Gregory S Karczmar

Hospital Vera Cruz, Conceição de Campinas, São Paulo, Brazil

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Publications (148)403.13 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim: To evaluate the feasibility of using therapeutic ultrasound as an alternative treatment option for organ-confined prostate cancer. Methods: In this study, a trans-urethral therapeutic ultrasound applicator in combination with 3T magnetic resonance imaging (MRI) guidance was used for real-time multi-planar MRI-based temperature monitoring and temperature feedback control of prostatic tissue thermal ablation in vivo. We evaluated the feasibility and safety of MRI-guided trans-urethral ultrasound to effectively and accurately ablate prostate tissue while minimizing the damage to surrounding tissues in eight canine prostates. MRI was used to plan sonications, monitor temperature changes during therapy, and to evaluate treatment outcome. Real-time temperature and thermal dose maps were calculated using the proton resonance frequency shift technique and were displayed as two-dimensional color-coded overlays on top of the anatomical images. After ultrasound treatment, an evaluation of the integrity of cavernosal nerves was performed during prostatectomy with a nerve stimulator that measured tumescence response quantitatively and indicated intact cavernous nerve functionality. Planned sonication volumes were visually correlated to MRI ablation volumes and corresponding histo-pathological sections after prostatectomy. Results: A total of 16 sonications were performed in 8 canines. MR images acquired before ultrasound treatment were used to localize the prostate and to prescribe sonication targets in all canines. Temperature elevations corresponded within 1 degree of the targeted sonication angle, as well as with the width and length of the active transducer elements. The ultrasound treatment procedures were automatically interrupted when the temperature in the target zone reached 56 °C. In all canines erectile responses were evaluated with a cavernous nerve stimulator post-treatment and showed a tumescence response after stimulation with an electric current. These results indicated intact cavernous nerve functionality. In all specimens, regions of thermal ablation were limited to areas within the prostate capsule and no damage was observed in periprostatic tissues. Additionally, a visual analysis of the ablation zones on contrast-enhanced MR images acquired post ultrasound treatment correlated excellent with the ablation zones on thermal dose maps. All of the ablation zones received a consensus score of 3 (excellent) for the location and size of the correlation between the histologic ablation zone and MRI based ablation zone. During the prostatectomy and histologic examination, no damage was noted in the bladder or rectum. Conclusion: Trans-urethral ultrasound treatment of the prostate with MRI guidance has potential to safely, reliably, and accurately ablate prostatic regions, while minimizing the morbidities associated with conventional whole-gland resection or therapy.
    No preview · Article · Jan 2016
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    ABSTRACT: Multiparametric magnetic resonance (MR) imaging combines anatomic and functional imaging techniques for evaluating the prostate and is increasingly being used in diagnosis and management of prostate cancer. A wide spectrum of anatomic and pathologic processes in the prostate may masquerade as prostate cancer, complicating the imaging interpretation. The histopathologic and imaging findings of these potential mimics are reviewed. These entities include the anterior fibromuscular stroma, surgical capsule, central zone, periprostatic vein, periprostatic lymph nodes, benign prostatic hyperplasia (BPH), atrophy, necrosis, calcification, hemorrhage, and prostatitis. An understanding of the prostate zonal anatomy is helpful in distinguishing the anatomic entities from prostate cancer. The anterior fibromuscular stroma, surgical capsule, and central zone are characteristic anatomic features of the prostate with associated low T2 signal intensity due to dense fibromuscular tissue or complex crowded glandular tissue. BPH, atrophy, necrosis, calcification, and hemorrhage all have characteristic features with one or more individual multiparametric MR imaging modalities. Prostatitis constitutes a heterogeneous group of infective and inflammatory conditions including acute and chronic bacterial prostatitis, infective and noninfective granulomatous prostatitis, and malacoplakia. These entities are associated with variable clinical manifestations and are characterized by the histologic hallmark of marked inflammatory cellular infiltration. In some cases, these entities are indistinguishable from prostate cancer at multiparametric MR imaging and may even exhibit extraprostatic extension and lymphadenopathy, mimicking locally advanced prostate cancer. It is important for the radiologists interpreting prostate MR images to be aware of these pitfalls for accurate interpretation. Online supplemental material is available for this article. (©)RSNA, 2015.
