Semiautomatic landmark-based two-dimensional-three-dimensional image fusion in living mice: correlation of near-infrared fluorescence imaging of Cy5.5-labeled antibodies with flat-panel volume computed tomography.

Connecting fluorescence signals with anatomic structures enhances our ability to monitor biologic processes in mice. Here, we present a semiautomated approach to correlate two-dimensional (2D) noninvasive near-infrared fluorescence (NIRF) imaging with three-dimensional (3D), high-resolution, flat-panel volume computed tomography (fpVCT). We developed an algorithm to colocalize fluorescence signals of NIRF-labeled antibodies directed against matriptase and urokinase plasminogen activator receptor (uPAR) to orthotopic carcinomas in mice visualized by fpVCT. For this purpose, mice were anesthetized and fixed on a multimodality animal bed containing fiducial markers filled with iodine-containing contrast agent and fluorescent dye. After intravenous administration of contrast agent and Cy5.5-labeled antibodies, NIRF and fpVCT images were obtained, without repositioning the mice. Binding of Cy5.5-labeled matriptase-specific antibody to pancreatic tumors and Cy5.5-labeled uPAR-specific antibody to mammary carcinomas was assessed by time-domain NIRF imaging measuring the location of fluorescence intensity and its lifetime. In summary, we developed a novel 2D-3D registration technique for image fusion with NIRF imaging and fpVCT to provide complementary information in tumor models on the in vivo association of functional information with anatomic structures. The combination of fpVCT with NIRF imaging will now allow targeted and effective monitoring of preclinical tumor therapies.

Comparison of 1.0 M gadobutrol and 0.5 M gadopentate dimeglumine-enhanced MRI in 471 patients with known or suspected renal lesions: results of a multicenter, single-blind, interindividual, randomized clinical phase III trial.

The purpose of this phase III clinical trial was to compare two different extracellular contrast agents, 1.0 M gadobutrol and 0.5 M gadopentate dimeglumine, for magnetic resonance imaging (MRI) in patients with known or suspected focal renal lesions. Using a multicenter, single-blind, interindividual, randomized study design, both contrast agents were compared in a total of 471 patients regarding their diagnostic accuracy, sensitivity, and specificity to correctly classify focal lesions of the kidney. To test for noninferiority the diagnostic accuracy rates for both contrast agents were compared with CT results based on a blinded reading. The average diagnostic accuracy across the three blinded readers ('average reader') was 83.7% for gadobutrol and 87.3% for gadopentate dimeglumine. The increase in accuracy from precontrast to combined precontrast and postcontrast MRI was 8.0% for gadobutrol and 6.9% for gadopentate dimeglumine. Sensitivity of the average reader was 85.2% for gadobutrol and 88.7% for gadopentate dimeglumine. Specificity of the average reader was 82.1% for gadobutrol and 86.1% for gadopentate dimeglumine. In conclusion, this study documents evidence for the noninferiority of a single i.v. bolus injection of 1.0 M gadobutrol compared with 0.5 M gadopentate dimeglumine in the diagnostic assessment of renal lesions with CE-MRI.

Morphologic changes of mammary carcinomas in mice over time as monitored by flat-panel detector volume computed tomography.

Noninvasive methods are strongly needed to detect and quantify not only tumor growth in murine tumor models but also the development of vascularization and necrosis within tumors. This study investigates the use of a new imaging technique, flat-panel detector volume computed tomography (fpVCT), to monitor in vivo tumor progression and structural changes within tumors of two murine carcinoma models. After tumor cell inoculation, single fpVCT scans of the entire mice were performed at different time points. The acquired isotropic, high-resolution volume data sets enable an accurate real-time assessment and precise measurements of tumor volumes. Spreading of contrast agent-containing blood vessels around and within the tumors was clearly visible over time. Furthermore, fpVCT permits the identification of differences in the uptake of contrast media within tumors, thus delineating necrosis, tumor tissues, and blood vessels. Classification of tumor tissues based on the decomposition of the underlying mixture distribution of tissue-related Hounsfield units allowed the quantitative acquisition of necrotic tissues at each time point. Morphologic alterations of the tumor depicted by fpVCT were confirmed by histopathologic examination. Concluding, our data show that fpVCT may be highly suitable for the noninvasive evaluation of tumor responses to anticancer therapies during the course of the disease.

