Robert Lenkinski

University of Texas Southwestern Medical Center at Dallas, Radiology, Faculty Member

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Robert Lenkinski is a chemist by training. He received his PhD in Chemistry in 1973 from the University of Houston. Dr. Lenkinski was a post-doctoral fellow at the Weizmann Institute from 1973-1975. In 1986, he was recruited to the Department of Radiology at the University of Pennsylvania, where he was involved in the technical development of MRI and MRS and their translation to clinical studies. One of his first contributions was as one of the four co-inventors of the endorectal coil for prostate MRI. In the early 1990’s, Dr. Lenkinski became involved in MR imaging of breast cancer in patients. His group designed and constructed a biopsy capable Multicoil array for MR imaging and localized MR spectroscopy (MRS). Dr. Lenkinski participated successful MRI based clinical trials in both prostate and breast cancer. 1999, he was recruited to the Department of Radiology of the Beth Israel Deaconess Medical Center, one of the major teaching hospitals of Harvard Medical School, where he continued to pursue the technical development of both MRI and MRS on the first 3T Whole Body MRI system with a body coil. Dr. Lenkinski was recruited to the Department of Radiology at the UT Southwestern Medical Center in Dallas in 2011 with a multimillion Grant Award, the first Missing Link award from the Cancer Prevention and Research Institute of Texas (CPRIT). As part of this award, Dr. Lenkinski was named a CPRIT Cancer Scholar in Residence. The University of Texas at Southwestern Medical Center awarded Dr. Lenkinski two named endowed Chairs; the Jan and Bob Pickens Distinguished Professorship in Medical Science, and the Charles A. and Elizabeth Ann Sanders Chair in Translational Research. He retired from this position in 2019 and moved to Tel Aviv Israel, retaining an academic appointment in the Department of Radiology at UT Southwestern Medical Center.
Phone: 617-275-4481
Address: A.D. Gordon st 4
Apt 3
Tel Aviv, Israel
6340704

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Papers by Robert Lenkinski

Noise reduction for T2 derived magnetic resonance images

Computerized Medical Imaging and Graphics, 1990

Calculation of magnetic resonance images composed of signals arising from T, and proton densities... more Calculation of magnetic resonance images composed of signals arising from T, and proton densities can be performed using a least squares fitting procedure from three or four multiple spin-echo images. This procedure works well in regions of high signal-to-noise (S/N) in the multiple spin-echoes. Erroneous T, values predominate in regions of low S/N, precluding the routine use of T, images in diagnostic and quantitative analysis. This study demonstrates that only three spin-echoes signals (TE = 20, 40, and 60 msec) and a simple preprocessing selection criteria are necessary to significantly reduce erroneous T, values. This simple selection criteria obviates the need to apply a median filter to the T, image and thus preserve both the high inherent contrast and spatial resolution of the T, derived image.

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A Novel Modality Enables New Evidence-Based Individual Risk Stratification That Can Lead To Decisive Management and Treatment Decisions in Prostate Cancer

A key step in providing management/treatment options to men with suspected prostate cancer (PCa) ... more A key step in providing management/treatment options to men with suspected prostate cancer (PCa) is categorizing the risk for the presence of benign, low risk, intermediate risk, or high-risk disease. Our novel modality brings new evidence, based on the long-known hallmark characteristic of PCa – decreased Zinc (Zn), which is the most direct metabolic sign of malignancy and its aggressiveness. To date, this approach has not been adopted for clinical use for a number of reasons that are described in this article and which have been addressed by our approach: Zn has to be measured on fresh samples, prior to fixating in formalin, therefore samples have to be scanned during the biopsy session; as Zn depletion occurs in the glands, where the tumors develop, estimation of the glands’ levels in the scanned tissue along with their compactness, are essential for accurate diagnosis. Combined with the Zn depletion, this facilitates a reliable assessment of the disease aggressiveness. Data gath...

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MADplots: A methodology for visualizing and characterizing energy-dependent attenuation of tissues in spectral computed tomography

Research in Diagnostic and Interventional Imaging

Proton spectroscopy of radiation-induced injury to the brain

Human Cardiac MRI at 3 Tesla Using a Whole Body Radio Frequency Coil

Introduction Concern over non-uniform signal intensity due to the attenuation and distortion of t... more Introduction Concern over non-uniform signal intensity due to the attenuation and distortion of the excitation (B1) field by dielectric and conductive effects at high field strengths (1,2) has hampered the development of high-field human cardiac applications. Nearly all existing 3T and higher field strength scanners have been installed without a body RF coil. This has necessitated most high-field human cardiac studies to be performed using surface coils, which may have highly inhomogeneous field patterns for spin excitation. We report on the evaluation of a prototype whole body radio frequency (RF) coil for MR imaging in a 3T scanner. We have acquired cardiac images using the prototype body RF coil for both excitation and reception to demonstrate the signal uniformity across the heart using the high flip angle RF pulses of a black blood fast spin echo (FSE) pulse sequence (3). Methods A quadrature high-pass whole body birdcage coil was designed and fabricated at the General Electric...

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Does Tumor FDG-PET Avidity Represent Enhanced Glycolytic Metabolism in Non-Small Cell Lung Cancer?

The Annals of Thoracic Surgery, 2019

Background: In non-small cell lung cancer (NSCLC), fluorodeoxyglucose positron emission tomograph... more Background: In non-small cell lung cancer (NSCLC), fluorodeoxyglucose positron emission tomography (FDG-PET) assists in diagnosis, staging, and evaluating treatment response. One parameter of FDG-PET, the maximum standard uptake value (SUV m), is considered an objective measure of glucose uptake. However, little is known about the fate of glucose in FDG-avid lung tumors in vivo. The objective is to use stable glucose isotope tracing to determine if the SUV m predicts glycolytic metabolism, or other glucose fates in tumors. Methods: In this prospective IRB-approved clinical trial, 52 untreated potentially-resectable confirmed NSCLC patients underwent FDG-PET computed tomography. During surgery, the patients were infused with 13 C-glucose. Blood, tumor (T) and normal lung (NL) samples were analyzed by mass spectrometry to determine 13 C enrichment in glycolytic intermediates. These

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Separating High-Z Oral Contrast From Intravascular Iodine Contrast in an Animal Model Using Dual-Layer Spectral CT

Academic Radiology, 2019

IACUC institutional animal care and use committee MIP maximum intensity projection Rationale and ... more IACUC institutional animal care and use committee MIP maximum intensity projection Rationale and Objectives: To show that water and iodine two-material decomposition images from dual-layer dual-energy spectral X-ray computed tomography (DECT) can be used to separate intravascular iodine contrast from simultaneously administered oral tantalum, tungsten, or rhenium contrast in an animal model. Materials and Methods: In this Institutional Animal Care and Use Committee approved study, four female Fischer rats were given simultaneous intravenous and oral X-ray computed tomography contrast. Intravenous iodine contrast was administered via tail vein injection. Oral barium, tantalum, tungsten, or rhenium contrast was administered via gavage. The animals were imaged on a dual-layer DECT system at 120 kVp. Water and iodine two-material decomposition images (water equivalent and iodine equivalent images) were used for qualitative analysis. Computer simulations were performed using a customized DECT simulator to better understand why certain high-Z elements disappear in the iodine equivalent images and what is the theoretical range of elements with this property. Results: The iodine and barium contrast appeared only in the iodine equivalent images and could not be differentiated from each other. However, the tantalum, tungsten, and rhenium contrast only appeared in the water equivalent images. This allowed iodine contrast in the bowel wall to be easily segmented from tantalum, tungsten, and rhenium contrast in the bowel lumen. Simulations confirmed that certain high-Z elements will have pixel values of 0 mg iodine/mL in the iodine equivalent images due to a K-edge effect associated with DECT systems. Conclusions: Dual-layer DECT can separate iodine from certain high-Z elements using water equivalent and iodine equivalent images with an increased element range compared to other DECT systems. This K-edge effect could promote the development and approval of new high-Z contrast agents for DECT.

