Publications by authors named "Steve H Fung"

24 Publications

  • Page 1 of 1

Diverse data augmentation for learning image segmentation with cross-modality annotations.

Med Image Anal 2021 Jul 20;71:102060. Epub 2021 Apr 20.

Department of Radiology and Biomedical Research Imaging Center (BRIC), University of North Carolina, Chapel Hill, NC, USA. Electronic address:

The dearth of annotated data is a major hurdle in building reliable image segmentation models. Manual annotation of medical images is tedious, time-consuming, and significantly variable across imaging modalities. The need for annotation can be ameliorated by leveraging an annotation-rich source modality in learning a segmentation model for an annotation-poor target modality. In this paper, we introduce a diverse data augmentation generative adversarial network (DDA-GAN) to train a segmentation model for an unannotated target image domain by borrowing information from an annotated source image domain. This is achieved by generating diverse augmented data for the target domain by one-to-many source-to-target translation. The DDA-GAN uses unpaired images from the source and target domains and is an end-to-end convolutional neural network that (i) explicitly disentangles domain-invariant structural features related to segmentation from domain-specific appearance features, (ii) combines structural features from the source domain with appearance features randomly sampled from the target domain for data augmentation, and (iii) train the segmentation model with the augmented data in the target domain and the annotations from the source domain. The effectiveness of our method is demonstrated both qualitatively and quantitatively in comparison with the state of the art for segmentation of craniomaxillofacial bony structures via MRI and cardiac substructures via CT.
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http://dx.doi.org/10.1016/j.media.2021.102060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184609PMC
July 2021

Obstructive hydrocephalus due to aqueductal stenosis from developmental venous anomaly draining bilateral medial thalami: a case report.

Radiol Case Rep 2020 Jun 8;15(6):730-732. Epub 2020 Apr 8.

Department of Neurology, Houston Methodist Hospital, 6560 Fannin St, Scurlock Suite 802, Houston, TX 77030, USA.

Hydrocephalus is a pathological buildup of cerebrospinal fluid within the ventricles leading to ventricular enlargement out of proportion to sulci and subarachnoid spaces. Developmental venous anomaly is a common benign and usually asymptomatic congenital cerebrovascular malformation. Hydrocephalus caused by aqueductal developmental venous anomaly is extremely rare. We describe a case of a 47-year-old man who presents with short-term memory impairment who was found to have a developmental venous anomaly draining bilateral medial thalami through a common collector vein that causes aqueductal stenosis and obstructive hydrocephalus.
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http://dx.doi.org/10.1016/j.radcr.2020.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152591PMC
June 2020

Combinatorial Anatomic and Functional Neural Tract Mapping for Stereotactic Radiosurgery Planning.

Cureus 2019 Nov 14;11(11):e6161. Epub 2019 Nov 14.

Neurosurgery, Houston Methodist Hospital, Houston, USA.

Introduction Stereotactic radiosurgery (SRS) is effective and safe for the treatment of the vast majority of brain metastases (BMs). SRS is increasingly used for the simultaneous treatment of multiple lesions, retreatment of recurrence, or subsequent treatment of new lesions. Although radiation injury is relatively uncommon, with the increased utilization of SRS, it is imperative to develop approaches to assess and mitigate radiation-induced neurologic toxicity. Multiple factors influence the development of radiation injury, including patient age, genomic variations, prior treatment, dose and volume treated, and anatomic location. Functional neural structure proximity to SRS targets is a critical factor in developing a systematic integrated risk assessment for SRS patients. Methods We developed an approach for risk assessment based on the combinatorial application of i) the anatomic localization of target lesions using a reference neuroanatomical/functional imaging atlas merged with patient-specific imaging and ii) validation with functional MRI (fMRI) and diffusion tensor imaging MRI (DTI-MRI) to identify neural tracts. Results In the case of a thalamic/midbrain junction breast carcinoma metastasis, the reference image analysis revealed proximity to the corticospinal tract (CST), which was validated by functional DTI-MRI. Dose-volume exposure of the CST could be estimated and considered in the development of a final treatment plan. Conclusion Merging pretreatment MR imaging with neuroanatomical/functional reference MRIs and subsequent validation with fMRI or DTI-MRI may prove to be a valuable approach to screen for neural risks in individual SRS patients. Incorporating this approach in larger studies could further our understanding of dose tolerances in a broad range of neural structures.
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http://dx.doi.org/10.7759/cureus.6161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913981PMC
November 2019

One-Shot Generative Adversarial Learning for MRI Segmentation of Craniomaxillofacial Bony Structures.