Photosensitizing and radiosensitizing effects of hypericin on human renal carcinoma cells in vitro.

The renal cell carcinoma (RCC) is extremely resistant to chemotherapy and radiotherapy. The prognosis of patients with metastatic RCC still remains poor, the median survival is less than 12 months. Therefore, new therapeutic options are desirable. The aim of this study was to investigate the photosensitizing and radiosensitizing effects of hypericin on human RCC cells in vitro. First the RCC-derived cell lines A498 and ACHN were incubated with different concentrations of hypericin. In vitro uptake and intracellular distribution of hypericin were confirmed by fluorescence microscopy. Subsequently cells were illuminated and irradiated with a dose of 2-8 Gy, respectively. Finally, metabolic activity, apoptosis and clonogenic survival were investigated. Uptake of hypericin was observed for almost all cells. Hypericin treatment combined with illumination led to a 94-97% decrease in metabolic activity and caused apoptosis in nearly 100% of RCC cells. Hypericin enhanced the radiosensitivity of A498 cells in vitro. The clonogenic survival after irradiation was significantly reduced by hypericin treatment. Taken together, the photosensitizing and radiosensitizing effects of hypericin on human RCC cells we found in this investigation could be of clinical relevance, e.g. for radiotherapy and intraoperative photodynamic therapy, respectively.

Chemotherapy-induced suppression to adenoma or complete suppression of the primary in patients with stage IV colorectal cancer: report of four cases.

BACKGROUND: Although modern chemotherapy of stage IV advanced colorectal cancer (CRC) has impressively improved overall survival, the response of the primary tumor has not been studied because surgical resection of the primary continues to be the standard procedure in stage IV CRC. AIM: Long-term follow-up of the primary in patients with stage IV CRC under chemotherapy. METHODS AND RESULTS: Here we report on the histological changes in the primary tumor in four patients suffering from stage IV CRC. Systemic chemotherapy was started immediately after endoscopic tumor debulking in three cases. In one case no endoscopic intervention was performed before chemotherapy. Neither macroscopic nor histological evidence for malignant tumor growth was found at the former site of the primary after 6, 23, 26 or 48 months, respectively. Two patients had a complete suppression of the primary, two patients had an adenoma at the former site of the primary. To date, three patients have died because of progression of liver metastases and one patient is still alive with no signs of tumor growth. CONCLUSION: The four cases illustrate that today's chemotherapy may effectively induces suppression of the primary in CRC. The development of CRC may follow different pathways.

Flat-panel detector-based volume computed tomography: a novel 3D imaging technique to monitor osteolytic bone lesions in a mouse tumor metastasis model.

Skeletal metastasis is an important cause of mortality in patients with breast cancer. Hence, animal models, in combination with various imaging techniques, are in high demand for preclinical assessment of novel therapies. We evaluated the applicability of flat-panel volume computed tomography (fpVCT) to noninvasive detection of osteolytic bone metastases that develop in severe immunodeficient mice after intracardial injection of MDA-MB-231 breast cancer cells. A single fpVCT scan at 200-microm isotropic resolution was employed to detect osteolysis within the entire skeleton. Osteolytic lesions identified by fpVCT correlated with Faxitron X-ray analysis and were subsequently confirmed by histopathological examination. Isotropic three-dimensional image data sets obtained by fpVCT were the basis for the precise visualization of the extent of the lesion within the cortical bone and for the measurement of bone loss. Furthermore, fpVCT imaging allows continuous monitoring of growth kinetics for each metastatic site and visualization of lesions in more complex regions of the skeleton, such as the skull. Our findings suggest that fpVCT is a powerful tool that can be used to monitor the occurrence and progression of osteolytic lesions in vivo and can be further developed to monitor responses to antimetastatic therapies over the course of the disease.

Semi-automatic classification of skeletal morphology in genetically altered mice using flat-panel volume computed tomography.

