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Functional neuroimaging methods hold promise for the identification of cognitive function and communication capacity in some severely brain-injured patients who may not retain sufficient motor function to demonstrate their abilities. We studied seven severely brain-injured patients and a control group of 14 subjects using a novel hierarchical functional magnetic resonance imaging assessment utilizing mental imagery responses. Whereas the control group showed consistent and accurate (for communication) blood-oxygen-level-dependent responses without exception, the brain-injured subjects showed a wide variation in the correlation of blood-oxygen-level-dependent responses and overt behavioural responses. Specifically, the brain-injured subjects dissociated bedside and functional magnetic resonance imaging-based command following and communication capabilities. These observations reveal significant challenges in developing validated functional magnetic resonance imaging-based methods for clinical use and raise interesting questions about underlying brain function assayed using these methods in brain-injured subjects. [ABSTRACT FROM AUTHOR]

Background: Cerliponase alfa is a recombinant human tripeptidyl peptidase 1 (TPP1) enzyme replacement therapy for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2 disease), which is caused by mutations in the TPP1 gene. We aimed to determine the long-term safety and efficacy of intracerebroventricular cerliponase alfa in children with CLN2 disease., Methods: This analysis includes cumulative data from a primary 48-week, single-arm, open-label, multicentre, dose-escalation study (NCT01907087) and the 240-week open-label extension with 6-month safety follow-up, conducted at five hospitals in Germany, Italy, the UK, and the USA. Children aged 3-16 years with CLN2 disease confirmed by genetic analysis and enzyme testing were eligible for inclusion. Treatment was intracerebroventricular infusion of 300 mg cerliponase alfa every 2 weeks. Historical controls with untreated CLN2 disease in the DEM-CHILD database were used as a comparator group. The primary efficacy outcome was time to an unreversed 2-point decline or score of 0 in the combined motor and language domains of the CLN2 Clinical Rating Scale. This extension study is registered with ClinicalTrials.gov, NCT02485899, and is complete., Findings: Between Sept 13, 2013, and Dec 22, 2014, 24 participants were enrolled in the primary study (15 female and 9 male). Of those, 23 participants were enrolled in the extension study, conducted between Feb 2, 2015, and Dec 10, 2020, and received 300 mg cerliponase alfa for a mean of 272·1 (range 162·1-300·1) weeks. 17 participants completed the extension and six discontinued prematurely. Treated patients were significantly less likely than historical untreated controls to have an unreversed 2-point decline or score of 0 in the combined motor and language domains (hazard ratio 0·14, 95% CI 0·06 to 0·33; p<0·0001). All participants experienced at least one adverse event and 21 (88%) experienced a serious adverse event; nine participants experienced intracerebroventricular device-related infections, with nine events in six participants resulting in device replacement. There were no study discontinuations because of an adverse event and no deaths., Interpretation: Cerliponase alfa over a mean treatment period of more than 5 years was seen to confer a clinically meaningful slowing of decline of motor and language function in children with CLN2 disease. Although our study does not have a contemporaneous control group, the results provide crucial insights into the effects of long-term treatment., Funding: BioMarin Pharmaceutical., Competing Interests: Declaration of interests AS and MN have received payments to their institution as a study site according to clinical trial budget, medical writing support, honoraria, and travel support from BioMarin Pharmaceutical. EDLR has received salary support as the primary investigator and salary support for the research personnel, honoraria, and travel support from BioMarin Pharmaceutical and consulting fees from Zogenix. NS has received consulting fees from BioMarin Pharmaceutical, JAZZ Pharma, UCB, Takeda, and Angeun; honoraria from BioMarin Pharmaceutical, JAZZ Pharma, UCB, and Zogenix; travel fees from BioMarin Pharmaceutical and Jazz Pharma; and current research funding from the Italian Ministry of Health. PG has received payments to his institution as a study site according to clinical trial budget and honoraria and travel support from BioMarin Pharmaceutical. MT has received honoraria from BioMarin Pharmaceutical and current research funding from the Italian Ministry of Health. SCA has received research salary support from BioMarin Pharmaceutical, research effort support for a study of erenumab from Amgen, research effort support for a study of rimegepant from Pfizer, grant support for fellowship training from NINDS/Neuronext, and honoraria as associate editor from Pediatric Neurology. DJB and JPD have received contractor fees paid by BioMarin Pharmaceutical for analysing imaging data that appears in the paper. PS is an employee and stockholder of BioMarin Pharmaceutical. SB and AChe are employees of BioMarin Pharmaceutical. JLCP is an employee and stockholder of BioMarin Pharmaceutical and a scientific advisor for NPKUA. ACha, CS, EW, and LMW reported no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Based on studies in experimental animals demonstrating that administration of adeno-associated virus (AAV) vectors to the cerebrospinal fluid (CSF) is an effective route to transfer genes to the nervous system, there are increasing number of clinical trials using the CSF route to treat nervous system disorders. With the knowledge that the CSF turns over four to five times daily, and evidence in experimental animals that at least some of CSF administered AAV vectors are distributed to systemic organs, we asked: with AAV administration to the CSF, what fraction of the total dose remains in the nervous system and what fraction goes off target and is delivered systemically? To quantify the biodistribution of AAV capsids immediately after administration, we covalently labeled AAV capsids with iodine 124 (I-124), a cyclotron generated positron emitter, enabling quantitative positron emission tomography scanning of capsid distribution for up to 96 h after AAV vector administration. We assessed the biodistribution to nonhuman primates of I-124-labeled capsids from different AAV clades, including 9 (clade F), rh.10 (E), PHP.eB (F), hu68 (F), and rh91(A). The analysis demonstrated that 60-90% of AAV vectors administered to the CSF through either the intracisternal or intrathecal (lumbar) routes distributed systemically to major organs. These observations have potentially significant clinical implications regarding accuracy of AAV vector dosing to the nervous system, evoking systemic immunity at levels similar to that with systemic administration, and potential toxicity of genes designed to treat nervous system disorders being expressed in non-nervous system organs. Based on these data, individuals in clinical trials using AAV vectors administered to the CSF should be monitored for systemic as well as nervous system adverse events and CNS dosing considerations should account for a significant AAV systemic distribution.

