Publications by authors named "Warren D Foltz"

46 Publications

CFTR Therapeutics Normalize Cerebral Perfusion Deficits in Mouse Models of Heart Failure and Subarachnoid Hemorrhage.

JACC Basic Transl Sci 2019 Dec 27;4(8):940-958. Epub 2019 Nov 27.

Department of Physiology, University of Toronto, Toronto, Ontario, Canada.

Heart failure (HF) and subarachnoid hemorrhage (SAH) chronically reduce cerebral perfusion, which negatively affects clinical outcome. This work demonstrates a strong relationship between cerebral artery cystic fibrosis transmembrane conductance regulator (CFTR) expression and altered cerebrovascular reactivity in HF and SAH. In HF and SAH, CFTR corrector compounds (C18 or lumacaftor) normalize pathological alterations in cerebral artery CFTR expression, vascular reactivity, and cerebral perfusion, without affecting systemic hemodynamic parameters. This normalization correlates with reduced neuronal injury. Therefore, CFTR therapeutics have emerged as valuable clinical tools to manage cerebrovascular dysfunction, impaired cerebral perfusion, and neuronal injury.
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http://dx.doi.org/10.1016/j.jacbts.2019.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939007PMC
December 2019

Sensitivity of radiomic features to inter-observer variability and image pre-processing in Apparent Diffusion Coefficient (ADC) maps of cervix cancer patients.

Radiother Oncol 2020 Feb 30;143:88-94. Epub 2019 Aug 30.

Radiation Medicine Program, Princess Margaret Cancer Center, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Canada. Electronic address:

Purpose: The aims of this study are to evaluate the stability of radiomic features from Apparent Diffusion Coefficient (ADC) maps of cervical cancer with respect to: (1) reproducibility in inter-observer delineation, and (2) image pre-processing (normalization/quantization) prior to feature extraction.

Materials And Methods: Two observers manually delineated the tumor on ADC maps derived from pre-treatment diffusion-weighted Magnetic Resonance imaging of 81 patients with FIGO stage IB-IVA cervical cancer. First-order, shape, and texture features were extracted from the original and filtered images considering 5 different normalizations (four taken from the available literature, and one based on urine ADC) and two different quantization techniques (fixed-bin widths from 0.05 to 25, and fixed-bin count). Stability of radiomic features was assessed using intraclass correlation coefficient (ICC): poor (ICC < 0.75); good (0.75 ≤ ICC ≤ 0.89), and excellent (ICC ≥ 0.90). Dependencies of the features with tumor volume were assessed using Spearman's correlation coefficient (ρ).

Results: The approach using urine-normalized values together with a smaller bin width (0.05) was the most reproducible (428/552, 78% features with ICC ≥ 0.75); the fixed-bin count approach was the least (215/552, 39% with ICC ≥ 0.75). Without normalization, using a fixed bin width of 25, 348/552 (63%) of features had an ICC ≥ 0.75. Overall, 26% (range 25-30%) of the features were volume-dependent (ρ ≥ 0.6). None of the volume-independent shape features were found to be reproducible.

Conclusion: Applying normalization prior to features extraction increases the reproducibility of ADC-based radiomics features. When normalization is applied, a fixed-bin width approach with smaller widths is suggested.
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http://dx.doi.org/10.1016/j.radonc.2019.08.008DOI Listing
February 2020

Changes in apparent diffusion coefficient radiomics features during dose-painted radiotherapy and high dose rate brachytherapy for prostate cancer.

Phys Imaging Radiat Oncol 2019 Jan 19;9:1-6. Epub 2018 Dec 19.

Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

Background And Purpose: Dose escalation has improved cancer outcomes for patients with localized prostate cancer. Targeting subprostatic tumor regions for dose intensification may further improve outcomes. Apparent Diffusion Coefficient (ADC) maps may enable early radiation response assessment and dose adaptation. This study was a proof-of-principle investigation of early changes in ADC radiomics features for patients undergoing radiotherapy with dose escalation to the gross tumor volume (GTV).

Materials And Methods: Fifty-nine patients were enrolled on a prospective tumor dose-escalation trial. Multi-parametric MRI was performed at baseline and week six, corresponding to the time of peak ADC change. GTV and prostate contours were deformably registered between baseline and week six T2-weighted images, and applied to ADC maps, to account for diminished image contrast post-EBRT and possible differences in prostate gland volume, shape, and orientation. A total of 101 radiomics features were tested for significant change post-EBRT using two-tailed Student's -test. All ADC features of the prostate and GTV volumes were correlated using Pearson's coefficient (p < 0.00008, based on Bonferroni correction).

Results: ADC feature extraction was insensitive to b = 0 s/mm exclusion, and to gradient non-linearity bias. GTV presented predominant changes in first-order features, particularly 10Percentile, and prostate volumes presented predominant changes in second-order features. Changes in both first and second-order features of GTV and prostate ROIs were strongly correlated.

Conclusions: Our data confirmed significant changes in numerous GTV and prostate features assessed from ADC and T2-weighted images during radiotherapy; all of which may be potential biomarkers of early radiation response.
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http://dx.doi.org/10.1016/j.phro.2018.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807683PMC
January 2019

The mTOR Targets 4E-BP1/2 Restrain Tumor Growth and Promote Hypoxia Tolerance in PTEN-driven Prostate Cancer.

Mol Cancer Res 2018 04 16;16(4):682-695. Epub 2018 Feb 16.

Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.

The mTOR signaling pathway is a central regulator of protein synthesis and cellular metabolism in response to the availability of energy, nutrients, oxygen, and growth factors. mTOR activation leads to phosphorylation of multiple downstream targets including the eukaryotic initiation factor 4E (eIF4E) binding proteins-1 and -2 (EIF4EBP1/4E-BP1 and EIF4EBP2/4E-BP2). These binding proteins inhibit protein synthesis, but are inactivated by mTOR to stimulate cell growth and metabolism. However, the role of these proteins in the context of aberrant activation of mTOR, which occurs frequently in cancers through loss of PTEN or mutational activation of the PI3K/AKT pathway, is unclear. Here, even under conditions of aberrant mTOR activation, hypoxia causes dephosphorylation of 4E-BP1/4E-BP2 and increases their association with eIF4E to suppress translation. This is essential for hypoxia tolerance as knockdown of 4E-BP1 and 4E-BP2 decreases proliferation under hypoxia and increases hypoxia-induced cell death. In addition, genetic deletion of 4E-BP1 and 4E-BP2 significantly accelerates all phases of cancer development in the context of PTEN loss-driven prostate cancer in mice despite potent PI3K/AKT and mTOR activation. However, even with a more rapid onset, tumors that establish in the absence of 4E-BP1 and 4E-BP2 have reduced levels of tumor hypoxia and show increased cell death within hypoxic tumor regions. Together, these data demonstrate that 4E-BP1 and 4E-BP2 act as essential metabolic breaks even in the context of aberrant mTOR activation and that they are essential for the creation of hypoxia-tolerant cells in prostate cancer. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0696DOI Listing
April 2018

Corrigendum to "Generating level-dependent models of cervical and thoracic spinal cord injury: Exploring the interplay of neuroanatomy, physiology, and function" Neurobiology of Disease 105 (2017) 194-212.

