Effect of age, period of diagnosis and birth cohort on large bowel cancer incidence in a well-defined French population, 1976-1995.

The objective of this study was to present trends in colorectal cancer incidence by sex and subsite in a well-defined French population. All of the 4486 large bowel cancer cases registered between 1976 and 1995 in the Burgundy registry of digestive tract cancers was included in this study. Time trends in colorectal cancer incidence were analysed over the 1976-95 period. The effects of age, period and cohort were evaluated using a log-linear Poisson model. The incidence rates for right colon cancer increased over time: + 21.6% (95% CI: + 13.5; + 29.7) per 5-year period in males and +10.4% (95% CI: + 3.4; + 17.3) in females. Left colon cancer rates increased in males (+ 10.6% 95% CI: + 4.6; + 16.6). Left colon cancer in females and rectal cancer incidence rates did not significantly change. Between the 1901 cohort to the 1941 cohort, estimated cumulative risks for right colon cancer increased sharply. The increase was less marked for left colon and the cumulative risk for rectal cancer remained almost stable. Temporal trends were different by subsites and sexes. In conclusion, our results confirm the existence of different trends in colorectal cancer incidence between subsites and sexes. These differences probably reflect aetiological distinctions.

Caenorhabditis elegans is a model host for Salmonella typhimurium.

The idea of using simple, genetically tractable host organisms to study the virulence mechanisms of pathogens dates back at least to the work of Darmon and Depraitère [1]. They proposed using the predatory amoeba Dictyostelium discoideum as a model host, an approach that has proved to be valid in the case of the intracellular pathogen Legionella pneumophila [2]. Research from the Ausubel laboratory has clearly established the nematode Caenorhabditis elegans as an attractive model host for the study of Pseudomonas aeruginosa pathogenesis [3]. P. aeruginosa is a bacterium that is capable of infecting plants, insects and mammals. Other pathogens with a similarly broad host range have also been shown to infect C. elegans [3,4]. Nevertheless, the need to determine the universality of C. elegans as a model host, especially with regards pathogens that have a naturally restricted host specificity, has rightly been expressed [5]. We report here that the enterobacterium Salmonella typhimurium, generally considered to be a highly adapted pathogen with a narrow range of target hosts [6], is capable of infecting and killing C. elegans. Furthermore, mutant strains that exhibit a reduced virulence in mammals were also attenuated for their virulence in C. elegans, showing that the nematode may constitute a useful model system for the study of this important human pathogen.

Molecular analysis of the trimethylamine N-oxide (TMAO) reductase respiratory system from a Shewanella species.

Trimethylamine N-oxide (TMAO) is an abundant compound of tissues of marine fish and invertebrates. During fish spoilage, certain marine bacteria can reduce TMAO to nauseous trimethylamine (TMA). One such bacterium has been isolated and identified as a new Shewanella species, and called Shewanella massilia. The anaerobic growth of S. massilia is greatly increased when TMAO is added, indicating that TMAO reduction involves a respiratory pathway. The TorA enzyme responsible for TMAO reduction is a molybdenum cofactor-containing protein of 90 kDa located in the periplasm. Whereas TorA is induced by both TMAO and dimethylsulfoxide (DMSO), this enzyme has a high substrate specificity and appears to only efficiently reduce TMAO as a natural compound. The structural torA gene encoding the TMAO reductase (TorA) and its flanking regions were amplified using PCR techniques. The torA gene is the third gene of a TMAO-inducible operon (torECAD) encoding the TMAO respiratory components. The torC gene, located upstream from torA encodes a pentahemic c-type cytochrome, likely to be involved in electron transfer to the TorA terminal reductase. TorC was shown to be anchored to the membrane and, like TorA, is induced by TMAO. Except for the TorE protein, which is encoded by the first gene of the torECAD operon, all the tor gene products are homologous to proteins found in the TMAO/DMSO reductase systems from Escherichia coli and Rhodobacter species. In addition, the genetic organization of these systems is similar. Although these bacteria are found in different ecological niches, their respiratory systems appear to be phylogenetically related, suggesting that they come from a common ancestor.

[Superficial cancer of the stomach: evolution of their characteristics over a 20 year period in one population]. / Les cancers superficiels de l'estomac: évolution de leurs caractéristiques sur une période de 20 ans dans une population.

