Causes of death in people with chronic HBV infection: A population-based cohort study.

BACKGROUND & AIMS: Mortality related to hepatitis B virus (HBV) is not well known in developed countries. The aim of this study was to investigate in a population-based cohort the excess risk of death in HBV patients compared with mortality in the general population and to identify risk factors related to all-cause mortality and HBV-related mortality. METHODS: A specialized population-based registry has recorded data from patients with chronic HBV infection in a population of one million inhabitants in France since 1994. Standardized mortality rates for all-cause death and HBV-related death were calculated. Cumulative mortality rates were calculated using the Kaplan-Meier method. Multivariate analysis was performed using a Cox model. RESULTS: Between 1994 and 2009, 1117 people were diagnosed with chronic HBV infection. Of these 136 (12.2%) died. All-cause mortality was significantly higher in HBV-infected people (standardized mortality ratio (SMR) 1.7 [1.4-2.0]). There was substantial excess mortality due to hepatocellular carcinoma (SMR 15.9 [10-24.1]), non-Hodgkin lymphoma (SMR 8.6 [3.1-18.6]) and liver disease (SMR 10.2 [5.8-16.6]). The cumulative rates for all-cause mortality were 8.6% at 5 years, 12.6% at 10 years and 18.5% at 15 years. The corresponding values for HBV-related mortality were 3.5%, 4.2%, and 5.8%. The multivariate analysis for all-cause mortality and for HBV-related mortality showed that male sex, age over 45 at diagnosis, current alcoholism and nosocomial risk factors were predictors of increased mortality. CONCLUSION: This study shows increased all-cause mortality in HBsAg-positive patients, with considerable excess mortality due to chronic liver disease, hepatocellular carcinoma and non-Hodgkin lymphoma.

Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data.

UNLABELLED: The incidence of hepatocellular carcinoma (HCC) is increasing in Western countries. Although several clinical factors have been identified, many individuals never develop HCC, suggesting a genetic susceptibility. However, to date, only a few single-nucleotide polymorphisms have been reproducibly shown to be linked to HCC onset. A variant (rs738409 C>G, encoding for p.I148M) in the PNPLA3 gene is associated with liver damage in chronic liver diseases. Interestingly, several studies have reported that the minor rs738409[G] allele is more represented in HCC cases in chronic hepatitis C (CHC) and alcoholic liver disease (ALD). However, a significant association with HCC related to CHC has not been consistently observed, and the strength of the association between rs738409 and HCC remains unclear. We performed a meta-analysis of individual participant data including 2,503 European patients with cirrhosis to assess the association between rs738409 and HCC, particularly in ALD and CHC. We found that rs738409 was strongly associated with overall HCC (odds ratio [OR] per G allele, additive model=1.77; 95% confidence interval [CI]: 1.42-2.19; P=2.78 × 10(-7) ). This association was more pronounced in ALD (OR=2.20; 95% CI: 1.80-2.67; P=4.71 × 10(-15) ) than in CHC patients (OR=1.55; 95% CI: 1.03-2.34; P=3.52 × 10(-2) ). After adjustment for age, sex, and body mass index, the variant remained strongly associated with HCC. CONCLUSION: Overall, these results suggest that rs738409 exerts a marked influence on hepatocarcinogenesis in patients with cirrhosis of European descent and provide a strong argument for performing further mechanistic studies to better understand the role of PNPLA3 in HCC development.

Trends in the management of gastric cancer over a 32-year period: a French population-based study.

