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TWO DISTINCT AETIOLOGIES OF CARDIA CANCER: EVIDENCE FROM PREMORBID SEROLOGICAL MARKERS OF GASTRIC ATROPHY AND HELICOBACTER PYLORI STATUS

The aetiology of cardia cancer and the role of Helicobacter pylori in its pathogenesis remain unclear. The junctional position of this cancer is a source of misclassification; some cases may be oesophageal adenocarcinomas while others may be gastric adenocarcinomas. If the aetiology of this cancer is to be understood, we need a way of separating the two entities. Hansen et al addressed this question by comparing the premorbid state of the stomach in cardia vs non-cardia cancers. They used a nested case–control design that included 129 non-cardia cancers and 44 cardia cancers in Norway (each case had three matched controls). Serum collected a median of 11.9 years before the diagnosis of cancer was tested for anti-H pylori antibodies, pepsinogen I:II and gastrin. Cardia cancer was negatively associated with H pylori (OR 0.27, 95% CI 0.12 to 0.59), but H pylori-positive cardia cancer showed a positive association with gastric atrophy (OR 3.33, 95% CI 1.06 to 10.5) and were equally diffuse or intestinal according to Lauren classification (see fig). In contrast, H pylori negative cardia cancers without atrophy were largely intestinal. These findings confirm two aetiologies of cardia cancer and suggest that serological markers of gastric atrophy may provide the key to determining a gastric or oesophageal origin of cancer.
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Serum pepsinogen I to serum pepsinogen II ratio (PGI:II) in patients with cardia cancer and their controls stratified by Helicobacter pylori status.

IS GASTRIC CANCER PART OF THE TUMOUR SPECTRUM OF HEREDITARY NON-POLYPOSIS COLORECTAL CANCER? A MOLECULAR GENETIC STUDY

Individuals with hereditary non-polyposis colorectal cancer (HNPCC) develop cancers of the colon and rectum and a variety of extra-colonic malignancies. Despite being the second most common extra-colonic malignancy in HNPCC, gastric cancer is currently not included in the Amsterdam Criteria II. Gylling et al determined whether or not gastric cancer is a true HNPCC spectrum malignancy. They studied the molecular and clinicopathological profiles of gastric cancers (n  =  13) from HNPCC mutation carriers and compared them with the profiles of sporadic gastric cancers (n  =  46) stratified by histology and microsatellite instability (MSI) status. Gastric cancers from HNPCC mutation carriers resembled sporadic intestinal MSI gastric cancers, except that MLH1 promoter methylation was absent (p  =  0.001) and the general methylation index was lower (p  =  0.038), suggesting similar, but not identical, developmental pathways (see table). The authors conclude that the present molecular evidence justifies considering gastric cancers as true HNPCC spectrum malignancies.
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Molecular markers in HNPCC cancer and microsatellite instability

TOLL-LIKE RECEPTOR 4 (TLR4) AND THE EXACERBATION OF ILEITIS BY COMMENSAL ESCHERICHIA COLI

Commensal bacteria are known to play a key role in inflammatory bowel disease (IBD). Escherichia coli has been shown to accumulate at the site of inflammation and may exacerbate the inflammatory response. This accumulation is seen in mice infected with Toxoplasma gondii, an animal model used to study ileitis. E coli lipopolysaccharide is known to activate the innate immune system via Toll-like receptor 4 (TLR4). Heimesaat et al demonstrated that mice lacking TLR4 had a much reduced inflammatory response (see fig) and cytokine production compared with normal mice, in spite of a similar increase in E coli. Furthermore, while gnotobiotic animals infected with T gondii fail to develop ileitis when E coli was introduced, the ileitis was aggravated in wild-type but not TLR4-knockout mice. This study demonstrates the importance of the TLR4 signalling pathway in this model and suggests this may be an appropriate therapeutic target in IBD.
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Histological inflammation score in mice lacking TLR2 and/or TLR4.

HELPER CD4+ T CELLS MEDIATE INCREASED 5-HYDROXYTRYPTAMINE (5H-T) PRODUCTION IN ENTERIC INFECTION

5-hydroxytryptamine (5H-T), which plays a key role in controlling secretion, motility and sensation in the gut, is found mainly in the enterochromaffin (EC) cell. EC cells are increased in a range of inflammatory conditions including nematode infections such as Trichuris muris, which was the subject of this study. Infected mice showed a marked increase in colonic EC cells and mucosal 5H-T content, a response that was much reduced in mice with severe combined immune deficiency (SCID). This defective response could be corrected (see fig) by reconstituting the SCID mice with helper CD4+ T cells derived from infected but not noninfected wild-type mice. This manoeuvre also restored production of the key Th2 cytokines interleukin (IL)4 and IL13. The authors then lasered dissected EC cells and showed that EC cells produced mRNA for the IL13 receptor but not the IL4. This study defines the mechanism of EC hyperplasia and offers the opportunity for intervention with possible benefit in a range of inflammatory conditions.
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Colonic 5-hydroxytryptamine (5H-T) content in severe combined immune deficiency (SCID) mice before and after reconstitution with CD4+ T helper cells from Trichuris muris-infected mice.

RISK OF COLORECTAL CANCER IN JUVENILE POLYPOSIS

Juvenile polyposis (JP) is an autosomal dominant syndrome characterised by the development of hamartomatous gastrointestinal polyps and is associated with colorectal cancer, but the relative and absolute risk in these patients is not known. Brosens et al compared the incidence rates of colorectal cancer in patients with JP with that of the general population through person-year analysis, with adjustment for demographics. In patients with JP, the relative risk (95% CI) of colorectal cancer was markedly increased at 34.0 (14.4 to 65.7) and the risks were similar in both genders. The cumulative life-time absolute risk for colorectal cancer was 38.7% and the mean (SD) age of diagnosis of cancer was 43.9 (10.4) years. The authors conclude that such patients require vigilant colorectal surveillance starting at a young age and merit a low threshold for recommending panproctocolectomy.
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Patients with juvenile polyposis who developed colorectal cancer

TRANSIENT ELASTOGRAPHY (TE) IN THE EVALUATION OF LIVER FIBROSIS IN PATIENTS WITH CHRONIC LIVER DISEASE

Many important decisions in hepatology depend on assessing the severity of fibrosis, which often involves a liver biopsy. Transient elastography (TE) is a recently developed, noninvasive assessment of fibrosis that measures the speed of propagation of a pressure wave across the liver. This study evaluated the reproducibility, sensitivity and specificity of TE in 200 patients with chronic liver disease. Two TE examinations were performed by two operators and the resulting 800 scans were compared with the results of a liver biopsy taken within 2 weeks. Only 2.4% of attempted scans were unsatisfactory. Interobserver agreement was mostly excellent and there was a correlation between TE and fibrosis score (see fig). However, TE increases with inflammatory activity and the reliability is reduced in fatty livers and those with minimal fibrosis. Furthermore, the average difference between cirrhosis and the lowest score for fibrosis is only around 10, while the limits of agreement of two observers was approximately SD 4. The authors conclude by suggesting that combining serum tests with TE is likely to improve its diagnostic accuracy, although for cirrhosis at least, the sensitivity of 91% and specificity of 89% seems acceptable.
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Transient elastography result according to the fibrosis score of liver biopsy.

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