Randomised clinical trial: a leucine-metformin-sildenafil combination (NS-0200) vs placebo in patients with non-alcoholic fatty liver disease.

BACKGROUND: Sirtuin 1 (Sirt1) is suppressed in non-alcoholic fatty liver disease (NAFLD), while its' stimulation or overexpression results in reduced disease severity in pre-clinical NAFLD models. Leucine allosterically activates Sirt1 and synergise with other Sirt/AMPK/NO pathway activators. We developed a triple combination of leucine, metformin and sildenafil (NS-0200), which was effective in a mouse model of non-alcoholic steatohepatitis (NASH). AIM: To report the results from a Phase 2, randomised clinical trial of of NS-0200 in 91 subjects with NAFLD (liver fat ≥15% by magnetic resonance imaging-proton-density fat fraction (MRI-PDFF)). METHODS: Subjects were randomised to placebo, low-dose (1.1 g leucine/0.5 g metformin/0.5 mg sildenafil) or high-dose NS-0200 (1.1 g leucine/0.5 g metformin/1.0 mg sildenafil) b.d. for 16 weeks; change in hepatic fat was assessed via MRI-PDFF, and lipid metabolism was assessed via changes in the lipidomic signature. Seventy subjects completed the trial and met a priori compliance criteria. Analyses were conducted on the full cohort and on those with alanine aminotransferase (ALT) values above median (50 U/L; n = 35). RESULTS: In the full cohort, active treatments did not separate from placebo. High dose NS-0200 reduced hepatic fat by 15.7% (relative change from baseline) in the high ALT group (P < 0.005) while low dose NS-0200 and placebo did not significantly change hepatic fat. Lipidomic analysis showed dose-responsive treatment effects in both overall and high ALT cohorts, with significant decreases in metabolically active lipids and up-regulation of fatty acid oxidation. CONCLUSION: These data support further evaluation of high-dose NS-0200 for treating NASH, especially in those with elevated ALT (NCT 02546609).

Bone marrow fat content is correlated with hepatic fat content in paediatric non-alcoholic fatty liver disease.

AIM: To investigate the relationship between bone marrow fat content and hepatic fat content in children with known or suspected non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: This was an institutional review board-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant, cross-sectional, prospective analysis of data collected between October 2010 to March 2013 in 125 children with known or suspected NAFLD. Written informed consent was obtained for same-day research magnetic resonance imaging (MRI) of the lumbar spine, liver, and abdominal adiposity. Lumbar spine bone marrow proton density fat fraction (PDFF) and hepatic PDFF were estimated using complex-based MRI (C-MRI) techniques and magnitude-based MRI (M-MRI), respectively. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SCAT) were quantified using high-resolution MRI. All images were acquired by two MRI technologists. Hepatic M-MRI images were analysed by an image analyst; all other images were analysed by a single investigator. The relationship between lumbar spine bone marrow PDFF and hepatic PDFF was assessed with and without adjusting for the presence of covariates using correlation and regression analysis. RESULTS: Lumbar spine bone marrow PDFF was positively associated with hepatic PDFF in children with known or suspected NAFLD prior to adjusting for covariates (r=0.33, p=0.0002). Lumbar spine bone marrow PDFF was positively associated with hepatic PDFF in children with known or suspected NAFLD (r=0.24, p=0.0079) after adjusting for age, sex, body mass index z-score, VAT, and SCAT in a multivariable regression analysis. CONCLUSION: Bone marrow fat content is positively associated with hepatic fat content in children with known or suspected NAFLD. Further research is needed to confirm these results and understand their clinical and biological implications.

A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis.

BACKGROUND: Children with non-alcoholic steatohepatitis are insulin-resistant and metformin has been proposed as a potential therapy. However, paediatric safety and efficacy data are absent. AIM: To test the hypothesis that metformin therapy will safely improve markers of liver disease in paediatric non-alcoholic steatohepatitis. METHODS: Single-arm open-label pilot study of metformin 500 mg twice daily for 24 weeks in non-diabetic children with biopsy-proven non-alcoholic steatohepatitis. RESULTS: Ten obese children (mean body mass index 30.4) enrolled and completed the trial. Mean alanine aminotransferase and aspartate aminotransferase (AST) improved significantly (P < 0.01) from baseline (184, 114 U/L) to end of treatment (98, 68 U/L). Alanine aminotransferase normalized in 40% and AST normalized in 50% of subjects. Children demonstrated significant improvements in liver fat measured by magnetic resonance spectroscopy (30-23%, P < 0.01); insulin sensitivity measured by quantitative insulin sensitivity check index (0.294-0.310, P < 0.05); and quality of life measured by pediatric quality of life inventory 4.0 (69-81, P < 0.01). CONCLUSION: Open-label treatment with metformin for 24 weeks was notable for improvement in liver chemistry, liver fat, insulin sensitivity and quality of life. A large randomized-controlled trial is needed to definitively determine the efficacy of metformin for paediatric non-alcoholic steatohepatitis.

