Analysis of glioblastoma tumor coverage by oncolytic virus-loaded neural stem cells using MRI-based tracking and histological reconstruction.

In preclinical studies, neural stem cell (NSC)-based delivery of oncolytic virus has shown great promise in the treatment of malignant glioma. Ensuring the success of this therapy will require critical evaluation of the spatial distribution of virus after NSC transplantation. In this study, the patient-derived GBM43 human glioma line was established in the brain of athymic nude mice, followed by the administration of NSCs loaded with conditionally replicating oncolytic adenovirus (NSC-CRAd-S-pk7). We determined the tumor coverage potential of oncolytic adenovirus by examining NSC distribution using magnetic resonance (MR) imaging and by three-dimensional reconstruction from ex vivo tissue specimens. We demonstrate that unmodified NSCs and NSC-CRAd-S-pk7 exhibit a similar distribution pattern with most prominent localization occurring at the tumor margins. We were further able to visualize the accumulation of these cells at tumor sites via T2-weighted MR imaging as well as the spread of viral particles using immunofluorescence. Our analyses reveal that a single administration of oncolytic virus-loaded NSCs allows for up to 31% coverage of intracranial tumors. Such results provide valuable insights into the therapeutic potential of this novel viral delivery platform.

Neural stem cell-mediated CE/CPT-11 enzyme/prodrug therapy in transgenic mouse model of intracerebellar medulloblastoma.

Medulloblastoma is a heterogeneous diffuse neoplasm that can be highly disseminated, and is the most common malignant childhood brain tumor. Although multimodal treatments have improved survival rates for patients with medulloblastoma, these tumors are associated with high morbidity and mortality. New treatment strategies are urgently needed to improve cure rates and, importantly, to spare normal brain tissue from neurotoxicity and patients from life-long cognitive and functional deficits associated with current therapies. In numerous preclinical brain tumor models, neural stem cells (NSCs) have shown great promise as delivery vehicles for therapeutic genes. Here, we have used an established, genetically modified human NSC line (HB1.F3.CD) to deliver carboxylesterase (CE) to cerebellar tumor foci and locally activate the prodrug camptothecin-11 (CPT-11) (Irinotecan) to the potent topoisomerase I inhibitor SN-38. HB1.F3.CD NSC tumor tropism, intratumoral distribution and therapeutic efficacy were investigated in clinically relevant experimental models. Magnetic resonance imaging was used for in vivo tracking of iron nanoparticle-labeled NSCs, and to assess the therapeutic efficacy of CE-expressing HB1.F3.CD cells. As compared with controls, a significant decrease in tumor growth rate was seen in mice that received both NSCs and CPT-11 as their treatment regimen. Thus, this study provides proof-of-concept for NSC-mediated CE/CPT-11 treatment of medulloblastoma, and serves as a foundation for further studies toward potential clinical application.

Fulminant herpes hepatitis in an immunocompetent pregnant woman: CT imaging features.

Fulminant hepatitis due to herpes simplex virus (HSV) is rare in immunocompetent adults. Most reported cases have clearly established pregnancy as a condition that can predispose to disseminated HSV infection. We report a case of a 25-year-old previously healthy pregnant woman who presented with fatigue, fever, and anicteric hepatitis. Triphasic contrast-enhanced computed tomography demonstrated a miliary pattern of multiple, hypovascular, subcentimeter lesions scattered throughout the liver. Familiarity with the clinical findings and computed tomographic appearance may prompt early recognition of fulminant HSV hepatitis and allow differentiation from other hepatic disease during pregnancy.

MR cholangiography.

MR cholangiography (MRC) uses the inherent contrast of fluid on magnetic resonance imaging to image the biliary tree and gallbladder noninvasively. The images produced are similar in appearance to those of invasive methods. Visualization of bile duct morphology with MRC equals or exceeds that of the invasive methods. MRC increases diagnostic certainty of pathology, thereby enabling the use of invasive procedures to be reserved for necessary therapy.

