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IF 7.522; International audience; Background: Pancreatic cancer is one of the most lethal. Most countries have exhibited a stable or decreasing incidence over time. The aim of this study was to provide updated French temporal trends in pancreatic cancer incidence and mortality over the past three decades.Methods: Incidence was estimated using the French National Network of Cancer Registries (FRANCIM) and mortality using the French Mortality Statistics Office. World age-standardized incidence and mortality were modelled by age-period-cohort models. The net cumulative risk of developing pancreatic cancer by birth cohort was calculated, as were annual percentage changes (APCs) in incidence and mortality.Results: Between 1982 and 2012, age-standardized incidence increased from 4.8 in 1980 to 9.6 per 100 000 in men and from 2.3 to 6.8 in women. The mean APC was 2.3% (2.1–2.6) and 3.6% (3.3–3.9), respectively. The cumulative risk of developing pancreatic cancer before age 75 rose from 0.62% for males born around 1920 to 1.17% for those born around 1950. It was respectively 0.31% and 0.86% for women. Mortality did not vary in men (8.1 per 100 000). It slightly increased in women from 4.0 in 1982 to 5.4 in 2012.Conclusion: Pancreatic cancer incidence and mortality exhibited diverging trends. Incidence increased over the last 30 years in France whereas mortality did not vary in men and moderately increased in women. Incidence remained lower than mortality up to 2002. One cannot exclude the possibility that a similar trend may appear in other countries. Etiological studies are required to further explain this increase.

Background and Aims Data concerning the risk of long-term liver metastasis following surgery of colorectal cancer in the general population are scarce. The 10-year incidence and prognosis of metachronous liver metastases remain unknown. Methods Among 4584 patients resected for cure for colorectal cancer recorded in two French digestive population-based cancer registries between 1985 and 2000, 602 presented metastases including liver metastases. Results The cumulated incidence of liver metastasis was 15% at 5 years and 17% at 10 years, and was mainly related to stage at diagnosis. The 10-year cumulative incidence was 6% for stage I and 30% for stage III. The hazard ratio was 3.2 [2.4–4.3] for stage II and 6.9 [5.1–9.2] for stage III compared with stage I. Among survivors with no recurrence five years after diagnosis, 2.2% developed liver metastasis between 5 and 10 years. Resection for cure of liver metastases was performed in 35% of patients aged under 75 years and in 10% of patients over 75 (P

International audience; BACKGROUND:Using potential surrogate end-points for overall survival (OS) such as Disease-Free- (DFS) or Progression-Free Survival (PFS) is increasingly common in randomised controlled trials (RCTs). However, end-points are too often imprecisely defined which largely contributes to a lack of homogeneity across trials, hampering comparison between them. The aim of the DATECAN (Definition for the Assessment of Time-to-event End-points in CANcer trials)-Pancreas project is to provide guidelines for standardised definition of time-to-event end-points in RCTs for pancreatic cancer.METHODS:Time-to-event end-points currently used were identified from a literature review of pancreatic RCT trials (2006-2009). Academic research groups were contacted for participation in order to select clinicians and methodologists to participate in the pilot and scoring groups (>30 experts). A consensus was built after 2 rounds of the modified Delphi formal consensus approach with the Rand scoring methodology (range: 1-9).RESULTS:For pancreatic cancer, 14 time to event end-points and 25 distinct event types applied to two settings (detectable disease and/or no detectable disease) were considered relevant and included in the questionnaire sent to 52 selected experts. Thirty experts answered both scoring rounds. A total of 204 events distributed over the 14 end-points were scored. After the first round, consensus was reached for 25 items; after the second consensus was reached for 156 items; and after the face-to-face meeting for 203 items.CONCLUSION:The formal consensus approach reached the elaboration of guidelines for standardised definitions of time-to-event end-points allowing cross-comparison of RCTs in pancreatic cancer.

International audience; This article investigates the influence of distance to health care and material deprivation on cancer survival for patients diagnosed with a colorectal cancer between 1997 and 2004 in France and England. This population-based study included all cases of colorectal cancer diagnosed between 1997 and 2004 in 3 cancer registries in France and 1 cancer registry in England (N=40,613). After adjustment for material deprivation, travel times in England were no longer significantly associated with survival. In France patients living between 20 and 90min from the nearest cancer unit tended to have a poorer survival, although this was not statistically significant. In England, the better prognosis observed for remote patients can be explained by associations with material deprivation; distance to health services alone did not affect survival whilst material deprivation level had a major influence, with lower survival for patients living in deprived areas. Increases in travel times to health services in France were associated with poorer survival rates. The pattern of this influence seems to follow an inverse U distribution, i.e. maximal for average travel times.

Long-term recurrences of rectal cancer raised questions about the possible benefit of prolonging the recommended active 5-year clinical and endoscopic surveillance. The aim of this study was to determine for the first time, incidence and patterns of late 10-year recurrence after curative resection of rectal cancer. The study included 1,222 patients with rectal cancer resected for cure between 1985 and 2000 from those registered in two French population-based digestive cancer registries. Information about local recurrences and distant metastases at 10 years was retrospectively and actively collected up to January 1, 2011. Although the overall 5-year cumulated rate was 39.5 %, the 10-year cumulated rate was 44.1 % (25.6 % for local recurrence and 29.9 % for distant metastases). In multivariate analyses, TNM stage was associated with a higher risk of local recurrence (hazard ratio [HR] stage III vs. stage I = 3.98 [95 % confidence interval, 2.66–5.94]) and of distant metastasis (HR = 3.60 [2.65–4.91]). Preoperative radiotherapy decreased the risk of local recurrence (HR = 0.43 [0.28–0.66]), but not the risk of metastasis. Patients diagnosed between 1995 and 2000 were less prone to develop long-term metastasis than those diagnosed between 1985 and 1989 (HR = 0.66 [0.49–0.88]). Among patients without recurrence 5 years after diagnosis, one patient in 13 developed a recurrence between 5 and 10 years. Late recurrences do exist. A personalised surveillance could be extended until 10 years according to the characteristics of primary tumour and the patient.

Background We investigated the impact of municipality of residence on colonoscopic surveillance and colorectal cancer risk after adenoma resection in a French well-defined administrative area. Methods This registry-based study included all patients residing in Cote d’Or (n = 5769) first diagnosed with colorectal adenomas between January 1, 1990, and December 31, 1999. Information about colonoscopic surveillance and colorectal cancer incidence was collected until December 31, 2003. Results A rural place of residence reduced the probability of colonoscopic surveillance in men [HR = 0.89 (95%CI: 0.79–0.99), p = 0.041] and in patients without family history of colorectal cancer [HR = 0.91(0.82–0.99), p = 0.044]. After a median follow-up of 7.7 years, 87 patients developed invasive colorectal cancer. After advanced adenoma removal, the standardized incidence ratio for colorectal cancer was 3.03 (95%CI: 1.92–4.54) for rural patients and 1.87 (95%CI: 1.26–2.66) for urban patients compared with the general population. The risk of colorectal cancer was higher in rural patients than in urban ones only after removal of the initial advanced adenoma [HR = 1.73 (95%CI: 1.01–3.00, p = 0.048)]. Further adjustment for surveillance colonoscopy, physician location, and other confounders had little impact on these results. Conclusion The increased risk of subsequent colorectal cancer after advanced adenoma removal in French rural patients was not explained by a lower rate of colonoscopic surveillance. The role of socio-economic and environmental factors requires further exploration.

