- Email: [email protected]
686 PROGRESSION AND PATHOGENESIS ROLE OF RNA BINDING PROTEIN La-RELATED PROTEIN 1 IN HEPATOCELLULAR CARCINOMAS
POSTERS 684 IMPACT OF REGIONAL Foxp3 EXPRESSION WITHIN THE TUMOR MICROENVIRONMENT ON TUMOR BIOLOGY AND MORTALITY IN HEPATITIS B-ASSOCIATED HEPATOCELLULAR CARCINOMA Q. Wang1 , W. Luan1 , M.I. Fiel2 , S. Blank1 , H. Kadri1 , K.W. Kim1 , S.P. Hiotis1 . 1 Surgery, 2 Pathology, Mount Sinai School of Medicine, New York, NY, USA E-mail: [email protected] Background and Aims: Foxp3-expressing regulatory T cells impede effective immune surveillance against cancer and inhibit anti-tumor immune responses, thereby influencing the biological behavior of many, but not all tumors. This study aims to determine the microenvironment-specific influence of Foxp3 expression on tumor biology of hepatitis B-associated hepatocellular carcinoma (HBVHCC). Methods: This prospective study includes 90 HBV-HCC surgical resection patients enrolled between 2008–2012 at the Mount Sinai Medical Center in New York. Foxp3 mRNA in four regions of the resection specimens (center of the tumor, periphery of the tumor, non-neoplastic liver bordering tumor, non-neoplastic liver distant from tumor) was quantitated for each case using real-time PCR. Resection specimens were assessed by a single dedicated liver pathologist to evaluate tumor characteristics as well as liver fibrosis using the Ishak method. Results: Foxp3 mRNA was detectable in all four regions of all the samples. While no differences were observed in median Foxp3 expression between tumor and non-neoplastic liver, Foxp3 expression in center of the tumor showed the greatest variance and skewed most towards the highest values (variance: 1603, 371, 66 and 110; and skewness: 6.8, 4.0, 3.4, 2.3, in center of the tumor, periphery of the tumor, non-neoplastic liver bordering tumor, nonneoplastic liver distant from tumor, respectively). This high variance in the tumor was due to the high variance in the highest quintile of Foxp3 expression, and was not observed in tumors that were associated with less fibrotic liver (Ishak stage 1–4), or in tumors that were well-differentiated. High Foxp3 expression in the tumor (highest quintile) was associated with mortality (6/17 (35%) vs. 5/64 (8%), p = 0.009). Likewise, mortality was associated with high Foxp3 expression (13.1 vs. 2.7, p = 0.015) and high variance (9325 vs. 524) in center of the tumor, but not in the other three compartments. Conclusions: A small population of HBV-HCC patients (20%) had high Foxp3 expression within the tumor microenvironment that is highly variable and associated with mortality following surgical resection. Therefore, HCC predominated by a Foxp3dependent immune-suppressive environment is associated with poor prognosis following surgical resection. 685 ALPHA-FETOPROTEIN MEASUREMENT IN THE DIAGNOSIS OF HEPATOCELLULAR CARCINOMA IN REAL-LIFE PRACTICE: A MULTI-CENTRE, RETROSPECTIVE ANALYSIS G. Webb1 , K. Wright2 , E. Harrod3 , D. Gorard1 , J. Collier2 , A. Evans3 . 1 Gastroenterology, Wycombe Hospital, High Wycombe, 2 Gastroenterology, John Radcliffe Hospital, Oxford, 3 Gastroenterology, Royal Berkshire Hospital, Reading, UK E-mail: [email protected] Background and Aims: In hepatocellular carcinoma (HCC), earlier diagnosis improves outcome but the optimum method of surveillance in high-risk groups is controversial. Recent AASLD and EASL guidelines [1,2] have recommended sixmonthly ultrasound surveillance (USS) alone. British guidelines [3] currently recommend combining serial alpha-fetoprotein (aFP) measurements with six-monthly USS. This study aimed to assess the role of aFP measurement in HCC surveillance programmes. Methods: This large retrospective multicentre study assessed newly diagnosed HCC over a 5-year period (2006–2011) at three centres: S278
