Transarterial chemoembolization of hepatocellular carcinoma in a rat model: the effect of additional injection of survivin siRNA to the treatment protocol.

BACKGROUND: Transarterial chemoembolization is one of the most widely accepted interventional treatment options for treatment of hepatocellular carcinoma. Still there is a lack of a standard protocol regarding the injected chemotherapeutics. Survivin is an inhibitor of Apoptosis protein that functions to inhibit apoptosis, promote proliferation, and enhance invasion. Survivin is selectively up-regulated in many human tumors. Small interfering RNA (siRNA) can trigger an RNA interference response in mammalian cells and induce strong inhibition of specific gene expression including Survivin. The aim of the study is to assess the effectiveness of the additional injection of Survivin siRNA to the routine protocol of Transarterial Chemoembolization (TACE) for the treatment of hepatocellular carcinoma in a rat model. METHODS: The study was performed on 20 male ACI rats. On day 0 a solid Morris Hepatoma 3924A was subcapsullary implanted in the liver. On day 12 MRI measurement of the initial tumor volume (V1) was performed. TACE was performed on day 13. The rats were divided into 2 groups; Group (A, n = 10) in which 0.1 mg mitomycin, 0.1 ml lipiodol and 5.0 mg degradable starch microspheres were injected in addition 2.5 nmol survivin siRNA were injected. The same agents were injected in Group (B,=10) without Survivin siRNA. MRI was repeated on day 25 to assess the tumor volume (V2). The tumor growth ratio (V2/V1) was calculated. Western blot and immunohistochemical analysis were performed. RESULTS: For group A the mean tumor growth ratio (V2/V1) was 1.1313 +/- 0.1381, and was 3.1911 +/- 0.1393 in group B. A statistically significant difference between both groups was observed regarding the inhibition of tumor growth (P < 0.0001) where Group A showed more inhibition compared to Group B. Similarly immunohistochemical analysis showed significantly lower (p < 0.002) VEGF staining in group A compared to group B. Western Blot analysis showed a similar difference in VEGF expression (P < 0.0001). CONCLUSION: The additional injection of Survivin siRNA to the routine TACE protocol increased the inhibition of the hepatocellular carcinoma growth in a rat animal model compared to regular TACE protocol.

Percutaneous microwave ablation of thyroid nodules: effects on thyroid function and antibodies.

PURPOSE: Microwave ablation (MWA) is a new minimally invasive method for thermal ablation of benign thyroid nodules with promising results. The aim of this study was to investigate whether MWA has an impact on thyroid function. MATERIALS AND METHODS: Thirty patients with a total of 34 benign thyroid nodules underwent MWA between January 2013 and July 2014. Serum levels of triiodothyronine (T3), thyroxine (T4), thyrotropin (TSH), thyroglobuline (Tg) and additionally antibodies against Tg (anti-Tg), thyrotropin receptors (TRAb) and thyroid peroxidase (anti-TPO) were measured at enrolment, 24 h after MWA, as well as at the 3-month and 6-month follow-up. Moreover, the nodule volume was evaluated to determine effectiveness. RESULTS: Serum TSH, T4, T3 and Tg levels did not change significantly at the 3-month or 6-month follow-up (p > 0.05); thyroid function was not affected by MWA. Antibody levels did not change significantly either; however, two patients developed antibodies after treatment. A volume reduction of 51.4% or 7.85 mL could be demonstrated after 3 months and a reduction of 55.8% or 14.0 mL after 6 months. Slight complications such as mild pain during the ablation or superficial haematomas emerged. The development of Graves' disease and mild Horner's syndrome were observed as more severe side effects. CONCLUSIONS: The data suggest MWA as an alternative for the treatment of benign thyroid nodules. While first results for preservation of thyroid function are positive, further measurements of laboratory data and especially antibodies are necessary.

Contrast enhancement of the brain by folate-conjugated gadolinium-diethylenetriaminepentaacetic acid-human serum albumin nanoparticles by magnetic resonance imaging.