Improved prognostic stratification of patients with TNM stage II colorectal cancer (CRC) is desired, since 20–30% of high-risk stage II patients may die within five years of diagnosis. This study was conducted to investigate REarranged during Transfection ( RET ) gene promoter CpG island methylation as a possible prognostic marker for TNM stage II CRC patients. The utility of RET promoter CpG island methylation in tumors of stage II CRC patients as a prognostic biomarker for CRC related death was studied in three independent series (including 233, 231, and 294 TNM stage II patients, respectively) by using MSP and pyrosequencing. The prognostic value of RET promoter CpG island methylation was analyzed by using Cox regression analysis. In the first series, analyzed by MSP, CRC stage II patients ( n = 233) with RET methylated tumors had a significantly worse overall survival as compared to those with unmethylated tumors (HR multivariable = 2.51, 95%-CI: 1.42–4.43). Despite a significant prognostic effect of RET methylation in stage III patients of a second series, analyzed by MSP, the prognostic effect in stage II patients ( n = 231) was not statistically significant (HR multivariable = 1.16, 95%-CI 0.71–1.92). The third series ( n = 294), analyzed by pyrosequencing, confirmed a statistically significant association between RET methylation and poor overall survival in stage II patients (HR multivariable = 1.91, 95%-CI: 1.04–3.53). Our results show that RET promoter CpG island methylation, analyzed by two different techniques, is associated with a poor prognosis in stage II CRC in two independent series and a poor prognosis in stage III CRC in one series. RET methylation may serve as a useful and robust tool for clinical practice to identify high-risk stage II CRC patients with a poor prognosis. This merits further investigation.

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.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.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 (p0.001) 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 (p0.001). 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.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.

Etat de la question Le role de l’endotoxemie liee a la translocation bacterienne sur l’aggravation de la cirrhose fait l’objet de nombreuses etudes, mais son impact sur la mortalite au cours de la cirrhose est mal connu. Le but de ce travail etait d’etudier l’impact de la concentration sanguine de 3-hydroxymyristate (3-HM) total (composant specifique des lipopolysaccharides, endotoxine), sur le risque de deces et de complications des malades cirrhotiques. Materiel et methodes Au total, 593 patients atteints de cirrhose alcoolique ou virale, sans carcinome hepatocellulaire ont ete inclus entre 2008 et 2012 dans six centres hospitalo-universitaires francais. Le dosage de 3-HM total, libre et lie aux lipoproteines a ete realise en l’absence de complication aigue de la cirrhose par une methode innovante et brevetee de dosage massique des LPS. Le suivi annuel pendant cinq ans a permis de relever la survenue de complications ou du deces. L’analyse de survie a ete realisee par un modele de Cox multivarie avec stratification sur le centre et la severite de la cirrhose. Resultats Les patients avec une concentration de 3-HM elevee avait une cirrhose plus severe que les autres selon les scores de Child-Pugh et de Meld (p Conclusion Une concentration elevee de 3-HM, marqueur specifique de l’endotoxemie, est associee a un sur-risque de deces a cinq ans chez les patients avec cirrhose alcoolique ou virale compensee (Child Pugh A) suggerant un role majeur de la translocation bacterienne dans l’aggravation de la cirrhose.

Etat de la question Estimer la survie nette et les indicateurs guerison par sous-type de leucemie aigue myeloide (LAM) en France. Materiel et methodes Au total, 6460 cas de LAM dont l’âge ≥ 15 ans, diagnostiques entre 1989 et 2010 ont ete inclus. Cinq sous-types de LAM ont ete definis a l’aide de la classification ICD-O-3 et HAEMACARE. La survie nette a ete obtenue en utilisant le modele flexible ajuste sur l’âge, le sexe et l’annee de diagnostic pour chaque sous-type de LAM. Lorsque l’hypothese de guerison etait acceptable, un modele de guerison flexible a ete utilise pour estimer la proportion de gueri (P), le temps de guerison (TTC) et le temps de survie median pour les patients non gueris (Med Sunc). Resultats En 2010, une disparite de survie par sous-types des LAM persistait avec une survie nette a 10 ans de 56 % pour les LAM avec anomalies genetiques recurrentes, 16 % avec LAM-NOS, 9 % avec myelofibrose, 8 % LAM avec myelodysplasie et 5 % LAM post-therapeutique. La guerison variait en fonction du sous-type, du sexe et de l’âge. En 2010, p variait de 5 % chez les patients âges atteints de LAM avec myelodysplasie a 75 % chez les patients plus jeunes presentant des anomalies genetiques recurrentes. TTC variait de 6,2 ans pour les jeunes femmes atteintes de LAM-NOS a 11,2 ans pour les patients plus âges presentant des anomalies genetiques recurrentes. Med Sunc etait plus long chez les patients plus jeunes atteints de LAM avec myelodysplasie (1,8 an) que chez les hommes plus âges atteints de LAM-NOS (6 mois). Un effet significatif de l’annee sur la survie et la guerison a ete trouve dans la LAM avec des anomalies genetiques recurrentes et LAM-NOS. Conclusion L’etude des indicateurs de guerison permet d’avoir une meilleure caracterisation de la survie a long terme des LAM. Grâce a leur meilleur pronostic, les LAM avec anomalies genetiques recurrentes necessitent ainsi une attention particuliere.

To describe trends in survival of non-resectable metastatic colorectal cancer (MCRC) over a 34-year period in a French population-based registry taking into account major advances in medical therapy.3804 patients with non-resectable metastatic colorectal cancer diagnosed between 1976 and 2009 were included. Three periods (1976-96, 1997-2004 and 2005-09) were considered.The proportion of patients receiving chemotherapy dramatically increased from 19% to 57% between the first two periods, then increased steadily thereafter reaching 59% during the last period (p0.001). Median relative survival increased from 5.9 months during the 1976-96 period to 10.2 months during the 1997-2004 period but, despite the availability of targeted therapies, remained at 9.5 months during the 2005-09 period. During the last study period, less than 10% of elderly patients received targeted therapies compared to more than 40% for younger patients. Their median relative survival was 5.0 months compared to 15.6 months in younger patients.There was an improvement in survival in relation with the increased use of more effective medical treatment. However, at a population-based level, patients are not all treated equally and most of them, especially the elderly, do not benefit from the most up-to-date treatment options.

IF 2.755; International audience; To assess the risk of second primary malignancy (SPM) in patients with gastric mucosa-associated lymphoid tissue (MALT) Lymphoma (GML), we included 175 patients with GML in the present study. The incidence of SPM in the general population, used for reference, was determined from the French network of cancer registries. During the 1442.9 patient-years of follow-up, 29 patients were diagnosed with incident SPM, including five patients diagnosed with gastric cancer (20.1/1000 patient-years). An increased incidence of SPM was observed in patients with GML (standardized incidence ratios [SIR]: 1.71 [1.14-2.45]) compared to the general French population especially for gastric cancer (SIR: 16.1 [5.19-37.56]). This elevated risk of SPM was significantly increased only in patients treated with immuno/chemotherapy but not in patients treated with Helicobacter pylori eradication alone. Long-term follow-up of patients with GML is mandatory even in patients who have achieved complete remission.

