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Background : In the diagnosis of lumbar spinal stenosis (LSS), finding stenosis with magnetic resonance imaging (MRI) does not always correlate with symptoms such as sciatica or intermittent claudication. We perform decompression surgery only for cases where the levels diagnosed from neurological findings are symptomatic, even if multiple stenoses are observed on MRI. The objective of this study was to examine the time course of asymptomatic stenosis in patients with LSS after they underwent decompression surgery for symptomatic stenosis. Materials and Methods : The participants in this study comprised 137 LSS patients who underwent single-level L4-5 decompression surgery from 2003 to 2013. The dural sac cross-sectional area at the L3-4 disc level was calculated based on preoperative MRI. A cross-sectional area less than 50 mm 2 was defined as stenosis. The patients were grouped, according to additional spinal stenosis at the L3-4 level, into a double group (16 cases) with L3-4 stenosis, and a single group (121 cases) without L3-4 stenosis. Incidences of new-onset symptoms originating from L3-4 and additional L3-4-level surgery were examined. Results : Five years after surgery, 98 cases (72%) completed follow-up. During follow-up, 2 of 12 patients in the double group (16.7%) and 9 of 86 patients in the single group (10.5%) presented with new-onset symptoms originating from L3-4, showing no significant difference between groups. Additional L3-4 surgery was performed for one patient (8.3%) in the double group and three patients (3.5%) in the single group; again, no significant difference was shown. Conclusion : Patients with asymptomatic L3-4 stenosis on preoperative MRI were not prone to develop new symptoms or need additional L3-4-level surgery within 5 years after surgery when compared to patients without preoperative L3-4 stenosis. These results indicate that prophylactic decompression for asymptomatic levels is unnecessary.

Objective: Magnetic resonance thoracic ductography (MRTD), concomitant with blood vessel imaging, provides useful anatomical information. The purpose of this study was to assess the visibility of the thoracic duct and blood vessels simultaneously by MRTD using balanced turbo-field-echo (bTFE) and turbo spin-echo (TSE)., Methods: MRTDs concomitant with blood vessel imaging on bTFE and TSE were obtained for 10 healthy volunteers with a 1.5T-magnetic resonance unit. Visibility of the thoracic duct, blood vessels in the thoracic region; motion artifacts; and overall image quality were scored by two radiologists using three-to-five-point scales; those were compared between bTFE and TSE., Results: The thoracic duct was generally well-visualized on MRTD sequences. The upper part of the thoracic duct was better visualized on TSE than on bTFE ( p < 0.05). The blood vessels were well visualized on bTFE and TSE; the bilateral subclavian arteries and the right subclavian veins were better visualized on TSE than on bTFE (all p < 0.05). Motion artifacts and overall image quality were better on TSE than on bTFE ( p = 0.0039 and 0.0020, respectively)., Conclusion: MRTD concomitant with blood vessel imaging on TSE has better visibility of the thoracic duct and blood vessels than bTFE.

Background: We recently discovered that individuals with complete spinal cord injury (SCI) have a higher grip force control ability in their intact upper limbs than able-bodied subjects. However, the neural basis for this phenomenon is unknown., Objective: This study aimed to investigate the neural basis of the higher grip force control in the brains of individuals with SCI using multimodal magnetic resonance imaging (MRI)., Methods: Eight SCI subjects and 10 able-bodied subjects performed hand grip force control tasks at 10%, 20%, and 30% of their maximal voluntary contraction during functional MRI (fMRI). Resting-state fMRI and T1-weighted structural images were obtained to investigate changes in brain networks and structures after SCI., Results: SCI subjects showed higher grip force steadiness than able-bodied subjects ( P < .05, corrected), smaller activation in the primary motor cortex ( P < .05, corrected), and deactivation of the visual cortex ( P < .001, uncorrected). Furthermore, SCI subjects had stronger functional connectivity between the superior parietal lobule and the left primary motor cortex ( P < .001, uncorrected), as well as larger gray matter volume in the bilateral superior parietal lobule ( P < .001, uncorrected)., Conclusions: The structural and functional reorganization observed in the superior parietal lobule of SCI subjects may represent the neural basis underlying the observed higher grip force control, and is likely responsible for the smaller activation in the primary motor cortex observed in these individuals. These findings could have applications in the fields of neurorehabilitation for improvement of intact limb functions after SCI.

There is a lack of an international consensus on adenomyosis classification that is useful for clinical practice and research. This article reviews advancements in the classification of adenomyosis, and the existing limitations. We collected a literature search from PubMed and Embase database up to March 2019. The proposed adenomyosis classification is based on magnetic resonance imaging and clinically relevant parameters. Adenomyosis is not a disease of homogeneity but is composed of multiple heterogeneous subtypes. Adenomyosis represents a spectrum of lesions, ranging from increased thickness of the junctional zone to focal or diffuse lesions involving the entire uterine wall. Potentially important parameters to be included in the classification could be affected area (internal or external adenomyosis), pattern (focal or diffuse), size or volume (myometrial involvement <1/3, <2/3, or >2/3 of uterine wall), concomitant pathologies (none, peritoneal endometriosis, ovarian endometrioma, deep infiltrating endometriosis, uterine fibroids, or others) and localization (anterior, posterior, left lateral, right lateral, or fundal). We propose a simplified classification system to monitor symptom severity against morphological types or extent of adenomyosis using the combination of previously published classifications as a starting point. More studies are needed to investigate whether this classification represents a useful tool for disease assessment in clinical practice and research., (© 2020 S. Karger AG, Basel.)

Background: Common cancerous histological types associated with endometriosis are clear cell carcinoma (CCC) and endometrioid carcinoma (EC). CCC is regarded as an aggressive, chemoresistant histological subtype. Magnetic resonance imaging (MRI) offers some potential advantages to diagnose ovarian tumors compared with ultrasonography or computed tomography. This study aimed to identify MRI features that can be used to differentiate between CCC and EC., Methods: We searched medical records of patients with ovarian cancers who underwent surgical treatment at Nara Medical University Hospital between January 2008 and September 2018; we identified 98 patients with CCC or EC who had undergone preoperative MRI. Contrasted MRI scans were performed less than 2 months before surgery. Patients were excluded from the study if they had no pathology, other pathological subtype of epithelial ovarian cancer, and/or salvage treatment for recurrence and metastatic ovarian cancer at the time of study initiation. Clinically relevant variables that were statistically significant by univariate analysis were selected for subsequent multivariate regression analysis to identify independent factors to distinguish CCC from EC., Results: MRI of CCC and EC showed a large cystic heterogeneous mixed mass with mural nodules protruding into the cystic space. Univariate logistic regression analysis revealed that the growth pattern (broad-based nodular structures [multifocal/concentric sign] or polypoid structures [focal/eccentric sign]), surface irregularity (a smooth/regular surface or a rough/irregular/lobulated surface), "Width" of mural nodule, "Height-to-Width" ratio (HWR), and presence of preoperative ascites were factors that significantly differed between CCC and EC. In the multivariate logistic regression analysis, the growth pattern of the mural nodule (odds ratio [OR] = 0.69, 95% confidence interval [CI]: 0.013-0.273, p = 0.0004) and the HWR (OR = 3.71, 95% CI: 1.128-13.438, p = 0.036) were independent predictors to distinguish CCC from EC., Conclusions: In conclusion, MRI data showed that the growth pattern of mural nodules and the HWR were independent factors that could allow differentiation between CCC and EC. This finding may be helpful to predict patient prognosis before operation.

