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Magnetic resonance images of leukemic bone marrow were acquired over large regions of the pelvis and lower abdomen with minimal interference from overlying tissues using diffusion and T2 weighted echo planar imaging. Data acquisition times were on the order of 1 min for scanning volumes of up to 25 l at a spatial resolution of 31 ml. A survey of 21 patients with leukemia and eight healthy adult volunteers was undertaken to determine the magnitude of the observed effect and its dependence upon specific pathologies. The acquisition methods yielded high- quality segmentation of leukemic bone marrow prior to therapy in seven of seven patients with acute lymphocytic leukemia, chronic lymphocytic leukemia or chronic myelogenous leukemia, and who had hypercellular (>95%) bone marrow at the time of the study. The quality of the segmentation was sufficient to allow the use of maximum intensity projection images which afforded a convenient evaluation of both intra- and extramedullary disease. The measured signal-to-noise ratios agreed with a theoretical estimate that accounted for the percentage cellularity, T2 relaxation time of water, and self-diffusion coefficient of water in iliac bone marrow. In addition, the mean signal-to-noise ratios from iliac marrow were strongly dependent upon the time after the initiation of chemotherapeutic regimens, implying that the methods may be useful for therapeutic monitoring. Copyright © 2000 John Wiley & Sons, Ltd.

An iterative, outlier exclusion, second-order surface fitting algorithm has been developed to solve the well-known phase wraparound problem associated with in vivo applications of the three-point Dixon magnetic resonance imaging method. The technique was optimized for speed by reducing the problem to a pair of planar fits. The spatial misalignment between water and fat components due to the chemical shift was handled on a subpixel level by invoking the shift theorem of Fourier transformation. From the chemical shift corrected water and fat images, high quality recombined MR images were generated. The algorithm was validated in both phantom and patient studies. In vivo breast images and pelvic images are provided as a demonstration of the method.

A fully quadrature dome-shaped resonator is presented that has been dual-tuned for proton and phosphorus operation at 1.5 T. The resonator is 16.5 cm in length and 23 cm in diameter. Phantom studies were performed to demonstrate the utility of the resonator for proton imaging, shimming, and proton-decoupled phosphorus spectroscopy. In human subjects, proton-decoupled phosphorus chemical shift imaging spectra of the brain were acquired at 27 cm 3 resolution in 34 min. Volunteer studies demonstrated improved resolution of phosphomonoesters, phosphodiesters, and nucleoside triphosphates due to proton decoupling. Sensitive coverage of the brain extended from the most superior cerebral cortex to the cerebellum. Acquisition of good quality 31 P spectra over this volume is due to the dome structure as well as quadrature operation at both proton and phosphorus frequencles.

The combination of N-(phosphonacetyl)-L-aspartate (PALA), 6-methylmercaptopurine riboside (MMPR), and 6-aminonicotinamide (6AN) has been shown to be an effective antineoplastic regimen and also to enhance the effects of other antineoplastic agents (1-4). To further enhance the effect of this combination, we investigated the effects of adding adriamycin, at its maximally tolerated dose, to this regimen. The response rate (complete regression+partial regression) for the four-drug regimen was higher than for the three-drug regimen, and the tumor growth delay was also significantly higher than for treatment with PALA, MMPR, 6AN, or after treatment with maximally tolerated doses of adriamycin alone (11 mg/kg). The addition of adriamycin to PALA, MMPR, 6AN did not result in enhancement of the effect of radiation, as measured by tumor growth delay studies and tumor control (complete and partial regression rate). The mechanism of action of the combination of PALA, MMPR, and 6AN is not known definitively, but a possible mechanism previously suggested is biochemical modulation of energy metabolism and inhibition of production of tumor ATP. Treatment with PALA, MMPR, 6AN, and adriamycin (at 2.5 hr post MMPR, 6AN) resulted in a nadir NTP/Pi value, as determined by 31P NMR spectroscopy, at approximately 10 hr post MMPR + 6AN (7.5 hr post adriamycin), which was not significantly different from the NTP/Pi value determined after treatment with the three-drug combination.

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 [11C]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 × 105, the cocaine occupancy was reduced to levels of

In this work a 5 x 5 mesh dome resonator that has been optimized for functional brain imaging is presented. The resonator was reduced in length and diameter compared with previous versions to reduce sample losses, thus enhancing the signal-to-noise ratio of the acquired data. In addition, a 5 x 5 mesh design was employed, which offered improved axial homogeneity over an earlier 3 x 3 mesh version. The new resonator exhibited high sensitivity and good homogeneity over the brain volume, permitting analysis of functional activation over large areas of the cerebral cortex. In a direct comparison with a standard clinical head-imaging resonator, the high sensitivity of the 5 x 5 mesh dome resonator resulted in greater statistical confidence in functional activation.

