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Cumulative incidence and mortality of liver cancer according screening status in males stratified by age group at study entry. Poisson regression models were used to calculate P values.
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Current Chinese national guidelines recommend routine screening for liver cancer in patients positive for HBsAg, irrespective of fibrosis status, age, or family history of liver cancer. We aim to evaluate whether the recommended screening strategy could reduce liver-cancer-specific mortality. We conducted a liver cancer mass screening trial in Xiao...
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Context 1
... 95% CI = 0.88, 1.68, P = 0.244). Specifically, liver cancer incidence increased in 2012 (the initial year of screening, P = 0.042), but was not increased in the subsequent years. Stratified analyses showed that liver cancer incidence did not differ significantly between participants and non-participants in different sex and age groups (Table 3; Fig. 2A,B for males, and Fig. S1A,B for females). Liver cancer cases detected among participants had better prognosis than those detected among non-participants (sex-and age-adjusted HR = 0.64, 95% CI = 0.42, 0.98; Fig. S2). Multivariable models further adjusting for clinical stage, treatment, serum alanine transaminase (ALT) levels, albumin, ...
Context 2
... cancer incidence did not differ significantly between participants and non-participants in different sex and age groups (Table 3; Fig. 2A,B for males, and Fig. S1A,B for females). Liver cancer cases detected among participants had better prognosis than those detected among non-participants (sex-and age-adjusted HR = 0.64, 95% CI = 0.42, 0.98; Fig. S2). Multivariable models further adjusting for clinical stage, treatment, serum alanine transaminase (ALT) levels, albumin, bilirubin, and pro- thrombin showed that HR was attenuated (HR = 0.78, 95% CI = 0.48, 1.27). The 1-year and 3-year overall survival proportions for liver cancer cases identified among participants were 48.7% (95% CI ...
Context 3
... P = 0.856) or by age group (Table 3). Because all 5 female liver cancer cases detected among participants were still alive at the end of follow-up, we could not estimate the RR for liver cancer-specific mortality among females. Nevertheless, analysis limited to males showed no significant differences between participants and non-participants (Fig. ...
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Background: Hepatitis D virus (HDV) is a defective RNA pathogen that requires the presence of the hepatitis B virus (HBV) for infection. Middle East countries are endemic areas for HDV infection. So, it is important to estimate the prevalence of HDV in these countries. This study aimed to estimate the prevalence of HDV in HBsAg positive patients pa...
Citations
... between 2012 and 2019. 30 The cases and controls were both tested positive for serum HBV surface antigen (HBsAg) and frequency-matched by age and sex. In the evaluation phase, we assessed the use of ccfDNA fragmentation analysis in differentiating pre-clinical HCC from controls in a nested case-control study based on the same cohort, including 63 incident HCC cases with available pre-diagnosis blood samples and 50 controls frequency-matched to the cases on age at recruitment to the screening trial (G1 year), sex, and time from last blood collection to diagnosis or end of follow-up (G3 months). ...
Genome-wide circulating cell-free DNA (ccfDNA) fragmentation for cancer detection has been rarely evaluated using blood samples collected before cancer diagnosis. To evaluate ccfDNA fragmentation for detecting early hepatocellular carcinoma (HCC), we first modeled and tested using hospitalized HCC patients and then evaluated in a population-based study. A total of 427 samples were analyzed, including 270 samples collected prior to HCC diagnosis from a population-based study. Our model distinguished hospital HCC patients from controls excellently (area under curve 0.999). A high ccfDNA fragmentation score was highly associated with an advanced tumor stage and a shorter survival. In evaluation, the model showed increasing sensitivities in detecting HCC using ‘pre-samples’ collected ≥4 years (8.3%), 3–4 years (20.0%), 2–3 years (31.0%), 1–2 years (35.0%), and 0–1 year (36.4%) before diagnosis. These findings suggested ccfDNA fragmentation is sensitive in clinical HCC detection and might be helpful in screening early HCC.
... Compared with other screening studies conducted in community settings, our study had a higher adherence to the study protocol because of a high degree of organization and effective invitation, that is, 88.0% in the prevalent round and 81.6-83.1% in the incident rounds versus 23.5-80.6% in other studies 14,15,42,43 . The overall detection rate in our study was significantly higher than in two previous community-based screening cohorts with semi-annual screening intervals in China 42,43 . ...