Different from regular small molecule contrast agents, nanoparticle-based contrast agents have a longer circulation time and can be modified with ligands to confer tissue-specific contrasting properties. We evaluated the tissue distribution of polymeric nanoparticles (NPs) prepared from human serum albumin (HSA), loaded with gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) (Gd-HSA-NP), and coated with folic acid (FA) (Gd-HSA-NP-FA) in mice by magnetic resonance imaging (MRI). FA increases the affinity of the Gd-HSA-NP to FA receptor-expressing cells. Clinical 3 T MRI was used to evaluate the signal intensities in the different organs of mice injected with Gd-DTPA, Gd-HSA-NP, or Gd-HSA-NP-FA. Signal intensities were measured and standardized by calculating the signal to noise ratios. In general, the NP-based contrast agents provided stronger contrasting than Gd-DTPA. Gd-HSA-NP-FA provided a significant contrast enhancement (CE) in the brain (p  =  .0032), whereas Gd-DTPA or Gd-HSA-NP did not. All studied MRI contrast agents showed significant CE in the blood, kidney, and liver (p < .05). Gd-HSA-NP-FA elicited significantly higher CE in the blood than Gd-HSA-NP (p  =  .0069); Gd-HSA-NP and Gd-HSA-NP-FA did not show CE in skeletal muscle and gallbladder; Gd-HSA-NP, but not Gd-HSA-NP-FA, showed CE in the cardiac muscle. Gd-HSA-NP-FA has potential as an MRI contrast agent in the brain.

Different signal intensity at Gd-EOB-DTPA compared with Gd-DTPA-enhanced MRI in hepatocellular carcinoma transgenic mouse model in delayed phase hepatobiliary imaging.

PURPOSE: To evaluate hyperintense Gd-DTPA- compared with hyper- and hypointense Gd-EOB-DTPA-enhanced magnet resonance imaging (MRI) in c-myc/TGFα transgenic mice for detecting hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Twenty HCC-bearing transgenic mice with overexpression of the protooncogene c-myc and transforming growth factor-alpha (TGF-α) were analyzed. MRI was performed using a 3-T MRI scanner and an MRI coil. The imaging protocol included Gd-DTPA- and Gd-EOB-DTPA-enhanced T1-weighted images. The statistically evaluated parameters are signal intensity (SI), signal intensity ratio (SIR), contrast-to-noise ratio (CNR), percentage enhancement (PE), and signal-to-noise ratio (SNR). RESULTS: On Gd-DTPA-enhanced MRI compared with Gd-EOB-DTPA-enhanced MRI, the SI of liver was 265.02 to 573.02 and of HCC 350.84 to either hyperintense with 757.1 or hypointense with 372.55 enhancement. Evaluated parameters were SNR of HCC 50.1 to 56.5/111.5 and SNR of liver parenchyma 37.8 to 85.8, SIR 1.32 to 1.31/0.64, CNR 12.2 to 26.1/-30.08 and PE 42.08% to 80.5/-98.2%, (P < 0.05). CONCLUSION: Gd-EOB-DTPA is superior to Gd-DTPA for detecting HCC in contrast agent-enhanced MRI in the c-myc/TGFα transgenic mouse model and there was no difference between the hyperintense or hypointense appearance of HCC. Either way, HCCs can easily be distinguished from liver parenchyma in mice.

Dose levels at coronary CT angiography--a comparison of Dual Energy-, Dual Source- and 16-slice CT.