OBJECTIVES: The aim of this study was to analyse the incidence, treatment and prognosis of early gastric cancer in a population-based series and to draw a picture of time trends. METHODS: Over a 20-year period (1976-1995), 80 early gastric cancers were diagnosed in the Côte-d'Or area (493,000 residents). Incidence rates were calculated by sex, age groups and 5-year periods. Prognostic factors were determined using the Kaplan-Meier method and the Cox model. RESULTS: Age-standardized incidence rates were 0.8/100,000 in men and 0.3/100,000 in women. Incidence increased slightly over time (NS) and their proportion among gastric cancers increased from 3.4% (1976-1980) to 7.9% (1991-1995) (P < 0.01). Among these cancers, 25 were intramucosal (31.3%), 55 were submucosal (68.8%) and 8 had lymph node metastases (10.0%). Overall 21 patients (24.1%) had already been treated for a peptic ulcer. The 5-year crude survival rate was 63.1% and the corresponding net survival rate was 86.3%. Lymph node metastases, location, sex and cancer extension and age were independent prognostic factors. CONCLUSIONS: Though it is on the increase, the proportion of early gastric cancers remains low among gastric cancers. This study confirms the importance of performing a gastroscopy with biopsy upon each bout of ulcer and that the prognosis is lower than suggested by hospital based series.

Non-Hodgkin's lymphoma: time trends for incidence and survival in Côte-d'Or, France.

BACKGROUND: A generally reported increased incidence of non-Hodgkin's lymphomas (NHL) and a recent evolution in treatment strategies, as well as several clinical trials suggesting improved survival, have prompted this study to evaluate time trends in incidence and prognosis of NHL. METHOD: NHL recorded by the population-based Registry of Hematopoietic Malignancies in Côte-d'Or (France) were considered over three 4-year periods from 1980 to 1992. A multivariate survival analysis was carried out in terms of both crude and relative survivals. RESULTS: Overall incidence, increased over the 12 years considered, by an average of 6.8% per annum (P < 0.05). Only two cases of AIDS-related NHL were registered during this period. NHL incidence has increased slightly more for males than for females, further widening the gap in incidence between the sexes. In terms of histological grade the increase in incidence was more pronounced for low-grade and high-grade NHL than for intermediate-grade NHL. The overall 5-year relative survival rate was 69.3%. In multivariate relative survival analysis, neither sex, age, period of diagnosis nor place of hospitalization were significant prognostic factors. Only place of residence, with RR 2.2 (1.41-3.42) for people living in rural areas compared to urban areas and histological type, according to the working formulation with RR 3.8 (2.22-6.61) for high-grade tumours compared to low-grade tumours, remained informative for prognosis. CONCLUSIONS: Although incidence of NHL has increased in Côte-d'Or, this trend has remained independent of the AIDS epidemic. Contrary to the findings of clinical trials, the patients' survival in this population-based series has not been shown to have improved over the study period.

Population-based study of diagnosis, treatment and prognosis of gastric cancer.

BACKGROUND: Gastric cancer remains a common cancer with a poor prognosis. Improving trends seen in Japan have not yet been observed in Western countries. METHODS: A population-based series of 1329 patients with gastric cancer diagnosed over an 18-year period in Côte d'Or, France, was used to establish time trends in diagnostic strategy, treatment and prognosis. RESULTS: The use of endoscopy alone increased from 2.7 per cent in 1976-1978 to 76.6 per cent in 1991-1993 (P < 0.0001). This trend was associated at first with a significant decrease in the use of radiography alone, then by a significant decrease in the use of both radiography and endoscopy. The proportion of resections for cure increased from 37.9 per cent in 1976-1978 to 50.0 per cent in 1991-1993 (mean 3-year variation + 5.8 per cent, P < 0.01). The proportion of cases confined to the gastric wall increased from 6.1 to 11.7 per cent (mean 3-year variation + 13.1 per cent, P < 0.01), while the proportion of other stages remained stable. The operative mortality rate decreased dramatically from 25.6 per cent in 1976-1978 to 13.6 per cent in 1991-1993 (P < 0.001) and the 5-year relative survival rate rose from 12.8 per cent in 1976-1978 to 26.4 per cent in 1988-1990 (P < 0.001). CONCLUSION: This study has demonstrated that improvements in the care of patients with gastric cancer have been achieved, but that further progress may be made.