BACKGROUND: Gastric cancer is still generating interest because of its poor prognosis. The aim of this study was to investigate time trends in diagnostic assessment, patterns of care, and survival of gastric cancers. METHODS: We considered 5,010 gastric cancers diagnosed between 1976 and 2007 in a well-defined French population. Logistic regressions were used to identify factors associated with R0 resection and operative mortality. A multivariate relative survival analysis was performed. RESULTS: Diagnostic modalities have changed. Since 1988, endoscopy is performed when gastric cancer is suspected (95.5%). However, there has been no strong variation in stage over time: the proportion of stage I cancers increased from 5.5% to 13.4% between the periods 1976-1979 and 2004-2007 (p < 0.001) whereas that of advanced cases remained stable, 64.8% and 65.0%, respectively. R0 resections rose from 36.7% (1976-1979) to 46.7% between 1980 and 1999, and decreased to 32.7% thereafter. Age, tumor location, and period were associated with R0 resection. Neoadjuvant and adjuvant chemotherapy were rarely used before 2000, then reached 15.0% and 19.1%, respectively, during the later period. Operative mortality after R0 resection decreased from 18.3% during the 1976-1979 period to 4.3% during the 2004-2007 period (p < 0.001). Prognosis slightly improved during the three first periods, from 13.0% to 22.6%, then leveled off, not exceeding 26.0% thereafter. Stage, age, histology, and time period significantly influenced survival. CONCLUSION: Changes in diagnostic modalities were associated with minor changes in stage and prognosis for gastric cancer. Earlier diagnosis and new therapeutic strategies are the best way to improve the prognosis.

Toxicity of oxaliplatin plus fluorouracil/leucovorin adjuvant chemotherapy in elderly patients with stage III colon cancer: a population-based study.

BACKGROUND: Results concerning the side effects of oxaliplatin associated with fluorouracil and leucovorin (FOLFOX) in older patients are controversial. The objective of this study was to assess the use and the toxicity of FOLFOX in patients aged 70 years and older as administered in current practice. METHODS: Among 305 stage III colon cancers registered in a well-defined population in Burgundy between 2004 and 2009, 210 had adjuvant chemotherapy, including 156 with FOLFOX. The cumulated rates of toxicity were calculated by using the Kaplan-Meier method. The risks of overall toxicity and of severe toxicity (grade 3 or 4) in patients less than 70 years and in older patients were compared by using a Cox model. RESULTS: There was no difference between the group of the patients less than 70 years and the older age group for the cumulative incidence of hematologic, neurologic, digestive, and general toxicity. There was also no difference between the two groups for the severity of side effects (grade 3 or 4, 31.4 vs. 39.0 %; p = 0.576). The multivariate analysis indicated after adjustment on sex and the Charlson comorbidity score that there was no difference between the two age groups for toxicity (hazard ratio = 1.28; 95 % CI 0.68-2.41; p = 0.439). CONCLUSIONS: Cancer registries can be used to evaluate the toxicity of chemotherapy at the population level. Tolerance to the FOLFOX regimen among elderly patients did not significantly differ from that in younger patients. This treatment should be considered regardless of patients' age alone, but consideration should be given to the capacity of patients to tolerate adverse events.

Prediction for steatosis in type-2 diabetes: clinico-biological markers versus 1H-MR spectroscopy.

OBJECTIVES: The SteatoTest, fatty liver index (FLI) and hepatic steatosis index (HSI) are clinico-biological scores of steatosis validated in general or selected populations. Serum adiponectin (s-adiponectin) and retinol binding protein 4 (s-RBP4) are adipokines that could predict liver steatosis. We investigated whether the Steatotest, FLI, HSI, s-adiponectin and s-RBP4 could be valid predictors of liver steatosis in type-2 diabetic (T2D) patients. METHODS: We enrolled 220 consecutive T2D patients. Reference standard was 3.0 T (1)H-MR spectroscopy (corrected for T1 and T2 decays). Intraclass correlation coefficients (ICCs), Kappa statistic measures of agreement, receiver operating characteristic (ROC) curves were assessed. RESULTS: Median liver fat content was 91 mg triglyceride/g liver tissue (range: 0-392). ICCs among the Steatotest, FLI, HSI, s-adiponectin, s-RBP4 and spectroscopy were low: 0.384, 0.281, 0.087, -0.297 and 0.048. Agreement between scores and spectroscopy was poor (Kappa range: 0.042-0.281). The areas under the ROC curves were low: 0.674, 0.647, 0.637, 0.616 and 0.540. S-adiponectin and s-RBP4 levels were strongly related to the presence of diabetic nephropathy (P = 0.0037 and P = 0.004; Mann-Whitney). CONCLUSION: The SteatoTest, FLI, HSI, s-adiponectin, s-RBP4 are not valid predictors of steatosis in T2D patients. Clino-biological markers cannot replace (1)H-MR spectroscopy for the assessment of liver fat in this population. KEY POINTS: (1) H-MR spectrosopy can reliably estimate the weight fraction of liver steatosis. Type-2 diabetes provides an interesting model for assessing liver steatosis. Clinico-biological markers seem to be invalid predictors for steatosis in type-2 diabetes.