... Compared with other screening studies conducted in community settings, our study had a higher adherence to the study protocol because of a high degree of organization and effective invitation, that is, 88.0% in the prevalent round and 81.6-83.1% in the incident rounds versus 23.5-80.6% in other studies 14,15,42,43 . The overall detection rate in our study was significantly higher than in two previous community-based screening cohorts with semi-annual screening intervals in China 42,43 . In our study, US exams were performed by experienced sonographers with extensive training. ...
Current guidelines recommend hepatocellular carcinoma (HCC) surveillance for at-risk individuals, including individuals with hepatitis B virus infection. However, the performance and survival benefits of annual screening have not been evaluated through multicenter prospective studies in a Chinese population. Between 2017 and 2021, we included 14,426 participants with hepatitis B surface antigen seropositivity in an annual HCC screening study in China using a multicenter prospective design with ultrasonography and serum alpha-fetoprotein. After four rounds of screening and follow-up, the adjusted hazard ratios of death after correction for lead-time and length-time biases for screen-detected cancers at the prevalent and incident rounds were 0.74 (95% confidence interval = 0.60–0.91) and 0.52 (95% confidence interval = 0.40–0.68), respectively. A meta-analysis demonstrated that HCC screening was associated with improved survival after adjusting for lead-time bias. Our findings highlight the ‘real-world’ feasibility and effectiveness of annual HCC screening in community settings for the early detection of HCC and to improve survival.
... It was reported that the sensitivity of screening using US alone or combined US/AFP reached 47% and 63%, respectively, for early-stage HCC (BCLC 0-A) [8]. It was also reported that the compliance of US screening was only 46.87% for a single screening, and was as low as 7.3% for six consecutive screening [9,10]. This compromised the screening capability of US or combined US/ AFP screening. ...
... As described by retrospective studies, the compliance of US screening was only 46.87% for a single screening, and was only 7.3% for six consecutive screening [9,10]. This suggested that the US screening capability was largely compromised by the low compliance, although it is a non-invasive convenient test. ...
Abstract Background The methylation SEPT9 (mSEPT9) appeared to be effective for hepatocellular carcinoma (HCC) detection. However, its performance in high-risk population has not been validated. We designed a pilot study and aimed to investigate the performance of mSEPT9, AFP, PIVKA-II and their combination in hepatic cirrhosis (HC) population. Methods A training cohort was established including 103 HCC and 114 HC patients. 10 ml blood was collected from each patient with K2EDTA tubes, and 3–4 ml plasma was extracted for subsequent tests. The performance of mSEPT9, AFP, PIVKA-II and their combination was optimized by the training cohort. Test performance was prospectively validated with a validation cohort, including 51 HCC and 121 HC patients. Results At the optimal thresholds in the training cohort, the sensitivity, specificity and area under curve (AUC) was 72.82%, 89.47%, 0.84, and 48.57%, 89.92%, 0.79, and 63.64%, 95.95%, 0.79 for mSEPT9, AFP and PIVKA-II, respectively. The combined test significantly increased the sensitivity to 84.47% (P
... In China, nearly onetenth of the population between ages 1 and 59 years are chronic carriers of HBV, which confers a 25-40% lifetime risk of HCC [7]. Accordingly, approximately 80% of HCCs in China occur among chronic HBV carriers [8,9]. ...
... BMC Cancer (2023) 23:250 China). Samples were collected and tested in 2012 when a mass liver cancer screening program was launched in Zhongshan City [9]. Because chronic HBV infection is nearly universally acquired at birth or during early childhood in southern China [15], HBsAg seropositivity in adulthood generally reflects long-term chronic infection. ...
Background
We aimed to investigate associations between pre-diagnostic anti-Epstein-Barr virus (EBV) antibodies, including interactions with hepatitis B virus (HBV), and risk of primary liver cancer in southern China.
Methods
In a population-based nested case-control study, we measured pre-diagnostic immunoglobulin A (IgA) against EBV nuclear antigen 1 (EBNA1) and viral capsid antigen (VCA) in 125 primary liver cancer cases and 2077 matched controls. We also explored the interaction between HBV surface antigen (HBsAg) and anti-EBV antibodies.