Environmental and familial risk factors in relation to the colorectal adenoma--carcinoma sequence: results of a case-control study in Burgundy (France).

A case-control study in the Cote-d'Or area (Burgundy, France) investigated the relationship between environmental and familial risk factors and the different steps of the adenoma-carcinoma sequence. Two adenoma groups (< 10 mm and > or = 10 mm), a polyp-free control group, a colorectal cancer group and a general population control group were recruited. Tobacco was associated with the risk of adenomas, and alcohol with the risk of large adenomas. They proved to be independently related to large adenoma formation when compared with controls. There was no association with cancer risk. Refined cereals, delicatessen, offal and fats appear to be risk factors along the adenoma-carcinoma sequence. This data does not support an increased risk with high consumption of fresh meat, or a protective effect of dairy products and calcium. A high consumption of vegetables was a protective factor for cancer, mainly in men. Excess weight and body mass index influenced the earlier step of the adenoma carcinoma sequence and excess calorie intake was risk factor for cancer. The decision to study precancerous lesions as well as cancer appears fruitful. Results suggest that the three stages of large bowel carcinogenesis are partly related to diet in different ways. They are concordant with risk factors recorded for colorectal cancer, but suggest some local specificities.

Chemoprevention of metachronous adenomas of the large bowel: design and interim results of a randomized trial of calcium and fibre. ECP Colon Group.

A European multicentric intervention study, led by the colon group of the European Cancer Prevention Organization, is under way. The main aim of the study is to test the efficacy of oral calcium supplementation with 2 g calcium per day and oral dietary supplementation with mucilaginous substances (as 3.8 g of ispaghula husk) on adenoma recurrence. Secondary aims are the study of treatment efficacy on colonic cell proliferation and on stool bile acid and sterol concentration. Serum and plasma samples are also collected. To better interpret the effect of the intervention, a diet history questionnaire and an aspirin and anti-inflammatory drug questionnaire are administered. The aim will be achieved through a randomized placebo-controlled clinical trial using a parallel design in patients aged 35 to 75 at entry with a complete colonoscopy and a clean colon. Overall, 655 subjects have been included. All randomized patients are followed up every six months for 3 years. If one of the evaluated interventions proves efficient, the benefits of a simple, safe and inexpensive prophylaxy for a very common cancer will be clear.

Time trends in diagnostic strategy, treatment, and prognosis of gastric cancer in the elderly: a population based study.

The impact of changes in diagnostic strategies for gastric cancer and attitudes towards surgery in elderly patients is not known. A population-based series of 842 gastric cancers diagnosed between 1976 and 1993 in patients aged 70 and older in Côte-dOr, France, was used to establish trends in diagnostic strategy, treatment, and prognosis. The use of endoscopy alone increased from 3% (1976-78) to 81% (1991-93). This trend was initially associated with a decrease in the use of x-ray alone, then with a decrease in the use of both x-ray and endoscopy. The proportion of resection for cure increased from 26% during 1976-78 to 43% during 1991-93 (P < 0.001). The proportion of cancers not extending beyond the gastric wall increased from 12% to 24% (P < 0.05). Operative mortality decreased from 38.7% (1976-78) to 13.3% (1991-93) and the corresponding 3-year crude survival rate rose from 7% to 18%. Improvements in the care of gastric cancer in elderly patients have been achieved, but further progress is warranted.

Calcium, phosphorus, vitamin D, dairy products and colorectal carcinogenesis: a French case--control study.

A protective effect of calcium against colorectal cancer has been described in Anglo-Saxon but not in Latin communities, and no such effect has been observed regarding adenomas. We investigated the relationship between calcium, dairy products and the adenoma-carcinoma sequence in a French region by comparing small adenoma ( < 10 mm, n = 154), large adenoma (n = 208) and polyp-free (n = 426) subjects, and cancer cases (n = 171) with population controls (n = 309). There was no protective effect of calcium against colorectal tumours except for low fat calcium and large adenomas in men (OR for highest quintile = 0.3, P for trend = 0.06). There was even a trend towards an increased risk of cancer with dairy calcium in men and non-dairy calcium in women. Vitamin D was inversely related to the risk of small adenomas in women (OR for highest quintile = 0.4, P for trend = 0.04). Regarding dairy products, only consumption of yoghurt displayed an inverse relationship with risk of large adenomas, in both men and women. These data failed to demonstrate a protective effect of calcium against colorectal carcinogenesis. They suggest that the type of dairy product might be the important factor with regard to prevention of colorectal tumours.

