Alcohol does not impact chronic hepatitis C treatment outcomes but increases risk for progressive liver disease: Findings from a prospective multicentre Australian study (OPERA-C).

INTRODUCTION: Alcohol use is common in patients with chronic hepatitis C virus (HCV) infection. We examined the impact of alcohol use on direct-acting antiviral (DAA) therapy outcome and the clinical course of liver disease and 2-year survival for patients receiving HCV DAA therapy. METHODS: Adults (n = 2624) recruited from 26 Australian hospital liver clinics during 2016-2021 were followed up for 2 years. Risky alcohol use was defined by a combination of self-report (≥40 g/day of ethanol), physician-reported history of problematic alcohol use, and anti-craving medication prescription via population-based database linkage. We examined factors associated with advanced liver fibrosis and survival using multivariable logistic and Cox regression. RESULTS: Among 1634 patients (62.3%) with risky alcohol use, 24.6% reported consuming ≥40 g/day of alcohol, 98.3% physician-reported problematic alcohol use; only 4.1% were dispensed naltrexone/acamprosate. One hundred and forty-three patients with cirrhosis reported ≥40 g/day of alcohol, 6 (4.3%) were prescribed naltrexone/acamprosate. Risky alcohol use was associated with advanced fibrosis (adjusted-odds ratio 1.69, 95% confidence interval 1.32-2.17) and patients were over-represented for cirrhosis (45.1% vs. 25.6% in no-risky alcohol use [p < 0.001]) and hepatocellular carcinoma (5.7% vs. 2.5% [p < 0.001]). Sustained viral response (p = 0.319) and 2-year survival (adjusted-hazard ratio 1.98, 95% confidence interval 0.84-4.63) after DAA therapy were not associated with risky alcohol use. DISCUSSION AND CONCLUSIONS: Risky alcohol use in HCV patients was prevalent, but did not reduce HCV cure. Treatment for alcohol dependence was low. Risky alcohol use may be under-recognised in liver clinics. Better integration of addiction medicine into liver services and increased resourcing and addiction medicine training opportunities for hepatologists may help address this.

Australians with metabolic dysfunction-associated steatotic liver disease have a twofold increase in the incidence of cancer.

Background and Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with an increased risk of extrahepatic morbidity. We compared the incidence of cancers in adults admitted to Queensland hospitals with MASLD with that for the Queensland population and examined the association between cirrhosis and type 2 diabetes and the development of extrahepatic cancers. Methods: In this retrospective study, we identified all cancers (Queensland Cancer Registry) after the first hospitalization with MASLD during Jul-2007 to Dec-2019, estimated age-standardized incidence (ASI) of cancers, and compared that with the ASI in the Queensland population (incidence rate ratios [IRR]). Among the MASLD cohort, we examined the association between diabetes and cancer risk (Cox regression). Median follow-up was 3.8 years (54 204 person-years). Results: Totally 1104 new cancers were diagnosed in 1018 patients (8.9% of 9771 non-cirrhotic and 1712 adults with cirrhosis). The ASI (all cancers) of 1668.2 per 100 000 person-years in men (95% CI 1523.7-1827.4) and 1284.0 per 100 000 person-years in women (95% CI 1169.6-1408.2) was 2-fold higher than that of the Queensland population (IRR = 1.94, 95% CI 1.75-2.16 and IRR = 1.99, 95% CI 1.78-2.22, respectively). Incidence of stomach cancer, unknown primary, and pancreas was 3- to 5-fold higher compared to the general population (all P < 0.001). In multivariable analysis of the MASLD cohort, older age (e.g. ≥70 years adjusted hazard ratio [adj-HR] = 4.59, 95% CI 3.61-5.83), male gender (adj-HR = 1.20, 95% CI 1.05-1.37), and cirrhosis (adj-HR = 1.37, 95% CI 1.11-1.70) were independently associated with extrahepatic cancer risk, while diabetes was not. Conclusions: Our findings will help to raise awareness among clinicians about the importance of cancer vigilance in this patient group.

Spontaneous remission of Cronkhite-Canada syndrome without immunosuppressive medication in the context of decompensated cirrhosis: A case report.

