Small bowel polyp resection using device-assisted enteroscopy in Peutz-Jeghers Syndrome: Results of a specialised tertiary care centre.

INTRODUCTION: Enteroscopy resection of small bowel polyps in Peutz-Jeghers syndrome has only been described in small case series. Herein, we aimed to assess the efficacy of enteroscopy resection of small bowel polyps within a specialised tertiary care centre and the impact on intraoperative enteroscopy. METHODS: This was an observational single-centre study. All adult Peutz-Jeghers syndrome patients followed in the Predisposition Digestive Ile-de-France network who underwent an endoscopic resection of at least one small bowel polyp ≥ 1 cm by enteroscopy between 2002-2015 were included. Small bowel polyps were detected under a dedicated screening programme by previous capsule endoscopy and/or magnetic resonance enterography, performed every 2-3 years. Complete treatment was defined as the absence of polyps ≥ 1 cm after conventional endoscopic resection. Intraoperative enteroscopy or surgical resection were indicated in incomplete treatments. The overall complete treatment rate including conventional enteroscopy and intraoperative enteroscopy was also considered. RESULTS: Endoscopic resection of 216 small bowel polyps (median: 8.6 per patient, size: 6-60 mm) was performed by 50 enteroscopies in 25 patients (mean age: 36 years, range: 18-71, 56% male) with small bowel polyp ≥ 1 cm. Twenty-three patients (92%) underwent 42 screening capsule endoscopies and 14 (57%) had 23 magnetic resonance enterographies during a median follow-up of 60 months. Complete treatment was achieved in 76%. Intraoperative enteroscopy and surgical resection were performed in four (16%) and two (8%) patients. Intraoperative enteroscopy improved by 16% the complete treatment rate and the overall rate was 92%. The complication rate was 6%. CONCLUSION: This long-term study confirmed the efficacy and safety of endoscopic resection of small bowel polyps in Peutz-Jeghers syndrome. Intraoperative enteroscopy can be a complementary approach in selected cases.

Radiological evaluation of response to treatment: application to metastatic renal cancers receiving anti-angiogenic treatment.

Targeted therapies have considerably improved the prognosis of patients with metastatic renal cancer (mRCC) but there are no reliable response assessment criteria reflecting the clinical benefits, because there is no regression in size, or it is delayed. Such criteria would help early identification of non-responders, who would then benefit from a change of treatment, and would avoid their being subjected to unnecessary side effects related to the treatment. We will review the imaging techniques currently available for evaluating tumour response in mRCC patients, including the response evaluation criteria in solid tumours (RECIST), the Choi criteria, the modified Choi criteria, and the CT size and attenuation criteria (SACT). We will also discuss functional imaging techniques, which are based on the physiological characteristics of the tumours, such as perfusion CT, magnetic resonance imaging or ultrasound (DCE-CT, DCE-MRI, DCE-US), diffusion MRI, BOLD MRI and new positron emission tomography (PET) tracers. It is not possible at present to propose a unanimously acknowledged criterion for evaluating tumour response to targeted therapy. However, there is a real need for this according to oncologists and the pharmaceutical industry, and radiologists need to be involved in reflecting on the subject.

Imaging criteria for assessing tumour response: RECIST, mRECIST, Cheson.

Most methods define a limited number of "target" lesions to be measured and other "non-target" lesions to be evaluated qualitatively. RECIST criteria are the most widely used although other criteria have been proposed that are derived from them based on size alone, or size and attenuation. Modified RECIST (mRECIST) criteria only concern hepatocellular carcinoma and only take into account the viable portion (enhanced after injection during the arterial phase). Cheson criteria are more complex as target lesions are defined differently depending on the organ (lymph nodes, liver or spleen, other organs), and involve both CT and PET scans, as well as the clinical examination and bone marrow biopsy.

Real time shear waves elastography monitoring of thermal ablation: in vivo evaluation in pig livers.

