Publications by authors named "Kyle R Padgett"

27 Publications

  • Page 1 of 1

Repeatability of CBCT radiomic features and their correlation with CT radiomic features for prostate cancer.

Med Phys 2021 Feb 18. Epub 2021 Feb 18.

Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, USA.

Purpose: Radiomic features of cone-beam CT (CBCT) images have potential as biomarkers to predict treatment response and prognosis for patients of prostate cancer. Previous studies of radiomic feature analysis for prostate cancer were assessed in a variety of imaging modalities, including MRI, PET, and CT, but usually limited to a pretreatment setting. However, CBCT images may provide an opportunity to capture early morphological changes to the tumor during treatment that could lead to timely treatment adaptation. This work investigated the quality of CBCT-based radiomic features and their relationship with reconstruction methods applied to the CBCT projections and the preprocessing methods used in feature extraction. Moreover, CBCT features were correlated with planning CT (pCT) features to further assess the viability of CBCT radiomic features.

Methods: The quality of 42 CBCT-based radiomic features was assessed according to their repeatability and reproducibility. Repeatability was quantified by correlating radiomic features between 20 CBCT scans that also had repeated scans within 15 minutes. Reproducibility was quantified by correlating radiomic features between the planning CT (pCT) and the first fraction CBCT for 20 patients. Concordance correlation coefficients (CCC) of radiomic features were used to estimate the repeatability and reproducibility of radiomic features. The same patient dataset was assessed using different reconstruction methods applied to the CBCT projections. CBCT images were generated using 18 reconstruction methods using iterative (iCBCT) and standard (sCBCT) reconstructions, three convolution filters, and five noise suppression filters. Eighteen preprocessing settings were also considered.

Results: Overall, CBCT radiomic features were more repeatable than reproducible. Five radiomic features are repeatable in > 97% of the reconstruction and preprocessing methods, and come from the gray-level size zone matrix (GLSZM), neighborhood gray-tone difference matrix (NGTDM), and gray-level-run length matrix (GLRLM) radiomic feature classes. These radiomic features were reproducible in > 9.8% of the reconstruction and preprocessing methods. Noise suppression and convolution filter smoothing increased radiomic features repeatability, but decreased reproducibility. The top-repeatable iCBCT method (iCBCT-Sharp-VeryHigh) is more repeatable than the top-repeatable sCBCT method (sCBCT-Smooth) in 64% of the radiomic features.

Conclusion: Methods for reconstruction and preprocessing that improve CBCT radiomic feature repeatability often decrease reproducibility. The best approach may be to use methods that strike a balance repeatability and reproducibility such as iCBCT-Sharp-VeryLow-1-Lloyd-256 that has 17 repeatable and eight reproducible radiomic features. Previous radiomic studies that only used pCT radiomic features have generated prognostic models of prostate cancer outcome. Since our study indicates that CBCT radiomic features correlated well with a subset of pCT radiomic features, one may expect CBCT radiomics to also generate prognostic models for prostate cancer.
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http://dx.doi.org/10.1002/mp.14787DOI Listing
February 2021

Assessment of daily dose accumulation for robustly optimized intensity modulated proton therapy treatment of prostate cancer.

Phys Med 2021 Jan 11;81:77-85. Epub 2021 Jan 11.

Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address:

Purpose: To implement a daily CBCT based dose accumulation technique in order to assess ideal robust optimization (RO) parameters for IMPT treatment of prostate cancer.

Methods: Ten prostate cancer patients previously treated with VMAT and having daily CBCT were included. First, RO-IMPT plans were created with ± 3 mm and ± 5 mm patient setup and ± 3% proton range uncertainties, respectively. Second, the planning CT (pCT) was deformably registered to the CBCT to create a synthetic CT (sCT). Both daily and weekly sampling strategies were employed to determine optimal dose accumulation frequency. Doses were recalculated on sCTs for both ± 3 mm/±3% and ± 5 mm/±3% uncertainties and were accumulated back to the pCT. Accumulated doses generated from ± 3 mm/±3% and ± 5 mm/±3% RO-IMPT plans were evaluated using the clinical dose volume constraints for CTV, bladder, and rectum.

Results: Daily accumulated dose based on both ± 3mm/±3% and ±5 mm/±3% uncertainties for RO-IMPT plans resulted in satisfactory CTV coverage (RO-IMPT CTV = 99.01 ± 0.87% vs. RO-IMPT CTV = 99.81 ± 0.2%, P = 0.002). However, the accumulated dose based on ± 3 mm/3% RO-IMPT plans consistently provided greater OAR sparing than ±5 mm/±3% RO-IMPT plans (RO-IMPT rectum = 2.93 ± 2.39% vs. RO-IMPT rectum = 4.38 ± 3%, P < 0.01; RO-IMPT bladder = 5.2 ± 7.12% vs. RO-IMPT bladder = 7.12 ± 9.59%, P < 0.01). The gamma analysis showed high dosimetric agreement between weekly and daily accumulated dose distributions.

Conclusions: This study demonstrated that for RO-IMPT optimization, ±3mm/±3% uncertainty is sufficient to create plans that meet desired CTV coverage while achieving superior sparing to OARs when compared with ± 5 mm/±3% uncertainty. Furthermore, weekly dose accumulation can accurately estimate the overall dose delivered to prostate cancer patients.
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http://dx.doi.org/10.1016/j.ejmp.2020.11.035DOI Listing
January 2021

Assessment of online adaptive MR-guided stereotactic body radiotherapy of liver cancers.

Phys Med 2020 Sep 8;77:54-63. Epub 2020 Aug 8.

Department of Radiation Oncology, University of Miami, Miami, FL, USA; Department of Biomedical Engineering, University of Miami, Miami, FL, USA.

Purpose/objective: Online Adaptive Radiotherapy (ART) with daily MR-imaging has the potential to improve dosimetric accuracy by accounting for inter-fractional anatomical changes. This study provides an assessment for the feasibility and potential benefits of online adaptive MRI-Guided Stereotactic Body Radiotherapy (SBRT) for treatment of liver cancer.

