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Abstract The limited performance of guideline‐recommended abdominal ultrasound and serum alpha‐fetoprotein (AFP) highlights the urgent, unmet need for new biomarkers for more accurate detection of early hepatocellular carcinoma (HCC). To this end, we have conducted a prospective clinical validation study to evaluate the performance of the HelioLiver Test, a multi‐analyte blood test combining cell‐free DNA methylation patterns, clinical variables, and protein tumor markers. A blinded, multicenter validation study was performed with 247 subjects, including 122 subjects with HCC and 125 control subjects with chronic liver disease. The performance of the HelioLiver Test was compared with AFP and the GALAD score as established HCC surveillance blood tests. The performance of the HelioLiver Test (area under the receiver operating characteristic curve [AUROC] = 0.944) was superior to both AFP (AUROC = 0.851; p < 0.0001) and GALAD (AUROC = 0.899; p < 0.0001). Using a prespecified diagnostic algorithm, the HelioLiver Test showed sensitivities of 85% (95% confidence interval [CI], 78%–90%) for HCC of any stage and 76% (95% CI, 60%–87%) for early stage (American Joint Committee on Cancer [AJCC] I and II) HCC. In contrast, AFP (≥20 ng/mL) alone and the GALAD score (≥−0.63) showed lower sensitivities of 62% (95% CI, 54%–70%) and 75% (95% CI, 67%‐82%) for HCC overall, and 57% (95% CI, 40%–71%) and 65% (95% CI, 49%–79%) for early stage (AJCC I and II) HCC, respectively. The specificities of the HelioLiver Test (91%; 95% CI, 85%–95%), AFP (97%; 95% CI, 92%–99%), and the GALAD score (94%; 95% CI, 88%–97%) were similar for control subjects. The HelioLiver Test showed superior performance for HCC detection compared to with both AFP and the GALAD score and warrants further evaluation in HCC surveillance settings.

Summary: Hepatocellular carcinoma (HCC) is a major public health problem worldwide for which the incidence and mortality are similar, pointing to the lack of effective treatment options. Knowing the different issues involved in the management of HCC, from risk factors to screening and management, is essential to improve the prognosis and quality of life of affected individuals. This document summarises the current state of knowledge and the unmet needs for all the different stakeholders in the care of liver cancer, meaning patients, relatives, physicians, regulatory agencies and health authorities so that optimal care can be delivered to patients. The document was commissioned by the International Liver Cancer Association and was reviewed by senior members, including two ex-presidents of the Association. This document lays out the recommended approaches to the societal management of HCC based on the economic status of a given region.

Summary: Outside of expert centres, surveillance programmes for hepatocellular carcinoma (HCC) are not well executed. There are deficiencies in every stage of the process. Overcoming these obstacles is the most important method for improving surveillance. However, even if these obstacles were overcome, there would still be room for improvement. Assessing who is at risk of developing HCC remains incompletely validated. At present, risk scores have been developed for different causes of liver disease, but scores developed in different parts of the world for the same disease do not always agree. Furthermore, most scores stratify patients by risk but do not examine what level of risk should trigger surveillance. Which surveillance tools to use remains controversial – schemes have been proposed that use biomarkers alone, ultrasound alone, or a combination of both. However, the requisite level of test sensitivity that would be associated with high cure rates has not been defined, so at this point it is not clear whether surveillance requires both ultrasound and biomarkers, or whether the use of biomarkers alone is sufficient. Finally, surveillance should result in the identification of HCC at a very early stage. Diagnosing these lesions is difficult and optimal algorithms for lesions that are atypical on radiology have yet to be developed. Algorithms for the follow-up of abnormal biomarkers in the absence of ultrasound have also not been developed yet. Keywords: hepatocellular carcinoma, Risk Score, Surveillance, LI-RADS