Rapid progress in exploring the human and mouse genome has resulted in the generation of a multitude of mouse models to study gene functions in their biological context. However, effective screening methods that allow rapid noninvasive phenotyping of transgenic and knockout mice are still lacking. To identify murine models with bone alterations in vivo, we used flat-panel volume computed tomography (fpVCT) for high-resolution 3-D imaging and developed an algorithm with a computational intelligence system. First, we tested the accuracy and reliability of this approach by imaging discoidin domain receptor 2- (DDR2-) deficient mice, which display distinct skull abnormalities as shown by comparative landmark-based analysis. High-contrast fpVCT data of the skull with 200 microm isotropic resolution and 8-s scan time allowed segmentation and computation of significant shape features as well as visualization of morphological differences. The application of a trained artificial neuronal network to these datasets permitted a semi-automatic and highly accurate phenotype classification of DDR2-deficient compared to C57BL/6 wild-type mice. Even heterozygous DDR2 mice with only subtle phenotypic alterations were correctly determined by fpVCT imaging and identified as a new class. In addition, we successfully applied the algorithm to classify knockout mice lacking the DDR1 gene with no apparent skull deformities. Thus, this new method seems to be a potential tool to identify novel mouse phenotypes with skull changes from transgenic and knockout mice on the basis of random mutagenesis as well as from genetic models. However for this purpose, new neuronal networks have to be created and trained. In summary, the combination of fpVCT images with artificial neuronal networks provides a reliable, novel method for rapid, cost-effective, and noninvasive primary screening tool to detect skeletal phenotypes in mice.

Preclinical evaluation by flat-panel detector-based volumetric CT versus MRI of intervertebral spacers implanted in a porcine model.

BACKGROUND CONTEXT: Image quality and implant detectability by conventional imaging methods are suboptimal for perioperative spinal diagnostics, primarily limited by implant-related artifacts. PURPOSE: To evaluate the imaging quality of various intervertebral spacers examined by flat-panel detector-based volumetric computed tomography (FD-VCT) versus magnetic resonance imaging (MRI). STUDY DESIGN/SETTING: A preclinical comparative study on an experimental porcine model. The study was performed at a university research facility. METHODS: Three different intervertebral spacer types (titanium, carbon fiber-reinforced polymer, cobalt-chrome-molybdenum) were implanted in a cadaveric porcine spine and then examined by MRI using T1-weighted spin echo (T1w-SE) and turbo spin echo (T1w-TSE) sequences. Comparative imaging was performed with an experimentally approved FD-VCT prototype featuring two-dimensional and three-dimensional imaging and high isotropic spatial resolution. Data analysis focused on spacer shape, implant positioning, and implant-bone interface. RESULTS: Compared with MRI, and despite the use of T1w-SE and T1w-TSE sequences, the image quality and detectability of all target characteristics were better with FD-VCT absent the usual artifacts. Using its option for implant-specific imaging, the experimental FD-VCT imager allowed reliable determination of additional variables such as dimension and volume. CONCLUSIONS: This experimental study provides initial evidence that FD-VCT produces excellently sharp, high-accuracy, artifact-free imaging quality that is superior to MRI in distinguishing key characteristics of intervertebral implants in a preclinical setting.

Follicular dendritic cell sarcoma of the spleen.

Diagnosis of primary spindle cell tumors of the spleen is challenging because of the limited immunologic and cytogenetic characterization of this rare entity. We report a case of primary follicular dendritic cell (FDC) sarcoma of the spleen in a 44-year-old woman. Indications for FDC included positive staining for CD21, Ki-M4P, CD14, and fascin. Expression of both standard FDC markers CD23 and CD35 was detected immunohistochemically using tyramide signal amplification. Cytogenetic analysis revealed multiple clonal chromosomal aberrations involving unbalanced translocations of chromosomes X, 3, 5, 7, 8, 9, and 10, leading to net gains at 3q, 7p, 8q, and 9q and net losses at Xp, 8p, 9p, and 10p. Loss at Xp has been described previously in another tumor with FDC features, suggesting that this aberration might play a common role in this malignancy.

Implant detectibility of intervertebral disc spacers in post fusion MRI: evaluation of the MRI scan quality by using a scoring system--an in vitro study.

