for 91.1%-100% of the vessels. At parallel GRE MR imaging, the readers diagnosed variant hepatic vessels and arterial stenosis with 94%-100% accuracy. They concluded that parallel GRE MR imaging, as compared with 64-detector row CT, is feasible for hepatic vascular mapping and enables reliable and accurate detection of variant hepatic vasculature and diagnosis of arterial stenosis. Supplemental material: http://radiology.rsnajnls.org/cgi/content/full/2453062103/DC1.
View details for DOI 10.1148/radiol.2453062103
View details for Web of Science ID 000251070700030
View details for PubMedID 17954617
Assessment of aortoiliac and renal arteries: MR angiography with parallel acquisition versus conventional MR angiography and digital subtraction angiography
2007; 245 (1): 276-284
To prospectively compare the image quality, sensitivity, and specificity of three-dimensional gadolinium-enhanced magnetic resonance (MR) angiography accelerated by parallel acquisition (ie, fast MR angiography) with MR angiography not accelerated by parallel acquisition (ie, conventional MR angiography) for assessment of aortoiliac and renal arteries, with digital subtraction angiography (DSA) as the reference standard.The study was approved by the institutional review board; informed consent was obtained from all patients. Forty consecutive patients (33 men, seven women; mean age, 63 years) suspected of having aortoiliac and renal arterial stenoses and thus examined with DSA underwent both fast (mean imaging time, 17 seconds) and conventional (mean imaging time, 29 seconds) MR angiography. The arterial tree was divided into segments for image analysis. Two readers independently evaluated all MR angiograms for image quality, presence of arterial stenosis, and renal arterial variants. Image quality, sensitivity, and specificity were analyzed on per-patient and per-segment bases for multiple comparisons (with Bonferroni correction) and for dependencies between segments (with patient as the primary sample unit). Interobserver agreement was evaluated by using kappa statistics.Overall, the image quality with fast MR angiography was significantly better (P=.001) than that with conventional MR angiography. At per-segment analysis, the image quality of fast MR angiograms of the distal renal artery tended to be better than that of conventional MR angiograms of these vessels. Differences in sensitivity for the detection of arterial stenosis between the two MR angiography techniques were not significant for either reader. Interobserver agreement in the detection of variant renal artery anatomy was excellent with both conventional and fast MR angiography (kappa=1.00).Fast MR angiography and conventional MR angiography do not differ significantly in terms of arterial stenosis grading or renal arterial variant detection.
View details for DOI 10.1148/radiol.2451062081
View details for Web of Science ID 000249577500032
View details for PubMedID 17717331
2-Deoxy-2-[F-18]fluoro-D-glucose accumulation in ovarian carcinoma cell lines
MOLECULAR IMAGING AND BIOLOGY
2007; 9 (5): 260-266
To evaluate 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) accumulation in human ovarian carcinoma cell lines compared with control tumor cell lines known to accumulate FDG.FDG accumulation assays were performed in 15 different ovarian carcinoma cell lines at 1, 2, and 3 hours after incubation with 1 microCi of FDG. Results were compared with FDG accumulation in six different control tumor cell lines. 2-deoxy-2-[F-18]fluoro-D-glucose accumulation was expressed as counts per minute (cpm) in cells and normalized to initial cpm in medium and total protein content of cell lysates.FDG accumulation in all 15 ovarian carcinoma cell lines was equal to or higher than 0.0005 +/- 8.6 10(-5) cpm in cells/cpm in medium/mug protein at all three different time points. In two ovarian carcinoma cell lines (ES-2, poorly differentiated clear cell carcinoma, and OVCAR-3, poorly differentiated papillary adenocarcinoma), FDG accumulation was not statistically, significantly different compared to the control cell line with the highest FDG accumulation (LS 174T human colorectal adenocarcinoma) at two or more time points (P > or = 0.07). In 2 of 15 (13%) ovarian carcinoma cell lines (OVCAR5 epithelial carcinoma and SKOV3 clear cell carcinoma), FDG accumulation was lower than that in the control cell line with the lowest FDG accumulation (HT-29 human colorectal adenocarcinoma) at one or more time points (P < 0.05).Most human ovarian carcinoma cell lines showed comparable FDG accumulations with control cell lines known to accumulate FDG. This study lays the foundations for further comparisons with other ovarian cancer cell lines and for other positron emission tomography tracers.
View details for DOI 10.1007/s11307-007-0105-4
View details for Web of Science ID 000248865200002
View details for PubMedID 17610017
- Adrenal angiomyolipoma in lymphangioleiomyomatosis EUROPEAN RADIOLOGY 2007; 17 (2): 565-566
Assessment of the abdominal aorta and its visceral branches by contrast-enhanced dynamic volumetric hepatic parallel magnetic resonance imaging: feasibility, reliability and accuracy
2007; 17 (2): 541-551
The purpose of this study was to evaluate a new three-dimensional gradient-echo (GRE) MR sequence performed with a parallel acquisition technique to shorten breath-hold times (parallel GRE MRI) in the detection of arterial variants and stenosis of the abdominal aorta and its visceral branches. A total of 102 patients underwent dynamic parallel GRE MRI, timed to the arterial phase by a test bolus (mean breath-hold time, 17 s). For both quantitative and qualitative analysis, the abdominal aorta and its visceral branches were divided into 13 arterial segments. In a subanalysis of 55/102 patients, the accuracy of parallel GRE MRI compared to MDCT in the detection arterial variants and stenosis was calculated for two independent readers. Mean SNRs and CNRs were 47.2 and 35.6, respectively. Image quality was rated good or excellent in 1,234/1,326 segments (93%). Hepatic and renal arterial variants were identified with an accuracy of 93 and 95%, respectively (reader 1) and 98 and 100%, respectively (reader 2). Both readers detected arterial stenosis with an accuracy of 98%. Interobserver agreement was good to excellent for the detection of hepatic (kappa=0.69) and renal (kappa=0.92) variants and for the diagnosis of stenosis (kappa=0.96). Dynamic three-dimensional parallel GRE MRI is feasible and allows a reliable and accurate diagnosis of arterial variants and stenosis of the abdominal aorta and its visceral branches in a short breath-hold-time.
View details for DOI 10.1007/s00330-006-0384-1
View details for Web of Science ID 000243604500025
View details for PubMedID 16947013
Functional Ureteral obstruction due to complex pelvic venous anomaly
2007; 79 (3): 284-286
Venous anomalies are rare causes of ureteral obstruction. We report the case of a 31-year-old woman with obstruction of the right distal ureter by a complex pelvic venous anomaly. Beside benign and malignant lesions of the retroperitoneum, venous anomalies should also be considered in the differential diagnosis of extrinsic ureteral obstruction. Due to its abilities of three-dimensional visualization, multi-detector row computed tomography is helpful in the depiction of venous anomalies.
