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Hepatocellular carcinoma (HCC) is the third deadliest and sixth most common cancer in the world. Histone‐lysine N‐methyltransferase EHMT2 (also known as G9a) is a histone methyltransferase frequently overexpressed in many cancer types, including HCC. We showed that Myc‐driven liver tumours have a unique H3K9 methylation pattern with corresponding G9a overexpression. This phenomenon of increased G9a was further observed in our c‐Myc‐positive HCC patient‐derived xenografts. More importantly, we showed that HCC patients with higher c‐Myc and G9a expression levels portend a poorer survival with lower median survival months. We demonstrated that c‐Myc interacts with G9a in HCC and cooperates to regulate c‐Myc‐dependent gene repression. In addition, G9a stabilises c‐Myc to promote cancer development, contributing to the growth and invasive capacity in HCC. Furthermore, combination therapy between G9a and synthetic‐lethal target of c‐Myc, CDK9, demonstrates strong efficacy in patient‐derived avatars of Myc‐driven HCC. Our work suggests that targeting G9a could prove to be a potential therapeutic avenue for Myc‐driven liver cancer. This will increase our understanding of the underlying epigenetic mechanisms of aggressive tumour initiation and lead to improved therapeutic and diagnostic options for Myc‐driven hepatic tumours. [ABSTRACT FROM AUTHOR]

Down-staging is commonly used to select patients with hepatocellular carcinoma (HCC) beyond Milan criteria (MC) for liver transplantation (LT), but outcomes are heterogenous. We aimed to estimate pooled down-staging success rates, HCC recurrence, and overall survival (OS), stratified by criteria used for baseline tumor burden. We searched Pubmed and EMBASE databases from inception until August 2021 for studies reporting down-staging success (reduction of tumor burden to within MC) and outcomes of adult HCC patients. In addition, we performed a pooled analysis using reconstructed individual participant data to obtain robust estimates for OS. We screened 1059 articles and included 25 articles involving 3997 patients. Overall, 55.16% (45.49%–64.46%) underwent successful down-staging, and 31.52% (24.03%–40.11%) received LT (by intention-to-treat analysis [ITT]). Among patients who received LT, 16.01% (11.80%–21.37%) developed HCC recurrence. Comparing studies that used the United Network for Organ Sharing Down-Staging (UNOS-DS) criteria versus studies beyond UNOS-DS or did not specify criteria, down-staging success (by ITT) was 83.21% versus 45.93%, P <.001; the proportion who received LT (by ITT) was 48.61% vs 28.60%, P =.030; and HCC recurrence (among patients who received LT) occurred in 9.06% versus 20.42%, P <.001. Among studies that used UNOS-DS criteria, ITT 1- and 5-year OS from the initiation of down-staging treatment was 86% and 58%, respectively, whereas 1- and 5-year post-LT OS was 94% and 74%, respectively. Among studies that adhered to UNOS-DS criteria, down-staging was successful in four-fifths of patients, >50% received LT, and post-LT outcomes were excellent. These data provide clinical validation for the utilization of UNOS-DS criteria. [Display omitted] [ABSTRACT FROM AUTHOR]

Atrial Fibrillation (AF) is the most commonly diagnosed cardiac arrhythmia. It is associated with significant morbidity and mortality, as it is a major risk factor for cerebral vascular accidents (CVA). Our aim was to determine the prevalence of pre-existing and new-onset AF among patients undergoing liver transplantation (LT) and its impact on post-transplant outcomes. Medline and Embase were searched. Single-arm analysis was conducted using the generalized linear mixed model to determine the prevalence of pre-existing and new-onset AF. Logistic regression was performed to analyze risk factors. Comparative meta-analysis in odds ratio was conducted for binary outcomes. Twenty articles were included, with 17 studies on pre-existing AF, and 7 including data on new-onset AF post-LT. The prevalence of pre-existing AF was 3.3% (CI 2.3–4.7) (14 studies, 45,070 patients) in pooled analysis. Significantly higher prevalence of pre-existing AF patients from North America was noted when compared to Europe (4.5%, CI 3.4–5.8 vs 1.5%, CI 0.8–2.7; p = 0.001). Body mass index (BMI), history of hypertension, diabetes, coronary artery disease (CAD), and cerebrovascular accidents (CVA) were risk factors for pre-existing AF. Pre-existing AF was significantly associated with major adverse cardiac or cerebrovascular events (MACCE) postoperatively (OR 8.02, 95%CI 5.40–11.90, p < 0.001). New-onset AF post-LT had an incidence of 6.8% (CI 4.9–9.3), and was associated with increased risk of mortality (OR 2.31, 95% CI 1.76–3.02, p < 0.001) and graft failure (OR 2.98, CI 1.99–4.47, p < 0.001). AF is relatively more common among patients undergoing LT compared to the general non-transplant population. Additionally, it is associated with adverse outcomes including MACCE, thus warranting clinical attention. Thorough cardiac assessment, and close surveillance of post-operative AF may be clinically prudent. [ABSTRACT FROM AUTHOR]