Sonodynamic therapy (SDT) is used to treat various malignancies and can be applied to brain tumors using a transcranial magnetic resonance imaging-guided focused ultrasound (TcMRgFUS) device. This study investigated the efficacy of 220-kHz TcMRgFUS combined with 5-aminolevulinic acid (5-ALA) on malignant glioma in vitro and in vivo. F98 cells were irradiated with focused ultrasound (FUS) (4000 J, 20 W, 240 s, 100% duty cycle, target medium temperature <40°C) after treatment with 200 µg/mL 5-ALA, and cell viability and apoptosis were evaluated with the water-soluble tetrazolium-1 assay, triple fluorescent staining and Western blot analysis 20 h later. The anti-tumor effects of 5-ALA combined with FUS (500 J, 18 W, 30 s, 100% duty cycle, 10 repeats, target tissue temperature ≤42°C) were assessed on the basis of changes in tumor volume determined by MRI and histopathological analysis before and after treatment. The FUS/5-ALA combination reduced cell viability by inducing apoptosis and suppressed tumor proliferation and invasion as well as angiogenesis in vivo, while causing minimal damage to normal brain tissue. SDT with 220-kHz TcMRgFUS and 5-ALA can be safely used for the treatment of malignant glioma., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

To investigate the prevalence and clinical value of abnormal findings detected via brain magnetic resonance imaging (MRI) in patients with intravascular large B-cell lymphoma (IVLBCL), we identified 33 patients with IVLBCL pathologically diagnosed and evaluated with pretreatment brain MRI. Abnormal findings on brain MRI were categorized into four patterns: (1) hyperintense lesion in the pons on T2-weighted imaging (T2WI), (2) nonspecific white matter lesions, (3) infarct-like lesions, and (4) meningeal thickening and/or enhancement. Abnormal cerebral findings were detected in 29 patients (87.9%). Hyperintense lesion in the pons was the most common finding (n = 19 (57.6%) patients), followed by nonspecific white matter lesions (n = 14 (42.4%) patients), infarct-like lesions (n = 8 (24.2%) patients), and meningeal thickening and/or enhancement (n = 4 (12.1%) patients). Impaired consciousness was seen in most of the patients with infarct-like lesions (87.5%) but less frequently in patients with hyperintense lesion in the pons (47.4%). We reviewed brain MRI findings in 39 patients with diffuse large B cell lymphoma with central nervous system (CNS) involvement and/or high-risk extranodal lesions for CNS involvement as a control group. In contrast to the patients with IVLBCL, no patient had hyperintense lesion in the pons in the control group (P < 0.001). Follow-up brain MRI revealed improvement of abnormal findings in most of the patients who responded to chemotherapy. This study highlighted the diagnostic implication of hyperintense lesion in the pons on T2WI and the clinical usefulness of pretreatment brain MRI in IVLBCL even in patients without impaired consciousness.

Purpose: Mural nodules and papillary projections can be seen in benign ovarian endometriosis (OE) and malignant transformation of OE (endometriosis-associated ovarian cancer [EAOC]), which can pose a challenging diagnostic dilemma to clinicians. We identify the preoperative imaging characteristics helpful to the differential diagnosis between benign OE with mural nodules and EAOC., Materials and Methods: This was a retrospective study of 82 patients who were diagnosed pathologically to have OE with mural nodules (n = 42) and malignant transformations of these tumors (n = 40) at the Nara Medical University Hospital from January 2008 to January 2015. All patients were assessed with contrast-enhanced MRI before surgery. Patient demographics, and clinical and pathologic features were analyzed to detect the significant differences between the two groups., Results: Histological examinations of resected OE tissue specimens revealed that a majority (78.6%) of the mural nodular lesions were retracted blood clots. We found that the patients with malignant mural nodules, when compared to those with benign nodules, were older, had larger cyst diameters and larger mural nodule sizes, and were more likely to exhibit a taller than wider lesion. They were also more likely to present with various signal intensities on T 1 -weighted images (T 1 WI), high-signal intensity on T 2 -weighted images (T 2 WI), a lower proportion of shading on T 2 WI, and were more likely to show an anterior location of the cyst. In the multivariate logistic regression analysis, "Height" (>1.5 cm) and "Height-Width ratio (HWR)" (>0.9) of mural nodules, maximum diameter of the cyst (>7.9 cm), and age at diagnosis (>43 years) were independent predictors to distinguish EAOC from OE with mural nodules., Conclusion: The "Height" and "HWR" of the mural nodules in the cyst may yield a novel potential diagnostic factor for differentiating EAOC from benign OE with mural nodules.

Purpose: The purpose of this study was to identify the magnetic resonance imaging (MRI) features of uterine endometrial carcinoma (EC) with DNA mismatch repair (MMR) deficiency., Materials and Methods: This was a retrospective study approved by our institutional review board. The study included 118 patients pathologically diagnosed as having EC in our institution from April 2014 to December 2016. Of 118 patients, 8 were excluded because of insufficient data. Immunohistochemical analysis of MMR was performed retrospectively to observe the expressions of MLH1, MSH2, MSH6, and PMS2. A tumor with MMR deficiency was detected in 17 of 110 cases (15%). Clinical background characteristics and MRI findings were reviewed. These findings were compared between MMR deficiency group and the other group as a control group. Statistical significance was determined using the Fisher's exact test and the Mann-Whitney U test, as appropriate., Results: The clinical background characteristics of patients with EC with MMR deficiency were not significantly different from those of other patients. On MRI, the tumor was significantly more often located in the lower uterine site (MMR(-) vs. MMR(+): 29.4 vs. 8.9% [p = 0.0366])., Conclusion: EC with MMR deficiency tends to be located lower in the uterus, though most other findings were not significantly different from those of EC without MMR deficiency.

Purpose: We proposed to detect the in vivo enzyme activity of γ-glutamyl transferase (GGT) within mouse models of human ovarian cancers using catalyCEST MRI with a diamagnetic CEST agent., Methods: A CEST-FISP MRI protocol and a diamagnetic CEST agent were developed to detect GGT enzyme activity in biochemical solution. A quantitative Michaelis-Menten enzyme kinetics study was performed to confirm that catalyCEST MRI can measure enzyme activity. In vivo catalyCEST MRI studies generated pixel-wise activity maps of GGT activities. Ex vivo fluorescence imaging was performed for validation., Results: CatalyCEST MRI selectively detected two CEST signals from a single CEST agent, whereby one CEST signal was responsive to GGT enzyme activity and the other CEST signal was an unresponsive control signal. The comparison of these CEST signals facilitated in vivo catalyCEST MRI studies that detected high GGT activity in OVCAR-8 tumors, low GGT activity in OVCAR-3 tumors, and low or no GGT activity in muscle tissues., Conclusion: CatalyCEST MRI with a diamagnetic CEST agent can detect the level of GGT enzyme activity within in vivo tumor models of human ovarian cancers. Magn Reson Med 77:2005-2014, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

Purpose: Heme and iron accumulation due to repeated hemorrhage in endometriosis may contribute to a pivotal role in carcinogenesis. We evaluate the clinical application of MR relaxometry in a series of ovarian endometriosis (OE) and endometriosis-associated ovarian cancer (EAOC)., Materials and Methods: A prospective study of diagnostic accuracy was conducted among 82 patients (67 OE and 15 EAOC) to compare MR relaxometry and biochemical measurement of cyst fluid total iron concentration. Transverse relaxation rate R2 value was determined using a single-voxel, multi-echo MR sequence (HISTO) by a 3T-MR system. Phantom experiments were also performed to assess the correlation between the ex vivo R2 values and total iron concentrations., Results: Both the results of phantom experiments and in vivo human data confirmed that in vivo R2 values were highly correlated with total iron concentrations. Compared to OE, EAOC exhibit decreased in vivo R2 values and total iron levels, regardless of their age, menopausal status and cyst size. The use of in vivo R2 values retained excellent accuracy in distinguishing EAOC versus OE (sensitivity and specificity: 86% and 94%)., Conclusions: We have demonstrated that MR relaxometry provides a noninvasive predictive tool to discriminate between EAOC and OE.