    No preview · Article · Nov 2015 · Radiographics
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    ABSTRACT: Measurements of arterial input function (AIF) can have large systematic errors at standard contrast agent doses in dynamic contrast enhanced MRI (DCE-MRI). We compared measured AIFs from low dose (AIFLD) and standard dose (AIFSD) contrast agent injections, as well as the AIF derived from a muscle reference tissue and artery (AIFref). Twenty-two prostate cancer patients underwent DCE-MRI. Data were acquired on a 3T scanner using an mDixon sequence. Gadobenate dimeglumine was injected twice, at doses of 0.015 and 0.085mmol/kg. Directly measured AIFs were fitted with empirical mathematical models (EMMs) and compared to the AIF derived from a muscle reference tissue (AIFref). EMMs accurately fitted the AIFs. The 1st and 2nd pass peaks were visualized in AIFLD, but not in AIFSD, thus the peak and shape of AIFSD could not be accurately measured directly. The average scaling factor between AIFSD and AIFLD in the washout phase was only 56% of the contrast dose ratio (~6:1). The shape and magnitude of AIFref closely approximated that of AIFLD after empirically determined dose-dependent normalization. This suggests that AIFref may be a good approximation of the local AIF.
    No preview · Article · Nov 2015 · Magnetic Resonance Imaging
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    ABSTRACT: Dynamic contrast-enhanced MRI (DCE-MRI) has become a standard component of multiparametric protocols for MRI examination of the prostate, and its use is incorporated into current guidelines for prostate MRI examination. Analysis of DCE-MRI data for the prostate is usually based on the distribution of gadolinium-based agents, such as gadodiamide, into two well-mixed compartments, and it assumes that gadodiamide does not enter into the glandular lumen. However, this assumption has not been directly tested. The purpose of this study was to use x-ray fluorescence microscopy (XFM) imaging in situ to measure the concentration of gadodiamide in the epithelia and lumens of the prostate of healthy mice after IV injection of the contrast agent. Six C57Bl6 male mice (age, 28 weeks) were sacrificed 10 minutes after IV injection of gadodiamide (0.13 mmol/kg), and three mice were sacrificed after saline injection. Prostate tissue samples obtained from each mouse were harvested and frozen; 7-μm-thick slices were sectioned for XFM imaging, and adjacent 5-μm-thick slices were sectioned for H and E staining. Elemental concentrations were determined from XFM images. A mean (± SD) baseline concentration of gadolinium of 0.01 ± 0.01 mM was determined from XFM measurements of prostatic tissue samples when no gadodiamide was administered, and it was used to determine the measurement error. When gadodiamide was added, the mean concentrations of gadolinium in the epithelia and lumens in 32 prostatic glands from six mice were 1.00 ± 0.13 and 0.36 ± 0.09 mM, respectively. Our data suggest that IV administration of gadodiamide results in uptake of contrast agent by the glandular lumens of the mouse prostate. We were able to quantitatively determine gadodiamide distributions in mouse prostatic epithelia and lumens.
    No preview · Article · Sep 2015 · American Journal of Roentgenology
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    ABSTRACT: BNip3 is a hypoxia-inducible protein that targets mitochondria for autophagosomal degradation. We report a novel tumor suppressor role for BNip3 in a clinically relevant mouse model of mammary tumorigenesis. BNip3 delays primary mammary tumor growth and progression by preventing the accumulation of dysfunctional mitochondria and resultant excess ROS production. In the absence of BNip3, mammary tumor cells are unable to reduce mitochondrial mass effectively and elevated mitochondrial ROS increases the expression of Hif-1α and Hif target genes, including those involved in glycolysis and angiogenesis-two processes that are also markedly increased in BNip3-null tumors. Glycolysis inhibition attenuates the growth of BNip3-null tumor cells, revealing an increased dependence on autophagy for survival. We also demonstrate that BNIP3 deletion can be used as a prognostic marker of tumor progression to metastasis in human triple-negative breast cancer (TNBC). These studies show that mitochondrial dysfunction-caused by defects in mitophagy-can promote the Warburg effect and tumor progression, and suggest better approaches to stratifying TNBC for treatment. © 2015 The Authors.