Lack of a body-sized, bore-mounted, radiofrequency (RF) body coil for ultrahigh field (UHF) magnetic resonance imaging (MRI) is one of the major drawbacks of UHF, hampering the clinical potential of the technology. Transmit field (B 1 ) nonuniformity and low specific absorption rate (SAR) efficiencies in UHF MRI are two challenges to be overcome. To address these problems, and ultimately provide a pathway for the full clinical potential of the modality, we have designed and simulated two-dimensional cylindrical high-pass ladder (2D c-HPL) architectures for clinical bore-size dimensions, and demonstrated a simplified proof of concept with a head-sized prototype at 7 T. A new dispersion relation has been derived and electromagnetic simulations were used to verify coil modes. The coefficient of variation (CV) for brain, cerebellum, heart, and prostate tissues after B 1 + shimming in silico is reported and compared with previous works. Three prototypes were designed in simulation: a head-sized, body-sized, and long body-sized coil. The head-sized coil showed a CV of 12.3%, a B 1 + efficiency of 1.33 μT/√W, and a SAR efficiency of 2.14 μT/√(W/kg) for brain simulations. The body-sized 2D c-HPL coil was compared with same-sized transverse electromagnetic (TEM) and birdcage coils in silico with a four-port circularly polarized mode excitation. Improved B 1 + uniformity (26.9%) and SAR efficiency (16% and 50% better than birdcage and TEM coils, respectively) in spherical phantoms was observed. We achieved a CV of 12.3%, 4.9%, 16.7%, and 2.8% for the brain, cerebellum, heart, and prostate, respectively. Preliminary imaging results for the head-sized coil show good agreement between simulation and experiment. Extending the 1D birdcage coil concept to 2D c-HPLs provides improved B 1 + uniformity and SAR efficiency., (© 2022 John Wiley & Sons, Ltd.)

Background: The availability of non-invasive means to evaluate and monitor tendon-bone healing processes in-vivo is limited. Micro Positron-Emission-Tomography (µPET) using 18 F-Fluoride is a minimally invasive imaging modality, with which osteoblast activity and bone turnover can be assessed. The aim of this study was to investigate the use of serial in-vivo µPET/CT scans to evaluate bone turnover along the graft-tunnel interface in a rat ACL (anterior cruciate ligament) reconstruction model., Methods: Unilateral autograft ACL reconstruction was performed in six rats. µPET/CT-scans using 18 F-Fluoride were performed 7, 14, 21, and 28 days postoperatively. Standard uptake values (SUV) were calculated for three tunnel regions (intraarticular aperture (IAA), mid-tunnel, and extraarticular aperture (EAA)) of the proximal tibia. Animals were sacrificed at 28 days and evaluated with µCT and histological analysis., Results: SUVs in both bone tunnels showed an increased 18 F-Fluoride uptake at 7 days when compared to 14, 21, and 28 days. SUVs showed a gradient on the tibial side, with most bone turnover in the IAA and least in the EAA. At 7, 14, 21, and 28 days, there were significantly higher SUV values in the IAA compared to the EAA ( p = .01, < .01, < .01, < .01). SUVs positively correlated with new bone volumetric density obtained with μCT (r = 0.449, p = .013). Volumetric density of newly formed bone detected on μCT correlated with osteoblast numbers observed along the tunnels in histological sections (r = 0.452, p < .016)., Conclusions: Serial in-vivo µPET/CT-scanning has the potential to provide insight into bone turnover and therefore osteoblastic activity during the healing process. As a result, it allows us to directly measure the effect of interventional strategies in tendon-bone healing.

Metachromatic leukodystrophy, a fatal pediatric neurodegenerative lysosomal storage disease caused by mutations in the arylsulfatase A ( ARSA ) gene, is characterized by intracellular accumulation of sulfatides in the lysosomes of cells of the central nervous system (CNS). In previous studies, we have demonstrated efficacy of AAVrh.10hARSA, an adeno-associated virus (AAV) serotype rh.10 vector coding for the human ARSA gene to the CNS of a mouse model of the disease, and that catheter-based intraparenchymal administration of AAVrh.10hARSA to the CNS of nonhuman primates (NHPs) white matter results in widespread expression of ARSA. As a formal dose-escalating safety/toxicology study, we assessed the safety of intraparenchymal delivery of AAVrh.10hARSA vector to 12 sites in the white matter of the CNS of NHPs at 2.85 × 10 10 (total low dose, 2.4 × 10 9 genome copies [gc]/site) and 1.5 × 10 12 (total high dose, 1.3 × 10 11 gc/site) gc, compared to AAVrh.10Null (1.5 × 10 12 gc total, 1.3 × 10 11 gc/site) as a vector control, and phosphate buffered saline for a sham surgical control. No significant adverse effects were observed in animals treated with low dose AAVrh.10hARSA. However, animals treated with the high dose AAVrh.10ARSA and the high dose Null vector had highly localized CNS abnormalities on magnetic resonance imaging scans at the sites of catheter infusions, and histopathology demonstrated that these sites were associated with infiltrates of T cells, B cells, microglial cells, and/or macrophages. Although these findings had no clinical consequences, these safety data contribute to understanding the dose limits for CNS white matter direct intraparenchymal administration of AAVrh.10 vectors for treatment of CNS disorders.

Late infantile Batten disease (CLN2 disease) is an autosomal recessive, neurodegenerative lysosomal storage disease caused by mutations in the CLN2 gene encoding tripeptidyl peptidase 1 (TPP1). We tested intraparenchymal delivery of AAVrh.10hCLN2, a nonhuman serotype rh.10 adeno-associated virus vector encoding human CLN2 , in a nonrandomized trial consisting of two arms assessed over 18 months: AAVrh.10hCLN2-treated cohort of 8 children with mild to moderate disease and an untreated, Weill Cornell natural history cohort consisting of 12 children. The treated cohort was also compared to an untreated European natural history cohort of CLN2 disease. The vector was administered through six burr holes directly to 12 sites in the brain without immunosuppression. In an additional safety assessment under a separate protocol, five children with severe CLN2 disease were treated with AAVrh.10hCLN2. The therapy was associated with a variety of expected adverse events, none causing long-term disability. Induction of systemic anti-AAVrh.10 immunity was mild. After therapy, the treated cohort had a 1.3- to 2.6-fold increase in cerebral spinal fluid TPP1. There was a slower loss of gray matter volume in four of seven children by MRI and a 42.4 and 47.5% reduction in the rate of decline of motor and language function, compared to Weill Cornell natural history cohort ( P < 0.04) and European natural history cohort ( P < 0.0001), respectively. Intraparenchymal brain administration of AAVrh.10hCLN2 slowed the progression of disease in children with CLN2 disease. However, improvements in vector design and delivery strategies will be necessary to halt disease progression using gene therapy., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