IEEE Trans Med Imaging 2020 03 14;39(3):787-796. Epub 2019 Aug 14.

Compared to computed tomography (CT), magnetic resonance imaging (MRI) delineation of craniomaxillofacial (CMF) bony structures can avoid harmful radiation exposure. However, bony boundaries are blurry in MRI, and structural information needs to be borrowed from CT during the training. This is challenging since paired MRI-CT data are typically scarce. In this paper, we propose to make full use of unpaired data, which are typically abundant, along with a single paired MRI-CT data to construct a one-shot generative adversarial model for automated MRI segmentation of CMF bony structures. Our model consists of a cross-modality image synthesis sub-network, which learns the mapping between CT and MRI, and an MRI segmentation sub-network. These two sub-networks are trained jointly in an end-to-end manner. Moreover, in the training phase, a neighbor-based anchoring method is proposed to reduce the ambiguity problem inherent in cross-modality synthesis, and a feature-matching-based semantic consistency constraint is proposed to encourage segmentation-oriented MRI synthesis. Experimental results demonstrate the superiority of our method both qualitatively and quantitatively in comparison with the state-of-the-art MRI segmentation methods.
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http://dx.doi.org/10.1109/TMI.2019.2935409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219540PMC
March 2020

Sleep-Disordered Breathing and Idiopathic Normal-Pressure Hydrocephalus: Recent Pathophysiological Advances.

Curr Neurol Neurosci Rep 2019 05 29;19(7):39. Epub 2019 May 29.

Department of Neurology, Methodist Neurological Institute and Houston Methodist Hospital Research Institute for Academic Medicine, Houston, TX, USA.

Purpose Of Review: Idiopathic normal-pressure hydrocephalus (iNPH) is characterized clinically by ventriculomegaly, abnormal gait, falls, incontinence, and cognitive decline. This article reviews recent advances in the pathophysiology of iNPH concerning sleep-disordered breathing (SDB) and glymphatic circulation during deep sleep.

Recent Findings: The authors found iNPH frequently associated with obstructive sleep apnea (OSA). A critical factor in iNPH is intracranial venous hypertension delaying drainage of cerebrospinal fluid (CSF) into the cerebral venous sinuses. CSF-venous blood circulates in the jugular veins and finally drains into the heart. During SDB, repeated reflex attempts to breathe induce strong respiratory efforts against a closed glottis thereby increasing the negative intrathoracic pressure. This causes atrial distortion and decreases venous return to the heart resulting in retrograde intracranial venous hypertension. Additionally, repeated awakenings from OSA impede sleep-associated circulation of interstitial CSF into the glymphatic circulation contributing to hydrocephalus. Sleep has become a critical element in the cognitive changes of aging including iNPH.
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http://dx.doi.org/10.1007/s11910-019-0952-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541578PMC
May 2019

Craniomaxillofacial Bony Structures Segmentation from MRI with Deep-Supervision Adversarial Learning.

Med Image Comput Comput Assist Interv 2018 Sep 13;11073:720-727. Epub 2018 Sep 13.

Department of Radiology and BRIC, University of North Carolina at Chapel Hill, Chapel Hill, USA.

