John Kurhanewicz

University of California, San Francisco, San Francisco, California, United States

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Publications (270)845.65 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Osteoarthritis (OA) is a common multifactorial and heterogeneous degenerative joint disease, and biochemical changes in cartilage matrix occur during the early stages of OA before morphological changes occur. Thus, it is desired to measure regional biochemical changes in the joint. High-resolution magic angle spinning (HRMAS) NMR spectroscopy is a powerful method of observing cartilaginous biochemical changes ex vivo, including the concentrations of alanine and N-acetyl, which are markers of collagen and total proteoglycan content, respectively. Previous studies have observed significant changes in chondrocyte metabolism of OA cartilage via the altered gene expression profiles of ACAN, COL2A1 and MMP13, which encode aggrecan, type II collagen and matrix metalloproteinase 13 (a protein crucial in the degradation of type II collagen), respectively. Employing HRMAS, this study aimed to elucidate potential relationships between N-acetyl and/or alanine and ACAN, COL2A1 and/or MMP13 expression profiles in OA cartilage. Thirty samples from the condyles of five subjects undergoing total knee arthroplasty to treat OA were collected. HRMAS spectra were obtained at 11.7 T for each sample. RNA was subsequently extracted to determine gene expression profiles. A significant negative correlation between N-acetyl metabolite and ACAN gene expression levels was observed; this provides further evidence of N-acetyl as a biomarker of cartilage degeneration. The alanine doublet was distinguished in the spectra of 15 of the 30 specimens of this study. Alanine can only be detected with HRMAS NMR spectroscopy when the collagen framework has been degraded such that alanine is sufficiently mobile to form a distinguished peak in the spectrum. Thus, HRMAS NMR spectroscopy may provide unique localized measurements of collagenous degeneration in OA cartilage. The identification of imaging markers that could provide a link between OA pathology and chondrocyte metabolism will facilitate the development of more sensitive diagnostic techniques and will improve methods of monitoring treatment for patients suffering from OA. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    NMR in Biomedicine 03/2015; 28(5). DOI:10.1002/nbm.3285 · 3.56 Impact Factor
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    ABSTRACT: To demonstrate simultaneous hyperpolarization and imaging of three (13) C-labeled perfusion MRI contrast agents with dissimilar molecular structures ([(13) C]urea, [(13) C]hydroxymethyl cyclopropane, and [(13) C]t-butanol) and correspondingly variable chemical shifts and physiological characteristics, and to exploit their varying diffusibility for simultaneous measurement of vascular permeability and perfusion in initial preclinical studies. Rapid and efficient dynamic multislice imaging was enabled by a novel pulse sequence incorporating balanced steady state free precession excitation and spectral-spatial readout by multiband frequency encoding, designed for the wide, regular spectral separation of these compounds. We exploited the varying bilayer permeability of these tracers to quantify vascular permeability and perfusion parameters simultaneously, using perfusion modeling methods that were investigated in simulations. "Tripolarized" perfusion MRI methods were applied to initial preclinical studies with differential conditions of vascular permeability, in normal mouse tissues and advanced transgenic mouse prostate tumors. Dynamic imaging revealed clear differences among the individual tracer distributions. Computed permeability maps demonstrated differential permeability of brain tissue among the tracers, and tumor perfusion and permeability were both elevated over values expected for normal tissues. Tripolarized perfusion MRI provides new molecular imaging measures for specifically monitoring permeability, perfusion, and transport simultaneously in vivo. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 12/2014; 72(6). DOI:10.1002/mrm.25071 · 3.40 Impact Factor
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    ABSTRACT: External beam radiation treatment (EBRT) is a popular method for treating prostate cancer (CaP) involving destroying tumor cells with ionizing radiation. Following EBRT, biochemical failure has been linked with disease recurrence. However, there is a need for methods for evaluating early treatment related changes to allow for an early intervention in case of incomplete disease response. One method for looking at treatment evaluation is to detect changes in MRI markers on a voxel-by-voxel basis following treatment. Changes in MRI markers may be correlated with disease recurrence and complete or partial response. In order to facilitate voxel-by-voxel imaging related treatment changes, and also to evaluate morphologic changes in the gland post treatment, the pre- and post-radiated MRI must first be brought into spatial alignment via image registration. However, EBRT induces changes in the prostate volume and distortion to the internal anatomy of the prostate following radiation treatment. The internal substructures of the prostate, the central gland (CG) and peripheral zone (PZ), may respond to radiation differently, and their resulting shapes may change drastically. Biomechanical models of the prostate that have been previously proposed tend to focus on how external forces affect the surface of the prostate (not the internals), and assume that the prostate is a volume-preserving entity. In this work we present DoCD, a biomechanical model for automatically registering pre-, post-EBRT MRI with the aim of expressly modeling the (1) changes in volume, and (2) changes to the CG and PZ. DoCD was applied to a cohort of 30 patients and achieved a root mean square error of 2.994 mm, which was statistically significantly better a traditional biomechanical model which did not consider changes to the internal anatomy of the prostate (mean of 5.071 mm).