Objective We sought to detect the presence of left ventricular regional dysfunction and myocardial abnormalities in systemic sclerosis (SSc) patients without cardiac symptoms using a complementary cardiac magnetic resonance (CMR) imaging approach. Methods Consecutive patients with SSc without cardiac symptoms and healthy controls underwent CMR on a 1.5 T scanner. The peak systolic regional function in the circumferential and radial strain (Ecc, % and Err, %) were calculated using a feature tracking analysis on the mid-left ventricular slices obtained with cine MRI. In addition, we investigated the myocardial characteristics by contrast MRI. Pharmacological stress and rest perfusion scans were performed to assess perfusion defect (PD) due to micro- or macrovascular impairment, and late gadolinium enhancement (LGE) images were obtained for the assessment of myocarditis and/or fibrosis. Results We compared 15 SSc patients with 10 healthy controls. No statistically significant differences were observed in the baseline characteristics between the patients and healthy controls. The mean peak Err and Ecc of all segments was significantly lower in the patients than the controls (p=0.011 and p=0.003, respectively). Four patients with LGE (28.6%) and seven patients with PD (50.0%) were observed. PD was significantly associated with digital ulcers (p=0.005). Utilizing a linear regression model, the presence of myocardial LGE was significantly associated with the peak Ecc (p=0.024). After adjusting for age, the association between myocardial LGE and the peak Ecc was strengthened. Conclusion A subclinical myocardial involvement, as detected by CMR, was prevalent in the SSc patients without cardiac symptoms. Regional dysfunction might predict the myocardial abnormalities observed in SSc patients without cardiac symptoms.

Aims: To demonstrate the use of gadolinium (Gd)-labeled dendrimers as lymphatic imaging agents and establish the long-term biodistribution (90-day) of this type of agent in mice., Materials & Methods: A G5-Gd-BnDOTA dendrimer was prepared and injected into mice and monkeys for MR lymphangiography, and long-term biodistribution of the conjugate was studied., Results: Administration of G5-Gd-BnDOTA in mice demonstrated a rapid uptake in the deep lymphatic system while injection in monkeys showed enhanced internal iliac nodes, indicating its general utility for lymphatic tracking. Biodistribution studies to 90 days showed that gadolinium conjugate is slowly being eliminated from the liver and other organs., Conclusion: The use of G5-Gd-BnDOTA holds great promise for lymphatic imaging, but its slow clearance from the body might hamper its eventual clinical translation.

Rationale and Objectives: To determine if intraprostatic injection of gadofosveset trisodium mixed with human serum albumin (HSA) can identify sentinel lymph nodes (LNs) draining the prostate on magnetic resonance imaging (MRI) in a canine model., Materials and Methods: Three male canines weighing between 25.7 and 41.3 kg were anesthetized, placed in a 3-T MRI, and a needle was placed transrectally into one side of the prostate using a commercially available intrarectal needle guide. Gadofosveset trisodium premixed with 10% HSA was then administered at doses ranging from 0.1 to 2.5 mL. T1W MRI was performed immediately after injection, and two readers evaluated images for visualization of LNs draining the prostate., Results: Intraprostatic injection of 0.2 mL gadofosveset trisodium premixed with HSA identified the draining periprostatic LNs in all cases. Delayed images demonstrated upper echelon nodes in the pelvis and the abdomen. Higher volume injections resulted in excessive periprostatic extravasation, whereas lower volume injections resulted in suboptimal visualization of LNs., Conclusions: We demonstrate that gadofosveset trisodium (premixed with 10% HSA) injected intraprostatically at 0.2 mL visualized LNs draining the prostate. This approach can be readily adapted for clinical applications such as sentinel LN imaging in prostate cancer patients before surgery., (Published by Elsevier Inc.)

Neuropsychiatric systemic lupus erythematosus (NPSLE) is speculated to be caused by disturbed microcirculation of the central nervous system. However, characteristic imaging findings of NPSLE have not been established. Hence, we investigated whether high-resolution images obtained using ultrahigh field MRI at 7 T can detect microcerebrovascular lesions in patients with NPSLE that have never been detected by conventional MRI. We prospectively examined 20 patients with SLE, including five with NPSLE, using a 7 T MRI scanner. High-resolution two-dimensional T2-weighted images and high-resolution three-dimensional T1-weighted images (T1WIs) before and after the administration of contrast agents were obtained. On the high-resolution T1WIs obtained at 7 T, minute punctate/linear hyperintense lesions in subcortical and/or cortical areas were found in four (80%) NPSLE patients and one (7%) non-NPSLE patient. Further, the minute punctate enhanced lesions in these areas were found on contrast-enhanced T1WIs in only three (60%) NPSLE patients. These findings suggesting microvascular thrombi or inflammation were significantly more frequent in NPSLE than in non-NPSLE patients (P=0.001). In contrast, other imaging findings, laboratory findings, and clinical characteristics were not different between the two groups. High-resolution T1WIs obtained at 7 T can detect minute lesions, indicating intracerebral microvascular lesions in patients with NPSLE.

Purpose: To investigate MR lymphangiography in mice and primates with intradermal Gadofosveset and human serum albumin. Gadofosveset is a US FDA approved small molecule Gadolinium (Gd) chelate (957 Da) which reversibly binds serum albumin and temporally behaves as a macromolecule. As the structure of albumin varies among species, the affinity of Gadofosveset is optimized for human albumin. In this study, Gadofosveset premixed with 10% human serum albumin (HSA) was injected intradermally in mice and monkeys, and then MR lymphangiography was performed on a 3.0 Tesla clinical scanner., Materials and Methods: Twenty microliters of each agent was injected intradermally at both sides of the front and back paws using a 30-gauge needle into female athymic nude mice (6-8 weeks old, n = 3 mice in each group). The performance of Gadofosveset-HSA was compared with Gd-labeled dendrimers (G4: 6 nm, G6: 10 nm) or Gd-DTPA. The target-to-muscle ratio (TMR = target signal intensity (SI)/muscle SI) was calculated at each time point. The TMRs were compared with a one-way analysis of variance followed by a Bonferroni multiple comparison test., Results: Images taken as early as 2.5 min after intradermal (id) injection depicted enhanced lymph nodes using Gadofosveset-HSA (2.41 ± 0.20). Up to 7.5 min after injection, TMRs of Gadofosveset-HSA were greater than those of dendrimers (G4 or G6-Gd-DTPA: 2.24 ± 0.10, 2.12 ± 0.11, respectively). By 15 min postinjection, TMRs of Gadofosveset-HSA (2.18 ± 0.19) were comparable to Gd-labeled dendrimers (G4-Gd-DTPA: 2.37 ± 0.15, G6-Gd-DTPA: 2.25 ± 0.18). Gadofosveset-HSA and Gd labeled dendrimers resulted in satisfactory MR lymphography in mice and monkeys., Conclusion: Because both Gadofosveset and HSA are approved for human use and Gadofosveset clears rapidly through the kidneys, this method has advantages over Gd-dendrimers and could be used for visualizing lymphatic drainage and detecting lymph nodes., (© 2013 Wiley Periodicals, Inc.)