BACKGROUND: Thermal ablation is a widely used minimally invasive treatment modality for different cancers. However, lack of a real-time imaging system for accurate evaluation of the procedure is one of the reasons of local recurrences. Shear waves elastography (SWE) is a new ultrasound (US) imaging modality to quantify tissue stiffness. The aim of the study was to assess the feasibility and accuracy of US elastography for quantitative monitoring of thermal ablation and to determine the elasticity threshold predictive of coagulation necrosis. METHODS: A total of 29 in vivo thermal lesions were performed in pig livers with radiofrequency system. SWE and B-mode images were acquired simultaneously. Liver elasticity was quantified by using SWE data and expressed in kilopascal. After the procedure, pathologic analysis of treated tissues was compared with US images. The sensitivity and positive predictive value of the SWE maps of tissue elasticity were calculated and compared with the boundaries of the pale coagulation necrosis areas found at pathology. RESULTS: The liver mean elasticity values before and after thermal therapy were 6.4 ± 0.3 and 38.1 ± 2.5 kPa, respectively (P < 0.0001). For a threshold of 20 kPa, sensitivity (i.e., the rate of pixels correctly detected as necrosed tissue) was 0.8, and the positive predictive value (i.e., the rate of pixels in the elastographic map >20 kPa that actually developed coagulation necrosis) was 0.83. CONCLUSIONS: Tissue areas with coagulation necrosis are significantly stiffer than the surrounding tissue. SWE permits the real-time detection of coagulation necrosis produced by radiofrequency and could potentially be used to monitor US-guided thermal ablation.

MR perfusion for pelvic female imaging.

Perfusion MRI of the female pelvis is based on a T1-weighted imaging acquired repeatedly at high temporal resolution. Post-processing can be carried out either from a visual analysis, by description of the curves or by compartmental modeling. Many studies have shown this method to be useful in detecting cervical cancers (initial tumor or identification of recurrence), and in staging endometrial cancers (assessment of cervical invasion). More recent studies have described perfusion MRI as a tool for characterizing adnexal tumors based on the properties of the microvascular wall. When it is combined with morphological MRI findings and diffusion sequences, it incorporates a decision-making algorithm which has a diagnostic performance of 95.4% in characterizing complex adnexal masses (Thomassin-Naggara et al., 2011).

Shear wave elastography of tumour growth in a human breast cancer model with pathological correlation.

OBJECTIVE: To assess stiffness in a human breast cancer implanted in mice using shear wave elastography (SWE) during tumour growth and to correlate the results with pathology. METHODS: Local ethics committee for animal research approval was obtained. A human invasive ductal carcinoma was implanted subcutaneously in 24 athymic nude female mice. Ultrasound was longitudinally performed in 22 tumours, every 1-2 weeks. Maximum diameter and mean stiffness were collected. Seven tumours were measured both in vivo and ex vivo. Tumours of different sizes were removed for pathological analysis on which the percentages of viable cellular tissue, fibrosis and necrosis were measured. RESULTS: A total of 63 SWE measurements were performed. Stiffness increased during tumour growth with an excellent correlation with size (r = 0.94, P < 0.0001). No differences were found between the values of stiffness in vivo and ex vivo (P = 0.81). There was a significant correlation between elasticity and fibrosis (r = 0.83, P < 0.0001), a negative correlation with necrosis (r = -0.76, p = 0.0004) but no significant correlation with cellular tissue (r = 0.40, p = 0.1). CONCLUSION: Fibrosis plays an important role in stiffness as measured by SWE, whereas necrosis is correlated with softness. KEY POINTS: • In a breast cancer model, ultrasound tumour stiffness is correlated with size. • Stiffness changes with tumour growth are correlated with pathological changes. • Stiffness is very well correlated with proportion of tumour fibrosis. • Stiffness is inversely correlated with proportion of tumour necrosis. • Tumour stiffness measurements are similar in vivo and ex vivo.

[Angiogenesis inhibition: review of the activity of sorafenib, sunitinib and bevacizumab]. / Inhibiteurs de l'angiogenèse : revues de l'apport thérapeutique du sorafenib, du sunitinib et du bevacizumab dans le cancer du rein métastatique.

Renal cell carcinoma accounts for approximately 3% of all human malignancies. The use of cytokines in metastatic stage of disease has been the standard until last decades, presenting partial and short duration responses. Research on angiogenesis in renal carcinoma has brought important advances to understand tumor biology and to allow us development of new antiangiogenic drugs. Sunitinib (SUTENT), sorafenib (NEXAVAR) and bevacizumab (AVASTIN) are actually three molecules accepted to use in metastatic renal cell carcinoma (mRCC), with a good tolerability demonstrated in different studies. Clinical evidence shows sunitinib to be reference standard of care for the first-line treatment of mRCC. The use of bevacizumab in combination with interferon alfa (IFN alfa) can also be considered in this setting. Sorafenib is recommended for second-line treatment in cytokine-refractory patients, sunitinib being also accepted in this situation. Other combination of these molecules and their use as neo-adjuvant and adjuvant therapy is being evaluated and should change in the short term the management of the disease.