    Neurocomputing 11/2014; 144:3–12. DOI:10.1016/j.neucom.2014.01.058 · 2.01 Impact Factor
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    ABSTRACT: Oxidative stress has been proposed to be a unifying cause for diabetic nephropathy, and a target for novel therapies. Here we apply a new endogenous redox sensor, hyperpolarized (HP) (13)C dehydroascorbate (DHA), in conjunction with magnetic resonance imaging to noninvasively interrogate the renal redox capacity in a mouse diabetes model. The diabetic mice demonstrate early decrease in renal redox capacity, as shown by the lower in vivo HP (13)C DHA reduction to the antioxidant Vitamin C, prior to histological evidence of nephropathy. This correlates to lower tissue reduced glutathione (GSH) concentration and higher NADPH Oxidase 4 (Nox4) expression, consistent with increased superoxide generation and oxidative stress. Angiotensin converting enzyme inhibition restores the HP (13)C DHA reduction to Vitamin C with concomitant normalization of GSH concentration and Nox4 expression in the diabetic mice. HP (13)C DHA enables rapid in vivo assessment of altered redox capacity in diabetic renal injury and following successful treatment.
    Diabetes 09/2014; DOI:10.2337/db13-1829 · 8.47 Impact Factor
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    ABSTRACT: PurposeHyperpolarized 13C magnetic resonance allows for the study of real-time metabolism in vivo, including significant hyperpolarized 13C lactate production in many tumors. Other studies have shown that aggressive and highly metastatic tumors rapidly transport lactate out of cells. Thus, the ability to not only measure the production of hyperpolarized 13C lactate but also understand its compartmentalization using diffusion-weighted MR will provide unique information for improved tumor characterization.Methods We used a bipolar, pulsed-gradient, double spin echo imaging sequence to rapidly generate diffusion-weighted images of hyperpolarized 13C metabolites. Our methodology included a simultaneously acquired B1 map to improve apparent diffusion coefficient (ADC) accuracy and a diffusion-compensated variable flip angle scheme to improve ADC precision.ResultsWe validated this sequence and methodology in hyperpolarized 13C phantoms. Next, we generated ADC maps of several hyperpolarized 13C metabolites in a normal rat, rat brain tumor, and prostate cancer mouse model using both preclinical and clinical trial-ready hardware.ConclusionADC maps of hyperpolarized 13C metabolites provide information about the localization of these molecules in the tissue microenvironment. The methodology presented here allows for further studies to investigate ADC changes due to disease state that may provide unique information about cancer aggressiveness and metastatic potential. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 09/2014; DOI:10.1002/mrm.25422 · 3.40 Impact Factor
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    ABSTRACT: The purpose of this study is to determine if the severity of visually-assessed image distortion is less in prostate MR apparent diffusion coefficient (ADC) maps generated from a reduced-field-of-view (rFOV) diffusion-weighted-imaging (DWI) technique than from a conventional DWI sequence (CONV) and to determine if the rFOV ADC contrast between untreated tumors and healthy-appearing tissue within subjects is as high as or better than that of the CONV sequence. Fifty patients underwent a 3 T prostate MRI with phased-array and fluid-filled endorectal coils. CONV and rFOV sequences, utilizing a 2D, echo-planar, rectangularly-selective RF pulse, were acquired using b = 600, 0 s/mm2. Distortion was visually scored 0–4 by three independent observers. Distortion scores were significantly lower with the rFOV sequence (p < 0.012, Wilcoxon Signed-Rank Test, n = 50). The difference in distortion score did not differ significantly among observers (p = 0.99, Kruskal-Wallis Rank Sum Test). For seventeen untreated patients, regions of interest to calculate contrast were selected on radiologist-identified tumor regions and healthy-appearing contralateral tissue. The rFOV sequence afforded significantly higher ADC contrast between untreated tumor and healthy tissue (44.0% versus 35.9%, p < 0.0012, paired t-test, n = 17). The rFOV sequence yielded significantly decreased rectal susceptibility artifact and provided significantly higher contrast between tumor and healthy tissue.