The chemotherapeutic regimen of N-(phosphonacetyl)-L-aspartate (PALA) followed 17 h later by 6-methylmercaptopurine riboside (MMPR) and 6-aminonicotanamide (6AN) has been shown to be a potent sensitizer of anti-neoplastic therapy. We undertook this study to compare the therapeutic and metabolic effects of this triple drug combination vs one of its components, 6AN, in a murine mammary carcinoma. After treatment with PALA, MMPR and 6AN, a new peak was detected which was assigned to 6-phosphogluconate (6PG), which is a marker of inhibition of the pentose phosphate pathway at the 6-phosphogluconate dehydrogenase step. Treatment with PALA, MMPR and 6AN also induced a decrease in the ratios of nucleoside triphosphate/inorganic phosphate (NIP/P i ) and phosphocreatine/inorganic phosphate (PCr/P i ) similar to previous results with a different tumor model. These effects were most pronounced at 6 and 10 h. In addition, an increase in PME'/phosphocholine (PME'=downfield peak in the phosphomonoester region) was detected, which was expected because of the cytotoxic effect of this regimen. Treatment with 6AN alone also resulted in the detection of 6PG with a maximum intensity at 6 h post-6AN. Treatment with 6AN alone induced a smaller change in PME'/PC and failed to cause a decrease in PCr/P i or NTP/P i at 6 and 10 h. The enhanced response to the combination of PALA, MMPR and 6AN vs 6AN alone, both with regard to cytotoxicity and radiosensitization, may be due to energy depletion.

A noninvasive assay for the spatial distribution of the percentage cellularity in human bone marrow is presented. Twelve individuals were studied using two magnetic resonance imaging techniques: (1) fast spin echo imaging with frequency selective presaturation, and (2) three-point chemical shift imaging. The data were compared to results obtained using a previously validated stimulated echo spectroscopic method. The results of this study demonstrate that a measure of the percentage cellularity in bone marrow is possible using magnetic resonance imaging techniques provided that high-quality water or lipid suppression is achieved across the region of interest. Since the method is applicable to bone marrow at any anatomic location, it may prove useful in dosimetric calculations during and after a course of internal or external beam radiotherapy.

The effect of 6-aminonicotinamide on the metabolism of RIF-1 tumor cells was investigated using 13C and 31P NMR spectroscopy. 6-Aminonicotinamide can be metabolized to 6-amino-NAD(P), a competitive inhibitor of NAD(P)-requiring processes. 40 microM 6-aminonicotinamide led to an inhibition of 6-phosphogluconate dehydrogenase and an accumulation of 6-phosphogluconate. A subsequent accumulation of the 6-phosphogluconate precursor 6-phosphoglucono-delta-lactone was observed in the 13C NMR spectrum. These metabolites were shown to be intracellular, although a small amount of leakage of 6-phosphoglucono-delta-lactone occurred. The intracellular concentrations of 6-phosphogluconate and 6-phosphoglucono-delta-lactone were 1.9 +/- 0.8 micromol/108 cells (+/-1 standard deviation) and 0.8 +/- 0.4 micromol/10(8) cells, respectively, after 15 h. Glucose utilization and lactate production were significantly inhibited by 6-aminonicotinamide (both p < 0.05), indicating inhibition of glycolysis. 31P NMR data showed that phosphocreatine was significantly depleted in cells exposed to 6-aminonicotinamide (p < 0.05). Exposure of RIF-1 cells to 6-aminonicotinamide prior to 3- or 6-Gy x-irradiation induced a supra-additive cell kill, indicating that 6-aminonicotinamide is acting as a radiosensitizer. There was no effect of 6-aminonicotinamide alone or when the drug was given postradiation, suggesting that its mechanism of action may be by inhibition of radiation-induced repair.