Materials/methods: Ten patients with liver cancer treated with MR-Guided SBRT were included. Prescription doses ranged between 27 and 50 Gy in 3-5 fx. All SBRT fractions employed daily MR-guided setup while utilizing cine-MR gating. Organs-at-risk (OARs) included duodenum, bowel, stomach, kidneys and spinal cord. Daily MRIs and contours were utilized to create each adapted plan. Adapted plans used the beam-parameters and optimization-objectives from the initial plan. Planning target volume (PTV) coverage and OAR constraints were used to compare non-adaptive and adaptive plans.

Results: PTV coverage for non-adapted treatment plans was below the prescribed coverage for 32/47 fractions (68%), with 11 fractions failing by more than 10%. All 47 adapted fractions met prescribed coverage. OAR constraint violations were also compared for several organs. The duodenum exceeded tolerance for 5/23 non-adapted and 0/23 for adapted fractions. The bowel exceeded tolerance for 5/34 non-adaptive and 1/34 adaptive fractions. The stomach exceeded tolerance for 4/19 non-adapted and 1/19 for adaptive fractions. Accumulated dose volume histograms were also generated for each patient.

Conclusion: Online adaptive MR-Guided SBRT of liver cancer using daily re-optimization resulted in better target conformality, coverage and OAR sparing compared with non-adaptive SBRT. Daily adaptive planning may allow for PTV dose escalation without compromising OAR sparing.
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http://dx.doi.org/10.1016/j.ejmp.2020.07.027DOI Listing
September 2020

Dichotomous Locomotor Recoveries Are Predicted by Acute Changes in Segmental Blood Flow after Thoracic Spinal Contusion Injuries in Pigs.

J Neurotrauma 2019 05 20;36(9):1399-1415. Epub 2018 Nov 20.

1 The Miami Project to Cure Paralysis, University of Miami, Miller School of Medicine, Miami, Florida.

Neuroimaging facilitates the translation of animal pre-clinical research to human application. The large porcine spinal cord is useful for testing invasive interventions. Ideally, the safety and efficacy of a delayed intervention is tested in pigs that have recovered sufficiently after spinal cord injury (SCI) to allow either deterioration or improvement of function to be detected. We set out to create moderate severity T9 injuries in Yucatan minipigs by conducting a bridging study adapting methods previously developed in infant piglets. The injury severity was varied according to two pneumatic impactor parameters: the piston compression depth into tissue or the velocity. To stratify locomotor recovery, a 10-point scale used in prior piglet studies was redefined through longitudinal observations of spontaneous recovery. Using hindlimb body weight support to discriminate injury severity, we found that end-point recovery was strongly bimodal to either non-weight-bearing plegia with reciprocating leg movements (<5/10) or recovery of weight bearing that improved toward a ceiling effect (≥ 8/10). No intermediate recovery animals were observed at 2 months post-injury. The ability of intra-operative ultrasound and acute magnetic resonance imaging (MRI) to provide immediate predictive feedback regarding tissue and vascular changes following SCI was assessed. There was an inverse association between locomotor outcome and early gray matter hemorrhage on MRI and ultrasound. Epicenter blood flow following contusion predicted recovery or non-recovery of weight-bearing. The depth of the dorsal cerebrospinal fluid space, which varied between animals, influenced injury severity and confounded the results in this fixed-stroke paradigm.
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http://dx.doi.org/10.1089/neu.2018.6087DOI Listing
May 2019

Dosimetric Benefits and Practical Pitfalls of Daily Online Adaptive MRI-Guided Stereotactic Radiation Therapy for Pancreatic Cancer.

Pract Radiat Oncol 2019 Jan 25;9(1):e46-e54. Epub 2018 Aug 25.

Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, Miami, Florida. Electronic address:

Purpose: Magnetic resonance imaging guided (MRI-g) radiation therapy provides visualization of the target and organs at risk (OARs), allowing for daily online adaptive radiation therapy (OART). We hypothesized that MRI-g OART would improve OAR sparing and target coverage in patients with pancreatic cancer treated with stereotactic body radiation therapy (SBRT).

Methods And Materials: Ten patients received pancreas SBRT to a dose of 33 to 40 Gy in 5 fractions. The dose was prescribed to 90% coverage of the planning target volume at 100% isodose (PTV100). After each fraction's setup magnetic resonance imaging scan, the target position was aligned by 3-dimensional shifts, the normal anatomy was recontoured, and the original radiation therapy plan was recalculated to create a nonadaptive plan. A reoptimized (adaptive) plan was then generated for each fraction and renormalized to 90% coverage of PTV100. Target and OAR doses between nonadaptive and adaptive plans were compared to assess the dosimetric impact of daily adaptation.

Results: The PTV100 mean for adaptive and nonadaptive techniques was 90% and 80.4% (range, 46%-97%), respectively (P = .0008). Point maximum (Dmax) 38 Gy duodenum objectives were met in 43 adaptive fractions compared with 32 nonadaptive fractions (P = .022). Both PTV100 ≥90% and all OAR objectives were achieved in 28 adaptive fractions compared with only 3 nonadaptive fractions. For nonadaptive plans, interfraction increases in stomach volume correlated with higher stomach V33 (P = .004), stomach Dmax (P = .009), duodenum V33 (P = .021), and duodenum Dmax (P = .105). No correlation was observed between stomach volume and OAR doses for adaptive plans. OART plans with Dmax violations of the spinal cord (20 Gy) in 4 fractions and large bowel (38 Gy) in 5 fractions were identified (although not delivered).

Conclusions: MRI-g OART improves target coverage and OAR sparing for pancreas SBRT. This benefit partially results from mitigation of interfraction variability in stomach volume. Caution must be exercised to evaluate all OARs near the treatment area.
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http://dx.doi.org/10.1016/j.prro.2018.08.010DOI Listing
January 2019

Towards a universal MRI atlas of the prostate and prostate zones : Comparison of MRI vendor and image acquisition parameters.

Strahlenther Onkol 2019 Feb 23;195(2):121-130. Epub 2018 Aug 23.