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839: Gene Expression Profiles that Underlie the Biological Events Visualized by Magnetic Resonance Spectra (MRS) of Human Prostate Cancer: Choline Kinase

Journal of Urology, 2004

In a pilot study, androgen receptor protein levels were higher in the radical prostatectomy speci... more In a pilot study, androgen receptor protein levels were higher in the radical prostatectomy specimens from 25 African compared to 25 Caucasian Americans-18% higher in benign prostate and 80% higher in prostate cancer (Gaston, J Urol, 2003). We sought to determine if these differences in androgen receptor levels result from racial differences in ligand availability within the prostatic microenvironment. METHODS: Steroid hormones were extracted from snap frozen tissue obtained intra-operatively from radical prostatectomy specimens of 36 African and 59 Caucasian Americans. Testosterone, dihydrotestosterone (DHT), androstenedione (ASD), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S04), sex hormone-binding globulin (SHBG) and prostate-specific antigen (PSA) were measured using radioimmunoassay. Wilcoxon two group tests were performed to compare clinical characteristics and tissue steroid levels between African and Caucasian Americans. Nonparametric rank analysis of covariance was used to consider race and other clinical factors in a multivariable way. RESULTS: African and Caucasian American men were similar with respect to serum PSA levels and pathologic grade and stage; however, African Americans were younger in years (p=O.Ol) and had significantly higher body mass indices (BMI) (p=0.02). African and Caucasian Americans had similar testosterone and DHT levels; however, African Americans had higher ASD (p=0.006) and SHBG (p=0.009) levels. Racial differences in ASD (p=O.Ol5) and SHBG (p=0.008) persisted after controlling for age, BMI, PSA and pathologic Gleason sum and stage. CONCLUSIONS: Tissue levels of testosterone and DHT did not differ by race; however, African Americans had higher ASD and SHBG tissue levels than Caucasian Americans. Higher ASD tissue levels did not result in greater conversion of ASD to testosterone in the prostates of African Americans. Higher SHBG tissue levels may activate the androgen receptor through cAMP-dependent pathways. The cause(s) of increased androgen receptor expression in African compared to Caucasian Americans should be investigated further.

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Pseudoenhancement effects on iodine quantification from dual-energy spectral CT systems: A multi-vendor phantom study regarding renal lesion characterization

European Journal of Radiology, 2018

attenuating background (10 mg iodine/mL). In this study we found iodine quantification to be more... more

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Prostate: MR imaging with an endorectal surface coil

Radiology, 1989

An endorectal surface coil has been developed to obtain high-resolution magnetic resonance images... more An endorectal surface coil has been developed to obtain high-resolution magnetic resonance images of the prostate. The probe consists of a surface coil mounted on the inner surface of a balloon. The balloon is concave to ensure tight seating against the prostate. The coil has been used in 15 patients with biopsy-proved prostatic carcinoma and in two healthy volunteers. The axial images were obtained with a 12-16-cm field of view and a 3-mm section thickness. Compared with images obtained with a body coil, the surface coil images better demonstrate prostatic anatomy and pathologic conditions.

31P localized magnetic resonance spectroscopy of head and neck tumors—preliminary findings

Otolaryngology–Head and Neck Surgery, 1990

Magnetic resonance imaging (MRI) is a powerful tool for accurate assessment of the anatomic exten... more Magnetic resonance imaging (MRI) is a powerful tool for accurate assessment of the anatomic extent of head and neck neoplasms. The development of methods for spatial localization by use of multiply tuned radio frequency colls that permit the measurement of multiple nuclear MR spectra (1H and 31P) from precisely defined volumes of interest has provided a basis for integrating spectroscopy into the clinical MRI examination. This offers a means for noninvasive monitoring of relative concentrations of mobile metabolites within a tumor. With the use of imaging to determine proper coll placement, a test‐retest variance of about 17% is seen on MR spectroscopy. Data are presented from MRI/MRS studies for four head and neck lesions: (1) a squamous cell carcinoma of the lip; (2) a Juvenile angiofibroma extending into the nasal cavity; (3) a massive chondrosarcoma of the nasal septum; and (4) a cervical nodal metastasis of a squamous ceil carcinoma of the pharynx. Spectra are evaluated by comp...

Human breast lesions: characterization with proton MR spectroscopy

Radiology, 1998

To assess the clinical usefulness of spatially localized hydrogen-1 magnetic resonance (MR) spect... more To assess the clinical usefulness of spatially localized hydrogen-1 magnetic resonance (MR) spectroscopy in distinguishing benign from malignant lesions on the basis of total choline levels. These studies were performed at 1.5 T with a four-channel multicoil that compresses the breast sagittally. Contrast material-enhanced MR imaging and single-voxel H-1 MR spectroscopy were performed in 17 patients (age range, 25-68 years) who had nonspecific mammographic findings. Histopathologic correlations were made from biopsy or surgical specimens. Ten patients had various malignant breast lesions 1-4 cm in diameter, and seven patients had benign processes. Most studies were performed with nominal voxel sizes (&lt; 2 cm3). Spectra obtained with an echo time of 31 msec showed resonances from water and mobile fatty acids and, in some cases, the N-trimethyl resonance of choline-containing compounds (Cho) at 3.2 ppm. The absolute concentration of Cho in each lesion was determined with a phantom containing 1 mmol/L Cho as an external reference. On the basis of reference measurements, the least detectable level of Cho was 0.2 mmol/L. With this threshold, seven of 10 malignant lesions showed detectable levels of Cho. In contrast, Cho was seen in only one patient with an extremely rare benign process, a tubular adenoma. The remaining six patients with benign processes demonstrated no detectable Cho levels. Spatially localized H-1 MR spectroscopy can provide sufficient sensitivity and spectral resolution at 1.5 T to demonstrate Cho in human breast lesions with a spectroscopic protocol that provides up to 1-cm3 resolution. Determining the presence of Cho may provide a useful test for malignancy.

Prostate cancer: local staging with endorectal surface coil MR imaging

Radiology, 1991

Endorectal surface coil magnetic resonance (MR) imaging was used to stage the local extent of pro... more Endorectal surface coil magnetic resonance (MR) imaging was used to stage the local extent of prostate cancer in 22 patients. The endorectal coil images were acquired with a 10-12-cm field of view and a 4-mm section thickness. All pathologic specimens were reviewed by one pathologist. Endorectal surface coil MR imaging was 82% accurate in the differentiation of stage B from stage C cancer. One case was overestimated, and three cases were underestimated. The three underestimated cases consisted of two cases of microscopic capsular invasion and one case of minimal seminal vesicle invasion. In a comparison of retrospective, blinded readings of endorectal coil and body coil images, there was an average improvement in accuracy of 16% in staging prostate cancer with endorectal coil images.

Proton Spectroscopy in Asymptomatic HIV-Infected Adults: Initial Results in a Prospective Cohort Study

Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, 1996

The purpose of our study was to determine whether proton magnetic resonance spectroscopy (MRS) co... more The purpose of our study was to determine whether proton magnetic resonance spectroscopy (MRS) could detect early brain involvement by human immunodeficiency virus (HIV). We recruited 19 asymptomatic HIV-infected patients, 9 with and 10 without a history of intravenous drug use (IDU), as well as 10 control subjects. All subjects had to have normal MR imaging to be enrolled. We identified the following peaks on proton MRS: n-acetyl aspartate, creatine, choline, and a conglomerate amino acid peak between 2.1 and 2.6 parts per million that we call the marker peaks. Proton MRS was able to demonstrate a statistically significant difference between HIV-infected subjects and controls. The marker/Cr was the best ratio to separate patients from controls, with controls having a mean ratio of 0.50 +/- 0.51 and patients having a mean ratio of 1.8 +/- 0.85 (p = 0.001). There was no difference between HIV-infected subjects with and without a history of IDU. No significant relationship was found between either neuropsychological test scores or CD4 count and metabolite ratios. In brief, MRS seems more sensitive than magnetic resonance imaging (MRI), being able to detect abnormalities in HIV-infected patients when imaging is normal.

Rotator cuff tears: diagnostic performance of MR imaging

Radiology, 1989

To determine the diagnostic performance of magnetic resonance (MR) imaging in the evaluation of s... more To determine the diagnostic performance of magnetic resonance (MR) imaging in the evaluation of suspected rotator cuff tears, eight asymptomatic volunteers and 32 patients with rotator cuff tendonopathy who underwent surgery were examined with MR imaging. Twenty-four of these patients also underwent contrast arthrography. The ability of MR imaging to depict the size of cuff tears and the quality of torn tendon edges was also evaluated. The MR imaging and arthrographic studies were reviewed without knowledge of surgical results or of the other studies. A scoring system was developed and a score assigned to each patient&amp;amp;amp;amp;#39;s MR study. The sensitivity of MR imaging for all tears (partial and full thickness) was 0.91, and the specificity was 0.88; whereas the sensitivity and specificity of arthrography were each 0.71. The scoring system improved the sensitivity to 1.0 and the specificity to 0.92. Linear regression analysis showed excellent correlation between preoperative assessment of the size of rotator cuff tears and measurement at surgery (r = .95).