The optimal therapeutic strategy in nucleoside analogue (NA) experienced chronic hepatitis B (CHB) using peginterferon is still unclear; hence we explored a switch to or add-on peginterferon strategy versus continued NA. We conducted a randomized controlled trial of CHB patients on NA >12 months with HBV DNA(–) randomized to switch or add-on peginterferon-alpha2b (1.5 μg/kg/weekly) for 48 weeks versus continuing NA (controls) (allocation 2:2:1; Clinicaltrial.gov: NCT01928511) in tertiary Singapore hospitals. The primary composite endpoint at week 72 was hepatitis B e antigen (HBeAg) loss or quantitative HBsAg (qHBsAg) >1 log IU/mL reduction, and secondary endpoints were HBsAg loss, HBsAg seroconversion, qHBsAg <200 IU/mL, qHBsAg <100 IU/mL, HBV DNA(–), viral relapse, and safety. Analysis was by intention-to-treat (ITT). A total of 253 patients (controls 51, switch 103, add-on 99) were randomized. The primary ITT endpoint was achieved in 3.9% of controls, 33.3% of switch, and 26.7% of add-on (P <.0001, switch/add-on versus controls). HBsAg loss occurred in 0% of controls, 7.8% of switch, and 10.1% of add-on (ITT, P <.001, switch/add-on versus controls). HBeAg(+) patients on peginterferon had higher HBeAg loss than controls but poor HBsAg responses, whereas HBeAg(–) patients on peginterferon achieved better HBsAg responses than controls. Reduction in qHBsAg in HBeAg(+) was 0.14 log IU/mL versus 0.51 log IU/mL in HBeAg(–) (P <.0001) in peginterferon-treated patients. Clinical relapse was higher in switch (13.6% overall, 27% in HBeAg(+)) versus 1% add-on and 0% controls. Adverse events were typically interferon-related symptoms, with one death (myocardial infarction unrelated to therapy). ITT analysis showed that either peginterferon strategies were superior to NA for the primary endpoint and HBsAg loss, but add-on peginterferon is preferred to switch due to improved safety and similar efficacy. ClincialTrials.gov number: NCT01928511. [ABSTRACT FROM AUTHOR]

Background: Smartphone apps have shown potential in enhancing weight management in Western populations in the short to medium term. With a rapidly growing obesity burden in Asian populations, researchers are turning to apps as a service delivery platform to reach a larger target audience to efficiently address the problem. Objective: This systematic review and meta-analysis aims to determine the efficacy of interventions that incorporate apps in facilitating weight loss and health behavior change in the Asian population. Methods: A total of 6 databases were searched in June 2020. The eligible studies included controlled trials in which an app was used in the intervention. The participants were aged 18 years or older and were of Asian ethnicity. A meta-analysis to test intervention efficacy, subgroup analyses, and post hoc analyses was conducted to determine the effects of adding an app to usual care and study duration. The primary outcome was absolute or percentage weight change, whereas the secondary outcomes were changes to lifestyle behaviors. Results: A total of 21 studies were included in this review, and 17 (81%) were selected for the meta-analysis. The pooled effect size across 82% (14/17) of the randomized controlled trials for weight change was small to moderate (Hedges g=–0.26; 95% CI –0.41 to –0.11), indicating slightly greater weight loss achieved in the intervention group; however, this may not be representative of long-term studies (lasting for more than a year). Supplementing multicomponent usual care with an app led to greater weight loss (Hedges g=–0.28; 95% CI –0.47 to –0.09). Asian apps were largely culturally adapted and multifunctional, with the most common app features being communication with health professionals and self-monitoring of behaviors and outcomes. Conclusions: More evidence is required to determine the efficacy of apps in the long term and address the low uptake of apps to maximize the potential of the intervention. Future research should determine the efficacy of each component of the multicomponent intervention to facilitate the designing of studies that are most effective and cost-efficient for weight management. [ABSTRACT FROM AUTHOR]