INTRODUCTION: Intervertebral spacers for anterior spine fusion are made of different materials, such as titanium and cobalt chromium alloys and carbon fiber-reinforced polymers. Implant-related susceptibility artifacts can decrease the quality of MRI scans. The aim of this cadaveric study was to demonstrate the extent that implant-related MRI artifacting affects the postfusion differentiation of determined regions of interest (ROIs). METHODS: In six cadaveric porcine spines, we evaluated the postimplantation MRI scans of a titanium, cobalt-chromium and carbon spacer that differed in shape and surface qualities. A spacer made of human cortical bone was used as a control. A defined evaluation unit was divided into ROIs to characterize the spinal canal as well as the intervertebral disc space. Considering 15 different MRI sequences read independently by an interobserver-validated team of specialists the artifact-affected image quality of the median MRI slice was rated on a score of 0-3. A maximum score of 18 points (100%) for the determined ROIs was possible. RESULTS: Turbo spin echo sequences produced the best scores for all spacers and the control. Only the control achieved a score of 100%. For the determined ROI maximum scores for the cobalt-chromium, titanium and carbon spacers were 24%, 32% and 84%, respectively. CONCLUSION: By using favored T1 TSE sequences the carbon spacer showed a clear advantage in postfusion spinal imaging. Independent of artifact dimensions, the scoring system used allowed us to create an implant-related ranking of MRI scan quality in reference to the bone control.

Flat-panel-detector-based volumetric CT: performance evaluation of imaging for skeletal structures of small animals in comparison to multislice CT.

OBJECTIVES: The aim of this study was to compare the image performance of silicon-based flat-panel-detector-based volumetric computed tomography (fpVCT) to multislice spiral computed tomography (MSCT) for the visualization and detail detectability of skeletal structures in rodents of different development stages. MATERIALS AND METHODS: Rodents of different development stages were imaged with fpVCT (GE prototype with circular gantry with two 1024 x 1024, 200-microm pixel size, amorphous silicon/Cesium lodid (Csl) flat-panel detector) and eight-slice MSCT (LightSpeed Ultra). Imaging parameters (80 kVp, 100 mA) and the position of the rodents were identical in both techniques. Image quality, detail detectability, and contour of skeletal structures were judged by two observers in consensus using a 4-point scale (1 = unsatisfactory...4 = good). Findings were displayed and evaluated in axial slices, multiplanar reconstructions (MPR), maximum intensity projections (MIP) and volume rendering technique (VRT) in both modalities. Mean and standard of error of mean were calculated. RESULTS: In axial slices, visualization and detail detectability of very subtle skeletal structures, e.g., the basis of the skull was better in fpVCT than in MSCT (4 vs. 2 points). The MPRs of fpVCT showed less artifacts and more details than those of the MSCT. The MIPs and VRTs of the fpVCT demonstrated best image quality in all rodents of different development stages, whereas MSCT showed significant artifacts. CONCLUSION: fpVCT outperformed MSCT in imaging of small rodents. Due to the truly isotropic volume data set with high spatial resolution, fpVCT is a powerful tool in evaluating detailed skeletal structures.

Impact of breast density on computer-aided detection in full-field digital mammography.

The goal of this study was to evaluate the performance of a computer-aided detection (CAD) system in full-field digital mammography (Senographe 2000D, General Electric, Buc, France) in finding out carcinomas depending on the parenchymal density. A total of 226 mediolateral oblique (MLO) and 186 craniocaudal (CC) mammographic views of histologically proven cancers were retrospectively evaluated with a digital CAD system (ImageChecker V2.3 R2 Technology, Los Altos, CA, USA). Malignant tumors were detected correctly by CAD in MLO view in 84.85% in breasts with parenchymal tissue density of the American College of Radiology (ACR) type 1, in 70.33% of the ACR type 2, in 68.12% of the ACR type 3, and in 69.70% of the ACR type 4. For the CC view, similar results were found according to the ACR types. Using the chi-square and McNemar tests, there was no statistical significance. However, a trend of better detection could be seen with decreasing ACR type. In conclusion, there seems to be a tendency for breast tissue density to affect the detection rate of breast cancer when using the CAD system.

Volumetry of human molars with flat panel-based volume CT in vitro.