View details for DOI 10.1159/000107965
View details for Web of Science ID 000250309100019
View details for PubMedID 17940365
Prospective intraindividual comparison between respiratory-triggered balanced steady-state free precession and breath-hold gradient-echo and time-of-flight magnetic resonance imaging for assessment of portal and hepatic veins
2007; 17 (1): 229-240
The purpose of this study was to compare respiratory-triggered balanced steady-state free precession (bSSFP) with breath-hold contrast-enhanced dynamic two-dimensional (2D) gradient-echo (GRE) and time-of-flight (TOF) magnetic resonance imaging (MRI) for portal and hepatic vein visualization and assessment of portal and hepatic venous variants. Sixty patients with liver disease underwent nonenhanced bSSFP and contrast-enhanced GRE, bSSFP, and TOF imaging. Contrast-to-noise ratios (CNRs) for portal and hepatic veins were measured. Two readers rated the quality of portal and hepatic vein visualization on a 5-point Likert scale. The diagnostic performance of each MRI series in the detection of portal and hepatic venous variants was assessed in 40/60 patients who also underwent contrast-enhanced multidetector-row computed tomography (MDCT). CNRs for portal and hepatic veins were highest on contrast-enhanced bSSFP images. Image quality of portal and hepatic veins was rated higher for nonenhanced bSSFP than for contrast-enhanced GRE (p<0.03) and TOF (p<0.003) and higher for contrast-enhanced than for nonenhanced bSSFP (p<0.003). Compared with MDCT, portal and hepatic venous variants were identified with an accuracy of 99% on bSSFP images, with an excellent interobserver agreement (kappa=0.97). Compared with MDCT, presence of surgically important portal and hepatic venous anatomical variants can be predicted with high accuracy on bSSFP images.
View details for DOI 10.1007/s00330-006-0305-3
View details for Web of Science ID 000243396700027
View details for PubMedID 16703307
- Pancreatic tuberculosis - a diagnostic chameleon ROFO-FORTSCHRITTE AUF DEM GEBIET DER RONTGENSTRAHLEN UND DER BILDGEBENDEN VERFAHREN 2006; 178 (4): 446-448
Multidetector-row CT angiography of upper- and lower-extremity peripheral arteries
MDCT Symposium Radiologys Powerhouse
SPRINGER. 2005: D3–D9
With the introduction of multidetector-row CT (MDCT) technology indications for MDCT angiography have expanded to include assessment of the peripheral arteries of the upper and lower extremities. Combined with patient- and scanner-adjusted CT data acquisition and contrast medium application strategies, an accurate and reliable evaluation of the peripheral arteries of the upper and lower extremities is possible. MDCT angiography is cost-effective and accurate for detection of arterial stenosis and occlusion in patients with peripheral arterial disease (PAD). MDCT angiography allows postoperative assessment of peripheral arterial bypass grafts, including bypass graft stenosis and occlusion, as well as presence of aneurysms or arteriovenous fistulas. In addition, MDCT angiography is helpful in particular for visualization of arterial bypass grafts with a complicated extra-anatomical course. Furthermore, pre-operative peripheral vascular mapping can be performed by using MDCT angiography. Finally, due to the integration of MDCT scanners in many trauma centres, MDCT angiography is increasingly being used for assessment of traumatic arterial injuries. This article gives an overview of technical aspects of peripheral MDCT angiography, including scanning parameters, contrast medium application, image postprocessing and radiation exposure, and summarizes the most frequent acute and non-acute indications of MDCT angiography for assessment of the upper- and lower-extremity peripheral arteries.
View details for DOI 10.1007/s10406-005-0132-7
View details for Web of Science ID 000233976200002
View details for PubMedID 16479637
Hepatocellular carcinoma in cirrhosis: Enhancement patterns at dynamic gadolinium-and superparamagnetic iron oxide-enhanced T1-weighted MR imaging
2005; 237 (2): 520-528
To prospectively compare intraindividual differences in enhancement patterns between gadolinium- and superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance (MR) imaging in patients with histologically proved hepatocellular carcinoma (HCC).Institutional review board approval and informed consent were obtained. Twenty-two patients (18 men, four women; mean age, 58.9 years) with 36 pathologically proved HCC lesions underwent contrast material-enhanced dynamic T1-weighted gradient-echo MR imaging twice. Gadopentetate dimeglumine was used at the first session. After a mean interval of 5 days, a second session was performed with a bolus-injectable SPIO agent, ferucarbotran. Qualitative analysis of contrast enhancement patterns with each agent during hepatic arterial, portal venous, and equilibrium phases was performed by two readers who classified lesions as isointense, hypointense, or hyperintense compared with surrounding liver parenchyma and searched for presence of hyperintense peritumoral ring enhancement. Results of signal intensity analysis during different vascular phases at both sessions were compared by using the McNemar test, and kappa statistic was used to evaluate agreement between signal intensity and enhancement pattern of lesions during different vascular phases.On gadolinium-enhanced hepatic arterial phase images, HCC lesions (n = 36) were hyperintense in 21 (58%) cases, hypointense in 10 (28%), and isointense in five (14%). On ferucarbotran-enhanced hepatic arterial phase images, HCC lesions were isointense in 18 (50%) cases, hypointense in 11 (31%), and hyperintense in seven (19%). On gadolinium-enhanced portal venous and equilibrium phase images, respectively, HCC lesions were hypointense in 17 (47%) and 21 (58%) cases, hyperintense in 10 (28%) cases and one (3%) case, and isointense in nine (25%) and 14 (39%) cases. On ferucarbotran-enhanced portal venous and equilibrium phase images, respectively, HCC lesions were hypointense in 15 (42%) and 11 (31%) cases, hyperintense in three (8%) and three (8%) cases, and isointense in 18 (50%) and 22 (61%) cases.For HCC, contrast enhancement pattern on T1-weighted gradient-echo MR images shows marked variability with gadolinium or SPIO contrast agents.