Silicone gel breast implant rupture, extracapsular silicone, and health status in a population of women.

OBJECTIVE: To assess whether breast implant rupture or extracapsular silicone are associated with selected symptoms of self-reported physician-diagnosed connective tissue disease (CTD). METHODS: Women with silicone gel breast implants responded to a questionnaire that included questions on health status, satisfaction with implants, symptoms of CTD, and physician-diagnosed disease. These women then had magnetic resonance imaging (MRI) of their breasts to determine the status of the implants with respect to rupture and extracapsular silicone. RESULTS: Women with breast implant rupture diagnosed by MRI were no more likely to report a diagnosis of selected CTD than those with intact implants or those with implants of indeterminate status. Women with extracapsular silicone (silicone gel outside of the fibrous scar that forms around breast implants) were more likely to report having fibromyalgia (FM, p = 0.004) or other CTD, which included dermatomyositis, polymyositis, Hashimoto's thyroiditis, mixed CTD, pulmonary fibrosis, eosinophilic fasciitis, and polymyalgia (p = 0.008) than other women in the study. The association with FM remained statistically significant when adjusted for multiple comparisons (7 diagnoses) and implant age, implant location, or implant manufacturer (p < 0.05 in all cases), but became of borderline statistical significance when adjusted for multiple comparisons and self-perceived health status (p = 0.094) or self-perceived rupture status (p = 0.051). The association with other CTD remained statistically significant when adjusted for multiple comparisons and implant location or implant manufacturer, but became borderline or insignificant when adjusted for multiple comparisons and for implant age (p = 0.051), self-perceived health status (p = 0.434), or self-perceived rupture status (p = 0.145). Logistic regression was used to compute odds ratios of self-reported diagnoses comparing women with and without extracapsular silicone. The odds ratios were 2.8 (95% CI 1.2 to 6.3) for FM, and 2.6 (95% CI 0.8 to 8.5) for other CTD after adjustment for implant age, implant location, implant manufacturer, implant type, self-perceived health, self-perceived rupture status, and site of surgery practice. CONCLUSION: These data suggest an association between extracapsular silicone from ruptured silicone breast implants and FM. If this association persists in other studies, women with silicone gel breast implants should be informed of the potential risk of developing fibromyalgia if their breast implants rupture and the silicone gel escapes the fibrous scar capsule.

Prevalence of rupture of silicone gel breast implants revealed on MR imaging in a population of women in Birmingham, Alabama.

OBJECTIVE: Silicone gel breast implants have been reported to rupture, but the prevalence of implant rupture in an unreferred population of women is not known. The objective of this study was to assess the prevalence of implant rupture and the presence of extracapsular silicone gel in an unreferred population of women without regard to the absence or presence of any local or systemic symptoms. SUBJECTS AND METHODS: Women identified as part of a National Cancer Institute cohort study on breast implants, living in the Birmingham, AL, area were invited to undergo MR imaging of their current silicone gel breast implants at the Kirklin Clinic at the University of Alabama at Birmingham. Three radiologists independently examined and rated all MR images for signs of implant rupture and extracapsular silicone. RESULTS: A total of 344 women with silicone gel breast implants underwent MR imaging. Breast implant rupture was reported by at least two of three radiologists for 378 (55.0%) of the 687 implants in this study. Another 50 implants (7.2%) were rated as indeterminate (suspicious) for rupture. A majority of women in this study, 265 (77.0%) of 344, had at least one breast implant that was rated as ruptured or indeterminate. Radiologists also agreed that silicone gel could be seen outside the fibrous capsule that forms around the implant in 85 (12.4%) of the 687 implants affecting 73 women (21.2%). Factors that affected implant rupture were implant age and location (submuscular or subglandular). The median implant age at rupture was estimated to be 10.8 years with a 95% confidence interval of 8.4-13.9 years. CONCLUSION: The prevalence of silent or occult silicone gel breast implant rupture is higher than was previously suspected. Most women in this study had MR imaging evidence of at least one ruptured silicone gel breast implant.