High resolution nuclear magnetic resonance (NMR) studies of cation transport across model and living biological membranes: aqueous shift reagents for 23Na, 39K and 25Mg NMR

Journal of the Less Common Metals, 1983

Radio-Frequency Thermal Ablation with NaCl Solution Injection: Effect of Electrical Conductivity on Tissue Heating and Coagulation—Phantom and Porcine Liver Study

Radiology, 2001

PURPOSE: To characterize the effects of NaCl concentration on tissue electrical conductivity, rad... more PURPOSE: To characterize the effects of NaCl concentration on tissue electrical conductivity, radio-frequency (RF) deposition, and heating in phantoms and optimize adjunctive NaCl solution injection for RF ablation in an in vivo model. MATERIALS AND METHODS: RF was applied for 12-15 minutes with internally cooled electrodes. For phantom experiments (n ϭ 51), the NaCl concentration in standardized 5% agar was varied (0%-25.0%). A nonlinear simplex optimization strategy was then used in normal porcine liver (n ϭ 44) to determine optimal pre-RF NaCl solution injection parameters (concentration, 0%-38.5%; volume, 0-25 mL). NaCl concentration and tissue conductivity were correlated with RF energy deposition, tissue heating, and induced coagulation. RESULTS: NaCl concentration had significant but nonlinear effects on electrical conductivity, RF deposition, and heating of agar phantoms (P Ͻ .01). Progressively greater heating was observed to 5.0% NaCl, with reduced temperatures at higher concentrations. For in vivo liver, NaCl solution volume and concentration significantly influenced both tissue heating and coagulation (P Ͻ .001). Maximum heating 20 mm from the electrode (102.9°C Ϯ 4.3 [SD]) and coagulation (7.1 cm Ϯ 1.1) occurred with injection of 6 mL of 38.5% (saturated) NaCl solution. CONCLUSION: Injection of NaCl solution before RF ablation can increase energy deposition, tissue heating, and induced coagulation, which will likely benefit clinical RF ablation. In normal well-perfused liver, maximum coagulation (7.0 cm) occurs with injection of small volumes of saturated NaCl solution. 157 Volume 219 ⅐ Number 1 Radio-Frequency Thermal Ablation with NaCl Solution Injection ⅐ 159 Volume 219 ⅐ Number 1 Radio-Frequency Thermal Ablation with NaCl Solution Injection ⅐ 165

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<title>In vivo imaging of small animals with optical tomography and near-infrared fluorescent probes</title>

Biomedical Nanotechnology Architectures and Applications, 2002

ABSTRACT

Transient MRI enhancement in a patient with seizures and previously resected glioma: Use of MRS

Neurology, 1999

5307814 Externally moveable intracavity probe for MRI imaging and spectroscopy

Magnetic Resonance Imaging, 1995

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Noise reduction for T2 derived magnetic resonance images

Computerized Medical Imaging and Graphics, 1990

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A Novel Modality Enables New Evidence-Based Individual Risk Stratification That Can Lead To Decisive Management and Treatment Decisions in Prostate Cancer

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MADplots: A methodology for visualizing and characterizing energy-dependent attenuation of tissues in spectral computed tomography

Research in Diagnostic and Interventional Imaging

Proton spectroscopy of radiation-induced injury to the brain

Human Cardiac MRI at 3 Tesla Using a Whole Body Radio Frequency Coil

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Does Tumor FDG-PET Avidity Represent Enhanced Glycolytic Metabolism in Non-Small Cell Lung Cancer?

The Annals of Thoracic Surgery, 2019

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Separating High-Z Oral Contrast From Intravascular Iodine Contrast in an Animal Model Using Dual-Layer Spectral CT

Academic Radiology, 2019

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839: Gene Expression Profiles that Underlie the Biological Events Visualized by Magnetic Resonance Spectra (MRS) of Human Prostate Cancer: Choline Kinase

Journal of Urology, 2004

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Pseudoenhancement effects on iodine quantification from dual-energy spectral CT systems: A multi-vendor phantom study regarding renal lesion characterization

European Journal of Radiology, 2018

attenuating background (10 mg iodine/mL). In this study we found iodine quantification to be more... more

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Prostate: MR imaging with an endorectal surface coil

Radiology, 1989

31P localized magnetic resonance spectroscopy of head and neck tumors—preliminary findings

Otolaryngology–Head and Neck Surgery, 1990

Human breast lesions: characterization with proton MR spectroscopy

Radiology, 1998

Prostate cancer: local staging with endorectal surface coil MR imaging

Radiology, 1991

Proton Spectroscopy in Asymptomatic HIV-Infected Adults: Initial Results in a Prospective Cohort Study

Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, 1996

Rotator cuff tears: diagnostic performance of MR imaging

Radiology, 1989

High resolution nuclear magnetic resonance (NMR) studies of cation transport across model and living biological membranes: aqueous shift reagents for 23Na, 39K and 25Mg NMR

Journal of the Less Common Metals, 1983

Radio-Frequency Thermal Ablation with NaCl Solution Injection: Effect of Electrical Conductivity on Tissue Heating and Coagulation—Phantom and Porcine Liver Study

Radiology, 2001

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<title>In vivo imaging of small animals with optical tomography and near-infrared fluorescent probes</title>

Biomedical Nanotechnology Architectures and Applications, 2002

ABSTRACT

Transient MRI enhancement in a patient with seizures and previously resected glioma: Use of MRS

Neurology, 1999

5307814 Externally moveable intracavity probe for MRI imaging and spectroscopy

Magnetic Resonance Imaging, 1995

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Dedicated PET device for breast PET and MRI/PET correlations

Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS

Objective: Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizum... more Objective: Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab therapy in patients with multiple sclerosis (MS), which is often accompanied by an immune reconstitution inflammatory syndrome (IRIS) after removal of the drug. We describe a patient with MS who presented with simultaneous PML-IRIS 2 months after stopping natalizumab for other reasons. Case Report and Results: The patient had widespread PML and severe IRIS. He received corticosteroids and displayed a vigorous JC virus-specific cellular immune response. Elevated myoinositol and lipid/creatine peaks measured in PML lesions by proton magnetic resonance spectroscopy ( 1H-MRS) corresponded to episodes of contrast enhancement on MRI scans and persisted after the enhancement subsided. He demonstrated steady clinical improvement, but developed marked residual atrophy in areas affected by PML and inflammation, as well as seizures. Conclusions: New enhancing white matter lesions, occurring after discontinuation of natalizumab, can be the manifestation of PML-IRIS rather than an MS exacerbation. Elevated myoinositol and lipid/creatine peaks appear to be more sensitive markers of inflammation in PML lesions than contrast enhancement. 1H-MRS may become useful as a biomarker for PML-IRIS by helping clinicians determine the need for corticosteroid administration and anticipate continuing clinical recovery. Copyright {\textcopyright} 2012 by AAN Enterprises, Inc.

Keyhole chemical exchange saturation transfer

The keyhole technique, which involves the acquisition of dynamic data at low resolution in combin... more The keyhole technique, which involves the acquisition of dynamic data at low resolution in combination with a high-resolution reference, is developed for the purposes of chemical exchange saturation transfer (CEST) imaging, i.e., Keyhole CEST. Low-resolution data are acquired with saturation applied at different frequencies for Z-spectra, along with a high-resolution reference image taken without saturation. Three methods for high-resolution reconstruction of Keyhole CEST are evaluated using the values from quantitative high-resolution CEST maps. In addition, Keyhole CEST is applied for collection of data used for B0 correction. The keyhole approach is evaluated for CEST contrast generation using exchanging protons in hydroxyl groups. First, the techniques are evaluated in vitro using samples of dextrose and chondroitin sulfate. Next, the work is extended in vivo to explore its applicability for gagCEST. Comparable quantitative gagCEST values are found using Keyhole CEST, provided the structure or region of interest is not limited by the low-resolution dataset. {\textcopyright} 2012 Wiley Periodicals, Inc.

Clinical application of pharmacokinetic analysis as a biomarker of solitary pulmonary nodules: Dynamic contrast-enhanced MR imaging

The purpose of this study is to evaluate perfusion indices and pharmacokinetic parameters in soli... more The purpose of this study is to evaluate perfusion indices and pharmacokinetic parameters in solitary pulmonary nodules (SPNs). Thirty patients of 34 enrolled with SPNs (15-30 mm) were evaluated in this study. T1 and T2-weighted structural images and 2D turbo FLASH perfusion images were acquired with shallow free breathing. B-spline nonrigid image registration and optimization by $\pi$2 test against pharmacokinetic model curve were performed on dynamic contrast-enhanced MRI. This allowed voxel-by-voxel calculation of kep, the rate constant for tracer transport to and from plasma and the extravascular extracellular space. Mean transit time, time-to-peak, initial slope, and maximum enhancement (Emax) were calculated from time-intensity curves fitted to a gamma variate function. After blinded data analysis, correlation with tissue histology from surgical resection or biopsy samples was performed. Histologic evaluation revealed 25 malignant and five benign SPNs. All benign SPNs had kep < 1.0 min -1. Nineteen of 25 (76%) malignant SPNs showed kep > 1.0 min-1. Sensitivity to diagnose malignant SPNs at a cutoff of kep = 1.0 min-1 was 76%, specificity was 100%, positive predictive value was 100%, negative predictive value was 45%, and accuracy was 80%. Of all indices studied, kep was the most significant in differentiating malignant from benign SPNs. Copyright {\textcopyright} 2012 Wiley Periodicals, Inc.