Neurobiol Dis 2017 12;108:363-364

Division of Genetics and Development, Toronto Western Research Institute, University Health Network, ON M5T 2S8, Canada; Institute of Medical Science and Spinal Program, University of Toronto, ON M5S 1A8, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.nbd.2017.10.008DOI Listing
December 2017

Generating level-dependent models of cervical and thoracic spinal cord injury: Exploring the interplay of neuroanatomy, physiology, and function.

Neurobiol Dis 2017 Sep 31;105:194-212. Epub 2017 May 31.

Division of Genetics and Development, Toronto Western Research Institute, University Health Network, ON M5T 2S8, Canada; Institute of Medical Science and Spinal Program, University of Toronto, ON M5S 1A8, Canada. Electronic address:

The majority of spinal cord injuries (SCI) occur at the cervical level, which results in significant impairment. Neurologic level and severity of injury are primary endpoints in clinical trials; however, how level-specific damages relate to behavioural performance in cervical injury is incompletely understood. We hypothesized that ascending level of injury leads to worsening forelimb performance, and correlates with loss of neural tissue and muscle-specific neuron pools. A direct comparison of multiple models was made with injury realized at the C5, C6, C7 and T7 vertebral levels using clip compression with sham-operated controls. Animals were assessed for 10weeks post-injury with numerous (40) outcome measures, including: classic behavioural tests, CatWalk, non-invasive MRI, electrophysiology, histologic lesion morphometry, neuron counts, and motor compartment quantification, and multivariate statistics on the total dataset. Histologic staining and T1-weighted MR imaging revealed similar structural changes and distinct tissue loss with cystic cavitation across all injuries. Forelimb tests, including grip strength, F-WARP motor scale, Inclined Plane, and forelimb ladder walk, exhibited stratification between all groups and marked impairment with C5 and C6 injuries. Classic hindlimb tests including BBB, hindlimb ladder walk, bladder recovery, and mortality were not different between cervical and thoracic injuries. CatWalk multivariate gait analysis showed reciprocal and progressive changes forelimb and hindlimb function with ascending level of injury. Electrophysiology revealed poor forelimb axonal conduction in cervical C5 and C6 groups alone. The cervical enlargement (C5-T2) showed progressive ventral horn atrophy and loss of specific motor neuron populations with ascending injury. Multivariate statistics revealed a robust dataset, rank-order contribution of outcomes, and allowed prediction of injury level with single-level discrimination using forelimb performance and neuron counts. Level-dependent models were generated using clip-compression SCI, with marked and reliable differences in forelimb performance and specific neuron pool loss.
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http://dx.doi.org/10.1016/j.nbd.2017.05.009DOI Listing
September 2017

Delayed decompression exacerbates ischemia-reperfusion injury in cervical compressive myelopathy.

JCI Insight 2017 Jun 2;2(11). Epub 2017 Jun 2.

Division of Genetics & Development, Toronto Western Research Institute and Spine Program, Krembil Neuroscience Center, University Health Network, Toronto, Ontario, Canada.

Degenerative cervical myelopathy (DCM) is the most common progressive nontraumatic spinal cord injury. The most common recommended treatment is surgical decompression, although the optimal timing of intervention is an area of ongoing debate. The primary objective of this study was to assess whether a delay in decompression could influence the extent of ischemia-reperfusion injury and alter the trajectory of outcome in DCM. Using a DCM mouse model, we show that decompression acutely led to a 1.5- to 2-fold increase in levels of inflammatory cytokines within the spinal cord. Delayed decompression was associated with exacerbated reperfusion injury, astrogliosis, and poorer neurological recovery. Additionally, delayed decompression was associated with prolonged elevation of inflammatory cytokines and an exacerbated peripheral monocytic inflammatory response (P < 0.01 and 0.001). In contrast, early decompression led to resolution of reperfusion-mediated inflammation, neurological improvement, and reduced hyperalgesia. Similar findings were observed in subjects from the CSM AOSpine North America and International studies, where delayed decompressive surgery resulted in poorer neurological improvement compared with patients with an earlier intervention. Our data demonstrate that delayed surgical decompression for DCM exacerbates reperfusion injury and is associated with ongoing enhanced levels of cytokine expression, microglia activation, and astrogliosis, and paralleled with poorer neurological recovery.
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http://dx.doi.org/10.1172/jci.insight.92512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453710PMC
June 2017

MR elastography to measure the effects of cancer and pathology fixation on prostate biomechanics, and comparison with T , T and ADC.

Phys Med Biol 2017 02;62(3):1126-1148

Radiation Medicine Program, Princess Margaret Hospital, University Health Network, Toronto, Ontario M5G 2M9, Canada.

MRI is under evaluation for image-guided intervention for prostate cancer. The sensitivity and specificity of MRI parameters is determined via correlation with the gold-standard of histopathology. Whole-mount histopathology of prostatectomy specimens can be digitally registered to in vivo imaging for correlation. When biomechanical-based deformable registration is employed to account for deformation during histopathology processing, the ex vivo biomechanical properties are required. However, these properties are altered by pathology fixation, and vary with disease. Hence, this study employs magnetic resonance elastography (MRE) to measure ex vivo prostate biomechanical properties before and after fixation. A quasi-static MRE method was employed to measure high resolution maps of Young's modulus (E) before and after fixation of canine prostate and prostatectomy specimens (n  =  4) from prostate cancer patients who had previously received radiation therapy. For comparison, T , T and apparent diffusion coefficient (ADC) were measured in parallel. E (kPa) varied across clinical anatomy and for histopathology-identified tumor: peripheral zone: 99(±22), central gland: 48(±37), tumor: 85(±53), and increased consistently with fixation (factor of 11  ±  5; p  <  0.02). T decreased consistently with fixation, while changes in T and ADC were more complex and inconsistent. The biomechanics of the clinical prostate specimens varied greatly with fixation, and to a lesser extent with disease and anatomy. The data obtained will improve the precision of prostate pathology correlation, leading to more accurate disease detection and targeting.
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http://dx.doi.org/10.1088/1361-6560/aa52f4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318143PMC
February 2017

Tumor Necrosis Factor/Sphingosine-1-Phosphate Signaling Augments Resistance Artery Myogenic Tone in Diabetes.

Diabetes 2016 07 5;65(7):1916-28. Epub 2016 Apr 5.

Department of Physiology, University of Toronto, Toronto, Ontario, Canada Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada

Diabetes strongly associates with microvascular complications that ultimately promote multiorgan failure. Altered myogenic responsiveness compromises tissue perfusion, aggravates hypertension, and sets the stage for later permanent structural changes to the microcirculation. We demonstrate that skeletal muscle resistance arteries isolated from patients with diabetes have augmented myogenic tone, despite reasonable blood glucose control. To understand the mechanisms, we titrated a standard diabetes mouse model (high-fat diet plus streptozotocin [HFD/STZ]) to induce a mild increase in blood glucose levels. HFD/STZ treatment induced a progressive myogenic tone augmentation in mesenteric and olfactory cerebral arteries; neither HFD nor STZ alone had an effect on blood glucose or resistance artery myogenic tone. Using gene deletion models that eliminate tumor necrosis factor (TNF) or sphingosine kinase 1, we demonstrate that vascular smooth muscle cell TNF drives the elevation of myogenic tone via enhanced sphingosine-1-phosphate (S1P) signaling. Therapeutically antagonizing TNF (etanercept) or S1P (JTE013) signaling corrects this defect. Our investigation concludes that vascular smooth muscle cell TNF augments resistance artery myogenic vasoconstriction in a diabetes model that induces a small elevation of blood glucose. Our data demonstrate that microvascular reactivity is an early disease marker and advocate establishing therapies that strategically target the microcirculation.
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http://dx.doi.org/10.2337/db15-1450DOI Listing
July 2016

Nanotexaphyrin: One-Pot Synthesis of a Manganese Texaphyrin-Phospholipid Nanoparticle for Magnetic Resonance Imaging.