Magnetic resonance evaluation of breast implants and soft-tissue silicone.

After several years of research in many disciplines, concern for the safety of silicone gel-filled breast implants continues. Although systemic effects of silicone are debated, there is growing consensus that implant rupture and other local breast complications from implants are very real concerns. This paper reviews the history of breast augmentation with an emphasis on the great variety of implants manufactured during the last generation. A classification scheme consisting of 14 breast implant categories is described, and the MR appearance of many is illustrated. The MR signs of implant rupture and pitfalls associated with those signs are reviewed. Indications and contraindications for MR imaging of implants and soft tissue silicone are presented. The author's breast implant and soft-tissue silicone MR imaging experience with follow-up surgical experience over the last 6 years is summarized and discussed. For 1,626 single lumen silicone gel-filled implants imaged, the sensitivity for rupture was 74% and the specificity was 98%. For those implants, 64.9% showed no evidence rupture on MR, 7.9% were indeterminate, and 27.2% were definitely ruptured. Of those that were ruptured, 26.2% had silicone outside as well as within the fibrous capsule. Of the 442 implants that were shown to be ruptured, 54.8% were in a state of uncollapsed rupture, 12.9% minimally collapsed rupture, 4.1% partially collapsed rupture, and 28.3% fully collapsed rupture.

Quantitative analysis of signal intensities and contrast after fat suppression in contrast-enhanced magnetic resonance imaging of the spine.

RATIONALE AND OBJECTIVES: We studied the effect of fat suppression on signal intensity and contrast on contrast-enhanced magnetic resonance (MR) images of the spine. METHODS: Contrast-enhanced T1-weighted MR images were obtained at identical levels with and without fat suppression. Signal intensity and contrast were measured in regions of interest in fat, muscle, spinal bone marrow, and enhancing lesions. The differences in the mean values of these signal intensities and the mean values of contrast between enhanced tissues and bone marrow, fat, and muscle were subjected to statistical validation. RESULTS: Mean signal intensity of the extraspinal fat and bone marrow was lower after fat suppression (70% and 46% reduction, p < .001 and p < .05, respectively), whereas the signal intensity of muscle showed no significant change (p < .9). Enhancing spinal lesions showed a difference in mean signal intensity after fat suppression (22% increase, p < .2). Contrast between enhanced lesions and bone marrow and fat was higher after fat suppression (78% increase, p < .01 for bone marrow; 8% increase, p < .001 for fat). CONCLUSION: In contrast-enhanced MR examinations of the spine, the use of fat suppression may increase the signal intensity of the enhancing lesion by expanding the dynamic gray scale of the image and increases the contrast between the lesion and adjacent bone marrow and suppressed fat.

Fat-suppression contrast-enhanced MRI in the failed back surgery syndrome: a prospective study.

We examined 25 patients with recurrent pain after lumbar disk surgery with MRI to evaluate the usefulness of gadolinium (Gd)-enhanced fat-suppression (FS) imaging in patients with failed back surgery. Pulse sequences included T1-weighted (T1W) images, Gd-enhanced T1W images, and Gd-enhanced T1W images with FS. The addition of FS to Gd-enhanced T1W images improved visualization of enhancing scar in all cases, helped distinguish scar from recurrent herniated disk, and showed more clearly the relationship of scar to the nerve roots and thecal sac. The images also demonstrated enhancement of the facet joints and theca in 23 and 11 cases, respectively. Intradural nerve roots were more conspicuous with FS in 21 cases. The combination of unenhanced and Gd-enhanced T1W images with FS is recommended for routine examination of the postoperative back.

Clinical impact of breast implant magnetic resonance imaging.

Magnetic resonance imaging has become the state-of-art technique to diagnose the loss of silicone gel-filled mammary implant integrity (rupture, gel leak). In a series of 39 patients considering implant removal (40 procedures, 74 devices), the impact of magnetic resonance imaging on the decisions made by the patient and surgeon was examined. In this selected group of patients, implant rupture or gel leak was found in 17 patients (16 grossly ruptured devices and 7 with gel leak). In 9 (53%) of these patients, magnetic resonance imaging was the decisive factor leading to the request for explantation by the patient. Diagnosis of implant rupture based on history and physical examination was made in 4 patients (confirmed in 3 and negated by magnetic resonance imaging and intraoperatively in 1). In 10 of the 14 remaining patients (26%) with "unexpected" loss of implant integrity (negative history and physical examination), magnetic resonance imaging evidence was the decisive factor for advising explantation by the surgeon. Negative magnetic resonance imaging results did not influence the patient's or surgeon's decisions. Magnetic resonance imaging appears to be a sensitive and specific technique, and there were no false-negative and one false-positive (gel-leak diagnosis) findings in this series.

