Development and validation of a risk score for advanced colorectal adenoma recurrence after endoscopic resection

AIM: To develop and validate a risk score for advanced colorectal adenoma(ACA) recurrence after endoscopic polypectomy.METHODS: Out of 3360 patients who underwent colon polypectomy at University of Foggia between 2004 and 2008, data of 843 patients with 1155 ACAs was retrospectively reviewed. Surveillance intervals were scheduled by guidelines at 3 years and primary endpoint was considered 3-year ACA recurrence. Baseline clinical parameters and the main features of ACAs were entered into a Cox regression analysis and variables with P < 0.05 in the univariate analysis were then tested as candidate variables into a stepwise Cox regression model(conditional backward selection). The regression coefficients of the Cox regression model were multiplied by 2 and rounded in order to obtain easy to use point numbers facilitating the calculation of the score. To avoid overoptimistic results due to model fitting and evaluation in the same dataset, we performed an internal 10-fold cross-validation by means of bootstrap sampling. RESULTS: Median lesion size was 16 mm(12-23) while median number of adenomas was 2.5(1-3), whereof the number of ACAs was 1.5(1-2). At 3 years after polypectomy, recurrence was observed in 229 ACAs(19.8%), of which 157(13.5%) were metachronous neoplasms and 72(6.2%) local recurrences. Multivariate analysis, after exclusion of the variable "type of resection" due to its collinearity with other predictive factors, confirmed lesion size, number of ACAs and grade of dysplasia as significantly associated to the primary outcome. The score was then built by multiplying the regression coefficients times 2 and the cut-off point 5 was selected by means of a Receiver Operating Characteristic curve analysis. In particular, 248 patients with 365 ACAs fell in the higher-risk group(score ≥ 5) where 3-year recurrence was detected in 174 ACAs(47.6%) whereas the remaining 595 patients with 690 ACAs were included in the low-risk group(score < 5) where 3-year recurrence rate was 7.9%(55/690 ACAs). Area under the curve of the model was 0.81(0.72-0.86) with an overall classification error rate of 0.09. The model was finally validated by means of 10-fold cross validation.CONCLUSION: Our study provides support for the use of a novel risk score as a clinical predictor of ACA recurrence after colon polypectomy.

Local ablative treatments for hepatocellular carcinoma:An updated review

Ablative treatments currently represent the first-line option for the treatment of early stage unresectable hepatocellular carcinoma(HCC).Furthermore,they are effective as bridging/downstaging therapies before orthotopic liver transplantation.Contraindications based on size,number,and location of nodules are quite variable in literature and strictly dependent on local expertise.Among ablative therapies,radiofrequency ablation(RFA) has gained a pivotal role due to its efficacy,with a reported 5-year survival rate of 40%-70%,and safety.Although survival outcomes are similar to percutaneous ethanol injection,the lower local recurrence rate stands for a wider application of RFA in hepato-oncology.Moreover,RFA seems to be even more cost-effective than liver resection for very early HCC(single nodule ≤ 2 cm) and in the presence of two or three nodules ≤ 3 cm.There is increasing evidence that combining RFA to transarterial chemoembolization may increase the therapeutic benefit in larger HCCs without increasing the major complication rate,but more robust prospective data is still needed to validate these pivotal findings.Among other thermal treatments,microwave ablation(MWA) uses high frequency electromagnetic energy to induce tissue death via coagulation necrosis.In comparison to RFA,MWA has several theoretical advantages such as a broader zone of active heating,higher temperatures within the targeted area in a shorter treatment time and the lack of heatsink effect.The safety concerns raised on the risks of this procedure,due to the broader and less predictable necrosis areas,have been recently overcome.However,whether MWA ability to generate a larger ablation zone will translate into a survival gain remains unknown.Other treatments,such as high-intensity focused ultrasound ablation,laser ablation,and cryoablation,are less investigated but showed promising results in early HCC patients and could be a valuable therapeutic option in the next future.

Impact of sodium glucose cotransporter-2 inhibitors on liver steatosis/fibrosis/inflammation and redox balance in non-alcoholic fatty liver disease