Angew Chem Int Ed Engl 2016 05 13;55(21):6187-91. Epub 2016 Apr 13.

Princess Margaret Cancer Centre, University Health Network, Canada.

The discovery and synthesis of novel multifunctional organic building blocks for nanoparticles is challenging. Texaphyrin macrocycles are capable and multifunctional chelators. However, they remain elusive as building blocks for nanoparticles because of the difficulty associated with synthesis of texaphyrin constructs capable of self-assembly. A novel manganese (Mn)-texaphyrin-phospholipid building block is described, along with its one-pot synthesis and self-assembly into a Mn-nanotexaphyrin. This nanoparticle possesses strong resilience to manganese dissociation, structural stability, in vivo bio-safety, and structure-dependent T1 and T2 relaxivities. Magnetic resonance imaging (MRI) contrast enhanced visualization of lymphatic drainage is demonstrated with respect to proximal lymph nodes on the head and neck VX-2 tumors of a rabbit. Synthesis of 17 additional metallo-texaphyrin building blocks suggests that this novel one-pot synthetic procedure for nanotexaphyrins may lead to a wide range of applications in the field of nanomedicines.
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http://dx.doi.org/10.1002/anie.201600234DOI Listing
May 2016

Technical Note: Method to correlate whole-specimen histopathology of radical prostatectomy with diagnostic MR imaging.

Med Phys 2016 Mar;43(3):1065-72

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48108.

Purpose: Validation of MRI-guided tumor boundary delineation for targeted prostate cancer therapy is achieved via correlation with gold-standard histopathology of radical prostatectomy specimens. Challenges to accurate correlation include matching the pathology sectioning plane with the in vivo imaging slice plane and correction for the deformation that occurs between in vivo imaging and histology. A methodology is presented for matching of the histological sectioning angle and position to the in vivo imaging slices.

Methods: Patients (n = 4) with biochemical failure following external beam radiotherapy underwent diagnostic MRI to confirm localized recurrence of prostate cancer, followed by salvage radical prostatectomy. High-resolution 3-D MRI of the ex vivo specimens was acquired to determine the pathology sectioning angle that best matched the in vivo imaging slice plane, using matching anatomical features and implanted fiducials. A novel sectioning device was developed to guide sectioning at the correct angle, and to assist the insertion of reference dye marks to aid in histopathology reconstruction.

Results: The percentage difference in the positioning of the urethra in the ex vivo pathology sections compared to the positioning in in vivo images was reduced from 34% to 7% through slicing at the best match angle. Reference dye marks were generated, which were visible in ex vivo imaging, in the tissue sections before and after processing, and in histology sections.

Conclusions: The method achieved an almost fivefold reduction in the slice-matching error and is readily implementable in combination with standard MRI technology. The technique will be employed to generate datasets for correlation of whole-specimen prostate histopathology with in vivo diagnostic MRI using 3-D deformable registration, allowing assessment of the sensitivity and specificity of MRI parameters for prostate cancer. Although developed specifically for prostate, the method is readily adaptable to other types of whole tissue specimen, such as mastectomy or liver resection.
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http://dx.doi.org/10.1118/1.4941016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744234PMC
March 2016

Custom-designed Laser-based Heating Apparatus for Triggered Release of Cisplatin from Thermosensitive Liposomes with Magnetic Resonance Image Guidance.

J Vis Exp 2015 Dec 13(106):e53055. Epub 2015 Dec 13.

Leslie Dan Faculty of Pharmacy, University of Toronto;

Liposomes have been employed as drug delivery systems to target solid tumors through exploitation of the enhanced permeability and retention (EPR) effect resulting in significant reductions in systemic toxicity. Nonetheless, insufficient release of encapsulated drug from liposomes has limited their clinical efficacy. Temperature-sensitive liposomes have been engineered to provide site-specific release of drug in order to overcome the problem of limited tumor drug bioavailability. Our lab has designed and developed a heat-activated thermosensitive liposome formulation of cisplatin (CDDP), known as HTLC, to provide triggered release of CDDP at solid tumors. Heat-activated delivery in vivo was achieved in murine models using a custom-built laser-based heating apparatus that provides a conformal heating pattern at the tumor site as confirmed by MR thermometry (MRT). A fiber optic temperature monitoring device was used to measure the temperature in real-time during the entire heating period with online adjustment of heat delivery by alternating the laser power. Drug delivery was optimized under magnetic resonance (MR) image guidance by co-encapsulation of an MR contrast agent (i.e., gadoteridol) along with CDDP into the thermosensitive liposomes as a means to validate the heating protocol and to assess tumor accumulation. The heating protocol consisted of a preheating period of 5 min prior to administration of HTLC and 20 min heating post-injection. This heating protocol resulted in effective release of the encapsulated agents with the highest MR signal change observed in the heated tumor in comparison to the unheated tumor and muscle. This study demonstrated the successful application of the laser-based heating apparatus for preclinical thermosensitive liposome development and the importance of MR-guided validation of the heating protocol for optimization of drug delivery.
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http://dx.doi.org/10.3791/53055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694025PMC
December 2015

Riluzole blocks perioperative ischemia-reperfusion injury and enhances postdecompression outcomes in cervical spondylotic myelopathy.

Sci Transl Med 2015 Dec;7(316):316ra194

Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Division of Genetics and Development, Toronto Western Research Institute, and Spinal Program, Krembil Neuroscience Centre, University Health Network, Toronto, Ontario M5T 2S8, Canada. Department of Surgery, Division of Neurosurgery and Spinal Program, University of Toronto, Toronto, Ontario M5T 2S8, Canada.

Although surgical decompression is considered the gold standard treatment for cervical spondylotic myelopathy (CSM), a proportion of cases show postoperative decline or continue to exhibit substantial neurological dysfunction. To investigate this further, we first examined data from the prospective multicenter AOSpine North America CSM study, finding that 9.3% of patients exhibited postoperative functional decline (ΔmJOA, ≤-1) and that 44% of patients were left with substantial neurological impairment 6 months postoperatively. Notably, 4% of patients experienced perioperative neurological complications within 20 days after surgery in otherwise uneventful surgeries. To shed light on the mechanisms underlying this phenomenon and to test a combination therapeutic strategy for CSM, we performed surgical decompression in a rat model of CSM, randomizing some animals to also receive the U.S. Food and Drug Administration-approved drug riluzole. Spinal cord blood flow measurements increased after decompression surgery in rats. CSM rats showed a transient postoperative neurological decline akin to that seen in some CSM patients, suggesting that ischemia-reperfusion injury may occur after decompression surgery. Riluzole treatment attenuated oxidative DNA damage in the spinal cord and postoperative decline after decompression surgery. Mechanistic in vitro studies also demonstrated that riluzole preserved mitochondrial function and reduced oxidative damage in neurons. Rats receiving combined decompression surgery and riluzole treatment displayed long-term improvements in forelimb function associated with preservation of cervical motor neurons and corticospinal tracts compared to rats treated with decompression surgery alone.
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http://dx.doi.org/10.1126/scitranslmed.aac6524DOI Listing
December 2015

Variation in apparent diffusion coefficient measurements among women with locally advanced cervical cancer.