    Full-text · Article · Jul 2015 · EMBO Reports
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    ABSTRACT: Ex vivo MRI may aid in the evaluation of surgical specimens, and provide valuable information regarding the micro-anatomy of mammary/breast cancer. The use of ex vivo MRI to study mouse mammary cancer would be enhanced if there is a strong correlation between parameters derived from in vivo and ex vivo scans. Here, we report the correlation between apparent diffusion coefficient (ADC) and T2 values measured in vivo and ex vivo in mouse mammary glands with in situ cancers (mammary intraepithelial neoplasia (MIN)) and invasive cancers (those which spread outside the ducts into surrounding tissue). MRI experiments were performed on the Polyoma middle T oncoprotein breast cancer mouse model (n = 15) in a 9.4T scanner. For in vivo experiments, T2-weighted (T2W) images were acquired to identify abnormal regions, then ADC and T2 values were measured for nine selected slices. For ex vivo experiments, a midline incision was made along the spine, and then skin, glands, and tumors were gently peeled from the body. Tissue was fixed in formalin, placed around a mouse-sized sponge, and sutured together mimicking the geometry of the gland when attached to the mouse. The same pulse sequences used for in vivo experiments were repeated for ex vivo scans at room temperature. Regions of interest were manually traced on T2W images defining features that could be identified on in vivo and ex vivo images. The results demonstrate a strong positive correlations between in vivo and ex vivo invasive cancers for ADC (r = 0.89, p <0.0001) and T2 (r = 0.89, p <0.0001) values; and weak to moderate positive correlations between in vivo and ex vivo in situ cancers for ADC (r = 0.61, p <0.0001) and T2 (r = 0.79, p <0.0001) values. The average ex vivo ADC value was about 54% of the in vivo value; and the average ex vivo T2 was similar to the in vivo value for cancers. Although motion, fixation, and temperature differences affect ADC and T2, these results show a reliable relationship between ADC and T2 in vivo and ex vivo. As a result ex vivo images can provide valuable information with clinical and research applications.
    Preview · Article · Jul 2015 · PLoS ONE
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    ABSTRACT: MRI methods that accurately identify various stages of mouse mammary cancer could provide new knowledge that may have a direct impact on the management of breast cancer in patients. This research investigates whether we can accurately follow the progression from in situ to invasive cancer by the evaluation of in vivo and ex vivo MRI, and in comparison with histology as the gold standard for the diagnosis and staging of cancer. Six C3(1)SV40Tag virgin female mice, aged 12–16 weeks, were studied. At this age, these mice develop in situ cancer that resembles human ductal carcinoma in situ (DCIS). Fast spin-echo images of inguinal mammary glands were acquired at 9.4 T. After in vivo MRI, mice were sacrificed; inguinal mammary glands were excised and fixed in formalin for ex vivo MRI. Three-dimensional, volume-rendered, in vivo and ex vivo MR images were then correlated with histology. High-resolution ex vivo scans facilitated the comparison of in vivo scans with histology. The sizes of mammary cancers classified as in situ on the basis of histology ranged from 150 to 400 µm in largest diameter, and the average signal intensity relative to muscle was 1.40 ± 0.18 on T2-weighted images. Cancers classified as invasive on the basis of histology were >400 µm in largest diameter, and the average intensity relative to muscle on T2-weighted images was 2.34 ± 0.26. Using a cut-off of 400 µm in largest diameter to distinguish between in situ and invasive cancers, a T2-weighted signal intensity of at least 1.4 times that of muscle for in situ cancer, and at least 2.3 times that of muscle for invasive cancer, 96% of in situ and 100% of invasive cancers were correctly identified on in vivo MRI, using histology as the gold standard. Precise MRI–histology correlation demonstrates that MRI reliably detects early in situ cancer and differentiates in situ from invasive cancers in the SV40Tag mouse model of human breast cancer. Copyright
    No preview · Article · Jul 2015 · NMR in Biomedicine
