Comparative Assessment of the Activity of Racemic and Dextrorotatory Forms of Thioctic (Alpha-Lipoic) Acid in Low Back Pain: Preclinical Results and Clinical Evidences From an Open Randomized Trial.

Peripheral neuropathies, characterized by altered nociceptive and muscular functions, are related to oxidative stress. Thioctic acid is a natural antioxidant existing as two optical isomers, but most clinically used as racemic mixture. The present study investigated the central nervous system's changes which followed loose-ligation-derived compression of sciatic nerve, the putative neuroprotective role of thioctic acid and the pain-alleviating effect on low-back pain suffering patients. Loose ligation of the right sciatic nerve was performed in spontaneously hypertensive rats (SHR), a model of increased oxidative stress, and in normotensive Wistar-Kyoto rats (WKY). Animals with sciatic nerve ligation were left untreated or were treated intraperitoneally for 15 days with 250 µmol·kg-1·die-1 of (+/-)-thioctic acid; 125 µmol·kg-1·die-1 of (+/-)-thioctic acid; 125 µmol·kg-1·die-1 of (+)-thioctic acid lysine salt; 125 µmol·kg-1·die-1 of (-)-thioctic acid; 300 µmol·kg-1·die-1 pregabalin. Control SHR and WKY rats received the same amounts of vehicle. The clinical trial NESTIORADE (Sensory-Motor Neuropathies of the Sciatic Nerve: Comparative evaluation of the effect of racemic and dextro-rotatory forms of thioctic acid) examined 100 patients (49 males and 51 females aged 53 ± 11 years) dividing them into two equal-numbered groups, each treated daily for 60 days with 600 mg of (+/-)-thioctic acid or (+)-thioctic acid, respectively. The trial was registered prior to patient enrollment at EudraCT website (OSSC Number: 2011-000964-81). In the preclinical study, (+)-thioctic acid was more active than (+/-)- or (-)-enantiomers in relieving pain and protecting peripheral nerve as well as in reducing oxidative stress and astrogliosis in the spinal cord. Main findings of NESTIORADE clinical trial showed a greater influence on painful symptomatology, a quicker recovery and a better impact on quality of life of (+)-thioctic acid vs. (+/-)-thioctic acid. These data may have a pharmacological and pharmacoeconomical relevance and suggest that thioctic acid, above all (+)-enantiomer, could be considered for treatment of low-back pain involving neuropathy.

Rapid switching kVp dual energy CT: Value of reconstructed dual energy CT images and organ dose assessment in multiphasic liver CT exams.

PURPOSE: Clinical applications of dual energy computed tomography (DECT) have been widely reported; however, the importance of the different image reconstructions and radiation organ dose remains a relevant area of investigation, particularly considering the different commercially available DECT equipment. Therefore, the purpose of this study was to assess the image reliability and compare the information content between several image reconstructions in a rapid-switching DECT (rsDECT), and assess radiation organ dose between rsDECT and conventional single-energy computed tomography (SECT) exams. MATERIALS AND METHODS: This Institutional Review Board-approved retrospective study included 98 consecutive patients who had a history of liver cancer and underwent multiphasic liver CT exams with rsDECT applied during the late arterial phase between June 2015 and December 2015. Virtual monochromatic 70 keV, material density images (MDI) iodine (-water) and virtual unenhanced (VUE) images were generated. Radiation dose analysis was performed in a subset of 44 patients who had also undergone a multiphasic SECT examination within 6 months of the rsDECT. Four board-certified abdominal radiologists reviewed 24-25 patients each, and a fifth radiologist re-evaluated all the scans to reach a consensus. The following imaging aspects were assessed by the radiologists: (a) attenuation measurements were made in the liver and spleen in VUE and true unenhanced (TUE) images; (b) subjective evaluation for lesion detection and conspicuity on MDI iodine (-water)/VUE images compared with the virtual monochromatic images/TUE images; and (c) overall image quality using a five-point Likert scale. The radiation dose analyses were evaluated in the subset of 44 patients regarding the following parameters: CTDIvol, dose length product, patient's effective diameter and organ dose using a Monte Carlo-based software, VirtualDose™ (Virtual Phantoms, Inc.) to 21 organs. RESULTS: On average, image noise on the TUE images was 49% higher within the liver (p < 0.0001) and 48% higher within the spleen (p < 0.0001). CT numbers for the spleen were significantly higher on VUE images (p < 0.0001). Twenty-eight lesions in 24/98 (24.5%) patients were not observed on the VUE images. The conspicuity of vascular anatomy was considered better on MDI iodine (-water) Images 26.5% of patients. Using the Likert scale, the rsDECT image quality was considered to be satisfactory. Considering the subset of 44 patients with recent SECT, the organ dose was, on average, 37.4% less with rsDECT. As the patient's effective diameter decreased, the differences in dose between the rsDECT and SECT increased, with the total average organ dose being less by 65.1% when rsDECT was used. CONCLUSION: VUE images in the population had lower image noise than TUE images; however, a few small and hyperdense findings were not characterized on VUE images. Delineation of vascular anatomy was considered better in around a quarter of patients on MDI iodine (-water) images. Finally, radiation dose, particularly organ dose, was found to be lower with rsDECT, especially in smaller patients.