Radiother Oncol 2015 Dec 14;117(3):532-5. Epub 2015 Sep 14.

Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Canada.

ADC variability from mixed data sets acquired from women with locally advanced cervical cancer appears to be predominantly of biologic origin. Intra-histology ADC variance was similar when pooled across technical factors. Inter-histology pooling increased ADC variance. Normalization to urine ADC improved intra-histology variance and receiver-operator curve test performance.
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http://dx.doi.org/10.1016/j.radonc.2015.09.010DOI Listing
December 2015

Readout-segmented echo-planar diffusion-weighted imaging improves geometric performance for image-guided radiation therapy of pelvic tumors.

Radiother Oncol 2015 Dec 8;117(3):525-31. Epub 2015 Aug 8.

Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.

Background And Purpose: Diffusion-weighted imaging using echo-planar imaging (EPI) is prone to geometric inaccuracy, which may limit application to image-guided radiation therapy planning, as well as for voxel-based quantitative multi-parametric or multi-modal approaches. This research investigates pelvic applications at 3 T of a standard single-shot (ssEPI) and a prototype readout-segmented (rsEPI) technique.

Materials And Methods: Apparent diffusion coefficient (ADC) accuracy and geometric performance of rsEPI and ssEPI were compared using phantoms, and in vivo, involving 8 patients prior to MR-guided brachytherapy for locally advanced cervical cancer, and 19 patients with prostate cancer planned for tumor-targeted radiotherapy. Global and local deviations in geometric performance were tested using Dice Similarity Coefficients (DC) and Hausdorff Distances (HD).

Results: In cervix patients, DC increased from 0.76±0.14 to 0.91±0.05 for the high risk clinical target volume, and 0.62±0.26 to 0.85±0.08 for the gross tumor target volume. Tumors in the peripheral zone of the prostate gland were partly projected erroneously outside of the posterior anatomic boundary of the gland by 3.1±1.6 mm in 11 of 19 patients using ADC-ssEPI but not with ADC-rsEPI.

Conclusions: Both cervix and prostate ssEPI are prone to clinically relevant geometric distortions at 3T. rsEPI provides improved geometric performance without post-processing.
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http://dx.doi.org/10.1016/j.radonc.2015.07.046DOI Listing
December 2015

Therapeutically Targeting Tumor Necrosis Factor-α/Sphingosine-1-Phosphate Signaling Corrects Myogenic Reactivity in Subarachnoid Hemorrhage.

Stroke 2015 Aug 2;46(8):2260-70. Epub 2015 Jul 2.

From the Department of Physiology (D.L., J.C.F., A.M., S.-S.B.), Physical Sciences, Sunnybrook Research Institute and Medical Biophysics (H.W.), and Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research (S.-S.B.), University of Toronto, Toronto, Canada; Department of Neurosurgery, St. Michael's Hospital, Toronto, Canada (K.Y., M.S., J.A., R.L.M.); Department of Neurosurgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan (K.Y., M.S., S.N.); Toronto Centre for Microvascular Medicine, University of Toronto at the Li Ka Shing Knowledge Institute at St. Michael's Hospital, Toronto, Canada (D.L., S.-S.B.); Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada (H.W., J.A., R.L.M., S.-S.B.); Department of Radiation Oncology, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Canada (W.D.F.); Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia (S.A.N.); and Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.).

Background And Purpose: Subarachnoid hemorrhage (SAH) is a complex stroke subtype characterized by an initial brain injury, followed by delayed cerebrovascular constriction and ischemia. Current therapeutic strategies nonselectively curtail exacerbated cerebrovascular constriction, which necessarily disrupts the essential and protective process of cerebral blood flow autoregulation. This study identifies a smooth muscle cell autocrine/paracrine signaling network that augments myogenic tone in a murine model of experimental SAH: it links tumor necrosis factor-α (TNFα), the cystic fibrosis transmembrane conductance regulator, and sphingosine-1-phosphate signaling.

Methods: Mouse olfactory cerebral resistance arteries were isolated, cannulated, and pressurized for in vitro vascular reactivity assessments. Cerebral blood flow was measured by speckle flowmetry and magnetic resonance imaging. Standard Western blot, immunohistochemical techniques, and neurobehavioral assessments were also used.

Results: We demonstrate that targeting TNFα and sphingosine-1-phosphate signaling in vivo has potential therapeutic application in SAH. Both interventions (1) eliminate the SAH-induced myogenic tone enhancement, but otherwise leave vascular reactivity intact; (2) ameliorate SAH-induced neuronal degeneration and apoptosis; and (3) improve neurobehavioral performance in mice with SAH. Furthermore, TNFα sequestration with etanercept normalizes cerebral perfusion in SAH.

Conclusions: Vascular smooth muscle cell TNFα and sphingosine-1-phosphate signaling significantly enhance cerebral artery tone in SAH; anti-TNFα and anti-sphingosine-1-phosphate treatment may significantly improve clinical outcome.
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http://dx.doi.org/10.1161/STROKEAHA.114.006365DOI Listing
August 2015

Manganese oxide and docetaxel co-loaded fluorescent polymer nanoparticles for dual modal imaging and chemotherapy of breast cancer.

J Control Release 2015 Jul 20;209:186-96. Epub 2015 Apr 20.

Advanced Pharmaceutics and Drug Delivery Laboratory, Leslie L. Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada. Electronic address:

Multifunctional nanoparticles (NPs) have found important applications in diagnosis, chemotherapy, and image-guided surgery of tumors. In this work, we have developed polymeric theranostic NPs (PTNPs) containing the anticancer drug docetaxel (DTX), a fluorescent dye, and magnetic manganese oxide (MnO) NPs for dual modal imaging and chemotherapy. PTNPs ~150 nm in diameter were synthesized by co-loading hydrophobic DTX and MnO NPs ~5 nm in diameter, into the matrix of a fluorescent dye-labeled amphiphilic polymer. The PTNPs enabled high loading efficiency and sustained in vitro release of DTX. Energy-dependent cellular uptake and extended cytoplasmic retention of the PTNPs in MDA-MB-231 human breast cancer cells were observed by fluorescence microscopy examination. DTX-loaded PTNPs exhibited higher cytotoxicity than free DTX with a 3 to 4.4-fold decrease in drug dose required for 50% cell growth inhibition. The hydrophilic backbone of the amphiphilic polymer improved the fluidity of PTNPs which enhanced the longitudinal relaxivity (r1) of loaded MnO NPs by 2.7-fold with r1=2.4mM(-1)s(-1). Whole body fluorescence imaging (FI) and magnetic resonance imaging (MRI) showed significant accumulation and prolonged retention of PTNPs in orthotopic MDA-MB-231 breast tumors. These results suggest that the new amphiphilic polymer-based PTNP system, able to simultaneously deliver a poorly soluble anticancer drug, enhance MRI contrast, and stain tumor tissue by fluorescence, is a good candidate for cancer theranostic applications.
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http://dx.doi.org/10.1016/j.jconrel.2015.04.020DOI Listing
July 2015

A multifunctional polymeric nanotheranostic system delivers doxorubicin and imaging agents across the blood-brain barrier targeting brain metastases of breast cancer.