High body mass index (BMI) is a major risk factor for cancer development, but its impact on the global burden of cancer remains unclear. We estimated global and regional temporal trends in the burden of cancer attributable to high BMI, and the contributions of various cancer types using the framework of the Global Burden of Disease Study. From 2010 to 2019, there was a 35 % increase in deaths and a 34 % increase in disability-adjusted life-years from cancers attributable to high BMI. The age-standardized death rates for cancer attributable to high BMI increased over the study period (annual percentage change [APC] +0.48 %, 95 % CI 0.22 to 0.74 %). The greatest number of deaths from cancer attributable to high BMI occurred in Europe, but the fastest-growing age-standardized death rates and disability-adjusted life-years occurred in Southeast Asia. Liver cancer was the fastest-growing cause of cancer mortality (APC: 1.37 %, 95 % CI 1.25 to 1.49 %) attributable to high BMI. The global burden of cancer-related deaths attributable to high BMI has increased substantially from 2010 to 2019. The greatest increase in age-standardized death rates occurred in Southeast Asia, and liver cancer is the fastest-growing cause of cancer mortality attributable to high BMI. Urgent and sustained measures are required at a global and regional level to reverse these trends and slow the growing burden of cancer attributed to high BMI. • From 2010 to 2019, there was a 35 % increase in deaths from cancers due to high BMI. • Similarly, there was a 34 % increase in disability-adjusted life-years. • The greatest number of deaths from cancer due to high BMI occurred in Europe. • Liver cancer is the fastest-growing cause of cancer mortality due to high BMI. [ABSTRACT FROM AUTHOR]

Metabolic associated fatty liver disease (MAFLD) was recently proposed as an alternative name change for better encapsulation of disease. However, there exists a spectrum of MAFLD where both metabolically healthy (MH) and metabolically unhealthy (MU) individuals are included. In view of limited evidence, we sought to examine the prevalence, clinical characteristics, and differences in outcomes of MH-MAFLD at the population level. Data were used from the United States National Health and Nutrition Examination Survey 1999 to 2018. Multivariate logistic regression analysis was used to obtain odds ratios for the estimation of events. Survival analysis was conducted with Cox regression and the Fine-Gray subdistribution model. There were 32,683 overweight and obese individuals included in the analysis. In MAFLD patients, the prevalence of MH-MAFLD was 6.92% (95% confidence interval [CI], 6.58%–7.27%), and 93.08% (95% CI, 92.73%–93.42%) were considered as MU-MAFLD. Multivariate analysis found a significantly higher risk of MACE (odds ratio, 1.38; 95% CI, 1.28–1.49; P <.01), all-cause (hazard ratio, 1.24; 95% CI, 1.17–1.32; P <.01), cardiovascular disease (SHR, 1.20; 95% CI, 1.02–1.42; P =.03), and cancer mortality (SHR, 1.24; 95% CI, 1.07–1.44; P <.01) in MU-MAFLD relative to non-MAFLD. However, MH-MAFLD individuals were not associated with a statistically significant increased risk of these adverse outcomes compared with non-MAFLD. MU-MAFLD diabetics were also at a higher risk of adverse events compared with non-diabetics. This study reports on the heterogeneity and spectrum of metabolic dysfunction that exists in overweight and obese MAFLD. Although MAFLD may potentially be advantageous in improving awareness and patient outcomes, there remains substantial heterogeneity within patients included in MAFLD on the basis of the underlying metabolic burden. [ABSTRACT FROM AUTHOR]