BACKGROUND Sodium glucose cotransporter-2 inhibitors(SGLT2-I)are the most recently approved drugs for type 2 diabetes(T2D).Recent clinical trials of these compounds reported beneficial cardiovascular(CV)and renal outcomes.A major cause of vascular dysfunction and CV disease in diabetes is hyperglycemia associated with inflammation and oxidative stress.Pre-clinical studies demonstrated that SGLT2-I reduce glucotoxicity and promote anti-inflammatory effects by lowering oxidative stress.AIM To investigate the effects of SGLT2-I on markers of oxidative stress,inflammation,liver steatosis,and fibrosis in patients of T2D with non-alcoholic fatty liver disease(NAFLD).METHODS We referred fifty-two consecutive outpatients treated with metformin monotherapy and exhibiting poor glycemic control to our centre.We introduced the outpatients to an SGLT2-I(dapagliflozin,empagliflozin,or canagliflozin;n=26)or a different hypoglycemic drug[other glucose-lowering drugs(OTHER),n=26].We evaluated circulating interleukins and serum hydroxynonenal(HNE)-or malondialdehyde(MDA)-protein adducts,fatty liver index(FLI),NAFLD fibrosis score,aspartate aminotransferase(AST)/alanine aminotransferase(ALT)ratio,AST-to-platelet-ratio index(APRI),and fibrosis-4 on the day before(T0)and following treatment for six months(T1).We also performed transient elastography at T0 and T1.RESULTS Add-on therapy resulted in improved glycemic control and reduced fasting blood glucose in both groups.Of note,following treatment for six months,a reduction of FLI and APRI,as well as of the FibroScan result,was reported in patients treated with SGLT2-I,but not in the OTHER group;furthermore,in the SGLT2-I group,we reported lower circulating levels of interleukin(IL)-1β,IL-6,tumor necrosis factor,vascular endothelial growth factor,and monocyte chemoattractant protein-1,and higher levels of IL-4 and IL-10.We did not observe any modification in circulating interleukins in the OTHER group.Finally,serum HNE-and MDA-protein adducts decreased significantly in SGLT2-I rather than OTHER patients and correlated with liver steatosis and fibrosis scores.CONCLUSION The present data indicate that treatment with SGLT2-I in patients with T2D and NAFLD is associated with improvement of liver steatosis and fibrosis markers and circulating pro-inflammatory and redox status,more than optimizing glycemic control.

Lymphocyte-to-monocyte ratio predicts survival after radiofrequency ablation for colorectal liver metastases

AIM: To test the correlation between lymphocyte-tomonocyte ratio(LMR) and survival after radiofrequency ablation(RFA) for colorectal liver metastasis(CLMs). METHODS: From July 2003 to Feb 2012, 127 consecutive patients with 193 histologically-proven unresectable CLMs were treated with percutaneous RFA at the University of Foggia. All patients had undergone primary colorectal tumor resection before RFA and received systemic chemotherapy. LMR was calculated by dividing lymphocyte count by monocyte count assessed at baseline. Treatment-related toxicity was defined as any adverse events occurred within 4 wk after the procedure. Overall survival(OS) and time to recurrence(TTR) were estimated from the date of RFA by Kaplan-Meier with plots and median(95%CI). The inferential analysis for time to event data was conducted using the Cox univariate and multivariate regression model to estimate hazard ratios(HR) and 95%CI. Statistically significant variables from the univariate Cox analysis were considered for the multivariate models.RESULTS: Median age was 66 years(range 38-88) and patients were prevalently male(69.2%). Median LMR was 4.38%(0.79-88) whereas median number of nodules was 2(1-3) with a median maximum diameter of 27 mm(10-45). Median OS was 38 mo(34-53) and survival rate(SR) was 89.4%, 40.4% and 33.3% at 1, 4 and 5 years respectively in the whole cohort. Running log-rank test analysis found 3.96% as the most significant prognostic cut-off point for LMR and stratifying the study population by this LMR value median OS resulted 55 mo(37-69) in patients with LMR > 3.96% and 34(26-39) mo in patients with LMR ≤ 3.96%(HR = 0.53, 0.34-0.85, P = 0.007). Nodule size and LMR were the only significant predictors for OS in multivariate analysis. Median TTR was 29 mo(22-35) with a recurrence-free survival(RFS) rate of 72.6%, 32.1% and 21.8% at 1, 4 and 5 years, respectively in the whole study group. Nodule size and LMR were confirmed as significant prognostic factors for TTR in multivariate Cox regression. TTR, when stratified by LMR, was 35 mo(28-57) in the group > 3.96% and 25 mo(18-30) in the group ≤ 3.96%(P = 0.02).CONCLUSION: Our study provides support for the use of LMR as a novel predictor of outcome for CLM patients.

Transarterial radioembolization vs chemoembolization for hepatocarcinoma patients:A systematic review and metaanalysis

AIM: To compare the efficacy and safety of yttrium-90 radioembolization(Y90RE) and transarterial chemoembolization(TACE) in hepatocellular carcinoma patients. METHODS: Bibliographic research was conducted on main scientific databases. When there was no statistically significant heterogeneity, pooled effects were calculated using a fixed-effects model by means of Mantel-Haenszel test, otherwise, a random-effects model was used with Der Simonian and Laird test. Summary estimates were expressed in terms of odds ratios(ORs) and 95%CI. The probability of publication bias was assessed using funnel plots and with Begg and Mazumdar's test. Sensitivity analysis was finally conducted using the method of excluding extreme data.RESULTS: A total of 10 studies were analyzed, of which 2 randomized controlled trials. Survival rate(SR) assessed at 1 year showed an absolute similarity between the two treatment groups(OR = 1.01, 95%CI: 0.78-1.31, P = 0.93). As long as time elapsed since the treatment, ORs for survival rate tended to significantly increase, thus meaning better long-term outcomes in patients who underwent Y90RE(2-year SR: OR = 1.43, 1.08-1.89, P = 0.01; 3-year SR: OR = 1.48, 1.03-2.13, P = 0.04). Meta-analysis of plotted hazard ratios(HRs) determined a non-significant overall estimate in favor of Y90RE(HR = 0.91, 0.80-1.04, P = 0.16). Y90 RE showed a statistically significant benefit as compared to TACE in terms of higher progression-free survival rateassessed at 1 year(OR = 1.67; 95%CI: 1.10-2.55; P = 0.02). Pooled analyses do not revealed a statistically significant increase in OR for tumor objective responses after Y90 RE with respect to TACE(OR = 1.22, 95%CI: 0.69-2.16, P = 0.50). A non-significant trend in favor of Y90 RE was observed according to adverse event rate(OR = 0.70, 0.38-1.30, P = 0.26).CONCLUSION: Our meta-analysis reveals that Y90 RE and TACE show similar effects in terms of survival, response rate and safety profile, although tumor progression is delayed after radioembolization.