A method is presented for quantitative analysis of the biodistribution of adeno-associated virus (AAV) gene transfer vectors following in vivo administration. We used iodine-124 (I-124) radiolabeling of the AAV capsid and positron emission tomography combined with compartmental modeling to quantify whole-body and organ-specific biodistribution of AAV capsids from 1 to 72 h following administration. Using intravenous (IV) and intracisternal (IC) routes of administration of AAVrh.10 and AAV9 vectors to nonhuman primates in the absence or presence of anticapsid immunity, we have identified novel insights into initial capsid biodistribution and organ-specific capsid half-life. Neither I-124-labeled AAVrh.10 nor AAV9 administered intravenously was detected at significant levels in the brain relative to the administered vector dose. Approximately 50% of the intravenously administered labeled capsids were dispersed throughout the body, independent of the liver, heart, and spleen. When administered by the IC route, the labeled capsid had a half-life of ∼10 h in the cerebral spinal fluid (CSF), suggesting that by this route, the CSF serves as a source with slow diffusion into the brain. For both IV and IC administration, there was significant influence of pre-existing anticapsid immunity on I-124-capsid biodistribution. The methodology facilitates quantitative in vivo viral vector dosimetry, which can serve as a technique for evaluation of both on- and off-target organ biodistribution, and potentially accelerate gene therapy development through rapid prototyping of novel vector designs.

Objective: Surgical infusion of gene therapy vectors has provided opportunities for biological manipulation of specific brain circuits in both animal models and human patients. Transient focal opening of the blood-brain barrier (BBB) by MR-guided focused ultrasound (MRgFUS) raises the possibility of noninvasive CNS gene therapy to target precise brain regions. However, variable efficiency and short follow-up of studies to date, along with recent suggestions of the potential for immune reactions following MRgFUS BBB disruption, all raise questions regarding the viability of this approach for clinical translation. The objective of the current study was to evaluate the efficiency, safety, and long-term stability of MRgFUS-mediated noninvasive gene therapy in the mammalian brain., Methods: Focused ultrasound under the control of MRI, in combination with microbubbles consisting of albumin-coated gas microspheres, was applied to rat striatum, followed by intravenous infusion of an adeno-associated virus serotype 1/2 (AAV1/2) vector expressing green fluorescent protein (GFP) as a marker. Following recovery, animals were followed from several hours up to 15 months. Immunostaining for GFP quantified transduction efficiency and stability of expression. Quantification of neuronal markers was used to determine histological safety over time, while inflammatory markers were examined for evidence of immune responses., Results: Transitory disruption of the BBB by MRgFUS resulted in efficient delivery of the AAV1/2 vector to the targeted rodent striatum, with 50%-75% of striatal neurons transduced on average. GFP transgene expression appeared to be stable over extended periods of time, from 2 weeks to 6 months, with evidence of ongoing stable expression as long as 16 months in a smaller cohort of animals. No evidence of substantial toxicity, tissue injury, or neuronal loss was observed. While transient inflammation from BBB disruption alone was noted for the first few days, consistent with prior observations, no evidence of brain inflammation was observed from 2 weeks to 6 months following MRgFUS BBB opening, despite delivery of a virus and expression of a foreign protein in target neurons., Conclusions: This study demonstrates that transitory BBB disruption using MRgFUS can be a safe and efficient method for site-specific delivery of viral vectors to the brain, raising the potential for noninvasive focal human gene therapy for neurological disorders.

Late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a rare lysosomal storage disorder caused by a monogenetic deficiency of tripeptidyl peptidase-1 (TPP1). Despite knowledge that lipofuscin is the hallmark disease product, the relevant TPP1 substrate and its role in neuronal physiology/pathology is unknown. We hypothesized that untargeted metabolite profiling of cerebrospinal fluid (CSF) could be used as an effective tool to identify disease-associated metabolic disruptions in CLN2 disease, offering the potential to identify biomarkers that inform on disease severity and progression. Accordingly, a mass spectrometry-based untargeted metabolite profiling approach was employed to differentiate CSF from normal vs. CLN2 deficient individuals. Of 1,433 metabolite features surveyed, 29 linearly correlated with currently employed disease severity scores. With tandem mass spectrometry 8 distinct metabolite identities were structurally confirmed based on retention time and fragmentation pattern matches, vs. standards. These putative CLN2 biomarkers include 7 acetylated species - all attenuated in CLN2 compared to controls. Because acetate is the major bioenergetic fuel for support of mitochondrial respiration, deficient acetylated species in CSF suggests a brain energy defect that may drive neurodegeneration. Targeted analysis of these metabolites in CSF of CLN2 patients offers a powerful new approach for monitoring CLN2 disease progression and response to therapy.

OBJECTIVE The objective of this study was to evaluate the utility of diffusion tensor imaging (DTI) tractography-based targeting of the dentatorubrothalamic tract (DRT) for magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy in patients with essential tremor (ET) and correlate postprocedural tract disruption with clinical outcomes. METHODS Four patients received preprocedural and immediate postprocedural DTI in addition to traditional anatomical MRI sequences for MRgFUS thalamotomy. Optimal ablation sites were selected based on the patient-specific location of the DRT as demonstrated by DTI (direct targeting) and correlated with traditional atlas-based measurements for thalamic ventral intermediate nucleus (Vim) lesioning (indirect targeting). Fiber tracts were displayed three-dimensionally during the procedure and used in conjunction with clinical signs of tremor control for fine correction of the ablation site. Immediately following the conclusion of the procedure, the MRgFUS head frame was removed and patients were placed in a 32-channel MRI head coil for follow-up DTI and anatomical MRI sequences. RESULTS All patients had excellent postoperative tremor control and successful pre- and postprocedural DTI fiber tracking of the corticospinal tract, medial lemniscus, and DRT. Immediate postprocedure DTI failed to track the DRT ipsilateral to the lesion site with a preserved contralateral DRT, coincident with substantial resolution of contralateral tremor. CONCLUSIONS DTI can reliably identify the optimal ablation target and demonstrates tract disruption on immediate postprocedural imaging. A clinical improvement of ET was observed immediately following the procedure, correlating with DRT disruption and suggesting that interruption of the DRT is a consequence of clinically successful MRgFUS thalamotomy. These findings may have utility for both MRgFUS procedure planning in surgically naive patients and retreatment of patients who have previously undergone unsuccessful thalamic Vim lesioning.