We retrospectively reviewed the data from a cohort of 44 patients with one initial negative transrectal ultrasound-guided prostate biopsy who underwent a repeat biopsy from 2006 to 2013. At each biopsy session, we checked patient age, serum prostate specific antigen (PSA), prostate volume, PSA density, PSA velocity, months from the initial biopsy session, multiparametric magnetic resonance imaging (MRI) findings (T2-weighted, dynamic contrast-enhanced and diffusion-weighted, 1.5 Tesla pelvic-phased array) prior to repeat biopsy and initial negative biopsy. Mean age was 68.2±8.82 years. PSA was 11.5±7.65 ng/ml before repeat biopsy. Prostate cancer was detected in 15 (34.0%) patients at repeat biopsy. In univariate and multivariate analysis, positive MRI findings before repeat biopsy were significant independent predictors of a positive repeat biopsy. At per patient analysis, the sensitivity, specificity, positive and negative predictive values were 66.6, 68.9, 71.4 and 80.0% for MRI before repeat biopsy. No suspicious lesion on MRI before repeat biopsy was relevant to negative biopsy. According to the comparison of MRI findings prior to repeat biopsy and negative initial biopsy, suspicious MRI findings at the peripheral zone before repeat biopsy and initial negative biopsy were relevant to a high cancer detection rate (83.3%) at repeat prostate biopsy. These results suggested that the absence of a suspicious lesion on MRI before repeat biopsy could guide the avoidance of repeat biopsy and suspicious MRI findings at the peripheral zone before repeat biopsy and initial negative biopsy could guide repeat biopsy.

Dendrimers are versatile macromolecules with tremendous potential as magnetic resonance imaging (MRI) contrast agents. Dendrimer-based agents provide distinct advantages over low-molecular-weight gadolinium chelates, including enhanced r1 relaxivity due to slow rotational dynamics, tunable pharmacokinetics that can be adapted for blood pool, liver, kidney, and lymphatic imaging, the ability to be a drug carrier, and flexibility for labeling due to their inherent multivalency. Clinical applications are increasingly being developed, particularly in lymphatic imaging. Herein we present a broad overview of dendrimer-based MRI contrast agents with attention to the unique chemistry and physical properties as well as emerging clinical applications., (© 2013 Wiley Periodicals, Inc.)

Four gadolinium (Gd)-based macromolecular contrast agents, G3-(Gd-DOTA)(24), G5-(Gd-DOTA)(96), G3-(Gd-DTPA)(24), and G5-(Gd-DTPA)(96), were prepared that varied in the size of dendrimer (generation three and five), the type of chelate group (DTPA or DOTA), and the theoretical number of metalated chelates (24 and 96). Synthesis relied on a dichlorotriazine derivatized with a DOTA or DTPA ligand that was incorporated into the dendrimer and ultimately metalated with Gd ions. Paramagnetic characteristics and in vivo pharmacokinetics of all four contrast agents were investigated. The DOTA-containing agents, G3-(Gd-DOTA)(24) and G5-(Gd-DOTA)(96), demonstrated exceptionally high r1 relaxivity values at off-peak magnetic fields. Additionally, G5-(Gd-DOTA)(96) showed increased r1 relaxivity in serum compared to that in PBS, which was consistent with in vivo images. While G3-(Gd-DOTA)(24) and G3-(Gd-DTPA)(24) were rapidly excreted into the urine, G5-(Gd-DOTA)(96) and G5-(Gd-DTPA)(96) did not clear as quickly through the kidneys. Molecular simulation of the DOTA-containing dendrimers suggests that a majority of the metalated ligands are accessible to water. These triazine dendrimer-based MRI contrast agents exhibit several promising features such as high in vivo r1 relaxivity, desirable pharmacokinetics, and well-defined structure.

Few imaging methods are available for depicting in vivo cancer cell migration within the lymphatic system. Detection of such early micrometastases requires extremely high target to background. In this study, we dual-labeled human breast cancer cells (MDA-MB468) with a small particle of iron oxide (SPIO) and a quantum dot (QD), and tracked these cells in the lymphatic system in mice using in vivo MRI and optical imaging. A generation-6 gadolinium-dendrimer-based MRI contrast agent (Gd-G6) was employed for visualizing regional lymphatic channels and nodes. Since Gd-G6 shortened T(1) leading to high signal, whereas SPIO-labeled cancer cells greatly lowered signal, a small number of cells were simultaneously visualized within the draining lymphatic basins. One million dual-labeled cancer cells were subcutaneously injected into the paws of mice 24 h prior to imaging. Then whole body images were acquired pre- and post-intracutaneous injection of Gd-G6 with 3D-T(1) w-FFE and balanced-FFE sequences for cancer cell tracking and MR lymphangiography. In vivo MRI clearly visualized labeled cancer cells migrating from the paw to the axillary lymph nodes using draining lymphatics. In vivo optical imaging using a fluorescence surgical microscope demonstrated tiny cancer cell clusters in the axillary lymph node with high spatial resolution. Thus, using a combination of MRI and optical imaging, it is possible to depict macro- and early micrometastases within the lymphatic system. This platform offers a versatile research tool for investigating and treating lymphatic metastases in animal models., (Copyright © 2011 John Wiley & Sons, Ltd.)

A careful combination of biological targeting moieties (C3 fragments), imaging reagents (a small particle of iron oxide), and appropriate technology (T2-weighted magnetic resonance imaging) is the key to the successful development of an imaging agent for glomerulonephritis. This recipe applies to virtually any molecular imaging probe for the kidney and throughout the body. However, each organ and disease requires a unique combination of these three components in order to achieve success.

Polyethylene glycol (PEG) surface modification can make nanomaterials highly hydrophilic, reducing their sequestration in the reticuloendothelial system. In this study, polyamidoamine (PAMAM) dendrimers bearing gadolinium (Gd) chelates were PEGylated with different PEG-chain lengths, and the effects on paramagnetic and pharmacokinetic properties were evaluated. Specifically, Gd chelate-bearing PAMAM dendrimers (generations 4 and 5; G4 and G5) were conjugated with two different PEG chains (2 kDa and 5 kDa; 2k and 5k). Long PEG chains (5k) on the smaller (G4) dendrimer resulted in reduced relaxivity compared to non-PEGylated dendrimers, whereas short PEG chains (2k) on a larger (G5) dendrimer produced relaxivities comparable to non-PEGylated G4 dendrimers. The relaxivity of all PEGylated or lysine-conjugated dendrimers increased at higher temperature, whereas that of intact G4 Gd-PAMAM dendrimer decreased. All PEGylated dendrimers had minimal liver and kidney uptake and remained in circulation for at least 1 hour. Thus, surface-PEGylated Gd-PAMAM dendrimers showed decreased plasma clearance and prolonged retention in the blood pool. Shorter PEG, higher generation conjugates led to higher relaxivity., From the Clinical Editor: In this study, polyamidoamine dendrimers bearing gadolinium (Gd) chelates were PEGylated with different PEG-chain lengths, and the effects on paramagnetic and pharmacokinetic properties were evaluated., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The processes of tumor invasion and metastasis have been well characterized at the molecular level, and numerous biomarkers of tumor aggressiveness have been discovered. Molecular imaging offers the opportunity to depict specific cell markers relevant to tumor aggressiveness. Here, we describe the role of MRI in identifying tumor invasiveness and metastasis with reference to other methods. Target-specific molecular imaging probes for tumor invasiveness have been developed for positron emission tomography and optical imaging, but progress in MRI has been slower. For example, proteases associated with tumor invasion, such as specific matrix metalloproteinases or cathepsins, can be targeted in vivo using optical and positron emission tomography methods, but have not yet been successful with MRI. In addition, we describe the use of MRI to detect metastases. Novel MR contrast agents based on iron oxide and dendrimer nanomaterials allow for better characterization of tumor metastases. Organ-specific MR contrast agents are used to identify metastatic disease in the liver. Finally, diffusion-weighted whole-body MRI is discussed as an alternative offered by MRI that does not require the use of molecular probes to screen distant metastases., (Published in 2010 by John Wiley & Sons, Ltd.)