Optimizing the size variation threshold for the CT evaluation of response in metastatic renal cell carcinoma treated with sunitinib.

BACKGROUND: In metastatic renal cell carcinoma (mRCC), antiangiogenic treatments rarely achieve a reduction of -30% in the sum of longest diameters (SLD) of target lesions required by RECIST for an 'objective response', although they objectively improve progression-free survival (PFS). We sought to determine a threshold for the computed tomography evaluation of these patients' best reflecting patient outcome. PATIENTS AND METHODS: In 334 mRCC patients treated with sunitinib, we tested thresholds from -45% to +10%. We classified patients as 'responders' when the best relative variation of the sum of longest diameters (DeltaSLD) reached the tested threshold and as 'nonresponders' otherwise. For each tested threshold, the median PFS of the two groups were compared. Receiver operating characteristic (ROC) analysis was also carried out among the 103 patients that progressed during follow-up. Finally, the 'optimal' threshold was retested on an independent cohort of 39 patients. RESULTS: The DeltaSLD threshold of -10% gave the most significant difference. It divided patients into 256 responders and 78 nonresponders (median PFS 11.1 and 5.6 months). The same -10% threshold was found using the ROC analysis. Results were confirmed on the external validation cohort. CONCLUSION: A variation of -10% in the SLD accurately and rapidly identifies mRCC patients benefiting from sunitinib.

Fibrin glue sealing in the treatment of a recto-urethral fistula in Crohn's disease: a case report.

Recto-urethral fistulas in Crohn's disease are rare, and managing them is difficult. The various surgical techniques are not reliably effective and are associated with a significant risk of morbidity. The rectal mucosal transposition flap technique, which is used most frequently, requires the rectal mucosa to be in a healthy condition. We report here on a case where treatment was by injecting fibrin glue into a complex fistula with a single anorectal point of origin but combining a median recto-urethrocutaneous tract with two deep lateral rectoperineal tracts. The patient had presented with active rectal Crohn's disease. This treatment produced complete closure, verified by MRI, of all the fistula tracts, which was still maintained after three years, and with normal anal continence. When confronted with this type of fistula, and particularly when the condition of the rectal mucosa is poor, the specialist should be encouraged by this good result to consider the injection of fibrin glue, a technique without risk of morbidity, as a first course of action.

[Imaging of response to treatment in oncology]. / Imagerie de la réponse aux traitements en cancérologie.

Imaging plays a crucial role in oncology to assist in the management of patients and selection of drug regimen. Recent advances in imaging techniques allowing to predict and evaluate response to treatments in oncology will be reviewed. The standard in the evaluation of response to treatment is based on the measurement of lesion size. Functional imaging assesses physiological or molecular processes that may be earlier indicators of early response to treatment. Dynamic imaging of tumor vascularization assesses the biodistribution of a contrast agent within tumoral tissues. Diffusion-weighted MR imaging can differentiate free water from water restricted by tissues, providing an assessment of tumor cellularity. MR spectroscopy assesses the relative quantity of specific chemical components within normal and tumoral tissues. 18 FDG PET imaging provides an assessment of the metabolic activity of tissues. FDG uptake is proportional to cellular proliferation and number of viable cells within a tumor. Results from studies assessing the role of these emerging imaging techniques remain preliminary and the medical community must determine their respective role in the routine evaluation of response to treatment in oncological patients.

[Treatment response evaluation by functional imaging]. / Evaluation de la réponse au traitement par imagerie fonctionnelle.