two general hospitals and one tertiary referral centre. Electronic and multi-disciplinary team data were reviewed. Results: 111 patients with a confirmed diagnosis of HCC were identified. Of these, 91 (81.9%) were male and the median age was 69 years (range 24–87). 52 (46.8%) patients with newly diagnosed HCC had established liver disease prior to diagnosis. Of these, 21 (40.4%) were participating in combined USS-aFP surveillance, 2 (3.8%) USS alone and 1 (1.9%) aFP alone. A diagnosis of HCC was confirmed by liver biopsy in 43 (38.7%), CT in 41 (36.9%), MRI in 25 (22.5%) and USS combined with elevated aFP in 2 (1.8%). At diagnosis, aFP was elevated in 81 (73.0%), normal in 22 (19.8%) and unmeasured in 8 (7.2%) patients. Of those 21 diagnosed in an established surveillance program of six-monthly USS and aFP, 17 (81.0%) showed a rise in aFP. When assessing the trigger for confirmatory cross-sectional imaging ± biopsy across all data, a solely elevated aFP prompted further investigation in 11 (9.9%); in those under surveillance, this number was 7 (29.2%) with no abnormality detected on USS within the preceding three-month period in 6 (85.7%) of these. Conclusions: These results demonstrate that a significant number of patients would have had a delayed diagnosis of HCC if aFP measurement was removed from UK screening programmes. Potential contributing factors limiting the success of USS-based screening programmes include: small lesion size, sonographer error, patient factors limiting USS accuracy (e.g. body habitus) and irregular attendance for USS. This study supports continued serial measurement of aFP in patients with liver cirrhosis in contrast to European and American guidelines. Reference(s) [1] Hepatology, vol. 53(3)1020–1022, Mar. 2011. [2] Journal of Hepatology, vol. 56(4)908–943, Apr. 2012. [3] Gut, vol. 52(3)iii1–iii8, 2003.
686 PROGRESSION AND PATHOGENESIS ROLE OF RNA BINDING PROTEIN La-RELATED PROTEIN 1 IN HEPATOCELLULAR CARCINOMAS C. Xie, Q.-S. Zhang, J.-Q. Xie, L. Peng, G.-L. Zhang, D.-Y. Xie, Z.-L. Gao. Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China E-mail: [email protected] Background: La-related protein 1 (LARP1), was first described in Drosophila and shown to be required for embryogenesis, spermatogenesis, cell cycle progression and epithelial–mesenchymal transition (EMT). However, the functional significance of LARP1 in human cancer remains unknown. Methods: We investigated LARP1 expression in 263 hepatocellular carcinomas (HCC) paraffin-embedded archival samples using immunohistochemistry. mRNA and protein levels of LARP1 expression in 15 HCC cell lines, and 6 paired HCC lesions and the adjacent noncancerous tissues were examined. Statistical analyses were applied to derive prognostic and diagnostic associations between LARP1 and clinical characters. The effect of endogenous LARP1 on cell invasion and anchorage-independent growth ability was examined in vitro. Western blotting and Immunofluorescence analyses were performed to identify the effects of LARP1overexpression or -knockdown on expression of cell EMT markers. Results: The expression of LARP1 was markedly up-regulated in HCC cell lines and surgical HCC specimens at both transcriptional and translational levels. Immunohistochemical analysis revealed that 160 of 263 (60.8%) HCC specimens exhibited high levels of LARP1 expression. Statistical analysis suggested the upregulation of LARP1 was significantly correlated with the clinical staging of the HCC patients (P = 0.001), TNM classification (P = 0.002), and tumor number (P = 0.045) and those patients with high LARP1 levels exhibited shorter survival time (P < 0.001). Importantly, this