PURPOSE: To compare the dose estimates and image quality of Dual Energy CT (DECT), Dual Source CT (DSCT) and 16-slice CT for coronary CT angiography (cCTA). METHODS: Sixty-eight patients were examined with 16 - slice MDCT (group 1), 68 patients with DSCT (group 2) and 68 patients using DSCT in dual energy mode (DECT group 3). CT dose index volume, dose length product, effective dose, signal-to-noise, and contrast-to-noise ratio were compared. Subjective image quality was rated by two observers, blinded to technique. RESULTS: The mean estimated radiation dose of all patients investigated on a 16 - slice MDCT was 12 ± 3.59 mSv, for DSCT in single energy 9.8 ± 4.77 mSv and for DECT 4.54 ± 1.87 mSv. Dose for CTA was significantly lower in group 3 compared to group 1 and 2. The image noise was significantly lower in Group 2 in comparison to group 1 and group 3. There was no significant difference in diagnostic image quality comparing DECT and DSCT. CONCLUSION: cCTA shows better dose levels at both DECT and DSCT compared to 16-slice CT. Further, DECT delivers significantly less dose than regular DSCT or single source single energy cCTA while maintaining diagnostic image quality.

Image-quality perception as a function of dose in digital radiography.

OBJECTIVE: The purpose of this article is to determine the degree to which the skin entrance dose could be lowered, by adjusting exposure parameters and filtration, and the subsequent effect on readers' confidence levels of digital radiographs. MATERIALS AND METHODS: The study was prospectively performed on a cadaver. Digital radiographs of bones were evaluated and scored on a 9-point scale separately by four radiologists who were blinded to the types of filtration and doses used. The study entailed three phases: phase 1, random dose and filter; phase 2, fixed filter and varying radiation doses (100%, 75%, 50%, and 25% of the standard recommended dose); and phase 3, fixed dose and varying filtration (no filtration, aluminum filter, and aluminum-copper filter). Skin entrance dose was measured using a dosimeter placed on the skin. Differences in scores were tested using a Friedman test. RESULTS: The mean scores given to images with 100%, 75%, 50%, and 25% of the recommended standard dose were 6.18, 6.1, 5.11, and 4.07, respectively. No significant difference was noted between 100%- and 75%-dose images (p = 0.1). A significant difference (p < 0.0001) was noted when we compared the 100%- and 75%-dose images with the 50%- and 25%-dose images. The mean scores given for no filtration, aluminum filtration, and aluminum-copper filtration were 5.67, 5.43, and 5.18, respectively. No significant difference between no filtration and aluminum filtration (p = 0.411) was noted. A significant difference was detected between no filtration and aluminum-copper filtration (p = 0.012). The combination of an aluminum filter and a 75% standard dose achieved a 31.1% reduction in skin entrance dose. CONCLUSION: It is possible to achieve a 31.1% reduction in skin entrance dose for imaging bony structures by using 75% of the standard dose and aluminum filtration without significantly affecting image quality.

Dual energy CT for the assessment of reperfused chronic infarction - a feasibility study in a porcine model.

BACKGROUND: Detection of myocardial infarction has been the focus of considerable research over the past few decades. Recently developed dual source computed tomography (DSCT) scanners with dual energy mode have been used to detect myocardial infarction, but the studies on this topic are few. PURPOSE: To evaluate the feasibility and performance of dual energy CT (DECT) during arterial phase in coronary CT angiography for the detection of chronic infarction compared with late enhancement MRI (LE-MRI) and histopathology in a porcine model of reperfused myocardial infarction. MATERIAL AND METHODS: Myocardial infarctions were induced by 30 min occlusion of the proximal left anterior descending coronary artery in eight minipigs. DECT, post-contrast LE-MRI and histopathology were performed 60 days after infarct induction. The CT scan was performed in dual energy mode using a dedicated protocol. Myocardial iodine distribution was superimposed as color maps on grey scale multiplanar reformats of the heart. Two radiologists in consensus interpreted all imaging studies for presence of gadolinium uptake at LE-MRI reduced iodine content at DECT and hypoenhanced areas in the initial 100 kV coronary CT angiography images that were acquired during the DECT-acquisition. Results were compared with histopathology. RESULTS: Based on evaluable segments, DECT showed a sensitivity and specificity of 0.72 and 0.88; LE-MRI showed a sensitivity and specificity of 0.78 and 0.92; and the 100 kV data-set of the DECT scan showed a sensitivity and specificity of 0.60 and 0.93, respectively, for the detection of histological proved ischemia. CONCLUSION: DECT during arterial phase coronary CT angiography, which is ordinarily used for coronary artery evaluation, is feasible for the detection of a chronic reperfused myocardial infarction.