[Epidemiology and screening of colon cancer]. / Epidémiologie et recommandations pour le dépistage du cancer colorectal.

Colon cancer is a major health problem in industrialized countries. It ranks at the first place among digestive cancers, with a sex ratio of 1. Colon cancer incidence increased between 1975 and 2005. France belongs to high risk countries for colorectal cancers. Since eighties, there was a progressive switch from left to right colon cancers. Owing to its frequency, and its epidemiological characteristics, colorectal cancer is, in France, justifiable of a national population-based mass screening. In France, national screening relies on biennial testing in subjects between 50 and 74 followed by total colonoscopy in case of positive test. In order to decrease significantly colorectal cancer mortality participation rate has to be over 50%. The colorectal cancer mortality decrease in this case varies between 15 and 28% in the general population, and between 33 and 39% among participants to screening. On the basis of available data, the European Commission recommended organizing colorectal cancer screening in the EU. Colonoscopy screening is recommended for subjects at high risk, or very high risk for colorectal cancer.

Influence of sample return time and ambient temperature on the performance of an immunochemical faecal occult blood test with a new buffer for colorectal cancer screening.

The haemoglobin concentration measured by faecal immunochemical tests (FIT) may be decreased in cases of delayed sample return or high temperature. It is an issue of great importance. The aim of this study was to investigate the effects of sample return time and of season on the performance of an FIT (FOB-Gold) with a new buffer. The study included 20 371 participants involved in the French organized colorectal cancer (CRC) screening programme. The probability of a positive screening test, detection rates and positive predictive values for CRC and advanced adenoma were analysed according to sample return time and season of screening. A sample of positive FIT was stored for 7 days in an incubator at 20°C or 30°C. The positivity rate was 4.1% for a sample return time of up to 3 days, 4.1% for 4-5 days and 4.6% for 6-7 days (P=0.25). In multivariate analysis, there was no association between positivity rates, detection rates and positive predictive values for CRC and advanced adenoma and the sample return time or the season of screening. At a constant temperature of 20°C, there was a decrease in the haemoglobin concentration of 5.1% after 7 days. The decrease reached 20.5% at a temperature of 30°C. It was only 4.5% during the first 4 days of storage in the incubator. With the new buffer, delay in sample return or season did not affect the clinical outcome. When temperatures reach 30°C, the faecal sample must be returned promptly.

Long-term effect of faecal occult blood screening on incidence and mortality from colorectal cancer.

BACKGROUND: Several randomized trials have shown a reduction of colorectal cancer mortality by screening using guaiac-based faecal occult blood tests. However, little is known on the long-term effect of screening at the population level in everyday practice. METHODS: Small-sized geographic areas including a total of 91,199 individuals were allocated to either biennal screening using the Hemoccult-II test or no screening. The expected mortality and incidence in the cohort invited to screening was determined using mortality and incidence in the non-screened population. RESULTS: Colorectal cancer mortality was significantly lower in the population invited to screening than in the non-screened population after 11 screening rounds (standardized mortality ratio: 0.87; 0.80-0.94). The standardized mortality ratio remained significant whatever the duration of follow-up. This reduction in colorectal cancer mortality was more pronounced in those who participated in the first screening campaign, who were regular participants in screening rounds (standardized mortality ratio: 0.67; 0.59-0.76). In contrast, colorectal cancer incidence was not different between the screened and non-screened populations (standardized incidence ratio: 1.01; 0.96-1.06). CONCLUSION: Our findings confirm, in the long term, that screening with Hemoccult can reduce colorectal cancer mortality. The data also highlight the benefit of regular participation in screening and the absence of effect of screening on colorectal cancer incidence.