Department of Radiation Oncology, Miller School of Medicine University of Miami, 1475 NW 12th Avenue, Suite 1515J, 33136, Miami, FL, USA.

Background And Purpose: The aim of this study was to evaluate an automatic multi-atlas-based segmentation method for generating prostate, peripheral (PZ), and transition zone (TZ) contours on MRIs with and without fat saturation (±FS), and compare MRIs from different vendor MRI systems.

Methods: T2-weighted (T2) and fat-saturated (T2FS) MRIs were acquired on 3T GE (GE, Waukesha, WI, USA) and Siemens (Erlangen, Germany) systems. Manual prostate and PZ contours were used to create atlas libraries. As a test MRI is entered, the procedure for atlas segmentation automatically identifies the atlas subjects that best match the test subject, followed by a normalized intensity-based free-form deformable registration. The contours are transformed to the test subject, and Dice similarity coefficients (DSC) and Hausdorff distances between atlas-generated and manual contours were used to assess performance.

Results: Three atlases were generated based on GE_T2 (n = 30), GE_T2FS (n = 30), and Siem_T2FS (n = 31). When test images matched the contrast and vendor of the atlas, DSCs of 0.81 and 0.83 for T2 ± FS were obtained (baseline performance). Atlases performed with higher accuracy when segmenting (i) T2FS vs. T2 images, likely due to a superior contrast between prostate vs. surrounding tissue; (ii) prostate vs. zonal anatomy; (iii) in the mid-gland vs. base and apex. Atlases performance declined when tested with images with differing contrast and MRI vendor. Conversely, combined atlases showed similar performance to baseline.

Conclusion: The MRI atlas-based segmentation method achieved good results for prostate, PZ, and TZ compared to expert contoured volumes. Combined atlases performed similarly to matching atlas and scan type. The technique is fast, fully automatic, and implemented on commercially available clinical platform.
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http://dx.doi.org/10.1007/s00066-018-1348-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358462PMC
February 2019

Magnetic resonance imaging (MRI)-based radiomics for prostate cancer radiotherapy.

Transl Androl Urol 2018 Jun;7(3):445-458

Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

In radiotherapy (RT) of prostate cancer, dose escalation has been shown to reduce biochemical failure. Dose escalation only to determinate prostate tumor habitats has the potential to improve tumor control with less toxicity than when the entire prostate is dose escalated. Other issues in the treatment of the RT patient include the choice of the RT technique (hypo- or standard fractionation) and the use and length of concurrent/adjuvant androgen deprivation therapy (ADT). Up to 50% of high-risk men demonstrate biochemical failure suggesting that additional strategies for defining and treating patients based on improved risk stratification are required. The use of multiparametric MRI (mpMRI) is rapidly gaining momentum in the management of prostate cancer because of its improved diagnostic potential and its ability to combine functional and anatomical information. Currently, the Prostate Imaging, Reporting and Diagnosis System (PIRADS) is the standard of care for region of interest (ROI) identification and risk classification. However, PIRADS was not designed for 3D tumor volume delineation; there is a large degree of subjectivity and PIRADS does not accurately and reproducibly elucidate inter- and intra-lesional spatial heterogeneity. "Radiomics", as it refers to the extraction and analysis of large number of advanced quantitative radiological features from medical images using high throughput methods, is perfectly suited as an engine to effectively sift through the multiple series of prostate mpMRI sequences and quantify regions of interest. The radiomic efforts can be summarized in two main areas: (I) detection/segmentation of the suspicious lesion; and (II) assessment of the aggressiveness of prostate cancer. As related to RT, the goal of the latter is in particular to identify patients at high risk for metastatic disease; and the aim of the former is to identify and segment cancerous lesions and thus provide targets for radiation boost. The article is structured as follows: first, we describe the radiomic approach; and second, we discuss the radiomic pipeline as tailored for RT of prostate cancer. In this process we summarize the current efforts and progress in integrating mpMRI radiomics into the radiotherapeutic management of prostate cancer with emphasis placed on its role in treatment target definition, treatment plan strategizing, and prognostic assessment. The described concepts, methods and tools are not currently applicable to the radiation oncology practice outside of the research setting. More data are required in the form of clinical trials to assess the robustness of radiomics-based predictive models, and to maximize the efficacy of these models.
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http://dx.doi.org/10.21037/tau.2018.06.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043736PMC
June 2018

Magnetic Resonance-guided External Beam Radiation and Brachytherapy for a Patient with Intact Cervical Cancer.

Cureus 2018 May 4;10(5):e2577. Epub 2018 May 4.

Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, USA.

Radiation treatment verification has improved significantly over the past decades. The field has moved from film X-rays and skin marks to fiducial tracking and daily cone beam computed tomography (CBCT) for tumor localization. We now have the ability to perform daily on-board magnetic resonance imaging (MRI), which provides superior soft tissue contrast compared to computed tomography (CT). In the management of cervical cancer, the brachytherapy literature has demonstrated that MRI allows for better delineation of the high-risk clinical target volume (HR-CTV) and the use of MRI-guided brachytherapy has translated into improved treatment outcomes. Consensus contouring guidelines for intensity modulated radiation therapy (IMRT) for cervical cancer advise including the whole uterus in the target volume and adding large planning target volume (PTV) margins to account for inter-fractional uterine motion and target motion resulting from variable rectal and bladder filling. MRI-guided radiation therapy (MRgRT) systems enable the possibility to precisely delineate the target volume on a daily basis and to perform truly adaptive delivery. This advancement in technology provides the opportunity to explore how external beam treatment volumes could be safely reduced for better sparing of pelvic organs for the benefit of our patients with cervical cancer. We describe the MR-guided definitive external beam radiation therapy and brachytherapy for a 32-year-old woman with intact cervical cancer. We contoured the uterus, bladder, rectum, and gross tumor volume (GTV) on each of her 25 set-up MRIs. We demonstrate a steady reduction in the GTV and increased displacement of the uterus and GTV as the GTV decreased in size. The findings presented suggest that cervical cancer could greatly benefit from an adaptive MRgRT approach.
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http://dx.doi.org/10.7759/cureus.2577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034762PMC
May 2018

An Automated Multiparametric MRI Quantitative Imaging Prostate Habitat Risk Scoring System for Defining External Beam Radiation Therapy Boost Volumes.