Nonalcoholic steatohepatitis (NASH) is the fastest growing indication of liver transplantation (LT) and is projected to be the leading cause of LT in the near future. The systemic pathogenesis of NASH increases risks of adverse clinical outcomes in patients with NASH receiving LT. Thus, this study aimed to conduct a time-dependent survival analysis between LT recipients with and without NASH using hazard ratios. A search was conducted on Medline and Embase databases for articles relating to LT outcomes for NASH recipients. A survival analysis was conducted of hazard ratios using the DerSimonian and Laird random-effects model with meta-regression. To account for censoring, survival data were reconstructed from published Kaplan–Meier curves and pooled to derive more accurate hazard estimates and all-cause mortality in NASH patients after LT. Pairwise meta-analysis was conducted to analyze secondary outcomes. Fifteen studies involving 119,327 LT recipients were included in our analysis with a prevalence of NASH of 20.2% (95% CI, 12.9–30.2). The pooled 1-year, 5-year, and 10-year all-cause mortality in NASH patients after LT were 12.5%, 24.4%, and 37.9%, respectively. Overall survival was comparable between LT recipients for NASH vs non-NASH (hazard ratio, 0.910; 95% CI, 0.760 to 1.10; P =.34). Meta-regression showed that a higher model for end-stage liver disease score was associated with significantly worse overall survival in NASH compared with non-NASH after LT (95% CI, -0.0856 to -0.0181; P =.0026). This study shows that patients undergoing LT for NASH cirrhosis have comparable complication rates, overall survival, and graft survival compared with non-NASH patients, although close monitoring may be indicated for those with higher model for end-stage liver disease scores. [Display omitted] [ABSTRACT FROM AUTHOR]

Cardiovascular disease remains the leading cause of death in patients with nonalcoholic fatty liver disease (NAFLD). Studies examining the association of coronary heart disease (CHD) and NAFLD are cofounded by various cardiometabolic factors, particularly diabetes and body mass index. Hence, we seek to explore such association by investigating the global prevalence, independent risk factors, and influence of steatosis grade on manifestation of CHD among patients with NAFLD. Two databases, Embase and Medline, were utilized to search for articles relating to NAFLD and CHD. Data including, but not limited to, continent, diagnostic methods, baseline characteristics, prevalence of CHD, CHD severity, NAFLD severity, and risk factors were extracted. Of the 38 articles included, 14 reported prevalence of clinical coronary artery disease (CAD) and 24 subclinical CAD. The pooled prevalence of CHD was 44.6% (95% confidence interval [CI], 36.0%–53.6%) among 67,070 patients with NAFLD with an odds ratio of 1.33 (95% CI, 1.21%–1.45%; P <.0001). The prevalence of CHD was higher in patients with moderate to severe steatosis (37.5%; 95% CI, 15.0%–67.2%) than those with mild steatosis (29.6%; 95% CI, 13.1%–54.0%). The pooled prevalence of subclinical and clinical CAD was 38.7% (95% CI, 29.8%–48.5%) and 55.4% (95% CI, 39.6%–70.1%), respectively. Steatosis was found to be related with CHD involvement, with moderate to severe steatosis related to clinical CAD. Early screening and prompt intervention for CHD in NAFLD are warranted for holistic care in NAFLD. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: There is no satisfactory treatment for nonalcoholic steatohepatitis (NASH). The Bioenterics intragastric balloon (BIB) can be an effective treatment for weight reduction in obese patients. Objective: We evaluated the efficacy of the BIB in improving the histology of NASH in obese patients. Design: Randomized, controlled study. Setting: University hospital. Patients: Obese patients with body mass indexes (BMI) ≥27 kg/m2 and who had histologic evidence of NASH were recruited. Intervention: Patients were randomly assigned to a step 1 American Heart Association (AHA) diet plus exercise and BIB placement or step 1 AHA diet plus exercise and sham BIB placement for a period of 6 months. Main Outcome Measurements: Liver histology was the primary outcome measure recorded before and after treatment. Results: A total of 18 patients completed the study. Baseline characteristics of the BIB and sham groups were similar. At 6 months, a significant reduction in the mean BMI was seen in the BIB group (1.52 vs 0.8; P = .0008). The median nonalcoholic fatty liver disease activity scores at the end of treatment were significantly lower in the BIB-treated compared with the sham-treated groups (2 [0.75] vs 4 [2.25]; P = .03). There was a trend toward improvement in the median steatosis scores (1 [0.75] vs 1 [1]; P = .075). There was no change in the median loblular inflammation, hepatocellular ballooning, or fibrosis scores in both groups after treatment. Limitations: Pilot study with small numbers and short duration. Conclusion: Results from this pilot study demonstrated that addition of BIB for 6 months provided a greater loss of BMI and improvement in 2 of 5 histologic parameters of nonalcoholic fatty liver disease. A longer study with larger numbers will be required to prove whether or not the therapy is meaningful in the treatment of NASH. [Copyright &y& Elsevier]