Folate and alcohol intakes: related or independent roles in the adenoma-carcinoma sequence?

Epidemiologic studies have suggested that high alcohol and low folate intakes might be jointly associated with colorectal tumors via DNA metabolism. We investigated this hypothesis in a case-control study comparing small adenoma (< 10 mm, n = 154), large adenoma (n = 208), and polyp-free (n = 426) subjects, recruited after colonoscopy, and cancer cases (n = 171) with population controls (n = 309). Odds ratios for the fifth vs. the first quintile of intake (OR5) were as follows: Folate intake was related to the risk of small and large adenomas compared with polyp-free subjects [OR5 = 0.5, 95% confidence interval (CI) 0.3-1.0; OR5 = 0.5, 95% CI 0.3-1.0, respectively], whereas alcohol was related to risk of large adenomas (OR5 = 4.1, 95% CI 2.1-8.1), but not of small adenomas (OR5 = 1.2, 95% CI 0.7-2.2). In large adenomas, there was some interaction between alcohol and folate, with a stronger protective effect of folate with high alcohol intake and a stronger risk with alcohol with low folate intake. For cancer patients compared with general population controls, neither alcohol (OR5 = 1.6, 95% CI 0.8-3.0) nor folates (OR5 = 1.0, 95% CI 0.5-2.0) were related to risk. Our data support the hypothesis that folate intake might be mostly beneficial to prevent adenoma formation but might have an additional protective effect against adenoma growth associated with alcohol.

Intervention trials on colorectal cancer prevention.

Epidemiological studies have emphasized the major role played by diet in the etiology of large-bowel cancer. Attempts to identify causative or protective factors in epidemiological and experimental studies have led to some discrepancies. The time has come to test the most important hypotheses within the framework of intervention studies. Of 14 studies specifically devoted to colorectal carcinogenesis, nine have been completed and five are ongoing; all the studies evaluate the effect of the intervention on adenoma recurrence and three studies also examine adenoma growth. In addition, five intervention trials considering cardiovascular diseases and various cancer sites will provide data on the effect of the intervention on colorectal cancer incidence. The interventions being evaluated are supplements of vitamins (with or without other antioxidants), fibre or calcium, as well as dietary modifications. Most available data do not support a protective effect of vitamins and antioxidants on colorectal carcinogenesis. There are some arguments in favour of a protective effect of dietary fibre and/or a low-fat diet on adenoma growth. The results of ongoing studies will be available within two to three years. If one of the evaluated interventions proves effective, it will indicate a simple, safe and inexpensive prophylaxis for a very common cancer.

[Primary prevention of colorectal cancer]. / Prévention primaire du cancer colorectal.

Results from case-control studies and prospective studies suggest that diet is involved in the causation of large bowel cancer either as initiator, promoter or inhibitor of carcinogenesis. Available data are not sufficient to serve as a basis for firm specific dietary advice. In the present situation it is attractive to investigate available hypotheses within the frame work of intervention trials. The adenoma appears to be one of the most appropriate end point of intervention studies. Several arguments indicate that the adenoma-carcinoma sequence is a multistep process. Colorectal cancer could possibly be prevented by intervening in the development of a small adenoma or in the growth into a large adenoma. Four intervention trials have been published so far. One of them suggest a protective effect of antioxidants vitamins on adenoma recurrence and three of them conclude to the absence of effect of these vitamins. A protective effect of lactulose on adenoma recurrence has also been suggested. Three studies are currently evaluating the effect of calcium supplementation on adenoma recurrence or growth of calcium supplementation, three studies the effect of fibre supplements, two studies the effect of antioxidants (one of them with calcium) and two studies the effect of diet intervention. The results of these studies will be available within three years.