Glioblastoma multiforme (GBM) is the most common and aggressive primary intracranial brain tumor in adults with a mean survival of 14 to 15 months. Aberrant activation of the epidermal growth factor receptor (EGFR) plays a significant role in GBM progression, with amplification or overexpression of EGFR in 60% of GBM tumors. To target EGFR expressed by GBM, we have developed a strategy to deliver the coding sequence for cetuximab, an anti-EGFR antibody, directly to the CNS using an adeno-associated virus serotype rh.10 gene transfer vector. The data demonstrates that single, local delivery of an anti-EGFR antibody by an AAVrh.10 vector coding for cetuximab (AAVrh.10Cetmab) reduces GBM tumor growth and increases survival in xenograft mouse models of a human GBM EGFR-expressing cell line and patient-derived GBM. AAVrh10.CetMab-treated mice displayed a reduction in cachexia, a significant decrease in tumor volume and a prolonged survival following therapy. Adeno-associated-directed delivery of a gene encoding a therapeutic anti-EGFR monoclonal antibody may be an effective strategy to treat GBM.

Twenty-five patients with prostatic cancer were pro- spectively examined with a prototype endorectal surface coil featuring a birdcage resonator circuit design. The purpose was to determine the safety of an intracavitary probe for magnetic resonance (MR) imaging of the pelvis that incorporates the “inside-out” characteristics of a volume coil design and allows high-resolution MR imaging of the prostate and potentially serves as an alternative to single-loop intracavitary surface coils. Clinically useful images supplementing images obtained with the body or external surface coils were obtained with the prototype probe. It was tolerated by all patients enrolled in the study, and none experienced side effects. The cylindrically symmetric sensitivity profile of the probe allowed identification of prostate tumors and pelvic lymph node and bone me-tastases. Volume-type coils may improve endopelvic MR imaging when used alone or in combination with external coil systems.

A new radiofrequency resonator for MR imaging of the human head is presented. The geometry consists of a single end-ring connected to eight legs which extend along a cylinder and are joined in pairs on a hemispherical dome. The most homogeneous normal mode of this structure is doubly degenerate and affords quadrature operation. The high sensitivity in the hemispherical end is particularly suited to human brain studies. This resonator represents a clinical application of two-dimensional ladder network resonant structures whose operation may be understood by analogy to the mechanical problem of oscillating two-dimensional membranes.

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.

A broad class of radiofrequency resonators is identified by a correspondence between their associated eigenvalue problems and those of discrete two-dimensional coupled harmonic oscillators. The utility of the theory as a tool for describing complex circuit designs is demonstrated by the explicit treatment of the subclass of M × N square-mesh planar resonators. The success of the electromechanical analogy and boundary-value analysis in describing these structures combined with the fact that they are easy to build and evaluate underscores their potential applicability to magnetic resonance studies.

An approach to model the hidden neuronal and hemodynamic sources of the blood-oxygenation-level-dependent (BOLD) signal observed in optogenetic functional MRI experiments is presented. In these experiments, genetically modified light-sensitive neurons are directly stimulated by laser light. A proof-of-principle demonstration is provided by estimating hidden hemodynamic and neuronal states in the Buxton-Mandeville-Friston BOLD model applied to simulated and experimental optogenetic fMRI data of the mouse. The estimation procedure is based on the continuous unscented Kalman filter. In simulations, under a given model, unobserved BOLD source signals such as cerebral blood flow and deoxygenation could be estimated with good accuracy, although neuronal signal sources appeared lagged in time. In experimental data, this approach was able to describe positive and negative BOLD signals. Translated into human applications, it could have the potential to provide novel functional markers for imaging cerebrovascular accidents or altered vascularity of brain tumors in a more specific way than standard clinical MRI protocols.

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.

A technique is described which reduced the magnetic susceptibility induced line broadening in NMR spectra obtained from three biological systems at 4.7 Tesla. Proton spectra from a sealed suspension of HL60 leukemic myeloblasts yielded minimum linewidths of 1.3 Hz at 200 MHz (0.0065 ppm) after 10 min of automated shimming. 31P spectra from an in vivo murine MCa mammary carcinoma yielded a well-resolved phosphorylcholine resonance without proton decoupling and with the resistive shim coil currents set to zero. 31P spectra from a perfused suspension of RIF-1 fibrosarcoma cells exhibited a gamma-nucleoside triphosphate resonance which was resolved into purine and pyrimidine components.

