Chromosomal and microsatellite instability in sporadic gastric cancer

BACKGROUND: Gastric cancer can progress through two pathways of genomic instability: chromosomal (CIN) and microsatellite instability (MSI). It is hypothesized that these two pathways are not always independent and that some tumors show overlap between these two mechanisms. METHODS: A total of 98 sporadic gastric cancers were classified based on their MSI status, using microsatellite assay with BAT26. Evidence for CIN was investigated by identifying loss of heterozygosity (LOH) events on chromosome arms, 5q, 10p, 17p, 17q, and 18q, which are regions harboring tumor suppressor genes that are significant in gastric cancer development. RESULTS: Twelve tumors (12%) showed high-frequency MSI (MSI-H). Overall, 43 of the tumors (44%) had at least one LOH event, with most frequent chromosomal losses observed on 10p and 18q (30%, respectively), followed by 5q (21%), 17p (14%), and 17q (12%). Interestingly, overlap was observed between CIN and MSI pathways. Of 43 cancers with LOH events, four (9%) were also MSI-H. It was also found that 48% of cancers without MSI-H had no LOH events identified, comprising a subgroup of tumors that were not representative of either of these two pathways of genomic instability. CONCLUSION: These results suggest that molecular mechanisms of genomic instability are not necessarily independent and may not be fully defined by either the MSI or CIN pathways in sporadic gastric cancers.     

Disruption of beta-catenin pathway or genomic instability define two distinct categories of liver cancer in transgenic mice

BACKGROUND & AIMS: Human liver cancer can be divided into 2 categories that are characterized by activation of beta-catenin and genomic instability. Here we investigate whether similar categories exist among 5 transgenic models of liver cancer, including c-myc, transforming growth factor-alpha, E2F-1, c-myc/transforming growth factor-alpha, and c-myc/E2F-1 mice. METHODS: The random amplified polymorphic DNA method was used to assess the overall genomic instability, and chromosomal loci affected by genomic alterations were determined by microsatellite analysis. beta-Catenin mutations and deletions were analyzed by polymerase chain reaction and sequencing screening. Cellular localization of beta-catenin and expression of alpha-fetoprotein, a prognostic marker of hepatocellular carcinoma, were investigated by immunohistochemistry. RESULTS: Liver tumors from the transgenic mice could be divided into 2 broad categories characterized by extensive genomic instability (exemplified by the c-myc/transforming growth factor-alpha mouse) and activation of beta-catenin (exemplified by the c-myc/E2F-1 mouse). The c-myc/transforming growth factor-alpha tumors displayed extensive genomic instability with recurrent loss of heterozygosity at chromosomes 1, 2, 4, 6, 7, 9, 12, 14, and X and a low rate of beta-catenin activation. The genomic instability was evident from the early dysplastic stage and occurred concomitantly with increased expression of alpha-fetoprotein. The c-myc/E2F-1 tumors were characterized by a high frequency of beta-catenin activation in the presence of a relatively stable genome and low alpha-fetoprotein levels. CONCLUSIONS: We have identified 2 prototype experimental models, i.e., c-myc/transforming growth factor-alpha and c-myc/E2F-1 mice, for the 2 categories of human hepatocellular carcinoma characterized by genomic instability and beta-catenin activation, respectively. These mouse models will assist in the elucidation of the molecular basis of human hepatocellular carcinoma.     

Cancer in inflammatory bowel disease

Patients with long-standing inflammatory bowel disease （IBD） have an increased risk of developing colorectal cancer （CRC）. Many of the molecular alterations responsible for sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also play a role in colitis-associated colon carcinogenesis. Colon cancer risk in inflammatory bowel disease increases with longer duration of colitis, greater anatomic extent of colitis, the presence of primary sclerosing cholangitis, family history of CRC and degree of inflammation of the bowel. Chemoprevention includes aminosalicylates, ursodeox, ycholic acid, and possibly folic acid and statins. To reduce CRC mortality in IBD, colonoscopic surveillance with random biopsies remains the major way to detect early mucosal dysplasia. When dysplasia is confirmed, proctocolectomy is considered for these patients. Patients with small intestinal Crohn＇s disease are at increased risk of small bowel adenocarcinoma. Ulcerative colitis patients with total proctocolectomy and ileal pouch anal- anastomosis have a rather low risk of dysplasia in the ileal pouch, but the anal transition zone should be monitored periodically. Other extra intestinal cancers, such as hepatobiliary and hematopoietic cancer, have shown variable incidence rates. New endoscopic and molecular screening approaches may further refine our current surveillance guidelines and our understanding of the natural history of dysplasia.     

Effect of elastic bandage on postural control in subjects with chronic ankle instability: a randomised clinical trial

Purpose: To report the immediate and prolonged (one week) effects of elastic bandage (EB) on balance control in subjects with chronic ankle instability.