Nanoparticles present a new collection of contrast agents for the field of in vivo molecular imaging. This review focuses on promising molecular imaging probes for optical and magnetic resonance imaging based on four representative nanomaterial(s) platforms: quantum dots, upconversion phosphors, superparamagnetic iron oxides, and dendrimer-based agents. Quantum dots are extremely efficient fluorescent nanoparticles with size-tunable emission properties, enabling high sensitivity and greater depth penetration. Their heavy metal composition and long retention in the body, however, pose concerns for clinical translational applications. Upconversion phosphors generate excellent signal-to-background contrast because they emit light with higher energy than the excitation photons and autofluorescence signals. For MRI, iron oxide particles also generate excellent signal and have been used in liver imaging and for cell tracking studies. As they are metabolized through endogenous iron salvage pathways, they have already been introduced as clinical contrast agents. Lastly, dendrimers, a 'soft' nanoparticle, can be used as a structural basis for the attachment of small molecule imaging agents and/or targeting groups. This array of nanoparticles should offer insights into the uses and potentials of nanoparticles for the molecular imaging.

The development of imaging technologies that have sufficient specificity and sensitivity to enable early, accurate detection of cancer and response to therapy has long been a goal in oncology. Various radiological techniques have been used for diagnosis and surveillance of disease recurrence and imaging has revolutionised oncology. However, despite the widespread use of technologies, the ability of currently available imaging methods to facilitate early detection, precise characterisation, and accurate localisation of malignant disease could be improved. The simultaneous use of two or more techniques, contrast reagents, signalling methods, or the coupling of agent and tissue properties to achieve so-called multiplexed imaging is a promising approach. In this review, we provide a broad overview of current and emerging multiplexed, imaging technologies., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Paramagnetic nanomaterials for use as magnetic resonance imaging (MRI) contrast agents have higher relaxivity than conventional low molecular weight MRI agents. However, the biocompatibility and pharmacokinetics of such nanomaterials will strongly affect the likelihood of clinical approval. We synthesized MRI contrast agents based on biocompatible lysine-dendri-grafts: Gd-BzDTPA-lysineG2 and Gd-BzDTPA-lysineG3. The relaxivity of Gd-BzDTPA-lysineG2 and Gd-BzDTPA-lysineG3 increased with sample temperature, while the relaxivity of Gd-BzDTPA-PAMAMG4 decreased with increasing sample temperature. The increase in relaxivity with increasing temperature may be attributed to accessibility of water to the internal Gd chelates with lysine-dendri-grafts, which does not occur with PAMAM dendrimers. Gd-BzDTPA-lysineG3 had a long intravascular half-life but were largely excreted by the kidneys. Therefore, Gd-BzDTPA-lysineG3 enhanced the blood vessels for longer periods than Gd-BzDTPA-PAMAMG4, but was still excreted through the kidney. Because of their biocompatibility, desirable magneto-physical characteristics and favorable pharmacokinetics, which are derived from different interior structures rather than the physical size, lysine-dendri-graft MR contrast agents may be feasible for clinical use.

Neuronavigation in epilepsy surgery enables surgeons to accurately resect deep targets inside the brain, especially lesions that are unable to be visually differentiated from adjacent normal brain. The usefulness of visualizing subdural electrodes with postimplantation fusion CT/MRI was investigated. The use of platinum subdural electrodes made it possible to obtain postimplantation MRI. The postimplantation MRI and CT scans were fused on the surgical navigation system workstation to form three-dimensional (3D) images, and the epileptogenic regions were marked using the visualized electrodes. Immediately after a craniotomy was performed, the subdural electrodes were removed and the epileptogenic region was successfully resected using the neuronavigation guide. During neuronavigation-guided surgery to target deep brain epileptogenic lesions adjacent to eloquent areas, which are often invisible, we found visualization of the subdural electrodes with postimplantation fusion CT/MRI very useful., ((c) 2009 Elsevier Ltd. All rights reserved.)

Introduction: Rheumatoid arthritis (RA) is a multi-organ inflammatory disorder associated with high cardiovascular morbidity and mortality. We sought to assess cardiac involvement using a comprehensive cardiac magnetic resonance imaging (cMRI) approach and to determine its association with disease characteristics in RA patients without symptomatic cardiac disease., Methods: RA patients with no history and/or clinical findings of systemic or pulmonary hypertension, coronary artery disease, severe valvular heart disease, atrial fibrillation, diabetes mellitus, or echocardiographic abnormalities underwent contrast-enhanced cMRI on a 1.5T scanner. Adenosine triphosphate was used to assess perfusion defects due to microvascular impairment or ischemia, and delayed enhanced imaging was obtained for the assessment of myocardial inflammation/fibrosis. We explored the associations of cMRI abnormalities with RA disease activity and severity measures., Results: Eighteen patients (78% female) with a mean age of 57 ± 10 years were studied. Eight patients (45%) demonstrated a myocardial abnormality. Perfusion defects under pharmacologic stress were seen in two patients (11%), one of whom had a circumferential subendocardial perfusion defect and one had a non-segmental subendocardial perfusion defect. Seven patients (39%) were found to have delayed enhancement, only one of whom also demonstrated a perfusion defect. Mean disease activity score (DAS)28 was significantly higher in the group with delayed enhancement compared to the group without by an average of 1.32 DAS28 units (4.77 vs. 3.44 units, respectively; P = 0.011). Corresponding trends to statistical significance were noted in systemic inflammatory markers, with both C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) quantitatively higher in the group with delayed enhancement. Other RA characteristics, such as disease duration, autoantibody status, and current treatments were not significantly associated with cardiac involvement., Conclusions: Myocardial abnormalities, as detected by cMRI, were frequent in RA patients without known cardiac disease. Abnormal cMRI findings were associated with higher RA disease activity, suggesting a role for inflammation in the pathogenesis of myocardial involvement in RA.

Objective: To assess cardiac involvement in asymptomatic patients with systemic sclerosis (SSc) by cardiac magnetic resonance imaging (MRI)., Methods: Ten asymptomatic patients with SSc (all female; mean age 59.5+/-9.4 yrs) underwent contrast enhanced cardiac MRI on a 1.5 T MRI device. Adenosine triphosphate was used for stress and rest perfusion to assess perfusion defects due to microvascular impairment or ischemia, and delayed enhanced (DE) imaging was obtained for the assessment of myocardial necrosis and fibrosis. We evaluated the pathophysiological associations of stress perfusion combined with DE imaging with SSc disease severity measures., Results: Stress perfusion defects were seen in 5 out of 9 patients (56%): 4 had nonsegmental subendocardial perfusion defects and one had a segmental subendocardial perfusion defect. Three patients were found to have DE. DE was not observed in any patient without perfusion defect; and among the 5 patients with perfusion defects, 3 (60%) had DE. Two of the 3 had DE in segments not matching the region of nonsegmental perfusion defects. The remaining one had a segmental subendocardial DE matching the region of a segmental perfusion defect. Perfusion defects were seen in 75% of patients with a history of digital ulceration compared to only 20% of those without history of ulceration., Conclusion: Subclinical myocardial involvement, as detected by cardiac MRI, was frequent in asymptomatic patients with SSc. Cardiac MRI may aid in understanding the pathophysiological mechanism of SSc.

