Clinicopathological Comparison of Adenocarcinoma of Cervix and Endometrium Using Cell Cycle Markers: P16ink4a, P21waf1, and p27Kip1 on 132 Cancers

Objective. We studied the clinicopathological parameters of adenocarcinoma arising from endocervix (ECA) and from endometrium (EMA) based on the expression of P16ink4a, P21waf1, and p27Kip1 proteins. Study Design. Immunohistochemistry was done on sections of confirmed ECA and EMA from hysterectomy specimens which have had no prior chemotherapy/radiotherapy. Results. There were 40 ECAs and 92 EMAs. The mean age of ECA was 49.82 (SD 10.29); the youngest was 30 years old and the oldest 75 years old. The mean age of EMA was 54.45 (SD 10.92); the youngest was 30 years old and the oldest was 82 years old. For ECA, the size of the tumour is significantly associated with age and with depth of infiltration. FIGO stage is associated with histological grade. p21WAF1 expression is significantly associated with infiltration of the corpus and lymph node metastasis. p27Kip1 expression is significantly associated with lymph node invasion. The presence of lymph node metastasis is strongly associated when p16INK4a and p27Kip1 expressions are analyzed in combination. For EMA, p16INK4a expression is associated with histologic grade. Conclusion. Our study shows that we could use these cell cycle markers as predictors for more aggressive subsets of adenocarcinoma of the cervix and endometrium

A Randomized Trial of Silymarin for the Treatment of Nonalcoholic Steatohepatitis

Background & Aims Silymarin is a complex mixture of 6 major flavonolignans and other minor polyphenolic compounds derived from the milk thistle plant Silybum marianum; it has shown antioxidant, anti-inflammatory and antifibrotic effects, and may be useful in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to study the efficacy of silymarin in patients with nonalcoholic steatohepatitis (NASH)—the more severe form of NAFLD. Methods We performed a randomized, double-blind, placebo-controlled trial of consecutive adults with biopsy-proven NASH and a NAFLD activity score (NAS) of 4 or more at a tertiary care hospital in Kuala Lumpur, Malaysia, from November 2012 through August 2014. Patients were randomly assigned to groups given silymarin (700 mg; n = 49 patients) or placebo (n = 50 patients) 3 times daily for 48 weeks. After this 48-week period, liver biopsies were repeated. The primary efficacy outcome was a decrease of 30% or more in NAS; findings from 48-week liver biopsies were compared with those from the baseline biopsy. Secondary outcomes included changes in steatosis, lobular inflammation, hepatocyte ballooning, NAS and fibrosis score, and anthropometric measurements, as well as glycemic, lipid, and liver profiles and liver stiffness measurements. Results The percentage of patients achieving the primary efficacy outcome did not differ significantly between the groups (32.7% in the silymarin group vs 26.0% in the placebo group; P =.467). A significantly higher proportion of patients in the silymarin group had reductions in fibrosis based on histology (reductions of 1 point or more; 22.4%) than did the placebo group (6.0%; P =.023), and based on liver stiffness measurements (decrease of 30% or more; 24.2%) than did the placebo group (2.3%; P =.002). The silymarin group also had significant reductions in mean aspartate aminotransferase to platelet ratio index (reduction of 0.14, P =.011 compared with baseline), fibrosis-4 score (reduction of 0.20, P =.041 compared with baseline), and NAFLD fibrosis score (reduction of 0.30, P <.001 compared with baseline); these changes were not observed in the placebo group (reduction of 0.07, P =.154; increase of 0.18, P =.389; and reduction of 0.05, P =.845, respectively). There was no significant difference between groups in number of adverse events; adverse events that occurred were not attributed to silymarin. Conclusions In a randomized trial of 99 patients, we found that silymarin (700 mg, given 3 times daily for 48 weeks) did not reduce NAS scores by 30% or more in a significantly larger proportion of patients with NASH than placebo. Silymarin may reduce liver fibrosis but this remains to be confirmed in a larger trial. It appears to be safe and well tolerated. ClinicalTrials.gov: NCT02006498

Limited utility of plasma M30 in discriminating non-alcoholic steatohepatitis from steatosis--a comparison with routine biochemical markers.

INTRODUCTION: The utility of Cytokeratin-18 fragment, namely CK18Asp396 (M30), for the diagnosis of non-alcoholic steatohepatitis (NASH) is currently uncertain. We aimed to provide further data in this area among multi-ethnic Asian subjects with NAFLD. MATERIALS AND METHODS: The accuracy of M30 for detecting NASH was compared with serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transpeptidase (GGT) levels in consecutive adult subjects with biopsy-proven non-alcoholic fatty liver disease (NAFLD). RESULTS: Data for 93 NAFLD subjects (mean age 51.0 ± 11.1 years old and 51.6% males) and 20 healthy controls (mean age 50.2 ± 16.4 years old and 33.3% males) were analyzed. There were 39 NASH subjects (41.9%) and 54 non-NASH subjects (58.1%) among the NAFLD subjects. Plasma M30 (349 U/L vs. 162 U/L), and serum ALT (70 IU/L vs. 26 IU/L), AST (41 IU/L vs. 20 IU/L) and GGT (75 IU/L vs. 33 IU/L) were significantly higher in NAFLD subjects than in healthy controls. Serum ALT (86 IU/L vs. 61 IU/L), AST (58 IU/L vs. 34 IU/L) and GGT (97 IU/L vs. 56 IU/L) were significantly higher in NASH subjects compared to non-NASH subjects, but no significant difference was observed with plasma M30 (435 U/L vs. 331 U/L). The accuracy of plasma M30, and serum ALT, AST and GGT was good for predicting NAFLD (AUROC 0.91, 0.95, 0.87 and 0.85, respectively) but less so for NASH (AUROC 0.59, 0.64, 0.75 and 0.68, respectively). Serum ALT and AST, but not plasma M30 showed a significant trend with increasing grades of ballooning and lobular inflammation. CONCLUSION: The utility of M30 in the detection of NASH in clinical practice appears limited, in comparison to routine biochemical markers