ACS Nano 2014 Oct 13;8(10):9925-40. Epub 2014 Oct 13.

Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Ontario M5S 3M2, Canada.

Metastatic brain cancers, in particular cancers with multiple lesions, are one of the most difficult malignancies to treat owing to their location and aggressiveness. Chemotherapy for brain metastases offers some hope. However, its efficacy is severely limited as most chemotherapeutic agents are incapable of crossing the blood-brain barrier (BBB) efficiently. Thus, a multifunctional nanotheranostic system based on poly(methacrylic acid)-polysorbate 80-grafted-starch was designed herein for the delivery of BBB-impermeable imaging and therapeutic agents to brain metastases of breast cancer. In vivo magnetic resonance imaging and confocal fluorescence microscopy were used to confirm extravasation of gadolinium and dye-loaded nanoparticles from intact brain microvessels in healthy mice. The targetability of doxorubicin (Dox)-loaded nanoparticles to intracranially established brain metastases of breast cancer was evaluated using whole body and ex vivo fluorescence imaging of the brain. Coexistence of nanoparticles and Dox in brain metastatic lesions was further confirmed by histological and microscopic examination of dissected brain tissue. Immuno-histochemical staining for caspase-3 and terminal-deoxynucleotidyl transferase dUTP nick end labeling for DNA fragmentation in tumor-bearing brain sections revealed that Dox-loaded nanoparticles selectively induced cancer cell apoptosis 24 h post-injection, while sparing normal brain cells from harm. Such effects were not observed in the mice treated with free Dox. Treatment with Dox-loaded nanoparticles significantly inhibited brain tumor growth compared to free Dox at the same dose as assessed by in vivo bioluminescence imaging of the brain metastases. These findings suggest that the multifunctional nanoparticles are promising for the treatment of brain metastases.
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http://dx.doi.org/10.1021/nn501069cDOI Listing
October 2014

MR-guided prostate biopsy for planning of focal salvage after radiation therapy.

Radiology 2015 Jan 8;274(1):181-91. Epub 2014 Sep 8.

From the Radiation Medicine Program (C.M., D.I., J.P., J.L., J.A., A.S., W.D.F., M.M., C.C., R.B., A.B., D.A.J., P.C., K.K.B.) and Department of Biostatistics (E.G.A.), Princess Margaret Cancer Centre, 610 University Ave, Room 5-809, Toronto, ON, Canada M4X 1C3; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada (C.M., D.I., A.S., M.M., C.C., G.M., R.B., A.B., D.A.J., P.C., K.K.B.); Department of Radiation Oncology, Wellington Cancer Centre, Wellington, New Zealand (D.I.), Departments of Anesthesia (G.O.) and Pathology (A.J.E.), University Health Network, University of Toronto, Toronto, Ontario, Canada; Department of Radiation Oncology, Odette Cancer Center, Toronto, Ontario, Canada (G.M.); Department of Radiation Oncology, Wellington Cancer Centre, Wellington, New Zealand (D.I.); and Joint Department of Medical Imaging, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada (M.A.H.).

Purpose: To determine if the integration of diagnostic magnetic resonance (MR) imaging and MR-guided biopsy would improve target delineation for focal salvage therapy in men with prostate cancer.

Materials And Methods: Between September 2008 and March 2011, 30 men with biochemical failure after radiation therapy for prostate cancer provided written informed consent and were enrolled in a prospective clinical trial approved by the institutional research ethics board. An integrated diagnostic MR imaging and interventional biopsy procedure was performed with a 1.5-T MR imager by using a prototype table and stereotactic transperineal template. Multiparametric MR imaging (T2-weighted, dynamic contrast material-enhanced, and diffusion-weighted sequences) was followed by targeted biopsy of suspicious regions and systematic sextant sampling. Biopsy needle locations were imaged and registered to diagnostic images. Two observers blinded to clinical data and the results of prior imaging studies delineated tumor boundaries. Area under the receiver operating characteristic curve (Az) was calculated based on generalized linear models by using biopsy as the reference standard to distinguish benign from malignant lesions.

Results: Twenty-eight patients were analyzed. Most patients (n = 22) had local recurrence, with 82% (18 of 22) having unifocal disease. When multiparametric volumes from two observers were combined, it increased the apparent overall tumor volume by 30%; however, volumes remained small (mean, 2.9 mL; range, 0.5-8.3 mL). Tumor target boundaries differed between T2-weighted, dynamic contrast-enhanced, and diffusion-weighted sequences (mean Dice coefficient, 0.13-0.35). Diagnostic accuracy in the identification of tumors improved with a multiparametric approach versus a strictly T2-weighted or dynamic contrast-enhanced approach through an improvement in sensitivity (observer 1, 0.65 vs 0.35 and 0.44, respectively; observer 2, 0.82 vs 0.64 and 0.53, respectively; P < .05) and improved further with a 5-mm expansion margin (Az = 0.85 vs 0.91 for observer 2). After excluding three patients with fewer than six informative biopsy cores and six patients with inadequately stained margins, MR-guided biopsy enabled more accurate delineation of the tumor target volume be means of exclusion of false-positive results in 26% (five of 19 patients), false-negative results in 11% (two of 19 patients) and by guiding extension of tumor boundaries in 16% (three of 19 patients).

Conclusion: The integration of guided biopsy with diagnostic MR imaging is feasible and alters delineation of the tumor target boundary in a substantial proportion of patients considering focal salvage.
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http://dx.doi.org/10.1148/radiol.14122681DOI Listing
January 2015

Bilateral contusion-compression model of incomplete traumatic cervical spinal cord injury.

J Neurotrauma 2014 Nov 12;31(21):1776-88. Epub 2014 Sep 12.

1 Division of Genetics and Development, Toronto Western Research Institute, Krembil Neuroscience Center, University Health Network , Toronto, Ontario, Canada .