Diagnosis of fatty liver with MR imaging.

The diagnosis of fatty liver with magnetic resonance (MR) imaging was evaluated in experimental rat models of simple fatty infiltration and fatty liver with hepatocellular injury. T1 and T2 were measured ex vivo and correlated with the histologic degree of fatty infiltration. Enhancement of fatty liver with four different cells-specific contrast agents was studied with ex vivo relaxometry and in vivo MR imaging. Quantitative analysis of conventional and chemical shift MR images was correlated with biochemically determined fat content of the liver. Diet-induced simple fatty infiltration of the liver caused a decrease in T1 of 15%, whereas the T1 of L-ethionine-induced fatty liver with hepatocellular injury increased by 12%. T2 showed a positive correlation with the degree of fatty infiltration in both models. Cell-specific hepatobiliary contrast agents showed the same liver uptake and relaxation enhancement in fatty livers as in normal livers. Conventional T1-weighted images and chemical shift images showed good correlation (r = .83 and .80, respectively) between signal intensity and the degree of fatty infiltration. However, only chemical shift imaging was reliable in the diagnosis of fatty liver.

Increased detection of intracranial metastases with intravenous Gd-DTPA.

Three patients with intracranial metastases were studied with magnetic resonance imaging at 1.5 T before and after intravenous administration of 0.1 mmol/kg gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA). Axial pre- and postcontrast images demonstrated a total of six and 38 metastases, respectively. Of the 35 lesions detected only after administration of contrast material, all were less than 10 mm, and none had evidence of surrounding edema. Lesion conspicuity was comparable on postcontrast mixed (T1, proton density, and T2) images and T1-weighted images, indicating the feasibility of effectively screening for metastases with a single postcontrast spin-echo sequence providing mixed and T2-weighted images. Sagittal and coronal images depicted temporal lobe lesions not seen on axial images. No discomfort, side effects, or complications resulted from the contrast medium. The detection of additional lesions with Gd-DTPA increased the radiologic suspicion of metastatic disease, revealed locations more favorable for biopsy, prompted the search for a primary tumor, and modified therapeutic objectives and methods.

Detection of hepatic metastases: analysis of pulse sequence performance in MR imaging.

Forty-three patients with liver metastases were imaged using 14 different pulse sequences (average, 7.5 sequences per patient) to allow direct comparison of their performance. "T2-weighted" spin-echo (SE) images, "T1-weighted" inversion recovery (IR) images, and "T1-weighted" SE images were obtained using a wide range of timing parameters. Pulse sequence performance was quantitated by measuring liver signal-to-noise (S/N) ratios and cancer-liver signal difference-to-noise (SD/N) ratios. Data were standardized to reflect a constant imaging time of 9 minutes for all pulse sequences. The SE 2,000/120 (TR [repetition time]/TE [echo time]) sequence resulted in the greatest SD/N ratio of the T2-weighted SE sequences but also yielded the low S/N ratios, poor anatomic resolution, and motion artifacts common to all T2-weighted SE images. IR sequence images were also sensitive to motion artifacts because of the use of a long TR (1,500 msec). Short TR/TE T1-weighted SE sequences (SE 260/18) had the greatest SD/N ratio (P less than .05), S/N ratio, and anatomic resolution. Furthermore, extensive signal averaging appears to be a powerful solution to all types of motion artifacts in the abdomen.

Liver metastases: detection by phase-contrast MR imaging.

Forty patients with biopsy-proved metastatic liver cancers were studied by magnetic resonance (MR) imaging using one or more conventional (in-phase) pulse sequences and a corresponding phase-contrast (opposed-phase) pulse sequence. Pulse-sequence performance was quantitated by measuring signal-difference-to-noise (SD/N) ratios between cancerous tissue and liver. The SD/N performance of T2-weighted spin-echo (SE) pulse sequences improved when used with the phase-contrast technique. SE 2,000/30 opposed-phase images showed improved (P less than .001) SD/N in 72% of patients over in-phase images. The SD/N of T1-weighted SE or inversion recovery pulse sequences deteriorated when used with the phase-contrast technique. Changes in measured SD/N correlated well with image appearance and actual lesion detectability in individual cases. Phase-contrast imaging should be employed routinely when T2-weighted SE pulse sequences are relied on to detect liver cancer.