Background & Aims: Population endoscopic screening for gastric cancer is generally deemed not to be cost-effective except in Japan, where its prevalence is very high. However, in the absence of screening, patients present with advanced disease, and prognosis is poor. We conducted a cost utility analysis to determine whether endoscopic screening for stomach cancer in intermediate-risk population would be cost-effective and to better define the high-risk groups in the population who would benefit from such strategy. Methods: Cost-effectiveness analysis was performed by using a Markov Model. Simulation was performed on Singapore (intermediate-risk) population and various high-risk subgroups. Comparison was made between 2-yearly endoscopic mass screening program versus no screening. Data sources were extracted from relevant studies published from 1980–2004 identified via systematic PUBMED search. Main outcome measures were deaths caused by stomach cancer averted, cost per life saved, and incremental cost-effectiveness ratio expressed as cost per quality-adjusted life year (QALY) saved. Results: Screening of high-risk group of Chinese men (age-standardized rate, 25.9/100,000) from 50–70 years old is highly cost-effective, with cost benefit of United States $26,836 per QALY. Screening this cohort of 199,000 subjects prevents 743 stomach cancer deaths and saves 8234 absolute life years. Cost of averting 1 cancer death is United States $247,600. Cost-effectiveness was most sensitive to incidence of stomach cancer and cost of screening endoscopy. Conclusions: Screening of stomach cancer in moderate to high-risk population subgroups is cost-effective. Targeted screening strategies for stomach cancer should be explored. [Copyright &y& Elsevier]

The presence of gastroesophageal varices is a major complication of portal hypertension associated with significant morbidity and mortality.1 The Baveno VI criteria state that patients with liver stiffness measurement (LSM) <20 kPa by transient elastography (TE) and platelet count >150,000/μL can avoid screening endoscopy for high-risk varix (HRV).2 However, because TE is not widely available, the Baveno VI criteria could not be applied in many clinical settings. As such, we aim to determine a concise clinical criterion as an alternative noninvasive tool to predict absence of HRV among patients with compensated cirrhosis to avoid screening esophagogastroduodenoscopy (EGD). [ABSTRACT FROM AUTHOR]

There are few in vitro models for studying the 3-dimensional interactions among different liver cell types during organogenesis or disease development. We aimed to generate hepatic organoids that comprise different parenchymal liver cell types and have structural features of the liver, using human pluripotent stem cells. We cultured H1 human embryonic stem cells (WA-01, passage 27-40) and induced pluripotent stem cells (GM23338) with a series of chemically defined and serum-free media to induce formation of posterior foregut cells, which were differentiated in 3 dimensions into hepatic endoderm spheroids and stepwise into hepatoblast spheroids. Hepatoblast spheroids were reseeded in a high-throughput format and induced to form hepatic organoids; development of functional bile canaliculi was imaged live. Levels of albumin and apolipoprotein B were measured in cell culture supernatants using an enzyme-linked immunosorbent assay. Levels of gamma glutamyl transferase and alkaline phosphatase were measured in cholangiocytes. Organoids were incubated with troglitazone for varying periods and bile transport and accumulation were visualized by live-imaging microscopy. Organoids were incubated with oleic and palmitic acid, and formation of lipid droplets was visualized by staining. We compared gene expression profiles of organoids incubated with free fatty acids or without. We also compared gene expression profiles between liver tissue samples from patients with nonalcoholic steatohepatitis (NASH) versus without. We quantified hepatocyte and cholangiocyte populations in organoids using immunostaining and flow cytometry; cholangiocyte proliferation of cholangiocytes was measured. We compared the bile canaliculi network in the organoids incubated with versus without free fatty acids by live imaging. Cells in organoids differentiated into hepatocytes and cholangiocytes, based on the expression of albumin and cytokeratin 7. Hepatocytes were functional, based on secretion of albumin and apolipoprotein B and cytochrome P450 activity; cholangiocytes were functional, based on gamma glutamyl transferase and alkaline phosphatase activity and proliferative responses to secretin. The organoids organized a functional bile canaliculi system, which was disrupted by cholestasis-inducing drugs such as troglitazone. Organoids incubated with free fatty acids had gene expression signatures similar to those of liver tissues from patients with NASH. Incubation of organoids with free fatty acid–enriched media resulted in structural changes associated with nonalcoholic fatty liver disease, such as decay of bile canaliculi network and ductular reactions. We developed a hepatic organoid platform with human cells that can be used to model complex liver diseases, including NASH. [ABSTRACT FROM AUTHOR]