Alzheimer's disease (AD) is a progressive degenerative neurological disorder affecting nearly one in nine elderly people in the United States. Population studies have shown that an inheritance of the apolipoprotein E (APOE) variant APOE4 allele increases the risk of developing AD, whereas APOE2 homozygotes are protected from late-onset AD. It was hypothesized that expression of the "protective" APOE2 variant by genetic modification of the central nervous system (CNS) of APOE4 homozygotes could reverse or prevent progressive neurologic damage. To assess the CNS distribution and safety of APOE2 gene therapy for AD in a large-animal model, intraparenchymal, intracisternal, and intraventricular routes of delivery to the CNS of nonhuman primates of AAVrh.10hAPOE2-HA, an AAVrh.10 serotype coding for an HA-tagged human APOE2 cDNA sequence, were evaluated. To evaluate the route of delivery that achieves the widest extent of APOE2 expression in the CNS, the expression of APOE2 in the CNS was evaluated 2 months following vector administration for APOE2 DNA, mRNA, and protein. Finally, using conventional toxicology assays, the safety of the best route of delivery was assessed. The data demonstrated that while all three routes are capable of mediating ApoE2 expression in AD relevant regions, intracisternal delivery of AAVrh.10hAPOE2-HA safely mediated wide distribution of ApoE2 with the least invasive surgical intervention, thus providing the optimal strategy to deliver vector-mediated human APOE2 to the CNS.

We analyze the pulsatile signal component of dynamic echo planar imaging data from the brain by modeling the dependence between local temporal and spatial signal variability. The resulting magnetic resonance advection imaging maps depict the location of major arteries. Color direction maps allow for visualization of the direction of blood vessels. The potential significance of magnetic resonance advection imaging maps is demonstrated on a functional magnetic resonance imaging data set of 19 healthy subjects. A comparison with the here introduced pulse coherence maps, in which the echo planar imaging signal is correlated with a cardiac pulse signal, shows that the magnetic resonance advection imaging approach results in a better spatial definition without the need for a pulse reference. In addition, it is shown that magnetic resonance advection imaging velocities can be estimates of pulse wave velocities if certain requirements are met, which are specified. Although for this application magnetic resonance advection imaging velocities are not quantitative estimates of pulse wave velocities, they clearly depict local pulsatile dynamics. Magnetic resonance advection imaging can be applied to existing dynamic echo planar imaging data sets with sufficient spatiotemporal resolution. It is discussed whether magnetic resonance advection imaging might have the potential to evolve into a biomarker for the health of the cerebrovascular system.

Objectives: To determine imaging protocol parameters for characterization of prostate tissue at histological length scales., Material and Methods: Rapid acquisition with relaxation enhancement, spin echo and gradient echo fast low angle shot data were acquired using ex vivo 3-Tesla or 7-Tesla magnetic field strengths from fresh prostatectomy specimens (n = 15) obtained from either organ donor or patients with prostate cancer (PCa). To achieve the closest correspondence between histopathological components and magnetic resonance imaging (MRI) results, in terms of resolution and sectioning planes, multiple high-resolution imaging protocols (ranging from a few minutes to overnight) were tested. Ductograms were generated as part of image post-processing. Specimens were subsequently submitted for histopathological evaluation., Results: A total of seven imaging protocols were tested. Ex vivo 7-Tesla MRI identified normal components of prostate glands, including ducts, blood vessels, concretions and stroma at a spatial resolution of 60 × 60 × 60 μm 3 to 107 × 107 × 500 μm 3 . Malignant glands and nests of tumour cells identified at 60 × 60 × 90 μm 3 were highly similar to low-magnification (×2) histopathology. Ductograms enhanced the differentiation between benign and malignant glands. The results of the present study were encouraging, and further work is warranted with a larger sample size., Conclusion: We showed that critical histopathological features of the prostate gland can be identified with high-resolution ex vivo MRI examination and this offers promise that MRI microscopy of PCa will ultimately be possible in vivo., (© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.)

Background and Purpose: Permeability surface-area product has been suggested as a marker for BBB permeability with potential applications in clinical care and research. However, few studies have demonstrated its correlation with actual quantitative measurements of BBB permeability. Our aim was to demonstrate the correlation of quantitative permeability surface-area product and BBB permeability in a murine model by histologic confirmation., Materials and Methods: Coronal MR imaging was performed on mice treated with mannitol (n = 6) for disruption of the BBB and controls treated with saline (n = 5). Permeability surface-area product was determined by ROI placement and was compared between saline- and mannitol-treated mice. Correlation was made with contrast-enhancement measurements and immunohistologic-stained sections of tripeptidyl peptidase-1 distribution in mice treated with mannitol and saline followed by injection of a viral vector containing the CLN2 gene, which directs production of tripeptidyl peptidase-1., Results: Significantly increased permeability surface-area product was seen in mannitol- compared with saline-treated mice in the whole brain (P = .008), MCA territory (P = .014), and mixed vascular territories (P = .008). These findings were compared with contrast-enhancement measurements of BBB permeability and were correlated with immunohistologic-stained sections demonstrating BBB permeability to a large vector., Conclusions: Permeability surface-area product is increased in situations with known disruptions of the BBB, as evidenced by immunologic staining of large-vector passage through the BBB and concordance with contrast-enhancement measurements in a murine model. Quantitative permeability surface-area product has potential as an imaging marker of BBB permeability., (© 2016 by American Journal of Neuroradiology.)

Pathologic evaluation of breast specimens requires a fixation and staining procedure of at least 12 hours duration, delaying diagnosis and post-operative planning. Here we introduce an MRI technique with a custom-designed radiofrequency resonator for imaging breast and lymph tissue with sufficient spatial resolution and speed to guide pathologic interpretation and offer value in clinical decision making. In this study, we demonstrate the ability to image breast and lymphatic tissue using 7.0 Tesla MRI, achieving a spatial resolution of 59 × 59 × 94 μm(3) with a signal-to-noise ratio of 15-20, in an imaging time of 56 to 70 minutes. These are the first MR images to reveal characteristic pathologic features of both benign and malignant breast and lymph tissue, some of which were discernible by blinded pathologists who had no prior training in high resolution MRI interpretation.

The median survival of glioblastoma multiforme (GBM) is approximately 1 year. Following surgical removal, systemic therapies are limited by the blood-brain barrier. To circumvent this, we developed a method to modify neurons with the genetic sequence for therapeutic monoclonal antibodies using adeno-associated virus (AAV) gene transfer vectors, directing persistent, local expression in the tumor milieu. The human U87MG GBM cell line or patient-derived early passage GBM cells were administered to the striatum of NOD/SCID immunodeficient mice. AAVrh.10BevMab, an AAVrh.10-based vector coding for bevacizumab (Avastin), an anti-human vascular endothelial growth factor (VEGF) monoclonal antibody, was delivered to the area of the GBM xenograft. Localized expression of bevacizumab was demonstrated by quantitative PCR, ELISA and western blotting. Immunohistochemistry showed that bevacizumab was expressed in neurons. Concurrent administration of AAVrh.10BevMab with the U87MG tumor reduced tumor blood vessel density and tumor volume, and increased survival. Administration of AAVrh.10BevMab 1 week after U87MG xenograft reduced growth and increased survival. Studies with patient-derived early passage GBM primary cells showed a reduction in primary tumor burden with an increased survival. These data support the strategy of AAV-mediated central nervous system gene therapy to treat GBM, overcoming the blood-brain barrier through local, persistent delivery of an anti-angiogenesis monoclonal antibody.