    Magnetic Resonance Imaging 09/2014; DOI:10.1016/j.mri.2014.08.040 · 2.02 Impact Factor
  • David M Wilson, John Kurhanewicz
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    ABSTRACT: Hyperpolarization using dissolution dynamic nuclear polarization has emerged as a versatile method to dramatically improve the MR signal of low-sensitivity nuclei. This technique facilitates the study of real-time metabolism in vitro and in vivo using (13)C-enriched substrates and has been applied to numerous models of human disease. In particular, several mechanisms underlying prostate cancer have been interrogated using hyperpolarized (13)C MR spectroscopy. This review highlights key metabolic shifts seen in prostate cancer, their study by hyperpolarized (13)C MR spectroscopy, and the development of new platforms for metabolic study.
    Journal of Nuclear Medicine 08/2014; 55(10). DOI:10.2967/jnumed.114.141705 · 5.56 Impact Factor
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    ABSTRACT: Purpose: To investigate the potential clinical utility of endorectal MRI-guided biopsy in patients with known or suspected prostate cancer. Materials and Methods: We prospectively recruited 24 men with known or suspected prostate cancer in whom MRI-guided biopsy was clinically requested after multiparametric endorectal MRI showed one or more appropriate targets. One to six 18-gauge biopsy cores were obtained from each patient. Transrectal ultrasound guided biopsy results and post MRI-guided biopsy complications were also recorded. Results: MRI-guided biopsy was positive in 5 of 7 patients with suspected prostate cancer (including 2 of 4 with prior negative ultrasound-guided biopsies), in 8 of 12 with known untreated prostate cancer (including 5 where MRI-guided biopsy demonstrated a higher Gleason score than ultrasound guided biopsy results), and in 3 of 5 with treated cancer. MRI-guided biopsies had a significantly higher maximum percentage of cancer in positive cores when compared with ultrasound guided biopsy (mean of 37 +/- 8% versus 13 +/- 4%; P = 0.01). No serious postbiopsy complications occurred. Conclusion: Our preliminary experience suggests endorectal MRI-guided biopsy may safely contribute to the management of patients with known or suspected prostate cancer by making a new diagnosis of malignancy, upgrading previously diagnosed disease, or diagnosing local recurrence.
    Journal of Magnetic Resonance Imaging 08/2014; 40(2). DOI:10.1002/jmri.24383 · 2.79 Impact Factor
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    ABSTRACT: Organic cation transporter 1, OCT1 (SLC22A1), is the major hepatic uptake transporter for metformin, the most prescribed antidiabetic drug. However, its endogenous role is poorly understood. Here we show that similar to metformin treatment, loss of Oct1 caused an increase in the ratio of AMP to ATP, activated the energy sensor AMP-activated kinase (AMPK), and substantially reduced triglyceride (TG) levels in livers from healthy and leptin-deficient mice. Conversely, livers of human OCT1 transgenic mice fed high-fat diets were enlarged with high TG levels. Metabolomic and isotopic uptake methods identified thiamine as a principal endogenous substrate of OCT1. Thiamine deficiency enhanced the phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase. Metformin and the biguanide analog, phenformin, competitively inhibited OCT1-mediated thiamine uptake. Acute administration of metformin to wild-type mice reduced intestinal accumulation of thiamine. These findings suggest that OCT1 plays a role in hepatic steatosis through modulation of energy status. The studies implicate OCT1 as well as metformin in thiamine disposition, suggesting an intriguing and parallel mechanism for metformin and its major hepatic transporter in metabolic function.