Trends in incidence and management of cancer of the ampulla of Vater.

AIM: To provide trends in incidence, management and survival of cancer of the ampulla of Vater in a well-defined French population. METHODS: Data were obtained from the population-based digestive cancer registry of Burgundy over a 34-year period. Age-standardized incidence rates were computed using the world standard population. Average annual variations in incidence rates were estimated using a poisson regression. A univariate and multivariate relative survival analysis was performed. RESULTS: Age-standardized incidence rates were 0.46 and 0.30 per 100000 inhabitants for men and women, respectively. Incidence rate increased from 0.26 (1976-1984) to 0.58 (2003-2009) for men and remained stable for women. Resection for cure was performed in 48.3% of cases. This proportion was stable over the study period. Among cases with curative resection, pancreatico-duodenectomy was performed in 94.0% of cases and ampullectomy in 6.0% of cases. A total of 50.8% of cancers of the ampulla of Vater were diagnosed at an advanced stage. Their proportion remained stable throughout the study period. The overall 1- and 5-year relative survival rates were 60.2% and 27.7%, respectively. Relative survival did not vary over time. Treatment and stage at diagnosis were the most important determinants of survival. The 5-year relative survival rate was 41.5% after resection for cure, 9.5% after palliative surgery and 6.7% after symptomatic treatment. In multivariate analysis, only stage at diagnosis significantly influenced the risk of death. CONCLUSION: Cancer of the ampulla of Vater is still uncommon, but its incidence increased for men in Burgundy. Diagnosis is often made at an advanced stage, dramatically worsening the prognosis.

Impact of liver disease severity and etiology on the occurrence of diabetes mellitus in patients with liver cirrhosis.

The association between liver cirrhosis (LC) and diabetes mellitus (DM) is well known. However, the impact of the severity or etiology of LC on the occurrence of DM is relatively unknown. We aimed to determine the prevalence and clinical correlates of DM in a large cohort of patients with cirrhosis. A total of 1,068 patients with LC were included in this cross sectional study (CIRCE study). The diagnosis of cirrhosis irrespective of its etiology was based on histological confirmation by liver biopsy or, in the absence of biopsy, on typical clinical, morphological and biological data. Data related to the cirrhosis etiology: alcohol, viral markers of hepatitis B, C, iron load parameters and autoimmune markers were collected for each patient. Venous blood samples were taken in the morning after 12-h overnight fasting. There were 383 patients with cirrhosis associated with hepatocellular carcinoma (HCC). DM was found in 412 (39.7 %) patients. Patients with DM were older and more likely to be overweight and male, with a family history of DM and a diagnosis of HCC. DM was not associated with a history of stroke or myocardial infarction. Cirrhosis secondary to hepatitis infection was less strongly associated with DM than with NASH or alcoholic cirrhosis. The severity of LC was not associated with DM. In multivariate analysis, the factors associated with DM were age, BMI, a family history of DM, and statin use. There was a significant interaction between HCC and cirrhosis etiology for the risk of DM. Cirrhosis secondary to hepatitis was associated with a lesser presence of DM only in patients with HCC (interaction p = 0.0015). LC was strongly associated with DM, with around 40 % of diabetic patients. In the group of patients with LC without HCC, diabetes was not associated with the etiology of cirrhosis.

Lipiodol trans-arterial chemoembolization of hepatocellular carcinoma with idarubicin: first experience.