We present a case of Cronkhite-Canada syndrome in a patient with decompensated cirrhosis who had successful induction of remission with nutritional supplementation alone. We propose that early institution of high-protein, high-energy enteral supplementation should be offered to all patients, especially those with compelling contraindications to immunosuppression.

High prevalence of diabetes among young First Nations Peoples with metabolic dysfunction-associated steatotic liver disease: a population-based study in Australia.

BACKGROUND: Liver disease is an important contributor to the mortality gap between First Nations Peoples and non-Indigenous Australian adults. Despite a high burden of metabolic comorbidities among First Nations Peoples, data about the epidemiology of metabolic dysfunction-associated steatotic liver disease (MASLD) in this population is scarce. METHODS: A retrospective analysis of all adults hospitalized with MASLD or metabolic dysfunction-associated steatohepatitis (MASH) with/without cirrhosis during 2007-2019 in the state of Queensland was performed. Patients were followed from the first admission with MASLD/MASH (identified based on validated algorithms) to decompensated cirrhosis and overall mortality. We explored differences according to Indigenous status using Multivariable Cox regression. FINDINGS: 439 First Nations Peoples and 7,547 non-Indigenous Australians were followed for a median of 4.6 years (interquartile range 2.7-7.2). Overall, women were overrepresented, but more so in the First Nations cohort (72.7% vs. 57.0%, p < 0.001). First Nations patients were younger, a higher proportion lived in remote and socioeconomic disadvantaged areas, and had higher comorbidity compared to non-Indigenous Australians (all p < 0.001). Diabetes, the most common comorbidity affecting both groups, was overrepresented in First Nations Peoples versus non-Indigenous Australians (43.5% vs. 30.8%, p < 0.001, respectively). Nineteen (4.3%) First Nations Peoples and 332 (4.4%) of non-Indigenous patients progressed to cirrhosis decompensation (9.0% [95%CI 4.5-17.7] vs. 7.7% [95%CI 6.6-8.9; p = 0.956] respectively within 10 years). In multivariable analysis, there was no association between Indigenous status and progression to decompensated cirrhosis (p = 0.759) and survival (p = 0.437). CONCLUSIONS: This study provides the first population-based epidemiological data on MASLD in First Nations Australians. The high prevalence of diabetes (that is associated with advanced fibrosis and liver disease mortality) among young First Nations Peoples with MASLD raises concern about future risk of progressive liver disease in this patient population. These data highlight the importance of early identification of MASLD, and providing culturally appropriate intervention to reduce disease progression in parallel with the management of cardiometabolic comorbidities.

Efficacy, safety, and pharmacokinetics of capsid assembly modulator linvencorvir plus standard of care in chronic hepatitis B patients.

BACKGROUND/AIMS: Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients. METHODS: This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks. RESULTS: 68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1-2, and no linvencorvir-related serious adverse events were reported. CONCLUSION: 48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.

Broadening and strengthening the health providers caring for patients with chronic hepatitis C may improve continuity of care.

BACKGROUND: Direct-acting antiviral (DAA) therapies for hepatitis C virus infection (HCV) lead to excellent rates of sustained virological response (SVR). However, loss to follow-up (LTFU) for SVR testing remains a challenge. We examine factors associated with LTFU in a real-world setting. METHODS: Adults who received DAA therapy for HCV in one of 26 centers across Australia during 2016-2021 were followed up for 2 years. Data sources included the patient medical records and the national Pharmaceutical and Medicare Benefits Schemes. Linkage to Medicare provided utilization data of other health-care providers and re-treatment with DAAs. LTFU was defined as no clinic attendance for SVR testing by at least 52 weeks after DAA treatment commencement. Multivariable logistic regression assessed factors associated with LTFU. RESULTS: In 3619 patients included in the study (mean age 52.0 years; SD = 10.5), 33.6% had cirrhosis (69.4% Child-Pugh class B/C), and 19.3% had HCV treatment prior to the DAA era. Five hundred and fifteen patients (14.2%) were LTFU. HCV treatment initiation in 2017 or later (adj-OR = 2.82, 95% confidence interval [CI] 2.25-3.54), younger age (adj-OR = 2.63, 95% CI 1.80-3.84), Indigenous identification (adj-OR = 1.99, 95% CI 1.23-3.21), current injection drug use or opioid replacement therapy (adj-OR = 1.66, 95% CI 1.25-2.20), depression treatment (adj-OR = 1.49, 95% CI 1.17-1.90), and male gender (adj-OR = 1.31, 95% CI 1.04-1.66) were associated with LTFU. CONCLUSIONS: These findings stress the importance of strengthening the network of providers caring for patients with HCV. In particular, services targeting vulnerable groups of patients such as First Nations Peoples, youth health, and those with addiction and mental health disorders should be equipped to treat HCV.