Perfusion imaging with a freely diffusible hyperpolarized contrast agent

Contrast agents that can diffuse freely into or within tissue have numerous attractive features f... more Contrast agents that can diffuse freely into or within tissue have numerous attractive features for perfusion imaging. Here we present preliminary data illustrating the suitability of hyperpolarized 13C labeled 2-methylpropan-2-ol (also known as dimethylethanol, tertiary butyl alcohol and tert-butanol) as a freely diffusible contrast agent for magnetic resonance perfusion imaging. Dynamic 13C images acquired in rat brain with a balanced steady-state free precession sequence following administration of hyperpolarized 2-methylpropan-2-ol show that this agent can be imaged with 2-4s temporal resolution, 2 mm slice thickness, and 700 $\mu$m in-plane resolution while retaining adequate signal-to-noise ratio. 13C relaxation measurements on 2-methylpropan-2-ol in blood at 9.4T yield T 1 = 46 ± 4s and T 2 = 0.55 ± 0.03s. In the rat brain at 4.7T, analysis of the temporal dynamics of the balanced steady-state free precession image intensity in tissue and venous blood indicate that 2-methylpropan-2-ol has a T 2 of roughly 2-4s and a T 1 of 43 ± 24s. In addition, the images indicate that 2-methylpropan-2-ol is freely diffusible in brain and hence has a long residence time in tissue; this in turn makes it possible to image the agent continuously for tens of seconds. These characteristics show that 2-methylpropan-2-ol is a promising agent for robust and quantitative perfusion imaging in the brain and body. Copyright {\textcopyright} 2011 Wiley-Liss, Inc.

High-resolution computed tomography of single breast cancer microcalcifications in vivo

Microcalcification is a hallmark of breast cancer and a key diagnostic feature for mammography. W... more Microcalcification is a hallmark of breast cancer and a key diagnostic feature for mammography. We recently described the first robust animal model of breast cancer microcalcification. In this study, we hypothesized that high-resolution computed tomography (CT) could potentially detect the genesis of a single microcalcification in vivo and quantify its growth over time. Using a commercial CT scanner, we systematically optimized acquisition and reconstruction parameters. Two ray-tracing image reconstruction algorithms were tested: a voxel-driven "fast" cone beam algorithm (FCBA) and a detector-driven "exact" cone beam algorithm (ECBA). By optimizing acquisition and reconstruction parameters, we were able to achieve a resolution of 104 $\mu$m full width at halfmaximum (FWHM). At an optimal detector sampling frequency, the ECBA provided a 28 $\mu$m (21%) FWHM improvement in resolution over the FCBA. In vitro, we were able to image a single 300 $\mu$m Times; 100 $\mu$m hydroxyapatite crystal. In a syngeneic rat model of breast cancer, we were able to detect the genesis of a single microcalcification in vivo and follow its growth longitudinally over weeks. Taken together, this study provides an in vivo "gold standard" for the development of calcification-specific contrast agents and a model system for studying the mechanism of breast cancer microcalcification. {\textcopyright} 2011 Decker Publishing.

Elastic registration of multimodal prostate MRI and histology via multiattribute combined mutual information

Purpose: By performing registration of preoperative multiprotocol in vivo magnetic resonance (MR)... more Purpose: By performing registration of preoperative multiprotocol in vivo magnetic resonance (MR) images of the prostate with corresponding whole-mount histology (WMH) sections from postoperative radical prostatectomy specimens, an accurate estimate of the spatial extent of prostate cancer (CaP) on in vivo MR imaging (MRI) can be retrospectively established. This could allow for definition of quantitative image-based disease signatures and lead to development of classifiers for disease detection on multiprotocol in vivo MRI. Automated registration of MR and WMH images of the prostate is complicated by dissimilar image intensities, acquisition artifacts, and nonlinear shape differences. Methods: The authors present a method for automated elastic registration of multiprotocol in vivo MRI and WMH sections of the prostate. The method, multiattribute combined mutual information (MACMI), leverages all available multiprotocol image data to drive image registration using a multivariate formulation of mutual information. Results: Elastic registration using the multivariate MI formulation is demonstrated for 150 corresponding sets of prostate images from 25 patient studies with T2-weighted and dynamic-contrast enhanced MRI and 85 image sets from 15 studies with an additional functional apparent diffusion coefficient MRI series. Qualitative results of MACMI evaluation via visual inspection suggest that an accurate delineation of CaP extent on MRI is obtained. Results of quantitative evaluation on 150 clinical and 20 synthetic image sets indicate improved registration accuracy using MACMI compared to conventional pairwise mutual information-based approaches. Conclusions: The authors' approach to the registration of in vivo multiprotocol MRI and ex vivo WMH of the prostate using MACMI is unique, in that (1) information from all available image protocols is utilized to drive the registration with histology, (2) no additional, intermediate ex vivo radiology or gross histology images need be obtained in addition to the routinely acquired in vivo MRI series, and (3) no corresponding anatomical landmarks are required to be identified manually or automatically on the images. {\textcopyright} 2011 American Association of Physicists in Medicine.

Impact of nonrigid motion correction technique on pixel-wise pharmacokinetic analysis of free-breathing pulmonary dynamic contrast-enhanced MR imaging

Purpose: To investigates the impact of nonrigid motion correction on pixel-wise pharmacokinetic a... more Purpose: To investigates the impact of nonrigid motion correction on pixel-wise pharmacokinetic analysis of free-breathing DCE-MRI in patients with solitary pulmonary nodules (SPNs). Misalignment of focal lesions due to respiratory motion in free-breathing dynamic contrast-enhanced MRI (DCE-MRI) precludes obtaining reliable time-intensity curves, which are crucial for pharmacokinetic analysis for tissue characterization. Materials and Methods: Single-slice 2D DCE-MRI was obtained in 15 patients. Misalignments of SPNs were corrected using nonrigid B-spline image registration. Pixelwise pharmacokinetic parameters Ktrans, $\upsilon$e, and $\kappa$ep were estimated from both original and motion-corrected DCE-MRI by fitting the two-compartment pharmacokinetic model to the time-intensity curve obtained in each pixel. The "goodness-of-fit" was tested with $\chi$2- test in pixel-by-pixel basis to evaluate the reliability of the parameters. The percentages of reliable pixels within the SPNs were compared between the original and motion-corrected DCE-MRI. In addition, the parameters obtained from benign and malignant SPNs were compared. Results: The percentage of reliable pixels in the motion-corrected DCE-MRI was significantly larger than the original DCE-MRI (P = 4 × 10-7). Both Ktrans and $\kappa$ep derived from the motion-corrected DCE-MRI showed significant differences between benign and malignant SPNs (P = 0.024, 0.015). Conclusion: The study demonstrated the impact of non-rigid motion correction technique on pixel-wise pharmacokinetic analysis of free-breathing DCE-MRI in SPNs. {\textcopyright} 2011 Wiley-Liss, Inc.

On-target inhibition of tumor fermentative glycolysis as visualized by hyperpolarized pyruvate

Many cancer cells display the Warburg effect, that is, enhanced glycolysis followed by fermentati... more Many cancer cells display the Warburg effect, that is, enhanced glycolysis followed by fermentation (conversion of pyruvate to lactate). Recently, the molecular basis for these effects has started to be elucidated, and the upregulation of the lactate dehydrogenase A (LDH-A) isoform of lactate dehydrogenase is felt to be a major molecular mediator of this phenomenon. Moreover, LDH-A expression in tumor tissue and LDH-A levels in blood portend a bad prognosis, and LDH-A blockade can lead to tumor growth inhibition in tumor transplant models. We have extended existing data (some of which were published during the time when we were carrying out our studies) in two important ways: 1) inhibition of LDH-A in a glycolytic lung cancer cell line results in reactive oxygen species- mediated apoptosis and increased sensitivity to the chemotherapeutic drug paclitaxel and 2) inhibition of fermentative glycolysis can also be accomplished by activation of the pyruvate dehydrogenase complex by the drugdichloroacetate, now undergoing clinical trials, and that this phenomenon can be monitored in vivo in a noninvasive real-time manner through magnetic resonance spectroscopy using hyperpolarized pyruvate. Collectively, these data suggest that in vivo effects of drugs that redirect the fate of pyruvate, and hence are aimed at reversing the Warburg effect, could be monitored through the use of hyperpolarized magnetic resonance spectroscopy, a method that is scalable to human use. {\textcopyright} 2011 Neoplasia Press, Inc.