Accuracy of cardiovascular magnetic resonance in myocarditis: comparison of MR and histological findings in an animal model.

BACKGROUND: Because endomyocardial biopsy has low sensitivity of about 20%, it can be performed near to myocardium that presented as late gadolinium enhancement (LGE) in cardiovascular magnetic resonance (CMR). However the important issue of comparing topography of CMR and histological findings has not yet been investigated. Thus the current study was performed using an animal model of myocarditis. RESULTS: In 10 male Lewis rats experimental autoimmune myocarditis was induced, 10 rats served as control. On day 21 animals were examined by CMR to compare topographic distribution of LGE to histological inflammation. Sensitivity, specificity, positive and negative predictive values for LGE in diagnosing myocarditis were determined for each segment of myocardium. Latter diagnostic values varied widely depending on topographic distribution of LGE and inflammation as well as on the used CMR sequence. Sensitivity of LGE was up to 76% (left lateral myocardium) and positive predictive values were up to 85% (left lateral myocardium), whereas sensitivity and positive predictive value dropped to 0-33% (left inferior myocardium). CONCLUSIONS: Topographic distribution of LGE and histological inflammation seem to influence sensitivity, specificity, positive and negative predictive values. Nevertheless, positive predictive value for LGE of up to 85% indicates that endomyocardial biopsy should be performed "MR-guided". LGE seems to have greater sensitivity than endomyocardial biopsy for the diagnosis of myocarditis.

Uterine artery embolization: optimization with preprocedural prediction of the best tube angle obliquity by using 3D-reconstructed contrast-enhanced MR angiography.

PURPOSE: To evaluate the effect of preprocedural prediction of the best tube angle obliquity for visualization of the uterine artery origin by using three-dimensional (3D)-reconstructed contrast material-enhanced magnetic resonance (MR) angiography on the radiation dose, fluoroscopy time, and contrast medium volume during uterine artery embolization (UAE). MATERIALS AND METHODS: The study was approved by the institutional review board. Informed consent was obtained. The prospective study included 20 consecutive prospective patients (age range, 37-56 years) for whom preprocedural prediction of the best tube angle obliquity was determined by using 3D-reconstructed contrast-enhanced MR angiography; the best tube angle obliquity was provided to the interventionist. Three-dimensional reconstruction was performed by using an application of the angiographic unit. The radiation dose, fluoroscopy time, and contrast medium volume for those patients were compared with those data in 20 retrospectively assessed control patients (age range, 39-56 years) from the prior 20 procedures performed by the same interventionist. RESULTS: Tube angle prediction resulted in a significant reduction in the radiation dose utilized (P < .001), fluoroscopy time (P = .002), and contrast medium volume (P < .001) for the sample patients compared with those for the control patients. Overall radiation dose was reduced from a mean of 11 044 microGy per square meter to a mean of 4172.5 microGy per square meter. Fluoroscopy time was reduced from a mean of 15 minutes 30 seconds to 8 minutes 49 seconds. Contrast medium volume was reduced from a mean of 135 mL to 75 mL. CONCLUSION: Preprocedural prediction of the best tube angle obliquity for visualization of the origin of the uterine artery by using 3D-reconstructed contrast-enhanced MR angiography results in significant reductions in radiation dose, fluoroscopy time, and contrast medium volume during UAE.

Acute myocarditis in a rat model: late gadolinium enhancement with histopathological correlation.