The delivery of therapeutics to neural tissue is greatly hindered by the blood brain barrier (BBB). Direct local delivery via diffusive release from degradable implants or direct intra-cerebral injection can bypass the BBB and obtain high concentrations of the therapeutic in the targeted tissue, however the total volume of tissue that can be treated using these techniques is limited. One treatment modality that can potentially access large volumes of neural tissue in a single treatment is intra-arterial (IA) injection after osmotic blood brain barrier disruption. In this technique, the therapeutic of interest is injected directly into the arteries that feed the target tissue after the blood brain barrier has been disrupted by exposure to a hyperosmolar mannitol solution, permitting the transluminal transport of the therapy. In this work we used contrast enhanced magnetic resonance imaging (MRI) studies of IA injections in mice to establish parameters that allow for extensive and reproducible BBB disruption. We found that the volume but not the flow rate of the mannitol injection has a significant effect on the degree of disruption. To determine whether the degree of disruption that we observed with this method was sufficient for delivery of nanoscale therapeutics, we performed IA injections of an adeno-associated viral vector containing the CLN2 gene (AAVrh.10CLN2), which is mutated in the lysosomal storage disorder Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL). We demonstrated that IA injection of AAVrh.10CLN2 after BBB disruption can achieve widespread transgene production in the mouse brain after a single administration. Further, we showed that there exists a minimum threshold of BBB disruption necessary to permit the AAV.rh10 vector to pass into the brain parenchyma from the vascular system. These results suggest that IA administration may be used to obtain widespread delivery of nanoscale therapeutics throughout the murine brain after a single administration., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Object: Tissue-engineered intervertebral discs (TE-IVDs) represent a new experimental approach for the treatment of degenerative disc disease. Compared with mechanical implants, TE-IVDs may better mimic the properties of native discs. The authors conducted a study to evaluate the outcome of TE-IVDs implanted into the rat-tail spine using radiological parameters and histology., Methods: Tissue-engineered intervertebral discs consist of a distinct nucleus pulposus (NP) and anulus fibrosus (AF) that are engineered in vitro from sheep IVD chondrocytes. In 10 athymic rats a discectomy in the caudal spine was performed. The discs were replaced with TE-IVDs. Animals were kept alive for 8 months and were killed for histological evaluation. At 1, 5, and 8 months, MR images were obtained; T1-weighted sequences were used for disc height measurements, and T2-weighted sequences were used for morphological analysis. Quantitative T2 relaxation time analysis was used to assess the water content and T1ρ-relaxation time to assess the proteoglycan content of TE-IVDs., Results: Disc height of the transplanted segments remained constant between 68% and 74% of healthy discs. Examination of TE-IVDs on MR images revealed morphology similar to that of native discs. T2-relaxation time did not differ between implanted and healthy discs, indicating similar water content of the NP tissue. The size of the NP decreased in TE-IVDs. Proteoglycan content in the NP was lower than it was in control discs. Ossification of the implanted segment was not observed. Histological examination revealed an AF consisting of an organized parallel-aligned fiber structure. The NP matrix appeared amorphous and contained cells that resembled chondrocytes., Conclusions: The TE-IVDs remained viable over 8 months in vivo and maintained a structure similar to that of native discs. Tissue-engineered intervertebral discs should be explored further as an option for the potential treatment of degenerative disc disease.

We have developed a novel minimally invasive technique for the intra-arterial delivery of therapeutics to the mouse brain. CD-1 mice were anesthetized and placed in a lateral decubitus position. A 10mm midline longitudinal incision was made over the thyroid bone. The omohyoid and sternomastoid muscles were retracted to expose the common carotid artery and external carotid artery (ECA). To maximize delivery of administered agents, the superior thyroid artery was ligated or coagulated, and the occipital artery and the pterygopalatine artery (PPA) were temporarily occluded with 6-0 prolene suture. The ECA was carefully dissected and a permanent ligature was placed on its distal segment while a temporary 6-0 prolene ligature was placed on the proximal segment in order to obtain a flow-free segment of vessel. A sterilized 169 μm outer diameter polyimide microcatheter was introduced into the ECA and advanced in retrograde fashion toward the carotid bifurcation. The catheter was then secured and manually rotated so that the microcatheter tip was oriented cephalad in the internal carotid artery (ICA). We were able to achieve reproducible results for selective ipsilateral hemispheric carotid injections of mannitol mediated therapeutics and/or gadolinium-based MRI contrast agent. Survival rates were dependent on the administered agent and ranged from 78 to 90%. This technique allows for reproducible delivery of agents to the ipsilateral cerebral hemisphere by utilizing anterograde catheter placement and temporary ligation of the PPA. This method is cost-effective and associated with a low rate of morbimortality., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Cocaine addiction is a major problem for which there is no approved pharmacotherapy. We have developed a vaccine to cocaine (dAd5GNE), based on the cocaine analog GNE linked to the capsid proteins of a serotype 5 adenovirus, designed to evoke anti-cocaine antibodies that sequester cocaine in the blood, preventing access to the CNS. To assess the efficacy of dAd5GNE in a large animal model, positron emission tomography (PET) and the radiotracer [(11)C]PE2I were used to measure cocaine occupancy of the dopamine transporter (DAT) in nonhuman primates. Repeat administration of dAd5GNE induced high anti-cocaine titers. Before vaccination, cocaine displaced PE2I from DAT in the caudate and putamen, resulting in 62±4% cocaine occupancy. In contrast, dAd5GNE-vaccinated animals showed reduced cocaine occupancy such that when anti-cocaine titers were >4 × 10(5), the cocaine occupancy was reduced to levels of <20%, significantly below the 47% threshold required to evoke the subjective 'high' reported in humans.