An intracavitary probe for magnetic resonance imaging of the pelvis has been developed that takes advantage of the “inside-out” spatial characteristics of a birdcage resonator. The probe consists of an eight-leg, birdcage resonator in a low-pass configuration operating in receive-only mode. The resonator circuit is mounted on a solid rod, is encased in Teflon®, and has been used to obtain detailed images of pelvic anatomy in a male canine. The approximate cylindrical symmetry of the external sensitivity profile of this type of circuit, employed in an intracavitary application, demonstrates the potential superiority of this type of probe design over single-loop intracavitary coils. Axial, coronal, and sagittal MR images, obtained with 8 and 16 cm fields of view, are presented to illustrate the advantages of this type of intracavitary probe compared with conventional body-coil images. The prototype described in this report has been designed for clinical use in human subjects and is currently undergoing testing to determine its efficacy in the evaluation of rectal, prostate, and gynecologic pathology.

Of Mice and Men Just how closely must mouse models replicate the known features of human disorders to be accepted as useful for mechanistic and therapeutic studies? Soliman et al. (p. 863 , published online 14 January) compared mice that vary only in their allelic composition at one position within the gene encoding brain-derived neurotrophic factor (BDNF) with humans exhibiting the same range of allelic variation. Individuals (mice and humans) carrying the allele that codes for a methionine-containing variant of BDNF retained a fearful response to a threatening stimulus even after its removal in comparison to those with the valine variant. Furthermore, in both cases, this linkage was mediated by diminished activity in the ventral-medial region of the prefrontal cortex. This deficit in extinction learning may contribute to differential responses to extinction-based therapies for anxiety disorders.

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.

Juvenile male zebra finches develop their song by imitation. Females do not sing but are attracted to males' songs. With functional Magnetic Resonance Imaging (fMRI) and Event Related Potentials (ERPs) we tested how early auditory experience shapes responses in the auditory forebrain of the adult bird. Adult male birds kept in isolation over the sensitive period for song learning showed no consistency in auditory responses to conspecific songs, calls, and syllables. Thirty seconds of song playback each day over development, which is sufficient to induce song imitation, was also sufficient to shape stimulus-specific responses. Strikingly, adult females kept in isolation over development showed responses similar to those of males that were exposed to songs. We suggest that early auditory experience with songs may be required to tune perception towards conspecific songs in males, whereas in females song selectivity develops even without prior exposure to song.

A radiofrequency resonator whose normal modes correspond to those of a ladder network of finite length is described. When formed into a semicylindrical geometry, the lowest frequency mode of the resulting “half-birdcage” resonator yields a B 1 distribution which can be exploited for imaging.

Bone marrow edema is seen in osteoarthritis, avascular necrosis, and other clinical conditions including the bone marrow edema syndrome. Bone marrow edema is associated with bone pain and may be related to the pathophysiology of osteoarthritis. Our hypothesis is that bone marrow edema is associated with a reduction in perfusion in subchondral bone, which contributes to focal and segmental bone necrosis and cartilage breakdown. We further hypothesize that altered fluid dynamics in subchondral bone comprise part of the physicochemical environment to which osteocytes are highly sensitive and alter their cytokine expression profile in response to changes in fluid flow, pressure, and oxygen gradients. We have used contrast-enhanced magnetic resonance imaging with Gd-DTPA to characterize changes in subchondral bone perfusion in two relevant and related models-the Dunkin-Hartley guinea pig model of osteoarthritis and human bone marrow edema associated with osteoarthritis and avascular necrosis. Pharmacokinetic modeling was used to extract dynamic parameters of perfusion. Representative time-intensity curves are derived, which characterize normal bone and bone with marrow edema. Dynamic contrast-enhanced magnetic resonance imaging may be a useful tool for the early diagnosis of bone perfusion abnormalities and may be used to characterize marrow edema associated with a number of clinical conditions. This technique may also shed light on the pathophysiology of subchondral perfusion in osteoarthritis and avascular necrosis.

Electrophysiological and activity-dependent gene expression studies of birdsong have contributed to the understanding of the neural representation of natural sounds. However, we have limited knowledge about the overall spatial topography of song representation in the avian brain. Here, we adapt the noninvasive functional MRI method in mildly sedated zebra finches ( Taeniopygia guttata ) to localize and characterize song driven brain activation. Based on the blood oxygenation level-dependent signal, we observed a differential topographic responsiveness to playback of bird's own song, tutor song, conspecific song, and a pure tone as a nonsong stimulus. The bird's own song caused a stronger response than the tutor song or tone in higher auditory areas. This effect was more pronounced in the medial parts of the forebrain. We found left–right hemispheric asymmetry in sensory responses to songs, with significant discrimination between stimuli observed only in the right hemisphere. This finding suggests that perceptual responses might be lateralized in zebra finches. In addition to establishing the feasibility of functional MRI in sedated songbirds, our results demonstrate spatial coding of song in the zebra finch forebrain, based on developmental familiarity and experience.