Int J Radiat Oncol Biol Phys 2018 11 13;102(4):821-829. Epub 2018 Jun 13.

Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida. Electronic address:

Purpose: To develop a prostate tumor habitat risk scoring (HRS) system based on multiparametric magnetic resonance imaging (mpMRI) referenced to prostatectomy Gleason score (GS) for automatic delineation of gross tumor volumes. A workflow for integration of HRS into radiation therapy boost volume dose escalation was developed in the framework of a phase 2 randomized clinical trial (BLaStM).

Methods And Materials: An automated quantitative mpMRI-based 10-point pixel-by-pixel method was optimized to prostatectomy GSs and volumes using referenced dynamic contrast-enhanced and apparent diffusion coefficient sequences. The HRS contours were migrated to the planning computed tomography scan for boost volume generation.

Results: There were 51 regions of interest in 12 patients who underwent radical prostatectomy (26 with GS ≥7 and 25 with GS 6). The resultant heat maps showed inter- and intratumoral heterogeneity. The HRS6 level was significantly associated with radical prostatectomy regions of interest (slope 1.09, r = 0.767; P < .0001). For predicting the likelihood of cancer, GS ≥7 and GS ≥8 HRS6 area under the curve was 0.718, 0.802, and 0.897, respectively. HRS was superior to the Prostate Imaging, Reporting and Diagnosis System 4/5 classification, wherein the area under the curve was 0.62, 0.64, and 0.617, respectively (difference with HR6, P < .0001). HRS maps were created for the first 37 assessable patients on the BLaStM trial. There were an average of 1.38 habitat boost volumes per patient at a total boost volume average of 3.6 cm.

Conclusions: An automated quantitative mpMRI-based method was developed to objectively guide dose escalation to high-risk habitat volumes based on prostatectomy GS.
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http://dx.doi.org/10.1016/j.ijrobp.2018.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245650PMC
November 2018

Feasibility of Adaptive MR-guided Stereotactic Body Radiotherapy (SBRT) of Lung Tumors.

Cureus 2018 Apr 4;10(4):e2423. Epub 2018 Apr 4.

Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, USA.

Online adaptive radiotherapy (ART) with frequent imaging has the potential to improve dosimetric accuracy by accounting for anatomical and functional changes during the course of radiotherapy. Presented are three interesting cases that provide an assessment of online adaptive magnetic resonance-guided radiotherapy (MRgRT) for lung stereotactic body radiotherapy (SBRT). The study includes three lung SBRT cases, treated on an MRgRT system where MR images were acquired for planning and prior to each treatment fraction. Prescription dose ranged from 48 to 50 Gy in four to five fractions, normalized to where 95% of the planning target volume (PTV) was covered by 100% of the prescription dose. The process begins with the gross tumor volume (GTV), PTV, spinal cord, lungs, heart, and esophagus being delineated on the planning MRI. The treatment plan was then generated using a step-and-shoot intensity modulated radiotherapy (IMRT) technique, which utilized a Monte Carlo dose calculation. Next, the target and organs at risk (OAR) contours from the planning MRI were deformably propagated to the daily setup MRIs. These deformed contours were reviewed and modified by the physician. To determine the efficacy of ART, two different strategies were explored: 1) Calculating the plan created for the planning MR on each fraction setup MR dataset (Non-Adapt) and 2) creating a new optimized IMRT plan on the fraction setup MR dataset (FxAdapt). The treatment plans from both strategies were compared using the clinical dose-volume constraints. PTV coverage constraints were not met for 33% Non-Adapt fractions; all FxAdapt fractions met this constraint. Eighty-eight percent of all OAR constraints studied were better on FxAdapt plans, while 12% of OAR constraints were superior on Non-Adapt fractions. The OAR that garnered the largest benefit would be the uninvolved lung, with superior sparing in 92% of the FxAdapt studied. Similar, but less pronounced, benefits from adaptive planning were experienced for the spinal cord, chest wall, and esophagus. Online adaptive MR-guided lung SBRT can provide better target conformality and homogeneity and OAR sparing compared with non-adaptive SBRT in selected cases. Conversely, if the PTV isn't adjacent to multiple OARs, then the benefit from ART may be limited. Further studies, which incorporate a larger cohort of patients with uniform prescriptions, are needed to thoroughly evaluate the benefits of daily online ART during MRgRT.
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http://dx.doi.org/10.7759/cureus.2423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985923PMC
April 2018

Analysis of Magnetic Resonance Image Signal Fluctuations Acquired During MR-Guided Radiotherapy.

Cureus 2018 Mar 28;10(3):e2385. Epub 2018 Mar 28.

Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, USA.

Magnetic resonance-guided radiotherapy (MRgRT) is a new and evolving treatment modality that allows unprecedented visualization of the tumor and surrounding anatomy. MRgRT includes daily 3D magnetic resonance imaging (MRI) for setup and rapidly repeated near real-time MRI scans during treatment for target tracking. One of the more exciting potential benefits of MRgRT is the ability to analyze serial MRIs to monitor treatment response or predict outcomes. A typical radiation treatment (RT) over the span of 10-15 minutes on the MRIdian system (ViewRay, Cleveland, OH) yields thousands of "cine" images, each acquired in 250 ms. This unique data allows for a glimpse in image intensity changes during RT delivery. In this report, we analyze cine images from a single fraction RT of a glioblastoma patient on the ViewRay platform in order to characterize the dynamic signal changes occurring during RT therapy. The individual frames in the cines were saved into DICOM format and read into an MIM image analysis platform (MIM Software, Cleveland, OH) as a time series. The three possible states of the three Cobalt-60 radiation sources-OFF, READY, and ON-were also recorded. An in-house Java plugin for MIM was created in order to perform principal component analysis (PCA) on each of the datasets. The analysis resulted in first PC, related to monotonous signal increase over the course of the treatment fraction. We found several distortion patterns in the data that we postulate result from the perturbation of the magnetic field due to the moving metal parts in the platform while treatment was being administered. The largest variations were detected when all Cobalt-60 sources were OFF. During this phase of the treatment, the gantry and multi-leaf collimators (MLCs) are moving. Conversely, when all Cobalt-60 sources were in the ON position, the image signal fluctuations were minimal, relating to very little mechanical motion. At this phase, the gantry, the MLCs, and sources are fixed in their positions. These findings were confirmed in a study with the daily quality assurance (QA) phantom. While the identified variations were not related to physiological processes, our findings confirm the sensitivity of the developed approach to identify very small fluctuations. Relating these variations to the physical changes that occur during treatment shows the methodical ability of the technique to uncover their underlying sources.
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http://dx.doi.org/10.7759/cureus.2385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973490PMC
March 2018