View details for DOI 10.1148/radiol.2372041183
View details for Web of Science ID 000232743300020
View details for PubMedID 16192317
Aortoiliac and lower extremity arteries assessed with 16-detector row CT angiography: Prospective comparison with digital subtraction angiography
2005; 236 (3): 1083-1093
To prospectively compare the accuracy of 16-detector row computed tomographic (CT) angiography with conventional digital subtraction angiography (DSA) as the reference standard in the assessment of aortoiliac and lower extremity arteries in patients with peripheral arterial disease.This study was approved by the institutional review board, and informed consent was obtained. A total of 39 consecutive patients (27 men [mean age, 66 years] and 12 women [mean age, 64 years]) with peripheral arterial disease underwent both conventional DSA and 16-detector row CT angiography. For data analysis, the arterial vascular system was divided into 35 segments. A total of 1365 arterial segments were analyzed for arterial stenosis by two independent blinded readers using a four-point grading system (grade 1, <10% luminal narrowing; grade 2, 10%-49% luminal narrowing; grade 3, 50%-99% luminal narrowing; grade 4, occlusion). Interobserver agreements were calculated by using kappa statistics. A third independent blinded reader assessed possible reasons for disagreements between 16-detector row CT angiographic findings and conventional DSA findings. Effective radiation dose was calculated for both imaging modalities.Sixteen-detector row CT angiographic and conventional DSA findings were diagnostic in all vascular segments. Compared with conventional DSA, the sensitivity and specificity of 16-detector row CT angiography with regard to detection of hemodynamically significant stenosis in all 35 arterial segments were 96% and 97%, respectively, for both readers. Readers 1 and 2 overestimated arterial stenosis in 42 (3%) and 34 (2%) arterial segments, respectively, and underestimated arterial stenosis in 13 (1%) and 10 (1%) arterial segments, respectively. Interobserver agreement was excellent (kappa = 0.84-1.00). Presence of anteroposteriorly located luminal narrowing and extensive vascular wall calcification were considered main reasons for disagreements between imaging modalities. Effective radiation dose was lower for 16-detector row CT angiography (1.6-3.9 mSv) than for conventional DSA (6.4-16.0 mSv).Sixteen-detector row CT angiography is an accurate and reliable noninvasive alternative to conventional DSA in the assessment of aortoiliac and lower extremity arteries in patients with peripheral arterial disease.
View details for DOI 10.1148/radiol.2362040895
View details for Web of Science ID 000231412600047
View details for PubMedID 16055691
Coronary artery bypass grafts: ECG-gated multi-detector row CT angiography-influence of image reconstruction interval on graft visibility
2004; 232 (2): 568-577
To evaluate the influence of different reconstruction intervals of retrospectively electrocardiographically (ECG)-gated multi-detector row computed tomographic (CT) angiography on image quality of different segments of various types of coronary artery bypass grafts.Twenty consecutive patients with 62 grafts underwent retrospectively ECG-gated four-channel multi-detector row CT angiography and conventional coronary angiography. Raw helical CT data were reconstructed at 0%-90% of the cardiac cycle in increments of 10%. Each graft was separated into three segments (proximal segment, graft body, and distal anastomosis). Three graft types were identified according to site of distal anastomosis. Two readers assessed image quality of segments and graft types. Effective radiation dose was calculated.Best image quality of all segments was obtained at a reconstruction interval of 50%-70% of the cardiac cycle. Image quality of the proximal segment did not vary significantly with different reconstruction intervals (analysis of variance, P =.8), whereas image quality of the graft body and distal anastomosis changed significantly with varying reconstruction intervals (P <.001). Distal anastomosis and body of types 1 and 2 grafts were best seen at 60%-70% of the cardiac cycle, whereas distal anastomosis and body of type 3 grafts were best visualized at 50%. Accuracy of CT angiography for detection of graft patency was 94% for reader 1 and 95% for reader 2. Effective dose for CT was 11.4 mSv for both men and women. Mean effective dose for angiography was 2.1 mSv for men and women.Optimal selection of reconstruction interval improves image quality of the graft body and of distal anastomosis in particular.
View details for DOI 10.1148/radiol.2322030788
View details for Web of Science ID 000222839500038
View details for PubMedID 15215552
Effects of ECG gating and postprocessing techniques on 3D MDCT of the bronchial tree
AMERICAN JOURNAL OF ROENTGENOLOGY
2004; 183 (1): 83-89
Our goal was to determine the impact of ECG gating and different postprocessing techniques on 3D imaging of the bronchial tree. SUBJECTS AND METHODS. Retrospective ECG-gated MDCT and non-ECG-gated MDCT of the chest were performed in 25 patients. ECG-gated MDCT data were reconstructed mid diastole using a fixed interval of -400 msec in 25 patients and then additionally at -200, -300, and -500 msec in 10 of those patients. Shaded surface display and volume rendering of the bronchial tree combined with virtual bronchoscopy were performed using all data sets. The extent of bronchial tree visualization in shaded surface display-virtual bronchoscopy and volume rendering-virtual bronchoscopy and the presence of artifacts in volume-rendered images were scored by three blinded reviewers. The effective radiation doses of the ECG-gated and nongated acquisitions were compared.The summary scores of all bronchial segments for gated shaded surface display-virtual bronchoscopy and gated volume rendering-virtual bronchoscopy did not differ significantly. The summary scores for nongated shaded surface display-virtual bronchoscopy and nongated volume rendering-virtual bronchoscopy were not significantly different. Non-gated acquisition yielded significantly better visualization of the bronchial tree for both post-processing techniques, regardless of the time interval used for reconstruction of the ECG-gated series. Artifact scores in volume-rendered images were significantly higher for ECG-gated MDCT compared with nongated MDCT. Effective radiation dose was significantly higher for the ECG-gated acquisition.Given the advantage of volume rendering for representing the entire data set and given the lower radiation dose and better 3D image quality of nongated acquisition, volume rendering performed on nongated MDCT data is the method of choice for 3D visualization of the bronchial tree.
View details for Web of Science ID 000222163900018
View details for PubMedID 15208116
Time-effectiveness, observer-dependence, and accuracy of measurements of left ventricular ejection fraction using 4-channel MDCT
ROFO-FORTSCHRITTE AUF DEM GEBIET DER RONTGENSTRAHLEN UND DER BILDGEBENDEN VERFAHREN
2004; 176 (4): 529-537
To evaluate the time-effectiveness, inter-observer variance, and accuracy of left ventricular ejection fraction (EF) measurements using retrospectively ECG-gated four-channel multi-detector row CT (MDCT) angiography in comparison with biplane cine-ventriculography.Twenty consecutive patients underwent retrospectively ECG-gated MDCT angiography and conventional coronary angiography with biplane ventriculography. Raw MDCT data were reconstructed at 0 % - 90 % of the cardiac cycle in increments of 10 %. Ten geometrically identical multiplanar reformations parallel to the short axis of the heart were reconstructed in each patient. Three blinded readers segmented the left ventricle in the end-systolic and end-diastolic phase using standardized window settings in order to determine the EF. The EF was measured with biplane cine-ventriculography by two blinded readers and was compared with MDCT. The time needed for post-processing was recorded and the inter-observer agreement for both imaging techniques was assessed.Mean post-processing time was 63 +/- 3 min per patient for MDCT and 5.5 +/- 1.2 min for ventriculography. MDCT and ventriculography showed a good correlation (r = 0.83, p < 0.0001) for measurement of the EF. Mean errors of EF measurements for the three MDCT readers compared with the mean of the ventriculography were - 6.3 +/- 6.6 %, - 4.7 +/- 7.1 % and - 4.6 +/- 5.7 %, respectively. The mean differences between the three readers assessing MDCT were - 1.6 +/- 3.2 % (reader 1 versus 2, r = 0.96), - 1.6 +/- 5.6 % (1 versus 3, r = 0.95) and - 0.011 +/- 2.9 % (2 versus 3, r = 0.97, p < 0.0001). The mean differences between the two readers assessing ventriculography was 0.32 +/- 5.1 % (r = 0.88, p < 0.0001).MDCT correlates well with biplane cine-ventriculography but has the tendency to underestimate the left ventricular EF. Measurements using MDCT have a high inter-observer agreement, however, the time needed for additional MDCT data post-processing is still unacceptably long.