Results
Participants with positive EBNA1-IgA, positive VCA-IgA or single-positive anti-EBV antibodies had two-fold odds of developing liver cancer, compared with seronegative subjects. The odds ratios (ORs) between the relative optical density of EBNA1-IgA and VCA-IgA and primary cancer, controlling for age and HBsAg, were 1.59 (95% confidence interval (CI): 1.17, 2.14) and 1.60 (95% CI: 1.07, 2.41), respectively. Subjects with both HBsAg and anti-EBV antibody seropositivity were at 50-fold increased risk compared with those negative for both biomarkers (OR: 50.67, 95% CI: 18.28, 140.46), yielding a relative excess risk due to interaction of 30.81 (95% CI: 3.42, 114.93).
Conclusion
Pre-diagnostic seropositivity for EBNA1-IgA and/or VCA-IgA was positively associated with primary liver cancer risk, especially in combination with HBsAg positivity. EBV may interact with HBV in the development of primary liver cancer, and anti-EBV antibodies might be potential biomarkers for primary liver cancer in this high-risk population.
... One randomized controlled trial in Qidong showed that, even after earlier diagnosis of liver cancer, it may not reduce overall liver cancer mortality with a screening strategy using serum α-fetoprotein detection for first-line screening and then B-mode ultrasound scan for suspicious cases [46]. Similarly, in another large-scale population study in Zhongshan city of Guangdong, no significant reduction of liver cancer mortality was achieved by the similar screening strategy [47]. In recent years, biomarkers, such as GALAD (gender × age × log alpha-fetoprotein [AFP] × des-gamma-carboxy prothrombin), have been applied in the surveillance of cirrhosis to detect earlystage liver cancer, which provides alternative approaches for non-invasive and effective screening [48]. ...
Background:
Over the past four decades, the Chinese government has conducted three surveys on the distribution of causes of death and built cancer registration. In order to shine a new light on better cancer prevention strategies in China, we evaluated the profile of cancer mortality over the forty years and analyzed the policies that have been implemented.
Methods:
We described spatial and temporal changes in both cancer mortality and the ranking of major cancer types in China based on the data collected from three national surveys during 1973-1975, 1990-1992, 2004-2005, and the latest cancer registration data published by National Central Cancer Registry of China. The mortality data were compared after conversion to age-standardized mortality rates based on the world standard population (Segi's population). The geographical distribution characteristics were explored by marking hot spots of different cancers on the map of China.
Results:
From 1973 to 2016, China witnessed an evident decrease in mortality rate of stomach, esophageal, and cervical cancer, while a gradual increase was recorded in lung, colorectal, and female breast cancer. A slight decrease of mortality rate has been observed in liver cancer since 2004. Lung and liver cancer, however, have become the top two leading causes of cancer death for the last twenty years. From the three national surveys, similar profiles of leading causes of cancer death were observed among both urban and rural areas. Lower mortality rates from esophageal and stomach cancer, however, have been demonstrated in urban than in rural areas. Rural areas had similar mortality rates of the five leading causes of cancer death with the small urban areas in 1973-1975. Additionally, rural areas in 2016 also had approximate mortality rates of the five leading causes with urban areas in 2004-2005. Moreover, stomach, esophageal, and liver cancer showed specific geographical distributions. Although mortality rates have decreased at most of the hotspots of these cancers, they were still higher than the national average levels during the same time periods.
Conclusions:
Building up a strong primary public health system especially among rural areas may be one critical step to reduce cancer burden in China.
... In China, nearly one-tenth of the population between ages 1 and 59 years are chronic carriers of HBV, which confers a 25-40% lifetime risk of HCC [7]. Accordingly, approximately 80% of HCCs in China occur among chronic HBV carriers [8,9]. ...
... HBsAg in serum was detected by ELISA following the manufacturer's instructions (Autobio Diagnostics Co., China). Samples were collected and tested in 2012 when a mass liver cancer screening program was launched in Zhongshan City [9]. Because chronic HBV infection is nearly universally acquired at birth or during early childhood in southern China [15], HBsAg seropositivity in adulthood generally re ects long-term chronic infection. ...
Background
We aimed to investigate associations between pre-diagnostic anti-Epstein-Barr virus (EBV) antibodies, including interactions with hepatitis B virus (HBV), and risk of primary liver cancer in southern China.