Imaging in cancer plays a capital role to guide the clinician in his choice of therapies. We will discuss the new techniques available to predict and evaluate treatment response in oncology. The method of reference to evaluate treatment response is based on the measure of lesion size. Functional imaging doesn't evaluate size, but rather a physiological or molecular feature, which is probably modified earlier in response to treatment. Dynamic contrast-enhanced functional imaging of microcirculation follows the biodistribution of a contrast agent and analyses tumour vascularization. Diffusion-weighted Magnetic Resonance Imaging differentiates free and restrained water molecules in tissues, reflecting tumor cellularity. Nuclear Magnetic Resonance spectroscopy is an application of MRI that yields information on the metabolic content of a tissue. It detects relative quantities of various molecules which differ in tumour compared to normal tissue. Positon-emission tomography using (18)FDG is a nuclear medicine technique which gives information on tissue metabolism. Captation of FDG is proportional to the proliferative activity and the number of viable cells in a tumour. Human studies concerning these techniques are still quite preliminary, and the medical community must determine their potential in clinical practice to evaluate treatment response in oncology.

Tumor angiogenesis: pathophysiology and implications for contrast-enhanced MRI and CT assessment.

The process of tumor neoangiogenesis plays a central role in the growth and spread of tumors. It is currently a leading theme in oncology, and many new drugs targeting the tumor neoangiogenic process are under development. Expanding tumors become hypoxic and tumor cells express transcription factors, such as the hypoxia-inducible factor (HIF), which induce the release of proangiogenic growth factors such as vascular endothelial growth factors (VEGF) and transforming growth factors that promote the formation of new capillaries by recruiting, activating, and stimulating endothelial cells. Activated endothelial cells secrete matrix metalloproteases, which degrade the basement membrane and the extracellular matrix, and adhesion receptors such as integrins alphavbeta(3), which allow their migration into the extracellular matrix toward the tumor cells. The newly grown vessels are immature and differ from normal capillaries. They are tortuous and irregular, resulting in poorly efficient perfusion, they are leaky (especially to macromolecules), and they are independent of the normal mechanisms of regulation of the capillary blood flow. Moreover, tumor microcirculation is heterogeneous. Evaluation of angiogenesis can be used as a prognostic marker to evaluate the aggressiveness of tumor and as a potential predictive marker of antiangiogenic treatment response. Histopathologic techniques of microvascular density indexes require invasive tissue sampling and need to be standardized. Hemodynamic characteristics of immature neovessels can be noninvasively assessed by dynamic contrast-enhanced magnetic resonance imaging or computed tomography. Tissue enhancement depends on arterial input function, kinetic of distribution of blood into the capillary bed, leakage across the capillary walls, and volume of the interstitial space. Pharmacodynamic models allow the evaluation of microvascular parameters of tissue blood flow, tissue blood volume, tissue interstitial volume, mean transit time, and permeability by surface of capillary wall. Methods based on dynamic contrast enhancement have been shown to correlate with conventional outcome methods such as histopathologic studies and survival. Radiologists must be convinced that, by using this emerging and promising approach, it is becoming possible to gain functional information during routine tumor imaging.

Evaluation of tumoral enhancement by superparamagnetic iron oxide particles: comparative studies with ferumoxtran and anionic iron oxide nanoparticles.

This study was designed to compare tumor enhancement by superparamagnetic iron oxide particles, using anionic iron oxide nanoparticles (AP) and ferumoxtran. In vitro, relaxometry and media with increasing complexity were used to assess the changes in r2 relaxivity due to cellular internalization. In vivo, 26 mice with subcutaneously implanted tumors were imaged for 24 h after injection of particles to describe kinetics of enhancement using T1 spin echo, T2 spin echo, and T2 fast spin echo sequences. In vitro, the r2 relaxivity decreased over time (0-4 h) when AP were uptaken by cells. The loss of r2 relaxivity was less pronounced with long (Hahn Echo) than short (Carr-Purcell-Meiboom-Gill) echo time sequences. In vivo, our results with ferumoxtran showed an early T2 peak (1 h), suggesting intravascular particles and a second peak in T1 (12 h), suggesting intrainterstitial accumulation of particles. With AP, the late peak (24 h) suggested an intracellular accumulation of particles. In vitro, anionic iron oxide nanoparticles are suitable for cellular labeling due to a high cellular uptake. Conversely, in vivo, ferumoxtran is suitable for passive targeting of tumors due to a favorable biodistribution.

Reduced capillary perfusion and permeability in human tumour xenografts treated with the VEGF signalling inhibitor ZD4190: an in vivo assessment using dynamic MR imaging and macromolecular contrast media.