View details for DOI 10.1055/s-2004-813012
View details for Web of Science ID 000221116000009
View details for PubMedID 15088177
Retrospectively ECG-gated multi-detector row CT of the chest: Does ECG-gating improve three-dimensional visualization of the bronchial tree?
ROFO-FORTSCHRITTE AUF DEM GEBIET DER RONTGENSTRAHLEN UND DER BILDGEBENDEN VERFAHREN
2004; 176 (4): 513-521
To determine the impact of retrospectively ECG-gated multi-detector row CT (MDCT) on three-dimensional (3D) visualization of the bronchial tree and virtual bronchoscopy (VB) as compared to non-ECG-gated data acquisition.Contrast-enhanced retrospectively ECG-gated and non-ECG-gated MDCT of the chest was performed in 25 consecutive patients referred for assessment of coronary artery bypass grafts and pathology of the ascending aorta. ECG-gated MDCT data were reconstructed in diastole using an absolute reverse delay of - 400 msec in all patients. In 10 patients additional reconstructions at - 200 msec, - 300 msec, and - 500 msec prior to the R-wave were performed. Shaded surface display (SSD) and virtual bronchoscopy (VB) for visualization of the bronchial segments was performed with ECG-gated and non-ECG-gated MDCT data. The visualization of the bronchial tree underwent blinded scoring. Effective radiation dose and signal-to-noise ratio (SNR) for both techniques were compared.There was no significant difference in visualizing single bronchial segments using ECG-gated compared to non-ECG-gated MDCT data. However, the total sum of scores for all bronchial segments visualized with non-ECG-gated MDCT was significantly higher compared to ECG-gated MDCT (P < 0.05). The summary scores for visualization of bronchial segments for different diastolic reconstructions did not differ significantly. The effective radiation dose and the SNR were significantly higher with the ECG-gated acquisition technique (P < 0.05).The bronchial tree is significantly better visualized when using non-ECG-gated MDCT compared to ECG-gated MDCT. Additionally, non-ECG-gated techniques require less radiation exposure. Thus, the current retrospective ECG-gating technique does not provide any additional benefit for 3D visualization of the bronchial tree and VB.
View details for DOI 10.1055/s-2004-812777
View details for Web of Science ID 000221116000007
View details for PubMedID 15088175
- Resovist for imaging of hepatocellular carcinoma in the cirrhotic liver Schering Lunch Symposium on Resovist held at the ESGAR Congress SPRINGER. 2004: C5–C6
Evaluation of peripheral arterial bypass grafts with multi-detector row CT angiography: Comparison with duplex US and digital subtraction angiography
2003; 229 (2): 465-474
To assess the technical feasibility of multi-detector row computed tomographic (CT) angiography in the assessment of peripheral arterial bypass grafts and to evaluate its accuracy and reliability in the detection of graft-related complications, including graft stenosis, aneurysmal changes, and arteriovenous fistulas.Four-channel multi-detector row CT angiography was performed in 65 consecutive patients with 85 peripheral arterial bypass grafts. Each bypass graft was divided into three segments (proximal anastomosis, course of the graft body, and distal anastomosis), resulting in 255 segments. Two readers evaluated all CT angiograms with regard to image quality and the presence of bypass graft-related abnormalities, including graft stenosis, aneurysmal changes, and arteriovenous fistulas. The results were compared with McNemar test with Bonferroni correction. CT attenuation values were recorded at five different locations from the inflow artery to the outflow artery of the bypass graft. These findings were compared with the findings at duplex ultrasonography (US) in 65 patients and the findings at conventional digital subtraction angiography (DSA) in 27.Image quality was rated as good or excellent in 250 (98%) and in 252 (99%) of 255 bypass segments, respectively. There was excellent agreement both between readers and between CT angiography and duplex US in the detection of graft stenosis, aneurysmal changes, and arteriovenous fistulas (kappa = 0.86-0.99). CT angiography and duplex US were compared with conventional DSA, and there was no statistically significant difference (P >.25) in sensitivity or specificity between CT angiography and duplex US for both readers for detection of hemodynamically significant bypass stenosis or occlusion, aneurysmal changes, or arteriovenous fistulas. Mean CT attenuation values ranged from 232 HU in the inflow artery to 281 HU in the outflow artery of the bypass graft.Multi-detector row CT angiography may be an accurate and reliable technique after duplex US in the assessment of peripheral arterial bypass grafts and detection of graft-related complications, including stenosis, aneurysmal changes, and arteriovenous fistulas.
View details for DOI 10.1148/radiol.2292021123
View details for Web of Science ID 000186169700026
View details for PubMedID 14595148
Thin-section CT of the lung: Does electrocardiographic triggering influence diagnosis?
2003; 229 (2): 483-491
To determine the impact of prospective electrocardiographic (ECG) triggering on image quality and diagnostic outcome of thin-section computed tomography (CT) of the lung.Forty-five consecutive patients referred for thin-section CT of the lung were examined with prospectively ECG-triggered and nontriggered thin-section CT of the lung with a multi-detector row helical CT scanner. Subjective image quality criteria (image noise, motion artifacts, and diagnostic accessibility) were rated by three radiologists in consensus for the upper lobe, middle lobe and/or lingula, and lower lobe. Pathologic changes were assessed for the various lobes, and a diagnosis was assigned. The diagnoses were compared by two radiologists in consensus to determine the effects of CT technique on diagnostic outcome. Quantitative measurements were performed, including determination of image noise and signal-to-noise ratios in different anatomic regions. The Wilcoxon signed rank test and paired sign test (both with Bonferroni correction) were used for statistical analysis.Subjective assessment showed significant differences in motion artifact reduction in the middle lobe, lingula, and left lower lobe. The diagnostic assessibility of triggered CT was rated significantly higher only for the left lower lobe compared with nontriggered data acquisition. No differences in diagnostic outcome were determined between triggered and nontriggered techniques. Mean image noise in tracheal air was 68.2 +/- 17 (SD) for triggered CT versus 37.4 +/- 9 for nontriggered CT (P <.05). Mean signal-to-noise ratio in the upper versus lower lobes was 22.5 +/- 8 versus 25.4 +/- 10 for triggered and 35.6 +/- 9 versus 39.2 +/- 10 for nontriggered techniques (P <.05).Given the lack of improvement in diagnostic accuracy and the need for additional resources, ECG-triggered thin-section CT of the lung is not recommended for routine clinical practice.
