Statin, aspirin and metformin use and risk of hepatocellular carcinoma related outcomes following liver transplantation: A retrospective study

BACKGROUND Liver transplantation(LT)is a potentially curative therapy for patients with hepatocellular carcinoma(HCC).HCC-recurrence following LT is associated with reduced survival.There is increasing interest in chemoprophylaxis to improve HCC-related outcomes post-LT.AIM To investigate whether there is any benefit for the use of drugs with proposed chemoprophylactic properties against HCC,and patient outcomes following LT.METHODS This was a retrospective study of adult patients who received Deceased Donor LT for HCC from 2005-2022,from a single Australian centre.Drug use was defined as statin,aspirin or metformin therapy for≥29 days,within 24 months post-LT.A cox proportional-hazards model with time-dependent covariates was used for survival analysis.Outcome measures were the composite-endpoint of HCC-recurrence and all-cause mortality,HCC-recurrence and HCC-related mortality.Sensitivity analysis was performed to account for immortality time bias and statin dosing.RESULTS Three hundred and five patients were included in this study,with 253(82.95%)males with a median age of 58.90 years.Aetiologies of liver disease were 150(49.18%)hepatitis C,73(23.93%)hepatitis B(HBV)and 33(10.82%)non-alcoholic fatty liver disease(NAFLD).56(18.36%)took statins,51(16.72%)aspirin and 50(16.39%)metformin.During a median follow-up time of 59.90 months,34(11.15%)developed HCC-recurrence,48(15.74%)died,17(5.57%)from HCC-related mortality.Statin,aspirin or metformin use was not associated with statistically significant differences in the composite endpoint of HCC-recurrence or all-cause mortality[hazard ratio(HR):1.16,95%CI:0.58-2.30;HR:1.21,95%CI:0.28-5.27;HR:0.61,95%CI:0.27-1.36],HCC-recurrence(HR:0.52,95%CI:0.20-1.35;HR:0.51,95%CI:0.14-1.93;HR 1.00,95%CI:0.37-2.72),or HCC-related mortality(HR:0.32,95%CI:0.033-3.09;HR:0.71,95%CI:0.14-3.73;HR:1.57,95%CI:0.61-4.04)respectively.Statin dosing was not associated with statist-ically significant differences in HCC-related outcomes.CONCLUSION Statin,metformin or aspirin use was not associated with improved HCC-related outcomes post-LT,in a largely historical cohort of Australian patients with a low proportion of NAFLD.Further prospective,multicentre studies are required to clarify any potential benefit of these drugs to improve HCC-related outcomes.

Stereotactic radiotherapy and the potential role of magnetic resonance-guided adaptive techniques for pancreatic cancer

BACKGROUND Pancreatic cancer is a malignancy with one of the poorest prognoses amongst all cancers.Patients with unresectable tumours either receive palliative care or undergo various chemoradiotherapy regimens.Conventional techniques are often associated with acute gastrointestinal toxicities,as adjacent critical structures such as the duodenum ultimately limits delivered doses.Stereotactic body radiotherapy(SBRT)is an advanced radiation technique that delivers highly ablative radiation split into several fractions,with a steep dose fall-off outside target volumes.AIM To discuss the latest data on SBRT and whether there is a role for magnetic resonance-guided techniques in multimodal management of locally advanced,unresectable pancreatic cancer.METHODS We conducted a search on multiple large databases to collate the latest records on radiotherapy techniques used to treat pancreatic cancer.Out of 1229 total records retrieved from our search,36 studies were included in this review.RESULTS Studies indicate that SBRT is associated with improved clinical efficacy and toxicity profiles compared to conventional radiotherapy techniques.Further dose escalation to the tumour with SBRT is limited by the poor soft-tissue visualisation of computed tomography imaging during radiation planning and treatment delivery.Magnetic resonance-guided techniques have been introduced to improve imaging quality,enabling treatment plan adaptation and re-optimisation before delivering each fraction.CONCLUSION Therefore,SBRT may lead to improved survival outcomes and safer toxicity profiles compared to conventional techniques,and the addition of magnetic resonance-guided techniques potentially allows dose escalation and conversion of unresectable tumours to operable cases.