    Proceedings of the National Academy of Sciences 06/2014; 111(27). DOI:10.1073/pnas.1314939111 · 9.81 Impact Factor
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    ABSTRACT: To evaluate a semiautomatic software-based method of registering in vivo prostate MR images to digital histopathology images using two approaches: (i) in which the prostates were molded to simulate distortion due to the endorectal imaging coil before fixation, and (ii) in which the prostates were not molded. T2-weighted MR images and digitized whole-mount histopathology images were acquired for 26 patients with biopsy-confirmed prostate cancer who underwent radical prostatectomy. Ten excised prostates were molded before fixation. A semiautomatic method was used to align MR images to histopathology. Percent overlap between MR and histopathology images, as well as distances between corresponding anatomical landmarks were calculated and used to evaluate the registration technique for molded and unmolded cases. The software successfully morphed histology-based prostate images into corresponding MR images. Percent overlap improved from 80.4 ± 5.8% before morphing to 99.7 ± 0.62% post morphing. Molded prostates had a smaller distance between landmarks (1.91 ± 0.75 mm) versus unmolded (2.34 ± 0.68 mm), P < 0.08. Molding a prostate before fixation provided a better alignment of internal structures within the prostate, but this did not reach statistical significance. Software-based morphing allowed for nearly complete overlap between the pathology slides and the MR images.J. Magn. Reson. Imaging 2013;00:000-000. © 2013 Wiley Periodicals, Inc.
    Journal of Magnetic Resonance Imaging 05/2014; 39(5). DOI:10.1002/jmri.24287 · 2.79 Impact Factor
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    ABSTRACT: To determine the ability of multiparametric MR imaging to predict disease progression in patients with prostate cancer managed by active surveillance. Sixty-four men with biopsy-proven prostate cancer managed by active surveillance were included in this HIPPA compliant, IRB approved study. We reviewed baseline MR imaging scans for the presence of a suspicious findings on T2-weighted imaging, MR spectroscopic imaging (MRSI), and diffusion-weighted MR imaging (DWI). The Gleason grades at subsequent biopsy were recorded. A Cox proportional hazard model was used to determine the predictive value of MR imaging for Gleason grades, and the model performance was described using Harrell's C concordance statistic and 95% confidence intervals (CIs). The Cox model that incorporated T2-weighted MR imaging, DWI, and MRSI showed that only T2-weighted MR imaging and DWI are independent predictors of biopsy upgrade (T2; HR = 2.46; 95% CI 1.36-4.46; P = 0.003-diffusion; HR = 2.76; 95% CI 1.13-6.71; P = 0.03; c statistic = 67.7%; 95% CI 61.1-74.3). There was an increasing rate of Gleason score upgrade with a greater number of concordant findings on multiple MR sequences (HR = 2.49; 95% CI 1.72-3.62; P < 0.001). Abnormal results on multiparametric prostate MRI confer an increased risk for Gleason score upgrade at subsequent biopsy in men with localized prostate cancer managed by active surveillance. These results may be of help in appropriately selecting candidates for active surveillance.
