Adult hepatocytes direct liver organogenesis through non-parenchymal cell recruitment in the kidney.

BACKGROUND & AIMS: Since the first account of the myth of Prometheus, the amazing regenerative capacity of the liver has fascinated researchers because of its enormous medical potential. Liver regeneration is promoted by multiple types of liver cells, including hepatocytes and liver non-parenchymal cells (NPCs), through complex intercellular signaling. However, the mechanism of liver organogenesis, especially the role of adult hepatocytes at ectopic sites, remains unknown. In this study, we demonstrate that hepatocytes alone spurred liver organogenesis to form an organ-sized complex 3D liver that exhibited native liver architecture and functions in the kidneys of mice. METHODS: Isolated hepatocytes were transplanted under the kidney capsule of monocrotaline (MCT) and partial hepatectomy (PHx)-treated mice. To determine the origin of NPCs in neo-livers, hepatocytes were transplanted into MCT/PHx-treated green fluorescent protein transgenic mice or wild-type mice transplanted with bone marrow cells isolated from green fluorescent protein-mice. RESULTS: Hepatocytes engrafted at the subrenal space of mice underwent continuous growth in response to a chronic hepatic injury in the native liver. More than 1.5 years later, whole organ-sized liver tissues with greater mass than those of the injured native liver had formed. Most remarkably, we revealed that at least three types of NPCs with similar phenotypic features to the liver NPCs were recruited from the host tissues including bone marrow. The neo-livers in the kidney exhibited liver-specific functions and architectures, including sinusoidal vascular systems, zonal heterogeneity, and emergence of bile duct cells. Furthermore, the neo-livers successfully rescued the mice with lethal liver injury. CONCLUSION: Our data clearly show that adult hepatocytes play a leading role as organizer cells in liver organogenesis at ectopic sites via NPC recruitment. LAY SUMMARY: The role of adult hepatocytes at ectopic locations has not been clarified. In this study, we demonstrated that engrafted hepatocytes in the kidney proliferated, recruited non-parenchymal cells from host tissues including bone marrow, and finally created an organ-sized, complex liver system that exhibited liver-specific architectures and functions. Our results revealed previously undescribed functions of hepatocytes to direct liver organogenesis through non-parenchymal cell recruitment and organize multiple cell types into a complex 3D liver at ectopic sites. Transcript profiling: Microarray data are deposited in GEO (GEO accession: GSE99141).

Detection and characterization of focal liver lesions: a Japanese phase III, multicenter comparison between gadoxetic acid disodium-enhanced magnetic resonance imaging and contrast-enhanced computed tomography predominantly in patients with hepatocellular carcinoma and chronic liver disease.

OBJECTIVES: To prospectively evaluate the safety and efficacy of combined unenhanced and gadoxetic acid disodium (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) imaging compared with unenhanced MR imaging and triphasic contrast-enhanced spiral computed tomography (CT) for the detection and characterization of focal liver lesions. MATERIALS AND METHODS: The study was reviewed and approved by the institutional review board at each of the 15 centers involved in the study, and informed written consent was given by all patients. In total, 178 patients with suspected focal hepatic lesions (based, in most patients, on CT, tumor marker and ultrasound examinations) underwent combined MR imaging with a single, rapid injection of Gd-EOB-DTPA 0.025 mmol/kg, including T1-weighted dynamic and delayed MR images 20 to 40 minutes postinjection. Triphasic contrast-enhanced CT, the comparator examination, was performed within 4 weeks of MR imaging. Standard of references (SOR) were resection histopathology and intraoperative ultrasonography, or combined CT during arterial portography and CT hepatic arteriography; in cases where, although the major lesions were treated, some lesion(s) were not treated, follow-up superparamagnetic iron oxide-enhanced MR imaging was additionally performed. All images were assessed for differences in lesion detection and characterization (specific lesion type) by on-site readers and 3, blinded (off-site) reviewers. All adverse events (AEs) occurring within 72 hours after Gd-EOB-DTPA administration were reported. RESULTS: Overall, 9.6% of patients who received Gd-EOB-DTPA reported 21 drug-related AEs. A total of 151 patients were included in the efficacy analysis. Combined MR imaging showed statistically higher sensitivity in lesion detection (67.5%-79.5%) than unenhanced MR imaging (46.5%-59.1%; P < 0.05 for all). Combined MR imaging also showed higher sensitivity in lesion detection than CT (61.1%-73.0%), with the results being statistically significant (P < 0.05) for on-site readers and 2 of 3 blinded readers. Higher sensitivity in lesion detection with combined MR imaging compared with CT was also clearly demonstrated in the following subgroups: lesions with a diameter

Early detection of therapeutic response to hepatic arterial infusion chemotherapy of liver metastases from colorectal cancer using diffusion-weighted MR imaging.