Introduction: Radiofrequency ablation (RFA) is a recommended curative intent treatment option for patients with early stage hepa-tocellular carcinoma (HCC). We investigated if wait times for RFA were associated with residual tumor, tumor recurrence, need for liver transplantation, or death. Material and methods: We conducted a retrospective study of patients diagnosed with HCC between January 2010 and December 2013 presenting to University Health Network (UHN) in Toronto, Canada. All patients receiving curative intent RFA for HCC were included. Multivariable Cox regression was used to determine if wait times were associated with clinical outcomes. Results: 219 patients were included in the study. 72.6% were male and the median age was 62.7 years (IQR 55.6-71). Median tumor size at diagnosis was 21.5 mm (IQR 17-26); median MELD was 8.7 (IQR 7.2-11.4) and 57.1% were Barcelona stage 0. The cause of liver disease was viral hepatitis in 73.5% (Hepatitis B and C). The median time from HCC diagnosis to RFA treatment was 96 days (IQR 75-139). In multivariate analysis, wait time was not associated with requiring liver transplant or tumor recurrence, however, each incremental 30-day wait time was associated with an increased risk of residual tumor (HR = 1.09; 95% CI 1.01-1.19; p = 0.033) as well as death (HR = 1.23; 95% CI 1.11-1.36; p ≤ 0.001). Conclusion: Incremental 30-day wait times are associated with a 9% increased risk of residual tumor and a 23% increased risk of death. We have identified system gaps where quality improvement measures can be implemented to reduce wait times and allocate resources for future RFA treatment, which may improve both quality and efficiency of HCC care.

BACKGROUND: The effectiveness of surveillance for hepatocellular carcinoma (HCC) using ultrasound (US) in North America has been questioned due to the predominance of patients of Caucasian ethnicity and larger body habitus.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide and its incidence has rapidly increased in North America in recent years. Although there are many published guidelines to assist the clinician, there remain gaps in knowledge and areas of controversy surrounding the diagnosis and management of HCC. In February 2014, the Canadian Association for the Study of the Liver organized a one-day single-topic consensus conference on HCC. Herein, the authors present a summary of the topics covered and the result of voting on consensus statements presented at this meeting.

Background and aim. The lack of information about hepatocellular carcinoma (HCC) in Brazil weakens health policy in preventing deaths from the illness. The aim of this study was to establish the cumulative incidence and the risk factors for hepatocellular carcinoma development in patients under a surveillance program.Material and methods. 884 patients with compensated cirrhosis were prospectively followed up for at least five years, from August 1998 until August 2008, with at least one annual ultrasonography liver examination and serum alpha fetoprotein (AFP) measurement.Results. Among 884 patients, 72 (8.1%) developed a tumor with a median follow up of 21.4 months. In the hepatocellular carcinoma group, hepatitis C virus infection was the major etiological factor (65.3%), 56.9% (41/72) were male and the mean average age was 57 ± 10 years. The annual incidence of hepatocellular carcinoma was 2.9%. 79.2% (57/72) of HCCs were detected within Milan Criteria, and the mean survival time was 52.3 months, significantly higher than for those outside Milan, with a mean time of 40.6 months (p = 0.0003).Conclusion. The annual incidence of HCC among this large series of Brazilian cirrhotic patients was around 2.9% with a detection rate of 8.1%, or a cumulative incidence rate over five years of 14.3%. The three variables related to HCC risk were low serum albumin [HR: 0.518 (0.46-0.78)], high AFP > 20 ng/mL [HR: 3.16 (1.86-5.38)], and ethnicity (Brazilian-East Asian descendants vs. other mixed Brazilian ethnicities) [HR: 2.86 (1.48-5.53)].

BACKGROUND: Chronic infection with hepatitis C virus (HCV) is a major cause of cirrhosis, hepatocellular carcinoma and liver transplantation.

OBJECTIVE: To determine whether there is a significant difference in tumour stage between patients initially found with hepatocellular carcinoma (HCC) at a tertiary hepatobiliary centre and patients referred with tumours detected elsewhere; and to determine variables associated with referral in a palliative stage.

BACKGROUND: The effect of chronic hepatitis B (CHB) infection on health-related quality of life (HRQoL) and health state utilities has not been well characterized.