Epidermal growth factor receptor (EGFR) is an attractive target for the treatment of glioblastoma (GBM), where deregulated expression or activity of EGFR has been associated to tumor development, progression and spread, and decreased survival. Systemic administration of an anti-EGFR antibody (CetuximabTM) reduces cellular proliferation in a variety of cancer models, but for GBM, efficacy is limited by the blood-brain barrier, where only ~ 0.1% of circulating antibodies reach the brain. To circumvent these limitations, we have developed a strategy to deliver the cDNA sequence for the anti-EGFR antibody directly to the CNS via adeno-associated virus (AAV) gene transfer vectors, resulting in local, persistent expression in the CNS. Efficacy of this therapeutic approach was evaluated by assessment of survival of NOD/SCID immunodeficient mice after CNS administration of human U87MG glioblastoma cells modified to express wild type EGFR to the striatum, either at the same time or 8 days prior to the administration of an AAVrh. 10-based vector coding for the anti-EGFR monoclonal antibody Cetuximab (AAVrh. 10CetMab). Localized expression of the antibody was confirmed by Western analysis and ELISA. Simultaneous administration of AAVrh. 10CetMab and GBM xenograft to the CNS was associated with survival of the treated animals compared to controls that received PBS (AAVrh. 10CetMab treated 5 ± days vs PBS-treated, 31±2 days, p

CO RR EC TE D P RO OF these abnormalities through motor tests. Homozyous mice performed poorly and showed no improvement on the inverted grip and rotarod tests. Together, these data suggest that the mice are impaired in their motor ability and strength, which may be due to gross accumulative manifestations in the brain. Additionally, they demonstrated increased stereotypic behavior in the open field test by entering the center zone less frequently and in categorized observation by spending more time chewing, but decreased stereotypic behavior in the marble burying test by burying fewer marbles. This study implicates particular sphingolipids in highly specific functions within the brain and a complex, but specific, system to regulate their expression. The detailed ceramide composition of the mouse brain illustrated in this study can serve as a reference point upon which brains from other neurological and storage disorders can be compared.

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 times 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

We used diffusion tensor imaging (DTI) to study 2 patients with traumatic brain injury. The first patient recovered reliable expressive language after 19 years in a minimally conscious state (MCS); the second had remained in MCS for 6 years. Comparison of white matter integrity in the patients and 20 normal subjects using histograms of apparent diffusion constants and diffusion anisotropy identified widespread altered diffusivity and decreased anisotropy in the damaged white matter. These findings remained unchanged over an 18-month interval between 2 studies in the first patient. In addition, in this patient, we identified large, bilateral regions of posterior white matter with significantly increased anisotropy that reduced over 18 months. In contrast, notable increases in anisotropy within the midline cerebellar white matter in the second study correlated with marked clinical improvements in motor functions. This finding was further correlated with an increase in resting metabolism measured by PET in this subregion. Aberrant white matter structures were evident in the second patient's DTI images but were not clinically correlated. We propose that axonal regrowth may underlie these findings and provide a biological mechanism for late recovery. Our results are discussed in the context of recent experimental studies that support this inference.

Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal childhood neurodegenerative lysosomal storage disease with no known therapy. There are estimated to be 200 to 300 children in the United States at any one time with the disease. LINCL is a genetic disease resulting from a deficiency of tripeptidyl peptidase I (TPP-I), a proteolytic enzyme encoded by CLN2, the gene that is mutated in individuals with LINCL. The subjects are chronically ill, with a progressive CNS disorder that invariably results in death, typically by age 8 to 12 years. The strategy of this clinical study is based on the concept that persistent expression in the CNS of the normal CLN2 cDNA with production of sufficient amounts of TPP-I should prevent further loss of neurons, and hence limit disease progression. To assess this concept, an adeno-associated virus vector (AAV2CUh-CLN2) will be used to transfer to and express the human CLN2 cDNA in the brain of children with LINCL. The vector consists of the AAV2 capsid enclosing the 4278-base single-stranded genome consisting of the two inverted terminal repeats of AAV serotype 2 and an expression cassette composed of the human cytomegalovirus (CMV) enhancer, the chicken beta-actin promoter/splice donor and 5' end of the intron, the 3' end of the rabbit P-globin intron and splice acceptor, the human CLN2 cDNA with an optimized Kozak translation initiation signal, and the polyadenylation/transcription stop codon from rabbit 3-globin. The proposed study will include 10 individuals and will be divided into two parts. Group A, to be studied first, will include four individuals with the severe form of the disease. Group B of the trial will include six individuals with a moderate form of the disease. After direct intracranial administration of the vector, there will be neurological assessment based on the LINCL clinical rating scale and magnetic resonance imaging/magnetic resonance spectroscopy assessment of the brain in regions of vector administration. The data generated will help evaluate two hypotheses: (1) that it is safe to carry out direct intracranial administration of the AAV2cuhCLN2 vector to the CNS of individuals with LINCL, and (2) that administration of the AAV2cuhCLN2 vector will slow down or halt the progression of the disease in the central nervous system.