IF 10.103; International audience; Cancer occurs frequently in dermatomyositis and is a major cause of mortality. Yves Allenbach et al. report that patients with necrotising auto-immune myopathies also have an increased risk of malignancy, and that myositis-specific antibodies can be used to identify those at greatest risk.Cancer occurs frequently in dermatomyositis and is a major cause of mortality. Yves Allenbach et al. report that patients with necrotising auto-immune myopathies also have an increased risk of malignancy, and that myositis-specific antibodies can be used to identify those at greatest risk.Cancer can occur in patients with inflammatory myopathies. This association is mainly observed in dermatomyositis, and myositis-specific antibodies have allowed us to delineate patients at an increased risk. Malignancy is also reported in patients with necrotizing autoimmune myopathies, but the risk remains elusive. Anti-signal recognition particle or anti-HMGCR antibodies have been specifically associated with necrotizing autoimmune myopathies. We aimed at screening the incidence of cancer in necrotizing autoimmune myopathies. A group of patients (n = 115) with necrotizing autoimmune myopathies with or without myositis-specific antibodies was analysed. Malignancy occurred more frequently in seronegative necrotizing autoimmune myopathies patients and in HMGCR-positive patients compared to anti-signal recognition particle positive patients. Synchronous malignancy was diagnosed in 21.4% and 11.5% of cases, respectively, and incidence of cancer was higher compared to the general population in both groups. No specific type of cancer was predominant. Patients suffering from a synchronous cancer had a decreased median survival time. Cancer screening is necessary in seronegative necrotizing autoimmune myopathies and in HMGCR-positive patients but not in anti-signal recognition particle-positive patients.

IF 2.415; International audience; Data on anal cancer epidemiology are rare. The aim of this study was to report on trends of incidence and survival for anal cancer in France before the implementation of the human papilloma virus vaccine. This analysis was carried out on 1150 squamous-cell carcinomas of the anal canal diagnosed from 1989 to 2004 in a population of 5.7 million people covered by eight population-based cancer registries. Time trends in incidence were modeled using an age-period-cohort model. Net survival rates were obtained using the recently validated unbiased Pohar-Perme estimator. The incidence of squamous-cell carcinoma of the anal canal increased from 0.2 to 0.5/100 000 person-years among men and from 0.7 to 1.3/100 000 person-years among women from 1982 to 2012. Among women, the increase peaked after 2005, with an annual percentage change of +3.4% between 2005 and 2012, as compared with +2.6% among men. The net survival was 56% (95% confidence interval, 49-64) at 5 years and 48% (33-70) at 10 years among men. It was higher among women, at 65% (61-69) and 56% (50-63) at 5 and 10 years, respectively. The prognosis improved between 1989-1997 and 1998-2004. This improvement was slightly greater for men than for women, thus progressively reducing the gap between sexes. The incidence of squamous-cell anal canal cancer increased slightly among both sexes, but the increase was more marked among women than among men. The potential benefit of prophylactic female human papilloma virus vaccination against cervical cancer in France should be further evaluated.

Background Already since the 1990s, promoter CpG island methylation markers have been considered promising diagnostic, prognostic, and predictive cancer biomarkers. However, so far, only a limited number of DNA methylation markers have been introduced into clinical practice. One reason why the vast majority of methylation markers do not translate into clinical applications is lack of independent validation of methylation markers, often caused by differences in methylation analysis techniques. We recently described RET promoter CpG island methylation as a potential prognostic marker in stage II colorectal cancer (CRC) patients of two independent series. Methods In the current study, we analyzed the RET promoter CpG island methylation of 241 stage II colon cancer patients by direct methylation-specific PCR (MSP), nested-MSP, pyrosequencing, and methylation-sensitive high-resolution melting (MS-HRM). All primers were designed as close as possible to the same genomic region. In order to investigate the effect of different DNA methylation assays on patient outcome, we assessed the clinical sensitivity and specificity as well as the association of RET methylation with overall survival for three and five years of follow-up. Results Using direct-MSP and nested-MSP, 12.0 % (25/209) and 29.6 % (71/240) of the patients showed RET promoter CpG island methylation. Methylation frequencies detected by pyrosequencing were related to the threshold for positivity that defined RET methylation. Methylation frequencies obtained by pyrosequencing (threshold for positivity at 20 %) and MS-HRM were 13.3 % (32/240) and 13.8 % (33/239), respectively. The pyrosequencing threshold for positivity of 20 % showed the best correlation with MS-HRM and direct-MSP results. Nested-MSP detected RET promoter CpG island methylation in deceased patients with a higher sensitivity (33.1 %) compared to direct-MSP (10.7 %), pyrosequencing (14.4 %), and MS-HRM (15.4 %). While RET methylation frequencies detected by nested-MSP, pyrosequencing, and MS-HRM varied, the prognostic effect seemed similar (HR 1.74, 95 % CI 0.97–3.15; HR 1.85, 95 % CI 0.93–3.86; HR 1.83, 95 % CI 0.92–3.65, respectively). Conclusions Our results show that upon optimizing and aligning four RET methylation assays with regard to primer location and sensitivity, differences in methylation frequencies and clinical sensitivities are observed; however, the effect on the marker’s prognostic outcome is minimal. Electronic supplementary material The online version of this article (doi:10.1186/s13148-016-0211-8) contains supplementary material, which is available to authorized users.

Pancreatic survival is one of the worst in oncology. To what extent wait times affect outcomes in unknown No population-based study has previously explored patient and treatment delays among individuals with pancreatic cancer. The aim of this study was to estimate patient and treatment delays in patients with pancreatic cancer and to measure their association with survival in a nonselected population. All patients diagnosed with pancreatic cancer for the first time between 2009 and 2011 and registered in two French digestive cancer registries were included. Patient delay (time from onset of symptoms until the first consultation categorized into1 or ≥1 month), and treatment delay (time between the first consultation and treatment categorized into less or more than 29 days, the median time) were collected. Overall delay was used to test associations between survival and the timeliness of care by combining patient delay and treatment delay. Patient delay was longer than 1 month in 46% of patients. A patient delay longer than one month was associated with the absence of jaundice (p 0.001) and the presence of metastasis (p = 0.003). After adjusting for other covariates, such as symptoms and treatment, the presence of metastasis was negatively associated with treatment delay longer than 29 days (p = 0.025). After adjustment for other covariates, especially metastatic dissemination and the result of the resection, overall delay was not significantly associated with prognosis. We found little evidence to suggest that timely care was associated with the survival of patients.

Background: Few data are available on the incidence, characteristics, treatment, and prognosis of inflammatory bowel disease (IBD)-associated colorectal cancer (CRC) in population-based cohorts. Methods: Among the 19,451 new cases of CRC recorded in the Burgundy digestive cancer registry between 1976 and 2008, all cases of IBD-associated CRC were identified. Incidence rates were age-standardized according to the world standard population. Prognosis was determined using univariate and multivariate relative survival. Results: Thirty-eight IBD-associated CRC were identified (ulcerative colitis, n = 29; Crohn's disease, n = 9). The mean age at CRC diagnosis was greater for patients without IBD than those with IBD (70.9 vs. 56.9 years, respectively; P < 0.001). Distributions of gender, stage at presentation, location, and histological type of CRC did not differ from those of sporadic cases. The overall world age-standardized incidence of IBD-associated CRC per 100,000 was 0.11 (standard deviation [SD]: 0.03) for men and 0.06 (SD: 0.02) for women. Only age was independently associated with IBD-associated CRC (odds ratio [OR]: 0.22; 95% confidence interval [CI]: 0.12–0.43; P < 0.001). Treatment modalities did not differ between IBD and non-IBD patients. Five-year relative survival was 51.9% (95% CI: 51.1–52.8%) in non-IBD patients and 41.3% (95% CI: 24.6–57.2%) in IBD patients (P = 0.201). After adjustment for age, gender, and stage at diagnosis, the excess hazard of death was 1.46 times higher in IBD than in non-IBD patients (95% CI: 0.94–2.27; P = 0.070). Conclusions: Apart from age, the characteristics of IBD-associated CRC were similar to those of non-IBD CRC. The prognosis of CRC may be poorer in patients with IBD than in those without IBD. (Inflamm Bowel Dis 2012;)

Three hundred and twenty-seven patients from two population-based cohorts with an established diagnosis of polycythaemia vera were studied for prognostic risk factors for survival and leukaemia in a long-term survey. The relative survival (RS) was 72% and 46% at 10 and 20 years respectively, from the time of diagnosis. Multivariate analysis identified age >70 years, white blood cell count >13 × 10(9) /l and thrombo-embolism at diagnosis as independent risk factors. Patients with two or three of these factors had a 10 year RS of 26%, compared with 59% and 84% in patients with one and no risk factors, respectively. Age and leucocyte count are the main predicting factors for survival in polycythaemia vera.