Improving palliative and supportive care in advanced cirrhosis: the HepatoCare model of integrated collaborative care.

BACKGROUND: Patients with advanced cirrhosis experience an unpredictable disease trajectory but are infrequently referred to palliative care (PC) services and rarely undertake advance care planning (ACP). AIM: We assessed whether a novel model of care increased provision of meaningful PC in advanced cirrhosis compared with standard of care (SOC). METHODS: Thirty consecutive hepatology clinic outpatients with advanced cirrhosis, meeting one or more cirrhosis-related PC referral criteria, consented to treatment in the HepatoCare clinic (PC physician, specialist liver nurse, pharmacist) in parallel with usual specialist hepatology care. A control cohort of 30 consecutive outpatients with advanced cirrhosis undergoing SOC treatment was retrospectively identified for comparison. The primary outcome was provision of meaningful PC using HepatoCare versus SOC. Additional clinical outcomes were assessed over 12 months or until death and significant differences were identified. RESULTS: The intervention and control cohorts had similarly advanced cirrhosis (mean Child-Pugh scores 8.7 vs 8.2, P = 0.46; mean model for end-stage liver disease scores 14.4 vs 14.6, P = 0.88) but a lower 12-month mortality rate (33% HepatoCare vs 67% SOC; P = 0.02). The intervention cohort experienced higher uptake of formal ACP (100% vs 25% for the control cohort) and outpatient PC referral (100% vs 40%), and were more likely to die at home or in a PC bed/hospice (80% vs 30%). The majority of the HepatoCare cohort (81%) had medications safely deprescribed and experienced fewer unplanned admission days (470 vs 794). CONCLUSIONS: HepatoCare is a novel multidisciplinary model of care that integrates effective PC and specialist hepatology management to improve outcomes in advanced cirrhosis.

Diabetes mellitus and the progression of non-alcoholic fatty liver disease to decompensated cirrhosis: a retrospective cohort study.

OBJECTIVE: To determine the incidence of decompensated cirrhosis and associated risk factors in people hospitalised with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) with or without cirrhosis. DESIGN: Retrospective cohort study; analysis of linked Queensland Hospital Admitted Patient Data Collection, Queensland Registry of Births, Deaths and Marriages, and Queensland Cancer Register data. SETTING, PARTICIPANTS: Queensland residents aged 20 years or older admitted to Queensland hospitals with NAFLD/NASH during 1 July 2009 - 31 December 2018. MAIN OUTCOME MEASURES: Progression to decompensated cirrhosis (ascites, hepatic encephalopathy, or oesophageal variceal bleeding). RESULTS: We included data for 8006 patients in our analysis (10 082 admissions), including 4632 women (58%) and 2514 people with diabetes mellitus (31%); median follow-up time was 4.6 years (interquartile range, 2.7-7.2 years). Three hundred and fifty-one people (4.4%) experienced decompensated cirrhosis during the follow-up period. Of the 6900 people without cirrhosis, 4.5% (95% confidence interval [CI], 3.6-5.7%) experienced decompensated cirrhosis within ten years (mean, 0.5% per year; 95% CI, 0.4-0.6% per year); risk of progression was greater for people aged 70 years or older (v 20-39 years: adjusted hazard ratio [aHR], 4.7; 95% CI, 2.0-11.0) and those who had extrahepatic cancers (aHR, 5.0; 95% CI, 3.0-8.2), history of major cardiovascular events (aHR, 1.9; 95% CI, 1.2-3.1), or diabetes mellitus (aHR, 2.8; 95% CI, 2.0-3.9). Of the 1106 people with cirrhosis, 32.4% (95% CI, 27.2-38.3%) experienced decompensated cirrhosis within ten years (mean, 5.5% per year; 95% CI, 4.8-6.3% per year); risk of progression was greater for those with portal hypertension (aHR, 1.8; 95% CI, 1.3-2.7), extrahepatic cancer (aHR, 1.8; 95% CI, 1.1-2.9), or diabetes mellitus (aHR, 1.5; 95% CI, 1.1-2.0). Compared with people who had neither cirrhosis nor diabetes mellitus, the risk of decompensation was greater for people with cirrhosis (aHR, 10.7; 95% CI, 7.6-15.0) or cirrhosis and diabetes mellitus (aHR, 14.4; 95% CI, 10.1-20.6). CONCLUSIONS: Given the greater risk of progression to cirrhosis decompensation in people with diabetes mellitus, a disorder common in people with NAFLD/NASH, identifying advanced fibrosis and providing appropriate treatment for averting disease progression is vital.

Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study.

BACKGROUND AND AIMS: ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA). APPROACH AND RESULTS: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events. CONCLUSIONS: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.

Relapsed nodular lymphocyte-predominant Hodgkin lymphoma presenting as severe paraneoplastic hepatitis: a case report.

BACKGROUND: Hematological malignancies are an infrequent but important cause of liver dysfunction. There are several mechanisms by which this can occur, including direct malignant infiltration of the hepatic parenchyma and/or vasculature, vanishing bile duct syndrome, and paraneoplastic hepatitis. Paraneoplastic hepatitis is an extremely rare mechanism by which a hematological malignancy can cause liver dysfunction, and we present the first case, to our knowledge, of paraneoplastic hepatitis caused by nodular lymphocyte-predominant Hodgkin lymphoma in the literature. CASE PRESENTATION: A 28-year-old Caucasian male presented with 3 weeks of fatigue, epigastric pain, and jaundice. His medical history was significant for early stage nodular lymphocyte-predominant Hodgkin lymphoma in the cervical region in remission for 5 years after primary treatment with involved-field radiotherapy. Liver biochemistry was normal at the time of treatment for lymphoma and there was no known liver disease before the current presentation. On physical examination, there was scleral icterus and ecchymoses, but no evidence of hepatic encephalopathy, other stigmata of chronic liver disease, or lymphadenopathy. A computed tomography scan of his neck, chest, abdomen, and pelvis showed heterogeneous enhancement of the liver, multiple enlarged upper abdominal lymph nodes, and an enlarged spleen with multiple rounded lesions. Portal and hepatic veins were patent. Initial workup for viral, autoimmune-, toxin-, and medication-related hepatitis was negative. A transjugular liver biopsy was performed with histology showing a predominantly T-cell mediated hepatitis with very extensive multiacinar hepatic necrosis, but no evidence of lymphoma within the liver. Retroperitoneal lymph node biopsy revealed nodular lymphocyte-predominant Hodgkin lymphoma. The patient's symptoms, bilirubin, and transaminases improved significantly after treatment with oral prednisolone and a staged introduction of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy. CONCLUSIONS: Nodular lymphocyte-predominant Hodgkin lymphoma may cause paraneoplastic hepatitis. Physicians should be aware of the possibility of this life-threatening presentation and the importance of early liver biopsy and treatment before acute liver failure occurs. Interestingly, paraneoplastic hepatitis did not occur when nodular lymphocyte-predominant Hodgkin lymphoma was first diagnosed and confined to the cervical region, but was the presenting feature of the recurrence below the diaphragm.

Liver Disease and Poor Adherence Limit Hepatitis C Cure: A Real-World Australian Treatment Cohort.