Predictors of prostate carcinoma: accuracy of gray-scale and color Doppler US and serum markers.

PURPOSE: To determine the accuracy of detecting prostate cancer by using (a) gray-scale and color Doppler transrectal ultrasonography (US), (b) serum and excess prostate-specific antigen (PSA) levels, and (c) targeted and sextant transrectal US-guided biopsy. The relationship between US-detected neovascularity and tumor biologic activity was also evaluated. MATERIALS AND METHODS: Between 1995 and 1999, 544 patients with elevated PSA levels and/or abnormal digital rectal examination underwent transrectal US-guided sextant biopsy and targeted biopsy of US abnormalities. Sensitivity, specificity, and accuracy of gray-scale US, color Doppler US, targeted biopsy, and PSA and excess PSA were calculated. RESULTS: Gray-scale US depicted 78 (41.1%) of 190 cancers, whereas color Doppler US depicted 30 (15.8%) additional cancers. Targeted biopsy was used to detect 108 (56.8%) cancers, whereas sextant biopsy was used to detect 82 (43.2%) additional cancers. Although US-visible cancers had a higher Gleason grade than did cancers discovered at sextant biopsy (P <.05), 25 of the 66 cancers identified with sextant biopsy alone were Gleason grade 6 or higher. Color Doppler US-depicted hypervascularity correlated with biologically aggressive tumors. Excess PSA was normal in 58 (30.5%) cancers, with an accuracy of 67.3%, resulting in better prediction of prostate tumors than with serum PSA level alone. CONCLUSION: Gray-scale transrectal US, even coupled with color Doppler US, is inadequate for prostate carcinoma screening; therefore, targeted biopsy should always be accompanied by complete sextant biopsy sampling.

Postmortem whole-body magnetic resonance imaging as an adjunct to autopsy: preliminary clinical experience.

The purpose of this study was to evaluate whole-body magnetic resonance imaging (MRI) of cadavers as an adjunct to autopsy. Eight consecutive patients underwent both whole-body MRI and autopsy [either conventional (six), limited (one), or percutaneous (one)] within 24 hours of death. Comparison was made of major and minor abnormalities and predicted cause of death recorded by independent readers at both MRI and autopsy. Major discrepancies between the recorded primary cause of death at imaging and autopsy occurred in five (5) patients. These included a myocardial infarction found at autopsy alone, bowel infarction and portal venous gas found at MRI alone, and aortic dissection and occipital infarct found at MRI alone in a patient on whom only limited autopsy was performed. Postmortem MRI may represent a useful adjunct to autopsy, particularly in patients in whom autopsy is limited due to patient/family consent, inoculation risks, and ethnic doctrines.

Virtual colonoscopy: a new tool for colorectal cancer screening.

Virtual colonoscopy or computed-tomography colonography is a promising new method for colorectal cancer screening. Helical computed tomography is used to generate high-resolution, two-dimensional axial images of the abdomen and pelvis. Three-dimensional images of the colon simulating those obtained with conventional colonoscopy can be reconstructed from the data obtained. Favorable attributes of virtual colonoscopy include its safety, high patient acceptance, and ability to provide a full structural evaluation of the entire colon. Multiple studies of virtual colonoscopy have been published in the literature in the past year regarding technique, image display, image reconstruction, clinical trial results, and feasibility as a screening tool. This manuscript will review the various studies in each of these areas.

Virtual colonoscopy and colorectal cancer screening.

Colorectal cancer (CRC) is the leading cause of cancer related death in the United States. Virtual colonoscopy is a new method for imaging the colon and has produced promising early results for polyp and cancer detection. The challenge remains to reproduce these favorable results in clinical practice and to evaluate the use of virtual colonoscopy in a purely screening population. Virtual colonoscopy may dramatically improve population participation in screening programs and play a major role in minimizing the impact of CRC.

Cholinergic stimulation enhances cytosolic calcium ion accumulation in mouse hippocampal CA1 pyramidal neurones during short action potential trains.