Summary Background & aims Non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity, metabolic syndrome and type 2 diabetes. Although dietary fat contributes substantially to the accumulation of liver fat, the role of individual fatty acids in this accumulation is unclear. Objective In this study, we set out to determine whether liver fat content (LFC), was associated with red blood cell fatty acid (RBC-FA) composition in people with type 2 diabetes. Design, settings, and participants One hundred and sixty-two type 2 diabetic patients were included in this study. LFC was measured using 1H-MR Spectroscopy. RBC-FA composition was measured by gas chromatography. Results One hundred and nine (67.2%) patients had steatosis. Patients with steatosis had a higher BMI (p = 0.0005), and higher plasma triglyceride levels (p = 0.009) than did patients without steatosis. We report a significant association between palmitic acid (16:0), palmitoleic acid (16:1n-7) concentrations and ratio of monounsaturated to saturated fatty acid (palmitoleic acid to palmitic acid) and higher liver fat content. Total polyunsaturated fatty acid (PUFA), homo-gamma-linolenic acid (20:3n-6), docosahexaenoic acid (22:6n-3), and arachidonic acid (20:4 n-6) were associated with lower LFC. Conclusions Our data showed that an increased erythrocytes long-chain n-3 and n-6 fatty acids was associated with a lower prevalence of steatosis in patients with type 2 diabetes. These results suggest that n-3 and n-6 fatty acids supplementation could be a promising treatment for NAFLD in patients with type 2 diabetes.

Regression-based relative survival models are commonly used in population-based cancer studies to estimate the real impact on the excess mortality of covariates that influence overall mortality. Usually, the mortality observed in a study cohort is corrected by the expected mortality hazard in the general population, which is given by life tables provided by national statistics institutes. These life tables are stratified by age, sex, calendar year, and, sometimes, other demographic data (ethnicity, deprivation, and others). However, in most cases, the same demographic data are not available for the study cohort and the general population; this leads to differences between the expected mortality of the general population and that of the study cohort. More generally, the absence of some demographic variables in life tables may introduce a measurement bias into the estimation of the excess mortality. In the present article, we used a simulation approach with different plausible scenarios to evaluate the impact of an additional life-table variable on excess mortality estimates and study the extent and the direction of the biases in estimating the effect of each covariate on the excess mortality. We showed that the use of life table that lacks stratification by a variable present in the excess hazard model results in a measurement bias not only in the estimate of the effect of this variable but also, to a lesser extent, in the estimates of the effects of the other covariates included in the model. We also demonstrated this measurement bias by a population-based colorectal cancer analysis.

Background The correct examination of lymph nodes is decisive for tumour classification into stage 2 and stage 3. The aim of this specialised population-based study was to investigate the influence of clinical factors and volume of surgical activity on lymph node assessment in France for patients diagnosed with localised colorectal cancer. Methods From 1997 to 2004, French digestive cancer registries recorded a total of 4197 cases of colorectal cancer. The volume of surgical activity was appreciated by the annual number of digestive surgery admissions in 2004. The probability of having at least 12 lymph nodes examined after surgical resection was analysed using a multilevel logistic regression model. Results Only 1900 patients had more than 12 lymph nodes examined (45.2%). The percentage of patients with at least 12 lymph nodes examined after tumour resection is directly associated with the volume of surgical activity within care centres for patients diagnosed between 1997 and 2000. This association was no longer significant during the second period study (2001–2004). Conclusion(s) This population-based study reports that only 55% of colorectal patients have a sufficient number of lymph nodes examined. This insufficient number of examined lymph nodes could be considered as a potential prospect for increasing treatment quality in cancer patients in France.

Background Because few data are available on this topic, we investigated the influence of geographical determinants on colorectal adenoma detection and cancer incidence rates. Methods Between 1990 and 1999, 6220 Cote d’Or inhabitants (France) were first-diagnosed with a colorectal adenoma, and 2389 with an invasive adenocarcinoma. The impact of the rural–urban place of residence and of a physician location in municipalities on adenoma and cancer detection rates was studied using Poisson regression. Results World-standardized adenoma detection rate was significantly higher in urban areas (102 [95%CI: 97–107]) than in rural areas (78 [95%CI: 72–84]). The impact of the absence of physicians in municipalities was only found in rural areas. The detection rate ratio associated with the absence of a primary care physician was 0.70 [95%CI:0.61–0.81], and the detection rate ratio associated with the absence of a gastroenterologist was 0.75 [95%CI:0.64–0.89]. Colorectal cancer incidence rates were similar in urban and rural areas with only marginal variations related to physician location. Conclusions These results suggested a differential impact of geographical variables on the detection rates of colorectal adenomas and cancers in the population. Further studies are needed to examine socio-economic factors likely to be involved in these disparities.

The association between hepatitis C infection and lymphoid malignancies is still a matter of debate. The hypothesis of a relationship between hepatitis B and lymphoid neoplasms is more recent and has been far less thoroughly explored.The aim of this study was to evaluate the association between hepatitis C and B infections and B cell non-Hodgkin and Hodgkin lymphomas.We took advantage of the co-existence in the French administrative area of Côte d'Or of two specialized registries - one for viral hepatitis and one for haematological diseases - to conduct a population-based, cohort study covering a 12-year period. The databases were anonymized and then linked using a probabilistic model.There were 8234 person-years at risk in the hepatitis C cohort and 2784 in the hepatitis B cohort. We found 6 cases of non-Hodgkin lymphoma in the hepatitis C cohort, resulting in an overall adjusted standardized incidence ratio of 3.42 (CI: 1.25-7.45). Three of these 6 cases were diffuse-large-B-cell-lymphoma. Cirrhosis was associated with a higher risk of non-Hodgkin lymphoma in the hepatitis C cohort (relative risk=8.4, p0.01, using a Poisson regression). We found one case of chronic lymphocytic leukaemia amongst the hepatitis B carriers.Hepatitis C carriers are at a higher risk of developing non-Hodgkin lymphoma than the general population. The role of cirrhosis and the association between hepatitis B and lymphoid malignancies deserve to be further assessed.

Context: Recently, it has been shown that an allele in the adiponutrin (PNPLA3) gene was strongly associated with increased liver fat content (LFC) and liver fibrosis independent of visceral adiposity and insulin resistance. Objective: In this study, we set out to determine whether the PNPLA3 rs738409 polymorphism was associated with liver fibrosis in unselected patients with type 2 diabetes. Design, setting and participants: Two hundred and thirty-four patients with type 2 diabetes were included in this study. Main outcome measures: LFC was evaluated using 1H-MR spectroscopy; fibrosis was measured using the non-invasive FibroTest®. Results: Advanced liver fibrosis (stage F2 or above) was observed in 10.2% of the patients while 149 (63.6%) patients had steatosis. The prevalence of steatosis and fibrosis was higher in minor G allele carriers than that in C allele homozygote carriers (70.3 vs 57.1%; P=0.04 and 14.7 vs 7.5%; P=0.07 respectively). In multivariate analysis, the predictive variables for advanced liver fibrosis were age (≥60) (P=0.005), sex (female) (P=0.004) and rs 738409 PNPLA3 polymorphism (P=0.01); body mass index (BMI) and LFC were not associated with liver fibrosis. Conclusions: This study confirms that in patients with type 2 diabetes who were not selected for liver abnormalities, liver fibrosis was related to the rs738409 polymorphism independent of BMI or LFC.