  • William A. Weiss · Milica Medved · Gregory S. Karczmar · Maryellen L. Giger
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    ABSTRACT: Water resonance lineshapes observed in breast lesions imaged with high spectral and spatial resolution (HiSS) magnetic resonance imaging have been shown to contain diagnostically useful non-Lorentzian components. The purpose of this work is to update a previous method of breast lesion diagnosis by including phase-corrected absorption and dispersion spectra. This update includes information about the shape of the complex water resonance, which could improve the performance of a computer-aided diagnosis breast lesion classification scheme. The non-Lorentzian characteristics observed in complex breast lesion water resonance spectra are characterized by comparing a plot of the real versus imaginary components of the spectrum to that of a perfect complex Lorentzian spectrum, a "dispersion versus absorption" (DISPA) analysis technique. Distortion in the shape of the observed spectra indicates underlying physiologic changes, which have been shown to be correlated with malignancy. These spectral shape distortions in each lesion voxel are quantified by summing the deviations in DISPA radius from an ideal complex Lorentzian spectrum over all Fourier components, yielding a "total radial difference" (TRD). We limited our analysis to those voxels in each lesion with the largest TRD. The number of voxels considered was dependent on the lesion size. The TRD was used to classify voxels from 15 malignant and 8 benign lesions ([Formula: see text] voxels after voxel elimination). Lesion discrimination performance was evaluated for both the average and variance of the TRD within each lesion. Area under the receiver operating characteristic curve (ROC AUC) was used to assess both the voxel- and lesion-based discrimination methods in the task of distinguishing between malignant and benign. In the task of distinguishing voxels from malignant and benign lesions, TRD yielded an AUC of 0.89 (95% confidence interval [0.84, 0.91]). In the task of distinguishing malignant from benign lesions, the average radial difference yielded an AUC of 0.90 (95% confidence interval [0.71, 1.00]) and the variance in the radial difference yielded an AUC of 0.84 (95% confidence interval [0.61, 0.99]). We have applied the DISPA spectroscopic analysis method to HiSS data in order to identify and quantify voxels in breast lesions displaying non-Lorentzian characteristics. We have shown that a breast lesion classification scheme based on the absorption and dispersion spectral data obtained from HiSS acquisitions may outperform a similar classifier based on single off-peak component analysis, as it uses shape details of the entire spectrum instead of the magnitude at a single spectral location.
    No preview · Article · May 2015
  • Federico D. Pineda · Milica Medved · Xiaobing Fan · Gregory S. Karczmar
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    ABSTRACT: PurposeTo develop a method for mapping the B1 field using a reference signal from a tissue with known T1.Methods Flip angle correction factors were calculated in a region with a known “gold standard” T1; by comparing T1 values from a variable flip angle (VFA) sequence to the “gold standard” and correcting the value of the Ernst angle. The resulting partial B1 map was interpolated for all other regions. In the breast, fat is an ideal reference tissue because its T1 is spatially homogeneous and interpatient variability is low. This method was tested with scans of phantoms and patients (n = 4) on a 3T magnet. The performance of the method was evaluated by comparing the results of VFA T1 mapping with and without B1 correction to inversion recovery (IR) T1 maps.ResultsPhantom data determined that a linear inverse distance weighted interpolation accurately recovered the full B1 map. Use of interpolated maps to correct the VFA data in vivo, reduced the average difference in the T1 of parenchyma between VFA and IR results from 58% to 8%.Conclusion This proof-of-principle study showed that it is possible to recover a full and accurate map of the B1 field in the breast by using a reference tissue (fat) with an accurately measured T1. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.