Daily Tracking of Glioblastoma Resection Cavity, Cerebral Edema, and Tumor Volume with MRI-Guided Radiation Therapy.

Cureus 2018 Mar 19;10(3):e2346. Epub 2018 Mar 19.

Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami.

Radiation therapy (RT) plays a critical role in the treatment of glioblastoma. Studies of brain imaging during RT for glioblastoma have demonstrated changes in the brain during RT. However, frequent or daily utilization of standalone magnetic resonance imaging (MRI) scans during RT have limited feasibility. The recent release of the tri-cobalt-60 MRI-guided RT (MR-IGRT) device (ViewRay MRIdian, Cleveland, OH) allows for daily brain MRI for the RT setup. Daily MRI of three postoperative patients undergoing RT and temozolomide for glioblastoma over a six-week course allowed for the identification of changes to the cavity, edema, and visible tumor on a daily basis. The volumes and dimensions of the resection cavities, edema, and T2-hyperintense tumor were measured. A general trend of daily decreases in cavity measurements was observed in all patients. For the one patient with edema, a trend of daily increases followed by a trend of daily decreases were observed. These results suggest that daily MRI could be used for onboard resimulation and adaptive RT for future fluctuations in the sizes of brain tumors, cavities, or cystic components. This could improve tumor targeting and reduce RT of healthy brain tissue.
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http://dx.doi.org/10.7759/cureus.2346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959724PMC
March 2018

Validation of a deformable MRI to CT registration algorithm employing same day planning MRI for surrogate analysis.

J Appl Clin Med Phys 2018 Mar 23;19(2):258-264. Epub 2018 Feb 23.

Department of Radiation Oncology, University of Miami School of Medicine, Miami, FL, USA.

Purpose: Validating deformable multimodality image registrations is challenging due to intrinsic differences in signal characteristics and their spatial intensity distributions. Evaluating multimodality registrations using these spatial intensity distributions is also complicated by the fact that these metrics are often employed in the registration optimization process. This work evaluates rigid and deformable image registrations of the prostate in between diagnostic-MRI and radiation treatment planning-CT by utilizing a planning-MRI after fiducial marker placement as a surrogate. The surrogate allows for the direct quantitative analysis that can be difficult in the multimodality domain.

Methods: For thirteen prostate patients, T2 images were acquired at two different time points, the first several weeks prior to planning (diagnostic-MRI) and the second on the same day as the planning-CT (planning-MRI). The diagnostic-MRI was deformed to the planning-CT utilizing a commercially available algorithm which synthesizes a deformable image registration (DIR) algorithm from local rigid registrations. The planning-MRI provided an independent surrogate for the planning-CT for assessing registration accuracy using image similarity metrics, including Pearson correlation and normalized mutual information (NMI). A local analysis was performed by looking only within the prostate, proximal seminal vesicles, penile bulb, and combined areas.

Results: The planning-MRI provided an excellent surrogate for the planning-CT with residual error in fiducial alignment between the two datasets being submillimeter, 0.78 mm. DIR was superior to the rigid registration in 11 of 13 cases demonstrating a 27.37% improvement in NMI (P < 0.009) within a regional area surrounding the prostate and associated critical organs. Pearson correlations showed similar results, demonstrating a 13.02% improvement (P < 0.013).

Conclusion: By utilizing the planning-MRI as a surrogate for the planning-CT, an independent evaluation of registration accuracy is possible. This population provides an ideal testing ground for MRI to CT DIR by obviating the need for multimodality comparisons which are inherently more challenging.
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http://dx.doi.org/10.1002/acm2.12296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849829PMC
March 2018

Are in-house diagnostic MR physicists necessary for clinical implementation of MRI guided radiotherapy?

J Appl Clin Med Phys 2017 Sep;18(5):6-9

Department of Radiation Oncology, University of California Davis Medical Center, Sacramento, CA, USA.

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http://dx.doi.org/10.1002/acm2.12171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874809PMC
September 2017

A review of nonstandardized applicators digitization in Nucletron™ HDR procedures.

J Appl Clin Med Phys 2017 Sep 30;18(5):89-96. Epub 2017 Aug 30.

Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, USA.

The major errors in HDR procedures were failures to enter the correct treatment distance, which could be caused by either entering wrong transmission lengths or imprecisely digitizing the dwelling positions. Most of those errors were not easily avoidable by enhancing the HDR management level because they were caused by implementations of nonstandardized applicators utilizing transmission tubes of different lengths in standard HDR procedures. We performed this comprehensive study to include all possible situations with different nonstandardized applicators that frequently occurred in HDR procedures, provide corresponding situations with standard applicator as comparisons, list all possible errors and in planning, clarify the confusions in offsets setting, and provide mathematical and quantitative solutions for each given scenarios. Training on HDR procedures with nonstandardized applicators are normally not included in most residential program for medical physics, thus this study could be meaningful in both clinical and educational purpose. At precision of 1 mm, our study could be used as the essential and practical reference for finding the correct treatment length as well as locating the accurate dwelling positions in any HDR procedure with nonstandardized applicators.
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http://dx.doi.org/10.1002/acm2.12156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875818PMC
September 2017

Evaluation of the tool "Reg Refine" for user-guided deformable image registration.