Deuteration of a molecular probe for DNP hyperpolarization - A new approach and validation for choline chloride

The promising dynamic nuclear polarization (DNP) for hyperpolarized 13C-MRI/MRS of real-time meta... more The promising dynamic nuclear polarization (DNP) for hyperpolarized 13C-MRI/MRS of real-time metabolism in vivo is challenged by the limited number of agents with the required physical and biological properties. The physical requirement of a liquid-state T 1 of tens of seconds is mostly found for 13C-carbons in small molecules that have no direct protons attached, i.e. carbonyl, carboxyl and certain quaternary carbons. Unfortunately, such carbon positions do not exist in a large number of metabolic agents, and chemical shift dispersion often limits detection of their chemical evolution. We have previously shown that direct deuteration of protonated carbon positions significantly prolongs the 13C T 1 in the liquid state and provides potential 13C-labeled agents with differential chemical shift with respect to metabolism. The Choline Molecular Probe [1,1,2,2-D 4, 2- 13C]choline chloride (CMP2) has recently been introduced as a means of studying choline metabolism in a hyperpolarized state. Here, the biophysical properties of CMP2 were characterized and compared with those of [1- 13C]pyruvate to evaluate the impact of molecular probe deuteration. The CMP2 solid-state polarization build-up time constant (30min) and polarization level (24%) were comparable to those of [1- 13C]pyruvate. Both compounds' liquid state T 1 increased with temperature. The high-field T 1 of CMP2 compared favorably with [1- 13C]pyruvate. Thus, a deuterated agent demonstrated physical properties comparable to a hyperpolarized compound of already proven value, whereas both showed chemical shift dispersion that allowed monitoring of their metabolism. It is expected that the use of deuterated carbon-13 positions as reporting hyperpolarized nuclei will substantially expand the library of agents for DNP-MR. {\textcopyright} 2011 John Wiley & Sons, Ltd.

PCEST: Positive contrast using Chemical Exchange Saturation Transfer

Chemical Exchange Saturation Transfer (CEST) contrast utilizes selective pre-saturation of a smal... more Chemical Exchange Saturation Transfer (CEST) contrast utilizes selective pre-saturation of a small pool of exchanging protons and subsequent detection of the decrease in bulk water signal. The CEST contrast is negative and requires detection of small signal change in the presence of a strong background signal. Here we develop a Positive CEST (pCEST) detection scheme utilizing the analogous nature of the CEST and off-resonance T 1$\rho$ experiments and exploring increased apparent relaxation rates in the presence of the selective pre-saturation. pCEST leads to the positive contrast, i.e., increased signal intensity as the result of the presence of the agent and RF pre-saturation. Simultaneously substantial background suppression is achieved. The contrast can be switched "ON" and "OFF", similar to the original CEST. {\textcopyright} 2011 Elsevier Inc. All rights reserved.

Determining histology-MRI slice correspondences for defining MRI-based disease signatures of prostate cancer

Mapping the spatial disease extent in a certain anatomical organ/tissue from histology images to ... more Mapping the spatial disease extent in a certain anatomical organ/tissue from histology images to radiological images is important in defining the disease signature in the radiological images. One such scenario is in the context of men with prostate cancer who have had pre-operative magnetic resonance imaging (MRI) before radical prostatectomy. For these cases, the prostate cancer extent from ex vivo whole-mount histology is to be mapped to in vivo MRI. The need for determining radiology-image-based disease signatures is important for (a) training radiologist residents and (b) for constructing an MRI-based computer aided diagnosis (CAD) system for disease detection in vivo. However, a prerequisite for this data mapping is the determination of slice correspondences (i.e. indices of each pair of corresponding image slices) between histological and magnetic resonance images. The explicit determination of such slice correspondences is especially indispensable when an accurate 3D reconstruction of the histological volume cannot be achieved because of (a) the limited tissue slices with unknown inter-slice spacing, and (b) obvious histological image artifacts (tissue loss or distortion). In the clinic practice, the histology-MRI slice correspondences are often determined visually by experienced radiologists and pathologists working in unison, but this procedure is laborious and time-consuming. We present an iterative method to automatically determine slice correspondence between images from histology and MRI via a group-wise comparison scheme, followed by 2D and 3D registration. The image slice correspondences obtained using our method were compared with the ground truth correspondences determined via consensus of multiple experts over a total of 23 patient studies. In most instances, the results of our method were very close to the results obtained via visual inspection by these experts. {\textcopyright} 2010 Elsevier Ltd.

Clinical effects and brain metabolic correlates in non-invasive cortical neuromodulation for visceral pain

Background and aims: Chronic visceral pain is frequent, extremely debilitating, and generally res... more Background and aims: Chronic visceral pain is frequent, extremely debilitating, and generally resistant to pharmacological treatment. It has been shown that chronic visceral inflammation, through altered afferent visceral sensory input, leads to plastic changes in the central nervous system that ultimately sustain pain. Therefore approaches aiming at modulation of brain activity are attractive candidates to control visceral pain. Methods: Here we report findings of a phase II, sham-controlled clinical trial assessing the clinical effects and brain metabolic correlates of a 10-day course of daily sessions of slow-frequency, repetitive transcranial magnetic stimulation (rTMS) targeting the right secondary somatosensory cortex (SII) in patients with chronic pancreatitis and severe visceral pain. Results: Our results show a significant reduction in pain after real rTMS that lasted for at least 3 weeks following treatment. These clinical changes were correlated with increases in glutamate and N-acetyl aspartate (NAA) levels - neurometabolites associated with cortical activity and brain damage - as measured by in vivo single-voxel proton magnetic resonance spectroscopy (1H-MRS). Adverse effects in the real rTMS group were mild and short-lasting. Conclusions: Our results support preliminary findings showing that modulation of right SII with rTMS is associated with a significant analgesic effect and that this effect is correlated with an increase in excitatory neurotransmitter levels such as glutamate and NAA. {\textcopyright} 2010 Published by Elsevier Ltd. on behalf of European Federation of International Association for the Study of Pain Chapters.

A concentration-independent method to measure exchange rates in PARACEST agents

The efficiency of chemical exchange dependent saturation transfer (CEST) agents is largely determ... more The efficiency of chemical exchange dependent saturation transfer (CEST) agents is largely determined by their water or proton exchange kinetics, yet methods to measure such exchange rates are variable and many are not applicable to in vivo measurements. In this work, the water exchange kinetics of two prototype paramagnetic agents (PARACEST) are compared by using data from classic NMR line-width measurements, by fitting CEST spectra to the Bloch equations modified for chemical exchange, and by a method where CEST intensity is measured as a function of applied amplitude of radiofrequency field. A relationship is derived that provides the water exchange rate from the X-intercept of a plot of steady-state CEST intensity divided by reduction in signal caused by CEST irradiation versus 1/$\omega$1 2, referred to here as an omega plot. Furthermore, it is shown that this relationship is independent of agent concentration. Exchange rates derived from omega plots using either high-resolution CEST NMR data or CEST data obtained by imaging agree favorably with exchange rates measured by the more commonly used Bloch fitting and linewidth methods. Thus, this new method potentially allows access to a direct measure of exchange rates in vivo, where the agent concentration is typically unknown. {\textcopyright} 2010 Wiley-Liss, Inc.

CEST and PARACEST MR contrast agents

In this review we describe the status of development for a new class of magnetic resonance (MR) c... more In this review we describe the status of development for a new class of magnetic resonance (MR) contrast agents, based on chemical exchange saturation transfer (CEST). The mathematics and physics relevant to the description of the CEST effect in MR are presented in an appendix published in the online version only. We discuss the issues arising when translating in vitro results obtained with CEST agents to using these MR agents in in vivo model studies and in humans. Examples are given on how these agents are imaged in vivo. We summarize the status of development of these CEST agents, and speculate about the next steps that may be taken towards the demonstration of CEST MR imaging in clinical applications. {\textcopyright} 2010 Informa Healthcare.