    No preview · Article · May 2015 · Magnetic Resonance in Medicine

  • No preview · Article · Apr 2015 · Gastroenterology
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    ABSTRACT: The purpose of the study is to determine short-term reproducibility of apparent diffusion coefficient (ADC) estimated from diffusion-weighted magnetic resonance (DW-MR) imaging of the prostate. Fourteen patients with biopsy-proven prostate cancer were studied under an Institutional Review Board-approved protocol. Each patient underwent two, consecutive and identical DW-MR scans on a 3T system. ADC values were calculated from each scan and a deformable registration was performed to align corresponding images. The prostate and cancerous regions of interest (ROIs) were independently analyzed by two radiologists. The prostate volume was analyzed by sextant. Per-voxel absolute and relative percentage variations in ADC were compared between sextants. Per-voxel and per-ROI variations in ADC were calculated for cancerous ROIs. Per-voxel absolute difference in ADC in the prostate ranged from 0 to 1.60 × 10(-3) mm(2)/s (per-voxel relative difference 0% to 200%, mean 10.5%). Variation in ADC was largest in the posterior apex (0% to 200%, mean 11.6%). Difference in ADC variation between sextants was not statistically significant. Cancer ROIs' per-voxel variation in ADC ranged from 0.001 × 10(-3) to 0.841 × 10(-3) mm(2)/s (0% to 67.4%, mean 11.2%) and per-ROI variation ranged from 0 to 0.463 × 10(-3) mm(2)/s (mean 0.122 × 10(-3) mm(2)/s). Variation in ADC within the human prostate is reasonably small, and is on the order of 10%.
    No preview · Article · Mar 2015 · Abdominal Imaging
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    ABSTRACT: To compare DCE-MRI parameters from scans of breast lesions at 1.5 Tesla and 3 Tesla. Eleven patients underwent paired MRI examinations on both Philips 1.5T and 3T systems using a standard clinical fat-suppressed, T1-weighted DCE-MRI protocol, with 70-76 s temporal resolution. Signal intensity-versus-time curves were fit with an empirical mathematical model to obtain semi-quantitative measures of uptake and washout rates as well as time-to-peak enhancement (TTP). Maximum percent enhancement and signal enhancement ratio (SER) were also measured for each lesion. Percent differences between parameters measured at the two field strengths were compared. TTP and SER parameters measured at 1.5T and 3T were similar; with mean absolute differences of 19% and 22% respectively. Maximum percent signal enhancement was significantly higher at 3T than at 1.5T (p=0.006). Qualitative assessment showed that image quality was significantly higher at 3T (p=0.005). Our results suggest that TTP and SER are more robust to field strength change than other measured kinetic parameters and therefore measurements of these parameters can be more easily standardized than measurements of other parameters derived from DCE-MRI. Semi-quantitative measures of overall kinetic curve shape showed higher reproducibility than discrete classification of kinetic curve early and delayed phases in a majority of the cases studied. Advances in knowledge: Qualitative measures of curve shape are not consistent across field strength even when acquisition parameters are standardized. Quantitative measures of overall kinetic curve shape, in contrast, have higher reproducibility.
    Full-text · Article · Mar 2015 · The British journal of radiology
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    ABSTRACT: Contrast agents that specifically enhance cancers on magnetic resonance imaging (MRI) will allow earlier detection. Vanadium-based chelates (VCs) selectively enhance rodent cancers on MRI, suggesting selective uptake of VCs by cancers. Here we report x-ray fluorescence microscopy (XFM) of VC uptake by murine colon cancer. Colonic tumors in mice treated with azoxymethane/dextran sulfate sodium were identified by MRI. Then a gadolinium-based contrast agent and a VC were injected intravenously; mice were sacrificed and colons sectioned. VC distribution was sampled at 120 minutes after injection to evaluate the long-term accumulation. Gadolinium distribution was sampled at 10 minutes after injection due to its rapid washout. XFM was performed on 72 regions of normal and cancerous colon from five normal mice and four cancer-bearing mice. XFM showed that all gadolinium was extracellular, with similar concentrations in colon cancers and normal colon. In contrast, the average VC concentration was twofold higher in cancers versus normal tissue (p < .002). Cancers also contained numerous "hot spots" with intracellular VC concentrations sixfold higher than the concentration in normal colon (p < .0001). No hot spots were detected in normal colon. This is the first direct demonstration that VCs selectively accumulate in cancer cells and thus may improve cancer detection.