    Abdominal Imaging 04/2014; 39(5). DOI:10.1007/s00261-014-0136-7 · 1.73 Impact Factor
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    ABSTRACT: In this study we explore the ability of a novel machine learning approach, in conjunction with computer-extracted features describing prostate cancer morphology on pre-treatment MRI, to predict whether a patient will develop biochemical recurrence within ten years of radiation therapy. Biochemical recurrence, which is characterized by a rise in serum prostate-specific antigen (PSA) of at least 2 ng/mL above the nadir PSA, is associated with increased risk of metastasis and prostate cancer-related mortality. Currently, risk of biochemical recurrence is predicted by the Kattan nomogram, which incorporates several clinical factors to predict the probability of recurrence-free survival following radiation therapy (but has limited prediction accuracy). Semantic attributes on T2w MRI, such as the presence of extracapsular extension and seminal vesicle invasion and surrogate measure- ments of tumor size, have also been shown to be predictive of biochemical recurrence risk. While the correlation between biochemical recurrence and factors like tumor stage, Gleason grade, and extracapsular spread are well- documented, it is less clear how to predict biochemical recurrence in the absence of extracapsular spread and for small tumors fully contained in the capsule. Computer{extracted texture features, which quantitatively de- scribe tumor micro-architecture and morphology on MRI, have been shown to provide clues about a tumor's aggressiveness. However, while computer{extracted features have been employed for predicting cancer presence and grade, they have not been evaluated in the context of predicting risk of biochemical recurrence. This work seeks to evaluate the role of computer-extracted texture features in predicting risk of biochemical recurrence on a cohort of sixteen patients who underwent pre{treatment 1.5 Tesla (T) T2w MRI. We extract a combination of first-order statistical, gradient, co-occurrence, and Gabor wavelet features from T2w MRI. To identify which of these T2w MRI texture features are potential independent prognostic markers of PSA failure, we implement a partial least squares (PLS) method to embed the data in a low{dimensional space and then use the variable importance in projections (VIP) method to quantify the contributions of individual features to classification on the PLS embedding. In spite of the poor resolution of the 1.5 T MRI data, we are able to identify three Gabor wavelet features that, in conjunction with a logistic regression classifier, yield an area under the receiver operating characteristic curve of 0.83 for predicting the probability of biochemical recurrence following radiation therapy. In comparison to both the Kattan nomogram and semantic MRI attributes, the ability of these three computer-extracted features to predict biochemical recurrence risk is demonstrated.
    SPIE Medical Imaging; 03/2014
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    ABSTRACT: Radical prostatectomy (RP) and radiation therapy (RT) are the most common treatment options for prostate cancer (PCa). Despite advancements in radiation delivery and surgical procedures, RP and RT can result in failure rates as high as 40% and >25%, respectively. Treatment failure is characterized by biochemical recurrence (BcR), which is defined in terms of prostate specific antigen (PSA) concentrations and its variation following treatment. PSA is expected to decrease following treatment, thereby its presence in even small concentrations (e.g 0.2 ng/ml for surgery or 2 ng/ml over the nadir PSA for radiation therapy) is indicative of treatment failure. Early identification of treatment failure may enable the use of more aggressive or neo-adjuvant therapies. Moreover, predicting failure prior to treatment may spare the patient from a procedure that is unlikely to be successful. Our goal is to identify differences on pre-treatment MRI between patients who have BcR and those who remain disease-free at 5 years post-treatment. Specifically, we focus on (1) identifying statistically significant differences in MRI intensities, (2) establishing morphological differences in prostatic anatomic structures, and (3) comparing these differences with the natural variability of prostatic structures. In order to attain these objectives, we use an anatomically constrained registration framework to construct BcR and non-BcR statistical atlases based on the pre-treatment magnetic resonance images (MRI) of the prostate. The patients included in the atlas either underwent RP or RT and were followed up for at least 5 years. The BcR atlas was constructed from a combined population of 12 pre-RT 1.5 Tesla (T) MRI and 33 pre-RP 3T MRI from patients with BcR within 5 years of treatment. Similarly, the non-BcR atlas was built based on a combined cohort of 20 pre-RT 1.5T MRI and 41 pre-RP 3T MRI from patients who remain disease-free 5 years post treatment. We chose the atlas framework as it enables the mapping of MR images from all subjects into the same canonical space, while constructing both an imaging and a morphological statistical atlas. Such co-registration allowed us to perform voxel-by-voxel comparisons of MRI intensities and capsule and central gland morphology to identify statistically significant differences between the BcR and non-BcR patient populations. To assess whether the morphological differences are valid, we performed an additional experiment where we constructed sub-population atlases by randomly sampling RT patients to construct the BcR and non-BcR atlases. Following these experiments we observed that: (1) statistically significant MRI intensity differences exist between BcR and non-BcR patients, specifically on the border of the central gland; (2) statistically significant morphological differences are visible in the prostate and central gland, specifically in the proximity of the apex, and (3) the differences between the BcR and non-BcR cohorts in terms of shape appeared to be consistent across these sub-population atlases as observed in our RT atlases.