Automatic segmentation of medical images finds abundant applications in clinical studies. Computed Tomography (CT) imaging plays a critical role in diagnostic and surgical planning of craniomaxillofacial (CMF) surgeries as it shows clear bony structures. However, CT imaging poses radiation risks for the subjects being scanned. Alternatively, Magnetic Resonance Imaging (MRI) is considered to be safe and provides good visualization of the soft tissues, but the bony structures appear invisible from MRI. Therefore, the segmentation of bony structures from MRI is quite challenging. In this paper, we propose a cascaded generative adversarial network with deep-supervision discriminator (Deep-supGAN) for automatic bony structures segmentation. The first block in this architecture is used to generate a high-quality CT image from an MRI, and the second block is used to segment bony structures from MRI and the generated CT image. Different from traditional discriminators, the deep-supervision discriminator distinguishes the generated CT from the ground-truth at different levels of feature maps. For segmentation, the loss is concentrated on the voxel level on the higher abstract perceptual levels. Experimental results show that the proposed method generates CT images with clearer structural details and also segments the bony structures more accurately compared with the state-of-the-art methods.
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http://dx.doi.org/10.1007/978-3-030-00937-3_82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235451PMC
September 2018

Idiopathic normal-pressure hydrocephalus and obstructive sleep apnea are frequently associated: A prospective cohort study.

J Neurol Sci 2018 12 3;395:164-168. Epub 2018 Oct 3.

Department of Radiology MRI Core, Houston Methodist Hospital and Methodist Research Institute for Academic Medicine, Houston, TX, USA; Department of Radiology, Weill Cornell Medical College, Cornell University, New York, NY, USA.

Background: Idiopathic normal-pressure hydrocephalus (iNPH) is defined by ventriculomegaly, cognitive decline, urinary incontinence and gait problems. Vascular risk factors (VRF) are associated with iNPH but obstructive sleep apnea (OSA) -a well-known independent VRF- is seldom mentioned.

Methods: We investigated the presence of sleep-disordered breathing in a prospective cohort of 31 consecutive unselected patients with iNPH using sleep questionnaires and nocturnal polysomnography (PSG).

Results: We found OSA in 90·3% (28/31) patients with iNPH; all had undiagnosed sleep abnormalities (snoring, awakenings, nocturia) and excessive daytime sleepiness (Epworth scale = 11·4 ± 6·4; normal <8). Nocturnal PSG showed moderate-to-severe OSA in 25 patients (80·6%) with mean apnea-hypopnea index (AHI) 31·6 ± 23·6/h; mean respiratory distress index (RDI) 34·5/h; and, mean SaO desaturation at nadir, 82·2 ± 7·5%. The observed OSA prevalence is statistically significant: 90·3%, 95%CI 74·3-97·5; p = 0·000007. Other VRF included overweight body-mass index (BMI >25- < 30 kg/m) in 59%, hyperhomocysteinemia 57%, hypertension 43%, hyperlipidemia 39%, diabetes 32%, smoking 21%, coronary disease 18%, and previous stroke 10%.

Conclusion: Abnormal sleep breathing is frequently associated with iNPH. Validation in larger series is required but we suggest including sleep evaluation in patients suspected of iNPH.
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http://dx.doi.org/10.1016/j.jns.2018.10.005DOI Listing
December 2018

Advanced neuroimaging in Balo's concentric sclerosis: MRI, MRS, DTI, and ASL perfusion imaging over 1 year.

Radiol Case Rep 2018 Oct 1;13(5):1030-1035. Epub 2018 Jun 1.

Houston Methodist Hospital, Texas Medical Center, Houston, TX, United States.

Balo concentric sclerosis (BCS) is a rare, atypical demyelinating disease, which may rapidly progress to become severe and fatal. Advanced neuroimaging has proven helpful for early diagnosis, classification, prognostication, and monitoring of progression in multiple sclerosis, but has not been fully explored in BCS. We present the case of a 27-year-old woman with BCS in whom advanced neuroimaging was used to correlate the evolution of disease with clinical findings over the course of 1 year. Magnetic resonance imaging, magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and arterial spin labeling cerebral perfusion were obtained at presentation (Day 0), and at Day 67 and Day 252. Imaging features include multilayered concentric ring lesion, reduced diffusion along the rim, hypoperfusion with possible mild central hyperperfusion, and MRS findings of increased choline, decreased -acetylaspartate (NAA), and possible presence of lactate and/or lipid peak. DTI tractography and relative apparent diffusion coefficient analyses correlated with clinical symptoms and may help to determine extent of white matter tract injury and prognosis.
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http://dx.doi.org/10.1016/j.radcr.2018.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137900PMC
October 2018

The long-term sequelae of palliative radiation therapy to lumbosacral spine using conventional PA-single portal technique.