The purpose of this study was to investigate whether diffusion-weighted magnetic resonance imaging (DWI) is useful for early detection of the response of hepatic colorectal metastases to hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil (5-FU). The subjects were 12 patients with hepatic colorectal metastases. The indwelling catheter for HAIC was placed in the hepatic artery, and 1000 mg/m(2) 5-FU was given repeatedly once a week. DWI was performed before and 9 days after HAIC. The minimum and mean apparent diffusion coefficient (ADC) values (minADC and meanADC) were measured. The relative change in ADC values (%ADC) and the relative change in tumor size on follow-up CT after 3 months (reduction ratio) were determined. Liver metastases were divided into two groups, responder and nonresponder. The correlation between %ADC and reduction ratio was determined, and %ADC was compared between the two groups. Eleven patients successfully completed HAIC over the 3-month period; 48 metastatic lesions were evaluated. Positive correlations were observed for relative change between %minADC and reduction ratio (r = 0.709) and between %meanADC and reduction ratio (r = 0.536). Both %minADC and %meanADC were significantly greater in the responder group than in the nonresponder group. With the threshold determined as < 3.5%, the receiver-operating curve analysis showed higher sensitivity and specificity values for %minADC (100% and 92.6%, respectively) than for %meanADC (66.7% and 74.1%, respectively). In conclusion, the relative change in minimum ADC values on DWI may be useful for early detection of the response of liver metastases to HAIC with 5-FU.

Safety of ferucarbotran in MR imaging of the liver: a pre- and postexamination questionnaire-based multicenter investigation.

PURPOSE: To prospectively investigate, by means of a pre-and postexamination questionnaire, the types and frequency of adverse reactions to ferucarbotran (Resovist), a superparamagnetic iron oxide (SPIO) contrast agent. MATERIALS AND METHODS: This study was approved by the ethics committee of each of the institutions involved, and all patients gave written informed consent. One questionnaire asking about baseline symptoms before the injection of ferucarbotran, and one about adverse events over a period of seven days after injection were given to 315 patients who underwent ferucarbotran-enhanced magnetic resonance imaging (MRI) of the liver at several institutions. The data for baseline symptoms were used for reference to exclude false-positive adverse reactions and were also compared with the adverse event data to determine with McNemar's chi-squared test the incidence of each symptom. RESULTS: Before MR examination, 249 clinical symptoms were reported by 102 of 315 patients (32.4%). After the injection of ferucarbotran, 169 adverse events were observed in 78 patients (24.8%). Eventually, 70 adverse events occurring in 45 patients (14.3%) were judged to be adverse reactions to ferucarbotran, defined as possibly or definitely ferucarbotran-related events. All reactions were of mild intensity. CONCLUSION: Ferucarbotran can be considered safe for clinical use in liver MRI.

Polypoid endometriosis of the ureter mimicking fibroepithelial polyps.

We present a case of polypoid endometriosis of the ureter that showed bilateral polypoid intraluminal masses in the lower part of the ureter mimicking ureteral fibroepithelial polyps, arising with a background of pelvic endometriosis and a history of gonadotropin releasing hormone (GnRH) therapy. Magnetic resonance imaging revealed the masses to have high signal intensity on T2-weighted imaging. The location and bilaterality of the polypoid intraluminal masses are considered useful points in the differential diagnosis of fibroepithelial polyps.

Displacement of the facial nerve course by vestibular schwannoma: preoperative visualization using diffusion tensor tractography.

PURPOSE: To preoperatively visualize the course of the facial nerve, which is displaced by vestibular schwannoma, using diffusion tensor (DT) tractography, and to evaluate the agreement with surgical findings. MATERIALS AND METHODS: The subjects were eight patients with vestibular schwannoma who had undergone removal surgery. DT MR images were obtained and tracts that were considered to represent the facial nerve were constructed. We assessed the success rate for tract construction and evaluated the agreement between tractography findings and surgery. RESULTS: We obtained a tract that connected the internal auditory meatus and brainstem, and was considered to represent the facial nerve in seven of eight cases. The course of the constructed tract agreed with surgical findings in five of these seven cases. One exception was a case in which the tumor was too large to enable intraoperative observation of the facial nerve; however, the facial nerve appeared to be displaced anteriorly at intracapsular resection, in agreement with tractography. In the other case, the schwannoma was mostly cystic. CONCLUSION: Tractographs constructed using MR tensor images enabled us to identify tracts considered to represent facial nerves. We consider DT tractography to be a useful tool for preoperatively predicting facial nerve displacement in vestibular schwannoma.