BACKGROUND AND AIMS: In 2016, direct-acting antiviral (DAA) treatment for hepatitis C (HCV) became available through Australia's universal health care system, with the aim of HCV elimination. We report real-world effectiveness of DAA HCV treatment in Australia from a clinically well-informed cohort, enriched for cirrhosis and prior HCV treatment. METHODS: 3413 patients were recruited from 26 hospital liver clinics across Australia from February 2016 to June 2020. Clinical history and sustained viral response (SVR) were obtained from medical records and data linkage to the Australian Pharmaceutical Benefits Scheme. Factors associated with SVR were assessed by multivariable logistic regression (MVR). RESULTS: At recruitment, 32.2% had cirrhosis (72.9% Child Pugh class B/C), and 19.9% were treatment experienced. Of the 2,939 with data, 93.3% confirmed SVR. 137 patients received second-line therapy. Patients with cirrhosis had lower SVR rate (88.4 vs. 95.8%; p < 0.001). On MVR, failure to achieve SVR was associated with Genotype 3 (adj-OR = 0.42, 95%CI 0.29-0.61), male gender (adj-OR = 0.49, 95%CI 0.31-0.77), fair/poor adherence (adj-OR = 0.52, 95%CI 0.28-0.94), cirrhosis (adj-OR = 0.57, 95%CI 0.36-0.88), FIB-4 > 3.25 (adj-OR = 0.52, 95%CI 0.33-0.83) and MELD score ≥ 20 (adj-OR = 0.25, 95%CI 0.08-0.80). Consistent results were seen in cirrhotic sub-analysis. CONCLUSIONS: Excellent SVR rates were achieved with DAAs in this real-world cohort of patients with chronic HCV infection. More advanced liver disease and clinician impression of poor adherence were associated with HCV treatment failure. Supports to improve liver fibrosis assessment skills for non-specialist DAA prescribers in the community and to optimize patient adherence are likely to enable more effective pursuit of HCV elimination in Australia.

Post-colonoscopy cancer rate at a tertiary referral hospital in Australia: A data linkage analysis.

BACKGROUND AND AIM: Colorectal cancer (CRC) diagnosed following a cancer-negative colonoscopy is termed as post-colonoscopy CRC (PCCRC). The World Endoscopy Organization has recently standardized the definition of PCCRC-3Y (CRC developing within 3 years of a cancer-negative colonoscopy). In the present study, we sought to assess PCCRC-3Y rate, perform root-cause analyses, and identify factors associated with development of PCCRC at a tertiary referral hospital in Australia. METHODS: All patients undergoing colonoscopy from 2011 to 2018 were matched to a population-based cancer register. PCCRC-3Y rate was assessed for years 2011-2015. All PCCRC cases that developed within 6-48 months after a cancer-negative colonoscopy underwent root-cause analyses. Descriptive statistics were used to summarize data. RESULTS: Among 17 828 patients undergoing colonoscopy, 367 CRC cases were diagnosed during the study period. This included nine PCCRC cases, which developed at a median of 14 months (range 7-34 months) after cancer-negative colonoscopy. The PCCRC-3Y rate for years 2011-2015 was 2.16% (95% CI 0.91-5.15). All nine PCCRC cases were moderately or poorly differentiated adenocarcinomas; seven of nine were early-stage CRC (stages I and II) and six of nine probably represented missed lesions at index colonoscopy despite an apparently adequate examination. History of inflammatory bowel disease (IBD) (odds ratio [OR] 21.9, 95% confidence interval [CI] 4.6-103.7, P < 0.001) and diverticulosis (OR 5.4, 95% CI 1.4-20.5, P = 0.01) were significantly associated with development of missed CRC. CONCLUSIONS: In our tertiary referral colonoscopy cohort, PCCRC-3Y rate was 2.16% (95% CI 0.91-5.15). IBD and diverticulosis were significantly associated with risk of PCCRC. The majority of PCCRC lesions were likely missed at index colonoscopy, despite an apparently adequate examination.

Comparative analysis of Illumina Mouse Methylation BeadChip and reduced-representation bisulfite sequencing for routine DNA methylation analysis.

Researching the murine epigenome in disease models has been hampered by the lack of appropriate and cost-effective DNA methylation arrays. Here we perform a comprehensive, comparative analysis between the Mouse Methylation BeadChip (MMB) and reduced-representation bisulfite sequencing (RRBS) in two murine models of colorectal carcinogenesis. We evaluate the coverage, variability, and ability to identify differential DNA methylation of RRBS and MMB. We show that MMB is an effective tool for profiling the murine methylome that performs comparably with RRBS, identifying similar differentially methylated pathways. Although choice of technology is experiment dependent and will be predicated on the underlying biology being probed, these analyses provide insights into the relative strengths and weaknesses of each approach.