    No preview · Article · Mar 2015 · Molecular Imaging
  • Sean Foxley · Miriam Domowicz · Gregory S Karczmar · Nancy Schwartz
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    ABSTRACT: Purpose: Widely used MRI methods show brain morphology both in vivo and ex vivo at very high resolution. Many of these methods (e.g., T 2 *-weighted imaging, phase-sensitive imaging, or susceptibility-weighted imaging) are sensitive to local magnetic susceptibility gradients produced by subtle variations in tissue composition. However, the spectral resolution of commonly used methods is limited to maintain reasonable run-time combined with very high spatial resolution. Here, the authors report on data acquisition at increased spectral resolution, with 3-dimensional high spectral and spatial resolution MRI, in order to analyze subtle variations in water proton resonance frequency and lineshape that reflect local anatomy. The resulting information compliments previous studies based on T 2 * and resonance frequency.
    No preview · Article · Mar 2015 · Medical Physics
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    ABSTRACT: IntroductionPrevious work from this laboratory demonstrated that magnetic resonance imaging (MRI) detects early murine mammary cancers and reliably differentiates between in situ and invasive cancer. Based on this previous work, we used MRI to study initiation and progression of murine mammary cancer, and monitor the transition from the in situ to the invasive phase.Methods In total, seven female C3(1) SV40 Tag mice were imaged every two weeks between the ages of 8 to 23 weeks. Lesions were identified on T2-weighted images acquired at 9.4 Tesla based on their morphology and growth rates. Lesions were traced manually on MR images of each slice. Volume of each lesion was calculated by adding measurements from individual slices. Plots of lesion volume versus time were analyzed to obtain the specific growth rate (SGR). The time at which in situ cancers (referred to as `mammary intraepithelial neoplasia (MIN)¿) and invasive cancers were first detected; and the time at which in situ cancers became invasive were recorded.ResultsA total of 121 cancers (14 to 25 per mouse) were identified in seven mice. On average the MIN lesions and invasive cancers were first detected when mice were 13 and 18 weeks old, respectively. The average SGR was 0.47¿±¿0.18 week-1 and there were no differences (P >0.05) between mice. 74 lesions had significantly different tumor growth rates before and after ~17 weeks of age; with average doubling times (DT) of 1.88 and 1.27 weeks, respectively. The average DT was significantly shorter (P <0.0001) after 17 weeks of age. However, the DT for some cancers was longer after 17 weeks of age, and about 10% of the cancers detected did not progress to the invasive stage.ConclusionsA wide range of growth rates were observed in SV40 mammary cancers. Most cancers transitioned to a more aggressive phenotype at approximately 17 weeks of age, but some cancers became less aggressive. The results suggest that the biology of mammary cancers is extremely heterogeneous. This work is a first step towards use of MRI to improve understanding of factors that control and/or signal the development of aggressive breast cancer.
    Full-text · Article · Dec 2014 · Breast cancer research: BCR
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    ABSTRACT: This pilot study compared the detectability of internal thermal marks produced with MRI-guided focused ultrasound (MRgFUS) on MRI, computed tomography (CT), ultrasonography (US), and color images from digital scanning. Internal marks made using MRgFUS could potentially guide surgical, biopsy or radiotherapy procedures. New Zealand White rabbits (n = 6) thigh muscle were marked using a Philips MRgFUS system. Before and after sonications, rabbits were imaged using T1- and T2-weighted MRI. Then rabbits were sacrificed and imaging was performed using CT and US. After surgical excision specimens were scanned for color conspicuity analysis. Images were read by a radiologist and quantitative analysis of signal intensity was calculated for marks and normal muscle. Of a total of 19 excised marks, approximately 79%, 63%, and 62% were visible on MRI, CT, and US, respectively. The average maximum temperature elevation in the marks during MRgFUS was 39.7 ± 10.1 °C, and average dose diameter (i.e., the diameter of the area that achieved a thermal dose greater than 240 cumulative equivalent minutes at 43 °C) of the mark at the focal plane was 7.3 ± 2.1 mm. On MRI the average normalized signal intensities were significantly higher in marks compared to normal muscle (p < 0.05). On CT, the marked regions were approximately 10 HU lower than normal muscle (p < 0.05). The results demonstrate that MRgFUS can be used to create internal marks that are visible on MRI, CT and US.
