Assessing strategies to target screening for advanced liver fibrosis among overweight and obese patients

Aim: The optimal screening strategy for advanced liver fibrosis in overweight and obese patients is unknown. The aim of this study is to compare the performance of different strategies to select patients at high risk of advanced liver fibrosis for screening using non-invasive tools.Methods: All patients underwent: liver 1H-MRS and percutaneous liver biopsy (in those with nonalcoholic fatty liver disease [NAFLD]). Unique selection strategies were compared to determine the best screening algorithm: (A) A "metabolic approach": selecting patients based on HOMA-IR ≥ 3; (B) A "diabetes approach": selecting only patients with type 2 diabetes; (C) An "imaging approach": selecting patients with hepatic steatosis based on 1H-MRS; (D) A "liver biochemistry approach": selecting patients with elevated ALT (i.e., ≥ 30 IU/L for males and ≥ 19 IU/L for females); and (E) Universal screening of overweight and obese patients. FIB-4 index, NAFLD fibrosis score, and APRI were applied as screening strategies.Results: A total of 275 patients were included in the study. Patients with advanced fibrosis (n = 29) were matched for age, gender, ethnicity, and BMI. Selecting patients by ALT elevation provided the most effective strategy, limiting the false positive rate while maintaining the sensitivity compared to universal screening. Selecting patients by any other strategy did not contribute to increasing the sensitivity of the approach and resulted in more false positive results.Conclusion: Universal screening of overweight/obese patients for advanced fibrosis with non-invasive tools is unwarranted, as selection strategies based on elevated ALT levels lead to the same sensitivity with a lower false positive rate (i.e., fewer patients that would require a liver biopsy or referral to hepatology)

Severity of non-alcoholic steatohepatitis is not linked to testosterone concentration in patients with type 2 diabetes.

BackgroundHypogonadism is reported to occur in non-alcoholic fatty liver disease (NAFLD), but earlier studies used low-sensitivity diagnostic techniques (CT, ultrasound), for NAFLD diagnosis. We hypothesized that if hypogonadism was due to NAFLD, and not solely attributable to underlying obesity/diabetes, it would be more severe in the presence of steatohepatitis (NASH). To examine the influence of liver disease on testosterone in males with type 2 diabetes mellitus (T2DM), we used gold-standard liver imaging with MR-spectroscopy (1H-MRS), and performed liver biopsies to grade/stage the NAFLD.MethodsIn this cross-sectional study, we measured in 175 males with T2DM total and free testosterone, markers of insulin resistance, and intrahepatic triglyceride content (IHTG) by 1H-MRS. Those with NAFLD on imaging underwent a liver biopsy.ResultsTotal testosterone was higher in the group without NAFLD ("No-NAFLD"; n = 48) compared to isolated steatosis (IS; n = 62) or NASH (n = 65) (385 ± 116 vs. 339 ± 143 vs. 335 ± 127 ng/ml, ptrend 0.03). Testosterone was also lower in obese vs. non-obese subjects in both the No-NAFLD and IS groups (p = 0.06 and p = 0.11, respectively), but not in obese vs. non-obese patients with NASH (p = 0.81). IHTG was independently associated with total testosterone (ß = -4.8, p = 0.004). None of the liver histology characteristics were associated with lower testosterone.ConclusionsNAFLD is linked to lower total testosterone in patients with T2DM, but likely given a common soil of insulin resistance/obesity and not from the severity of liver necroinflammation or fibrosis. Nevertheless, clinicians should consider screening patients with T2DM and NAFLD for hypogonadism

Genomic Landscape of Primary Mediastinal B-Cell Lymphoma Cell Lines.

Primary mediastinal B-Cell lymphoma (PMBL) is a recently defined entity comprising ~2-10% non-Hodgkin lymphomas (NHL). Unlike most NHL subtypes, PMBL lacks recurrent gene rearrangements to serve as biomarkers or betray target genes. While druggable, late chemotherapeutic complications warrant the search for new targets and models. Well characterized tumor cell lines provide unlimited material to serve as preclinical resources for verifiable analyses directed at the discovery of new biomarkers and pathological targets using high throughput microarray technologies. The same cells may then be used to seek intelligent therapies directed at clinically validated targets. Four cell lines have emerged as potential PMBL models: FARAGE, KARPAS-1106P, MEDB-1 and U-2940. Transcriptionally, PMBL cell lines cluster near c(lassical)-HL and B-NHL examples showing they are related but separate entities. Here we document genomic alterations therein, by cytogenetics and high density oligonucleotide/SNP microarrays and parse their impact by integrated global expression profiling. PMBL cell lines were distinguished by moderate chromosome rearrangement levels undercutting cHL, while lacking oncogene translocations seen in B-NHL. In total 61 deletions were shared by two or more cell lines, together with 12 amplifications (≥4x) and 72 homozygous regions. Integrated genomic and transcriptional profiling showed deletions to be the most important class of chromosome rearrangement. Lesions were mapped to several loci associated with PMBL, e.g. 2p15 (REL/COMMD1), 9p24 (JAK2, CD274), 16p13 (SOCS1, LITAF, CIITA); plus new or tenuously associated loci: 2p16 (MSH6), 6q23 (TNFAIP3), 9p22 (CDKN2A/B), 20p12 (PTPN1). Discrete homozygous regions sometimes substituted focal deletions accompanied by gene silencing implying a role for epigenetic or mutational inactivation. Genomic amplifications increasing gene expression or gene-activating rearrangements were respectively rare or absent. Our findings highlight biallelic deletions as a major class of chromosomal lesion in PMBL cell lines, while endorsing the latter as preclinical models for hunting and testing new biomarkers and actionable targets

Genomic array data.

<p>A: The respective breakpoints and FISH clones at ACTR2 and inside RAF1 of der(2)t(2;3)(p14;p25) in KARPAS-1106P as revealed by genomic arrays expands the FISH data. B: Color coded plots of FARAGE (purple), KARPAS-1106P (pink), MEDB-1 (blue), U-2940 (green)—show genomic copy number (solid) and LOH (barred) at 12 loci (1p12, 2p15, 2p16, 6q23, 7p22, 7q31, 8q24, 9p21, 9p24, 16p13, 15q23, 19q13, together with OMIM genes below. Copy number polymorphic regions (<a href="http://dgv.tcag.ca/dgv/app/home" target="_blank">http://dgv.tcag.ca/dgv/app/home</a>) are shown between, listing gains (blue), losses (red), and copy number neutral alterations, such as inversions (gray).</p

Spectral Karyotyping (SKY): FARAGE (A), KARPAS-1106P (B), MEDB-1 (C) and U-2940 (D).

<p>Inverse DAPI G-banding shown left of corresponding pseudocolored SKY. Arrows show deletions (white), duplications (red), and translocations (ochre). After trypsin G-banding (not shown) analyses were extended to prepare consensus karyotypes. Individual metaphases sometimes departed from consensus karyotypes, e.g. note loss of Y-chromosome in MEDB-1. Note absence of key cytogenetic rearrangements and relative lack of rearrangement when compared to cHL cell lines. Thus the salient cytogenetic features of PMBL are essentially negative with respect to neighboring entities, cHL and PMBL.</p