J Appl Clin Med Phys 2016 05 8;17(3):158-170. Epub 2016 May 8.

Miller School of Medicine, University of Miami.

"Reg Refine" is a tool available in the MIM Maestro v6.4.5 platform (www.mim-software.com) that allows the user to actively participate in the deformable image registration process. The purpose of this work was to evaluate the efficacy of this tool and investigate strategies for how to apply it effectively. This was done by performing DIR on two publicly available ground-truth models, the Pixel-based Breathing Thorax Model (POPI) for lung, and the Deformable Image Registration Evaluation Project (DIREP) for head and neck. Image noise matched in both magnitude and texture to clinical CBCT scans was also added to each model to simulate the use case of CBCT-CT alignment. For lung, the results showed Reg Refine effective at improving registration accuracy when controlled by an expert user within the context of large lung deformation. CBCT noise was also shown to have no effect on DIR performance while using the MIM algorithm for this site. For head and neck, the results showed CBCT noise to have a large effect on the accuracy of registration, specifically for low-contrast structures such as the brain-stem and parotid glands. In these cases, the Reg Refine tool was able to improve the registration accuracy when controlled by an expert user. Several strategies for how to achieve these results have been outlined to assist other users and provide feedback for developers of similar tools.
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http://dx.doi.org/10.1120/jacmp.v17i3.6025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690944PMC
May 2016

Monitoring steady flow effects on cell distribution in engineered valve tissues by magnetic resonance imaging.

Mol Imaging 2013 Oct;12(7):1-13

In heart valve tissue engineering, assessment of cell migration under dynamic states can provide insights on the evolving tissue structure. We labeled human vascular smooth muscle (SMCs), endothelial (ECs), and bone marrow-derived mesenchymal stem cells (BMSCs) with superparamagnetic iron oxide (SPIO) microparticles and visualized them using magnetic resonance imaging (MRI) under steady flow. We determined that vascular cells were able to remain reasonably viable and proliferate well after being labeled with SPIO microparticles (200 μg/mL) for 48 hours. SPIO-labeled cells were successfully visualized using T2* contrast. When physiologically representative shear stresses (5-6 dynes/cm2) were applied to SMC-EC coculture-seeded scaffolds, hypointense regions seemed to have decreased after 2 weeks in some locations, whereas others revealed sustained levels of T2* contrast; similar observations were seen in the case of BMSC-seeded scaffolds. This could be attributable to increased out-of-plane cell migratory activity, which occurred from the fluid-induced mechanical cues received, which was not previously evidenced in static culture. Vascular cells and BMSCs were labeled with remarkably high concentrations of SPIO. Moreover, steady fluid flow enhanced intrascaffold cell migration of vascular SMCs and ECs as well as BMSCs, which, in turn, significantly improved construct cellularity and extracellular collagen content.
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October 2013

A defect in the mitochondrial complex III, but not complex IV, triggers early ROS-dependent damage in defined brain regions.

Hum Mol Genet 2012 Dec 21;21(23):5066-77. Epub 2012 Aug 21.

Department of Neurology, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.

We have created two neuron-specific mouse models of mitochondrial electron transport chain deficiencies involving defects in complex III (CIII) or complex IV (CIV). These conditional knockouts (cKOs) were created by ablation of the genes coding for the Rieske iron-sulfur protein (RISP) and COX10, respectively. RISP is one of the catalytic subunits of CIII and COX10 is an assembly factor indispensable for the maturation of Cox1, one of the catalytic subunits of CIV. Although the rates of gene deletion, protein loss and complex dysfunction were similar, the RISP cKO survived 3.5 months of age, whereas the COX10 cKO survived for 10-12 months. The RISP cKO had a sudden death, with minimal behavioral changes. In contrast, the COX10 cKO showed a distinctive behavioral phenotype with onset at 4 months of age followed by a slower but progressive neurodegeneration. Curiously, the piriform and somatosensory cortices were more vulnerable to the CIII defect whereas cingulate cortex and to a less extent piriform cortex were affected preferentially by the CIV defect. In addition, the CIII model showed severe and early reactive oxygen species damage, a feature not observed until very late in the pathology of the CIV model. These findings illustrate how specific respiratory chain defects have distinct molecular mechanisms, leading to distinct pathologies, akin to the clinical heterogeneity observed in patients with mitochondrial diseases.
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http://dx.doi.org/10.1093/hmg/dds350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3490513PMC
December 2012

Investigation of nanoparticles using magnetic resonance imaging after intravitreal injection.

Clin Exp Ophthalmol 2012 Jan-Feb;40(1):100-7. Epub 2011 Sep 19.

Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.

Background: Magnetic nanoparticles may be used for focal delivery for cells, plasmids or drugs, and other applications. Here we asked whether magnetic nanoparticles could be detected in vivo at different time points after intravitreal injection by magnetic resonance imaging.

Methods: Adult Sprague-Dawley rats received intravitreal injections of 50-nm or 4-µm magnetic particles into the left eye, with an equal volume of phosphate-buffered saline into the right eye (as controls). Animals were examined by magnetic resonance imaging at 1 h, 1 day and 5 weeks after injection. Eyes, brain, liver, spleen and kidney were also imaged with high-resolution ex vivo magnetic resonance imaging scanning.

Results: In vivo magnetic resonance imaging at the 1 h and 1 day time points more clearly detected magnetic particles in the 4 µm group compared with the 50-nm group, although 50-nm magnetic nanoparticles were easily visualized with high-resolution magnetic resonance imaging ex vivo. Five weeks after intravitreal injection magnetic resonance imaging clearly detected 4-µm particles inside the eye, but by this time point the 50-nm magnetic nanoparticles could not be detected by either in vivo or ex vivo high-resolution magnetic resonance imaging. No magnetic particles were detected in any other organ.