The aim of the current study was to use an established animal model of autoimmune myocarditis and to judge the ability of cardiovascular MRI (CMR) in quantitatively measuring the extent of myocardial involvement compared with histopathological measurement of severity and extent. Experimental autoimmune myocarditis (EAM) was induced in 10 male Lewis rats. On day 21, all animals were investigated by CMR to measure the extent of late gadolinium enhancement (LGE). Subsequently, histopathological evaluation of the entire heart was performed. All animals of the experimental group fulfilled histopathological criteria of myocarditis, revealing necrosis in seven of eight cases. At reduced heart rate, area of LGE correlated highly with histologically proven area of myocarditis (r = 0.80-0.87, p < 0.05). LGE was mainly located in the anterior (range 50-62.5%) and lateral (range 62.5-75%) left ventricular wall and septum (range 25-50%) with a midwall to subepicardial accentuation. The LGE pattern found by CMR can be regarded as suggestive of EAM. With cellular necrosis being the main mechanism for LGE we were able to show high correlations between CMR examination results and histopathologically proven areas of myocarditis. Thus we think the current animal model can provide the opportunity for further fundamental research into myocarditis.

Risk factors involved in the development of pneumothorax during radiofrequency ablation of lung neoplasms.

OBJECTIVE: The purpose of this study was to retrospectively evaluate the risk factors involved in the development of pneumothorax during radiofrequency ablation of lung tumors. MATERIALS AND METHODS: This retrospective study covered 124 ablation sessions for lung tumors (10 primary lesions, 114 metastatic lesions) in 82 patients (46 men, 36 women; mean age, 64.0 years) treated between December 2005 and January 2008. The exclusion criteria for ablation therapy were lesions with a maximal diameter greater than 5 cm and the presence of more than five lesions. A bipolar electrode needle was used under CT guidance. Four patients were treated with two ablation electrodes simultaneously. RESULTS: The incidence of pneumothorax (detected with CT) was 11.3% (14 of 124 sessions). Pneumothorax was graded mild (lung surface retraction, < or = 2 cm), moderate (lung surface retraction, 2-4 cm), or severe (lung surface retraction, > or = 4 cm). Significant risk factors encountered in the development of pneumothorax were age greater than 60 years (p = 0.046), emphysema (p = 0.02), tumor diameter < or = 1.5 cm (p = 0.0008), lesions in lower part of lung, (p = 0.027), aerated lung parenchyma traversed by the needle track for a distance > or = 2.6 cm (p = 0.0017), and traversal of a major pulmonary fissure (p = 0.0004). Pneumothorax developed in one of the four patients in whom multiple electrodes were used. The mean depth of lung lesions complicated by pneumothorax was 2.9 +/- 1.55 cm (range, 0-5.5 cm). Conservative treatment was performed in four of the 14 pneumothorax sessions (28.6%). In six of the 14 sessions (42.9%), immediate complete evacuation was achieved with an intercostal catheter and manual evacuation; chest tube placement was indicated in four sessions (28.6%). Two patients were treated with manual evacuation because evidence of a progressive increase in pneumothorax on the 24-hour follow-up CT scan indicated failure of conservative treatment. CONCLUSION: The development of pneumothorax complicating radiofrequency ablation can be unpredictable, but the many risk factors involved can make the incidence higher among some patients than others. Some of these risk factors are technically avoidable and have to be ruled out.

Transpulmonary chemoembolization (TPCE) as a treatment for unresectable lung metastases.

To evaluate tumor response after treating unresectable lung metastases with transpulmonary chemoembolization (TPCE) in palliative intention. From 2001 to 2005, 52 patients (mean: 59.8 years; 32 males/20 females) suffering from 106 unresectable lung metastases (mean:6 metastases/patient; range,1-21) were treated with 2-10 TPCE-sessions (mean: 3.3 sessions/patient). Metastases originated from primaries, including colorectal carcinoma (n = 20), breast cancer (n = 6), renal cellular carcinoma (n = 5), thyroid cancer (n = 4), cholangiocellular carcinoma (n = 2), leiomyosarcoma (n = 2), and others (n = 13). Tumor-feeding pulmonary arteries were selectively probed after puncturing the femoral vein, and administering 10 ml lipiodol, mitomycin C, and microspheres (Spherex) each via balloon catheter over pulmonary approach. During therapy, follow-up was accomplished at 4-week intervals using unenhanced and contrast-enhanced CT. After sequential therapy, follow-up was performed every 3 months for a period of 6 months up to 2.25 years. All patients tolerated the treatments well without major side effects or complications. In 24% (n = 13) moderate to high lipiodol uptake was found, while 75% (n = 39) of the tumors showed a low uptake. According to the RECIST criteria, "partial response" was achieved in 16 cases, "stable disease" in 11 cases, and "progressive disease" in 25 cases [mean survival: 17 months/median: 21.1 months (Kaplan-Meyer)]. According to these findings, TPCE is a well-tolerated procedure for palliative treatment of unresectable lung metastases.