Evaluation of arteriosclerotic changes in the intracranial carotid artery using the calcium score obtained on plain cranial computed tomography scan: Correlation with angiographic changes and clinical outcome.

PURPOSE: This study evaluated the correlation between quantified calcification of the carotid siphon and arteriosclerotic changes on angiography as well as clinical outcome. We used the calcium score obtained from intracranial carotid arteries viewed on plain CT. METHOD/MATERIALS: We examined carotid siphons of 72 consecutive patients who had undergone both plain CT and angiography of the brain. We calculated calcium scores of the carotid siphon. Arteriosclerotic changes on angiography were categorized as "smooth," "irregular," or "stenosis." We assessed the correlation between the scores and arteriosclerotic changes both in the carotid siphon and the bifurcation. We reviewed clinical records approximately 2 years after examination and evaluated the scores of patients who did and did not experience cerebral strokes. RESULTS: In the evaluation between angiographic findings of siphon and calcium score of the siphon, there were statistically significant differences between the "smooth" and "irregular", "irregular" and "stenosis" and the "smooth" and "stenosis". In the evaluation between angiographic findings of bifurcation and the score of the siphon, a statistically significant difference was only seen between "smooth" and "stenosis". No significant differences in calcium scores were observed between patients groups who did or did not experience a cerebral stroke. CONCLUSIONS: There were a positive correlation between calcium scores on CT and angiographic changes of arteriosclerosis in the siphon as well as bifurcation, indicating angiographic changes can be predicted using calcium scores. However, the degree of calcification in the siphon cannot be used to predict the possibility of a future cerebral stroke.

Pituitary stalk compression by the dorsum sellae: possible cause for late childhood onset growth disorders.

PURPOSE: The purpose of this study was to evaluate the relationship between pituitary stalk compression by the dorsum sellae and clinical or laboratory findings in short stature children. MATERIALS AND METHODS: We retrospectively reviewed magnetic resonance images of the pituitary gland and pituitary stalk for 34 short stature children with growth hormone (GH) deficiency and 24 age-matched control cases. We evaluated the degree of pituitary stalk compression caused by the dorsum sellae. Body height, GH level, pituitary height and onset age of the short stature were statistically compared between cases of pituitary stalk compression with associated stalk deformity and cases without compression. RESULTS: Compression of the pituitary stalk with associated stalk deformity was seen in nine cases within the short stature group. There were no cases observed in the control group. There were no significant differences found for body height, GH level and pituitary height between the cases of pituitary stalk compression with associated stalk deformity and cases without compression. However, a significant difference was seen in the onset age between cases with and without stalk compression. CONCLUSION: Pituitary stalk compression with stalk deformity caused by the dorsum sellae was significantly correlated with late childhood onset of short stature.

Usefulness of 16-slice multislice spiral computed tomography for follow-up study of coronary stent implantation.

BACKGROUND: Although multislice spiral computed tomography (MSCT) is a promising technique for non-invasive coronary angiography, its usefulness in patients with stent implantation remains unclear. The aim of the present study was to compare the usefulness of MSCT with that of invasive coronary angiography for evaluating coronary stent patency. METHODS AND RESULTS: Thirty-one patients were enrolled after coronary stent implantation. Sixteen-slice MSCT scans were performed (39.0+/-21.8 days) before follow-up coronary angiography. After assigning an image score based on luminal visibility (1= poor, 2= fair, 3= good), factors determing image quality were analyzed. Among 42 implanted stents, 33 (78%) were assigned an image score of 3, 2 (5%) a score of 2, and 7 (17%) a score of 1. Image scores among stents with diameters >or=3.5 mm were significantly (p<0.05) higher than among smaller stents (

Safety and efficacy of a novel hepatobiliary MR contrast agent, Gd-DTPA-DeA: results of phase I and phase II clinical trials.