Bevacizumab (BV), a humanized monocolonal antibody directed against vascular endothelial growth factor (VEGF), is a standard intravenous (IV) treatment for recurrent glioblastoma multiforme (GBM), that has been introduced recently as an intra-arterial (IA) treatment modality in humans. Since preclinical models have not been reported, we sought to develop a tumor stem cell (TSC) xenograft model to investigate IA BV delivery in vivo. Firefly luciferase transduced patient TSC were injected into the cortex of 35 nude mice. Tumor growth was monitored weekly using bioluminescence imaging. Mice were treated with either intraperitoneal (IP) or IA BV, with or without blood-brain barrier disruption (BBBD), or with IP saline injection (controls). Tumor tissue was analyzed using immunohistochemistry and western blot techniques. Tumor formation occurred in 31 of 35 (89%) mice with a significant signal increase over time (p=0.018). Post mortem histology revealed an infiltrative growth of TSC xenografts in a similar pattern compared to the primary human GBM. Tumor tissue analyzed at 24 hours after treatment revealed that IA BV treatment with BBBD led to a significantly higher intratumoral BV concentration compared to IA BV alone, IP BV or controls (p<0.05). Thus, we have developed a TSC-based xenograft mouse model that allows us to study IA chemotherapy. However, further studies are needed to analyze the treatment effects after IA BV to assess tumor progression and overall animal survival., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Nonbiological total disc replacement is currently being used for the treatment of intervertebral disc (IVD) disease and injury, but these implants are prone to mechanical wear, tear and possible dislodgement. Recently, tissue-engineered total disc replacement (TE-TDR) has been investigated as a possible alternative to more fully replicate the native IVD properties. However, the performance of TE-TDRs has not been studied in the native disc space. In this study, MRI and microcomputed tomography imaging of the rat spine were used to design a collagen (annulus fibrosus)/alginate (nucleus pulposus) TE-TDR to a high degree of geometric accuracy, with less than 10% difference between TE-TDR and the native disc dimensions. Image-based TE-TDR implants were then inserted into the L4/L5 disc space of athymic rats (n = 5) and maintained for 16 weeks. The disc space was fully or partially maintained in three of five animals and proteoglycan and collagen histology staining was similar in composition to the native disc. In addition, good integration was observed between TE-TDR and the vertebral bodies, as well as remnant native IVD tissue. Overall, this study provides evidence that TE-TDR strategies may yield a clinically viable treatment for diseased or injured IVD., (Copyright © 2011 John Wiley & Sons, Ltd.)

Purpose: In this study we investigated the treatment response and survival of intra-arterial (IA) compared to intra-peritoneal (IP) delivery of bevacizumab (BV) in a glioblastoma (GBM) xenograft mouse model., Methods: 3x10(5) U87-Luc cells were stereotactically implanted into the cortex of 35 nude mice and grouped for treatment (n = 7 in each group): IP saline (group 1), single IP BV (group 2), biweekly IP BV for 3 weeks (group 3), single intra-arterial (IA) BV alone (group 4) and single IA BV with blood brain barrier disruption (BBBD) (group 5). Tumor growth was monitored every 3 to 4 days using bioluminescence imaging (BLI) and survival was analyzed by the Kaplan Meier method. Tumor tissue was analyzed using H&E staining and immunohistochemistry., Results: Based on BLI, BV treated mice showed a delayed tumor growth over time compared to control. Kaplan Meier analysis demonstrated a median survival time of 28 days for group 1,31 days for group 2, 34 days for group 3, 36 days for group 4 and 36 days for group 5 (p < 0.0001). Mice treated with repeated IP BV (p = 0.003) or single IA BV with (p = 0.015) or without (p = 0.005) BBBD showed a significant survival benefit compared to single IP BV treated mice. Post mortem analysis revealed a histological pattern with a more discontinuous border between tumor and mouse brain in the repeated IP BV and single IA BV with or without BBBD treated mice compared to the sharply defined edges of single IP BV treated and control mice., Conclusions: In this study we showed a significant survival benefit of repeated IP BV and single IA BV with or without BBBD treated mice compared to single IP BV treated and control mice in a U87 xenograft model.

Social learning is critical for engaging in complex interactions with other individuals. Learning from positive social exchanges, such as acceptance from peers, may be similar to basic reinforcement learning. We formally test this hypothesis by developing a novel paradigm that is based on work in nonhuman primates and human imaging studies of reinforcement learning. The probability of receiving positive social reinforcement from three distinct peers was parametrically manipulated while brain activity was recorded in healthy adults using event-related functional magnetic resonance imaging. Over the course of the experiment, participants responded more quickly to faces of peers who provided more frequent positive social reinforcement, and rated them as more likeable. Modeling trial-by-trial learning showed ventral striatum and orbital frontal cortex activity correlated positively with forming expectations about receiving social reinforcement. Rostral anterior cingulate cortex activity tracked positively with modulations of expected value of the cues (peers). Together, the findings across three levels of analysis--social preferences, response latencies, and modeling neural responses--are consistent with reinforcement learning theory and nonhuman primate electrophysiological studies of reward. This work highlights the fundamental influence of acceptance by one's peers in altering subsequent behavior.

Mouse models are useful for studying genes involved in behavior, but whether they are relevant to human behavior is unclear. Here, we identified parallel phenotypes in mice and humans resulting from a common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, which is involved in anxiety-related behavior. An inbred genetic knock-in mouse strain expressing the variant BDNF recapitulated the phenotypic effects of the human polymorphism. Both were impaired in extinguishing a conditioned fear response, which was paralleled by atypical frontoamygdala activity in humans. Thus, this variant BDNF allele may play a role in anxiety disorders showing impaired learning of cues that signal safety versus threat and in the efficacy of treatments that rely on extinction mechanisms, such as exposure therapy.

The combination of ATO and bortezomib (ATO+bortezomib) has been recently shown to enhance antimyeloma activity; nevertheless, the mechanisms remained unclear in these studies. However, both bortezomib and ATO have been shown to activate the p38 MAPK pathway, which may counteract the enhancement induced by this combination. We studied the cytotoxicity of bortezomib, ATO, and ATO+bortezomib with or without inhibiting p38 MAPK, along with associated molecular changes in myeloma cells. The treatment of myeloma cells with ATO+bortezomib induced higher cytotoxicity than either agent alone. This increased cytotoxicity was further synergistically enhanced by inhibiting p38 MAPK. This effect was preserved in the presence of marrow stromal cells designed to simulate the tumor micro-environment and in the CD138+ neoplastic plasma cells directly isolated from myeloma patients. The enhanced cytotoxicity of ATO+bortezomib was associated with augmented STAT3 inhibition and JNK activation, up-regulation of Bim, p21, p27, p53 as well as down-regulation of Bcl-2. Furthermore, the synergistically potentiated apoptosis by p38 MAPK inhibition was associated with the attenuation of ATO+bortezomib-mediated activation of Hsp27 as well as the enhancement of ATO+bortezomib-mediated JNK activation, p53 up-regulation, and Bcl-2 down-regulation. The results suggest the opportunity for using p38 MAPK inhibition to enhance the efficacy of ATO+bortezomib in myeloma., (2009 Elsevier Ltd. All rights reserved.)