Statement and Recommendations on Interventional Ultrasound as a Thyroid Diagnostic and Treatment Procedure.

The recently published guidelines of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) on interventional ultrasound (INVUS)-guided procedures summarize the intended interdisciplinary and multiprofessional approach. Herewith, we report on recommendations for interventional procedures for diagnosis and treatment of the thyroid gland.

Study on the effect of chemoembolization combined with microwave ablation for the treatment of hepatocellular carcinoma in rats.

PURPOSE: We aimed to evaluate the combining effects of transarterial chemoembolization (TACE) and open local thermal microwave ablation in a hepatocellular carcinoma animal model. METHODS: Tumor cubes were implanted into the liver of 30 male inbred ACI rats. Groups of 10 animals were treated at 13 days (TACE or microwave ablation) and 16 days (microwave ablation) postimplantation with combined therapy of TACE (0.1 mg mitomycin C; 0.1 mg iodized oil; 5.0 mg degradable starch microspheres) and microwave ablation (2450 Mhz; 45 s; 35 W) (study group A), TACE alone (control group B), or microwave ablation alone (control group C). At day 12 and day 25 tumor size was measured via magnetic resonance imaging and the relative growth ratio was calculated. Hepatic specimens were immunohistochemically examined for the expression of vascular endothelial growth factor (VEGF). RESULTS: Mean growth rates were 1.34±0.19 in group A, 3.19±0.13 in group B, and 4.18±0.19 in group C. Compared with control groups B and C, tumor growth rate in group A was significantly inhibited (P < 0.01). The VEGF-antibody reaction in peritumoral tissue (staining intensity at portal triad, percent antibody reaction and staining intensity at central vein) was significantly lower in group A compared with group B (P < 0.01). No significant difference between group A and group C could be observed. CONCLUSION: This investigation shows improved results of TACE followed by microwave ablation as treatment of hepatocellular carcinoma in a rat model, compared with single therapy regimen regarding the inhibition of growth rate and reduction of VEGF-level in peritumoral tissue.

Volume reduction of benign thyroid nodules 3 months after a single treatment with high-intensity focused ultrasound (HIFU).

BACKGROUND: High-intensity focused ultrasound (HIFU) is a promising, non-invasive technique in treating benign thyroid nodules (TNs). The aim of this study was to evaluate the efficacy of HIFU to induce clinically meaningful shrinkage in benign predominantly solid TNs and to identify variables that influence or predict the magnitude of TN volume reduction. METHODS: For each of ten subjects, HIFU treatment was conducted on a single nodule. Nodular volume was measured sonographically at baseline and at 3 months post-procedure. Nodular function and early treatment assessment was done scintigraphically. RESULTS: Median nodular volume reduction was 0.7 ml absolute and 48.8% relative to pre-interventional size (p < 0.05). Absolute shrinkage was negatively correlated with the average treatment depth (τ = -0.61, p < 0.05). Absolute nodular volume was positively correlated with the scintigraphic nodular uptake reduction (τ = 0.66, p < 0.05). CONCLUSIONS: HIFU treatment of benign predominantly solid TNs appears to be safe and effective for inducing nodular shrinkage. Despite potential for improvement, a single treatment session with HIFU is already a viable alternative to more standard methods. The feasibility of multiple HIFU treatments requires further investigation. Due to the small sample size, the findings of this analysis need conformation by larger studies.