View details for Web of Science ID 000186169700028
View details for PubMedID 14512510
Detection of submucosal gastric fundal varices with multi-detector row CT angiography
2003; 52 (6): 886-892
The diagnosis of submucosal fundal varices is challenging. Currently, endoscopy and endoscopic ultrasound (EUS) are considered most useful for this purpose. The aim of this study was to evaluate if multi-detector row CT (MDCT) angiography contributes to the diagnosis of submucosal fundal varices.Twenty two patients with endoscopically suspected fundal varices were prospectively included in the study. All patients underwent EUS and MDCT angiography. Levels of agreement between EUS and MDCT angiography for the detection of submucosal and perigastric fundal varices were evaluated by three blinded independent readers. In addition, variceal size and location, as well as afferent and efferent vessels of the submucosal varices, were determined.Good or excellent image quality of MDCT angiography was obtained in 21/22 patients (95%). Based on EUS, submucosal varices were detected in 16 of 22 patients (73%) and perigastric varices in 22/22 patients (100%). Using MDCT angiography, the presence of submucosal varices was confirmed in all of these 16 patients by all three readers. Perigastric varices were also confirmed in all 22 patients by all three readers. In addition, all three readers noted the presence of a submucosal varix in an additional patient which was not detected on initial EUS. MDCT angiography showed an excellent interobserver reliability with regard to variceal diameter (kappa=0.90) and variceal location (kappa=0.94). Based on MDCT angiography, afferent and efferent vessels of submucosal varices included the left gastric vein in 11 (65%), the posterior/short gastric veins in 15 (88%), gastrorenal shunts in 10 (59%), the left inferior phrenic vein in six (35%), and the left pericardiophrenic vein in six (35%) of 17 patients.MDCT angiography is equivalent to EUS in terms of detection and characterisation of fundal varices, in particular with regard to the distinction between submucosal and perigastric fundal varices.
View details for Web of Science ID 000182741300018
View details for PubMedID 12740347
Contrast-enhanced MR angiography for differentiation between perigastric and submucosal gastric fundal varices
ROFO-FORTSCHRITTE AUF DEM GEBIET DER RONTGENSTRAHLEN UND DER BILDGEBENDEN VERFAHREN
2003; 175 (4): 507-514
To evaluate contrast-enhanced MR angiography for the distinction between perigastric and submucosal fundal varices.Nineteen consecutive patients with clinically suspected fundal varices underwent contrast-enhanced MR angiography and endoscopic ultrasound (EUS) within one week. Diagnostic confidence for the detection of perigastric and submucosal fundal varices was compared between MR angiography (two radiologists) and EUS (one gastroenterologist), and the agreement of size and location was evaluated.Both MR angiography and EUS detected perigastric varices in all 19 patients and submucosal fundal varices in 14 of the 19 patients. The interobserver reliability of MR angiography was good for measuring the variceal diameter (kappa = 0.76) and excellent for localizing the varices (kappa = 1.0). EUS and MR angiography agreed in 12 of 14 patients (86 %) in determining variceal diameter and location.Contrast-enhanced MR angiography is comparable to endoscopic ultrasound in the detection and characterization of gastric fundal varices.
View details for Web of Science ID 000182382400009
View details for PubMedID 12677506
Evaluation of aortoiliac aneurysm before endovascular repair: Comparison of contrast-enhanced magnetic resonance angiography with multidetector row computed tomographic angiography with an automated analysis software tool
JOURNAL OF VASCULAR SURGERY
2003; 37 (3): 619-627
The purpose of this study was to assess accuracy and reliability of a volumetric analysis of abdominal aneurysms on the basis of multidetector row computed tomographic angiography (CTA) and magnetic resonance angiography (MRA) with a commercially available automated vessel analysis software program.Twenty patients with abdominal aortic aneurysms underwent preoperative CTA and MRA before endovascular repair. Postdeployment CTA was performed in 15 of these 20 patients (75%). All preoperative CTA and MRA and postdeployment CTA data sets were analyzed with an automated software tool. The length of the stent grafts on postdeployment CTA was measured and compared with the true length of the primary component. Two readers independently evaluated 13 vessel parameters on preoperative CTA and MRA, which are considered to be important in planning stent graft deployment.With the automated analysis software tool, all measurements could be performed on either CTA or MRA data sets. There was no statistically significant difference between postdeployment measurements of stent graft length on CTA and the true dimensions of the implanted stent grafts. Interobserver agreement for all of the measurements with either CTA or MRA was good to excellent (interclass coefficient, 0.71 to 0.99) with only minimal mean differences of measured dimensions between both readers (range, -2.0 to +2.3 mm, Bland-Altman). Intermodality agreement between CTA and MRA was good to excellent (interclass coefficient, 0.62 to 0.98) with small mean differences of measured dimensions between both methods (range, -4.1 to +2.1 mm, Bland-Altman).Volumetric measurement with an automated analysis software tool allows a fast, precise, and reliable noninvasive preoperative determination of all aortic dimensions on the basis of either CTA or MRA data sets.