PURPOSE: To assess the safety, effective dose, and efficacy of a novel hepatobiliary MR contrast agent Gd-DTPA-DeA for imaging liver tumors, from the clinical phase I and phase II trials in Japan. MATERIALS AND METHODS: In a phase I trial, 33 healthy volunteers were intravenously administered a single dose of 0.03-10 micromol/kg of Gd-DTPA-DeA. In a nationwide phase II trial, 80 patients suspected to have hepatic mass were divided into three dosing groups: 2.5, 5.0, or 7.5 micromol/kg. T1-weighted gradient echo images were obtained before and after Gd-DTPA-DeA administration at three time points. Liver signal-to-noise ratio (SNR) and lesion-liver contrast-to-noise ratio (CNR) were calculated at each time point. A reading committee evaluated the contrast, diagnostic, and overall efficacy using a five-point scale. RESULTS: In a phase I trial, dosages up to 10 micromol/kg were well tolerated by healthy volunteers. In a phase II trial, the contrast, diagnostic, and overall efficacy increased dose-dependently. The overall efficacy was 63.0%, 85.2%, and 88.0%, for 2.5, 5, and 7.5 micromol/kg, respectively. Liver SNR and CNR increase was greater at late phase than at early phase. No serious adverse events occurred. CONCLUSION: Gd-DTPA-DeA is a well-tolerated and promising contrast agent for liver MR imaging.

Diffusion tensor imaging in cases with visual field defect after anterior temporal lobectomy.

BACKGROUND AND PURPOSE: Visual defect due to optic radiation injury is a complication of temporal lobectomy for temporal epilepsy. To investigate whether diffusion tensor imaging can delineate the changes in optic radiations after lobectomy, we evaluated parameters on tensor images for optic radiations and correlated them with visual defect. METHODS: We examined 14 cases after temporal lobectomy. Durations after surgeries ranged from 3 weeks to 9 years. The cases were classified into three groups on the basis of the severity of visual field defect (A-C, with group C the most severe). We evaluated signals on T2-weighted images and parameters of tensor images, including fractional anisotropy (FA) and apparent diffusion coefficient (ADC), for the optic radiation in both the operated and intact side. RESULTS: On T2-weighted images, high signals in optic radiations were seen in four cases, occurring more than 4 weeks after surgery. The mean operated-to-intact side FA ratio in the optic radiation decreased according to severity of visual defect (group A, 0.88; group B, 0.89; group C, 0.73). The mean operated-to-intact side ADC ratio showed no significant difference in the overall cases. The ratio for ADC, however, tended to increase according to visual defect in cases after 10 weeks postsurgery. CONCLUSION: Optic radiation showed a decreased FA value in cases after temporal lobectomy. In later stages, ADC values tended to increase and high signal intensities on T2-weighted images were observed. The FA value can be used for evaluating Wallerian degeneration of optic radiation even in the early stages after surgery.

Distinguishing between anterior cerebral artery and middle cerebral artery perfusion by color-coded perfusion direction mapping with arterial spin labeling.

The purpose of this study was to evaluate collateral circulation by describing anterior cerebral artery and middle cerebral artery perfusion areas. Pairs of image sets spin labeled on the medial and lateral side were used. A pixel-by-pixel t test was performed, with blue gradation used to display lateral perfusion (ie, middle cerebral artery) and orange gradation for anterior cerebral artery perfusion. Extensions of anterior cerebral artery perfusion areas in cases of middle cerebral artery stenosis were described. This method may aid in estimation of collateral circulation for stroke treatment.

[A case of ovarian cystadenofibroma with papillary projections showing very high signal intensity on T2-weighted images].

Cystadenofibromas are rare benign or borderline malignant neoplasms containing both epithelial and stromal components. We report a case of endometrioid cystadenofibroma in a patient with endometriosis. In this case, the solid component showed very high signal intensity on T2-weighted images and was enhanced after Gd-DTPA administration, reflecting marked stromal edema of fibrous tissue. Endometrial cysts with malignant transformation are reported to have an enhancing solid component and to show various intensities on T2-weighted imaging. However, a solid component showing very high signal intensity on T2-weighted images should also be considered stromal edema in benign or borderline cystadenofibromas.

[Assessment of coronary artery by four-detector multislice computed tomography: diagnostic accuracy and limitations for coronary artery lesions].