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POSTERS correlation remained significant in patients with early-stage HCC or with normal serum AFP level. Multivariate analysis indicated that LARP1 expression might be an independent prognostic indicator of the survival of patients with HCC. Furthermore, we found that ectopic expression of LARP1 induced, while silencing LARP1 inhibited, cell invasion and anchorage-independent growth ability. Moreover, we demonstrated that the upregulation of LARP1 could reduce the expression of e-cadherin and induce the expression of fibronectin. Conclusions: Our findings suggest that the LARP1 protein is a valuable marker of HCC progression and may represent a novel prognostic biomarker and therapeutic target for the disease. 687 SERUM IP-10 LEVEL ASSOCIATED WITH HEPATOCELLULAR CARCINOMA DEVELOPMENT IN PATIENTS WITH CHRONIC HEPATITIS B H.-I. Yang1 , Y.-C. Chien2 , M.-H. Lee3 , J. Liu4 , H.-Y. Chen5 , C.-J. Liu4 , C.-L. Jen5 , D. Tsai5 , R. Batrla-Utermann6 , U. Iloeje7 , P.-J. Chen4 , C.-J. Chen5 , the REVEAL-HBV Study Group. 1 China Medical University, 2 China Medical University Hospital, Taichung, 3 National Yang-Ming University, 4 National Taiwan University, 5 Academia Sinica, Taipei, Taiwan R.O.C.; 6 Roche Diagnostics, Basel, Swaziland, 7 Bristol-Myers Squibb Company, Wallingford, CT, USA E-mail: [email protected] Background and Aims: Hepatocellular carcinoma (HCC) is considered a long-term sequelae of interaction between virus, host, and environmental factors. Interferon gamma-induced protein 10 (IP-10) is a member of the CXC chemokine family, which has been shown to be a chemoattractant and involve in a variety of immune and inflammatory reactions. This study aimed to investigate the serum level of IP-10 in association with HCC development in patients with chronic hepatitis B (CHB). Methods: This study was based on the community-based REVEAL HBV cohort involving 3,448 CHB participants without HCV coinfection and free of cirrhosis at enrollment. The baseline serum IP10 level was assayed using Millipore Human Cytokine/Chemokine Magnetic Bead kit. A total of 175 HCC cases were ascertained from enrollment to the end of 2008 by data linkage with the national Cancer Registry database. Multivariate Cox proportional hazards regression analysis was used to estimate the hazards ratio (HR) and 95% confidence interval (CI) of developing HCC for various IP10 levels with adjustment for other documented risk predictors. Results: Serum IP-10 level was positively associated with increasing age, hepatitis B e antigen (HBeAg) status, serum alanine aminotransferase (ALT), HBV DNA, and serum hepatitis B surface antigen (HBsAg) levels (all P < 0.0001). It was not associated with family history of HCC and alcohol consumption habit. The incidence rate of developing HCC per 100,000 person-year was 171.0, 345.0, 534.0, and 673.2, respectively, for IP-10 levels <333 pg/mL (median), 333-<414 pg/mL (70% percentile), 414-<615 pg/mL (90% percentile), and ≥615 pg/mL. The corresponding HR (95% CI) was 1.0 (referent), 1.54 (1.00–2.38), 1.62 (1.08–2.45), and 1.89 (1.17–3.06), respectively, after adjustment for gender, age, HBeAg, serum ALT, HBV DNA, and HBsAg levels. The IP-10 level was statistically significant with a substantial effect size in subgroups of HBeAg-seronegative or HBV DNA <106 copies/mL; the corresponding multivariateadjusted HR (95% CI) was 6.00 (2.64–13.64) and 5.95 (2.49–14.23), respectively, for per log10 increment in IP-10. Conclusions: Serum chemokine IP-10 level was an independent host risk factor of HCC. The predictability of IP-10 level on HCC was prominent in HBeAg-seronegative patients with moderate to low viral load.