Pract Radiat Oncol 2018 Nov - Dec;8(6):376-381. Epub 2018 Apr 10.

Department of Radiation Oncology, Houston Methodist Hospital, Houston, Texas. Electronic address:

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http://dx.doi.org/10.1016/j.prro.2018.04.003DOI Listing
January 2019

Technical Pitfalls of Signal Truncation in Perfusion MRI of Glioblastoma.

Front Neurol 2016 2;7:121. Epub 2016 Aug 2.

Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX, USA; Department of Radiology, Weill Cornell Medicine, Cornell University, New York, NY, USA.

Dynamic susceptibility contrast (DSC) perfusion-weighted imaging (PWI) is widely used in clinical settings for the radiological diagnosis of brain tumor. The signal change in brain tissue in gradient echo-based DSC PWI is much higher than in spin echo-based DSC PWI. Due to its exquisite sensitivity, gradient echo-based sequence is the preferred method for imaging of all tumors except those near the base of the skull. However, high sensitivity also comes with a dynamic range problem. It is not unusual for blood volume to increase in gene-mediated cytotoxic immunotherapy-treated glioblastoma patients. The increase of fractional blood volume sometimes saturates the MRI signal during first-pass contrast bolus arrival and presents signal truncation artifacts of various degrees in the tumor when a significant amount of blood exists in the image pixels. It presents a hidden challenge in PWI, as this signal floor can be either close to noise level or just above and can go no lower. This signal truncation in the signal intensity time course is a significant issue that deserves attention in DSC PWI. In this paper, we demonstrate that relative cerebral blood volume and relative cerebral blood flow (rCBF) are underestimated due to signal truncation in DSC perfusion, in glioblastoma patients. We propose the use of second-pass tissue residue function in rCBF calculation using least-absolute-deviation deconvolution to avoid the underestimation problem.
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http://dx.doi.org/10.3389/fneur.2016.00121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970430PMC
August 2016

Transulcal parafascicular minimally invasive approach to deep and subcortical cavernomas: technical note.

J Neurosurg 2016 12 4;125(6):1360-1366. Epub 2016 Mar 4.

Departments of 1 Neurological Surgery and.

Cavernomas comprise 8%-15% of intracranial vascular lesions, usually supratentorial in location and superficial. Cavernomas in the thalamus or subcortical white matter represent a unique challenge for surgeons in trying to identify and then use a safe corridor to access and resect the pathology. Previous authors have described specific open microsurgical corridors based on pathology location, often with technical difficulty and morbidity. This series presents 2 cavernomas that were resected using a minimally invasive approach that is less technically demanding and has a good safety profile. The authors report 2 cases of cavernoma: one in the thalamus and brainstem with multiple hemorrhages and the other in eloquent subcortical white matter. These lesions were resected through a transulcal parafascicular approach with a port-based minimally invasive technique. In this series there was complete resection with no neurological complications. The transulcal parafascicular minimally invasive approach relies on image interpretation and trajectory planning, intraoperative navigation, cortical cannulation and subcortical space access, high-quality optics, and resection as key elements to minimize exposure and retraction and maximize tissue preservation. The authors applied this technique to 2 patients with cavernomas in eloquent locations with excellent outcomes.
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http://dx.doi.org/10.3171/2015.12.JNS152185DOI Listing
December 2016

Epithelioid glioblastoma presenting as massive intracerebral hemorrhage: Case report and review of the literature.

Surg Neurol Int 2015 19;6(Suppl 2):S97-S100. Epub 2015 Mar 19.

Department of Neurological Surgery, Houston Methodist Neurological Institute, Houston, TX, USA.

Background: Glioblastoma multiforme (GBM) is a malignant transformation of glial tissue, which presents as intradural, intraaxial lesions with heterogenous contrast enhancement and mass effect. Intratumoral hemorrhage is a common finding in GBM although it is frequently asymptomatic. Massive, symptomatic, intratumoral hemorrhage is uncommon and poses a diagnostic challenge.