We describe the use of perfusion-permeability magnetic resonance imaging (ppMRI) to study hemodynamic parameters in human prostate tumor xenografts, following treatment with the vascular endothelial growth factor-A (VEGF) receptor tyrosine kinase inhibitor, ZD4190. Using a macromolecular contrast agent (P792), a fast MR imaging protocol and a compartmental data analysis, we were able to demonstrate a significant simultaneous reduction in tumor vascular permeability, tumor vascular volume and tumor blood flow (43%, 30% and 42%, respectively) following ZD4190 treatment (100 mg/kg orally, 24 h and 2 h prior to imaging). This study indicates that MR imaging can be used to measure multiple hemodynamic parameters in tumors, and that tumor vascular permeability, volume and flow, can change in response to acute treatment with a VEGF signaling inhibitor.

[MR imaging of ano-perineal suppurations]. / IRM des suppurations ano-périnéales.

A good digital examination is usually sufficient for the diagnosis and the treatment planning of anal fistulae. Cross-sectional imaging techniques, however, can accurately identify deep abscesses and characterize complex fistulae. MRI is well suited for this examination, with almost no motion artifact, excellent contrast between muscles and fatty spaces, and multiplanar acquisition. A fistula starts from an internal opening in the digestive tube and can end in an abscess cavity or open at the skin at an external opening. The cryptoglandular anal fistulae (fistula-in-ano) are non-specific in origin and are usually simple, whereas specific fistulae are due to many diseases such as Crohn's disease, tuberculosis, trauma, radiation, colloid carcinoma, hidradenitis suppurative, actinomycosis or lymphoma and are often complex. MRI appears useful in the cases with recurrent fistulae, Crohn's disease, when the secondary orifice is atypically placed, during a multistep treatment for complex fistulae, or when an anal stenosis forbids a clinical or ultrasound examination. A good knowledge of the perineum anatomy is required for analysing the fistula tracts. The muscle planes separate fatty spaces which have an important role in the spread of the disease: sub-mucosal space, marginal space, intersphincteric space, postanal space of Courtney, supralevator space, and the two ischioanal spaces on both sides of the anal canal. The anal canal is surrounded by the ring-like internal sphincter, which continues the internal muscularis propria of the rectum, and the external sphincter, which is intermingled with the puborectalis muscle. We perform our MRI examination with an external phased array coil, and we place a cannula to identify the anal canal. The T2W sequences give the more interesting information, but the sequences with fat-suppression and gadolinium chelate injection are also very useful. The MRI examination allows the analysis of: 1) the location of the fistula tracts according to Park's classification, 2) the location of the internal opening, 3) the locations of the external opening(s), 4) the location of deep abscesses, 5) the long distance extensions, 6) the state of the ano-rectal wall and the perirectal spaces, 6) the damages of the anal sphincter.

Confocal image characterization of human papillomavirus DNA sequences revealed with Eu in HeLa cell nuclei stained with Hoechst 33342.

OBJECTIVE: To visualize and localize specific viral DNA sequences revealed with Eu by fluorescence in situ hybridization, confocal laser scanning microscopy (CLSM) and factor analysis of biomedical image sequences (FAMIS). STUDY DESIGN: Human papillomavirus DNA (HPV-DNA) was identified in HeLa cells with biotinylated DNA probes recognizing HPV-DNA types 16/18. DNA-DNA hybrids were revealed by a three-step immunohistochemical amplification procedure involving an antibiotin mouse monoclonal antibody, a biotinylated goat antimouse polyclonal antibody and streptavidin-Eu. Cell nuclei were counterstained with Hoechst 33342. Image sequences were obtained using a CLSM that made possible ultraviolet excitation. The location of fluorescent signals inside cellular preparations was determined by FAMIS and selection of filters at emission. Image sequences were summarized into a reduced number of images, or factor images, and curves, or factors. Factors estimate spectral or temporal patterns and depth emission profiles. Factor images correspond to spatial distributions of the different factors. RESULTS: We distinguished between Eu corresponding to HPV-DNA hybridization signals and nuclear staining by taking into account differences in their spectral and temporal patterns and (using their decay rates). CONCLUSION: FAMIS, together with CLSM and Eu, made possible the detection and characterization of viral papillomavirus DNA sequences in HeLa cells.

Hepatocyte targeting with Gd-EOB-DTPA: potential application for gene therapy.