A dose- and time-controllable syngeneic animal model of breast cancer microcalcification

The development of novel diagnostic agents for the detection of breast cancer microcalcifications... more The development of novel diagnostic agents for the detection of breast cancer microcalcifications requires a reliable animal model. Based on previous work from our group, we hypothesized that a single systemic injection of recombinant bone morphogenetic protein-2 (rBMP-2) could be used to create such a model. The cDNA encoding mature human BMP-2 was expressed in BL21(DE3) bacteria, purified to homogeneity, and refolded as a dimer. Bioactivity was confirmed using a C2C12 alkaline phosphatase assay. rBMP-2 was radiolabeled with 99mTc, and its biodistribution and clearance were quantified after both intravenous (IV) and intraperitoneal (IP) injection. Fischer 344 rats bearing syngeneic R3230 breast tumors received a single intraperitoneal injection of rBMP-2 at a specified dose. Tumor microcalcification was quantified over time using micro-single photon emission computed tomography (SPECT) and microcomputed tomography (CT). rBMP-2 could be expressed in E. coli at high levels, isolated at >95% purity, and refolded to a bioactive dimer. Beta-phase half-life was 30.5 min after IV administration and 47.6 min after IP administration. Renal excretion was the primary mode of clearance. A single IP injection of ≥50 $\mu$g rBMP-2 when tumors were not yet palpable resulted in dose-dependent microcalcification in 8 of 8 R3230 tumors. No calcification was found in control tumors or in normal tissues and organs of animals injected with rBMP-2. Tumor calcification increased progressively between weeks 2 and 4 post-rBMP-2 injection. A single IP injection of rBMP-2 in rats bearing a syngeneic breast cancer will produce dose-dependent and time-dependent microcalcifications. This animal model lays the foundation for the development of novel diagnostic radiotracers for breast cancer. {\textcopyright} 2009 Springer Science+Business Media, LLC.

MR spectroscopy in translational neuroscience

A multislice gradient echo pulse sequence for CEST imaging

Chemical exchange-dependent saturation transfer and paramagnetic chemical exchange-dependent satu... more Chemical exchange-dependent saturation transfer and paramagnetic chemical exchange-dependent saturation transfer are agent-mediated contrast mechanisms that depend on saturating spins at the resonant frequency of the exchangeable protons on the agent, thereby indirectly saturating the bulk water. In general, longer saturating pulses produce stronger chemical and paramagnetic exchange-dependent saturation transfer effects, with returns diminishing for pulses longer than T1. This could make imaging slow, so one approach to chemical exchange-dependent saturation transfer imaging has been to follow a long, frequency-selective saturation period by a fast imaging method. A new approach is to insert a short frequency-selective saturation pulse before each spatially selective observation pulse in a standard, two-dimensional, gradient-echo pulse sequence. Being much less than T1 apart, the saturation pulses have a cumulative effect. Interleaved, multislice imaging is straightforward. Observation pulses directed at one slice did not produce observable, unintended chemical exchange-dependent saturation transfer effects in another slice. Pulse repetition time and signal-to noise ratio increase in the normal way as more slices are imaged simultaneously. {\textcopyright} 2009 Wiley-Liss, Inc.

Principal component analysis of dynamic contrast enhanced mri in human prostate cancer

Objectives: To develop and evaluate a fast, objective and standardized method for image processin... more Objectives: To develop and evaluate a fast, objective and standardized method for image processing of dynamic contrast enhanced MRI of the prostate based on principal component analysis (PCA). Materials and Methods:The study was approved by the institutional internal review board; signed informed consent was obtained. MRI of the prostate at 3 Tesla was performed in 21 patients with biopsy proven cancers before radical prostatectomy. Seven 3-dimensional gradient echo datesets, 2 pre and 5 post-gadopentetate dimeglumine injection (0.1 mmol/kg), were acquired within 10.5 minutes at high spatial resolution. PCA of dynamic intensity-scaled (IS) and enhancement-scaled (ES) datasets and analysis by the 3-time points (3TP) method were applied using the latter method for adjusting the PCA eigenvectors. Results: PCA of 7 IS datasets and 6 ES datasets yielded their corresponding eigenvectors and eigenvalues. The first IS-eigenvector captured the major part of the signal variance because of a signal change between the precontrast and the first postcontrast arising from the inhomogeneous surface coil reception profile. The next 2 IS-eigenvectors and the 2 dominant ES-eigenvectors captured signal changes because of tissue contrast-enhancement, whereas the remaining eigenvectors captured noise changes. These eigenvectors were adjusted by rotation to reach congruence with the wash-in and wash-out kinetic parameters defined according to the 3TP method. The IS and ES-eigenvectors and rotation angles were highly reproducible across patients enabling the calculation of a general rotated eigenvector base that served to rapidly and objectively calculate diagnostically relevant projection coefficient maps for new cases. We found for the a priori selected prostate cancer patients that the projection coefficients of the IS-2nd eigenvector provided a higher accuracy for detecting biopsy proven cancers (94% sensitivity, 67% specificity, 80% ppv, and 89% npv) than the projection coefficients of the ES-2nd rotated and non rotated eigenvectors. Conclusions: PCA adjusted to correlate with physiological parameters selects a dominant eigenvector, free of the inhomogeneous radio-frequency field reception-profile and noise-components. Projection coefficient maps of this eigenvector provide a fast, objective, and standardized means for visualizing prostate cancer. {\textcopyright} 2010 by Lippincott Williams & Wilkins.

Sodium MRI of a Human Transplanted Kidney

Rationale and Objectives: Sodium magnetic resonance imaging (MRI) of the kidneys has been used to... more Rationale and Objectives: Sodium magnetic resonance imaging (MRI) of the kidneys has been used to spatially map areas of sodium-concentrating activity and to quantify the corticomedullary sodium gradient in various physiologic and pathophysiologic conditions. In this case study, sodium MRI of a clinically well-functioning transplanted kidney was performed to determine whether its sodium gradient could be detected and quantified using this method. Materials and Methods: Sodium MRI was performed on a 3T scanner with a commercial rectangular sodium surface coil placed on the lower abdomen over the palpable transplanted kidney. A three-dimensional gradient echo sequence, modified for multinuclear imaging, was applied to acquire 23Na images. Results: Five main renal pyramids within the medulla were detected, and the corticomedullary sodium gradient was quantified in each renal pyramid by both region of interest-based and pixel-by-pixel analyses, resulting in a mean medulla/cortex signal-to-noise ratio of 1.8 ± 0.1 (n = 5) and a mean linear increase slope of 1.1 ± 0.1 relative arbitrary units per mm (n = 5). Conclusions: The feasibility and usability of 23Na MRI of a human renal allograft was demonstrated. Further studies are required to determine the clinical significance of this technique in the follow-up of patients after renal transplantation. {\textcopyright} 2009 AUR.

Enhanced multi-protocol analysis via intelligent supervised embedding (EMPrAvISE): Detecting prostate cancer on multi-parametric MRI

Currently, there is significant interest in developing methods for quantitative integration of mu... more Currently, there is significant interest in developing methods for quantitative integration of multi-parametric (structural, functional) imaging data with the objective of building automated meta-classifiers to improve disease detection, diagnosis, and prognosis. Such techniques are required to address the differences in dimensionalities and scales of individual protocols, while deriving an integrated multi-parametric data representation which best captures all disease-pertinent information available. In this paper, we present a scheme called Enhanced Multi-Protocol Analysis via Intelligent Supervised Embedding (EMPrAvISE); a powerful, generalizable framework applicable to a variety of domains for multi-parametric data representation and fusion. Our scheme utilizes an ensemble of embeddings (via dimensionality reduction, DR); thereby exploiting the variance amongst multiple uncorrelated embeddings in a manner similar to ensemble classifier schemes (e.g. Bagging, Boosting). We apply this framework to the problem of prostate cancer (CaP) detection on 12 3 Tesla pre-operative in vivo multi-parametric (T2-weighted, Dynamic Contrast Enhanced, and Diffusion-weighted) magnetic resonance imaging (MRI) studies, in turn comprising a total of 39 2D planar MR images. We first align the different imaging protocols via automated image registration, followed by quantification of image attributes from individual protocols. Multiple embeddings are generated from the resultant high-dimensional feature space which are then combined intelligently to yield a single stable solution. Our scheme is employed in conjunction with graph embedding (for DR) and probabilistic boosting trees (PBTs) to detect CaP on multi-parametric MRI. Finally, a probabilistic pairwise Markov Random Field algorithm is used to apply spatial constraints to the result of the PBT classifier, yielding a per-voxel classification of CaP presence. Per-voxel evaluation of detection results against ground truth for CaP extent on MRI (obtained by spatially registering pre-operative MRI with available whole-mount histological specimens) reveals that EMPrAvISE yields a statistically significant improvement (AUC=0.77) over classifiers constructed from individual protocols (AUC=0.62, 0.62, 0.65, for T2w, DCE, DWI respectively) as well as one trained using multi-parametric feature concatenation (AUC=0.67). {\textcopyright} 2011 SPIE.