View details for DOI 10.1067/mva.2003.143
View details for Web of Science ID 000181364400023
View details for PubMedID 12618702
Morton neuroma: MR imaging in prone, supine, and upright weight-bearing body positions
2003; 226 (3): 849-856
To assess the effect of prone, supine, and upright weight-bearing body positions on visibility, position, shape, and size of Morton neuroma during magnetic resonance (MR) imaging.Eighteen patients with 20 Morton neuromas underwent MR imaging of the forefoot in prone (plantar flexion of the foot), supine (dorsiflexion of the foot), and upright weight-bearing positions. Visibility (3 = good, 2 = moderate, 1 = poor), position relative to the metatarsal bone, shape, and transverse diameter of Morton neuroma were assessed on transverse T1-weighted MR images. Associations between different body positions and variables of interest were calculated with Wilcoxon signed rank test, chi2 test, and paired Student t test.In the prone position, visibility of all 20 Morton neuromas was rated with a score of 3; visibility in the supine and weight-bearing positions was inferior (mean score, 2.4). All 20 (100%) Morton neuromas changed their position relative to the metatarsal bone between prone and supine and between prone and weight-bearing positions. When compared with the prone position, there was a difference in the shape of all 20 Morton neuromas in the weight-bearing position (P <.001). Between prone (mean transverse diameter of Morton neuroma, 8 mm) and supine (mean transverse diameter of Morton neuroma, 6 mm) positions, the transverse diameter of Morton neuroma significantly decreased by 2 mm (P =.03); between prone and weight-bearing positions, the decrease of the mean transverse diameter was also significant (difference, 2 mm; P =.03).Morton neuroma appears significantly different during MR imaging in prone, supine, or weight-bearing positions. The transverse diameter of Morton neuroma is significantly larger on images obtained in the prone position than it is on images obtained in the supine and upright weight-bearing positions. Visibility of Morton neuroma is best on MR images obtained in the prone position.
View details for DOI 10.1148/radiol.2263011925
View details for Web of Science ID 000181220200031
View details for PubMedID 12601213
Aortoiliac and renal arteries: Prospective intraindividual comparison of contrast-enhanced three-dimensional MR angiography and multi-detector row CT angiography
2003; 226 (3): 798-811
To compare contrast material-enhanced three-dimensional (3D) magnetic resonance (MR) angiography and multi-detector row computed tomographic (CT) angiography in the same patients for assessment of the aortoiliac and renal arteries, with digital subtraction angiography (DSA) as the standard of reference.DSA, 3D MR angiography, and multi-detector row CT angiography were performed in 46 consecutive patients. A total of 769 arterial segments were analyzed for arterial stenosis by using a four-point grading system. Aneurysmal changes were noted. The time required for performing 3D reconstructions and image analysis of both MR and CT data sets was measured. Patient acceptance for each modality was assessed with a visual analogue scale. Statistical analysis of data was performed.Sensitivity of MR angiography for detection of hemodynamically significant arterial stenosis was 92% for reader 1 and 93% for reader 2, and specificity was 100% and 99%, respectively. Sensitivity of CT angiography was 91% for reader 1 and 92% for reader 2, and specificity was 99% and 99%, respectively. Differences between the two modalities were not significant. Interobserver and intermodality agreement was excellent (kappa = 0.88-0.90). The time for performance of 3D reconstruction and image analysis of CT data sets was significantly longer than that for MR data sets (P <.001). Patient acceptance was best for CT angiography (P =.016).There is no statistically significant difference between 3D MR angiography and multi-detector row CT angiography in the detection of hemodynamically significant arterial stenosis of the aortoiliac and renal arteries.
View details for Web of Science ID 000181220200025
View details for PubMedID 12601190
Secondary aortoenteric fistula: active bleeding detected with multi-detector-row CT.
2002; 12: S196-200
We report a case of active bleeding of a secondary aortoenteric fistula (SAEF), in which CT angiography with multi-detector-row CT (MDCT) was finally diagnostic after negative catheter angiography and unsatisfactory endoscopy. The MDCT angiography clearly demonstrated the fistulous tract between the abdominal aortic graft and the duodenum. The dynamic process of bleeding was confirmed as a net increase of contrast agent accumulation in the duodenum through different phases. The MDCT angiography with its excellent 3D image quality is therefore a valuable method in the assessment of active SAEF bleeding.
View details for PubMedID 12522640
- Secondary aortoenteric fistula: active bleeding detected with multi-detector-row CT EUROPEAN RADIOLOGY 2002; 12: S196-S200
ECG-gated multi-detector row CT for assessment of mitral valve disease: initial experience
14th Annual Meeting of the European-Congress-of-Radiology (ECR 2002)
SPRINGER. 2002: 2662–69
Our objective was to evaluate applicability and image quality of contrast-enhanced, retrospectively ECG-gated multi-detector row CT (MDCT) for visualization of anatomical details of the mitral valve and its apparatus, and to determine the value of MDCT for diagnosing abnormal findings of the mitral valve. Twenty consecutive patients with mitral valve disease underwent MDCT preoperatively. Two readers assessed visibility of the mitral valve annulus, mitral valve leaflets, tendinous cords, and papillary muscles by using a four-point Likert grading scale. Abnormal mitral valve findings [thickening of the mitral valve leaflets, presence of mitral annulus calcification (MAC), and calcification of the valvular leaflets] were compared with preoperative echocardiography and intraoperative findings. Visibility of the mitral valve annulus and mitral valve leaflets was good or excellent in 15 patients (75%) and in 19 patients (95%) for papillary muscles. The MDCT yielded a 95-100% agreement compared with echocardiography and surgery with regard to the assessment of mitral valve leaflet thickening and the presence of calcifications of the mitral valve annulus or mitral valve leaflets. Intermodality agreement between MDCT and echocardiography was excellent with regard to classification of mitral valve leaflet thickness (kappa=1.00) and good regarding classification of MAC thickness (kappa=0.73). Contrast-enhanced, retrospectively ECG-gated MDCT allows good to excellent visualization of anatomical details of the mitral valve and its apparatus, and demonstrates good agreement with echocardiography and surgery in diagnosing mitral valve abnormalities.
View details for DOI 10.1007/s00330-002-1454-7
View details for Web of Science ID 000179436500007
View details for PubMedID 12386755
Electrocardiographically gated multi-detector row CT for assessment of valvular morphology and calcification in aortic stenosis
2002; 225 (1): 120-128
To evaluate the applicability and image quality of nonenhanced and contrast material-enhanced multi-detector row computed tomography (CT) combined with retrospective electrocardiographic (ECG) gating for visualization of the aortic valve, determination of aortic valve morphology and diameter of the aortic valve annulus, and assessment of the degree of valvular calcification in patients with aortic valve stenosis, as compared with results of surgery and echocardiography.Prior to surgical valve replacement, 25 patients with aortic valve stenosis and sinus rhythm underwent nonenhanced (n = 15) and contrast-enhanced (n = 25) retrospectively ECG-gated multi-detector row CT. Two readers working in consensus evaluated image quality and assessed valvular morphology and the degree of valvular calcification. In addition, the diameter of the aortic valve annulus was measured. Results were compared with surgical and echocardiographic findings by using the paired sign test, kappa statistics, and the method of Bland and Altman.The aortic valve could be visualized nearly free of motion artifacts on all multi-detector row CT images. Image quality and diagnostic confidence for classification of aortic valve morphology were significantly superior on contrast-enhanced rather than nonenhanced images (P =.004 and P =.006, respectively). Nonenhanced and contrast-enhanced CT showed good agreement with surgical findings with regard to quantification of the degree of aortic valve calcification (kappa = 0.77 and kappa = 0.74, respectively). Measurement of the diameter of the aortic valve annulus was more reliable on contrast-enhanced images.Contrast-enhanced retrospectively ECG-gated multi-detector row CT allows determination of aortic valve morphology, measurement of the diameter of the aortic valve annulus, and assessment of the degree of aortic valve calcification in patients with aortic stenosis.