Nuclear factor erythroid 2-related factor 2-mediated signaling and metabolic associated fatty liver disease

Oxidative stress is a key driver in the development and progression of several diseases,including metabolic associated fatty liver disease(MAFLD).This condition includes a wide spectrum of pathological injuries,extending from simple steatosis to inflammation,fibrosis,cirrhosis,and hepatocellular carcinoma.Excessive buildup of lipids in the liver is strictly related to oxidative stress in MAFLD,progressing to liver fibrosis and cirrhosis.The nuclear factor erythroid 2-related factor 2(NRF2)is a master regulator of redox homeostasis.NRF2 plays an important role for cellular protection by inducing the expression of genes related to antioxidant,anti-inflammatory,and cytoprotective response.Consistent evidence demonstrates that NRF2 is involved in every step of MAFLD development,from simple steatosis to inflammation,advanced fibrosis,and initiation/progression of hepatocellular carcinoma.NRF2 activators regulate lipid metabolism and oxidative stress alleviating the fatty liver disease by inducing the expression of cytoprotective genes.Thus,modulating NRF2 activation is crucial not only in understanding specific mechanisms underlying MAFLD progression but also to characterize effective therapeutic strategies.This review outlined the current knowledge on the effects of NRF2 pathway,modulators,and mechanisms involved in the therapeutic implications of liver steatosis,inflammation,and fibrosis in MAFLD.

Impact of senescence on the transdifferentiation process of human hepatic progenitor-like cells

BACKGROUND Senescence is characterized by a decline in hepatocyte function,with impairment of metabolism and regenerative capacity.Several models that duplicate liver functions in vitro are essential tools for studying drug metabolism,liver diseases,and organ regeneration.The human HepaRG cell line represents an effective model for the study of liver metabolism and hepatic progenitors.However,the impact of senescence on HepaRG cells is not yet known.AIM To characterize the effects of senescence on the transdifferentiation capacity and mitochondrial metabolism of human HepaRG cells.METHODS We compared the transdifferentiation capacity of cells over 10(passage 10[P10])vs P20.Aging was evaluated by senescence-associated(SA)beta-galactosidase activity and the comet assay.HepaRG transdifferentiation was analyzed by confocal microscopy and flow cytometry(expression of cluster of differentiation 49a[CD49a],CD49f,CD184,epithelial cell adhesion molecule[EpCAM],and cytokeratin 19[CK19]),quantitative PCR analysis(expression of albumin,cytochrome P4503A4[CYP3A4],γ-glutamyl transpeptidase[γ-GT],and carcinoembryonic antigen[CEA]),and functional analyses(albumin secretion,CYP3A4,andγ-GT).Mitochondrial respiration and the ATP and nicotinamide adenine dinucleotide(NAD^(+))/NAD with hydrogen(NADH)content were also measured.RESULTS SAβ-galactosidase staining was higher in P20 than P10 HepaRG cells;in parallel,the comet assay showed consistent DNA damage in P20 HepaRG cells.With respect to P10,P20 HepaRG cells exhibited a reduction of CD49a,CD49f,CD184,EpCAM,and CK19 after the induction of transdifferentiation.Furthermore,lower gene expression of albumin,CYP3A4,andγ-GT,as well as reduced albumin secretion capacity,CYP3A4,andγ-GT activity were reported in transdifferentiated P20 compared to P10 cells.By contrast,the gene expression level of CEA was not reduced by transdifferentiation in P20 cells.Of note,both cellular and mitochondrial oxygen consumption was lower in P20 than in P10 transdifferentiated cells.Finally,both ATP and NAD^(+)/NADH were depleted in P20 cells with respect to P10 cells.CONCLUSION SA mitochondrial dysfunction may limit the transdifferentiation potential of HepaRG cells,with consequent impairment of metabolic and regenerative properties,which may alter applications in basic studies.

The effect of direct-acting antivirals on hepatocellular carcinoma recurrence: still waiting for the turning point

Hepatocellular carcinoma(HCC)is the fifth most commoncancer worldwide accounting for about 9%of all cancerdeaths(1).The natural history of HCC is extremely variabledue to high effectiveness of treatment only in early stagesand low overall survival rate in patients with advanceddisease who are poor responders to any treatment.