Hepatitis C treatment outcomes for Australian First Nations Peoples: equivalent SVR rate but higher rates of loss to follow-up.

BACKGROUND: First Nations Peoples of Australia are disproportionally affected by hepatitis C (HCV) infection. Through a prospective study we evaluated the outcome of direct-acting antiviral (DAA) therapy among First Nations Peoples with HCV infection. METHODS: Adults who initiated DAA therapy at one of 26 hospitals across Australia, 2016-2019 were included in the study. Clinical data were obtained from medical records and the Pharmaceutical and Medicare Benefits Schemes. Outcomes included sustained virologic response (SVR) and loss to follow-up (LTFU). A multivariable analysis assessed factors associated with LTFU. RESULTS: Compared to non-Indigenous Australians (n = 3206), First Nations Peoples (n = 89) were younger (p < 0.001), morel likely to reside in most disadvantaged (p = 0.002) and in regional/remote areas (p < 0.001), and had similar liver disease severity. Medicines for mental health conditions were most commonly dispensed among First Nations Peoples (55.2% vs. 42.8%; p = 0.022). Of 2910 patients with follow-up data, both groups had high SVR rates (95.3% of First Nations Peoples vs. 93.2% of non-Indigenous patients; p = 0.51) and 'good' adherence (90.0% vs. 86.9%, respectively; p = 0.43). However, 28.1% of First Nations Peoples were LTFU vs. 11.2% of non-Indigenous patients (p < 0.001). Among First Nations Peoples, younger age (adj-OR = 0.93, 95% CI 0.87-0.99) and treatment initiation in 2018-2019 vs. 2016 (adj-OR = 5.14, 95% CI 1.23-21.36) predicted LTFU, while higher fibrosis score was associated with better engagement in HCV care (adj-OR = 0.71, 95% CI 0.50-0.99). CONCLUSIONS: Our data showed that First Nations Peoples have an equivalent HCV cure rate, but higher rates of LTFU. Better strategies to increase engagement of First Nations Peoples with HCV care are needed.

Braf mutation induces rapid neoplastic transformation in the aged and aberrantly methylated intestinal epithelium.

OBJECTIVE: Sessile serrated lesions (SSLs) are common across the age spectrum, but the BRAF mutant cancers arising occur predominantly in the elderly. Aberrant DNA methylation is uncommon in SSL from young patients. Here, we interrogate the role of ageing and DNA methylation in SSL initiation and progression. DESIGN: We used an inducible model of Braf mutation to direct recombination of the oncogenic Braf V637E allele to the murine intestine. BRAF mutation was activated after periods of ageing, and tissue was assessed for histological, DNA methylation and gene expression changes thereafter. We also investigated DNA methylation alterations in human SSLs. RESULTS: Inducing Braf mutation in aged mice was associated with a 10-fold relative risk of serrated lesions compared with young mice. There were extensive differences in age-associated DNA methylation between animals induced at 9 months versus wean, with relatively little differential Braf-specific methylation. DNA methylation at WNT pathway genes scales with age and Braf mutation accelerated age-associated DNA methylation. In human SSLs, increased epigenetic age was associated with high-risk serrated colorectal neoplasia. CONCLUSIONS: SSLs arising in the aged intestine are at a significantly higher risk of spontaneous neoplastic progression. These findings provide support for a new conceptual model for serrated colorectal carcinogenesis, whereby risk of Braf-induced neoplastic transformation is dependent on age and may be related to age-associated molecular alterations that accumulate in the ageing intestine, including DNA methylation. This may have implications for surveillance and chemopreventive strategies targeting the epigenome.

Clinicopathological Correlates of Dysplastic Sessile Serrated Lesion: A Prospective Cohort Study With a High Detection Rate.