OBJECTIVES: To investigate the influence of comorbidities on treatment modalities of colorectal cancer according to the age of patients and French recommendations. DESIGN: Population-based study SETTING: French Digestive Cancer Registry, Burgundy. PARTICIPANTS: Two thousand nine hundred twenty-one incident colorectal cancers diagnosed between 2004 and 2007. MEASUREMENTS: The independent influence of comorbidities (recorded according to the Charlson index) on treatment was analyzed using multivariate logistic regressions controlling for age, sex, and their interaction. RESULTS: The association between comorbidities and resection for cure was significant only in patients younger than 75 (P interaction=.008). For Stage III colon cancer, 40.4% of the patients aged 75 and older had adjuvant chemotherapy, versus 90.5% of those younger than 75 (P

Recently, it has been shown in the general population that an allele in the adiponutrin (PNPLA3) gene was strongly associated with increased liver fat content (LFC), independently of visceral adiposity and insulin resistance.In this study, we set out to determine whether LFC, evaluated using (1)H-MR spectroscopy, was associated with PNPLA3 rs738409 polymorphism in people with type 2 diabetes. We also evaluated the influence of this polymorphism on the relationship between LFC and either visceral adiposity or carotid intima media thickness (CIMT).A total of 218 type 2 diabetic patients were included in this study.LFC, area of visceral fat, and CIMT were measured.A total of 139 (63.7%) patients had steatosis. The rs738409 minor G allele was associated with LFC. The number of patients with steatosis was significantly higher among minor G allele carriers in comparison to C allele homozygote carriers (70.3 vs. 57.2%; P=0.04) In the subgroup of C allele homozygote carriers, LFC correlated with body mass index (r=0.27; P=0.003) and visceral fat area (r=0.30; P=0.002), but not with CIMT. In the subgroup of minor G allele carriers, LFC correlated inversely with CIMT (r=-0.23; P=0.03), but not with body mass index or with visceral fat area. In multivariate logistic regression, the relationship between the highest quartile of CIMT and steatosis was different according to adiponutrin polymorphism.This study confirms that in people with type 2 diabetes, LFC is related to rs738409 polymorphism. The lack of a relationship with visceral obesity and the inverse correlation with CIMT suggest that fatty liver associated with the minor G allele of the PNPLA3 rs738409 polymorphism may not be linked to metabolic disorders.

Background and Purpose— Variations in stroke incidence could be explained by changes in vascular and environmental factors that affect the risk of stroke and changes in risk factors that are present in early life. The aim of this study was to identify and measure the effects of 3 interrelated factors, age, calendar period of stroke onset, and birth year cohort, on the incidence rates of stroke from 1985 through 2005. Methods— Age–period–cohort models were used to analyze stroke incidence in Dijon from 1985 to 2005 from a population-based registry that collects data on all stroke patients whatever the type of management, in the public hospital, private hospitals, or at home, in the population of Dijon (150 000 inhabitants). Results— For ischemic stroke, the incidence rose with time in men depending not only on age, but also on the period and cohort effects ( P =0.017). For women, the incidence only depended on age ( P P =0.019). Conclusions— Age, birth cohort, and calendar period contain relevant information to define and explain trends in stroke incidence rates over a long period.

Both the pre-apoptotic exposure of calreticulin (CRT) and the post-apoptotic release of high-mobility group box 1 protein (HMGB1) are required for immunogenic cell death elicited by anthracyclins. Here, we show that both oxaliplatin (OXP) and cisplatin (CDDP) were equally efficient in triggering HMGB1 release. However, OXP, but not CDDP, stimulates pre-apoptotic CRT exposure in a series of murine and human colon cancer cell lines. Subcutaneous injection of OXP-treated colorectal cancer (CRC), CT26, cells induced an anticancer immune response that was reduced by short interfering RNA-mediated depletion of CRT or HMGB1. In contrast, CDDP-treated CT26 cells failed to induce anticancer immunity, unless recombinant CRT protein was absorbed into the cells. CT26 tumors implanted in immunocompetent mice responded to OXP treatment in vivo, and this therapeutic response was lost when CRT exposure by CT26 cells was inhibited or when CT26 cells were implanted in immunodeficient mice. The knockout of toll-like receptor 4 (TLR4), the receptor for HMGB1, also resulted in a deficient immune response against OXP-treated CT26 cells. In patients with advanced (stage IV, Duke D) CRC, who received an OXP-based chemotherapeutic regimen, the loss-of-function allele of TLR4 (Asp299Gly in linkage disequilibrium with Thr399Ile, reducing its affinity for HMGB1) was as prevalent as in the general population. However, patients carrying the TLR4 loss-of-function allele exhibited reduced progression-free and overall survival, as compared with patients carrying the normal TLR4 allele. In conclusion, OXP induces immunogenic death of CRC cells, and this effect determines its therapeutic efficacy in CRC patients.

Introduction The objective of this study was to estimate prevalence of colorectal cancers requiring care or follow-up. Materials and methods Prevalence was observed in 2005 on the population-based digestive cancer registry of Burgundy (France). Total and 5-year partial prevalences were calculated. The prevalence of patients requiring follow-up was estimated using non-mixture cure models. The prevalence of patients with recurrence was estimated using annual recurrence rates. Results Total prevalence was 262,244 cases in France. The mean variation in 5-year partial prevalence between successive 5-year periods was +8.0%. Time to cure was estimated to be 9.3 years, suggesting that follow-up is needed over a 10-year period, corresponding to 71.7% of prevalent cases. In 2005, 5.4% of prevalent cases had recurrent cancer requiring treatment. Conclusion This study underlines the burden of colorectal cancer on the health system. Prevalence of patients requiring follow-up or treatment provides interesting information in addition to classic indicators.

Une etude epidemiologique menee en 2004 en Cote d’Or et dans le Doubs revelait que parmi 1 251 patients porteurs du VHC, un sur 4 etait traite et un sur 6 ne beneficiait d’aucune prise en charge. Une etude qualitative faite en Bourgogne en 2006-2008 visait a identifier les raisons de l’insuffisance de soins ; 25 medecins ont ete interroges sur leur confrontation a l’infection par le VHC et les difficultes de sa prise en charge, et 27 patients atteints d’hepatite chronique C sur les circonstances du depistage et du diagnostic, l’itineraire de soins, la representation et le vecu de la maladie et du traitement, les relations avec les soignants. L’etude a revele une grande variabilite dans les delais entre le diagnostic, la consultation en hepatologie et l’instauration du traitement ; celle-ci est en grande partie expliquee par les modalites du fonctionnement de la relation medecinspatients et des choix de prise en charge faits par les medecins impliques.