688 CO-EXPRESSION OF MST1R AND MET RECEPTORS AND DISTANT METASTASIS IN STAGE I HEPATOCELLULAR CARCINOMA E. Yu, Y.W. Koh, Y.-S. Park, H.J. Kang. Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea E-mail: [email protected] Background: The MST1R (RON) and MET receptors are tyrosine kinases that form a non-covalent complex on the cell surface that functions in several steps of invasive growth, including migration, cell dissociation, and matrix invasion. The purpose of this study was to determine the predictive or prognostic significance of MST1R and MET expressions in the prediction of distant metastases of stage 1 hepatocellular carcinoma (HCC) patients. Methods: The correlation between expressions of MST1R and MET and patient outcome was retrospectively examined by immunohistochemistry in 144 stage I HCC patients, including 72 patients with distant metastases and 72 age-, gender-, date of surgery-matched control patients with no evidence of metastatic disease, using logistic and Cox models. Results: Positive immunostaining for MST1R and MET was detected more frequently in the tumours of the metastasis group than in those of the control group (61.1% vs. 38.9%, P = 0.012 and 29.2% vs. 8.3%, P = 0.002, respectively). Multiple logistic regression analysis showed that co-expression of MST1R and MET was a significant independent predictor of distant metastasis (odds ratio, 7.709, P = 0.003). MST1R-positive patients had lower 10-year diseasefree survival (DFS) rates than MST1R-negative patients (P = 0.008). MET-positive patients had lower 10-year DFS rates than METnegative patients (P < 0.001). Multivariate Cox analysis identified co-expression of MST1R and MET as an independent prognostic marker for DFS, along with the type of surgery (hazard ratio, 2.739; 95% confidence interval, 1.48–5.07, P < 0.001). Conclusion: Co-expression of MST1R and MET appears to predict an aggressive phenotype in early stage HCC patients and may allow the identification of a subgroup of HCC patients who require more intensive therapy. 689 THE HUMAN DEVELOPMENT INDEX IS ASSOCIATED WITH THE GLOBAL INCIDENCE AND MORTALITY RATES OF LIVER CANCER Q.-D. Hu, Q. Zhang, W. Chen, T.-B. Liang. Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China E-mail: [email protected] Objectives: To identify the role of human development in the incidence and mortality rates of liver cancer worldwide. Methods: The age-standardized incidence and mortality rates for gastrointestinal cancers were obtained from the GLOBOCAN 2008 database. We estimated the mortality-to-incidence ratios (MIRs) at the national level, and excluded the extreme MIRs (0, 1, or >1) from further analysis. We then explored the association of the MIR with development levels as measured by the human development index (HDI). Results: The worldwide incidence and mortality rates of liver cancer were high. The MIR of liver cancer correlated inversely the HDI at the national level (r = −0.607, p < 0.0001). Based on a modified “drug dose to inhibition response” model, non-linear regression analysis revealed an inhibitory effect of high HDI on the MIR (Figure 1 and 2). The HDI value at half maximal MIR was 1.028±0.044 (95% confidential interval). Conclusion: The inverse correlation between HDI and MIR demonstrates that more developed areas have a relatively effective healthcare, resulting in low MIRs. Radical improvement in liver cancer care is needed in low HDI countries.
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two general hospitals and one tertiary referral centre. Electronic and multi-disciplinary team data were reviewed. Results: 111 patients with a confirmed diagnosis of HCC were identified. Of these, 91 (81.9%) were male and the median age was 69 years (range 24–87). 52 (46.8%) patients with newly diagnosed HCC had established liver disease prior to diagnosis. Of these, 21 (40.4%) were participating in combined USS-aFP surveillance, 2 (3.8%) USS alone and 1 (1.9%) aFP alone. A diagnosis of HCC was confirmed by liver biopsy in 43 (38.7%), CT in 41 (36.9%), MRI in 25 (22.5%) and USS combined with elevated aFP in 2 (1.8%). At diagnosis, aFP was elevated in 81 (73.0%), normal in 22 (19.8%) and unmeasured in 8 (7.2%) patients. Of those 21 diagnosed in an established surveillance program of six-monthly USS and aFP, 17 (81.0%) showed a rise in aFP. When assessing the trigger for confirmatory cross-sectional imaging ± biopsy across all data, a solely elevated aFP prompted further investigation in 11 (9.9%); in those under surveillance, this number was 7 (29.2%) with no abnormality detected on USS within the preceding three-month period in 6 (85.7%) of these. Conclusions: These results demonstrate that a significant number of patients would have had a delayed diagnosis of HCC if aFP measurement was removed from UK screening programmes. Potential contributing factors limiting the success of USS-based screening programmes include: small lesion size, sonographer error, patient factors limiting USS accuracy (e.g. body habitus) and irregular attendance for USS. This study supports continued serial measurement of aFP in patients with liver cirrhosis in contrast to European and American guidelines. Reference(s) [1] Hepatology, vol. 53(3)1020–1022, Mar. 2011. [2] Journal of Hepatology, vol. 56(4)908–943, Apr. 2012. [3] Gut, vol. 52(3)iii1–iii8, 2003.