In this report, we discuss the application of a methodology for high-contrast, high-resolution magnetic resonance microscopy (MRM) of murine tissue using a 3.0-T imaging system. We employed a threefold strategy that included customized specimen preparation to maximize image contrast, three-dimensional data acquisition to minimize scan time and custom radiofrequency resonator design to maximize signal sensitivity. Images had a resolution of 100 x 78 x 78 microm(3) with a signal-to-noise ratio per voxel greater than 25:1 and excellent contrast-to-noise ratios over a 30-min acquisition. We quantitatively validated the methods through comparisons of neuroanatomy across two lines of genetically engineered mice. Specifically, we were able to detect volumetric differences of as little as 9% between genetically engineered mouse strains in multiple brain regions that were predictive of underlying impairments in brain development. The overall methodology was straightforward to implement and provides ready access to basic MRM at field strengths that are widely available in both the laboratory and the clinic.

Background and Purpose: The internal carotid artery (ICA) in the rat has a single extracranial branch, which supplies the muscles of mastication. The rat ICA also has multiple intracranial branches including (from proximal to distal): multiple small perforating arteries which supply the hypothalamus and the anterior choroidal artery which supplies the choroid plexus and part of the basal ganglia. At the ICA terminus, the vessel bifurcates into the anterior and middle cerebral arteries. The purpose of this study was to demonstrate selective injection of ICA branches in the rat., Materials and Methods: Microcatheters (mucath1 and mucath2) were fabricated by plugging the tip of 169-mum outer diameter polyimide tubing and perforating the sidewalls. A 450-mum polydimethyl-siloxane cylinder was affixed to the distal tip of mucath2 but not mucath1. We evaluated the territory of mucath1 injection ex vivo using magnetization-prepared rapid acquisition of gradient echo MR imaging of brain specimens injected at necropsy. Territories of mucath1 and mucath2 injection were evaluated in vivo with dynamic susceptibility-weighted contrast-enhanced MR imaging. The territory of mucath2 also was evaluated in vivo with fused static microPET/T1 MR images performed after [(18)F] fluorodeoxyglucose ((18)FDG) injection. We evaluated additional catheterized and injected animals at 48 hours using physical examination, T2 MR images, and postmortem brain histologic specimens., Results: Gadolinium-diethylene-triamine pentaacetic acid (Gd-DTPA) and (18)FDG injected through mucath1 selectively opacified the ipsilateral cerebral hemisphere, with no contralateral opacification. Gd-DTPA injected through mucath2 selectively opacified the territories of the hypothalamic perforating arteries, and anterior choroidal artery. There was no iatrogenic complication 48 hours after 20- to 25-minute injections performed with mucath1 or mucath2., Conclusions: We have developed 2 microcatheters which can be placed in the ICA for selective injection of its branches. One microcatheter selectively injects the ipsilateral cerebral hemisphere. The other selectively injects only the hypothalamus and lateral thalamus.

An increasing body of evidence suggests that the nucleus accumbens (NAcc) is engaged in both incentive reward processes and in adaptive responses to conditioned and unconditioned aversive stimuli. Yet, it has been argued that NAcc activation to aversive stimuli may be a consequence of the rewarding effects of their termination, i.e., relief. To address this question we used fMRI to delineate brain response to the onset and offset of unpleasant and pleasant auditory stimuli in the absence of learning or motor response. Increased NAcc activity was seen for the onset of both pleasant and unpleasant stimuli. Our results support the expanded bivalent view of NAcc function and call for expansion of current models of NAcc function that are solely focused on reward.

The behavior of coupled harmonic oscillators in systems with specified boundary conditions is typically characterized by resonances whose frequency spectra represent harmonics according to properties of the individual oscillators, the interactions between them, and the overall symmetry of the system. Here it is demonstrated that classical one- and two-dimensional radio frequency resonators constrained to a Möbius topology are the formal partners of cylindrical ring resonators, and specifically give rise to half-integral harmonic excitations that are orthogonal to the integral excitations of a ring. In particular, the half-integral harmonics are formally invariant under rotations at a minimum of 4pi rather than 2pi rad, in analogy to the rotational symmetry of fermions in quantum mechanics. The results offer a pathway for discovery in other physical systems as well as the design of novel materials and electronic instrumentation.

The resistance to arsenic trioxide (ATO) treatment is relatively common (55-80%) in multiple myeloma patients. This study found that ATO at clinically achievable concentrations (2-7 mumol/l) activated p38 mitogen-activated protein kinase (MAPK) in both myeloma cell lines and primary myeloma cells, a finding not previously well-documented in myeloma cells. Inhibition of p38 MAPK activation by pharmacological inhibitors (SB203580) or downregulation of p38 MAPK by siRNA significantly increased the apoptosis and/or growth inhibition induced by ATO treatment in myeloma cells. Combination of ATO and p38 MAPK inhibition abolished the interleukin-6 enhanced protection of myeloma cells against ATO treatment. The ATO-resistant cell line developed in our laboratory showed an increase in p38 MAPK activation. The increase of apoptosis by the combination of ATO and SB203580 was accompanied by the activation of caspase-9 and caspase-8 suggesting that both extrinsic and intrinsic apoptotic pathways are involved. Additionally, the p38 MAPK activation by ATO was associated with increased phosphorylation and upregulated expression of Heat shock protein 27. These results suggest that ATO-induced p38 MAPK activation plays an important role in the resistance to ATO in myeloma cells and that p38 MAPK inhibition may overcome resistance to ATO treatment in myeloma patients.

The role of the base in the synthesis of 3'-deoxy-3'-[18F]fluorothymidine, [18F]FLT, via nucleophilic substitution of the nosyl group with [18F]fluoride was investigated. The rate of 18F-incorporation into the molecule dramatically changed as a function of the precursor-to-base ratio. In the presence of excess base, the precursor was consumed by elimination before substitution was complete. When the precursor-to-base ratio was optimal, an overall [18F]FLT yield of 30-40% was achieved even if the precursor amount was as small as 8-13 mg.

A novel two-dimensional ladder network resonator design is introduced for signal transmission and detection in magnetic resonance imaging. It is shown that planar structures consisting solely of inductively coupled elements have a high-pass eigenmode spectrum and exhibit eigenfunctions which can be used for magnetic resonance imaging, including quadrature operation. Two 5 x 5 element prototypes, a planar surface coil and a volume head coil, are presented to demonstrate the suitability of the design for imaging at 3.0 Tesla.