Flexible survival models, which avoid assumptions about hazards proportionality (PH) or linearity of continuous covariates effects, bring the issues of model selection to a new level of complexity. Each ‘candidate covariate’ requires inter-dependent decisions regarding (i) its inclusion in the model, and representation of its effects on the log hazard as (ii) either constant over time or time-dependent (TD) and, for continuous covariates, (iii) either loglinear or non-loglinear (NL). Moreover, ‘optimal’ decisions for one covariate depend on the decisions regarding others. Thus, some efficient model-building strategy is necessary. We carried out an empirical study of the impact of the model selection strategy on the estimates obtained in flexible multivariable survival analyses of prognostic factors for mortality in 273 gastric cancer patients. We used 10 different strategies to select alternative multivariable parametric as well as spline-based models, allowing flexible modeling of non-parametric (TD and/or NL) effects. We employed 5-fold cross-validation to compare the predictive ability of alternative models. All flexible models indicated significant non-linearity and changes over time in the effect of age at diagnosis. Conventional ‘parametric’ models suggested the lack of period effect, whereas more flexible strategies indicated a significant NL effect. Cross-validation confirmed that flexible models predicted better mortality. The resulting differences in the ‘final model’ selected by various strategies had also impact on the risk prediction for individual subjects. Overall, our analyses underline (a) the importance of accounting for significant non-parametric effects of covariates and (b) the need for developing accurate model selection strategies for flexible survival analyses. Copyright © 2008 John Wiley & Sons, Ltd.

Background The aim of this population-based study was to report on the incidence, treatment and prognosis of synchronous colorectal carcinomas. Methods Data were obtained from the population-based cancer registry of Burgundy. Results Between 1976 and 2004, 15 562 colorectal cancers were diagnosed. Some 3·8 per cent of patients had synchronous colorectal cancers. The risk of having synchronous cancers was higher in men (odds ratio (OR) 1·41 (95 per cent confidence interval (c.i.) 1·19 to 1·68)), when associated adenomas were present (OR 2·02 (95 per cent c.i. 1·69 to 2·41)), when there were adenomatous remnants on pathological examination (OR 2·10 (95 per cent c.i. 1·73 to 2·55)) and in patients aged over 75 years (OR 1·31 (95 per cent c.i. 1·08 to 1·59)). Synchronous tumours were more often located on the same intestinal segment, although the correlation was weak (κ = 0·26). Resection for cure was performed in 74·8 per cent of synchronous cancers and 72·0 per cent of single cancers (P = 0·131). Five-year relative survival for synchronous (48·7 per cent) and single (48·3 per cent) cancers was almost identical. Stage, age, associated adenomas and adenomatous remnants were independent prognostic factors. Conclusion Synchronous colorectal cancers convey a similar prognosis to single tumours. Men and patients aged over 65 years with associated adenomas are more prone to multiple colorectal cancers.

Summary Background Little is known about the descriptive epidemiology of colorectal adenomas diagnosed in the population. Aim To describe time trends in the rate of first diagnosis of colorectal adenomas and estimate the proportion of adenoma-bearing individuals detected over a 24-year period. Methods A total of 11 027 patients were first-diagnosed with colorectal adenomas among Cote-d’Or residents (France) between 1976 and 1999. Annual percentage changes were estimated using a Poisson regression model. The proportion of diagnosed adenoma-bearing individuals was estimated using the prevalence of adenomas in an autopsy study performed in the area. Results Standardized diagnosis rates were 89.6/100 000 men and 50.3/100 000 women. During the period 1976–1993, diagnosis rates significantly increased with annual percentage changes in men and women of respectively +17.1% and +22.3% for proximal adenomas, +7.5% and +9.1% for distal adenomas and +7.2% and +8.0% for advanced adenomas. Changes were less marked during the period 1994–1999. The estimated proportion of adenoma-bearing individuals diagnosed during the 24-year period was 20.0% in men and 16.0% in women. Conclusion Despite a marked increase in the rate of first adenoma diagnosis, the proportion of diagnosed adenoma-bearing individuals seems too low to induce a significant decrease in colorectal cancer incidence.

Hazard regression models and cure rate models can be advantageously used in cancer relative survival analysis. We explored the advantages and limits of these two models in colon cancer and focused on the prognostic impact of the year of diagnosis on survival according to the TNM stage at diagnosis. The analysis concerned 9,998 patients from three French registries. In the hazard regression model, the baseline excess death hazard and the time-dependent effects of covariates were modelled using regression splines. The cure rate model estimated the proportion of 'cured' patients and the excess death hazard in 'non-cured' patients. The effects of year of diagnosis on these parameters were estimated for each TNM cancer stage. With the hazard regression model, the excess death hazard decreased significantly with more recent years of diagnoses (hazard ratio, HR 0.97 in stage III and 0.98 in stage IV, P0.001). In these advanced stages, this favourable effect was limited to the first years of follow-up. With the cure rate model, recent years of diagnoses were significantly associated with longer survivals in 'non-cured' patients with advanced stages (HR 0.95 in stage III and 0.97 in stage IV, P0.001) but had no significant effect on cure (odds ratio, OR 0.99 in stages III and IV, P0.5). The two models were complementary and concordant in estimating colon cancer survival and the effects of covariates. They provided two different points of view of the same phenomenon: recent years of diagnosis had a favourable effect on survival, but not on cure.

The RAS-MAPK, PI (3)K signaling pathways form a network that play a central role in tumorigenesis. The BRAF, KRAS and PI3KCA genes code 3 partners of this network and have been found to be activated by mutation in colorectal cancer; these mutations lead to unrestricted cell growth. We evaluated the clinicopathological features and the prognosis of patients with activated-network colon cancers in a population-based study. A total of 586 colon adenocarcinomas were evaluated using sequencing for mutations of KRAS and PI3KCA, and allelic discrimination for mutation of BRAF. Clinicopathological characteristics were correlated to the risk of bearing a mutation of the network using logistic regression. Three-year survival rates were compared with the Log rank test. A multivariate survival analysis using the Cox model was performed. After adjustment for age and microsatellite instability, activation of the network by mutation of at least 1 of the 3 genes was significantly associated with female sex (p = 0.02) and proximal location (p < 0.001). Lower levels of 3-year survival were associated with activation of the network by mutation of at least 1 of the 3 genes (59.4 and 69.4%, respectively; p = 0.009). These results remained significant in a multivariate analysis adjusted for sex, age, location, stage and microsatellite instability (HR = 1.48; CI CI(95%) = [1.07-2.04]). Our study is the first report to underline the potential role of RAS-MAPK, PI (3)K network mutations on survival in colon cancers. Because of the role of this signaling network on anticancer agents, the evaluation of its mutations could have clinical implications.

International audience; Little is known about the epidemiology of early gastric cancer (EGC) in Western countries. The aim of this study was to analyze trends in the incidence, management, and survival of EGC in a well-defined population over a 30 year period.Data were obtained from the population-based cancer Registry of Burgundy (France). Incidence rates were calculated by sex, age, and 10 year period of diagnosis. Net survival rates were calculated and a multivariate relative survival analysis performed.EGC represented 6.7 % of gastric cancer diagnosed between 1982 and 2011. Age-standardized incidence rates were higher in men (0.79/100,000) than in women (0.40/100,000). Between the periods 1982-1991 and 2002-2011, it decreased from 0.97 to 0.53 per 100,000 in men and from 0.44 to 0.30 per 100,000 in women. Overall, 19 % of the tumors were limited to the mucosa, 69 % to the submucosa, and 15 % invaded lymph nodes. Node invasion and male sex were the only significant prognostic factors. Five-year net survival was 50 % in node-positive patients and 85 % in node-negative patients (p < 0.001). In multivariate analysis, the relative risk of death in men compared to women was 2.3 and was 10.4 in patients with positive nodes compared to patients with negative nodes.EGCs are rare in France. The prognosis is favorable, except for node-positive cancers, which may benefit from the recently developed adjuvant chemotherapy for gastric cancer.