Early assessment of high-intensity focused ultrasound treatment of benign thyroid nodules by scintigraphic means.

BACKGROUND: High-intensity focused ultrasound (HIFU) allows to inflict intracorporal thermal lesions without penetrating the skin or damaging the surrounding tissue. This analysis intends to assess the magnitude of HIFU-induced ablations within benign thyroid nodules using scintigraphic imaging with (99m)Tc. METHODS: Ten cold, hot, or indifferent nodules were treated using multiple pulses of HIFU to induce temperatures of around 85°C within the ablation zone. Pre- and posttreatment, uptake values of (99m)Tc-pertechnetate or (99m)Tc-MIBI were recorded. The pre-post reduction of nodular uptake was evaluated to assess ablation magnitude. RESULTS: Relative nodular uptake in relation to total thyroidal uptake decreased after one session of HIFU in all cases. Median (99m)Tc-MIBI uptake reduction was 35.5% (ranging from 11% to 57%; p < 0.1), while (99m)Tc-pertechnetate scintigraphy showed a median uptake reduction of 27% (range 10% to 44%; p < 0.1). No major complications were observed. CONCLUSIONS: HIFU appears to be safe and is an easy to perform means of thermal ablation. This study shows that HIFU treatment in thyroidal nodules can be evaluated by scintigraphic means shortly after the intervention. Due to small sample size, the exact magnitude of HIFU ablation efficiency in thyroidal nodules remains a value to be assessed in a larger study.

Transferrin-coated gadolinium nanoparticles as MRI contrast agent.

PURPOSE: In this study, the contrasting properties of human serum albumin nanoparticles (HSA-NPs) loaded with gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and coated with transferrin in MRI in mice are evaluated. PROCEDURES: HSA-NPs were conjugated with Gd-DTPA (Gd-HSA-NPs) and coupled with transferrin (Gd-HSA-NP-Tf). Mice underwent MRI before or after injection of Gd-DTPA, Gd-HSA-NP, or Gd-HSA-NP-Tf. RESULTS: All the studied contrast agents provided a contrast enhancement (CE) in the blood, heart muscle, and liver. Compared to Gd-DTPA, CE with HSA-NP was achieved at lower Gd doses. Gd-HSA-NP-Tf yielded significantly higher CE than Gd-HSA-NP in the skeletal muscle, blood, cardiac muscle, and liver (p < 0.05). Gd-HSA-NP-Tf achieved a significantly higher CE than Gd-HSA-NP and Gd-DTPA in the blood, cardiac muscle, and liver (p < 0.05). In the brain, only Gd-HSA-NP-Tf was found to cause a significant CE (p < 0.05). CONCLUSIONS: The Gd-HSA nanoparticles have potential as MRI contrast agents. In particular, Gd-HSA-NP-Tf has a potential as a specific contrast agent for the brain, while the blood-brain barrier is still intact, as well as in the heart, liver, and skeletal muscle.

Correlation of left ventricular wall thickness, heart mass, serological parameters and late gadolinium enhancement in cardiovascular magnetic resonance imaging of myocardial inflammation in an experimental animal model of autoimmune myocarditis.

For a definitive diagnosis of myocarditis, different strategies like analysis of late gadolinium enhancement (LGE) in cardiovascular magnetic resonance imaging (CMR) up to invasive endomyocardial biopsy have been applied. The objective of the study was to investigate inflammatory changes like left ventricular wall thickening and increase of ventricular mass and to quantitatively analyse their correlation with extent and localisation of myocardial damage in CMR and with subsequent changes of serological markers in an animal model of an experimental autoimmune myocarditis (EAM). In the current study, an EAM was induced in 10 male Lewis rats, 10 rats served as control. On day 21, animals were examined with four CMR protocols to assess the extent of LGE in a 12 segment model of the rat heart. Left myocardial wall thickness and mass and histological grade of inflammation were measured to determine localisation and severity of the induced myocarditis. Depending on the CMR sequence, LGE was mostly found in the left anterior (9.6%) and left lateral (8.7%) myocardial wall segments. Wall thickness correlated with the LGE area in CMR imaging and the histopathological severity of myocarditis for the left lateral myocardial wall segment. In a similar way, the heart mass correlated to the extent of LGE for the left lateral segment. We conclude that in our animal model left ventricular wall thickness and mass reflect the severity of myocardial changes in myocarditis and that the EAM rat model is well suited for further investigations of myocarditis.