Background: The invocation Namu Amida Butsu (Nembutsu), voices the hope of rebirth into Amida's Pure Land. In the Nembutsu, Buddhists imagine that they are absorbed into Amida's Pure Land. Shiritori, a Japanese word chain game, is a common task used to activate language related regions in Japanese. The purpose of this study was to identify the regions activated during praying of the Namo Amida Butsu (Nembutsu), and the reciting of Buddhist scriptures (Sutra)., Material and Method: Functional MRI (fMRI) was used to identify the regions activated by the Nenbutsu, the Sutra and the Shiritori in eight highlytrained Japanese monks., Results: The task of repeating the Nenbutsu activates the medial frontal gyrus, which is mainly related to mental concentration and visuospatial attention, similar to the areas activated by meditation. The task of reciting the Sutra activates the left lateral middle frontal gyrus, the right angular gyrus, and the right supramarginal gyrus, which are related to visuospatial attention also involved in the area activated by meditation., Conclusion: These results suggest that different types of meditation in Japanese Buddhism showed different brain regional activation. The Nenbutsu activated the prefrontal cortex, and the Sutra activated the left dorsolateral prefrontal cortex and right parietal cortex.

A novel approach for the preparation of a biotinylated dendrimer-based MRI agent 5 is described, in which a unique disulfide bond in the core of the Gd(III)-1B4M-DTPA chelated G2 PAMAM dendrimer was reduced and then attached to a maleimide-functionalized biotin. The new MRI agent 5 features a well-defined dendron structure and a unique biotin functionality. Immobilization of up to four copies of biotinylated dendrimer 5 to fluorescently labeled avidin yields a supramolecular avidin-biotin-dendrimer-Gd(III) complex. Validation of the complex in mice bearing ovarian cancer tumors demonstrates that the avidin-biotin-dendrimer targeting system efficiently targets and delivers sufficient amounts of chelated Gd(III) and fluorophores (e.g., Rhodamine green) to ovarian tumors to produce visible changes in the tumors by both MRI and optical imaging, respectively. Thus, the avidin-biotin-dendrimer complex may be used as a tumor-targeted probe for dual-modality magnetic resonance and fluorescence imaging.

Two different fourth-generation (G4) polyaminonamido dendrimer-based magnetic resonsance (MR) agents were prepared by a new synthetic approach wherein tert-butyl-protected forms of 2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriamine pentaacetic acid (1B4M-DTPA), bearing either an isothiocyanate or a succinimidyl ester moiety, respectively, were conjugated to the primary amines of the dendrimer. Purification was facilitated using a solid phase, N-(2-aminoethyl)aminomethyl polystyrene. After Gd(III) incorporation, molar relaxivity measurements of both new dendrimer-based agents as compared to a G4 agent prepared by an aqueous chemistry route indicated no significant changes in relaxivity. Comparative MR imaging revealed equivalent enhancement of the vessels and organs such as the kidney and liver, although slightly different vascular clearance rates were observed. This general synthesis provides a procedure for preparation of dendrimer-based MR agents for clinical applications with higher yields and efficiency while enhancing versatility. The latter aspect is further demonstrated by preparation of a novel maleimide analog of 1B4M-DTPA from a key synthetic intermediate aniline derivative.

Background: We report on the case of a patient with meningioma that was correctly identified through biopsy., Case Description: A 69-year-old woman presented with slight headache and was then examined at our hospital. Neurologic and physical examinations found no abnormality. Magnetic resonance imaging demonstrated a well-enhanced huge, dural-based, and plaque-like mass extending throughout the parietooccipital convexity and the posterior fossa. Tumors pressed the adjacent brain cortex while extending along the Virchow-Robin space. A CT scan also showed hyperostosis on the parietooccipital bone. Angiography demonstrated a vascular blush that appeared to be of a tumor-like shape. A biopsy was performed to confirm the diagnosis. The histologic findings demonstrated meningothelial meningioma with infiltration into the Virchow-Robin space., Conclusions: Many radiographic patterns of meningioma have been reported, but the present case is quite rare. The radiographic and pathologic findings in our patient are discussed.

Purpose: To preoperatively and intraoperatively localize the sentinel lymph node (SLN), a single hybrid probe for MR and near infrared (NIR) optical imaging was synthesized and tested., Materials and Methods: A macromolecular MR/NIR optical contrast agent was synthesized based on a approximately 191 gadolinium-labeled contrast agent using generation-6 polyamidoamine dendrimer (G6), which is also labeled with 2 Cy5.5, an NIR fluorophore. After establishing the optimal dose, the agent was injected into mammary glands of 10 normal mice to examine the lymphatic drainage from the breast using a 3T clinical scanner. Immediately after the MRI scan, NIR optical imaging and image-guided surgery were performed to compare the two imaging modalities., Results: To consistently identify the SLNs, we needed to inject 25 microL of 30 mM [Gd] G6-Cy5.5. All SLNs could be easily identified and resected under NIR optical imaging-guided surgery. Although external NIR optical imaging failed to identify SLNs close to the injection site due to shinethrough, MR lymphography (MRL) consistently identified all SLNs regardless of their location., Conclusion: We have successfully synthesized and tested a dual labeled MR/NIR optical hybrid contrast agent, G6-Cy5.5 for reoperative and intraoperative localization of SLNs., (Copyright (c) 2007 Wiley-Liss, Inc.)

Most macromolecular contrast agents (CAs) show lower r1 and higher r2 relaxivities at 3.0T than at 1.5T. MR lymphangiography in mice using a macromolecular G6 dendrimer-based CA was serially performed and compared at both 1.5T and 3.0T. The r1 and r2 relaxivities of the G6 CA were 25 and 78/s/mM at 1.5T and 17 and 82/s/mM at 3.0T, respectively. The lymph node (LN)-to-fat ratios (LN signal intensity (SI)/fat SI) of T1-weighted 3D-fast spoiled gradient-echo (3D-FSPGR) were 3.2+/-0.4 (mean+/-standard deviation (SD)) at 1.5T and 2.7+/-0.3 at 3.0T (P=0.021), and the LN-to-fat ratios of T2/T1-weighted 3D-fast imaging employing steady-state acquisition with phase cycling (3D-FIESTA-C) were 1.8+/-0.2 at 1.5T and 1.2+/-0.4 at 3.0T (P=0.003). Although 3D-FSPGR successfully delineated the LNs at both 1.5T and 3.0T, 3D-FIESTA-C at 3.0T failed to visualize the LNs., (Copyright (c) 2007 Wiley-Liss, Inc.)

Angiogenesis has long been accepted as a vital process in the growth and metastasis of tumors. As a result it is the target of several novel anti-cancer medications. Consequently, there is an urgent clinical need to develop accurate, non-invasive imaging techniques to improve the characterization of tumor angiogenesis and the monitoring of the response to anti-angiogenic therapy. Macromolecular MR contrast media (MMCM) offer this diagnostic potential by preferentially exploiting the inherent hyperpermeable nature of new tumor vessels compared with normal vessels. Over the last 10-15 years many classes of MMCM have been developed. When evaluated with dynamic contrast enhanced (DCE) MRI, a number of MMCM have demonstrated in vivo imaging properties that correlate with ex vivo histological features of angiogenesis. The enhancement patterns with some MMCM have been reported to correlate with tumor grade, as well as show response to anti-angiogenic and anti-vascular drugs. Future applications of MMCM include targeted angiogenesis imaging and drug delivery of anti-cancer 'payloads'. Herein we discuss the best known MMCMs along with their advantages and disadvantages.