686 PROGRESSION AND PATHOGENESIS ROLE OF RNA BINDING PROTEIN La-RELATED PROTEIN 1 IN HEPATOCELLULAR CARCINOMAS C. Xie, Q.-S. Zhang, J.-Q. Xie, L. Peng, G.-L. Zhang, D.-Y. Xie, Z.-L. Gao. Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China E-mail: [email protected] Background: La-related protein 1 (LARP1), was first described in Drosophila and shown to be required for embryogenesis, spermatogenesis, cell cycle progression and epithelial–mesenchymal transition (EMT). However, the functional significance of LARP1 in human cancer remains unknown. Methods: We investigated LARP1 expression in 263 hepatocellular carcinomas (HCC) paraffin-embedded archival samples using immunohistochemistry. mRNA and protein levels of LARP1 expression in 15 HCC cell lines, and 6 paired HCC lesions and the adjacent noncancerous tissues were examined. Statistical analyses were applied to derive prognostic and diagnostic associations between LARP1 and clinical characters. The effect of endogenous LARP1 on cell invasion and anchorage-independent growth ability was examined in vitro. Western blotting and Immunofluorescence analyses were performed to identify the effects of LARP1overexpression or -knockdown on expression of cell EMT markers. Results: The expression of LARP1 was markedly up-regulated in HCC cell lines and surgical HCC specimens at both transcriptional and translational levels. Immunohistochemical analysis revealed that 160 of 263 (60.8%) HCC specimens exhibited high levels of LARP1 expression. Statistical analysis suggested the upregulation of LARP1 was significantly correlated with the clinical staging of the HCC patients (P = 0.001), TNM classification (P = 0.002), and tumor number (P = 0.045) and those patients with high LARP1 levels exhibited shorter survival time (P < 0.001). Importantly, this
Journal of Hepatology 2013 vol. 58 | S229–S407
POSTERS correlation remained significant in patients with early-stage HCC or with normal serum AFP level. Multivariate analysis indicated that LARP1 expression might be an independent prognostic indicator of the survival of patients with HCC. Furthermore, we found that ectopic expression of LARP1 induced, while silencing LARP1 inhibited, cell invasion and anchorage-independent growth ability. Moreover, we demonstrated that the upregulation of LARP1 could reduce the expression of e-cadherin and induce the expression of fibronectin. Conclusions: Our findings suggest that the LARP1 protein is a valuable marker of HCC progression and may represent a novel prognostic biomarker and therapeutic target for the disease. 687 SERUM IP-10 LEVEL ASSOCIATED WITH HEPATOCELLULAR CARCINOMA DEVELOPMENT IN PATIENTS WITH CHRONIC HEPATITIS B H.-I. Yang1 , Y.-C. Chien2 , M.-H. Lee3 , J. Liu4 , H.-Y. Chen5 , C.-J. Liu4 , C.-L. Jen5 , D. Tsai5 , R. Batrla-Utermann6 , U. Iloeje7 , P.-J. Chen4 , C.-J. Chen5 , the REVEAL-HBV Study Group. 1 China Medical University, 2 China Medical University Hospital, Taichung, 3 National Yang-Ming University, 4 National Taiwan University, 5 Academia Sinica, Taipei, Taiwan R.O.C.; 6 Roche Diagnostics, Basel, Swaziland, 7 Bristol-Myers Squibb Company, Wallingford, CT, USA E-mail: [email protected] Background and Aims: Hepatocellular carcinoma (HCC) is considered a long-term sequelae of interaction between virus, host, and environmental factors. Interferon gamma-induced protein 10 (IP-10) is a member of the CXC chemokine family, which has been shown to be a chemoattractant and involve in a variety of immune and inflammatory reactions. This study aimed to investigate the serum level of IP-10 in association with HCC development in patients with chronic hepatitis B (CHB). Methods: This study was based on the community-based REVEAL HBV cohort involving 3,448 CHB participants without HCV coinfection and free of cirrhosis at enrollment. The baseline serum IP10 level was assayed using Millipore Human Cytokine/Chemokine Magnetic Bead kit. A total of 175 HCC cases were ascertained from enrollment to the end of 2008 by data linkage with the national Cancer Registry database. Multivariate Cox proportional hazards regression analysis was used to estimate the hazards ratio (HR) and 95% confidence interval (CI) of developing HCC for various IP10 levels with adjustment for other documented risk predictors. Results: Serum IP-10 level was positively associated with increasing age, hepatitis B e antigen (HBeAg) status, serum alanine aminotransferase (ALT), HBV DNA, and serum hepatitis B surface antigen (HBsAg) levels (all P < 0.0001). It was not associated with family history of HCC and alcohol consumption habit. The incidence rate of developing HCC per 100,000 person-year was 171.0, 345.0, 534.0, and 673.2, respectively, for IP-10 levels <333 pg/mL (median), 333-<414 pg/mL (70% percentile), 414-<615 pg/mL (90% percentile), and ≥615 pg/mL. The corresponding HR (95% CI) was 1.0 (referent), 1.54 (1.00–2.38), 1.62 (1.08–2.45), and 1.89 (1.17–3.06), respectively, after adjustment for gender, age, HBeAg, serum ALT, HBV DNA, and HBsAg levels. The IP-10 level was statistically significant with a substantial effect size in subgroups of HBeAg-seronegative or HBV DNA <106 copies/mL; the corresponding multivariateadjusted HR (95% CI) was 6.00 (2.64–13.64) and 5.95 (2.49–14.23), respectively, for per log10 increment in IP-10. Conclusions: Serum chemokine IP-10 level was an independent host risk factor of HCC. The predictability of IP-10 level on HCC was prominent in HBeAg-seronegative patients with moderate to low viral load.