Methods
In a nested population-based case-control study, we measured pre-diagnostic immunoglobulin A (IgA) against EBV nuclear antigen 1 (EBNA1) and viral capsid antigen (VCA) in 125 primary liver cancer cases and 2077 matched controls. We also explored the interaction between HBV surface antigen (HBsAg) and anti-EBV antibodies.
Results
Participants with positive EBNA1-IgA, positive VCA-IgA or single-positive anti-EBV antibodies had 50–60% greater risk of developing liver cancer, compared with seronegative subjects. The odds ratios (ORs) between the relative optical density of EBNA1-IgA and VCA-IgA and primary cancer, controlling for age and HBsAg, were 1.59 (95% confidence interval (CI): 1.17, 2.14) and 1.60 (95% CI: 1.07, 2.41), respectively. Subjects with both HBsAg and anti-EBV antibody seropositivity were at 50-fold increased risk compared with those negative for both biomarkers (OR: 50.67, 95% CI: 18.28, 140.46), yielding a relative excess risk due to interaction of 30.81 (95% CI: 3.42, 114.93).
Conclusion
Pre-diagnostic seropositivity for EBNA1-IgA and/or VCA-IgA was positively associated with primary liver cancer risk, especially in combination with HBsAg positivity. EBV may interact with HBV in the development of primary liver cancer, and anti-EBV antibodies might be potential biomarkers for primary liver cancer in this high-risk population.
... Liver cancer is the fourth leading cause of cancer-related death globally and its incidence is growing with estimates of over a million cases per year by 2025 [62]; however, a mass screening trial for liver cancer in China using serum alpha-fetoprotein and ultrasonography did not yield a reduction in liver cancer-specific mortality [63]. Incidence for this cancer type in the SEER database is higher amongst males (Fig W in S1 Appendix). ...
Cancer is one of the leading causes of death, but mortality can be reduced by detecting tumors earlier so that treatment is initiated at a less aggressive stage. The tradeoff between costs associated with screening and its benefit makes the decision of whom to screen and when a challenge. To enable comparisons across screening strategies for any cancer type, we demonstrate a mathematical modeling platform based on the theory of queuing networks designed for quantifying the benefits of screening strategies. Our methodology can be used to design optimal screening protocols and to estimate their benefits for specific patient populations. Our method is amenable to exact analysis, thus circumventing the need for simulations, and is capable of exactly quantifying outcomes given variability in the age of diagnosis, rate of progression, and screening sensitivity and intervention outcomes. We demonstrate the power of this methodology by applying it to data from the Surveillance, Epidemiology and End Results (SEER) program. Our approach estimates the benefits that various novel screening programs would confer to different patient populations, thus enabling us to formulate an optimal screening allocation and quantify its potential effects for any cancer type and intervention.
... The prognosis of liver cancer patients is generally poor, with a 5-year survival rate of less than 5%. 3 However, prognosis varies strongly by disease stage at diagnosis. Early-stage liver cancer is amenable to curative therapy, enabling a 5-year survival rate of 40%-70%. ...
China has made rapid progress in reducing the incidence of HBV infection in the past three decades, along with a rapidly changing lifestyle and aging population. We aimed to develop and validate an up‐to‐date liver cancer risk prediction model with routinely available predictors and evaluate its applicability for screening guidance. Using data from the China Kadoorie Biobank, we included 486 285 participants in this analysis. Fifteen risk factors were included in the model. Flexible parametric survival models were used to estimate the 10‐year absolute risk of liver cancer. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. A total of 2706 participants occurred liver cancer over the 4 814 320 person‐years of follow‐up. Excellent discrimination of the model was observed in both development and validation datasets, with c‐statistics (95% CI) of 0.80 (0.79‐0.81) and 0.80 (0.78‐0.82) respectively, as well as excellent calibration of observed and predicted risks. Decision curve analysis revealed that use of the model in selecting participants for screening improved benefit at a threshold of 2% 10‐year risk, compared to current guideline of screening all HBsAg carriers. Our model was more sensitive than current guideline for cancer screening (28.17% vs 25.96%). We developed and validated a CKB‐PLR (Prediction for Liver cancer Risk Based on the China Kadoorie Biobank Study) model to predict the absolute risk of liver cancer for both HBsAg seropositive and seronegative populations. Application of the model is beneficial for precisely identifying the high‐risk groups among the general population.