Acetylcholine is a regulatory cofactor for numerous activity-dependent processes of central nervous system development and plasticity in which increases in cytosolic calcium ion concentration ([Ca(2+)](cyto) couple membrane excitation to cellular changes. We examined how cholinergic receptor activation affects temporal and spatial aspects of increases in [Ca(2+)](cyto) during short trains of action potentials in hippocampal CA1 pyramidal neurones. Membrane-impermeant Ca(2+)-sensitive dye was introduced into the cytosol during whole-cell recordings, and Ca(2+)-dependent fluorescence was recorded from somatic, nuclear and proximal dendrite regions with high temporal resolution. In all neuronal compartments, the cholinergic agonist carbachol (5 microM) increased resting [Ca(2+)](cyto) and the maximum [Ca(2+)](cyto) attained during a short action potential train. Carbachol also slowed the recovery of [Ca(2+)](cyto) towards resting levels. The largest increases in peak cytosolic Ca(2+) concentration (delta [Ca(2+)](cyto) were seen in the dendrite and apical cell body, while relaxations of the carbachol-induced increase in delta [Ca(2+)](cyto) showed greater prolongation in the nucleus and basal cell body. Most significantly, the difference between Ca(2+) signals recorded before and during exposure to carbachol consistently showed a monotonic rise and smooth fall in all cell compartments, suggesting that the increase in [Ca(2+)](cyto) associated with each action potential was not altered by carbachol. Consistent with this view, changes in Ca(2+) signalling were not accompanied by changes in action potential waveforms. The effects of carbachol were partially reversed by simultaneous exposure to atropine, or partially inhibited by inclusion of heparin in the intracellular solution, indicating the involvement of muscarinic acetylcholine receptors and InsP(3)-sensitive Ca(2+)-release channels. Our data indicate that carbachol-induced slowing of [Ca(2+)]cyto relaxations after each action potential results in enhanced accumulation of Ca(2+) in the cytosol in the absence of changes in action potential-driven Ca(2+) entry. By modulating the time course of Ca(2+) signals, cholinergic stimulation may regulate the activation of Ca(2+)-dependent intracellular processes dependent on patterns of [Ca(2+)](cyto) changes.

Detection of choledocholithiasis with MR cholangiography: comparison of three-dimensional fast spin-echo and single- and multisection half-Fourier rapid acquisition with relaxation enhancement sequences.

PURPOSE: To compare the performance of three pulse sequences commonly used at magnetic resonance (MR) cholangiography in the diagnosis of choledocholithiasis. MATERIALS AND METHODS: MR cholangiography was performed in 57 patients who were suspected of having choledocholithiasis and referred for endoscopic retrograde cholangiography. Non-breath-hold three-dimensional fast spin-echo, breath-hold single-section half-Fourier rapid acquisition with relaxation enhancement (RARE), and breath-hold multisection half-Fourier RARE sequences were compared. Two radiologists independently interpreted the MR cholangiograms. Evaluated diagnostic performance parameters included sensitivity, specificity, receiver operating characteristic (ROC) curves, and interobserver agreement (kappa statistics). Endoscopic retrograde cholangiography was the standard of reference. RESULTS: Eight patients were excluded because of incomplete MR examinations (n = 4) or failure in the cannulation of the bile duct at retrograde cholangiography (n = 4). In 49 patients, the three MR cholangiographic sequences were completed successfully. In 24 (49%) of these patients, retrograde cholangiography demonstrated stones. Sensitivity and specificity of MR cholangiography exceeded 90%, and the area under the ROC curve was greater than 0.95 for both radiologists and for the three sequences. Interobserver agreement for presence of bile duct stones was at least 0.80 (very good) for the three sequences. CONCLUSION: The three MR cholangiographic sequences had similarly high sensitivities and specificities for the detection of choledocholithiasis.

A comparison of virtual and conventional colonoscopy for the detection of colorectal polyps.