Case Description: Here we discuss a case of GBM, which initially presented as massive, symptomatic intracerebral hemorrhage with underlying mass. Due to size of the hemorrhage and poor neurological status the patient was taken to the operating room for evacuation of this hematoma. On pathology, the mass was found to be epithelioid glioblastoma.

Conclusion: Identification and diagnosis of GBM is generally straightforward. In certain circumstances, the presentation of GBM can vary from the routine. The above case demonstrates how pitfalls in diagnosis can be avoided in order to initiate appropriate therapy.
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http://dx.doi.org/10.4103/2152-7806.153643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392545PMC
April 2015

Diffusion-weighted imaging in posterior ischemic optic neuropathy.

Can J Ophthalmol 2014 Feb;49(1):e21-5

Houston Methodist Hospital, Houston, Texas; Weill Cornell Medical College, Houston, Texas; University of Texas Medical School at Houston, Houston, Texas; University of Iowa Hospitals and Clinics, Iowa City, Iowa; University of Texas Medical Branch, Galveston, Houston, Texas; University of Texas M.D. Anderson Cancer Center, Houston, Texas.. Electronic address:

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http://dx.doi.org/10.1016/j.jcjo.2013.11.003DOI Listing
February 2014

Diffusion tensor imaging in traumatic optic tract syndrome.

J Neuroophthalmol 2014 Mar;34(1):95-8

Department of Ophthalmology, The Methodist Hospital, Houston, Texas, Departments of Ophthalmology, Neurology, and Neurosurgery, Weill Cornell Medical College, Houston, Texas The University of Texas Medical School at Houston, Houston, Texas Department of Radiology, The Methodist Hospital, Houston, Texas, Department of Radiology, Weill Cornell Medical College, Houston, Texas Department of Radiology, The Methodist Hospital, Houston, Texas, Department of Radiology, Weill Cornell Medical College, Houston, Texas, The University of Texas Medical School at Houston, Houston, Texas, Department of Ophthalmology, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, Department of Ophthalmology, The University of Texas Medical Branch, Galveston, Texas,

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http://dx.doi.org/10.1097/WNO.0000000000000069DOI Listing
March 2014

Graph theoretical connectivity analysis of the human brain while listening to music with emotional attachment: feasibility study.

Annu Int Conf IEEE Eng Med Biol Soc 2013 ;2013:6526-9

Benefits of listening to music with emotional attachment while recovering from a cerebral ischemic event have been reported. To develop a better understanding of the effects of music listening on the human brain, an algorithm for the graph-theoretical analysis of functional magnetic resonance imaging (fMRI) data was developed. From BOLD data of two paradigms (block-design, first piece: music without emotional attachment, additional visual guidance by a moving cursor in the score sheet; second piece: music with emotional attachment), network graphs were constructed with correlations between signal time courses as edge weights. Functional subunits in these graphs were identified with the MCODE clustering algorithm and mapped back into anatomical space using AFNI. Emotional centers including the right amygdala and bilateral insula were activated by the second piece (emotional attachment) but not by the first piece. Network clustering analysis revealed two separate networks of small-world property corresponding to task-oriented and resting state conditions, respectively. Functional subunits with highest interactions were bilateral precuneus for the first piece and left middle frontal gyrus and right amygdala, bilateral insula, left middle temporal gyrus for the second piece. Our results indicate that fMRI in connection with graph theoretical network analysis is capable of identifying and differentiating functional subunits in the human brain when listening to music with and without emotional attachment.
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http://dx.doi.org/10.1109/EMBC.2013.6611050DOI Listing
September 2015

A graph-theoretical analysis algorithm for quantifying the transition from sensory input to motor output by an emotional stimulus.