Measuring liver stiffness only in patients with indeterminate or high nonalcoholic fatty liver disease (NAFLD) fibrosis scores (called a 2-step approach) was reported to reduce indeterminate or discordant results while maintaining the accuracy to identify patients with advanced fibrosis. We aimed to validate this approach using data collected from the Gut and Obesity in Asia Workgroup. We performed a retrospective analysis of data from 759 patients with biopsy-proven NAFLD (24% with advanced fibrosis), seen at 10 centers in 9 countries in Asia, from 2006 through 2018. By u sing liver biopsies as the reference standard, we calculated percentages of misclassifications and indeterminate or discordant results from assessment s made based on fibrosis scores (NAFLD fibrosis score [NFS] or Fibrosis-4 score) and liver stiffness measurements (LSMs), alone or in combination. The analysis was repeated using randomly selected subgroups with a different prevalence of advanced fibrosis (histologic fibrosis stage ≥F3). In groups in which 3.7% and 10% of patients had advanced fibrosis, a 2-step approach (using the NFS followed by LSM only for patients with indeterminate or high NFS) and using a gray zone of 10 to 15 kPa for LSM, produced indeterminate or discordant results for 6.9% of patients and misclassified 2.7% of patients; only 25.6% of patients required LSM. In the group in which 10% of patients had advanced fibrosis, the same approach produced indeterminate or discordant results for 7.9% of patients and misclassified 6.6% of patients; only 27.4% of patients required LSM. In groups in which 24% and 50% of patients had advanced fibrosis, using LSM ≥10 kPa alone for the diagnosis of advanced fibrosis had the highest accuracy and misclassified 18.1% and 18.3% of patients, respectively. These results were similar when the Fibrosis-4 score was used in place of NFS. In a retrospective analysis, we found that a 2-step approach using fibrosis scores followed by LSM most accurately detects advanced fibrosis in populations with a low prevalence of advanced fibrosis. However, LSM ≥10 kPa identifies patients with advanced fibrosis with the highest level of accuracy in populations with a high prevalence of advanced fibrosis. [ABSTRACT FROM AUTHOR]

Background & Aims The high prevalence of chronic hepatitis B in Asian countries produces a substantial economic burden. Peginterferon has immunomodulatory effects and a finite course for treatment of hepatitis B, but also a high cost and side effects. The recent introduction of a 12-week stopping rule (stopping treatment after 12 weeks) has increased its appeal as a first-line treatment for hepatitis B. We aimed to determine the cost effectiveness of the 12-week stopping rule for peginterferon in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. Methods We used Markov modeling, with data from the Hong Kong population, to compare the cost effectiveness of peginterferon therapy with a 12-week stopping rule vs conventional therapy (48 weeks) and with other antiviral agents. Results For HBeAg-positive patients, stopping peginterferon therapy after 12 weeks had the lowest cost-effectiveness ratio (CER), of $9501/quality-adjusted life-year (QALY), compared with no treatment, making it the most cost-effective option. Conventional (48-week) peginterferon treatment had a CER of $9664/QALY. For HBeAg-negative patients, entecavir had the lowest CER ($34,310/QALY). Entecavir was more cost effective than either peginterferon strategies (CERs of $37,423/QALY for 12 weeks of peginterferon and $38,474/QALY for 48 weeks of treatment). Conclusions The 12-week stopping rule increases the cost effectiveness of peginterferon therapy, and is the most cost-effective treatment for HBeAg-positive patients. The need for long-term antiviral therapy for HBeAg-negative patients makes entecavir the most cost-effective strategy. [ABSTRACT FROM AUTHOR]

