Jonathan S. Lewin

Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols

Development of effective chemopreventive agents against prostate cancer (CaP) for humans requires conclusive evidence of their efficacy in animal models that closely emulates human disease. The autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which spontaneously develops metastatic CaP, is one such model that mimics progressive forms of human disease. Employing male TRAMP mice, we show that oral infusion of a polyphenolic fraction isolated from green tea (GTP) at a human achievable dose (equivalent to six cups of green tea per day) significantly inhibits CaP development and increases survival in these mice. In two separate experiments, the cumulative incidence of palpable tumors at 32 weeks of age in 20 untreated mice was 100% (20 of 20). In these mice, 95% (19 of 20), 65% (13 of 20), 40% (8 of 20), and 25% (5 of 20) of the animals exhibited distant site metastases to lymph nodes, lungs, liver, and bone, respectively. However, 0.1% GTP (wt/vol) provided as the sole source of drinking fluid to TRAMP mice from 8 to 32 weeks of age resulted in (i) significant delay in primary tumor incidence and tumor burden as assessed sequentially by MRI, (ii) significant decrease in prostate (64%) and genitourinary (GU) (72%) weight, (iii) significant inhibition in serum insulin-like growth factor-I and restoration of insulin-like growth factor binding protein-3 levels, and (iv) marked reduction in the protein expression of proliferating cell nuclear antigen (PCNA) in the prostate compared with water-fed TRAMP mice. The striking observation of this study was that GTP infusion resulted in almost complete inhibition of distant site metastases. Furthermore, GTP consumption caused significant apoptosis of CaP cells, which possibly resulted in reduced dissemination of cancer cells, thereby causing inhibition of prostate cancer development, progression, and metastasis of CaP to distant organ sites.

Suppression of Prostate Carcinogenesis by Dietary Supplementation of Celecoxib in Transgenic Adenocarcinoma of the Mouse Prostate Model

Epidemiological studies and clinical observations suggest that nonsteroidal anti-inflammatory drugs and certain selective cyclooxygenase (COX)-2 inhibitors may reduce the relative risk of clinically evident prostate cancer. This prompted us to investigate the chemopreventive potential of celecoxib, a selective COX-2 inhibitor, against prostate carcinogenesis in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Similar to prostate cancer in humans, prostate malignancies in TRAMP mice progress from precursor intraepithelial lesions, to invasive carcinoma that metastasizes to lymph nodes, liver, lungs, and occasionally to bone. The basal enzyme activity and protein expression of COX-2 is significantly higher (>4-fold) in the dorsolateral prostate of TRAMP mice up to 24 weeks of age compared with their nontransgenic littermates. Eight-week-old TRAMP mice were randomly divided and fed either control diet (AIN 76A) or a custom prepared AIN 76A diet containing 1500-ppm celecoxib ad libitum for 24 weeks, a dosage that would compare with the normal recommended dose for the treatment of human disease. Studies from two independent experiments, each consisting of 10 mice on test, showed that the cumulative incidence of prostate cancer development at 32 weeks of age in animals fed with AIN 76A diet was 100% (20 of 20) as observed by tumor palpation, whereas 65% (13 of 20), 35% (7 of 20), and 20% (4 of 20) of the animals exhibited distant site metastases to lymph nodes, lungs, and liver. Celecoxib supplementation to TRAMP mice from 8-32 weeks of age exhibited significant reduction in tumor development (5 of 20) with no signs of metastasis. Celecoxib feeding resulted in a significant decrease in prostate (56%; P < 0.0003) and genitourinary weight (48%; P < 0.008). Sequential magnetic resonance imaging analysis of celecoxib-fed mice documented lower prostate volume compared with the AIN 76A-fed group. Histopathological examination of celecoxib-fed animals showed reduced proliferation, and down-modulation of COX-2 and prostaglandin E2 levels in the dorsolateral prostate and plasma, respectively. These results correlated with retention of antimetastasis markers, viz E-cadherin, and alpha- and beta-catenin, along with a significant decrease in vascular endothelial growth factor protein expression. Celecoxib supplementation also resulted in enhanced in vivo apoptosis in the prostate as monitored by several techniques including a recently perfected technique of 99mTc-labeled annexin V in live animals followed by phosphor imaging. One striking observation in an additional study was that celecoxib feeding to mice with established tumors (16 weeks of age) significantly improved their overall survival (P = 0.014), compared with AIN 76A-fed group. Our findings suggest that celecoxib may be useful in chemoprevention of prostate cancer.