The flat panel-based volume computed tomography (fpVCT) is a new CT device applicable for experimental, three-dimensional evaluation of teeth at a resolution of about 150 microm in the high contrast region. The aim of this study was to investigate whether fpVCT was suitable for quantification of the volumes of dental hard tissues and the root canal system to establish a new method for morphological studies. Fifty-two extracted third molars (maxillary: 31, mandibular: 21) were examined with a prototype of an fpVCT using a volumetry algorithm at different levels according to the radiographic density of enamel and dentine. Volumetry of the root canal system was performed after "region growing segmentation": starting from a voxel in the centre of the root canal, this algorithm searches voxels of same density in the surrounding. The volumetry of the root canal system was stopped by the investigator at the apical constriction. Results showed that dentine, enamel and root canal system could be well distinguished in three-dimensional images. Volumetry yielded the following data (cm(3), mean+/-SD): dentine 0.438+/-0.111, enamel 0.227+/-0.051, root canal system 0.052+/-0.017 and total volume 0.753+/-0.159. In conclusion, the fpVCT is appropriate for non-destructive volumetry of large numbers of teeth in experimental laboratory studies.

Computer-aided detection in full-field digital mammography: detection in dependence of the BI-RADS categories.

The object of this study was to determine the performance of a computer-aided detection system in full-field digital mammography (Senographe 2000D, General Electric, Buc, France) in detecting carcinomas in breasts in dependence of the initial Breast Imaging Reporting and Data System (BI-RADS) categories. A total of 226 mediolateral oblique (MLO) and 186 craniocaudal (CC) view mammograms of histologically proven cancers were retrospectively evaluated with a primary digital computer-aided detection system (Image Checker V2.3; R2 Technology, Los Altos, CA). According to BI-RADS of the American College of Radiology (ACR), the lesions were classified in MLO view as BI-RADS 1 in 2 cases, BI-RADS 2 in 11 cases, BI-RADS 3 in 37 cases, BI-RADS 4 in 56 cases, and BI-RADS 5 in 120 cases, and in CC view as BI-RADS 1 in 2 cases, BI-RADS 2 in 8 cases, BI-RADS 3 in 26 cases, BI-RADS 4 in 46 cases, and BI-RADS 5 in 104 cases. The computer-aided detection system shows markers also in mammograms classified as BI-RADS categories 1-3 by the radiologist. Furthermore, BI-RADS categories 4 and 5 in most cases demonstrate masses in mammography. With increasing BI-RADS category, the computer-aided detection system shows decreasing numbers of overlooked carcinomas. In MLO view, no markers were found in 100% (2/2), 81.8% (9/11), 59.5% (22/37), 46.4% (26/56), and 15% (18/120) for BI-RADS categories 1-5, respectively. False-positive markers, however, were seen in 0.5 per image (205/412). In conclusion, the high rate of false-positive markers shows that the specificity of the computer-aided detection system is limited and that improvements are necessary.

Successful treatment of hepatocellular carcinoma with the tyrosine kinase inhibitor imatinib in a patient with liver cirrhosis.

Several mechanisms of development of hepatocellular carcinoma (HCC) in patients with liver cirrhosis have been discussed. One hypothesis suggests that the somatic stem cells of the liver, the so-called oval cells, may undergo malignant transformation. Oval cells are derived from the biliary cells of the canal of Hering and are characterized by c-kit-positivity, the transmembrane receptor of stem cell factor. Constitutively activated tyrosine kinases have been identified as major pathogenetic mechanisms in the development of malignant diseases like gastrointestinal stromal tumors (c-kit) and chronic myelogenous leukemia (bcr-abl). The prognosis of these diseases improved enormously since the drug imatinib, a tyrosine kinase inhibitor of c-kit and bcr-abl, was introduced. Here we report the successful cure of a patient with liver cancer by this tyrosine kinase inhibitor.

The challenge of the solitary pulmonary nodule: diagnostic assessment with multislice spiral CT.

The advent of fast multiscale computed tomography (MSCT) technology has sparked new interest in the noninvasive assessment of the solitary pulmonary nodule (SPN). Fast scanning within a single breath-hold period, simultaneous acquisition of multiple thin slices with subsequent morphologic characterization of the nodule, determination of perfusion patterns as well as growth rates has led to unprecedented improvements in this emerging field. This article reviews the capabilities of MSCT in the diagnostic assessment of the SPN.