Background & Aims: Performing single endoscopic examinations or selective screening based on risk might be more practical than recommended screening strategies for colorectal cancer (CRC). We investigated the cost effectiveness of these strategies, under real-life conditions of suboptimal compliance, and the societal cost perspective. Methods: We used Markov modeling to analyze data from 787,000 individuals in Singapore, aged 50 to 75 years, with an age-standardized rate of CRC of 30 to 40/100,000 in 2009. Potential outcomes, incremental cost-effectiveness ratio, and net health benefit were compared between single sigmoidoscopy or colonoscopy and current recommended screening strategies, and also with a strategy of selective screening based on risk of CRC. Results: Performing single sigmoidoscopies on individuals when they are 60 years old was the cheapest screening strategy; it would reduce CRC incidence by 19% and mortality by 16%, compared with no screening. A single colonoscopy is less cost effective than a single sigmoidoscopy, unless the proportion of right-sided lesions exceeds 65%. The fecal occult blood test (iFOBT) had the lowest incremental cost-effectiveness ratio when all strategies were compared with no screening; iFOBT and colonoscopic examinations every 10 years each had extended dominance over other strategies. Screening subjects 50 to 60 years old by iFOBT and subjects 60 to 72 years old with colonoscopies every 10 years was the most cost-effective strategy (US$25,000/quality-adjusted life-years). Risk for CRC, adherence, and cost of colonoscopy were the main determinants of cost effectiveness, based on sensitivity analysis. Conclusions: Markov modeling analysis indicates that selectively screening individuals for CRC based on risk is the most cost-effective approach; it limits the cost and number of colonoscopies needed and significantly reduces CRC mortality. [Copyright &y& Elsevier]

Background & Aims: p53 Mutations are very common in human hepatocellular carcinoma, and induction of hepatic p53 expression causes lysis of implanted hepatoblastoma cells in a chimeric mouse. Ataxia Telangiectasia Mutated (ATM) kinase senses DNA strand breaks and induces p53. Our aims were to establish whether ATM deficiency alters the carcinogenic response of hepatocytes to diethylnitrosamine (DEN). Methods: Male ATM-deficient (ATM−/−), heterozygote (ATM+/−), and wild-type (WT) mice were injected with DEN at age 15 days, and animals were killed up to 12 months to assess p53, cell cycle, apoptosis, and liver tumor development. Results: Whereas >80% of WT and ATM+/− mice developed hepatocellular carcinoma (HCC), at 9–12 months, ATM−/− mice remained refractory to DEN-induced HCC up to 15 months. At 6 and 9 months, and compared with WT mice, p53 and p19ARF expression were greatly enhanced in ATM−/− liver associated with up-regulation of ATR and Chk1; cleaved caspase-3 immunohistochemistry and caspase-3 activity were also significantly increased. Whereas livers of DEN-treated ATM−/− mice showed markers of senescence (β-galactosidase, Cxcl-1), up-regulation of telomerase occurred concurrently. The possibility that such balanced senescence could result in immortalization was demonstrated in hepatocytes prepared at 9 months from DEN-treated ATM−/− liver. Conclusions: Hepatocarcinogenesis is abrogated in ATM-deficient mice in association with induction of ATR, Chk1, p53, and p19ARF. Resultant cell cycle arrest and apoptosis of DNA-damaged cells are possible mechanisms that underlie this unique “refractoriness” to malignant transformation in DEN-initiated ATM−/− hepatocytes. The findings also show that prolonged up-regulation of p53 associated with some features of senescence does not inevitably cause organ failure. [Copyright &y& Elsevier]