View details for DOI 10.1148/radiol.2251011703
View details for Web of Science ID 000178264300019
View details for PubMedID 12354994
Multidetector CT: Detection of active hemorrhage in patients with blunt abdominal trauma
AMERICAN JOURNAL OF ROENTGENOLOGY
2002; 179 (2): 437-444
The aim of this study was to determine the imaging findings and the prevalence of active hemorrhage on contrast-enhanced multidetector CT in patients with blunt abdominal trauma.Contrast-enhanced multidetector CT images of 165 patients with blunt abdominal trauma were reviewed for the presence of extravasated contrast agent, a finding that represents active hemorrhage. The site and appearance of the hemorrhage were noted on multidetector CT images. These findings were compared with surgical and angiographic results or with clinical follow-up.On multidetector CT images, active hemorrhage was detected in 22 (13%) of 165 patients with a total of 24 bleeding sites (14 intraperitoneal sites and 10 extraperitoneal sites). Active hemorrhage was visible most frequently as a jet of extravasated contrast agent (10/24 bleeding sites [42%]). Diffuse or focal extravasation was less frequently seen (nine [37%] and five [21%] bleeding sites, respectively). CT attenuation values measured in the aorta (mean, 199 H) were significantly higher than those measured in extravasated contrast material (mean, 155 H) (p < 0.001). Sixteen (73%) of 22 patients with active bleeding on multidetector CT images underwent immediate surgical or angiographic intervention. One patient received angiographic therapy 10 hr after undergoing multidetector CT, and five patients died between 1 and 3 hr after multidetector CT examination.Active hemorrhage in patients after blunt abdominal trauma is most frequently visible as a jet of extravasated contrast agent on multidetector CT. When extravasation is detected, immediate surgical or angiographic therapy is required.
View details for Web of Science ID 000176934900024
View details for PubMedID 12130447
Experience of 4 years with open MR defecography: Pictorial review of anorectal anatomy and disease
86th Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America (RSNA)
RADIOLOGICAL SOC NORTH AMERICA. 2002: 817–32
Functional disorders of the pelvic floor are a common clinical problem. Diagnosis and treatment of these disorders, which frequently manifest with nonspecific symptoms such as constipation or incontinence, remain difficult. Fluoroscopic x-ray defecography has been shown to aid in detection of functional and morphologic abnormalities of the anorectal region. With the advent of open-configuration magnetic resonance (MR) imaging systems, MR defecography with the patient in a vertical position became possible. MR defecography permits analysis of the anorectal angle, the opening of the anal canal, the function of the puborectal muscle, and the descent of the pelvic floor during defecation. Good demonstration of the rectal wall permits visualization of intussusceptions and rectoceles. Excellent demonstration of the perirectal soft tissues allows assessment of spastic pelvic floor syndrome and descending perineum syndrome and visualization of enteroceles. MR defecography with an open-configuration magnet allows accurate assessment of anorectal morphology and function in relation to surrounding structures without exposing the patient to harmful ionizing radiation.
View details for Web of Science ID 000176780900007
View details for PubMedID 12110712
Traumatic injuries: imaging of abdominal and pelvic injuries
2002; 12 (6): 1295-1311
The availability of new imaging modalities has altered the diagnostic approach to patients with abdominal and pelvic trauma. Computed tomography and ultrasound have largely replaced diagnostic peritoneal lavage. Ultrasound is used in most trauma centers as the initial imaging technique for the detection of hemoperitoneum and helps to determine the need for emergency laparotomy. Computed tomography allows for an accurate diagnosis of a wide range of traumatic abdominal and pelvic conditions. The speed of single-detector helical and multi-detector row CT (MDCT) permits a rapid CT examination of the seriously ill patient in the emergency room. In particular, the technology of MDCT permits multiple, sequential CT scans to be quickly obtained in the same patient, which is a great advance in the rapid assessment of the multiple-injured patient. The evolving concepts in trauma care promoting non-operative management of liver and splenic injuries creates the need for follow-up cross-sectional imaging studies in these patients. Computed tomography and, less frequently, MR or ultrasound, are used for this purpose.
View details for DOI 10.1007/s00330-002-1462-7
View details for Web of Science ID 000176197400006
View details for PubMedID 12042933
Multidetector-row helical CT: analysis of time management and workflow
2002; 12 (3): 680-?
The purpose of this study was to evaluate time management and workflow for multidetector-row helical CT (MDCT). Time for patient and data handling of at total of 580 patients were evaluated at two different time periods (December 1999, August 2000), each for the following baseline measurements: (a) change of clothes/instruction; (b) patient placement on the CT table/i.v. catheter; (c) CT planning and programming; (d) CT data acquisition; (e) CT data reconstruction; (f) CT data storage/printing. All imaging was performed on a Somatom Volume Zoom (Siemens, Erlangen, Germany). Time measurements summarized for different CT protocols revealed the following: (a) 5:01 min (+/- 2.06 min); (b) 4:36 min (+/- 2.43 min); (c) 4:11 min (+/- 2.55 min); (d) 0:43 min (+/- 0.15 min); (e) 6:59 min (+/- 2.39 min); (f) 09:51 min (+/- 3.51 min). Planning and programming was most time-consuming for CT angiography, whereas chest and abdominal CT needed only 3:26 and 3:30 min, respectively. Reconstruction time was highest for HRCT (9:22 min) and CTA (9:03 min). Data storage/printing was most time-consuming for HRCT (13:02 min), followed by combined neck-chest-abdomen examinations (12:19 min). Comparing the two time periods, during which a software update was performed, a mean time reduction of 4:31 min per patient (15%, p<0.001) was achieved. Whereas CT data acquisition time is no longer a problem with MDCT, patient management, data reconstruction, and data storage are the most time-consuming parts. Well-trained technicians, state-of-the-art workstations, and fast networking are the most important factors to improve workflow.