A novel PAMAM dendrimer-based nanoprobe for dual magnetic resonance and fluorescence imaging modalities was synthesized. Fluorescence studies revealed that Gd(III) complexation to the probe has no effect on the quantum yield; however, increases in the dye content resulted in partial quenching. The potential of the new nanoprobe, G6-(Cy5.5)(1.25)(1B4M-Gd)(145), as a dual modality imaging agent was demonstrated in vivo by the efficient visualization of sentinel lymph nodes in mice by both MRI and fluorescence imaging modalities.

Background: Functional magnetic resonance (MR) imaging of the kidney relies on low-molecular-weight contrast agents. These agents are glomerular filtration markers and are neither secreted nor reabsorbed by the tubules but are filtered at the glomerulus. Low-molecular-weight contrast agents provide limited functional information. A new generation of macromolecular magnetic contrast agents is under development for MR angiography. These agents may provide additional renal functional information not provided by low-molecular-weight agents., Methods: We review the use of macromolecular contrast agents such as gadolinium-bound albumin (Gd-albumin), gadolinium-bound dendrimer (Gd-dendrimer), and ultrasmall particles of iron oxide (USPIO) in specific renal parenchymal diseases. These data are largely derived from animal studies because many of these agents have not been extensively deployed in human populations., Results: Different specific uses have been documented for macromolecular contrast agents. Gd-albumin appears to detect the source of proteinuria and localize the site of recurrent proteinuria after transplantation. Gd-dendrimer uptake reflects damage to the proximal straight tubule in the outer medulla. USPIO agents demonstrate sites of inflammatory changes within the kidney., Conclusions: Although not yet in widespread clinical use, macromolecular MR contrast agents may play a role in the evaluation of functional diseases of the kidneys.

Purpose: To report the cause and magnetic resonance imaging (MRI) findings in a case of abducent palsy following herpes zoster ophthalmicus., Case: A 76-year-old man presented with acute onset of pain, a vesicular cutaneous eruption and herpes zoster ophthalmicus on the right side. He developed complete abducent palsy on the right side two weeks after onset. MRI with gadolinium enhancement showed Meckel's sinus, which contains the trigeminal ganglion, and the abducent nerve on the right side. The patient was treated with intravenous acyclovir and methylprednisolone. The abnormal enhancement shown on MRI vanished immediately and the ophthalmoplegia resolved significantly., Conclusion: This is the first reported case where an affected cranial nerve was detected next to the inflammatory cavernous sinus in ophthalmoplegia following herpes zoster ophthalmicus. These MRI findings showed that this ophthlamoplegia was induced by direct viral invasion or extension of inflammation to the ipsilateral cranial nerve. Further studies need to be performed to clarify the role of specific antiviral therapy or anti-inflammatory agents in treating this complication of herpes zoster.

Acute renal failure (ARF) induced by sepsis has a high mortality but lacks effective treatments. To develop novel therapies we must diagnose renal injury early and accurately in septic patients and identify any additional insults such as nephrotoxic drugs and ischemia. In this short review we describe our experience using MRI with dendrimer-based contrast agents in mouse models of ARF. This technique can diagnose early renal injury before serum creatinine is elevated, distinguish different ARF etiologies, track drug therapy and predict outcome. As an ARF biomarker, MRI with dendrimer-based contrast is a promising technique deserving further development., (Copyright 2006 S. Karger AG, Basel.)

Gadolinium-based MRI contrast agents (CAs) can be effective at a approximately 100-fold lower concentration of Gadolinium ions in comparison to the concentration of Iodine atoms required for CT imaging. Therefore, a number of dendrimer based macromolecular MRI CAs of various sizes and properties prepared employing relatively simple chemistry are readily available that can provide sufficient contrast enhancement for various applications. Molecules up to 20 nm in diameter behave differently in the body depending on their size. Even if these molecules possess similar chemical properties, small changes in size can greatly impact their pharmacokinetics. Changes in molecular size up to 15 nm in diameter altered permeability across the vascular wall, excretion route, and recognition by the reticuloendothelial system. Smaller sized polyamidoamine (PAMAM) dendrimer-based contrast agents, i.e., less than 3 nm in diameter, easily "leak" across the vascular wall resulting in rapid perfusion throughout the body. Contrast agents 3-6 nm in diameter were quickly excreted through the kidney indicating these agents to be potentially suitable as functional renal contrast agents. Contrast agents 7-12 nm in diameter were retained in circulation and were better suited for use as blood pool contrast agents. Hydrophobic variants of CAs formed with polypropylenimine diaminobutane (DAB) dendrimer cores quickly accumulated in the liver and potentially have use as liver contrast agents. Larger hydrophilic agents have suitable characteristics for lymphatic imaging. Finally, contrast agents conjugated with either monoclonal antibodies or with avidin are able to function as tumor-specific contrast agents and might also be employed as either gadolinium neutron capture therapy or in conjunction with radioimmunotherapy.

Background: Benign osteoblastoma is an uncommon primary bone tumor that usually affects long bones and the vertebral column. Its occurrence in the calvarium is rare. Despite the characteristically benign nomenclature of osteoblastoma, it sometimes recurs with the possibility of transforming into a malignant form after an incomplete resection. Therefore, radical resection is recommended whenever possible. However, it has not been clarified whether the adjacent bones should also be completely resected when magnetic resonance (MR) images reveal abnormal signal intensity in the bone marrow., Case Description: Presented in this case report is a 12-year-old boy with occipital tenderness associated with occipitoparietal bone tumor. Neuroradiological studies demonstrated a solid tumor located in the occipital bone extending over the right parietal bone. Magnetic resonance images further revealed abnormal signal intensity in the bone marrow of the entire occipital and bilateral parietal bones. Macroscopically, the calvarial bone adjacent to the solid tumor appeared to be reddish, but it was not covering the entire area, contradicting the abnormal intensity found on the preoperative MR images. The resected area was determined according to macroscopic findings, and bones with normal color tone were preserved. Because histological examination did not clearly indicate tumor invasion at the margin of the resection site, no additional therapy was given. Although MR images revealed abnormal intensity in the bone marrow of the surgical margin immediately after the operation, the intensity had been normalized by degrees and there was no evidence of recurrence during a follow-up period of 34 months. This may suggest that bone marrow lesion showing abnormal intensity was edema rather than tumor invasion., Conclusions: The authors conclude that total resection, including a bone marrow lesion, is not always necessary for benign osteoblastoma. Macroscopic findings that show an abnormal color tone of the cortex could be a good indicator in revealing tumor activity invading bone marrow.

Background: Acute renal failure (ARF) induced by sepsis has a high mortality. In an aged mouse model of sepsis-induced ARF we have previously shown that renal injury occurs before serum creatinine is elevated. Development of a noninvasive biomarker that could diagnose renal dysfunction early in sepsis and monitor the response to therapy would be very valuable., Methods: We performed magnetic resonance imaging (MRI) with gadolinium-based G4 dendrimer intravenous contrast in a fluid- and antibiotic-treated cecal ligation and puncture (CLP) sepsis model in aged mice. Imaging was also performed in a mouse volume depletion model and in models of ARF induced by ischemia/reperfusion (I/R) and cisplatin., Results: Twenty hours post-CLP, aged mice had a distinct pattern of renal injury using dendrimer-enhanced MRI. This pattern was different from renal injury induced by either cisplatin or I/R. Prerenal azotemia induced by volume depletion was distinguished from sepsis by dendrimer-enhanced MRI. Dendrimer-enhanced MRI detected renal dysfunction 6 hours post-CLP, a time when serum creatinine was still normal. Ethyl pyruvate reversed the renal dysfunction detected by dendrimer-enhanced MRI at 20 hours, but not at 6 hours post-CLP. The appearance of renal dysfunction on dendrimer-enhanced MRI at 6 hours post-CLP predicted the length of survival., Conclusion: Dendrimer-enhanced MRI is a novel biomarker that provides information for the early diagnosis, drug responsiveness, and prognosis of sepsis-induced ARF.