Material and methods: Twenty-eight individuals successfully completed the study protocol, of whom 14 were randomly assigned to the EB group (7 men, 7 women) and 14 were assigned to the non-standardised tape (NST) group (9 men, 5 women). To objectively measure postural sway we used computerised dynamic posturography (CDP) with sensory organisation test (SOT) and unilateral stance (US) test. We analysed the following SOT parameters: the composite SOT score, the composite SOT strategy and the SOT condition 2 and its strategy. In addition, we studied the centre of gravity (COG) sway velocity with open eyes and close eyes during the US test.

Results: Repeated measures ANOVA showed a significant effect for time in composite SOT score (F=?34.98; p=?<0.01), composite SOT strategy (F=?12.082; p=?0.02), and COG sway with open eyes (F=?3.382; p=?0.039) in EB group and NST group. Therefore, there were improvements in balance control after bandage applications (defined as better scores in SOT parameters and decreased COG sway in US test). However, no differences between groups were observed in the most relevant parameters.

Conclusions: This study did not observe differences between EB and NST during the follow-up in the majority of measurements. Several outcome measures for SOT and US tests improved in both groups immediately after bandage applications and after one week of use. EB of the ankle joint has no advantage as compared to the non-standardised tape.

• Implications for rehabilitation

• Elastic bandage (EB) of the ankle joint has no advantage as compared to the non-standardised tape.

• The effects of the bandages could be due to a greater subjective sense of security.

• It is important to be prudent with the use of bandage, since a greater sense of safety could also bring with it a greater risk of injury.

• The application of the bandage on subjects with chronic ankle instability (CAI) should be prolonged and used alongside other physiotherapy treatments.

     

Factors affecting emotional instability in female rheumatoid arthritis outpatients with limited functional disorder

We attempted to identify which background factors were the most important indicators of such psychological problems as emotional instability, a feeling of hopelessness, and suicidal tendencies in female rheumatoid arthritis (RA) outpatients with limited functional disorder. Among female RA patients aged 20 years and older who visited the outpatient clinic, 101 class I and II patients were selected as subjects for the present study. An original questionnaire and a psychological test (CMI) were given to those subjects who had given their written consent to such testing, and an analysis was carried out on 85 patients who returned all the written forms. Their emotional instability was related to factors such as "not being able to understand the nature of RA disease and its treatment," "sense of value had changed after developing RA," "nonuse of drugs," and "duration of disease." A feeling of hopelessness was related to "smoking," and a suicidal tendency was related to "smoking" and "class I." We identified a characteristic correlation between emotional instability and background factors in this study. Paying close attention to these factors may thus be useful in preventing the appearance of psychological problems as well as in developing effective early treatment strategies. Received: April 5, 2000 / Accepted: July 19, 2000     

Microsatellite instability and the clinicopathological features of sporadic colorectal cancer

BACKGROUND AND AIMS: In this study, we prospectively examined the clinical significance of the microsatellite instability (MSI) phenotype in sporadic colorectal cancer, and investigated methods for effective identification of these tumours in routine pathology practice. METHODS: DNA was extracted from 310 tumours collected from 302 consecutive individuals undergoing curative surgery for sporadic colorectal cancer. Microsatellite status was determined by polymerase chain reaction amplification using standard markers, while immunostaining was used to examine expression of MLH1, MSH2, and p53. RESULTS: Eleven per cent of tumours showed high level instability (MSI-H), 6.8% had low level instability (MSI-L), and the remainder were stable. MSI-H tumours were significantly more likely to be of high histopathological grade, have a mucinous phenotype, and to harbour increased numbers of intraepithelial lymphocytes. They were also more likely to be right sided, occur in women, and be associated with improved overall survival. In total, 25 (8%) tumours showed loss of staining for MLH1 and a further three tumours showed absence of staining for MSH2. The positive and negative predictive value of immunohistochemistry in the detection of MSI-H tumours was greater than 95%. CONCLUSIONS: We conclude that the MSI-H phenotype constitutes a pathologically and clinically distinct subtype of sporadic colorectal cancer. Immunohistochemical staining for MLH1 and MSH2 represents an inexpensive and accurate means of identifying such tumours.     

Carpal instability in rheumatoid wrists

This study was conducted to identify patterns of carpal instability in the rheumatoid wrist. One hundred patients with proven rheumatoid arthritis were randomly chosen, and posteroanterior and lateral radiographs of right wrists were taken. The most common isolated pattern was volar intercalated segmental instability, apparent in 16 wrists, while nine wrists had scapholunate dissociations. Larsen grading scores revealed a correlation between disease duration, carpal height ratio, and ulnar translocation index. In the early stages of disease, the scapholunate angle was significantly increased and the lunate rotated volarly due to loosening of the intrinsic carpal ligament. In later phases, the capitolunate angle significantly increased and the capitate rotated dorsally. Patterns of carpal instability in rheumatoid wrists seem to be complicated, involving combined laxity of the intrinsic and extrinsic carpal ligaments.No benefits have been received from a commercial party directly or indirectly related to the subject of this article.An erratum to this article can be found at