Despite the increasing incidence and prevalence of cervical spinal cord injury (cSCI), we lack clinically relevant animal models that can be used to study the pathomechanisms of this injury and test new therapies. Here, we characterize a moderate cervical contusion-compression model in rats that is similar to incomplete traumatic cSCI in humans. We characterized the effects of 18-g clip-compression injury at cervical level C6 over an 8-week recovery period. Using Luxol fast blue/hematoxylin-eosin staining in combination with quantitative stereology, we determined that 18-g injury results in loss of gray matter (GM), white matter (WM), as well as in cavity formation. Magnetization transfer and T2-weighted magnetic resonance imaging were used to analyze lesion dynamics in vivo. This analysis demonstrated that both techniques are able to differentiate between the injury epicenter, subpial rim, and WM distal to the injury. Neurobehavioral assessment of locomotor function using Basso, Beattie, and Bresnahan (BBB) scoring and CatWalk revealed limited recovery from clip-compression injury at C6. Testing of forelimb function using grip strength demonstrated significant forelimb dysfunction, similar to the loss of upper-limb motor function observed in human cSCI. Sensory-evoked potentials recorded from the forelimb and Hoffman reflex recorded from the hindlimb confirmed the fore- and hindlimb deficits observed in our neurobehavioral analysis. Here, we have characterized a clip-compression model of incomplete cSCI that closely models this condition in humans. This work directly addresses the current lack of clinically relevant models of cSCI and will thus contribute to improved success in the translation of putative therapies into the clinic.
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http://dx.doi.org/10.1089/neu.2014.3388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186801PMC
November 2014

Heat-activated thermosensitive liposomal cisplatin (HTLC) results in effective growth delay of cervical carcinoma in mice.

J Control Release 2014 Mar 15;178:69-78. Epub 2014 Jan 15.

Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada; STTARR Innovation Center, University Health Network, Toronto, ON M5G 1L7, Canada. Electronic address:

Cisplatin (CDDP) has been identified as the primary chemotherapeutic agent for the treatment of cervical cancer, but dose limiting toxicity is a key issue associated with its clinical application. A suite of liposome formulations of CDDP has been developed in efforts to reduce systemic toxicity, but their therapeutic advantage over the free drug has been modest due to insufficient drug release at the tumor site. This report describes the development of a novel heat-activated thermosensitive liposome formulation containing CDDP (HTLC) designed to release approximately 90% of the loaded drug in less than 5min under mild heating conditions (42°C). Physico-chemical characteristics of HTLC were assessed in terms of gel to liquid crystalline phase transition temperature (Tm), drug loading efficiency, particle size, and stability. The pharmacokinetic profile and biodistribution of HTLC in non-tumor-bearing mice were evaluated over a 24h period. A sophisticated spatio-temporal elucidation of HTLC release in tumor-bearing mice was achieved by way of real-time monitoring using a magnetic resonance (MR) imaging protocol, wherein a custom-built laser-based conformal heat source was applied at the tumor volume to trigger the release of HTLC co-encapsulated with the MR contrast agent gadoteridol (Gd-HP-DO3A). MR thermometry (MRT) demonstrated that a relatively uniform temperature distribution was achieved in the tumor volume using the external laser-based heating setup. In mice bearing subcutaneously-implanted ME-180 cervical tumors, the combination of HTLC and heat resulted in a 2-fold increase in tumor drug levels at 1h post-administration compared to HTLC without heating. Furthermore, the overall tumor accumulation levels for the HTLC groups (with and without heat) at 1h post-injection were significantly higher than the corresponding free CDDP group. This translated into a significant improvement in therapeutic efficacy evaluated as tumor growth delay (p<0.05) for the heated HTLC treatment group compared to the unheated HTLC, heated or unheated free CDDP, and saline groups. Overall, findings from this study demonstrate that a heat-activated, triggered release formulation of CDDP results in a significant enhancement in the therapeutic index of this drug.
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http://dx.doi.org/10.1016/j.jconrel.2014.01.009DOI Listing
March 2014

Molecular alterations in the hippocampus after experimental subarachnoid hemorrhage.

J Cereb Blood Flow Metab 2014 Jan 25;34(1):108-17. Epub 2013 Sep 25.

Division of Neurosurgery, St Michael's Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre of the Li Ka Shing Knowledge Institute of St Michael's Hospital, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.

Patients with aneurysmal subarachnoid hemorrhage (SAH) frequently have deficits in learning and memory that may or may not be associated with detectable brain lesions. We examined mediators of long-term potentiation after SAH in rats to determine what processes might be involved. There was a reduction in synapses in the dendritic layer of the CA1 region on transmission electron microscopy as well as reduced colocalization of microtubule-associated protein 2 (MAP2) and synaptophysin. Immunohistochemistry showed reduced staining for GluR1 and calmodulin kinase 2 and increased staining for GluR2. Myelin basic protein staining was decreased as well. There was no detectable neuronal injury by Fluoro-Jade B, TUNEL, or activated caspase-3 staining. Vasospasm of the large arteries of the circle of Willis was mild to moderate in severity. Nitric oxide was increased and superoxide anion radical was decreased in hippocampal tissue. Cerebral blood flow, measured by magnetic resonance imaging, and cerebral glucose metabolism, measured by positron emission tomography, were no different in SAH compared with control groups. The results suggest that the etiology of loss of LTP after SAH is not cerebral ischemia but may be mediated by effects of subarachnoid blood such as oxidative stress and inflammation.
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http://dx.doi.org/10.1038/jcbfm.2013.170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887350PMC
January 2014

Docetaxel conjugate nanoparticles that target α-smooth muscle actin-expressing stromal cells suppress breast cancer metastasis.

Cancer Res 2013 Aug;73(15):4862-71

Drug Delivery and Formulation, Drug Discovery Program, Ontario Institute for Cancer Research, 101 College Street, MaRS Centre South Tower, Suite 800,Toronto, Ontario M5G 0A3, Canada.

Docetaxel-conjugate nanoparticles, known as Cellax, were synthesized by covalently conjugating docetaxel and polyethylene glycol to acetylated carboxymethylcellulose via ester linkages, yielding a polymeric conjugate that self-assembled into 120 nm particles suitable for intravenous administration. In 4T1 and MDA-MB-231 orthotopic breast tumor models, Cellax therapy reduced α-smooth muscle actin (α-SMA) content by 82% and 70%, respectively, whereas native docetaxel and nab-paclitaxel (albumin-paclitaxel nanoparticle, Abraxane) exerted no significant antistromal activity. In Cellax-treated mice, tumor perfusion was increased by approximately 70-fold (FITC-lectin binding), tumor vascular permeability was enhanced by more than 30% (dynamic contrast-enhanced magnetic resonance imaging), tumor matrix was decreased by 2.5-fold (immunohistochemistry), and tumor interstitial fluid pressure was suppressed by approximately 3-fold after Cellax therapy compared with the control, native docetaxel, and nab-paclitaxel groups. The antistromal effect of Cellax treatment corresponded to a significantly enhanced antimetastatic effect: lung nodules were reduced by 7- to 24-fold by Cellax treatment, whereas native docetaxel and nab-paclitaxel treatments were ineffective. Studies of the 4T1 tumor showed that more than 85% of the Cellax nanoparticles were delivered to the α-SMA+ stroma. Significant tumor stromal depletion occurred within 16 hours (∼50% depletion) postinjection, and the α-SMA+ stroma population was almost undetectable (∼3%) by 1 week. The 4T1 tumor epithelial cell population was not significantly reduced in the week after Cellax injection. These data suggest that Cellax targets tumor stroma and performs more efficaciously than docetaxel and nab-paclitaxel.
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http://dx.doi.org/10.1158/0008-5472.CAN-13-0062DOI Listing
August 2013

Multifunctional terpolymeric MRI contrast agent with superior signal enhancement in blood and tumor.