The approximate planimetric method: a simple, rapid and reliable method for estimation of lesion size in acute ischemic stroke.

Magnetic resonance imaging is increasingly used in stroke trials for early diagnosis and follow-up of lesion size. Since volumetric measurement remains a laborious and time-consuming task, a rapid and reliable method for the assessment of lesion size has been developed and validated in diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) sequences. These were serially obtained in 40 patients less than 8 h after the onset of symptoms of a middle cerebral artery territory stroke (day 1), as well as on days 3 and 18. For each of 16 (DWI) or 20 (FLAIR) transverse sections obtained on each occasion, lesion size was estimated as a percentage of the total hemisphere. Percentage values from all sections were summed up and expressed as arbitrary units. Results obtained using this approximate planimetric method (APM) were compared with those from a standard volumetric approach. Lesion volumes as determined by both methods were highly correlated (DWI: r = 0.966, FLAIR: r = 0.979, p < 0.001). To conclude, the APM is simple, rapid and reliable for the estimation of lesion size in acute ischemic stroke. It can be recommended for broader application in clinical trials.

Soft copy versus hard copy reading in digital mammography.

The objective of this study was to compare soft copy reading at a mammography work station with hard copy reading of full-field digital mammographic images. Mammograms of 60 patients ( n = 29 malignant, n = 31 benign) performed with full-field digital mammography (Senographe 2000D, GE, Buc, France) were evaluated. Reading was performed based on hard copy prints (Scopix, Agfa, Leverkusen, Germany) and on 2 k x 2.5 k high-resolution monitors (Sun Ultra 60, Sun Microsystems, Palo Alto, California, USA). Four readers with different levels of experience in mammography categorized the mammograms according to the BI-RADS classification. The comparative study was performed by four readers, and at least 2 months elapsed between the reading sessions. Postprocessing, of course, was available only at the work station (windowing and leveling, zooming, inversion). Sensitivity, specificity, and positive predictive value were evaluated. Diagnostic accuracy of the evaluation was determined. Sensitivity for malignant lesions in hard copy versus soft copy reading was 97% vs 90%, 97% vs 97%, 93% vs 97%, and 76% vs 76% for the four readers, respectively. Specificity was 52% vs 68%, 58% vs 74%, 65% vs 48%, and 61% vs 68%. Accuracy for the classification of malignant lesions according to the BI-RADS categories showed no difference between hard copy and soft copy reading. Soft copy reading is possible with the available system and enables radiologists to use the advantages of a digital system.

Gadobenate dimeglumine-enhanced MR angiography of the abdominal aorta and renal arteries.

OBJECTIVE: This study was conducted to determine the efficacy and safety of four different doses of gadobenate dimeglumine for contrast-enhanced three-dimensional MR angiography of the abdominal aorta and renal arteries. SUBJECTS AND METHODS: Ninety-four patients with suspected abnormality of the abdominal aorta or renal arteries underwent unenhanced three-dimensional gradient-recalled echo time-of-flight MR angiography and contrast-enhanced MR angiography after the IV injection of one of four doses of gadobenate dimeglumine (0.025, 0.05, 0.1, and 0.2 mmol/kg of body weight). Efficacy was assessed on-site and by two blinded off-site reviewers in terms of change in total diagnostic quality score and diagnostic quality score per vessel segment from baseline unenhanced time-of-flight MR angiography to contrast-enhanced MR angiography. Secondary efficacy end points included lesion count and level of confidence in lesion characterization. Safety assessments comprised adverse event monitoring, physical evaluation, vital signs, ECG, and laboratory investigations. RESULTS: A significant change in the total diagnostic quality score from unenhanced to contrast-enhanced MR angiography was observed at all doses. The change increased with increased dose, plateauing at the 0.1 mmol/kg dose level. More patients with lesions detected and increased reviewer confidence for lesion characterization were noted on contrast-enhanced MR angiography compared with unenhanced MR angiography, although no dose-related trends were observed. All doses were well tolerated, and no significant changes in safety parameters were observed. CONCLUSION: Gadobenate dimeglumine is an effective and safe agent for contrast-enhanced MR angiography of the abdominal aorta and renal arteries. A dose of 0.1 mmol/kg of body weight appears to be the most suitable.