Background and Aims: Sessile serrated lesions (SSLs) develop colorectal cancer (CRC), through a critical intermediary stage of SSL with dysplasia (SSLd). In this prospective observational study, we aimed to assess clinicopathological correlates of SSLd in the setting of a high lesion-detection rate. Methods: Patients diagnosed with SSL and SSLd from February 2018 until January 2020 were prospectively recruited, and SSLd specimens were re-evaluated by 2 expert pathologists in a blinded manner. Associations were analyzed using multivariate logistic regression models. Results: A total of 6425 patients underwent 7423 colonoscopies, and 2671 SSLs were resected from 1047 patients. The overall SSL detection rate per colonoscopy was 15.9%. The median age of patients with SSL was 54 years (interquartile range, 39-66), and 43.3% were male. After pathologist review, 24 SSLds were confirmed in 20 patients. The median size of SSLd was 8 mm (interquartile range, 5.75-15.25), and 13 of 24 SSLds were <10 mm in size. After multivariate analysis, older age (odds ratio = 1.07, 95% confidence interval = 1.03-1.1) and higher number of synchronous SSLs (odds ratio = 1.12, 95% confidence interval = 1.02-1.23) were associated with the presence of dysplasia. Patient sex and number and size of synchronous adenomas were not associated with the presence of SSLd. Seven of 20 patients with SSLd had synchronous or metachronous SSLd. Six of 20 patients with SSLd met the diagnostic criteria for serrated polyposis syndrome. Conclusion: The overall SSL detection rate was 15.9%, and 0.9% of SSLs were dysplastic. Older age and higher number of synchronous SSL were risk factors for the presence of dysplasia in SSLs. Thirty percent of patients with SSLd had serrated polyposis syndrome, and 35% had multiple SSLd.

Aspirin reduces the incidence of metastasis in a pre-clinical study of Braf mutant serrated colorectal neoplasia.

BACKGROUND: Aspirin reduces the incidence of conventional adenomas driven by APC mutation and thus colorectal cancer. The effect of aspirin on the ~20% of colorectal cancers arising via BRAF mutation is yet to be established. METHODS: BrafV637E/+;Villin-CreERT2/+ mice were allocated to a control (n = 86) or aspirin-supplemented (n = 83) diet. After 14 months the incidence of murine serrated lesions, carcinoma and distant metastases were measured by histological examination. RNA was extracted from carcinomas from each cohort and subjected to sequencing to identify differentially expressed genes and molecular pathways. RESULTS: Aspirin did not reduce the incidence of murine serrated lesions or carcinoma when compared to control, however, did significantly reduce lesion size (P = 0.0042). Among the mice with carcinoma there was a significant reduction in the incidence of distant metastasis with aspirin treatment (RR 0.69, 95% CI 0.48-0.90, P = 0.0134). Key pathways underlying metastasis of carcinoma cells include NOTCH, FGFR and PI3K signalling, were significantly downregulated in carcinomas sampled from mice on an aspirin-supplemented diet. CONCLUSIONS: Aspirin reduces the incidence of metastatic Braf mutant carcinoma, although this is not due to a reduction in primary disease. The reduction in metastasis could be attributed to a delay or prevention of molecular changes within the primary site driving metastatic growth.

Association of Fusobacterium nucleatum with Specific T-cell Subsets in the Colorectal Carcinoma Microenvironment.

PURPOSE: While evidence indicates that Fusobacterium nucleatum (F. nucleatum) may promote colorectal carcinogenesis through its suppressive effect on T-cell-mediated antitumor immunity, the specific T-cell subsets involved remain uncertain. EXPERIMENTAL DESIGN: We measured F. nucleatum DNA within tumor tissue by quantitative PCR on 933 cases (including 128 F. nucleatum-positive cases) among 4,465 incident colorectal carcinoma cases in two prospective cohorts. Multiplex immunofluorescence combined with digital image analysis and machine learning algorithms for CD3, CD4, CD8, CD45RO (PTPRC isoform), and FOXP3 measured various T-cell subsets. We leveraged data on Bifidobacterium, microsatellite instability (MSI), tumor whole-exome sequencing, and M1/M2-type tumor-associated macrophages [TAM; by CD68, CD86, IRF5, MAF, and MRC1 (CD206) multimarker assay]. Using the 4,465 cancer cases and inverse probability weighting method to control for selection bias due to tissue availability, multivariable-adjusted logistic regression analysis assessed the association between F. nucleatum and T-cell subsets. RESULTS: The amount of F. nucleatum was inversely associated with tumor stromal CD3+ lymphocytes [multivariable OR, 0.47; 95% confidence interval (CI), 0.28-0.79, for F. nucleatum-high vs. -negative category; P trend = 0.0004] and specifically stromal CD3+CD4+CD45RO+ cells (corresponding multivariable OR, 0.52; 95% CI, 0.32-0.85; P trend = 0.003). These relationships did not substantially differ by MSI status, neoantigen load, or exome-wide tumor mutational burden. F. nucleatum was not significantly associated with tumor intraepithelial T cells or with M1 or M2 TAMs. CONCLUSIONS: The amount of tissue F. nucleatum is associated with lower density of stromal memory helper T cells. Our findings provide evidence for the interactive pathogenic roles of microbiota and specific immune cells.