Annu Int Conf IEEE Eng Med Biol Soc 2013 ;2013:1374-7

Graph-theoretical analysis algorithms have been used for identifying subnetworks in the human brain during the Default Mode State. Here, these methods are expanded to determine the interaction of the sensory and the motor subnetworks during the performance of an approach-avoidance paradigm utilizing the correlation strength between the signal intensity time courses as measure of synchrony. From functional magnetic resonance imaging (fMRI) data of 9 healthy volunteers, two signal time courses, one from the primary visual cortex (sensory input) and one from the motor cortex (motor output) were identified and a correlation difference map was calculated. Graph networks were created from this map and visualized with spring-embedded layouts and 3D layouts in the original anatomical space. Functional clusters in these networks were identified with the MCODE clustering algorithm. Interactions between the sensory sub-network and the motor sub-network were quantified through the interaction strengths of these clusters. The percentages of interactions involving the visual cortex ranged from 85 % to 18 % and the motor cortex ranged from 40 % to 9 %. Other regions with high interactions were: frontal cortex (19 ± 18 %), insula (17 ± 22 %), cuneus (16 ± 15 %), supplementary motor area (SMA, 11 ± 18 %) and subcortical regions (11 ± 10 %). Interactions between motor cortex, SMA and visual cortex accounted for 12 %, between visual cortex and cuneus for 8 % and between motor cortex, SMA and cuneus for 6 % of all interactions. These quantitative findings are supported by the visual impressions from the 2D and 3D network layouts.
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http://dx.doi.org/10.1109/EMBC.2013.6609765DOI Listing
August 2015

Comparison of functional network integrity in TBI and orthopedic controlpatientsusing graph-theoretical analysis.

Annu Int Conf IEEE Eng Med Biol Soc 2013 ;2013:1366-9

The integrity of functional brain networks inpatients (n=12) diagnosed with traumatic brain injury (TBI) was compared to age-matched subjects (n=12) with orthopedic injury (OI) during a working memory task. A graph-theoretical analysis algorithm was developed and integrated into the AFNI software. Functional networks with correlations between time courses as edge-weights were automatically created and their integrity was quantified by determining the statistical significance of the following network parameters: diameter, density, clustering coefficient, average path length, two largest eigenvalues, spectral density, and minimum eccentricity. Network graphs using a spring-embedded layout (Cytoscape) and a 3D layout integrated into the anatomical space (Paraview) were created. Functional images were composed by color-coding the degree of each voxel (network node) and transformed into Talairach space. Using the AFNI Talairach atlas, degrees of distinct brain regions were quantified. Reduced averaged BOLD responses were found for the TBI group with a higher network integrity potentially as a compensatory mechanism. Regions of high functional connectivity varied in between groups with largest differences in the cerebellum, the temporal lobes and deep brain structures including the lentiform nucleus, caudate and thalamus.
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http://dx.doi.org/10.1109/EMBC.2013.6609763DOI Listing
August 2015

Enhanced MRI relaxivity of Gd(3+) -based contrast agents geometrically confined within porous nanoconstructs.

Contrast Media Mol Imaging 2012 Nov-Dec;7(6):501-8

Department of Chemistry, Smalley Institute for Nanoscale Science and Technology, Center for Biological and Environmental Nanotechnology, Rice University, Houston, TX 77251-1892, USA.

Gadolinium chelates, which are currently approved for clinical MRI use, provide relaxivities well below their theoretical limit, and they also lack tissue specificity. Recently, the geometrical confinement of Gd(3+) -based contrast agents (CAs) within porous structures has been proposed as a novel, alternative strategy to improve relaxivity without chemical modification of the CA. Here, we have characterized and optimized the performance of MRI nanoconstructs obtained by loading [Gd(DTPA)(H(2) O)](2-) (Magnevist®) into the pores of injectable mesoporous silicon particles. Nanoconstructs with three different pore sizes were studied, and at 60 MHz, they exhibited longitudinal relaxivities of ~24 m m(-1)  s(-1) for 5-10 nm pores and ~10 m m(-1)  s(-1) for 30 - 40 nm pores. No enhancement in relaxivity was observed for larger pores sizes. Using an outer-sphere compound, [GdTTHA](3-) , and mathematical modeling, it was demonstrated that the relaxivity enhancement is due to the increase in rotational correlation times (CA adsorbed on the pore walls) and diffusion correlation times (reduced mobility of the water molecules), as the pore sizes decreases. It was also observed that extensive CA adsorption on the outer surface of the silicon particles negates the advantages offered by nanoscale confinement. Upon incubation with HeLa cells, the nanoconstructs did not demonstrate significant cytotoxicity for up to 3 days post incubation, at different particle/cell ratios. In addition, the nanoconstructs showed complete degradation after 24 h of continuous agitation in phosphate-buffered saline. These data support and confirm the hypothesis that the geometrical confinement of Gd(3+) -chelate compounds into porous structures offers MRI nanoconstructs with enhanced relaxivity (up to 6 times for [Gd(DTPA)(H(2) O)](2-) , and 4 times for [GdTTHA](3-) ) and, potentially, improved stability, reduced toxicity and tissue specificity.
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http://dx.doi.org/10.1002/cmmi.1480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3846290PMC
August 2013