BACKGROUND: Virtual colonoscopy is a new method of imaging the colon in which thin-section, helical computed tomography (CT) is used to generate high-resolution, two-dimensional axial images. Three-dimensional images of the colon simulating those obtained with conventional colonoscopy are then reconstructed off-line. We compared the performance of virtual and conventional colonoscopy for the detection of colorectal polyps. METHODS: We prospectively studied 100 patients at high risk for colorectal neoplasia (60 men and 40 women; mean age, 62 years). We performed virtual colonoscopy immediately before conventional colonoscopy. We inserted a rectal tube and insufflated the colon with air to the maximal level that the patient could tolerate. We administered 1 mg of glucagon intravenously immediately before CT scanning to minimize the degree of smooth-muscle spasm and peristalsis and to reduce the patient's discomfort. RESULTS: The entire colon was clearly seen by virtual colonoscopy in 87 patients and by conventional colonoscopy in 89. Fifty-one patients had normal findings on conventional colonoscopy. In the other 49, we identified a total of 115 polyps and 3 carcinomas. Virtual colonoscopy identified all 3 cancers, 20 of 22 polyps that were 10 mm or more in diameter (91 percent), 33 of 40 that were 6 to 9 mm (82 percent), and 29 of 53 that were 5 mm or smaller (55 percent). There were 19 false positive findings of polyps and no false positive findings of cancer. Of the 69 adenomatous polyps, 46 of the 51 that were 6 mm or more in diameter (90 percent) and 12 of the 18 that were 5 mm or smaller (67 percent) were correctly identified by virtual colonoscopy. Although discomfort was not specifically recorded, none of the patients requested that virtual colonoscopy be stopped because of discomfort or pain. CONCLUSIONS: In a group of patients at high risk for colorectal neoplasia, virtual and conventional colonoscopy had similar efficacy for the detection of polyps that were 6 mm or more in diameter.

MR cholangiopancreatography techniques.

The tissue contrast principles and the technical aspects involved in the design of the imaging protocols currently used for clinical MR cholangiopancreatography are reviewed using a neutral terminology that is applicable to most of the high-field MRI equipment available from the major manufacturers. Furthermore, the technical discussions that follow are accompanied by a comprehensive set of tables listing the pulse sequence parameters used by the authors of the other articles in this issue. The tables are organized according to groups of parameters that determine the fundamental features of the protocols and of the generated images, specifically motion artifact reduction technique, scan geometry, image contrast, and recommended image post processing algorithm.

Modulation of a slowly inactivating potassium current, I(D), by metabotropic glutamate receptor activation in cultured hippocampal pyramidal neurons.

I(D) is a slowly inactivating 4-aminopyridine (4-AP)-sensitive potassium current of hippocampal pyramidal neurons and other CNS neurons. Although I(D) exerts multifaceted influence on CNS excitability, whether I(D) is subject to modulation by neurotransmitters or neurohormones has not been clear. We report here that one prominent effect of metabotropic glutamate receptor (mGluR) activation by short (3 min) exposure to 1S, 3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) (100 microM) is suppression of I(D) by acceleration of its inactivation. I(D) was identified as a target of mGluR-mediated modulation because inactivation of a component of outward current sensitive to 100-200 microM 4-AP was accelerated by 1S,3R-ACPD, and because 4-AP occluded any further actions of 1S,3R-ACPD. Enhancement of I(D) inactivation was induced by the group I-preferring agonist RS-3, 5-dihydroxyphenylglycine (3,5-DHPG) and the group II-preferring agonist 2S,2'R,3'R)-2-(2',3'dicarboxycyclopropyl)-glycine (DCG-IV), but not by the group III-preferring agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4); it was blocked by the broadly acting mGluR antagonist S-alpha-methyl-4-carboxyphenylglycine (S-MCPG). Furthermore, inactivation of I(D) was enhanced by inclusion of GTPgammaS in the internal solution and blocked by inclusion of GDPbetaS. Metabotropic GluR-induced suppression of I(D) was manifest in three aspects of excitability previously linked to I(D) by their sensitivity to 4-AP: reduction in input conductance and enhanced excitability at voltages just positive to the resting potential, reduced delay to action potential firing during depolarizing current injections, and delayed action potential repolarization. We suggest that mGluR-induced suppression of I(D) could contribute to enhancement of hippocampal neuron excitability and synaptic connections.