It has been shown that the hepatitis C virus (HCV) core protein reduces the activity of the microsomal triglyceride transfer protein (MTP) and could lead to steatosis in HCV-infected patients. Experimentally, apolipoprotein-AII (apoAII), which restores triglyceride secretion altered by the HCV core protein, could be protective against HCV steatosis. On the other hand, increasing plasma concentrations of mouse apoAII in transgenic mice produced several aspects of insulin-resistance syndrome, which also is implicated in the pathogenesis of HCV steatosis. This study was designed to investigate the role of apoAII in HCV-related steatosis in humans. Sixty-five hospitalized patients with chronic HCV were included in this study to assess the effects of apoAII, body mass index (BMI), age, insulin sensibility (HOMA), and leptin level on steatosis. Steatosis was observed in 55.3% of patients. Apo-AII was significantly associated with HOMA and with leptin concentrations. In univariate analyses, age, BMI, increased leptin level, increased HOMA, and increased apoAII concentration were associated with steatosis. In multivariate analysis, steatosis was associated with apoAII concentration, age, gender, and BMI. Contrary to previous hypotheses, apoAII is not a protective factor against HCV steatosis but is significantly associated with the development of liver steatosis. The fact that the plasma levels of apoAII correlate with HOMA and leptin levels in HCV-infected patients suggests that apoAII may contribute to hepatic steatosis progression in relationship to visceral obesity, insulin resistance, and metabolism of triglyceride-rich lipoproteins.

International audience; BACKGROUND/AIMS: In France, geographic access to medical care may affect the diagnosis of hepatitis C. The aims of this study were to compare the detection rates of hepatitis C in urban and rural areas after adjusting for distance to medical care, and evaluating the impact of the place of residence on patients' clinical characteristics. METHODS: Between 1994 and 2001, 1938 newly detected cases were recorded in a French population of 1,005,817 inhabitants. Age and sex-adjusted detection rates for 10(5) inhabitants were estimated for urban and rural areas and for classes of distance to the nearest practitioner. RESULTS: Detection rates were lower in rural than in urban areas [14.1, (95CI: 12.5-15.7) versus 24.7, (95CI: 23.5-26.0)] and decreased as the distance to the general practitioner increased [27.0, (95CI: 25.5-28.4) versus 13.7, (95CI: 12.1-15.3) for a cutoff value of 1.5 km]. In multivariate analyses, detection rates were only influenced by the distance to general practitioner. Hepatocellular carcinoma at diagnosis was more frequent among rural than among urban patients (adjusted OR = 2.28, 95CI: 0.97-5.39, P = 0.059). CONCLUSIONS: A poorer geographic access to care explained the lower detection of hepatitis C in rural areas. Hepatocellular carcinoma was more frequent in rural patients. It may result from later detection and/or involvement of environmental factors on hepatocarcinogenesis.

Long-term recurrences of colon cancer raised questions about the possible benefit of prolonging the recommended active 5-year surveillance. The aim of this study was to determine, for the first time, the incidence and patterns of late 10-year recurrence following curative resection of colon cancer. Data were obtained from two French digestive cancer registries. A total of 3,622 patients under 85 years resected for cure for colon cancer diagnosed between 1985 and 2000 were included. Information regarding recurrences was actively collected. Cumulative failure rates at 10 years were estimated using Kaplan-Meier estimates corrected by cause-specific hazards, and multivariable analysis was performed using a model for the subdistribution of a competing risk proposed by Fine and Gray. The overall cumulative recurrence rate between 5 and 10 years after initial surgery was 2.9% for local recurrence and 4.3% for distant metastasis. Among men with no recurrence 5 years after diagnosis of colon cancer, 1 in 12 developed a recurrence between 5 and 10 years, and the corresponding cumulative rate was 7.8%. The frequency was 1 in 19 for women, corresponding to a cumulative rate of 5.2%. In the multivariate analysis, non-emergency diagnostic feature, female sex and age under 75 were associated with a lower risk of recurrence. Stage at diagnosis was not a predictor of late recurrence. Late recurrence after colon cancer resection with curative intent can occur. A regular clinical follow-up is necessary to detect early signs of possible recurrence.

Data concerning the risk of long-term liver metastasis following surgery of colorectal cancer in the general population are scarce. The 10-year incidence and prognosis of metachronous liver metastases remain unknown.Among 4584 patients resected for cure for colorectal cancer recorded in two French digestive population-based cancer registries between 1985 and 2000, 602 presented metastases including liver metastases.The cumulated incidence of liver metastasis was 15% at 5 years and 17% at 10 years, and was mainly related to stage at diagnosis. The 10-year cumulative incidence was 6% for stage I and 30% for stage III. The hazard ratio was 3.2 [2.4-4.3] for stage II and 6.9 [5.1-9.2] for stage III compared with stage I. Among survivors with no recurrence five years after diagnosis, 2.2% developed liver metastasis between 5 and 10 years. Resection for cure of liver metastases was performed in 35% of patients aged under 75 years and in 10% of patients over 75 (P 0.001). After resection for cure, 10-year relative survival improved from 21% during the period 1985-1997 to 34% during the period 1998-2011 (P = 0.023). Survival in patients with liver metastasis diagnosed between six and 12 months after surgery was less than half that in patients with metastasis diagnosed later (HR: 0.6 [0.4-1.0]).Liver metastases from colorectal cancer remain a substantial problem and continue to occur long after five years. This study furnishes unbiased figures that can be used as a reference. Liver metastases that appear late have a better prognosis.

Purpose: Data on the prognostic significance of promoter CpG island methylation in colorectal cancer (CRC) are conflicting, possibly due to associations between methylation and other factors affecting survival such as genetic alterations and use of adjuvant therapy. Here, we examine the prognostic impact of promoter methylation in patients with CRC treated with surgery alone in the context of microsatellite instability (MSI), BRAF and KRAS mutations. Experimental Methods: One hundred and seventy-three CRCs were analyzed for promoter methylation of 19 tumor suppressor and DNA repair genes, the CpG island methylator phenotype (CIMP), MSI, the exon 15 V600E BRAF mutation and KRAS codon 12 and 13 mutations. Results: Unsupervised hierarchical clustering based on methylation status of 19 genes revealed three subgroups: cluster 1 [CL1, 57% (98/173) of CRCs], cluster 2 [CL2, 25% (43/173) of CRCs], and cluster 3 [CL3, 18% (32/173) of CRCs]. CL3 had the highest methylation index (0.25, 0.49, and 0.69, respectively, P = Conclusions: CHFR promoter CpG island methylation, which is associated with MSI, also occurs frequently in MSS CRCs and is a promising prognostic marker in stage II, MSS, BRAF WT CRCs. Clin Cancer Res; 20(12); 3261–71. ©2014 AACR.

Objective The aim of this study was to draw a picture of diagnostic assessment and patterns of care for rectal cancer in France using population-based registries data. Methods The study included a random sample of 669 cases of rectal cancers diagnosed in 2005. Results Diagnostic assessment was performed by colonoscopy in 91.4% of the cases. An abdominal computed tomography was performed in 59.4% of the cases and chest computed tomography in 47.8%. An R0 resection was performed in 65.8% of cases and an R1/R2 resection in 16.1%. A rectal endosocography was performed in 40.4% and MRI in 10.4%. The sphincter was preserved in 73.6% of patients aged younger than 75 years of age and in 62.5% of those older than 75 years of age (P=0.002). In cases of R0 resection, neoadjuvant radiotherapy was performed in 47.8% of patients younger than 75 years of age and in 34.1% of older patients (P=0.007). Postoperative chemotherapy was administered in 23.9% of stage II and 67.8% of stage III resected patients. Conclusion The management of rectal cancers can be improved. Preoperative staging has not reached its full development; very few patients received neoadjuvant treatment, whereas adjuvant chemotherapy was often performed, although its benefit is still unclear. The management of elderly patients was less optimal than that of younger patients.