Genetic medicine-based therapies have unlocked the potential for ameliorating diseases previously considered inevitably fatal. Inherent in the clinical trials of genetic medicines are ethical issues of therapeutic misconception, enrollment decisions as they relate to the risks and benefits of research, and the complex relationships among funding sources, investigators, and the families of affected individuals. The purpose of this paper is to help define these complex issues relevant to the use of genetic medicines and to describe the strategy we have used to confront these issues in a phase I trial of adeno-associated virus-mediated gene transfer to the central nervous system of children with late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal lysosomal storage disease associated with progressive neurodegeneration and death by mid-childhood. Our approach to these challenges should provide a useful paradigm for investigators initiating other genetic medicine- based studies to treat inevitably fatal diseases.

Objective: The purpose of this study was to determine the frequency of cancer and the positive predictive value of biopsy in the first screening round of breast MRI in women at high risk of developing breast cancer., Materials and Methods: Retrospective review was performed of the records of 367 consecutive women at high risk of developing breast cancer who had normal findings on mammography and their first breast MRI screening examination during a 2-year period. The frequency of recommending biopsy at the first screening MRI study and the biopsy results were reviewed., Results: Biopsy was recommended in 64 women (17%). Biopsy revealed cancer that was occult on mammography and physical examination in 14 (24%) of 59 women who had biopsy and in 14 (4%) of 367 women who underwent breast MRI screening. Histologic findings in 14 women with cancer were ductal carcinoma in situ in eight (57%) and infiltrating carcinoma in six (43%). The median size of infiltrating carcinoma was 0.4 cm (range, 0.1-1.2 cm). Two patients had nodes that were positive for cancer. Biopsy revealed high-risk lesions (atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, or radial scar) in 13 (4%) of 367 women and other benign findings in 32 (9%) of 367 women who had MRI screening., Conclusion: Among women at high risk of developing breast cancer, breast MRI led to a recommendation of biopsy in 17%. Cancer was found in 24% of women who underwent biopsy and in 4% of women who had breast MRI screening. More than half the MRI-detected cancers were ductal carcinoma in situ.

Objective: The purpose of this study was to analyze features of breast lesions detected on MR imaging that had subsequent biopsy and to determine the positive predictive value (PPV) of these features., Materials and Methods: Retrospective review was performed of 100 consecutive solitary MR imaging-detected breast lesions that had MR imaging-guided needle localization and surgical excision. We described lesions, using terms found in a proposed breast MR imaging lexicon. Histologic findings were reviewed., Results: Carcinoma was identified in 25 lesions (25%), including ductal carcinoma in situ (DCIS) in 13 (52%) and infiltrating carcinoma in 12 (48%). Carcinoma was found in 15 (25%) of 60 masses versus 10 (25%) of 40 nonmass lesions; most malignant masses (73%) were infiltrating carcinoma, whereas most malignant nonmass lesions (90%) were DCIS. The features with the highest PPV were spiculated margin (80% carcinoma), rim enhancement (40% carcinoma), and irregular shape (32% carcinoma) for mass lesions and segmental (67% carcinoma) or clumped linear and ductal enhancement (31% carcinoma) for nonmass lesions. Visually assessed kinetic patterns were not significant predictors of carcinoma, but washout was present in 70% of infiltrating carcinomas versus 9% of DCIS lesions (p < 0.01). Carcinoma was present in 17 (19%) of 88 lesions classified as suspicious versus eight (67%) of 12 lesions classified as highly suggestive of malignancy (p = 0.001)., Conclusion: Among MR imaging-detected breast lesions referred for biopsy, carcinoma was found in 25%, of which half were DCIS. Features with the highest PPV were spiculated margin, rim enhancement, and irregular shape for mass lesions and segmental or clumped linear and ductal enhancement for nonmass lesions. Final assessment categories were significant predictors of carcinoma.

Objective: MR imaging of the breast can depict cancer that is occult on mammography and at physical examination. Our study was undertaken to determine the ease of performance and the outcome of MR imaging-guided needle localization and surgical excision of breast lesions., Materials and Methods: Retrospective review revealed 101 consecutive breast lesions that had preoperative MR imaging-guided needle localization with commercially available equipment, including a 1.5-T magnet with a breast surface coil, a dedicated biopsy compression device, and MR imaging-compatible hookwires. Imaging studies and medical records were reviewed., Results: Histologic findings in these 101 lesions were carcinoma in 31 (30.7%), high-risk lesions (atypical ductal hyperplasia or lobular carcinoma in situ) in nine (8.9%), and benign lesions in 61 (60.4%). Fifteen (48.4%) of 31 carcinomas were ductal carcinoma in situ, and 16 (51.6%) were infiltrating carcinoma (size range, 0.1-2.0 cm; median, 1.2 cm). Carcinoma was found in 16 (45.7%) of 35 lesions detected in women with synchronous cancer, 10 (32.3%) of 31 lesions detected on MR imaging for problem solving, and five (14.3%) of 35 lesions detected on MR screening. The time range to perform MR imaging-guided localization was 15-59 min (median time, 31 min). Complications encountered in three cases were retained wire fragments in two and breakage of the wire tip in one., Conclusion: MR imaging-guided needle localization can be performed quickly and safely with commercially available equipment. The positive predictive value of MR imaging-guided needle localization (30.7%) was comparable to that reported for mammographically guided needle localization and was highest in women with synchronous breast cancer.

Objective: The purpose of this study was to assess whether the descriptive terminology and final assessment categories of the Breast Imaging Reporting and Data System (BI-RADS) lexicon can be used for breast carcinomas detected on MR imaging and to assess the inter- and intraobserver variabilities in the use of the descriptors and final assessment categories., Materials and Methods: In 82 patients, 101 masses, including 68 infiltrating carcinomas and 33 benign lesions, were interpreted independently by four radiologists and described by BI-RADS terminology with respect to mass shape and margin and BI-RADS final assessment categories. The enhancement pattern of the mass was also reported. In addition, two radiologists interpreted each case twice to evaluate intraobserver variability. The final case set for analysis was the 68 infiltrating carcinomas., Results: Most of the infiltrating carcinomas were described as irregular, spiculated, and heterogeneously enhancing masses. The final impression of the 68 carcinomas was BI-RADS category 5 (highly suggestive of malignancy) in 41 (61%), category 4 (suspicious abnormality) in 24 (35%), and category 3 (probably benign) in three (4%). Enhancement pattern was heterogeneous in 40 (59%), homogeneous in 14 (21%), and rim in 14 (21%). Interobserver agreement was moderate for mass margin, shape, enhancement, and final assessment category., Conclusion: This study suggests that the mammographic BI-RADS lexicon with some modifications may be applied to describe the features of infiltrating carcinoma seen on breast MR imaging.