RATIONALE AND OBJECTIVES: To evaluate the suitability of the liver-specific MRI contrast agent Gd-EOB-DTPA as a nonviral vector for gene therapy of hepatocellular carcinoma. METHODS: Specific uptake of Gd-EOB-DTPA was quantified by relaxometry in rat cultured hepatocytes and the hepatoma cells HepG2 and Huh7. Nonviral vectors for gene transfer were synthesized by coupling Gd-EOB-DTPA to polyethyleneimine or polylysine as DNA condensing agents, and their efficiency was studied using beta-galactosidase (lacZ) as the reporter gene. RESULTS: Gd-EOB-DTPA was specifically taken up by rat cultured hepatocytes (4.32 vs. 1.08 mmol/L in nonhepatocyte control cells) but not by the hepatoma cells; this uptake was concentration-dependently inhibited by Bromsulphtalein. Polycation linkages were achieved with yields of 0.9 Gd-EOB-DTPA molecule per polyethyleneimine molecule and 10 Gd-EOB-DTPA molecules per polylysine molecule. Incubating the cells with plasmids containing lacZ reporter gene and polyethyleneimine-Gd-EOB-DTPA resulted in a few blue (transfected) cells, whereas no blue cells were observed on incubation with polylysine-Gd-EOB-DTPA. CONCLUSIONS: Gd-EOB-DTPA is taken up by normal hepatocytes but not by HepG2 and Huh7 cells, probably because of the lack of the organic anion transporter in these hepatoma cells. The Gd-EOB-DTPA polycation conjugates, such as polyethyleneimine-Gd-EOB-DTPA, could serve as transfer vectors of interest for gene targeting imagery at the early stage of hepatocarcinogenesis. However, the transfer efficiency of such conjugates is low and requires improvement.

MR lymphography using iron oxide nanoparticles in rats: pharmacokinetics in the lymphatic system after intravenous injection.

The objective of the study was to quantify the kinetics of the superparamagnetic nanoparticle ferumoxtran (AMI 227, Sinerem(R), Combidex(R)) in the efferent lymph of the subdiaphragmatic lymph nodes and in various node groups of the rat to elucidate the uptake mechanism. The thoracic lymph duct was catheterized in 24 rats after an IV injection of 40 micromol Fe/kg ferumoxtran. Three rats were studied at several time points between 1.5 and 24 hours. At each time point, 0.3 ml of lymph were collected over 45 minutes. Lymph nodes were differentiated into five groups. The iron concentration in the samples and in plasma was measured by relaxometry at 0.47 T and atomic absorption spectrometry. Cytology was performed on the lymph. High concentrations of nanoparticles were found in the thoracic lymph soon after injection (90 minutes). No particle was found in the lymph cells, indicating that ferumoxtran was extracellular in the lymph fluid. The maximum concentration was reached later in all node groups, at 12 hours, and then plateaued. The transcapillary pathway and subsequent lymph drainage of the particles seem to play a major role in the delivery to the lymph nodes.

Distribution of iron oxide nanoparticles in rat lymph nodes studied using electron energy loss spectroscopy (EELS) and electron spectroscopic imaging (ESI).

Superparamagnetic iron nanoparticles have been developed as contrast agents for magnetic resonance lymphography. The kinetics of uptake of these particles has not yet been accurately determined. We have therefore monitored the distribution of individual iron particles (ferumoxtran, AMI-227, Sinerem) in rat lymph nodes 1.5, 3, 6, 12, and 24 hours after i.v. injection (two rats per time point). The ultrastructural distribution of the iron was determined by energy-filtered transmission electron microscopy (EFTEM). This method allows the identification of elements using element-specific energy-loss electrons. Iron was identified by the Fe-L(2,3) edge (EELS), and iron maps were obtained using iron-specific electrons for imaging (ESI). The background was calculated by simplex optimization (EELS) and by the two-window method (ESI). Ferumoxtran particles were regularly observed at the periphery of the lymph nodes but not in their centers. Isolated iron particles were seen extracellularly within lymph vessels and, 3 hours after injection, as small dots in phagocytic cells. Numerous dense clusters appeared within the cells at later times (6 and 12 hours after injection). These results suggest that the contrast agent moves rapidly across the capillary wall to the lymph and is then taken up by phagocytic cells. J. Magn. Reson. Imaging 2000;12:505-509.