Background. Current practice guidelines recommend liver biopsy prior to treatment of hepatitis C genotype-1 but not for genotype-2/3; this is based on expert opinion, not on published evidence. Methods. In retrospective analysis of a large trial database prior to the publication of recent guidelines, we compared outcomes in 985 treatment-naïve patients with hepatitis C who did or did not undergo liver biopsy before starting peginterferon alfa-2a plus ribavirin. Results. Physicians elected to treat 141/654 (21.6%) genotype-1 patients and 126/331 (38.1%) genotype-2/3 patients without liver biopsy. There were no differences in baseline characteristics among those with or without pre-treatment liver biopsy, except for female preponderance in genotype-1 patients with liver biopsy. The sustained viral response (SVR) rate was no different amongst genotype-2/3 patients who had a biopsy before treatment with 66.3% SVR vs. 69.8% of those treated without biopsy (p = 0.546), but significantly higher among genotype-1 patients with pre-treatment liver biopsy at 54.6 vs. 44.0% for those treated without a liver biopsy (p = 0.029). In genotype-1 patients with liver biopsy, more patients with cirrhosis had dose adjustments (p = 0.0057) rather than drug discontinuation. There was tendency for earlier discontinuation among patients without pre-treatment liver biopsy. Conclusions. Pre-treatment liver biopsy was associated with better SVR amongst genotype-1 patients. This improvement may reflect ongoing commitment to completing the treatment course by both patient and physician. In genotype-2/3 patients, pre-treatment liver biopsy may not be essential to maximize SVR rates. This study validates the recommendations of the most recent treatment guidelines for hepatitis C.

BACKGROUND: In patients chronically infected with the hepatitis C virus (HCV), it is not established whether viral outcomes or health-related quality of life (HRQoL) differ between individuals treated at academic or community centres.

BACKGROUND: Pegylated interferon (pegIFN) and ribavirin combination therapy remains the first-line treatment for chronic hepatitis C virus (HCV) infection. In contrast to the wealth of studies in treatment-naive patients, the effectiveness of retreatment in patients who have previously failed pegIFN-based therapy is largely unreported.

OBJECTIVES: Current guidelines, based on expert opinion, recommend that suspected 1 cm to 2 cm hepatocellular carcinoma (HCC) detected on screening be biopsied and, if positive, treated (eg, resection or transplantation). Alternative strategies are immediate treatment or observation until disease progression occurs.

Today, combination antiviral therapy with pegylated interferon-alpha and ribavirin (RBV) allows many patients infected with hepatitis C virus (HCV) to achieve a sustained virological response, which is equivalent to cure. Data also support the clinical benefit of combination antiviral therapy in patients coinfected with HCV and HIV, and in patients who have received a liver transplant.

Several government and nongovernment organizations held a consensus conference on the management of acute and chronic viral hepatitis to update previous management recommendations. The conference became necessary because of the introduction of new forms of therapy for both hepatitis B and hepatitis C. The conference issued recommendations on the investigation and management of chronic hepatitis B, including the use of lamivudine, adefovir and interferon. The treatment of hepatitis B in several special situations was also discussed. There were also recommendations on the investigation and treatment of chronic hepatitis C and hepatitis C-HIV coinfection. In addition, the document makes some recommendations about the provision of services by provincial governments to facilitate the delivery of care to patients with hepatitis virus infection. The present document is meant to be used by practitioners and other health care providers, including public health staff and others not directly involved in patient care.

Hepatocellular carcinoma most commonly occurs in patients with underlying liver disease or cirrhosis. We describe a case of hepatocellular carcinoma in a 34-year-old man with Crohn’s disease treated with azathioprine and infliximab. The patient had no history of liver disease and a complete autoimmune and viral workup was unremarkable. Unfortunately, the patient developed widespread metastatic disease and passed away 5 months after his initial diagnosis. The mechanism of hepatocellular carcinoma in patients’ with Crohn’s disease is poorly understood and may include both autoimmunity and treatment-related complications. Previous case reports suggest the possibility of a concerning association between azathioprine therapy and the development of hepatocellular carcinoma in patients with Crohn’s disease. Clinicians may consider early imaging in patients with Crohn’s disease presenting with concerning symptomatology or abnormal liver enzymes, especially in those being treated with azathioprine alone or in combination with infliximab. Future research may help to uncover additional risk factors for this exceedingly rare diagnosis in this patient population.