The aim of this study was to present estimates of national trends in the incidence of the most frequent digestive cancers over the period 1980-2005 and to provide projections up to 2010. World age-standardised estimates of national incidence were modelled using data from the French cancer registries and the incidence/mortality ratios observed in the area covered by the contributing registries, using an age-period-cohort model. The incidence of oesophageal cancers in men strongly decreased over time from 15.3 in 1980 to 7.9 per 100 000 in 2005, whereas the incidence in women slowly increased. A steadily decreasing trend in gastric cancer was found in both sexes. After a steady increase until 1995, the incidence of colorectal cancer stabilised in both sexes, with a slight decrease in men. In 2010, the projected incidence was 36.5 per 100 000 in men and 24.4 in women. The incidence of liver cancer showed the highest increase over time. In men, this increase was steeper until 1995 than later. The projected incidence in 2010 was 10.9 per 100 000 in men and 2.4 in women. The incidence of pancreatic cancer increased slowly between 1980 and 1990 and increased steeply after 1990, reaching an estimated 7.6 per 100 000 in men and 4.7 in women in 2005. This study on trends in the incidence of digestive cancers in France showed large changes between 1980 and 2010. The increase in the incidence of primary liver cancer and pancreatic cancer was striking. Colorectal cancer incidence is stabilising.

Background France stands among high-risk areas for colorectal cancer. Different trends in CRC incidence are reported around the world. The aim of this study was to provide temporal trends in CRC incidence over a 30-year period in a French well-defined population. Methods Between 1976 and 2005, 17,028 new cases were registered by the Burgundy digestive cancer registry. The mean variations in age-standardized incidence rates were estimated using a Poisson regression adjusted for age for each gender and location. The cumulative risk by birth cohort of developing a cancer over the age range 0-74 years was estimated using an age-cohort model. Results Incidence rates for right and left colon cancers increased more rapidly in males (respectively +11.7% and +10.3% on average by 5-year period) than in females (respectively +5.9% and +6.1%). It remained stable for sigmoid cancers in males (-0.1%) and decreased in females (-5.2%). It also decreased for rectal cancers both in males (-2.7%) and in females (-2.0%). The cumulative risk increased from 3.9% for males born around 1900 to 4.9% for those born around 1930 and then slightly decreased (4.5% among those born around 1950). It remained at the same level for females born around 1900 (2.7%) as for those born around 1930 (2.7%) and then slightly increased (2.9%) for those born around 1950. For right colon cancers, the cumulative risk increased strikingly in successive birth cohorts from 0.53% to 1.2% in males and 0.55% to 0.77% in females. The corresponding cumulative risks for the left colon were 0.24% and 0.42% in males and 0.14% and 0.29% in females. For sigmoid cancer, they decreased from 1.59% to 1.08% in males, and 0.88% to 0.80% in females. Conclusion Temporal variations in incidence rates of colorectal cancers differed according to subsite, suggesting different aetiological factors and implications for diagnosis and screening strategies. Total colonoscopy must be the preferred strategy in high-risk groups or after a positive faecal occult blood test.

Background In medical research, one common competing risks situation is the study of different types of events, such as disease recurrence and death. We focused on that situation but considered death under two aspects: "expected death" and "excess death", the latter could be directly or indirectly associated with the disease. Methods The excess hazard method allows estimating an excess mortality hazard using the population (expected) mortality hazard. We propose models combining the competing risks approach and the excess hazard method. These models are based on a joint modelling of each event-specific hazard, including the event-free excess death hazard. The proposed models are parsimonious, allow time-dependent hazard ratios, and facilitate comparisons between event-specific hazards and between covariate effects on different events. In a simulation study, we assessed the performance of the estimators and showed their good properties with different drop-out censoring rates and different sample sizes. Results We analyzed a population-based dataset on French colon cancer patients who have undergone curative surgery. Considering three competing events (local recurrence, distant metastasis, and death), we showed that the recurrence-free excess mortality hazard reached zero six months after treatment. Covariates sex, age, and cancer stage had the same effects on local recurrence and distant metastasis but a different effect on excess mortality. Conclusions The proposed models consider the excess mortality within the framework of competing risks. Moreover, the joint estimation of the parameters allow (i) direct comparisons between covariate effects, and (ii) fitting models with common parameters to obtain more parsimonious models and more efficient parameter estimators.

OBJECTIVES Time trends in the incidence of pancreatic cancer vary considerably between countries. The aim of this study was to provide time trends in incidence during a 25-year period in a well-defined French population. METHODS The cancer registry in Burgundy (France) was used to study time trends between 1981 and 2005 by sex, age, subsite, and histology. They were analyzed using an age-period cohort model. RESULTS Age-standardized incidence rates increased from 5.7 (1981-1985) to 7.9 per 100,000 (2001-2005) in men and from 2.6 to 4.6 in women. The mean percentage of variation by the 5-year period was +9.9% (P < 0.001, 95% confidence interval, 6.2%-13.6%) and +13.4% (P = 0.004, 95% confidence interval, 9.4%-17.5%), respectively. The increase in incidence was higher for cancers of the tail and corpus than for cancers of the head of pancreas and for malignant pancreatic endocrine tumors than for adenocarcinomas. The cumulative risk of developing a pancreatic cancer rose from 0.51% for men born in 1900 to 1.13% for those born in 1950. It was 0.34% and 0.55% for women, respectively. CONCLUSIONS The incidence of pancreatic cancer has increased sharply in France both by period and by birth cohort. Etiological studies are required to explain the increase in the incidence.

Objective Epidemiological data on synchronous and metachronous lung metastases from colorectal cancer are scarce. The aim of this study was to determine trends in the incidence, treatment and survival in colorectal cancer with lung metastases in the general population. Design and patients All cases of lung metastases from colorectal cancer registered in the Burgundy digestive cancer registry between 1976 and 2005 were included. Trends in the incidence of synchronous colorectal cancer lung metastases were estimated. A Cox model was used to analyse the risk of developing a metachronous metastasis. Multivariate analyses were performed using a relative survival model with proportional hazard applied to the net survival by interval. Results Overall, 11.0% of patients had synchronous lung metastases. The frequency of synchronous lung metastases significantly increased for both sexes over time, with a nearly threefold increase between the periods 1976–1985 and 1996–2005. The overall 5-year cumulative risk of developing metachronous lung metastases was 5.8%. It did not significantly vary with time. Compared to colon cancer, rectal cancers had a higher risk of developing synchronous (OR: 2.80 (1.65–4.76)) and metachronous (OR: 2.63 (1.69–4.08)) lung metastases. Overall, 4.1% of synchronous lung metastases and 14.3% of metachronous lung metastases were resected for cure. The 3-year relative survival was 11.3% for synchronous lung metastases and 13.8% for metachronous lung metastases. It was, respectively, 53.0% and 59.2% after resection for cure. In multivariate analysis, the relative risk of death for the 1996–2005 period was about one fifth of that for the 1976–1985 period. Conclusions The incidence of synchronous lung metastases increased over time, whereas the incidence of metachronous lung metastases remained stable. Lung metastases were more frequent in rectal cancer than in colon cancer. Unless surgical resection is possible, the prognosis for lung metastases remains very poor.