Conclusions: Magnetic resonance imaging could be used to track magnetic nanoparticles in the eye with the dosing selected for this study. Clearance varies by size, with 50-nm magnetic nanoparticles cleared more quickly than 4-µm particles. Thus, nanoparticles may provide advantages over micron-scale particles when considering risks associated with long-term persistence.
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http://dx.doi.org/10.1111/j.1442-9071.2011.02651.xDOI Listing
April 2012

Evaluation of a transgenic mouse model of multiple sclerosis with noninvasive methods.

Invest Ophthalmol Vis Sci 2011 Apr 14;52(5):2405-11. Epub 2011 Apr 14.

Bascom Palmer Eye Institute, University of Miami, Miami, Florida 33136, USA.

Purpose: To evaluate the ND4 transgenic mouse model of multiple sclerosis using noninvasive methods.

Methods: Assessment of neurologic/behavioral abnormalities was made using pattern electroretinogram (PERG), magnetic resonance imaging (MRI), optic coherence tomography (OCT), and end point histologic analysis.

Results: Electrophysiologic (PERG) recordings demonstrated functional deficits in vision commensurate with neurologic/behavioral abnormalities. In ND4 mice, the authors found PERG abnormalities preceded neurologic/gait abnormalities. MRI demonstrated subtle structural changes that progressed over time in correlation with behavioral abnormalities.

Conclusions: The ND4 mouse model has been evaluated using well-defined parameters of noninvasive methods (PERG, MRI, and OCT), enabling objective identification of functional and structural deficits and their correlation with neurologic/gait abnormality.
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http://dx.doi.org/10.1167/iovs.10-6425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081251PMC
April 2011

Safety and pharmacokinetic analysis of methotrexate administered directly into the fourth ventricle in a piglet model.

J Neurooncol 2010 Dec 4;100(3):397-406. Epub 2010 May 4.

Department of Neurological Surgery, University of Miami Miller School of Medicine, and Miami Children's Hospital, Miami, FL 33155, USA.

We have developed a piglet model to assess chemotherapy administration directly into the fourth ventricle as a potential treatment for medulloblastoma and other malignant posterior fossa tumors. The objective of this study was to assess safety and pharmacokinetics after methotrexate infusions into the fourth ventricle. Catheters were inserted into the fourth ventricle and lumbar cistern in five piglets. Two milligrams of Methotrexate (MTX) was infused into the fourth ventricle on five consecutive days. Safety was assessed by neurological examination, 4.7 T MRI, and post-mortem pathological analysis. MTX levels in serum and cerebrospinal fluid (CSF) were measured, and area under the concentration-time curve (AUC) was calculated for CSF samples. No neurological deficits were caused by MTX infusions. One piglet died from complications of anesthesia induction for MRI scanning. MRI scans showed accurate catheter placement without signal changes in the brainstem or cerebellum. One piglet had asymptomatic ventriculomegaly. Pathological analysis demonstrated meningitis and choroid plexitis consisting predominantly of CD-3 positive T-lymphocytes in all piglets and a small focal area of subependymal necrosis in one. In all piglets, mean peak MTX level in fourth ventricular CSF exceeded that in lumbar CSF by greater than five-fold. Serum MTX levels were undetectable or negligible. Statistically significant differences between fourth ventricle and lumbar AUC were detected at peaks (P = 0.01) and at all collection time points (P = 0.01) but not at troughs (P = 0.36). MTX can be infused into the fourth ventricle without clinical or radiographic evidence of damage. An inflammatory response without clinical correlate is observed. Significantly higher peak MTX levels are observed in the fourth ventricle than in the lumbar cistern.
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http://dx.doi.org/10.1007/s11060-010-0210-0DOI Listing
December 2010

Pharmacokinetic analysis of etoposide distribution after administration directly into the fourth ventricle in a piglet model.

J Neurooncol 2010 Mar 18;97(1):25-32. Epub 2009 Aug 18.

Department of Neurological Surgery, University of Miami Miller School of Medicine and Miami Children's Hospital, Ambulatory Care Building Suite 3109, Miami, FL 33155, USA.

We hypothesize that infusion of chemotherapeutic agents directly into the fourth ventricle potentially may play a role in treating malignant posterior fossa brain tumors. Accordingly, we used a piglet model developed in our laboratory to test the safety of etoposide infusions into the fourth ventricle and to study the pharmacokinetics associated with these infusions. In 5 piglets, closed-tip silicone catheters were inserted into the fourth ventricle and lumbar cistern. Five consecutive daily infusions of etoposide (0.5 mg) were administered via the fourth ventricle catheter. Serum and CSF from both catheters were sampled for measurement of etoposide level by reversed-phase high performance liquid chromatography (HPLC). For CSF samples, area under the concentration-time curve (AUC) was calculated. Piglets underwent daily neurological examinations, a 4.7 Tesla MRI scan, and then were sacrificed for post-mortem brain examination. No neurological deficits or signs of meningitis were caused by intraventricular chemotherapy infusions. MRI scans showed catheter placement within the fourth ventricle but no signal changes in the brain stem or cerebellum. In all piglets, the mean fourth ventricular CSF peak etoposide level exceeded the mean peak lumbar etoposide levels by greater than 10-fold. Statistically significant differences between fourth ventricle and lumbar AUC were noted at peaks (DeltaAUC = 3384196 ng h/ml with 95%CI: 1758625, 5009767, P = 0.0044) and at all collection time points (DeltaAUC = 1422977 ng h/ml with 95%CI: 732188, 2113766, P = 0.0046) but not at troughs (DeltaAUC = -29546 ng h/ml (95%CI: -147526, 88434.2, P = 0.5251). Serum etoposide was absent at two and four hours after intraventricular infusions in all animals. Pathological analysis demonstrated meningitis, choroid plexitis, and ependymitis in the fourth and occasionally lateral ventricles. Etoposide can be infused directly into the fourth ventricle without clinical or radiographic evidence of damage. Autopsy examination revealed ventriculitis and meningitis which did not have a clinical correlate. Etoposide does not distribute evenly throughout CSF spaces after administration into the fourth ventricle, and higher peak CSF levels are observed in the fourth ventricle than in the lumbar cistern.
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http://dx.doi.org/10.1007/s11060-009-9998-xDOI Listing
March 2010

Labeling of stem cells with monocrystalline iron oxide for tracking and localization by magnetic resonance imaging.