J Control Release 2013 Apr 23;167(1):11-20. Epub 2013 Jan 23.

Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada M5S 3M2.

A new multifunctional terpolymeric system for simultaneous imaging and drug delivery has been recently developed in our laboratory. Herein we report the investigation of terpolymeric contrast agent for magnetic resonance imaging and doxorubicin (Dox) delivery. The polymer was synthesized by graft polymerization of methacrylic acid (MAA) and polysorbate 80 (PS 80) onto starch with multiple, chemically bound diethylenetriaminepenta acetic acid (DTPA) groups for gadolinium chelating. The terpolymer self-assembled to form nanoparticles upon addition of doxorubicin which binds with the PMAA chain. The physicochemical, biological and pharmacokinetic properties of the polymeric system were characterized and their contrast enhancement capability was evaluated in vitro and in vivo. The polymer was able to load gadolinium with high thermodynamic stability and exhibited low cytotoxicity. The Gd-loaded polymer (PolyGd), and Gd-Dox co-loaded nanoparticles (PolyGd-Dox) significantly enhanced MR signals, with ionic T1 relaxivities 3-5 times higher than those from Omniscan®, a small molecule contrast agent. In vivo studies showed superior and prolonged contrast enhancement compared to Omniscan® at one fourth the equivalent dose, without adverse effects. The PolyGd and PolyGd-Dox accumulated in the tumor and painted the tumor boundaries clearly for at least 48h. The PolyGd also enhanced angiogram contrast with contrast to noise ratio values of up to 55-fold and a blood half-life time of 200min. Seven days after intravenous administration, only relatively small amounts of gadolinium could be detected in the major organs of the mice (supplementary materials). These results suggest that the new terpolymeric system is useful as a theranostic platform for contrast enhanced MR imaging of vasculature and tumor as well as Dox delivery.
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http://dx.doi.org/10.1016/j.jconrel.2013.01.014DOI Listing
April 2013

Tumor-stroma interaction in orthotopic primary pancreatic cancer xenografts during hedgehog pathway inhibition.

Int J Cancer 2013 Jul 5;133(1):225-34. Epub 2013 Feb 5.

Ontario Cancer Institute/Princess Margaret Hospital, ON, Canada.

To test the effects of hedgehog (Hh) pathway inhibition on the stroma of orthotopically grown primary pancreatic cancer xenografts, and investigate the potential to monitor these effects non-invasively using magnetic resonance imaging (MRI), mice bearing orthotopically grown primary pancreatic cancer xenografts were treated with the Hh neutralizing antibody 5E1. Pathway inhibition was determined by RT-PCR using primer sets for human and mouse Hh pathway genes, and effects on stroma assessed by automated image analysis of tissue sections stained for collagen and α-smooth muscle actin (αSMA). MRI provided quantitative biomarkers of stromal density based on magnetization transfer (MT-MRI) and dynamic contrast enhancement (DCE-MRI). Modest growth inhibition was seen in both models tested using 5E1, but was greater in OCIP19, which showed high expression of mouse Hh pathway genes and an extensive fibrous stroma. However, despite profound inhibition of both mouse and human Hh pathway genes, in neither model did we observe depletion of the stroma. Alignment of MT-MRI ratio images to histological sections showed co-registration with areas of fibrosis, although this was confounded by the presence of tumor necrosis. Due to the lack of stromal depletion by 5E1 it was not possible to determine the utility of MT-MRI for monitoring this effect. Cancer- and stromal cell-derived Hh signaling elements are expressed in orthotopic primary pancreatic cancer xenografts, and selective targeting is growth-inhibitory. In contrast to some recent reports, growth inhibition does not involve attenuation of the tumor stroma, pointing to additional effects of Hh signaling in pancreatic cancer.
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http://dx.doi.org/10.1002/ijc.28006DOI Listing
July 2013

MRI manifestations of persistent microvascular obstruction and acute left ventricular remodeling in an experimental reperfused myocardial infarction.

Quant Imaging Med Surg 2012 Mar;2(1):12-20

Imaging Research and Schulich Heart Program, Sunnybrook Health Sciences Centre, University of Toronto, Canada;

Purpose: To investigate varied manifestations of persistent microvascular obstruction (PMO) and acute left ventricular (LV) remodeling in an experimental reperfused myocardial infarction (MI) using MRI.

Methods: In eleven Yorkshire pigs an acute MI was produced through a 90-minute balloon occlusion of the middle left anterior descending coronary artery, followed by reperfusion. All animals underwent MRI examinations on a 1.5T system including a SSFP functional study, first pass myocardial perfusion (FPMP), T1 preparation Look-Locker and delayed contrast-enhanced MRI (DE-MRI). Imaging was performed immediately post-intervention (day 0) and at days 7-9. In four animals a repeat MRI examination was performed at day 2 as well. Upon study completion, animals underwent histological analysis including infarct assessment with triphenyltetrazolium chloride (TTC).

Results: Following reperfusion, Thrombolysis In Myocardial Infarction (TIMI) Flow grade 3 was achieved in all animals, demonstrated by repeat angiography following balloon deflation (day 0). Various MR appearances of PMO were noticed including predominance in the subendocardial region, a central core within the infarcted tissue and also multiple separate clusters. In ten of eleven animals PMO was demonstrated as a persistent hypo-enhanced area in FPMP and DE-MRI, and identified as bright regions in later T1 difference images. In one animal PMO was identified only at day 2. At day 7-9 PMO could be identified on early DE-MRI at 5-15 minutes post Gd injection but not on late DE-MRI and T1 difference images after 45-60 minutes post-contrast. A larger volume of PMO and MI at day 2 was noted in comparison to data from day 0 but the difference was not statistically significant. An increased end-diastolic LV volume (EDV) without changes in end-systolic LV volume (ESV) and LV mass at end-diastolic phase (LVM) was observed at day 7-9 in comparison to data from day 0. There was good correlation between the relative extent of persistent MO in the infarcted myocardium (% MO/MI) and EDV at day 7-9 (r=0.83, n=10, P=0.003). MI was confirmed in all animals by TTC staining and/or histology.

Conclusion: A variable MR appearance of persistent microvascular obstruction is observed during a short time course MRI study of reperfused acute MI. Acute negative LV remodeling was closely related to the relative extent of persistent microvascular obstruction within the infarct myocardium.
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http://dx.doi.org/10.3978/j.issn.2223-4292.2011.12.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496497PMC
March 2012

Changes in apparent diffusion coefficient and T2 relaxation during radiotherapy for prostate cancer.

J Magn Reson Imaging 2013 Apr 23;37(4):909-16. Epub 2012 Oct 23.

Radiation Medicine Program, Princess Margaret Hospital, and Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.

Purpose: To evaluate regional and temporal changes in apparent diffusion coefficient (ADC) and T2 relaxation during radiation therapy (RT) in patients with low and intermediate risk localized prostate cancer.

Materials And Methods: Seventeen patients enrolled on a prospective clinical trial where MRI was acquired every 2 weeks throughout eight weeks of image-guided prostate IMRT (78 Gy/39 fractions). ADC and T2 quantification used entire prostate, central gland, benign peripheral zone, and tumor-dense regions-of-interest, and mean values were evaluated for common response trends.