Curcumin Chemoprevention Reduces the Incidence of Braf Mutant Colorectal Cancer in a Preclinical Study.

BACKGROUND: Colorectal cancer is a leading cause of cancer-related death worldwide and approximately 20% of cases can be attributed to a mutation in the BRAF oncogene. Curcumin is a promising chemopreventive agent with various anti-cancer benefits. Although curcumin has been reported to have poor bioavailability, this limitation has been overcome by the formulation of nano-carriers. In this preclinical study, we investigated the ability of an improved formulation of curcumin to reduce the incidence of Braf mutant carcinoma. AIM: To investigate curcumin as a chemopreventive for Braf mutant colorectal cancer in a preclinical study utilizing a murine model of serrated neoplasia. METHODS: An intestine-specific Braf mutant murine model (BrafV637E/+/Villin-CreERT2/+) was administered curcumin micelles (240 mg/kg, n = 69) in normal drinking water. Mice in the control group consumed normal drinking water (n = 83). Mice were euthanized at 14 months and the incidence of murine serrated lesions and carcinoma in each cohort were determined by histologic examination. RESULTS: At completion of the study (14 months), it was found that curcumin did not reduce the incidence or multiplicity of murine serrated lesions but did significantly reduce the number of invasive carcinomas (RR 0.83, 95% CI 0.69-0.9985, P = 0.0360) compared to control. CONCLUSIONS: We have performed the first long-term study assessing curcumin's effect on the development of serrated neoplasia. We found that curcumin significantly reduces the risk of developing Braf mutant colorectal cancer. Our data supports further investigation of curcumin as a chemopreventive to reduce the risk of colorectal cancer arising via the serrated pathway.

Pathways to a cancer-free future: a protocol for modelled evaluations to minimise the future burden of colorectal cancer in Australia.

INTRODUCTION: With almost 50% of cases preventable and the Australian National Bowel Cancer Screening Program in place, colorectal cancer (CRC) is a prime candidate for investment to reduce the cancer burden. The challenge is determining effective ways to reduce morbidity and mortality and their implementation through policy and practice. Pathways-Bowel is a multistage programme that aims to identify best-value investment in CRC control by integrating expert and end-user engagement; relevant evidence; modelled interventions to guide future investment; and policy-driven implementation of interventions using evidence-based methods. METHODS AND ANALYSIS: Pathways-Bowel is an iterative work programme incorporating a calibrated and validated CRC natural history model for Australia (Policy1-Bowel) and assessing the health and cost outcomes and resource use of targeted interventions. Experts help identify and prioritise modelled evaluations of changing trends and interventions and critically assess results to advise on their real-world applicability. Where appropriate the results are used to support public policy change and make the case for optimal investment in specific CRC control interventions. Fourteen high-priority evaluations have been modelled or planned, including evaluations of CRC outcomes from the changing prevalence of modifiable exposures, including smoking and body fatness; potential benefits of daily aspirin intake as chemoprevention; increasing CRC incidence in people aged <50 years; increasing screening participation in the general and Aboriginal and Torres Strait Islander populations; alternative screening technologies and modalities; and changes to follow-up surveillance protocols. Pathways-Bowel is a unique, comprehensive approach to evaluating CRC control; no prior body of work has assessed the relative benefits of a variety of interventions across CRC development and progression to produce a list of best-value investments. ETHICS AND DISSEMINATION: Ethics approval was not required as human participants were not involved. Findings are reported in a series of papers in peer-reviewed journals and presented at fora to engage the community and policymakers.