OBJECTIVES: The applicability of four-detector multislice computed tomography (MSCT) was investigated for evaluating coronary arteries. METHODS: MSCT (Somatom Volume Zoom, Siemens) was used to evaluate the coronary arteries in 94 patients. The reconstructed images were analyzed using retrospective electrocardiographic gating to determine the image quality of the coronary arteries. In addition, the ability of MSCT to detect coronary artery lesions of > or = 70% (> or = 50% in the left main trunk) diameter stenoses documented by standard coronary angiography was assessed in 67 patients who underwent coronary angiography within the same period. RESULTS: Good image quality was displayed in 488 (58%) and fair in 184 (22%) of a total of 846 coronary segments, but non-assessable in 174 (21%) due to degraded image quality. MDCT detected 33 stenotic lesions correctly in 494 assessable segments, comparable to coronary angiography. The sensitivity and specificity of MSCT were 0.79 and 0.95, respectively. However, an additional 15 lesions were detected by coronary angiography among the non-assessable segments. In total, 24 lesions were missed by MSCT. Accordingly, coronary segments were completely assessable and correctly detected by MSCT in only 20 patients (30%), or 35 (52%) if the distal coronary segments were excluded from analysis. CONCLUSIONS: Four-detector MSCT for detection of coronary artery lesions was applicable to assessable segments. However, clinical use may presently be limited because of the insufficient overall accuracy. Further technical improvement is expected in the near future.

[Dose investigation of superparamagnetic iron oxide (SPIO) SH U 555 A in liver MR imaging].

SH U 555 A, a new superparamagnetic iron oxide (SPIO) contrast agent for liver MR imaging, was investigated in terms of safety and efficacy. Eighty-four patients with suspected malignant liver tumor were randomly allocated to two groups: the L dose group (8 mumol Fe/kg) and H dose group (12 mumol Fe/kg). Efficacy was qualitatively evaluated through blinded reading of the MR images. Assessment of the images revealed no consistent differences between the L and H dose groups. During the 3- to 4-day observation period, a total of 16 adverse events were observed in 11 patients: 8 patients in the L dose group and 3 patients in the H dose group. Nasal bleeding occurred in 2 of these cases in the H dose group 2 and 4 days, respectively, after injection. Although patients in the H dose group showed a significantly larger transient decrease in Coagulation Factor XI at 4-6 hr post-injection (p.i.) than patients in the L dose group, analysis of covariance revealed an estimated 6.5% difference. There was no prolongation of APTT or change in Factor XI at 72-96 hr p.i. Because there were no clinically significant differences between the L and H doses, both were considered to be safe and effective.

[Evaluation of appearance with high-speed CE-3dMRDSA in brain].

We evaluated the fitting scan technique for CE-3dMRDSA, and found common ground that determines spatial resolution and time resolution (slab thickness and partition number). We also examined the relation between appearance and time resolution (volume of contrast medium and injection speed). To obtain good image contrast, the volume of contrast medium needs to be at least 7 ml and suitable for an injection speed of 3-5 ml/sec. However, when we increased the volume of contrast medium and decreased injection speed, changes in MRDSA images with time became worse. The measure of the bolus with contrast medium was found to determine image contrast. When contrast medium is injected earlier, it circulates earlier within the brain. If the scan time is not short enough, it is not possible to observe changes in MRDSA images. And when spatial resolution is improved, time resolution becomes worse. Therefore, it is important to find the point of compromise between spatial resolution and time resolution. If we look for anterior MIP images, the CNR in the spatial resolution didn't change, when the slice thickness is more than 3 mm. Because, the partial volume effect decide the image contrast. However, unless the view is from the front, slice thickness influences spatial resolution. Therefore, when we view MIP images from the lateral direction, slice thickness must be set at less than 2 mm. Results indicated that, in CE-3dMRDSA with the fitting technique, slice thickness should be less than 3 mm, partition number 16-20, slab thickness 48 mm, contrast medium volume 7-10 ml, and injection speed 3-5 ml.

Qualitative diagnosis of hepatocellular carcinoma by contrast enhanced ultrasonography using Coded Harmonic Angio with Levovist.

We attempted to evaluate diagnosis and characterization and to access therapeutic effects in cases of hepatocellular carcinoma (HCC) by contrast enhanced ultrasound (CEUS) using Coded Harmonic Angio (CHA) with Levovist, an intravenous ultrasound contrast agent. Fifty-seven HCC foci in 39 patients, including 37 HCC foci in 28 patients before and after transcatheter arterial chemoembolization or radio frequency ablation, were examined by CEUS using the CHA mode, which is under development. This mode uses digitally encoded pulse sequences that identify and suppress nonmoving tissue signals and enhance contrast signals from Levovist in a gray-scale format. In all cases, abundant tortuous intratumoral blood flow was visualized in the early vascular phase by continuous transmission, while tumor stain was recognized by consecutive 1-to-2 second intermittent transmission. Residual tumor area after treatment was also clearly depicted by intratumoral blood flow and partial enhancement. CEUS using CHA with Levovist is likely to become important in the qualitative diagnosis of hepatic tumor and to improve the efficacy of treatment for HCC.