BACKGROUND: There is still no consensus about the best chemotherapeutic agent for transarterial chemoembolization (TACE). A recent in vitro study demonstrated that idarubicin, an anthracycline, was by far the most cytotoxic drug on human hepatocellular carcinoma (HCC) cell lines. Idarubicin is much more lipophilic than doxorubicin, leading to higher cell penetration through lipidic membranes and greater accumulation of the drug in the lipiodol. Furthermore, idarubicin has the ability to overcome multidrug resistance. Therefore, we designed this pilot human study to evaluate the safety and efficacy of lipiodol TACE using idarubicin. METHODS: In 21 consecutive patients treated by lipiodol TACE with idarubicin (10 mg) for HCC, safety data, tumor response (Response Evaluation Criteria in Solid Tumors, mRECIST), time to treatment failure (TTTF), and overall survival were evaluated. RESULTS: Postembolization syndrome was observed after 30.9% (17 of 55) of sessions. No patient died from a TACE-related complication. No hematological grade 3-5 adverse event was observed. At least one grade 3 or higher adverse event occurred in 19% (4 of 21) of patients. On imaging, no progression was encountered; four patients (24%) exhibited stable disease, 12 (57%) exhibited a partial response, and five (19%) exhibited a complete response. Median TTTF was 16.7 months (Kaplan-Meier analysis). At 6 months, 94.7% (95% confidence interval [CI] 68.1-99.2) of patients did not reach treatment failure, whereas treatment failure was not reached in 50.6% (95% CI 21.6-73.9) of patients at 1 year. Overall survival was 83.5% (95% CI 57-94.4) at 1 year. CONCLUSION: Idarubicin seems safe and effective in lipiodol TACE of HCC. This warrants further study to determine the potential of this drug to replace doxorubicin for TACE.

Transjugular intrahepatic portosystemic shunt for the management of acute variceal hemorrhage.

Acute variceal hemorrhage, a life-threatening condition that requires a multidisciplinary approach for effective therapy, is defined as visible bleeding from an esophageal or gastric varix at the time of endoscopy, the presence of large esophageal varices with recent stigmata of bleeding, or fresh blood visible in the stomach with no other source of bleeding identified. Transfusion of blood products, pharmacological treatments and early endoscopic therapy are often effective; however, if primary hemostasis cannot be obtained or if uncontrollable early rebleeding occurs, transjugular intrahepatic portosystemic shunt (TIPS) is recommended as rescue treatment. The TIPS represents a major advance in the treatment of complications of portal hypertension. Acute variceal hemorrhage that is poorly controlled with endoscopic therapy is generally well controlled with TIPS, which has a 90% to 100% success rate. However, TIPS is associated with a mortality of 30% to 50% in such a setting. Emergency TIPS should be considered early in patients with refractory variceal bleeding once medical treatment and endoscopic sclerotherapy failure, before the clinical condition worsens. Furthermore, admission to specialized centers is mandatory in such a setting and regional protocols are essential to be organized effectively. This review article discusses initial management and then focuses on the specific role of TIPS as a primary therapy to control acute variceal hemorrhage, particularly as a rescue therapy following failure of endoscopic approaches.

Pharmacokinetic and clinical evaluation of esomeprazole and ASA for the prevention of gastroduodenal ulcers in cardiovascular patients.

INTRODUCTION: Low-dose aspirin (ASA, 75 - 325 mg/day) is widely used for the primary and secondary prevention of cardiovascular (CV) diseases. However, the value of primary prevention ASA is uncertain as the reduction in occlusive events needs to be weighed against the significant increase in major bleedings. Prevention with antisecretory drugs has been proposed to reduce the incidence of ASA-induced gastrointestinal (GI) bleedings, but non-adherence to gastro-protection is of concern, as it significantly increases the risk of upper GI adverse events. Beside patients and physicians education, one approach to overcome non-adherence is the development of fixed-dose combination. AREA COVERED: This review explores the results of clinical studies on the influence of the combination esomeprazole (ESA) and ASA on pharmacokinetic (PK) parameters, and the role for such combination in prevention of CV events in patients at risk of gastric ulcers. EXPERT OPINION: Patients at risk of ASA-induced gastroduodenal ulcer might benefit from a fixed ASA and proton pump inhibitor (PPI) combination. PK and PD parameters suggest there is no significant interaction between these drugs. Nevertheless, attention must be paid on the appropriate use of such combination, that is, still balancing the risk:benefit ratio in a real-life setting, and any increase in the proportion of patients receiving ASA and PPI should be considered as a warning signal.