Purpose: To retrospectively evaluate the accuracy of magnetic resonance (MR) imaging in depicting posterior cul-de-sac obliteration in patients with endometriosis., Materials and Methods: Institutional review board approval was not required for this retrospective study, but informed consent was obtained from all patients. MR images obtained between January 1989 and December 2000 in 57 women (mean age, 39 years; age range, 26-52 years) with histologically confirmed endometriosis were retrospectively evaluated by four radiologists independently. All patients underwent laparotomy or laparoscopy less than 1 month after MR imaging. MR images were evaluated for the presence and location of endometrial implants and adhesions. MR images were also scored for the presence of five findings: retroflexed uterus, elevated posterior vaginal fornix, intestinal tethering or tethered appearance of rectum in direction of uterus, faint strands between uterus and intestine, and fibrotic plaque or nodule covering serosal surface of the uterus. Interobserver agreement for each of the five findings and for the overall diagnosis of cul-de-sac obliteration was calculated. Sensitivity, specificity, accuracy, positive and negative predictive values, and kappa statistics were determined., Results: Laparotomy or laparoscopy revealed posterior cul-de-sac obliteration in 30 patients. Overall, the four radiologists had mean accuracies of 89.0% and 76.3% for diagnosing endometrial implants and adhesions, respectively, at MR imaging. Overall, the radiologists achieved mean sensitivity, specificity, accuracy, and positive and negative predictive values of 68.4%, 76.0%, 71.9%, 76.6%, and 68.5%, respectively, in diagnosing posterior cul-de-sac obliteration. The best accuracy (mean value, 64.5%) was obtained with the finding of fibrotic plaque in the uterine serosal surface. Readers agreed on the observations 63.2%-91.2% of the time. For the impression of the presence or absence of posterior cul-de-sac obliteration, interobserver agreement varied between substantial and moderate: Mean interobserver agreement was 78.4% (range, 70.2%-84.2%), and mean kappa was 0.57 (range, 0.40-0.67). Mean accuracy of MR imaging for diagnosing posterior cul-de-sac obliteration was 71.9%., Conclusion: These results suggest that use of the described MR imaging findings may enable diagnosis of posterior cul-de-sac obliteration.

Paramagnetic metals can induce T1 shortening by interaction with free water molecules. Two metal ions, Gadolinium and Manganese, are currently available for human use. Gadolinium-based MRI contrast agents (CAs) can operate using a approximately 100-fold lower concentration of Gadolinium ions in comparison to the necessary concentration of Iodine atoms employed in CT imaging in the tissues. Therefore, numerous macromolecular MRI CAs prepared employing relatively simple chemistry are readily available that can provide sufficient enhancement for multiple applications. Herein, we describe the synthesis, characteristics, and potential applications of dendrimer-based macromolecular MRI CAs in our recently reported libraries. This entire series of dendrimer-based macromolecular MRI CAs have a spherical shape and possess similar surface charges. Changes in molecular size altered the route of excretion. Smaller sized contrast agents, of less than 60 kD molecular weight, were excreted through the kidney resulting in these agents being potentially suitable as functional renal contrast agents. Less hydrophilic and larger sized contrast agents were found better suited for use as blood pool contrast agents. Hydrophobic variants of CAs formed with polypropylenimine diaminobutane dendrimer cores quickly accumulated in the liver and can function as liver contrast agents. Larger hydrophilic agents are also useful for lymphatic imaging. Finally, contrast agents conjugated with either monoclonal antibodies or with avidin are able to function as tumor-specific contrast agents and might also be employed as therapeutic drugs for either gadolinium neutron capture therapy or in conjunction with radioimmunotherapy.

Purpose: To choose an efficacious renal functional MRI contrast agent to image early renal tubular damage. We synthesized and compared smaller polyamine dendrimer-based MRI contrast agents (<60 kD) that, unlike Gd-[DTPA], transiently accumulate in renal tubules and can be used to visualize renal structural and functional damage., Materials and Methods: Six dendrimer-based MRI contrast agents smaller than 60 kD were studied by high resolution dynamic micro-MRI and compared to Gd-[DTPA]-dimeglumine and Gadomer-17. The best agent, DAB-G2, was further tested in a mouse ischemia/reperfusion model to validate its efficacy., Results: Despite unequal renal clearance rates, all polyamine dendrimer agents visualized the renal functional anatomy of the mice better than Gd-[DTPA]-dimeglumine and Gadomer-17. DAB-G2 was excreted most rapidly, yet was able to visualize mild renal tubular injury very early after injury., Conclusion: DAB-G2 was found to be the best candidate for functional kidney imaging and enabled early diagnosis of acute renal injury.

Background: The presence of lymph node metastases is an important factor in breast cancer patient prognosis. Therefore, the precise identification of sentinel lymph nodes in these patients is critical. Improving current magnetic resonance (MR) imaging methods using a newly synthesized nano-size paramagnetic molecule, G6, as a contrast agent, provides an attractive means toward attaining this goal., Methods: A four-dimensional method of micro-MR lymphangiography using G6 (9 nm/240 kd) was developed to visualize the lymphatic ducts and lymph nodes draining mouse mammary tumors over time. The ability of micro-MR lymphangiography with the G6 contrast agent to visualize lymphatic drainage of normal mouse mammary tissue was compared with that of the conventional MR contrast agent, Gd-[DTPA]-dimeglumine (<1 kd). Lymphatic drainage in spontaneous and xenografted breast tumor models was visualized using the G6 contrast agent., Results: Draining lymphatic ducts and lymph nodes were clearly visualized in the mammary tissue of normal mice and in spontaneous and xenografted breast tumor models after a direct mammary gland or peritumoral injection of G6. Gd-[DTPA]-dime-glumine, by contrast, failed to depict lymphatic flow from the mammary tissue in normal mice using the same method. Micro-MR lymphangiography using the G6 contrast agent revealed the absence of filling in the metastatic foci of affected lymph nodes., Conclusions: The superior temporal and spatial resolution of micro-MR lymphangiography using the contrast agent G6 may facilitate the study of tumor lymphatic drainage and lymphatic metastasis in both experimental animals and clinical medicine. In addition, this may be a powerful new method for sentinel lymph node localization in human breast cancer.

Background: Mouse models of disease, especially using transgenic and knockout technologies, are powerful tools to analyze the molecular basis of disease. We recently reported that a new dynamic micro-MRI method with dendrimer-based contrast agents can visualize renal structure and function in normal living mice and mice with acute renal failure. While MRI contrast enhancement is useful for detecting functional impairment of the kidneys, this technology has limitations in assessing morphologic changes, particularly cystic disease, because contrast-enhanced micro-MRI depicts cysts as low-intensity areas that cannot be distinguished from fibrotic foci., Methods: In the current study, we evaluated if micro-MRI employing a new three-dimensional MR hydrography signal sequence [three-dimensional fast imaging employing steady-state acquisition (3D-FIESTA)] can visualize chronic cystic changes without any contrast agents., Results: We were able to positively depict multiple renal cortical cysts of approximately 0.2 mm diameter in a mouse model of sickle cell disease and observe serial changes of renal cysts (>0.2 mm diameter) in cyclooxygenase-2 (COX-2) knockout mice during a 21/2-month period. Some cysts decreased in size over time., Conclusions: Micro-MRI with 3D-FIESTA can depict cyst formation in the diseased kidneys of living mice without injection of contrast agents.