Corticosteroid therapy for acute alcoholic hepatitis has been demonstrated to enhance survival in patients who are encephalopathic, and who do not have renal failure or gastrointestinal bleeding. However, the complications of steroid therapy in such patients have been less well documented. The authors report two patients with alcoholic liver disease who developed life-threatening infections after steroid therapy was started. The first patient initially developed diabetes followed by Fournier's gangrene of the perineum, and a lung abscess following septic emboli. The second patient had established alcoholic cirrhosis rather than alcoholic hepatitis. She developed a necrotic ulcer on the arm at the site of an intravenous line, which was infected with a rhizopus species. Despite surgical debridement the lesion progressed and contributed to her death. Treatment of alcoholic hepatitis with steroids is not innocuous, and physicians should be aware of the potential for life-threatening complications.

BackgroundResearch has shown that people from higher socioeconomic status (SES) have better hepatocellular carcinoma (HCC) survival outcomes, although no such research has been carried out in Canada. We aimed to assess if an association between SES and HCC survival existed in the Canadian context.Methodology/principal findingsWe conducted a population-based cohort study linking HCC cases identified in the Ontario Cancer Registry between 1990 and 2009 to administrative and hospital data. Logistic regression and chi-squared tests were used to evaluate associations between SES (income quintile) and covariates. The Kaplan-Meier method was used to estimate survival. Sequential analysis of the proportional-hazards models were used to determine the association between SES and HCC survival controlling for potential prognostic covariates. During the period 1990-2009, 5,481 cases of HCC were identified. A significant association was found between SES and curative treatment (p = 0.0003), but no association was found between SES and non-curative treatment (p = 0.064), palliative treatment (p = 0.680), or ultrasound screening (p = 0.615). The median survival for the lowest SES was 8.5 months, compared to 8.8 months for the highest SES group. The age- and sex-adjusted proportional-hazards model showed statistically significant difference in HCC survival among the SES groups, with hazard ratio 0.905 (95% confidence intervals 0.821, 0.998) when comparing highest to lowest SES group. Further adjustments indicated that potentially curative treatment was the likely explanation for the association between SES and HCC survival.Conclusions/significanceOur findings suggest that a 10% HCC survival advantage exists for the higher SES groups. This association between SES and HCC survival is most likely a reflection of lack of access to care for low SES groups, revealing inequities in the Canadian healthcare system.

The present document presents the proceedings of the consensus development conference on the management of viral hepatitis held in January 2007 under the auspices of the Canadian Association for the Study of the Liver and the Association of Medical Microbiology and Infectious Disease Canada. Several new agents have become available since the last such document was published in 2004, and new information has become available to help assess risk of adverse outcomes and who should be treated. In addition, the participants at the meeting identified a number of structural barriers that exist uniquely in Canada and that prevent physicians from properly managing their patients. The conference discussed the selection of patients for treatment and the drugs that can be used to treat these patients, as well as the treatment of hepatitis B in special populations. The present document should be read in conjunction with the companion document on the management of chronic hepatitis C.

Since the last consensus conference on the management of chronic viral hepatitis, a number of studies looking at modifications of the standard course of treatment have been published. These changes have been sufficiently substantive to warrant review to determine whether any changes in the recommended treatment algorithms are needed. A consensus development conference was held in January 2007, and the present document highlights the results of the presentations and discussion about these issues. It reviews the epidemiology of hepatitis C in Canada, treatment of acute hepatitis C and new algorithms in chronic hepatitis C, including retreatment of previous treatment failures. In addition, sections on management of hepatitis C in special populations have been updated. There is also a section on the use of hematopoietic growth factors to help manage patients on therapy. The document should be read in conjunction with the previous document to identify changes. Some recommendations made in the previous document remain and are not discussed here.