The role of magnetic resonance imaging in prostate cancer imaging and staging

MRI of the prostate can be used to address several of the clinical issues associated with diagnos... more MRI of the prostate can be used to address several of the clinical issues associated with diagnosing and treating prostate cancer. We have found dynamic contrast enhanced MRI (DCEMRI) to be valuable tool in visualizing and characterizing malignancies. Our approach is based on the threetime point method (3TP), which is a simplified model based method for analyzing DCEMRI of the prostate. This method is a high-spatial, low temporal resolution approach. We have found that this approach can be combined with more conventional MRI methods to give highly accurate staging of prostate cancer. An unanticipated clinical benefit has been the ability to use DCEMRI to image men with elevated PSA and repeat negative biopsy. We have also used a model independent approach based on principal component analysis (PCA) to analyze the DCEMRI datasets. {\textcopyright} 2011 IEEE.

Empirical evaluation of bias field correction algorithms for computer-aided detection of prostate cancer on T2w MRI

In magnetic resonance imaging (MRI), intensity inhomogeneity refers to an acquisition artifact wh... more In magnetic resonance imaging (MRI), intensity inhomogeneity refers to an acquisition artifact which introduces a non-linear variation in the signal intensities within the image. Intensity inhomogeneity is known to significantly affect computerized analysis of MRI data (such as automated segmentation or classification procedures), hence requiring the application of bias field correction (BFC) algorithms to account for this artifact. Quantitative evaluation of BFC schemes is typically performed using generalized intensity-based measures (percent coefficient of variation, %CV) or information-theoretic measures (entropy). While some investigators have previously empirically compared BFC schemes in the context of different domains (using changes in %CV and entropy to quantify improvements), no consensus has emerged as to the best BFC scheme for any given application. The motivation for this work is that the choice of a BFC scheme for a given application should be dictated by application-specific measures rather than ad hoc measures such as entropy and %CV. In this paper, we have attempted to address the problem of determining an optimal BFC algorithm in the context of a computer-aided diagnosis (CAD) scheme for prostate cancer (CaP) detection from T2-weighted (T2w) MRI. One goal of this work is to identify a BFC algorithm that will maximize the CaP classification accuracy (measured in terms of the area under the ROC curve or AUC). A secondary aim of our work is to determine whether measures such as %CV and entropy are correlated with a classifier-based objective measure (AUC). Determining the presence or absence of these correlations is important to understand whether domain independent BFC performance measures such as %CV, entropy should be used to identify the optimal BFC scheme for any given application. In order to answer these questions, we quantitatively compared 3 different popular BFC algorithms on a cohort of 10 clinical 3 Tesla prostate T2w MRI datasets (comprising 39 2D MRI slices): N3, PABIC, and the method of Cohen et al. Results of BFC via each of the algorithms was evaluated in terms of %CV, entropy, as well as classifier AUC for CaP detection from T2w MRI. The CaP classifier was trained and evaluated on a per-pixel basis using annotations of CaP obtained via registration of T2w MRI and ex vivo whole-mount histology sections. Our results revealed that different BFC schemes resulted in a maximization of different performance measures, that is, the BFC scheme identified by minimization of %CV and entropy was not the one that maximized AUC as well. Moreover, existing BFC evaluation measures (%CV, entropy) did not correlate with AUC (application-based evaluation), but did correlate with each other, suggesting that domain-specific performance measures should be considered in making a decision regarding choice of appropriate BFC scheme. Our results also revealed that N3 provided the best correction of bias field artifacts in prostate MRI data, when the goal was to identify prostate cancer. {\textcopyright} 2011 SPIE.

Integrating an adaptive region-based appearance model with a landmark-free statistical shape model: Application to prostate MRI segmentation

In this paper we present a system for segmenting medical images using statistical shape models (S... more In this paper we present a system for segmenting medical images using statistical shape models (SSM's) which is landmark free, fully 3D, and accurate. To overcome the limitations associated with previous 3D landmark-based SSM's, our system creates a levelset-based SSM which uses the minimum distance from each voxel in the image to the object's surface to define a shape. Subsequently, an advanced statistical appearance model (SAM) is generated to model the object of interest. This SAM is based on a series of statistical texture features calculated from each image, modeled by a Gaussian Mixture Model. In order to segment the object of interest on a new image, a Bayesian classifier is first employed to pre-classify the image voxels as belonging to the foreground object of interest or the background. The result of the Bayesian classifier is then employed for optimally fitting the SSM so there is maximum agreement between the SAM and the SSM. The SAM is then able to adaptively learn the statistics of the textures of the foreground and background voxels on the new image. The fitting of the SSM, and the adaptive updating of the SAM is repeated until convergence. We have tested our system on 36 T2-w, 3.0 Tesla, in vivo, endorectal prostate images. The results showed that our system achieves a Dice similarity coefficient of.84±.04, with a median Dice value of.86, which is comparable (and in most cases superior) to other state of the art prostate segmentation systems. Further, unlike most other state of the art prostate segmentation schemes, our scheme is fully automated requiring no user intervention. {\textcopyright} 2011 Copyright Society of Photo-Optical Instrumentation Engineers (SPIE).

A structural-functional MRI-based disease atlas: Application to computer-aided-diagnosis of prostate cancer

Different imaging modalities or protocols of a single patient may convey different types of infor... more Different imaging modalities or protocols of a single patient may convey different types of information regarding a disease for the same anatomical organ/tissue. On the other hand, multi-modal/multi-protocol medical images from several different patients can also provide spatial statistics of the disease occurrence, which in turn can greatly aid in disease diagnosis and aid in improved, accurate biopsy and targeted treatment. It is therefore important to not only integrate medical images from multiple patients into a common coordinate frame (in the form of a population-based atlas), but also find the correlation between these multi-modal/multi-protocol data features and the disease spatial distribution in order to identify different quantitative structural and functional disease signatures. Most previous work on construction of anatomical atlases has focused on deriving a population-based atlas for the purpose of deriving the spatial statistics. Moreover, these models are typically derived from normal or healthy subjects, either explicitly or implicitly, where it is assumed that the inter-patient pathological variation is not large. These methods are not suitable for constructing a disease atlas, where significant differences between patients on account of disease related variations can be expected. In this paper, we present a novel framework for the construction of a multi-parametric MRI-based data-driven disease atlas consisting of multi-modal and multi-protocol data from across multiple patient studies. Our disease atlas contains 3 Tesla structural (T2) and functional (dynamic contrast enhanced (DCE)) prostate in vivo MRI with corresponding whole mount histology specimens obtained via radical prostatectomy. Our atlas construction framework comprises 3 distinct modules: (a) determination of disease spatial extent on the multi-protocol MR imagery for each patient, (b) construction of a multi-protocol MR imaging spatial atlas which captures the geographical proclivity of the disease, and (c) feature extraction and the construction of the data-driven multi-protocol MRI based prostate cancer atlas. The marriage of data driven and spatial atlases could serve as a useful tool for clinicians to identifying structural and functional imaging disease signatures so as to make better, more informed diagnoses. Each spatial location in this atlas can be associated with a high dimensional multi-attribute quantitative feature vector. Additionally, since the feature vectors are extracted from across multiple patient studies, each spatial location in the data-driven atlas can be characterized by a feature distribution (in turn characterized by a mean and standard deviation). Preliminary investigation in quantitatively correlating the disease signatures from across the spatial and data driven atlases suggests that our quantitative atlas framework could emerge as a powerful tool for discovering prostate cancer imaging signatures. {\textcopyright} 2010 Copyright SPIE - The International Society for Optical Engineering.

COLLINARUS: Collection of image-derived non-linear attributes for registration using splines

We present a new method for fully automatic non-rigid registration of multimodal imagery, includi... more We present a new method for fully automatic non-rigid registration of multimodal imagery, including structural and functional data, that utilizes multiple texutral feature images to drive an automated spline based non-linear image registration procedure. Multimodal image registration is significantly more complicated than registration of images from the same modality or protocol on account of difficulty in quantifying similarity between different structural and functional information, and also due to possible physical deformations resulting from the data acquisition process. The COFEMI technique for feature ensemble selection and combination has been previously demonstrated to improve rigid registration performance over intensity-based MI for images of dissimilar modalities with visible intensity artifacts. Hence, we present here the natural extension of feature ensembles for driving automated non-rigid image registration in our new technique termed Collection of Image-derived Non-linear Attributes for Registration Using Splines (COLLINARUS). Qualitative and quantitative evaluation of the COLLINARUS scheme is performed on several sets of real multimodal prostate images and synthetic multiprotocol brain images. Multimodal (histology and MRI) prostate image registration is performed for 6 clinical data sets comprising a total of 21 groups of in vivo structural (T2-w) MRI, functional dynamic contrast enhanced (DCE) MRI, and ex vivo WMH images with cancer present. Our method determines a non-linear transformation to align WMH with the high resolution in vivo T2-w MRI, followed by mapping of the histopathologic cancer extent onto the T2-w MRI. The cancer extent is then mapped from T2-w MRI onto DCE-MRI using the combined non-rigid and affine transformations determined by the registration. Evaluation of prostate registration is performed by comparison with the 3 time point (3TP) representation of functional DCE data, which provides an independent estimate of cancer extent. The set of synthetic multiprotocol images, acquired from the BrainWeb Simulated Brain Database, comprises 11 pairs of T1-w and proton density (PD) MRI of the brain. Following the application of a known warping to misalign the images, non-rigid registration was then performed to recover the original, correct alignment of each image pair. Quantitative evaluation of brain registration was performed by direct comparison of (1) the recovered deformation field to the applied field and (2) the original undeformed and recovered PD MRI. For each of the data sets, COLLINARUS is compared with the MI-driven counterpart of the B-spline technique. In each of the quantitative experiments, registration accuracy was found to be significantly (p < 0.05) for COLLINARUS compared with MI-driven B-spline registration. Over 11 slices, the mean absolute error in the deformation field recovered by COLLINARUS was found to be 0.8830 mm. {\textcopyright} 2009 Copyright SPIE - The International Society for Optical Engineering.