    SPIE Medical Imaging; 03/2014
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    ABSTRACT: PURPOSE: To investigate criteria that can identify dominant treatable prostate cancer foci with high certainty at endorectal magnetic resonance imaging (MRI) and MR spectroscopic (MRS) imaging, and thus facilitate selection of patients who are radiological candidates for MR-guided focal therapy. MATERIALS AND METHODS: We retrospectively identified 88 patients with biopsy-proven prostate cancer who underwent endorectal MRI and MRS imaging prior to radical prostatectomy with creation of histopathological tumor maps. Two independent readers noted the largest tumor foci at MRI, if visible, and the volume of concordant abnormal tissue at MRS imaging, if present. A logistic random intercept model was used to determine the association between clinical and MR findings and correct identification of treatable (over 0.5 cm(3) ) dominant intraprostatic tumor foci. RESULTS: Readers 1 and 2 identified dominant tumor foci in 50 (57%) and 58 (65%) of 88 patients; 42 (84%) and 48 (83%) of these were dominant treatable lesions at histopathology, respectively. Within the statistical model, the volume of concordant spectroscopic abnormality was the only factor that predicted correct identification of a dominant treatable lesion on T2-weighted images (odds ratio = 1.75; 95% confidence interval = 1.08 to 2.82; P value = 0.02). In particular, all visible lesions on T2-weighted imaging associated with at least 0.54 cm(3) of concordant spectroscopic abnormality were correctly identified dominant treatable tumor foci. CONCLUSION: Patients with dominant intraprostatic tumor foci seen on T2-weighted MRI and associated with at least 0.54 cm(3) of concordant MRS imaging abnormality may be radiological candidates for MR-guided focal therapy.J. Magn. Reson. Imaging 2013. © 2013 Wiley Periodicals, Inc.
    Journal of Magnetic Resonance Imaging 03/2014; 39(3). DOI:10.1002/jmri.24187 · 2.79 Impact Factor
  • Brachytherapy 03/2014; 13:S72. DOI:10.1016/j.brachy.2014.02.326 · 1.99 Impact Factor
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    ABSTRACT: To investigate the role of endorectal MR imaging and MR spectroscopic imaging in defining the contour of treatable intraprostatic tumor foci in prostate cancer, since targeted therapy requires accurate target volume definition. We retrospectively identified 20 patients with prostate cancer who underwent endorectal MR imaging and MR spectroscopic imaging prior to radical prostatectomy and subsequent creation of detailed histopathological tumor maps from whole-mount step sections. Two experienced radiologists independently reviewed all MR images and electronically contoured all suspected treatable (⩾0.5cm(3)) tumor foci. Deformable co-registration in MATLAB was used to calculate the margin of error between imaging and histopathological contours at both capsular and non-capsular surfaces and the treatment margin required to ensure at least 95% tumor coverage. Histopathology showed 17 treatable tumor foci in 16 patients, of which 8 were correctly identified by both readers and an additional 2 were correctly identified by reader 2. For all correctly identified lesions, both readers accurately identified that tumor contacted the prostatic capsule, with no error in contour identification. On the non-capsular border, the median distance between the imaging and histopathological contour was 1.4mm (range, 0-12). Expanding the contour by 5mm at the non-capsular margin included 95% of tumor volume not initially covered within the MR contour. Endorectal MR imaging and MR spectroscopic imaging can be used to accurately contour treatable intraprostatic tumor foci; adequate tumor coverage is achieved by expanding the treatment contour at the non-capsular margin by 5mm.