... In China, chronic HBV infection remains the leading risk factor of HCC [1]. Results of a HCC-screening demonstration program using US/AFP biannually to HBsAgpositive adults in some rural communities of China showed no reduction in liver cancer mortality within rst 4 years of follow-up [4]. Antiviral therapy rarely cures HBV infection and needs life-long medications, considerable carriers with seropositive for hepatitis B surface antigen (HBsAg) did not receive the therapy [1,5]. ...
... Previous studies conducted in rural community showed that < 40% of the HBsAg-positive adults complied to the biannually repeat US/AFP tests after initial 2-3 years for HCC-screening [4,17]. HCC development depends on presence of premalignant cells and signi cantly in uenced by the underlying severity and activity of liver diseases [1,18]. ...
BACKGROUND: Hepatocellular carcinoma (HCC) development among hepatitis B surface antigen (HBsAg) carriers shows gender disparity, influenced by underlying liver diseases that display variations in laboratory tests. We aimed to construct a risk-stratified HCC prediction model for HBsAg-positive male adults.
METHODS: HBsAg-positive, 35-69 years males (N=6 153) were recruited from a multi-center population-based liver cancer screening study. Randomly, three centers were set as training, the other three centers as validation. Within 2 years since initiation, we administrated at least two rounds of HCC screening using B-ultrasonography and α-fetoprotein (AFP). We used logistic regression models to determine potential risk factors, built and examined the operating characteristics of a point-based algorithm for HCC risk prediction.
RESULTS: With 2 years of follow-up, 302 HCC cases were diagnosed. A male-ABCD algorithm was constructed including participant’s Age, Blood levels of GGT (γ-glutamyl-transpeptidase), Counts of platelets, white cells, Concentration of DCP (des-γ-carboxy-prothrombin) and AFP, with scores ranging from 0 to 18.3. The area under receiver operating characteristic was 0.91(0.89-0.93), larger than existing models. At 1.5 points of risk-score, 26.10% of the participants in training, 14.94% in validation were recognized at-low-risk, with sensitivity of identifying HCC remained 100%. At 2.5 points, 46.51% of the participants in training, 33.68% in validation were recognized at-low-risk with 99.06% and 97.78% of sensitivity. At 4.5 points, only 20.86% of training, 23.73% of validation were recognized at-high-risk, with positive prediction value of 22.85% and 12.35% respectively.
DISCUSSION: Male-ABCD algorithm identified individual’s risk for HCC occurrence within short-term for their HCC precision surveillance.
... Although the evidence for the population efficacy of liver screening remains limited at a global level, 86,87 screening individuals at higher risk 88 or screening population with high incidence rates appears promising and is potentially cost-effective. 89 In China, the country with the highest burden of liver cancer worldwide, there is a great demand for identifying high-performance potential biomarkers, imaging examinations, and comprehensive prediction model for liver cancer screening and early detection and then translating/incorporating the use of these tests into effective clinical practice. ...
A substantial proportion of liver cancers is attributable to chronic infection with hepatitis B and C (HBV/HCV). Liver cancer could become the second cancer, after cervical, to be effectively controlled globally, if proven interventions such as vaccination can be implemented on a large scale. In 2018, the global mortality rate for liver cancer was estimated to be 8.5 per 100 000 individuals. Given patterns of HBV infection and immigration across countries, liver cancer control requires combined, global action. Liver cancer trends vary between countries, in some Western countries, the incidence rates were relatively low but have increased in recent decades; conversely, in several Asian countries, the incidence rates have decreased over time. China has in the past contributed more than half of the global burden of liver cancer but more recently a national decline in liver cancer incidence has been observed. Here, we review the liver cancer burden and exposure to risk factors in China, compared to other countries. We also review the implementation status for primary and secondary prevention interventions and major outcomes achieved over the past three decades. Using Bayesian age‐period‐cohort analysis, we examine recent trends and based on these, predict that by 2050, the incidence of liver cancer in China could fall by half. We additionally survey the literature to identify current research needs, and review relevant national policies on liver cancer control in China. A comprehensive set of interventions is proposed to progress toward the long‐term goal of liver cancer elimination based on the natural history and evidence‐based interventions.