Gadoxetate acid-enhanced MRI of hepatocellular carcinoma in a c-myc/TGFα transgenic mouse model including signal intensity and fat content: initial experience.

Genetically engineered mouse models, such as double transgenic c-myc/TGFα mice, with specific pathway abnormalities might be more successful at predicting the clinical response of hepatocellular carcinoma (HCC) treatment. But a major drawback of the tumour models is the difficulty of visualizing endogenously formed tumours. The optimal imaging procedure should be brief and minimally invasive. Magnetic resonance imaging (MRI) satisfies these criteria and gadoxetate acid-enhanced MRI improves the detection of HCC. Fat content is stated to be an additional tool to help assess tumour responses, for example, in cases of radiofrequency ablation. Therefore the aim of this study was to investigate if gadoxetate acid-enhanced MRI could be used to detect HCC in c-myc/TGFα transgenic mice by determining the relation between the signal intensity of HCC and normal liver parenchyma and the corresponding fat content as a diagnostic marker of HCC. In our study, 20 HCC in c-myc/TGFα transgenic male mice aged 20-34 weeks were analyzed. On gadoxetate acid-enhanced MRI, the signal intensity was 752.4 for liver parenchyma and 924.5 for HCC. The contrast to noise ratio was 20.4, the percentage enhancement was 267.1% for normal liver parenchyma and 353.9% for HCC. The fat content was 11.2% for liver parenchyma and 16.2% for HCC. There was a correlation between fat content and signal intensity with r = 0.7791. All parameters were statistically significant with P < 0.05. Our data indicate that gadoxetate acid contrast enhancement allows sensitive detection of HCC in c-myc/TGFα transgenic mice and determination of the fat content seems to be an additional useful parameter for HCC.

Reduced efficacy of the Plk1 inhibitor BI 2536 on the progression of hepatocellular carcinoma due to low intratumoral drug levels.

Highly promising preclinical data obtained in cultured cells and in nude mice bearing xenografts contrast with the rather modest clinical efficacy of Polo-like kinase 1 (Plk1) inhibitors. In the present study, we investigated if Plk1 might be a suitable target in hepatocellular carcinoma (HCC) and if a genetically engineered mouse tumor model that well reflects the tumor cell and micro-environmental features of naturally occurring cancers might be suitable to study anti-Plk1 therapy. Analysis of Plk1 expression in human HCC samples confirmed that HCC express much higher Plk1 levels than the adjacent normal liver tissue. Inhibition of Plk1 by an adenovirus encoding for a short hairpin RNA against Plk1 or by the small-molecule inhibitor BI 2536 reduced the viability of HCC cell lines and inhibited HCC xenograft progression in nude mice. Treatment of transforming growth factor (TGF) α/c-myc bitransgenic mice with BI 2536 during hepatocarcinogenesis reduced the number of dysplastic foci and of Ki-67-positive cells within the foci, indicating diminished tumorigenesis. In contrast, BI 2536 had no significant effect on HCC progression in the transgenic mouse HCC model as revealed by magnetic resonance imaging. Measurement of BI 2536 by mass spectrometry revealed considerably lower BI 2536 levels in HCC compared with the adjacent normal liver tissue. In conclusion, low intratumoral levels are a novel mechanism of resistance to the Plk1 inhibitor BI 2536. Plk1 inhibitors achieving sufficient intratumoral levels are highly promising in HCC treatment.