View details for DOI 10.1007/s003300101138
View details for Web of Science ID 000174361500026
View details for PubMedID 11870487
Thoracic aorta: Motion artifact reduction with retrospective and prospective electrocardiography-assisted multi-detector row CT
2002; 222 (1): 271-277
The authors compared prospective (n = 20) and retrospective (n = 20) electrocardiography (ECG)-assisted multi-detector row computed tomography (CT) with non-ECG-assisted multi-detector row CT (n = 20) of the thoracic aorta with regard to reduction of motion-related artifacts. Image quality was rated for transverse source and sagittal oblique images of the thoracic aorta, including the aortic valve. ECG-assisted multi-detector row CT compared with non-ECG-assisted multi-detector row CT showed a significant reduction in motion artifacts for the entire thoracic aorta.
View details for Web of Science ID 000172884800040
View details for PubMedID 11756736
Endotracheal neurofibroma in neurofibromatosis type 1: an unusual manifestation
2002; 12 (1): 190-192
Tracheal involvement is an extremely rare manifestation in patients with neurofibromatosis type 1 (NF-1). We present a 33-year-old women with NF-1 suffering from progressive dyspnea. Multislice spiral CT revealed a neurofibroma located within the trachea with intratracheal extension. To our knowledge, this is the first report of an intratracheal neurofibroma which has been documented by CT. This indicates that multislice spiral CT allows accurate demonstration of localization and extent of this rare manifestation of neurofibromas.
View details for Web of Science ID 000173840800029
View details for PubMedID 11868097
- Three-dimensional images of extra-anatomic arterial bypass graft using multidetector row spiral computed tomography data with volume rendering CIRCULATION 2001; 104 (25): E154-E155
Spiral-CT angiography to assess feasibility of endovascular aneurysm repair in patients with ruptured aortoiliac aneurysm
VASA-JOURNAL OF VASCULAR DISEASES
2001; 30 (4): 271-276
To evaluate spiral computed tomography (SCT) angiography for assessment of feasibility of endovascular aneurysm repair (EVAR) in patients with ruptured aortoiliac aneurysm (AAA).24 patients (mean age 74 years; range, 69 to 82 years) with suspicion of ruptured AAA and stable hemodynamics were preoperatively examined by using a SCT scanner in the emergency room. SCT angiography was performed from the suprarenal aorta to the femoral bifurcation after a fixed injection delay time of 30 seconds. After that a venous phase SCT scan, beginning at the last image position and ending at the upper thoracic aperture, was performed.The mean acquisition time of the SCT scan was 80 seconds (range 70 to 100 seconds), the mean overall procedure time, including image reconstruction, 5 minutes (range, 4 to 6 minutes). 2D images were directly evaluated during CT data acquisition, and 3D image reconstructions within 10 minutes (range, 8 to 11 minutes) after the SCT scan. AAA rupture was assessed in 14/24 patients (58%): in 10/14 patients (71%) rupture was contained to the retroperitoneum, and in 4/14 patients (29%) intraperitoneal rupture was observed. Successful EVAR was performed in 6/14 patients (43%) with ruptured AAA, and in 8/10 patients (80%) without ruptured AAA. Open surgery was exclusively performed in 6/24 patients (25%) with inappropriate anatomy for EVAR and in 4/24 patients (17%) with intraperitoneal rupture.Spiral computed tomography angiography is a reliable technique to assess feasibility of endovascular aneurysm repair in patients with ruptured aortic aneurysm. However, it can only be recommended for patients with stable hemodynamics, despite of the short acquisition time.
View details for Web of Science ID 000172626200006
View details for PubMedID 11771211
Multislice spiral CT follow-up of a patient with implanted DeBakey ventricular assist device.
2000; 102 (15): 1871-1872
View details for PubMedID 11023945
Worsening enterocolitis in neonates: diagnosis by CT examination of urine after enteral administration of iohexol
1999; 29 (2): 95-99
Perforation, a severe complication of necrotizing enterocolitis (NEC), has a high mortality rate. Recently, we presented a new technique for evaluation of NEC: measuring the CT attenuation coefficient of urine after oral administration of iohexol. We present three cases of neonates with NEC who demonstrated serial increases in urine CT attenuation coefficients, all of whom subsequently deteriorated clinically and radiographically. Surgery in all three cases confirmed severe necrosis and/or perforation. These three cases suggest that the CT attenuation coefficient of urine after oral administration of iohexol may be a more sensitive indicator of NEC severity, progression, and perforation than clinical evaluation and radiography. More investigation is necessary, but eventually, this noninvasive technique may be able to decrease morbidity and mortality by predicting the need for surgical intervention or more aggressive medical management of NEC before perforation occurs.
View details for Web of Science ID 000078689500006
View details for PubMedID 9933327
Systemic spread of meconium peritonitis
1998; 28 (9): 714-716
Meconium peritonitis is a chemical peritonitis which occurs following bowel perforation during fetal life. It is generally looked upon as benign, resulting in no long-term sequelae. We present a case of a newborn infant with meconium peritonitis who developed infarcts in several organs. At autopsy the infarcts proved to be caused by emboli as a result of intravascular dissemination of meconium. To our knowledge, this is the first reported case of systemic spread of meconium peritonitis in the literature and suggests that meconium peritonitis may have more serious implications than generally thought.
View details for Web of Science ID 000076131500014
View details for PubMedID 9732503
Amiloride-inhibitable Na+ conductance in rat proximal tubule
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
1997; 434 (2): 173-178
Previous single-channel recordings from the luminal membrane of the rabbit proximal tubule have revealed amiloride-inhibitable Na+ channels of a characteristic conductance range. The present study aimed to pursue this issue in rat proximal tubule. Control rats were compared to those put on a low-Na+ diet or pretreated by triamcinolone injections (s.c.). Stimulation of Na+ absorption by glucocorticoids was verified by examining the transepithelial voltage in Ussing chamber studies of the distal colon. The membrane voltage (Vm) of isolated, in-vitro-perfused proximal tubule segments was measured in patch-clamp and impalement studies. It was found that amiloride hyperpolarized Mv significantly by 2.1 +/- 0.9 mV (n = 26) in tubules of control rats, by 3.9 +/- 0.7 mV (n = 12) in rats put on a low-Na+ diet and by 3.7 +/- 1.0 mV (n = 17) in rats treated with glucocorticoids. The effect of amiloride was concentration dependent with a half-maximal effect at < 1 micromol/l. RT-PCR techniques were used to search for the presence of the alpha-, beta- and gamma-subunits of the epithelial Na+ channel in isolated proximal tubule segments. The presence of the respective mRNAs was verified. These data indicate that: (1) amiloride-inhibitable Na+ channels are present in rate proximal tubules; (2) the Na+ conductance may be up-regulated by Na+ deprivation but is still very limited when compared to total cell conductance; (3) therefore, the contribution of Na+-channel-mediated absorption to total proximal Na+ absorption is probably small.
View details for Web of Science ID A1997XB43100004
View details for PubMedID 9136671