Whole-body imaging of therapeutic response in human bone marrow was achieved without introduced contrast agents using diffusion-weighted echo-planar magnetic resonance imaging of physiologic water. Bone marrow disease was identified relative to the strong overlying signals from water and lipids in other anatomy through selective excitation of the water resonance and generation of image contrast that was dependent upon differential nuclear relaxation times and self-diffusion coefficients. Three-dimensional displays were generated to aid image interpretation. The geometric distortion inherent in echo-planar imaging techniques was minimized through the acquisition of multiple axial slices at up to 12 anatomic stations over the entire body. Examples presented include the evaluation of therapeutic response in bone marrow during cytotoxic therapy for leukemia and metastatic prostate cancer and during cytokine administration for marrow mobilization prior to stem cell harvest.

The objective of this work was to develop and then validate a stereotactic fiduciary marker system for tumor xenografts in rodents which could be used to co-register magnetic resonance imaging(MRI), PET, tissue histology, autoradiography, and measurements from physiologic probes. A Teflon™ fiduciary template has been designed which allows the precise insertion of small hollow Teflon rods (0.71 mm diameter) into a tumor. These rods can be visualized by MRI and PET as well as by histology and autoradiography on tissue sections. The methodology has been applied and tested on a rigid phantom, on tissue phantom material, and finally on tumor bearing mice. Image registration has been performed between the MRI and PET images for the rigid Teflon phantom and among MRI, digitized microscopy images of tissue histology, and autoradiograms for both tissue phantom and tumor-bearing mice. A registration accuracy, expressed as the average Euclidean distance between the centers of three fiduciary markers among the registered image sets, of 0.2±0.06 mm was achieved between MRI and microPET image sets of a rigid Teflon phantom. The fiduciary template allows digitized tissue sections to be co-registered with three-dimensional MRIimages with an average accuracy of 0.21 and 0.25 mm for the tissue phantoms and tumor xenografts, respectively. Between histology and autoradiograms, it was 0.19 and 0.21 mm for tissue phantoms and tumor xenografts, respectively. The fiduciary marker system provides a coordinate system with which to correlate information from multiple image types, on a voxel-by-voxel basis, with sub-millimeter accuracy—even among imaging modalities with widely disparate spatial resolution and in the absence of identifiable anatomic landmarks.

Dynamic contrast material-enhanced magnetic resonance (MR) images of primary osteogenic sarcoma (n = 19) and Ewing sarcoma (n = 10) were reviewed in 29 patients undergoing induction chemotherapy before surgery. Histogram distributions containing the initial slope and pharmacokinetic model parameters from individual voxels within each tumor were fitted for each patient. The histogram analysis of initial slope from the tumor correlated well with percentage necrosis as determined at pathologic examination (r = 0.60, P.001), as did a two-compartment pharmacokinetic model (r = 0.64, P.001). Both methods predicted tumors with clinically important degrees of necrosis (ie,or =90%) in a large majority of cases. The ability to determine response to induction chemotherapy by means of noninvasive monitoring of necrotic fraction with perfusion MR imaging methods may provide useful prognostic information and help surgical planning.

A multiple-mouse solenoidal MR coil was developed for in vivo imaging of up to 13 mice simultaneously to screen for tumors on a 1.5 T clinical scanner. For the coil to be effective as a screening tool, it should permit acquisition of MRIs in which orthotopic tumors with diameters >2 mm are detectable in a reasonable period of time (

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.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.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 (p0.01). 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).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.