Fetal lung maturity assessment with MRI fetal lung-to-liver signal-intensity ratio.

OBJECTIVE: The purpose of this study was to retrospectively determine whether the ratio of fetal lung-to-liver signal intensities at single-shot fast spin-echo MRI is associated with fetal gestational age. MATERIALS AND METHODS: All fetal MRI examinations over a 4-year period were reviewed. All MRI examinations were performed with a 1.5-T magnet for indications other than lung maturity. Only examinations performed with a single-shot fast spin-echo sequence of the fetal chest and abdomen were included in the study. Images from a total of 82 fetal MRI examinations were evaluated. Gestational age ranged from 20 weeks to 39 weeks 3 days. Two board-certified subspecialty-trained radiologists with 11 and 17 years of experience blinded to estimated gestational age (EGA) reviewed the images independently. The regions of interest (ROIs) of the fetal lung and liver were drawn in the same plane and on the same image in each case. Fetal EGA was determined either by first-trimester ultrasound when available or by last menstrual period. Linear regression analysis was used to analyze the relation between the lung-to-liver signal-intensity ratio (LLSIR) in the ROIs and fetal EGA for both readers. The association between the LLSIRs estimated by the two readers was assessed by Bland-Altman plot. RESULTS: Summary statistics for LLSIR showed a median value of 2.29 for reader 1 and 2.21 for reader 2. The mean value for reader 1 was 2.4 and for reader 2 was 2.5. The Pearson correlation coefficients between the LLSIR and EGA variables were 0.44 for reader 1 and 0.45 for reader 2. Linear regression analysis showed a statistically significant association between LLSIR and EGA for both readers (p < 0.0004). This ratio increased in a linear manner as EGA progressed. CONCLUSION: Fetal LLSIR at single-shot fast spin-echo MRI is associated with fetal gestational age.

Serial diffusion-weighted MRI in patients with hepatocellular carcinoma: Prediction and assessment of response to transarterial chemoembolization. Preliminary experience.

OBJECTIVE: To assess the role of apparent diffusion coefficient (ADC) measured with diffusion-weighted imaging (DWI) in predicting and assessing response of hepatocellular carcinoma (HCC) to transarterial chemoembolization (TACE). METHODS: Thirty-six patients with cirrhosis and untreated HCC who underwent TACE and MRI within 3 months before and after TACE were assessed. MRI included DWI and contrast-enhanced T1-weighted imaging. Two observers measured ADC of HCCs and liver parenchyma on pre- and post-TACE MRIs and measured degree of tumor necrosis on subtracted post-contrast images on post-TACE MRI. Pre-, post-TACE tumor ADC, and changes in tumor ADC (ΔADC) were compared between lesions stratified by degree of tumor necrosis (measured on post-TACE MRI). RESULTS: Forty seven HCCs were evaluated (mean size 4.4cm, range 1.0-14.1cm). HCCs with poor and incomplete response to TACE (<50% necrosis on post-TACE MRI) had significantly lower pre-treatment ADC and lower post TACE ADC compared to HCCs with good/complete response (≥50% necrosis): ADC pre-TACE 1.35±0.42 vs. 1.64±0.39×10(-3)mm(2)/s (p=0.042); post-TACE ADC 1.34±0.36 vs. 1.92±0.47 (p=0.0008). There was no difference in ΔADC values. CONCLUSION: This preliminary data suggests that pre-TACE tumor ADC can be used to predict HCC response to TACE.

Assessment of the liver strain among cirrhotic and normal livers using tagged MRI.

PURPOSE: To use magnetization tagged magnetic resonance imaging (MRI) (tag-MRI) to quantify cardiac induced liver strain and compare strain of cirrhotic and normal livers. MATERIALS AND METHODS: Tag-MRI was performed at 1.5T on eight subjects with no history of liver disease and 10 patients with liver cirrhosis. A breath-hold peripheral pulse-gated (PPG) conventional tag-MRI cine sequence was performed with planes to include the left lobe of the liver and the inferior wall of the heart. Commercially available software HARP (Diagnosoft, Palo Alto, CA) was used for image analysis and strain calculation. Three regions-of-interest (ROIs) were selected: segment II of the liver near the heart (A), right liver lobe far from the heart (B), and the left ventricular wall (C). The average and maximal (max) strain were measured in A, B, and C. The maximum strains were used to generate a cardiac-corrected strain gradient: (maxA-maxB)/maxC. Results were compared with Student's t-test (SPSS, Chicago, IL). RESULTS: In subjects with no history of liver disease vs. cirrhotic patients, the average strain was 22% ± 7% vs. 4% ± 3% (P < 0.001), the max strain was 63% ± 15% vs. 17% ± 5% (P < 0.001), and the corrected strain gradient was 0.52 ± 0.16 vs. 0.11% ± 0.08%. CONCLUSION: There is a significant difference in liver strain measured with tag-MRI between subjects with no history of liver disease and patients with cirrhosis.