Results: Overall, the RT responses were greater than volunteer measurement repeatability, and week 6 appeared to be an optimum time-point for early detection. RT effects on the entire prostate were best detected using ADC (5-7% by week 2, P < 0.0125), effects on peripheral zone were best detected using T2 (19% reduction at week 6; P = 0.004) and effects on tumors were best detected using ADC (14% elevation at week 6; P = 0.004).

Conclusion: ADC and T2 may be candidate biomarkers of early response to RT warranting further investigation against clinical outcomes.
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http://dx.doi.org/10.1002/jmri.23885DOI Listing
April 2013

Human aortic endothelial cell labeling with positive contrast gadolinium oxide nanoparticles for cellular magnetic resonance imaging at 7 Tesla.

Mol Imaging 2012 Apr;11(2):166-75

Department of Physiology and Experimental Medicine, The Research Institute, The Hospital for Sick Children, Toronto, ON, Canada.

Positive T₁ contrast using gadolinium (Gd) contrast agents can potentially improve detection of labeled cells on magnetic resonance imaging (MRI). Recently, gadolinium oxide (Gd₂O₃) nanoparticles have shown promise as a sensitive T₁ agent for cell labeling at clinical field strengths compared to conventional Gd chelates. The objective of this study was to investigate Gado CELLTrack, a commercially available Gd₂O₃ nanoparticle, for cell labeling and MRI at 7 T. Relaxivity measurements yielded r1  =  4.7 s⁻¹ mM⁻¹ and r₂/r₁  =  6.2. Human aortic endothelial cells were labeled with Gd₂O₃ at various concentrations and underwent MRI from 1 to 7 days postlabeling. The magnetic resonance relaxation times T₁ and T₂ of labeled cell pellets were measured. Cellular contrast agent uptake was quantified by inductively coupled plasma-atomic emission spectroscopy, which showed very high uptake compared to conventional Gd compounds. MRI demonstrated significant positive T₁ contrast and stable labeling on cells. Enhancement was optimal at low Gd concentrations, attained in the 0.02 to 0.1 mM incubation concentration range (corresponding cell uptake was 7.26 to 34.1 pg Gd/cell). Cell viability and proliferation were unaffected at the concentrations tested and up to at least 3 days postlabeling. Gd₂O₃ is a promising sensitive and stable positive contrast agent for cellular MRI at 7 T.
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April 2012

Tumor-targeted drug delivery using MR-contrasted docetaxel - carboxymethylcellulose nanoparticles.

Biomaterials 2012 May 25;33(15):3931-41. Epub 2012 Feb 25.

Drug Delivery and Formulation Group, Medicinal Chemistry Platform, Ontario Institute for Cancer Research, MaRS Centre South Tower, Toronto, Ontario M5G 0A3, Canada.

A carboxymethylcellulose-based polymer conjugate with nanoparticle forming properties (Cellax) has been shown to enhance the pharmacokinetics, specificity of biodistribution, anti-tumor efficacy and safety of docetaxel (DTX) in comparison to the Taxotere™ formulation. We examined Cellax and Taxotere efficacy in four tumor models (EMT-6, B16F10, PC3, and MDA-MB-231), and observed variances in efficacy. To explore whether differences in tumor uptake of Cellax were responsible for these effects, we incorporated superparamagnetic iron oxide nanoparticles (SPIONs) into Cellax particles to enable magnetic resonance (MR) imaging (Cellax-MR). In the EMT-6 tumor model, Cellax-MR nanoparticles exhibited peak tumor accumulation 3-24 h post intravenous injection, and 3 days post-treatment, significant MR contrast was still detected. The amount of Cellax-MR deposited in the EMT-6 tumors was quantifiable as a hypointense volume fraction, a value positively correlated with drug content as determined by LC/MS analysis (R(2) = 0.97). In the four tumor models, Cellax-MR uptake was linearly associated with anti-tumor efficacy (R(2) > 0.9), and was correlated with blood vessel density (R(2) > 0.9). We have affirmed that nanoparticle uptake is variable in tumor physiology, and that this efficacy-predictive parameter can be non-invasively estimated in real-time using a theranostic variant of Cellax.
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http://dx.doi.org/10.1016/j.biomaterials.2012.02.019DOI Listing
May 2012

A novel technique to enable experimental validation of deformable dose accumulation.

Med Phys 2012 Feb;39(2):765-76

Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.

Purpose: To propose a novel technique to experimentally validate deformable dose algorithms by measuring 3D dose distributions under the condition of deformation using deformable gel dosimeters produced by a novel gel fabrication method.

Method: Five gel dosimeters, two rigid control gels and three deformable gels, were manufactured and treated with the same conformal plan that prescribed 400 cGy to the isocenter. The control gels were treated statically; the deformable gels were treated while being compressed by an actuation device to simulate breathing motion (amplitude of compression  = 1, 1.5, and 2 cm, respectively; frequency  =  16 rpm). Comparison between the dose measured by the control gels and the corresponding static dose distribution calculated in the treatment planning system (TPS) has determined the intrinsic dose measurement uncertainty of the gel dosimeters. Doses accumulated using MORFEUS, a biomechanical model-based deformable registration and dose accumulation algorithm, were compared with the doses measured by the deformable gel dosimeters to verify the accuracy of MORFEUS using dose differences at each voxel as well as the gamma index test. Flexible plastic wraps were used to contain and protect the deformable gels from oxygen infiltration, which inhibits the gels' dose sensitizing ability. Since the wraps were imperfect oxygen barrier, dose comparison between MORFEUS and the deformable gels was performed only in the central region with a received dose of 200 cGy or above to exclude the peripheral region where oxygen penetration had likely affected dose measurements.

Results: Dose measured with the control gels showed that the intrinsic dose measurement uncertainty of the gel dosimeters was 11.8 cGy or 4.7% compared to the TPS. The absolute mean voxel-by-voxel dose difference between the accumulated dose and the dose measured with the deformable gels was 4.7 cGy (SD = 36.0 cGy) or 1.5% (SD = 13.4%) for the three deformable gels. The absolute mean vector distance between the 250, 300, 350, and 400 cGy isodose surfaces on the accumulated and measured distributions was 1.2 mm (SD < 1.5 mm). The gamma index test that used the dose measurement precision of the control gels as the dose difference criterion and 2 mm as the distance criterion was performed, and the average pass rate of the accumulated dose distributions for all three deformable gels was 92.7%. When the distance criterion was relaxed to 3 mm, the average pass rate increased to 96.9%.

Conclusion: This study has proposed a novel technique to manufacture deformable volumetric gel dosimeters. By comparing the doses accumulated in MORFEUS and the doses measured with the dosimeters under the condition of deformation, the study has also demonstrated the potential of using deformable gel dosimetry to experimentally validate algorithms that include deformations into dose computation. Since dose less than 200 cGy was not evaluated in this study, future investigations will focus more on low dose regions by either using bigger gel dosimeters or prescribing a lower dose to provide a more complete experimental validation of MORFEUS across a wider dose range.
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http://dx.doi.org/10.1118/1.3676185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272068PMC
February 2012