    No preview · Article · Dec 2014 · Physica Medica
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    ABSTRACT: Purpose: We previously showed that EGF receptor (EGFR) promotes tumorigenesis in the azoxymethane/dextran sulfate sodium (AOM/DSS) model, whereas vitamin D suppresses tumorigenesis. EGFR-vitamin D receptor (VDR) interactions, however, are incompletely understood. Vitamin D inhibits the renin-angiotensin system (RAS), whereas RAS can activate EGFR. We aimed to elucidate EGFR-VDR cross-talk in colorectal carcinogenesis. Experimental design: To examine VDR-RAS interactions, we treated Vdr(+/+) and Vdr(-/-) mice with AOM/DSS. Effects of VDR on RAS and EGFR were examined by Western blotting, immunostaining, and real-time PCR. We also examined the effect of vitamin D3 on colonic RAS in Vdr(+/+) mice. EGFR regulation of VDR was examined in hypomorphic Egfr(Waved2) (Wa2) and Egfr(wild-type) mice. Angiotensin II (Ang II)-induced EGFR activation was studied in cell culture. Results: Vdr deletion significantly increased tumorigenesis, activated EGFR and β-catenin signaling, and increased colonic RAS components, including renin and angiotensin II. Dietary VD3 supplementation suppressed colonic renin. Renin was increased in human colon cancers. In studies in vitro, Ang II activated EGFR and stimulated colon cancer cell proliferation by an EGFR-mediated mechanism. Ang II also activated macrophages and colonic fibroblasts. Compared with tumors from Egfr(Waved2) mice, tumors from Egfr(wild-type) mice showed upregulated Snail1, a suppressor of VDR, and downregulated VDR. Conclusions: VDR suppresses the colonic RAS cascade, limits EGFR signals, and inhibits colitis-associated tumorigenesis, whereas EGFR increases Snail1 and downregulates VDR in colonic tumors. Taken together, these results uncover a RAS-dependent mechanism mediating EGFR and VDR cross-talk in colon cancer.
    Full-text · Article · Sep 2014 · Clinical Cancer Research
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    ABSTRACT: The purpose of this study was to use high resolution 3D MRI to study mouse mammary gland ductal architecture based on intra-ductal injection of contrast agents. Female FVB/N mice age 12–20 weeks (n = 12), were used in this study. A 34G, 45° tip Hamilton needle with a 25uL Hamilton syringe was inserted into the tip of the nipple. Approximately 20–25uL of a Gadodiamide/Trypan blue/saline solution was injected slowly over one minute into the nipple and duct. To prevent washout of contrast media from ducts due to perfusion, and maximize the conspicuity of ducts on MRI, mice were sacrificed one minute after injection. High resolution 3D T1-weighted images were acquired on a 9.4 T Bruker scanner after sacrifice to eliminate motion artifacts and reduce contrast media leakage from ducts. Trypan blue staining was well distributed throughout the ductal tree. MRI showed the mammary gland ductal structure clearly. In spoiled gradient echo T1-weighted images, the signal-to-noise ratio of regions identified as enhancing mammary ducts following contrast injection was significantly higher than that of muscle (p < 0.02) and significantly higher than that of contralateral mammary ducts that were not injected with contrast media (p < 0.0001). The methods described here could be adapted for injection of specialized contrast agents to measure metabolism or target receptors in normal ducts and ducts with in situ cancers.