    Radiotherapy and Oncology 01/2014; 110(2). DOI:10.1016/j.radonc.2013.12.003 · 4.86 Impact Factor
  • Rahul Aggarwal, John Kurhanewicz
    Nature Reviews Urology 01/2014; DOI:10.1038/nrurol.2013.319 · 4.52 Impact Factor
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    ABSTRACT: The goal of this study was to correlate prostatic metabolite concentrations from snap-frozen patient biopsies of recurrent cancer after failed radiation therapy with histopathological findings, including Ki-67 immunohistochemistry and pathologic grade, in order to identify quantitative metabolic biomarkers that predict for residual aggressive versus indolent cancer. A total of 124 snap-frozen transrectal ultrasound (TRUS)-guided biopsies were acquired from 47 men with untreated prostate cancer and from 39 men with a rising prostate-specific antigen and recurrent prostate cancer following radiation therapy. Biopsy tissues with Ki-67 labeling index ≤ 5% were classified as indolent cancer, while biopsy tissues with Ki-67 labeling index > 5% were classified as aggressive cancer. The majority (15 out of 17) of cancers classified as aggressive had a primary Gleason 4 pattern (Gleason score ≥ 4 + 3). The concentrations of choline-containing phospholipid metabolites (PC, GPC, and free Cho) and lactate were significantly elevated in recurrent cancer relative to surrounding benign tissues. There was also a significant increase in [PC] and reduction in [GPC] between untreated and irradiated prostate cancer biopsies. The concentration of the choline-containing phospholipid metabolites was significantly higher in recurrent aggressive (≈twofold) than in recurrent indolent cancer biopsies, and the receiver operating characteristic (ROC) curve analysis of total choline to creatine ratio (tCho/Cr) demonstrated an accuracy of 95% (confidence interval = 0.88-1.00) for predicting aggressive recurrent disease. The tCho/Cr was significantly higher for identifying recurrent aggressive versus indolent cancer (tCho/Cr = 2.4 ± 0.4 versus 1.5 ± 0.2), suggesting that use of a higher threshold tCho/Cr ratio in future in vivo (1) H MRSI studies could improve the selection and therapeutic planning for patients who would benefit most from salvage focal therapy after failed radiation therapy. Copyright © 2013 John Wiley & Sons, Ltd.
    NMR in Biomedicine 01/2014; 27(1). DOI:10.1002/nbm.3007 · 3.56 Impact Factor
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    ABSTRACT: PURPOSE: Magnetic resonance spectroscopy of hyperpolarized substrates allows for the observation of label exchange catalyzed by enzymes providing a powerful tool to investigate tissue metabolism and potentially kinetics in vivo. However, the accuracy of current methods to calculate kinetic parameters has been limited by T(1) relaxation effects, extracellular signal contributions, and reduced precision at lower signal-to-noise ratio. THEORY AND METHODS: To address these challenges, we investigated a new modeling technique using metabolic activity decomposition-stimulated echo acquisition mode. The metabolic activity decomposition-stimulated echo acquisition mode technique separates exchanging from nonexchanging metabolites providing twice the information as conventional techniques. RESULTS: This allowed for accurate measurements of rates of conversion and of multiple T(1 ) values simultaneously using a single acquisition. CONCLUSION: The additional measurement of T(1 ) values for the reaction metabolites provides further biological information about the cellular environment of the metabolites. The new technique was investigated through simulations and in vivo studies of transgenic mouse models of cancer demonstrating improved assessments of kinetic rate constants and new T(1 ) relaxation value measurements for hyperpolarized (13) C-pyruvate, (13) C-lactate, and (13) C-alanine. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 01/2014; 71(1). DOI:10.1002/mrm.24634 · 3.40 Impact Factor

Publication Stats

9k Citations
845.65 Total Impact Points

Institutions

  • 1990–2015
    • University of California, San Francisco
      • • Department of Radiology and Biomedical Imaging
      • • Department of Urology
      • • Division of Hospital Medicine
      • • Department of Pharmaceutical Chemistry
      San Francisco, California, United States
  • 2008–2014
    • University of California, Berkeley
      • Department of Bioengineering
      Berkeley, California, United States
  • 2011
    • University of Toronto
      • Sunnybrook Health Sciences Centre
      Toronto, Ontario, Canada
  • 2009
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States
  • 2001–2004
    • Memorial Sloan-Kettering Cancer Center
      • Department of Radiology
      New York, New York, United States
  • 1998
    • Stanford University
      • Department of Radiology
      Palo Alto, California, United States