Introduction: PSMA is a non-secreted cell-surface protein that is expressed by the neovascular endothelium of most solid tumors (but not by vascular endothelium of normal tissue), making it a candidate for vascular-targeted therapy. The purpose of this study was to define the change in tumor perfusion and cellularity after 177Lu-J591 therapy in patients (pts) with advanced non-prostate solid tumors and PSMA expression as determined by radionuclide imaging (with 111In-J591) and/or by immunohistochemistry (IHC). Of note, radiolabeled J591 is hepatically cleared (negating accurate assessment of liver metastases by J591 imaging). Methods: In this pilot study, following confirmation of PSMA expression by 111In-J591 imaging and/or IHC of tumor neovasculature), 14 pts in 2 cohorts received 177Lu-J591 therapy (7 received a single dose at 70 mCi/m2; 7 received 2 fractionated doses at 35 mCi/m2 each). Pts underwent dynamic contrast enhanced (DCE)-MRI and diffusion weighted imaging (DWI) at baseline, then repeated at 1, 4, 8, and 12 wks post treatment to evaluate tumor perfusion (DCE-MRI) and cellularity (Apparent Diffusion Coefficient (ADC) values from DWI). Values were compared with paired t-testing using Wilcoxon signed-rank test for significance. Results: Among the 14 treated pts, tumor types included: lung (5), bladder (2), pancreas (2), colon, GE junction, renal, ovarian carcinomas and melanoma (1 each). Median age was 61.5 with a median of 3 prior therapies including 5 with prior anti-angiogenic agents; 8 pts received prior radiation. Metastatic sites included: bone, lymph nodes, liver, lung, brain, other. 11 of 14 pts had PSMA expression confirmed by imaging, 3 additional by IHC of archival tumor tissue (with liver metastases). DCE-MRI demonstrated that treatment significantly affected tumor perfusion, with decreased perfusion at the 1-wk (n=11, p=0.03) and 4-wk (n=6, p=0.01) post 177Lu-J591 time points. Compared to baseline, DCE slope was lower than baseline at 1 wk (p=0.045) and 4-wk (p=0.02). Week 8 (n=4) was non-significant for both % change and DCE slope and only 2 pts completed the wk 12 time point. In evaluation of cellularity, 5 of 9 pts had an increase in ADC at either the 1- or 4-wk time point (1 stable, 3 decreased). However, paired comparisons at individual time points were non-significant. Conclusion: Anti-PSMA radioimmunotherapy targeting tumor neovasculature is feasible using 177Lu-J591 and can alter tumor perfusion and cellularity, including in those with prior exposure to anti-angiogenic therapy and/or radiation. Refinement in patient selection with improved imaging (anti-PSMA immuno-PET) is ongoing. Citation Format: Orrin Pail, Gurveen Kaur, Jonathan Dyke, Yuliya Jhanwar, Paul Christos, Allyson Ocean, Manish Shah, Tsiporah Shore, Bryan Schneider, Ronald Scheff, Himisha Beltran, Douglas Ballon, Brian Robinson, David M. Nanus, Neil H. Bander, Scott T. Tagawa. Lutetium-177-labeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 (177Lu-J591) for metastatic non-prostate solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT413. doi:10.1158/1538-7445.AM2014-CT413

Nuclear magnetic resonance techniques have advanced to the point where functional, physiologic, and biochemical information may be obtained from patients. Magnetic resonance imaging of tissue water can be used to measure perfusion and diffusion with submillimeter resolution. Magnetic resonance spectroscopy may be applied to the assessment of tissue metabolites that contain protons, phosphorus, fluorine, or other nuclei. The combination of imaging and spectroscopy technologies has lead to spectroscopic imaging techniques that are capable of mapping proton metabolites at resolutions as small as 0.25 cm 3 within the time constraints of a clinical imaging study. This article provides a brief review of magnetic resonance techniques for imaging of tissue physiological function and addresses possible applications in the realm of radiation oncology.

Spatial maps of the percentage cellularity in pelvic bone marrow were calculated at a resolution of 15.6 mm3 from six volunteers and 10 patients treated for documented hematologic disease using a three-point Dixon MRI pulse sequence. The percentage cellularity calculation was aided by analyzing a two-dimensional feature space consisting of the apparent water fraction (Wa), and the T2 relaxation time of water (T2w). An extracellular water fraction was assigned to each voxel on the basis of a two-component T2w algorithm. In six cases, the method was compared to results obtained from core biopsies or aspirates of the posterior iliac crest. The results indicate that segmentation schemes that combine high-quality phase-contrast imaging with nuclear relaxation time measurements can potentially identify the true fractional marrow volume occupied by hematopoietic elements in a variety of clinical situations.