Integrating structural and functional imaging for computer assisted detection of prostate cancer on multi-protocol in vivo 3 tesla MRI

Screening and detection of prostate cancer (CaP) currently lacks an image-based protocol which is... more Screening and detection of prostate cancer (CaP) currently lacks an image-based protocol which is reflected in the high false negative rates currently associated with blinded sextant biopsies. Multi-protocol magnetic resonance imaging (MRI) offers high resolution functional and structural data about internal body structures (such as the prostate). In this paper we present a novel comprehensive computer-aided scheme for CaP detection from high resolution in vivo multi-protocol MRI by integrating functional and structural information obtained via dynamic-contrast enhanced (DCE) and T2-weighted (T2-w) MRI, respectively. Our scheme is fully-automated and comprises (a) prostate segmentation, (b) multimodal image registration, and (c) data representation and multi-classifier modules for information fusion. Following prostate boundary segmentation via an improved active shape model, the DCE/T2-w protocols and the T2-w/ex vivo histological prostatectomy specimens are brought into alignment via a deformable, multi-attribute registration scheme. T2-w/histology alignment allows for the mapping of true CaP extent onto the in vivo MRI, which is used for training and evaluation of a multi-protocol MRI CaP classifier. The meta-classifier used is a random forest constructed by bagging multiple decision tree classifiers, each trained individually on T2-w structural, textural and DCE functional attributes. 3-fold classifier cross validation was performed using a set of 18 images derived from 6 patient datasets on a per-pixel basis. Our results show that the results of CaP detection obtained from integration of T2-w structural textural data and DCE functional data (area under the ROC curve of 0.815) significantly outperforms detection based on either of the individual modalities (0.704 (T2-w) and 0.682 (DCE)). It was also found that a meta-classifier trained directly on integrated T2-w and DCE data (data-level integration) significantly outperformed a decision-level meta-classifier, constructed by combining the classifier outputs from the individual T2-w and DCE channels.{\textcopyright}2009 SPIE.

WERITAS - Weighted ensemble of regional image textures for ASM segmentation

In this paper we present WERITAS, which is based in part on the traditional Active Shape Model (A... more In this paper we present WERITAS, which is based in part on the traditional Active Shape Model (ASM) segmentation system. WERITAS generates multiple statistical texture features, and finds the optimal weighted average of those texture features by maximizing the correlation between the Euclidean distance to the ground truth and the Mahalanobis distance to the training data. The weighted average is used a multi-resolution segmentation system to more accurately detect the object border. A rigorous evaluation was performed on over 200 clinical images comprising of prostate images and breast images from 1.5 Tesla and 3 Tesla MRI machines via 6 distinct metrics. WERITAS was tested against a traditional multi-resolution ASM in addition to an ASM system which uses a plethora of random features to determine if the selection of features is improving the results rather than simply the use of multiple features. The results indicate that WERITAS outperforms all other methods to a high degree of statistical significance. For 1.5T prostate MRI images, the overlap from WERITAS is 83%, the overlap from the random features is 81%, and the overlap from the traditional ASM is only 66%. In addition, using 3T prostate MRI images, the overlap from WERITAS is 77%, the overlap from the random features is 54%, and the overlap from the traditional ASM is 59%, suggesting the usefulness of WERITAS. The only metrics in which WERITAS was outperformed did not hold any degree of statistical significance. WERITAS is a robust, efficient, and accurate segmentation system with a wide range of applications. {\textcopyright} 2009 Copyright SPIE - The International Society for Optical Engineering.

In vivo imaging of small animals with optical tomography and near infrared fluorescent probes

A developmental optical tomograph has been designed for imaging small animals in vivo using near ... more A developmental optical tomograph has been designed for imaging small animals in vivo using near infrared (NIR) fluorphores. The system employs epi-illumnation via a 450 W Xe arc lamp, filtered and collimated to illuminate a 10 cm square movable stage. Emission light is filtered then collected by a high-resolution, high quantum efficiency, cooled CCD camera. Stage movement and image acquisition are under the control of a personal computer running system integration and automation software. During an experiment, the anesthetized animal is secured to the stage and up to 200 projections can be acquired over 180° rotation. Angular sampling of the light distribution at a point on the surface is used to determine relative contributions from ballistic and diffuse photons. We have employed the system to investigate a number of applications of in-vivo fluorescent imaging. In dynamic studies, hepatic function has been visualized in nude mice following intravenous injection of indocyanine green (ICG) and cerebrospinal fluid flow as been measured by injection of ICG-lipoprotein conjugate in the subarachnoid space of the lumbar spine followed by dynamic imaging of the brain. Further applications in physiological imaging, cancer detection, and molecular imaging are under investigation in our laboratory.

Tumor localization and identification

To demonstrate the tissue differentiation potential of MR (magnetic resonance) imaging studies, p... more To demonstrate the tissue differentiation potential of MR (magnetic resonance) imaging studies, preliminary data were acquired on the distribution of proton spin-spin relaxation time, T2, in normal and malignant tissues in twenty patients with head and neck tumors. Malignant tissue generally has longer proton relaxation times than found in normal tissues. The T2 distributions within neck and neck tumors were both elevated and broader than found in normal issues. The regional distribution of the T2 values indicated that the maximum T2 values are near the tumor center and decreased in the MRI slices at the tumor periphery. It is concluded that the T2 distribution provides information for delineating the extent of abnormal tissue even without a complete understanding of the mechanism(s) leading to the elevated and broad T2 distribution within the tumor bed.

Practical strategies for chemical shift imaging on a human MR imager

Summary form only given. Issues associated with the design and operation of clinical chemical shi... more Summary form only given. Issues associated with the design and operation of clinical chemical shift imaging (CSI) protocols on a whole body scanner are discussed. Line volume CSI methods are compared to the echo offset, or Dixon, method. The potential sources of error for the Dixon method are examined. It is noted, however, that line volume CSI artifacts do not have the spatial resolution of conventional imaging, which is a strong argument in favor of the Dixon method.

A comprehensive segmentation, registration, and cancer detection scheme on 3 tesla in vivo prostate DCE-MRI

Recently, high resolution 3 Tesla (T) Dynamic Contrast-Enhanced MRI (DCE-MRI) of the prostate has... more Recently, high resolution 3 Tesla (T) Dynamic Contrast-Enhanced MRI (DCE-MRI) of the prostate has emerged as a promising modality for detecting prostate cancer (CaP). Computer-aided diagnosis (CAD) schemes for DCE-MRI data have thus far been primarily developed for breast cancer and typically involve model fitting of dynamic intensity changes as a function of contrast agent uptake by the lesion. Comparatively there is relatively little work in developing CAD schemes for prostate DCE-MRI. In this paper, we present a novel unsupervised detection scheme for CaP from 3 T DCE-MRI which comprises 3 distinct steps. First, a multi-attribute active shape model is used to automatically segment the prostate boundary from 3 T in vivo MR imagery. A robust multimodal registration scheme is then used to non-linearly align corresponding whole mount histological and DCE-MRI sections from prostatectomy specimens to determine the spatial extent of CaP. Non-linear dimensionality reduction schemes such as locally linear embedding (LLE) have been previously shown to be useful in projecting such high dimensional biomedical data into a lower dimensional subspace while preserving the non-linear geometry of the data manifold. DCE-MRI data is embedded via LLE and then classified via unsupervised consensus clustering to identify distinct classes. Quantitative evaluation on 21 histology-MRI slice pairs against registered CaP ground truth estimates yielded a maximum CaP detection accuracy of 77.20% while the popular three time point (3TP) scheme yielded an accuracy of 67.37%. {\textcopyright} 2008 Springer-Verlag Berlin Heidelberg.

Robert Lenkinski

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