Motion artifact control in body MR imaging.

The mechanisms involved in the generation of motion artifacts in MR imaging are complex and depend both on the type and direction of motion as well as on the parameters of the imaging sequence chosen. The methods used to control or reduce motion artifacts are multiple and the appropriate method for use with any given clinical situation will depend on the particular hardware and software of the MR imaging unit, the patient's clinical status, and the specific organ or disease state to be imaged. Some general guidelines for clinical use that are applicable in most scenarios can be defined, although preferences for the different techniques vary. Appropriate T1-weighted images of the upper abdomen and liver can be obtained with breath-hold T1-weighted gradient echo. These images should be acquired with inferior-superior spatial presaturation pulses to reduce vascular pulsation artifact and ghosting. The application of GMN will depend on the individual MR imaging system. If sufficient coverage cannot be obtained with gradient-echo imaging, then conventional T1-weighted images with phase-encoding reordering is suggested. The addition of spatial presaturation pulses (inferior-superior) may be valuable. The use of fat suppression will further improve image quality by reducing ghost artifact and improving CNR, although SNR will decrease. T2-weighted imaging of the upper abdomen will depend greatly on the hardware and software of the MR imaging unit. Recent techniques of breath-hold T2-weighted imaging require faster and stronger gradients, and may not be universally available. If available, these techniques provide excellent anatomic detail, although image contrast (e.g., liver to spleen) may decrease. Respiratory-triggered FSE techniques are the preferred method of imaging in most centers, because the imaging time is considerably less than conventional T2-weighted imaging whereas the image quality is improved. Liver lesion detection capability of the various techniques is still under study. The addition of fat suppression appears to improve image quality further with an increase in lesion detection. By understanding the principles underlying motion artifacts, one can choose the appropriate method of artifact control tailored for the individual clinical situation. In addition, the recognition of the variable appearances of motion artifacts will prevent interpretive errors and misdiagnoses. Careful attention to motion artifact reduction techniques can greatly improve patient care.

Black-blood MR angiography. Techniques, and clinical applications.

As there are limitations in WB-MR angiography, so there are limitations in BB-MR angiography. Vessel morphology is visualized by means of the innermost nonattenuated layer of tissue, which, under ideal conditions, coincides with the luminal surface of the vessel wall. Vessel morphology may be depicted inaccurately whenever a portion of the vessel wall is undetectable with the MR imaging technique used. In such cases, vessel segments with exaggerated lumen diameter may result at locations where tissues with either a very short T2 or a low proton density are present. Another phenomenon that could potentially degrade the accuracy of vessel depiction with BB techniques is the effect of slowly flowing blood near the vessel walls. Residual blood signal would result in apparent vessel narrowing. Preliminary clinical experience in the brain, however, suggests that this adverse effect is less prominent with a turbo-SE-based BB technique than with a TOF WB technique. BB-MR angiography data sets may also present image postprocessing difficulties arising from the isointensity between the vessels and other dark structures such as bones and air-filled cavities. A limitation that is more specific to hybrid-SE-based BB-MR pulse sequences, particularly for very high spatial resolution applications, stems from the comparatively high RF specific absorption rates that result from the intensive use of 180 degrees refocusing pulses. GRASE-based BB-MR techniques that generate a fraction of the RF energy constitute a promising alternative for very high spatial resolution applications. In summary, to be effective, a BB technique must produce strong signal attenuation from flowing spins, ideally to the level of the baseline noise. Simultaneously it should produce good depiction of tissues with the comparatively short T2s characteristic of vessel walls and muscle, hence the need to operate with the shortest possible TE. Finally, high spatial resolution combined with fast data acquisition are requisites for imaging small vessels in the presence of motion, such as the carotid arteries. The flow properties of BB-MR angiographic sequences that meet these criteria were reviewed for different anatomic locations.