    No preview · Article · Aug 2014 · Magnetic Resonance Imaging
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    ABSTRACT: Objective: The purpose of this study was to evaluate the effect of increasing the spatial resolution of the prostate DWI protocol on image quality and lesion conspicuity. Subjects and methods: Twenty-nine patients with biopsy-proven prostate cancer undergoing MRI examinations were imaged with two diffusion-weighted imaging (DWI) protocols: current standard clinical protocol (6.7 mm(3) voxels) and a new high-resolution protocol (3.1 mm(3) voxels). Diffusion-weighted images were independently and subjectively scored on lesion conspicuity, internal architecture definition, and overall image quality by two radiologists. Average apparent diffusion coefficient (ADC) values were measured in normal tissue and cancerous lesions on both sequences. Reader scores and ADC and contrast values were compared between the two protocols. Cancer ADC values were correlated with Gleason scores. Results: The signal-to-noise ratio of the new high-resolution DWI protocol was 40% lower than that of the standard protocol. The reader scores were higher by 0.73 (range, 0.29-1.16) grades, or 19% (range, 7-32%), on average, for the new protocol, indicating better image quality. The average ADC values were 8% higher with the new protocol, with ADC contrast values between cancer and normal prostate unchanged. There was marginally significant correlation of cancer ADC values with Gleason scores (p = 0.05, r ≈ -0.36). Conclusion: We showed that for DWI of the prostate at 3-7 mm(3) voxel sizes the benefits of higher spatial resolution outweigh the effects of reduced signal-to-noise and contrast-to-noise ratios, potentially improving the sensitivity to small or sparse prostate cancers. Radiologists can consider using higher-spatial-resolution DWI sequences in their practices.
    No preview · Article · Jul 2014 · American Journal of Roentgenology
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    ABSTRACT: Evaluate qualitative dynamic contrast-enhanced magnetic resonance imaging (MRI) characteristics of normal central zone based on recently described central zone MRI features. Institutional review board-approved, Health Insurance Portability and Accountability Act compliant study, 59 patients with prostate cancer, histopathology proven to not involve central zone or prostate base, underwent endorectal MRI before prostatectomy. Two readers independently reviewed T2-weighted images and apparent diffusion coefficient (ADC) maps identifying normal central zone based on low signal intensity and location. Next, two readers drew bilateral central zone regions of interest on dynamic contrast-enhanced magnetic resonance images in consensus and independently recorded enhancement curve types as type 1 (progressive), type 2 (plateau), and type 3 (wash-out). Identification rates of normal central zone and enhancement curve type were recorded and compared for each reviewer. The institutional review board waiver was approved and granted 05/2010. Central zone identified in 92%-93% of patients on T2-weighted images and 78%-88% on ADC maps without significant difference between identification rates (P = .63 and P = .15 and inter-reader agreement (κ) is 0.64 and 0.29, for T2-weighted images and ADC maps, respectively). All central zones were rated either curve type 1 or curve type 2 by both radiologists. No statistically significant difference between the two radiologists (P = .19) and inter-reader agreement was κ = 0.37. Normal central zone demonstrates either type 1 (progressive) or type 2 (plateau) enhancement curves on dynamic contrast-enhanced MRI that can be potentially useful to differentiate central zone from prostate cancer that classically demonstrates a type 3 (wash-out) enhancement curve.
    No preview · Article · May 2014 · Academic radiology

Publication Stats

3k Citations
403.13 Total Impact Points

Institutions

  • 2015
    • Hospital Vera Cruz
      Conceição de Campinas, São Paulo, Brazil
    • University of Illinois at Chicago
      • Department of Radiology (Chicago)
      Chicago, Illinois, United States
  • 1995-2015
    • University of Chicago
      • Department of Radiology
      Chicago, Illinois, United States
  • 1996-2014
    • The University of Chicago Medical Center
      • Department of Radiology
      Chicago, Illinois, United States