Brain Activation During Silent Word Generation Evaluated with Functional MRI

This is a study of word generation during functional MRI (fMRI). Eleven normal healthy subjects were instructed to generate words covertly, (i.e., silently) that began with particular letters. Images were acquired on a conventional 1.5T scanner at three contiguous axial planes encompassing language-related areas of the temporal and frontal lobe. The data were analyzed at the level of a Talairach box, after individually fitting the proportional Talairach grid system to each slice. The main variable of interest was the number of activated pixels within a Talairach box. Boxes with a significant increase in the proportion of activated pixels were located in three regions of the left neocortex: (1) Brodmann areas 44 and 45 in the dorsolateral frontal cortex (Brocas area), (2) areas 21 and 37 in the temporal cortex, (3) and the striate/extrastriate cortex (areas 17 & 18). The results are discussed in terms of a cognitive model of word generation and are compared, in detail, with the results of prior relevant imaging studies.

Cortical localization of human sustained attention: Detection with functional MR using a visual vigilance paradigm

PURPOSE Our goal was to determine whether functional MRI on a standard 1.5 T system can localize activation during a visual vigilance sustained attention task and whether this corresponds to results described in a PET investigation of a similar task. METHOD Sixteen volunteers were studied on a 1.5 T system using a gradient echo technique. A single axial section was oriented within a stereotaxic coordinate space, 40 mm superior to the anterior-posterior commissure line. Images with eyes closed were followed by images during subject concentration on a small dim spot. Motion correction and pixel-by-pixel statistical analysis were performed. Talairach grids were applied for summary statistical analysis and comparison to PET data, with analysis using a series of planned contrasts within a repeated measures analysis of variance. RESULTS Predominantly right-sided frontal and parietal activation was observed, with statistical significance across subjects in the right frontal lobe (F > or = 5.9, p < or = 0.041). Comparison with previously reported PET data yielded a very similar pattern of activation (F = 13.2; df = 1,8; p = 0.007). CONCLUSION Activation of the right middle frontal gyrus and right parietal lobe during visual vigilance is detectable across functional imaging modalities.

Semiautomatic 3-D image registration as applied to interventional MRI liver cancer treatment

The authors evaluated semiautomatic, voxel-based registration methods for a new application, the assessment and optimization of interventional magnetic resonance imaging (I-MRI) guided thermal ablation of liver cancer. The abdominal images acquired on a low-field-strength, open I-MRI system contain noise, motion artifacts, and tissue deformation. Dissimilar images can be obtained as a result of different MRI acquisition techniques and/or changes induced by treatments. These features challenge a registration algorithm. The authors evaluated one manual and four automated methods on clinical images acquired before treatment, immediately following treatment, and during several follow-up studies. Images were T2-weighted, T1-weighted Gd-DTPA enhanced, T1-weighted, and short-inversion-time inversion recovery (STIR). Registration accuracy was estimated from distances between anatomical landmarks. Mutual information gave better results than entropy, correlation, and variance of gray-scale ratio. Preprocessing steps such as masking and an initialization method that used two-dimensional (2-D) registration to obtain initial transformation estimates were crucial. With proper preprocessing, automatic registration was successful with all image pairs having reasonable image quality. A registration accuracy of /spl ap/3 mm was achieved with both manual and mutual information methods. Despite motion and deformation in the liver, mutual information registration is sufficiently accurate and robust for useful applications in I-MRT thermal ablation therapy.

Increased presence of white matter hyperintensities in adolescent patients with bipolar disorder

Several reports have noted an increase in white matter hyperintensities (WMH) on MRI scans of adult patients with bipolar disorder. We investigated whether this increase was also evident in a group of adolescent patients with bipolar disorder. The sample consisted of 15 bipolar patients, 19 patients with schizophrenia and 16 healthy comparison subjects. All subjects were adolescents. WMH were blindly rated on T2-weighted and PD-weighted MRI scans using our own scale with documented inter-rater reliability. WMH were present in 10 of 15 bipolar patients (67%), seven of 19 patients with schizophrenia (37%) and five of 16 comparison subjects (31%). The bipolar adolescent group had a statistically significant increased presence of WMH compared both with healthy comparison subjects and the schizophrenic group. The association between WMH and bipolar disorder appears to extend to the adolescent years.

Active device tracking and high-resolution intravascular MRI using a novel catheter-based, opposed-solenoid phased array coil.

A novel two‐element, catheter‐based phased array coil was designed and built for both active MR device tracking and high‐resolution vessel wall imaging. The device consists of two independent solenoid coils that are wound in opposite directions, connected to separate receive channels, and mounted collinearly on an angiographic catheter. The elements were used independently or together for tracking or imaging applications, respectively. The arrays dual functionality was tested on a clinical 1.5 T MRI scanner in vitro, in vivo, and in situ. During real‐time catheter tracking, each element gave rise to a high‐amplitude peak in the respective projection data, which enabled reliable and robust device tracking as well as automated slice positioning. In vivo microimaging with 240 μm in‐plane resolution was achieved in 9 s using the device and TrueFISP imaging. Therefore, a single device was successfully implemented that met the combined requirements of intravascular device tracking and imaging. Magn Reson Med 51:668–675, 2004.