688 CO-EXPRESSION OF MST1R AND MET RECEPTORS AND DISTANT METASTASIS IN STAGE I HEPATOCELLULAR CARCINOMA E. Yu, Y.W. Koh, Y.-S. Park, H.J. Kang. Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea E-mail: [email protected] Background: The MST1R (RON) and MET receptors are tyrosine kinases that form a non-covalent complex on the cell surface that functions in several steps of invasive growth, including migration, cell dissociation, and matrix invasion. The purpose of this study was to determine the predictive or prognostic significance of MST1R and MET expressions in the prediction of distant metastases of stage 1 hepatocellular carcinoma (HCC) patients. Methods: The correlation between expressions of MST1R and MET and patient outcome was retrospectively examined by immunohistochemistry in 144 stage I HCC patients, including 72 patients with distant metastases and 72 age-, gender-, date of surgery-matched control patients with no evidence of metastatic disease, using logistic and Cox models. Results: Positive immunostaining for MST1R and MET was detected more frequently in the tumours of the metastasis group than in those of the control group (61.1% vs. 38.9%, P = 0.012 and 29.2% vs. 8.3%, P = 0.002, respectively). Multiple logistic regression analysis showed that co-expression of MST1R and MET was a significant independent predictor of distant metastasis (odds ratio, 7.709, P = 0.003). MST1R-positive patients had lower 10-year diseasefree survival (DFS) rates than MST1R-negative patients (P = 0.008). MET-positive patients had lower 10-year DFS rates than METnegative patients (P < 0.001). Multivariate Cox analysis identified co-expression of MST1R and MET as an independent prognostic marker for DFS, along with the type of surgery (hazard ratio, 2.739; 95% confidence interval, 1.48–5.07, P < 0.001). Conclusion: Co-expression of MST1R and MET appears to predict an aggressive phenotype in early stage HCC patients and may allow the identification of a subgroup of HCC patients who require more intensive therapy. 689 THE HUMAN DEVELOPMENT INDEX IS ASSOCIATED WITH THE GLOBAL INCIDENCE AND MORTALITY RATES OF LIVER CANCER Q.-D. Hu, Q. Zhang, W. Chen, T.-B. Liang. Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China E-mail: [email protected] Objectives: To identify the role of human development in the incidence and mortality rates of liver cancer worldwide. Methods: The age-standardized incidence and mortality rates for gastrointestinal cancers were obtained from the GLOBOCAN 2008 database. We estimated the mortality-to-incidence ratios (MIRs) at the national level, and excluded the extreme MIRs (0, 1, or >1) from further analysis. We then explored the association of the MIR with development levels as measured by the human development index (HDI). Results: The worldwide incidence and mortality rates of liver cancer were high. The MIR of liver cancer correlated inversely the HDI at the national level (r = −0.607, p < 0.0001). Based on a modified “drug dose to inhibition response” model, non-linear regression analysis revealed an inhibitory effect of high HDI on the MIR (Figure 1 and 2). The HDI value at half maximal MIR was 1.028±0.044 (95% confidential interval). Conclusion: The inverse correlation between HDI and MIR demonstrates that more developed areas have a relatively effective healthcare, resulting in low MIRs. Radical improvement in liver cancer care is needed in low HDI countries.
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