Microvasc Res 2009 Jun 5;78(1):132-9. Epub 2009 Apr 5.

Program in Stem Cell Biology, Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA.

Precise localization of exogenously delivered stem cells is critical to our understanding of their reparative response. Our current inability to determine the exact location of small numbers of cells may hinder optimal development of these cells for clinical use. We describe a method using magnetic resonance imaging to track and localize small numbers of stem cells following transplantation. Endothelial progenitor cells (EPC) were labeled with monocrystalline iron oxide nanoparticles (MIONs) which neither adversely altered their viability nor their ability to migrate in vitro and allowed successful detection of limited numbers of these cells in muscle. MION-labeled stem cells were also injected into the vitreous cavity of mice undergoing the model of choroidal neovascularization, laser rupture of Bruch's membrane. Migration of the MION-labeled cells from the injection site towards the laser burns was visualized by MRI. In conclusion, MION labeling of EPC provides a non-invasive means to define the location of small numbers of these cells. Localization of these cells following injection is critical to their optimization for therapy.
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http://dx.doi.org/10.1016/j.mvr.2009.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755588PMC
June 2009

Chemotherapy administration directly into the fourth ventricle in a new piglet model. Laboratory Investigation.

J Neurosurg Pediatr 2008 May;1(5):373-80

Department of Neurological Surgery, University of Miami Miller School of Medicine and Miami Children's Hospital, Miami, Florida 33155, USA.

Object: The authors hypothesized that chemotherapy infusions directly into the fourth ventricle may potentially play a role in treating malignant posterior fossa tumors. In this study the safety and pharmacokinetics of etoposide administration into the fourth ventricle was tested using an indwelling catheter in piglets.

Methods: A closed-tip silicone lumbar drain catheter was inserted into the fourth ventricle via a posterior fossa craniectomy and 5 daily infusions of etoposide (0.5 mg in 5 animals) or normal saline (in 2 animals) were instilled. Piglets (10-18 kg, 2-3 months of age) underwent daily neurological examinations and 4.7-T magnetic resonance (MR) imaging after the final infusion and were then killed for postmortem examination. Pharmacokinetics were studied using reversed-phase high-performance liquid chromatography on cerebrospinal fluid (CSF) samples at 0.25, 1, 2, 4, 8, 12, and 24 hours after etoposide infusion. Peak and trough CSF etoposide levels were measured for each subsequent infusion. Serum etoposide levels were obtained at 2 and 4 hours after infusion.

Results: All piglets remained neurologically intact, and MR images demonstrated catheter placement within the fourth ventricle without signal changes in the brainstem or cerebellum. Serum etoposide was absent at 2 and 4 hours after intraventricular infusions. When adequate samples could be obtained for analysis, CSF etoposide levels peaked 15 minutes after infusion and progressively decreased. Cytotoxic levels (> 0.1 microg/ml) were maintained for 5 consecutive peak and trough measurements with 1 exception. Etoposide-related neuropathology included moderate-to-severe T-lymphocytic meningitis and fourth and lateral ventricular choroid plexitis with associated subependymal inflammation.

Conclusions: Etoposide can be infused directly into the fourth ventricle without clinical or imaging evidence of damage. Cytotoxic CSF etoposide levels can be maintained for 24 hours with a single daily infusion into the fourth ventricle using an indwelling catheter. Intraventricular etoposide elicits an inflammatory response, the long-term effects of which are as yet undetermined.
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http://dx.doi.org/10.3171/PED/2008/1/5/373DOI Listing
May 2008

Increased susceptibility of S100B transgenic mice to perinatal hypoxia-ischemia.

Ann Neurol 2004 Jul;56(1):61-7

Department of Pediatrics, Division of Neurology, Children's Memorial Hospital, Chicago, IL, USA.

S100B is a glial-derived protein that is a well-established biomarker for severity of neurological injury and prognosis for recovery. Cell-based and clinical studies have implicated S100B in the initiation and maintenance of a pathological, glial-mediated proinflammatory state in the central nervous system. However, the relationship between S100B levels and susceptibility to neurological injury in vivo has not been determined. We used S100B transgenic (Tg) and knockout (KO) mice to test the hypothesis that overexpression of S100B increases vulnerability to cerebral hypoxic-ischemic injury and that this response correlates with an increase in neuroinflammation from activated glia. Postnatal day 8 Tg mice subjected to hypoxia-ischemia showed a significant increase in mortality compared with KO and wild-type mice. Tg mice also exhibited greater cerebral injury and volume loss in the ischemic hemisphere after an 8-day recovery, as assessed by histopathology and magnetic resonance imaging. Measurement of glial fibrillary acidic protein and S100B levels showed a significant increase in the Tg mice, consistent with heightened glial activation and neuroinflammation in response to injury. This is the first demonstration to our knowledge that overexpression of S100B in vivo enhances pathological response to injury.
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http://dx.doi.org/10.1002/ana.20142DOI Listing
July 2004

Ex vivo high-resolution magnetic resonance imaging of the brain in Joubert's syndrome.

J Child Neurol 2002 Dec;17(12):911-3

McKnight Brain Institute, Department of Nuclear and Radiological Sciences, University of Florida, Gainesville, USA.

This study employs ex vivo high-resolution magnetic resonance imaging (MRI) to examine anatomic structures in an intact brain of a child with Joubert's syndrome. Several of the specific hindbrain malformations associated with Joubert's syndrome are well resolved with ex vivo MRI, including the "molar tooth sign," which arises from enlarged and maloriented superior cerebellar peduncles, hypoplastic vermis, and deepening of the interpeduncular fossa. Superior resolution was achieved compared with that of in vivo MRI and included visualization of the inferior olives. One high-resolution study also showed that the decreased width of the brainstem isthmus is probably caused by failure of superior cerebellar peduncles to cross the midline at that level. The results of this study suggest that high-resolution MRI may be useful in screening the brainstem for malformations that can be studied histologically in a much more targeted fashion.
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December 2002