MR diffusion imaging in ischemic stroke.

Neuroimaging Clin N Am 2011 May;21(2):345-77, xi

Neuroradiology Section, Department of Radiology, The Methodist Hospital, Weill Cornell Medical College, 6565 Fannin Street, Houston, TX 77030, USA.

Diffusion-weighted MRI provides image contrast that is dependent on the molecular motion of water. Diffusion-weighted imaging is the most reliable method for early detection of cerebral ischemia, for the definition of infarct core, and for the differentiation of acute ischemia from other disease processes that mimic stroke. Diffusion tensor imaging and diffusion kurtosis imaging may offer additional diagnostic information on the microstructural status of tissue. This review discusses the development and applications of diffusion-weighted imaging, diffusion tensor imaging, and diffusion kurtosis imaging in acute and chronic ischemia.
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http://dx.doi.org/10.1016/j.nic.2011.03.001DOI Listing
May 2011

Metabolically stable bradykinin B2 receptor agonists enhance transvascular drug delivery into malignant brain tumors by increasing drug half-life.

J Transl Med 2009 May 13;7:33. Epub 2009 May 13.

National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, USA.

Background: The intravenous co-infusion of labradimil, a metabolically stable bradykinin B2 receptor agonist, has been shown to temporarily enhance the transvascular delivery of small chemotherapy drugs, such as carboplatin, across the blood-brain tumor barrier. It has been thought that the primary mechanism by which labradimil does so is by acting selectively on tumor microvasculature to increase the local transvascular flow rate across the blood-brain tumor barrier. This mechanism of action does not explain why, in the clinical setting, carboplatin dosing based on patient renal function over-estimates the carboplatin dose required for target carboplatin exposure. In this study we investigated the systemic actions of labradimil, as well as other bradykinin B2 receptor agonists with a range of metabolic stabilities, in context of the local actions of the respective B2 receptor agonists on the blood-brain tumor barrier of rodent malignant gliomas.

Methods: Using dynamic contrast-enhanced MRI, the pharmacokinetics of gadolinium-diethyltriaminepentaacetic acid (Gd-DTPA), a small MRI contrast agent, were imaged in rodents bearing orthotopic RG-2 malignant gliomas. Baseline blood and brain tumor tissue pharmacokinetics were imaged with the 1st bolus of Gd-DTPA over the first hour, and then re-imaged with a 2nd bolus of Gd-DTPA over the second hour, during which normal saline or a bradykinin B2 receptor agonist was infused intravenously for 15 minutes. Changes in mean arterial blood pressure were recorded. Imaging data was analyzed using both qualitative and quantitative methods.

Results: The decrease in systemic blood pressure correlated with the known metabolic stability of the bradykinin B2 receptor agonist infused. Metabolically stable bradykinin B2 agonists, methionine-lysine-bradykinin and labradimil, had differential effects on the transvascular flow rate of Gd-DTPA across the blood-brain tumor barrier. Both methionine-lysine-bradykinin and labradimil increased the blood half-life of Gd-DTPA sufficiently enough to increase significantly the tumor tissue Gd-DTPA area under the time-concentration curve.