Liver stiffness assessment by tagged MRI of cardiac-induced liver motion.

Cirrhosis is an important and growing public health problem, affecting millions of Americans and many more people internationally. A pathological hallmark of the progression to cirrhosis is the development of liver fibrosis, so that monitoring the appearance and progression of liver fibrosis can be used to guide therapy. Here, we report a method to use magnetization-tagged magnetic resonance imaging to measure the cardiac-induced motion and deformation in the liver, as a means for noninvasively assessing liver stiffness, which is related to fibrosis. The initial results show statistically significant differences between healthy and cirrhotic subjects in the direct comparisons of the maximum displacement (mm), and the maximum (P1) and minimum (P2) two-dimensional strains, through the cardiac cycle (3.514 ± 0.793, 2.184 ± 0.611; 0.116 ± 0.043, 0.048 ± 0.011; -0.094 ± 0.020, -0.041 ± 0.015; healthy, cirrhosis, respectively; P < 0.005 for all). There are also significant differences in the displacement-normalized P1 and P2 strains (mm(-1) ) (0.030 ± 0.008, 0.017 ± 0.007; -0.024 ± 0.006, -0.013 ± 0.004; healthy, cirrhosis, respectively; P < 0.005 for all). Therefore, this noninvasive imaging-based method is a promising means to assess liver stiffness using clinically available imaging tools.

Hepatocellular carcinoma: assessment of response to transarterial chemoembolization with image subtraction.

PURPOSE: To assess the diagnostic accuracy of image subtraction compared with nonsubtracted images obtained with contrast-enhanced T1-weighted imaging (CE T1WI) for the diagnosis of hepatocellular carcinoma (HCC) necrosis after transarterial chemoembolization (TACE), using liver explant as the reference standard. MATERIALS AND METHODS: Thirty-four patients who underwent TACE within 90 days of liver transplantation and CE MRI scans were assessed by two independent observers who determined the percentage of tumor necrosis using nonsubtracted and subtracted postcontrast phases. Histopathologic percentage of necrosis was retrospectively determined by an experienced pathologist. Spearman rank correlation test was used to correlate the percentages of necrosis from MR evaluation and from pathology. Receiver operating characteristics curve analysis was performed to determine the performance of subtracted versus nonsubtracted datasets for the diagnosis of complete tumor necrosis. RESULTS: There were 57 HCCs (mean size, 2.4 cm; range, 1.2-4.2 cm) diagnosed at explant and identified on MRI, including 16 completely necrotic HCCs. Subtraction demonstrated better interobserver agreement than nonsubtraction dataset for the diagnosis of tumor necrosis. There was a strong correlation between image subtraction and histopathologic assessment of necrosis (r = 0.80-0.86, depending on the phase, P < 0.0001). Subtraction demonstrated significantly higher sensitivity and accuracy for the diagnosis of complete tumor necrosis compared with nonsubtracted dataset. CONCLUSION: Image subtraction enables accurate assessment of necrosis of HCC after TACE with the best accuracy observed at the arterial phase.

Assessment of tumor necrosis of hepatocellular carcinoma after chemoembolization: diffusion-weighted and contrast-enhanced MRI with histopathologic correlation of the explanted liver.

OBJECTIVE: The purpose of this study was to compare, with histopathologic examination of the liver explant as the reference standard, diffusion-weighted MRI with contrast-enhanced subtraction MRI in the assessment of necrosis of hepatocellular carcinoma (HCC) after trans arterial chemoembolization (TACE). MATERIALS AND METHODS: The cases of 21 patients with HCC who underwent MRI after TACE were evaluated. Two independent observers calculated the apparent diffusion coefficient (ADC) of HCC and measured percentage tumor necrosis on subtraction images. The ADCs of necrotic and viable tumor tissues were compared. ADC and percentage necrosis on subtraction images were correlated with percentage necrosis found at pathologic examination. Receiver operating characteristics analysis was performed on the diagnosis of complete tumor necrosis. RESULTS: Twenty-eight HCCs (mean diameter, 2.3 cm) were evaluated. There were significant differences between the ADC of viable tissue and that of necrotic tumor tissue (1.33 +/- 0.41 vs 2.04 +/- 0.38 x 10(-3) mm(2)/s, p < 0.0001). There was significant moderate correlation between ADC and the pathologic finding of percentage necrosis (r = 0.64, p < 0.001) and significant strong correlation between subtraction image and pathologic percentage necrosis (r = 0.89-0.91, depending on the phase; p < 0.001). In the diagnosis of complete tumor necrosis, ADC had an area under the curve, sensitivity, and specificity of 0.85, 75%, and 87.5% compared with 0.82-0.89, 100%, and 58.3-79.1% for subtraction imaging (p > 0.5 between ADC and subtraction imaging). CONCLUSION: Compared with diffusion-weighted imaging, contrast-enhanced MRI with subtraction technique had more significant correlation with the histopathologic findings in the evaluation of necrosis of HCC after TACE. There was no difference, however, between the two methods in diagnosis of complete tumor necrosis.