Testosterone therapy reduces hepatic steatosis in men with type 2 diabetes and low serum testosterone concentrations

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is highly prevalent in people with diabetes with no available treatment.AIM To explore the effect of testosterone treatment on liver.Testosterone therapy improves insulin resistance and reduces total body fat,but its impact on the liver remains poorly studied.METHODS This secondary analysis of a 40 wk,randomised,double-blinded,placebocontrolled trial of intramuscular testosterone undecanoate in men with type 2 diabetes and lowered serum testosterone concentrations evaluated the change in hepatic steatosis as measured by liver fat fraction on magnetic resonance imaging(MRI).RESULTS Of 88 patients enrolled in the index study,39 had liver MRIs of whom 20 received testosterone therapy and 19 received placebo.All patients had>5%hepatic steatosis at baseline and 38 of 39 patients met diagnostic criteria for NAFLD.Median liver fat at baseline was 15.0%(IQR 11.5%-21.1%)in the testosterone and 18.4%(15.0%-28.9%)in the placebo group.Median ALT was 34units/L(26-38)in the testosterone and 32units/L(25-52)in the placebo group.At week 40,patients receiving testosterone had a median reduction in absolute liver fat of 3.5%(IQR 2.9%-6.4%)compared with an increase of 1.2%in the placebo arm(between-group difference 4.7%P<0.001).After controlling for baseline liver fat,testosterone therapy was associated with a relative reduction in liver fat of 38.3%(95%confidence interval 25.4%-49.0%,P<0.001).CONCLUSION Testosterone therapy was associated with a reduction in hepatic steatosis in men with diabetes and low serum testosterone.Future randomised studies of testosterone therapy in men with NAFLD focusing on liver-related endpoints are therefore justified.

Hepatocellular carcinoma surveillance and quantile regression for determinants of underutilisation in at-risk Australian patients

BACKGROUND While clinical guidelines recommend hepatocellular carcinoma(HCC)surveillance for at-risk individuals,reported surveillance rates in the United States and Europe remain disappointingly low.AIM To quantify HCC surveillance in an Australian cohort,and assess for factors associated with surveillance underutilisation.METHODS All patients undergoing HCC surveillance liver ultrasounds between January 1,2018 to June 30,2018 at a tertiary hospital in Melbourne,Australia,were followed until July 31,2020,or when surveillance was no longer required.The primary outcome was the percentage of time up-to-date with HCC surveillance(PTUDS).Quantile regression was performed to determine the impact of factors associated with HCC surveillance underutilisation.RESULTS Among 775 at-risk patients followed up for a median of 27.5 months,the median PTUDS was 84.2%(IQR:66.3%-96.3%).85.0%of patients were followed up by specialist gastroenterologists.Amongst those receiving specialist care,quantile regression demonstrated differential associations at various quantile levels of PTUDS for several factors.Older age at the 25th quantile(estimate 0.002 per percent,P=0.03),and cirrhotic status at the 75th quantile(estimate 0.021,P=0.017),were significantly associated with greater percentage of time up-to-date.African ethnicity(estimate-0.089,P=0.048)and a culturally and linguistically diverse(CALD)background(estimate-0.063,P=0.01)were significantly associated with lower PTUDS at the 50th quantile,and again for CALD at the 75th quantile(estimate-0.026,P=0.045).CONCLUSION While median PTUDS in this Australian cohort study was 84.2%,awareness of the impact of specific factors across PTUDS quantiles can aid targeted interventions towards improved HCC surveillance.

Clinical outcomes of patients with two small hepatocellular carcinomas

BACKGROUND Management of single small hepatocellular carcinoma(HCC)is straightforward with curative outcomes achieved by locoregional therapy or resection.Liver transplantation is often considered for multiple small or single large HCC.Management of two small HCC whether presenting synchronously or sequentially is less clear.AIM To define the outcomes of patients presenting with two small HCC.METHODS Retrospective review of HCC databases from multiple institutions of patients with either two synchronous or sequential HCC≤3 cm between January 2000 and March 2018.Primary outcomes were overall survival(OS)and transplant-free survival(TFS).RESULTS 104 patients were identified(male n=89).Median age was 63 years(interquartile range 58-67.75)and the most common aetiology of liver disease was hepatitis C(40.4%).59(56.7%)had synchronous HCC and 45(43.3%)had sequential.36 patients died(34.6%)and 25 were transplanted(24.0%).1,3 and 5-year OS was 93.0%,66.1% and 62.3% and 5-year post-transplant survival was 95.8%.1,3 and 5-year TFS was 82.1%,45.85% and 37.8%.When synchronous and sequential groups were compared,OS(1,3 and 5 year synchronous 91.3%,63.8%,61.1%,sequential 95.3%,69.5%,64.6%,P=0.41)was similar but TFS was higher in the sequential group(1,3 and 5 year synchronous 68.5%,37.3% and 29.7%,sequential 93.2%,56.6%,48.5%,P=0.02)though this difference did not remain during multivariate analysis.CONCLUSION TFS in patients presenting with two HCC≤3 cm is poor regardless of the timing of the second tumor.All patients presenting with two small HCC should be considered for transplantation.