Assessing tumor response to chemotherapy in the liver has always been difficult. Most investigators estimate tumor volume as either a product of the two perpendicular diameters of a tumor nodule, or, in animal studies, simply count surface tumor nodules. The authors evaluated magnetic resonance (MR) imaging as a technique for determining absolute tumor volume in the liver in an animal model. Specifically, histologic volumetric and MR imaging measurements of tumor and liver volumes were quantitatively compared over a wide range of tumor burdens in a rat model of hepatic metastasis of a colorectal carcinoma. Twenty-three rats were imaged, with two different section thicknesses used in each animal. Both section thicknesses showed highly significant correlations between MR and histologic measurements for both tumor and liver volumes (P less than .001). MR imaging may be useful for noninvasively quantifying tumor burden and temporal response of metastatic disease in the liver to novel antineoplastic regimens.

Volume-localized proton NMR spectroscopy was used to estimate bone marrow cellularity in the posterior iliac crests of patients undergoing treatment with hematopoietic growth factors for a variety of hematologic and neoplastic disorders. Twelve patients were accrued, six of whom were studied more than once, yielding a total of 25 measurements. These data were compared to cellularity assessments derived from conventional bone marrow core biopsies obtained within a 24-h period before or after the NMR exam. The results obtained by the two methods are well correlated (R = 0.94, P < 0.001), suggesting that this noninvasive technique may preclude the need for biopsies in some cases. © 1991 Academic Press, Inc.

It is demonstrated that the basic radiofrequency pulse train used to generate stimulated echoes (90 x - τ TE -90 x - τ TM -90 x - τ TE -Acq.) is in general characterized by strong amplitude and phase modulations of the transverse magnetization as a function of the resonance offset. Two dephasing techniques which eliminate the modulations are investigated both theoretically and experimentally, and a simple formula is derived for calculating the relative modulation across a spectrum as a function of gradient strength and duration, echo delay, and spectral linewidth.

Although the preliminary results of treating refractory and relapsed multiple myeloma patents with ATO are promising, the data suggest that the resistance to ATO treatment frequently occurs (57 to 79%). We treated MM cells RPMI8226 with long-term low dosage ATO (0.5 μM) and harvested the ATO resistant cells. ATO resistant cells IC50 is 4 times higher and ATO resistant cells formed 2 times more colonies with 0.75 μM ATO treatment than parental RPMI8226. P-p38 MAPK, Bcl-2, XIAP and survivin were elevated to a relatively high level in ATO resistant cells under continuous ATO stress. We have established a custom designed miRNA microarray printed with a comprehensive panel of miRNAs in miRBase version 9.0 (238 mmu-mirs) and miRNA predictions including 2617 MED-MIR predictions, 321 ‘Cand” predictions discovered through a strategy based on pylogenetice-shadowing, 129 ‘MIR” predictions discovered through a search for miRNA targets in 3′ UTR sequences. We used this miRNA array to probe the miRNA expression profiles of RPMI8226 and resistant cells and observed differences in miRNA expression between the two lines. We also performed oligonucleotide microarray analysis using HG-U133 plus 2.0 array to screen the differential gene expression. Results showed that ATO resistant cells repressed the expression of has-miR-181a, has-miR-181b, has-let-7i, has-miR-19b, has-miR-18a, has-miR-20a and has-miR222. On the other hand, LMAN1, NPGPx, HSP73 and EIF1 genes expression were up-regulated. These data revealed the preliminary mechanism how MM cells adapt to ATO and provide potential targets to overcome the ATO in MM therapy.

We have used 31P NMR spectroscopy to study 22 patients with suspected sarcomas prior to any treatment. The spectra are characterized by the same peaks noted in murine tumors. The mean pH was 7.14 +/- 0.08 and PCr/Pi was 1.18 +/- 0.83. Comparison of pH and PCr/Pi ratios in human and a murine tumor with a low hypoxic cell fraction revealed no significant differences. Six patients subsequently received chemotherapy and three responded to therapy (based on pathologic examination and/or tumor reduction greater than 50%). The three responding patients were noted to have significantly lower PDE/PME in their pretreatment spectra than the three nonresponding patients. The three responding patients with sarcomas also showed a rise of greater than 100% in PDE/PME during the first cycle of therapy. Two of the responding patients had an increase of 0.37 pH units during this interval, which was not detected in the nonresponding patients. These data suggest that 31P NMR spectroscopy may be a useful prognostic indicator in conjunction with other clinical parameters.