An MRI study of adolescent patients with either schizophrenia or bipolar disorder as compared to healthy control subjects

BACKGROUND There are few imaging studies in adolescent patients with either schizophrenia or bipolar disorder. Such studies are of interest because adolescents may have a more severe illness and neurodevelopmental events may have a greater role in their pathophysiology. METHODS We compared 20 patients with schizophrenia and 15 patients with bipolar disorder (10 to 18 years) to 16 normal adolescents on magnetic resonance imaging (MRI) measures of intracranial volume and ventricular and sulcal enlargement. Two planned comparison contrasts were employed, one comparing the two patient groups to each other (contrast 1), and one comparing both patient groups combined to control subjects (contrast 2). RESULTS None of the contrast 1 comparisons (schizophrenia vs bipolar) were statistically significant. Contrast 2 comparisons (control subjects vs patients) were statistically significant for intracranial volume (reduced in patients) as well as frontal and temporal sulcal size (increased in patients). CONCLUSIONS The patient groups were not statistically significantly different from each other on any measure. The combined patient groups were different from control subjects on intracranial volume and frontal and temporal sulcal size. Also, there was evidence for ventricular enlargement, after removal of a control subject with an extreme value. These findings indicate that the same abnormalities noted in adult populations are present in adolescents.

Slice-to-volume registration and its potential application to interventional MRI-guided radio-frequency thermal ablation of prostate cancer

In this study, we registered live-time interventional magnetic resonance imaging (iMRI) slices with a previously obtained high-resolution MRI volume that in turn can be registered with a variety of functional images, e.g., PET, SPECT, for tumor targeting. We created and evaluated a slice-to-volume (SV) registration algorithm with special features for its potential use in iMRI-guided radio-frequency (RF) thermal ablation of prostate cancer. The algorithm features included a multiresolution approach, two similarity measures, and automatic restarting to avoid local minima. Imaging experiments were performed on volunteers using a conventional 1.5-T MR scanner and a clinical 0.2-T C-arm iMRI system under realistic conditions. Both high-resolution MR volumes and actual iMRI image slices were acquired from the same volunteers. Actual and simulated iMRI images were used to test the dependence of SV registration on image noise, receive coil inhomogeneity, and RF needle artifacts. To quantitatively assess registration, we calculated the mean voxel displacement over a volume of interest between SV registration and volume-to-volume registration, which was previously shown to be quite accurate. More than 800 registration experiments were performed. For transverse image slices covering the prostate, the SV registration algorithm was 100% successful with an error of <2 mm, and the average and standard deviation was only 0.4 mm /spl plusmn/ 0.2 mm. Visualizations such as combined sector display and contour overlay showed excellent registration of the prostate and other organs throughout the pelvis. Error was greater when an image slice was obtained at other orientations and positions, mostly because of inconsistent image content such as that from variable rectal and bladder filling. These preliminary experiments indicate that MR SV registration is sufficiently accurate to aid image-guided therapy.

An optical system for wireless detuning of parallel resonant circuits.

A new optical method of detuning parallel resonant circuits is described. This method involves the integration of a photoresistor in parallel with the inductor and capacitor of a parallel resonant circuit, in this case a magnetic resonance imaging (MRI) receiver coil. A fiberoptic cable extending the length of the interventional device is used in conjunction with an external light source to deliver light to the photoresistor. Exposing the photoresistor to light changes its bulk resistance and greatly lowers the Q of the parallel resonant circuit, effectively detuning it. By combining this optical detuning scheme with inductive coupling of the interventional device-mounted microcoils to a standard MRI coil, a completely wireless device for active device tracking has been created. This new device improves on current technology by simplifying device complexity and reducing patient risk by eliminating the need for electrical connections between the device-mounted microcoils to the MR receiver channel.A new optical method of detuning parallel resonant circuits is described. This method involves the integration of a photoresistor in parallel with the inductor and capacitor of a parallel resonant circuit, in this case a magnetic resonance imaging (MRI) receiver coil. A fiberoptic cable extending the length of the interventional device is used in conjunction with an external light source to deliver light to the photoresistor. Exposing the photoresistor to light changes its bulk resistance and greatly lowers the Q of the parallel resonant circuit, effectively detuning it. By combining this optical detuning scheme with inductive coupling of the interventional device‐mounted microcoils to a standard MRI coil, a completely wireless device for active device tracking has been created. This new device improves on current technology by simplifying device complexity and reducing patient risk by eliminating the need for electrical connections between the device‐mounted microcoils to the MR receiver channel. J. Magn. Reson. Imaging 2000;12:632–638.