Conclusion: Metabolically stable bradykinin B2 receptor agonists, methionine-lysine-bradykinin and labradimil, enhance the transvascular delivery of small chemotherapy drugs across the BBTB of malignant gliomas by increasing the blood half-life of the co-infused drug. The selectivity of the increase in drug delivery into the malignant glioma tissue, but not into normal brain tissue or skeletal muscle tissue, is due to the inherent porous nature of the BBTB of malignant glioma microvasculature.
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http://dx.doi.org/10.1186/1479-5876-7-33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689161PMC
May 2009

Effective transvascular delivery of nanoparticles across the blood-brain tumor barrier into malignant glioma cells.

J Transl Med 2008 Dec 18;6:80. Epub 2008 Dec 18.

National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, USA.

Background: Effective transvascular delivery of nanoparticle-based chemotherapeutics across the blood-brain tumor barrier of malignant gliomas remains a challenge. This is due to our limited understanding of nanoparticle properties in relation to the physiologic size of pores within the blood-brain tumor barrier. Polyamidoamine dendrimers are particularly small multigenerational nanoparticles with uniform sizes within each generation. Dendrimer sizes increase by only 1 to 2 nm with each successive generation. Using functionalized polyamidoamine dendrimer generations 1 through 8, we investigated how nanoparticle size influences particle accumulation within malignant glioma cells.

Methods: Magnetic resonance and fluorescence imaging probes were conjugated to the dendrimer terminal amines. Functionalized dendrimers were administered intravenously to rodents with orthotopically grown malignant gliomas. Transvascular transport and accumulation of the nanoparticles in brain tumor tissue was measured in vivo with dynamic contrast-enhanced magnetic resonance imaging. Localization of the nanoparticles within glioma cells was confirmed ex vivo with fluorescence imaging.

Results: We found that the intravenously administered functionalized dendrimers less than approximately 11.7 to 11.9 nm in diameter were able to traverse pores of the blood-brain tumor barrier of RG-2 malignant gliomas, while larger ones could not. Of the permeable functionalized dendrimer generations, those that possessed long blood half-lives could accumulate within glioma cells.

Conclusion: The therapeutically relevant upper limit of blood-brain tumor barrier pore size is approximately 11.7 to 11.9 nm. Therefore, effective transvascular drug delivery into malignant glioma cells can be accomplished by using nanoparticles that are smaller than 11.7 to 11.9 nm in diameter and possess long blood half-lives.
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http://dx.doi.org/10.1186/1479-5876-6-80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2639552PMC
December 2008

Validation of dynamic contrast-enhanced magnetic resonance imaging-derived vascular permeability measurements using quantitative autoradiography in the RG2 rat brain tumor model.

Neoplasia 2007 Jul;9(7):546-55

Diagnostic Radiology Department, Imaging Sciences Program, The Clinical Center of the National Institutes of Health, Bethesda, MD 20892, USA.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is widely used to evaluate tumor permeability, yet measurements have not been directly validated in brain tumors. Our purpose was to compare estimates of forward leakage K(trans) derived from DCE-MRI to the estimates K obtained using [(14)C]aminoisobutyric acid quantitative autoradiography ([(14)C]AIB QAR), an established method of evaluating blood-tumor barrier permeability. Both DCE-MRI and [(14)C]AIB QAR were performed in five rats 9 to 11 days following tumor implantation. K(trans) in the tumor was estimated from DCE-MRI using the threeparameter general kinetic model and a measured vascular input function. K(i) was estimated from QAR data using regions of interest (ROI) closely corresponding to those used to estimate K(trans). K(trans) and K(i) correlated with each other for two independent sets of central tumor ROI (R = 0.905, P = .035; R = 0.933, P = .021). In an additional six rats, K(trans) was estimated on two occasions to show reproducibility (intraclass coefficient = 0.9993; coefficient of variance = 6.07%). In vivo blood-tumor permeability parameters derived from DCE-MRI are reproducible and correlate with the gold standard for quantifying blood tumor barrier permeability, [(14)C]AIB QAR.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1939929PMC
http://dx.doi.org/10.1593/neo.07289DOI Listing
July 2007