Repeated liver stiffness measurement compared with paired liver biopsy in patients with non-alcoholic fatty liver disease

Introduction: The value of repeated liver stiffness measurement (LSM) in non-alcoholic fatty liver disease (NAFLD) has not been shown before. Methods: A longitudinal study of biopsy-proven NAFLD patients was conducted at the Asian tertiary hospital from November 2012 to January 2017. Patients with paired liver biopsies and LSM were followed prospectively for liver-related and non-liver related complications, and survival. Results: The data for 113 biopsy-proven NAFLD patients (mean age 51.3 ± 10.6 years, male 50%) were analyzed. At baseline, advanced fibrosis based on histology and LSM was observed in 22 and 46%, respectively. Paired liver biopsy and LSM at 1-year interval was available in 71 and 80% of patients, respectively. High-risk cases (defined as patients with advanced fibrosis at baseline who had no fibrosis improvement, and patients who developed advanced fibrosis on repeat assessment) were seen in 23 and 53% of patients, based on paired liver biopsy and LSM, respectively. Type 2 diabetes mellitus was independently associated with high-risk cases. The median follow-up was 37 months with a total follow-up of 328 person-years. High-risk cases based on paired liver biopsy had significantly higher rates of liver-related complications (p = 0.002) but no difference in other outcomes. High-risk patients based on paired LSM had a significantly higher rate of liver-related complications (p = 0.046), cardiovascular events (p = 0.025) and composite outcomes (p = 0.006). Conclusion: Repeat LSM can predict liver-related complications, similar to paired liver biopsy, and may be useful in identifying patients who may be at an increased risk of cardiovascular events. Further studies in a larger cohort and with a longer follow-up should be carried out to confirm these observations

Plasma M30 and serum ALT, AST and GGT levels according to fibrosis stages.

<p>The data between and across groups were analyzed using Mann-Whitney test and Kruskal-Wallis test, respectively. The p value between groups were only shown when there was a significant difference across groups. Fibrosis was staged 0–4 (0 = no fibrosis, 1 = mild fibrosis, 2 = moderate fibrosis, 3 = severe fibrosis, 4 = cirrhosis). F, fibrosis stage; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT; gamma glutamyl transpeptidase.</p

Limited applicability of cathepsin D for the diagnosis and monitoring of non‐alcoholic steatohepatitis

Background and Aim: To date, there are limited data on the applicability of cathepsin D for the diagnosis and monitoring of non-alcoholic steatohepatitis (NASH). Methods: This study included patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD) diagnosed between November 2012 and October 2015. Serum cathepsin D levels were measured using the CatD enzyme-linked immunosorbent assay (USCN Life Science, Wuhan, China) using stored samples collected on the same day of the liver biopsy procedure. The performance of cathepsin D in the diagnosis and monitoring of NASH was evaluated using receiver operating characteristic analysis. Results: Data for 216 liver biopsies and 34 healthy controls were analyzed. The mean cathepsin D level was not significantly different between NAFLD patients and controls; between NASH and non-NASH patients; and across the different steatosis, lobular inflammation, and hepatocyte ballooning grades. The area under receiver operating characteristic curve (AUROC) of cathepsin D for the diagnosis of NAFLD and NASH was 0.62 and 0.52, respectively. The AUROC of cathepsin D for the diagnosis of the different steatosis, lobular inflammation, and hepatocyte ballooning grades ranged from 0.51 to 0.58. Of the 216 liver biopsies, 152 were paired liver biopsies from 76 patients who had a repeat liver biopsy after 48 weeks. There was no significant change in the cathepsin D level at follow-up compared to baseline in patients who had histological improvement or worsening for steatosis, lobular inflammation, and hepatocyte ballooning grades. Cathepsin D was poor for predicting improvement or worsening of steatosis and hepatocyte ballooning, with AUROC ranging from 0.47 to 0.54. It was fair for predicting worsening (AUROC 0.73) but poor for predicting improvement (AUROC 0.54) of lobular inflammation. Conclusion: Cathepsin D was a poor biomarker for the diagnosis and monitoring of NASH in our cohort of Asian patients, somewhat inconsistent with previous observations in Caucasian patients. Further studies in different cohorts are needed to verify our observation. © 2019 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd

The receiver operating characteristic curves of plasma M30 and serum ALT, AST and GGT for prediction of (a) more severe lobular inflammation, and (b) ballooning.

<p>AUROC was interpreted as follows: 0.90–1.00 = excellent, 0.80–0.90 = good, 0.70–0.80 = fair, <0.70 = poor. ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT; gamma glutamyl transpeptidase.</p

Accuracy of plasma M30 and serum ALT, AST and GGT for prediction of NASH.

<p>Accuracy of plasma M30 and serum ALT, AST and GGT for prediction of NASH.</p

Patient characteristics.

<p>Patient characteristics.</p