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Two apparently independent mechanisms of instability are recognized in colorectal cancer, microsatellite instability and chromosomal instability. Evidence from colorectal cancer cell lines indicates the presence of either, or both, types of instability in the vast majority. Here, we sought to determine the prevalence of such instability in primary sporadic colorectal cancers. Microsatellite instability was established by demonstration of ovel clonal, nongerm-line alleles in at least two of four tested loci. Chromosomal abnormalities were identified by comparative genomic hybridization (CGH) and flow cytometric analysis of nuclear DNA content. Tumours harbouring chromosomal instability were distinguished from those with stable but aneuploid karyotypes by comparing chromosomal defects at multiple sites throughout each cancer. This analysis allowed assessment of both the number of chromosomal abnormalities and their heterogeneity throughout the tumour. The results confirm that microsatellite instability is consistently associated with multiple, repeated changes in microsatellites throughout the growth of the affected colorectal carcinomas. There were also several carcinomas in which major structural or numerical abnormalities in chromosomes had clearly continued to arise during tumour growth. However, a substantial subset of tumours showed neither microsatellite instability nor multiple, major chromosomal abnormalities. We suggest that the development of a proportion of colorectal cancers proceeds via a different pathway of carcinogenesis not associated with either of the currently recognized forms of genomic instability.

BAX gene mutations occur in approximately 50% of RER+ colorectal cancers. To determine the role of these mutations in tumour progression we analysed multiple di erent tumour sites from RER+ colorectal cancers for BAX mutations. Sixty colorectal carcinomas were analysed for microsatellite instability at loci BAT-26, L-myc, TGFbRII, D13S160 and D2S123. Twelve out of 60 tumours (20%) were RER+. Forty-®ve di erent tumour sites from the 12 RER+ carcinomas were analysed for BAX mutations at the [(G)8] tract in exon 3. Six out of 12 (50%) RER+ tumours showed BAX mutations, four of which showed a homogenous pattern of such mutations detected in all tumour sites. In the other two cases, BAX mutations were present in some but not all tumour sites sampled from the same patient. In contrast, TGFbRII mutations were found in 9/12 cases (75%) and in each of these were present in all the sampled sites. Two cases showed neither BAX nor TGFbRII mutation. These data suggest that mutations in TGFbRII may occur at a very early stage in tumour progression, perhaps in the founder clone. BAX mutations, however, are clearly not necessary for formation of the founder clone and can occur for the ®rst time later in tumour progression.

Current opinion of the genetic events driving colorectal tumourigenesis focuses on genomic instability. At least two apparently independent mechanisms are recognized, microsatellite instability and chromosomal instability. The genetic defects underlying each type of instability are only partially understood and controversy remains as to the role of p53 in the generation of chromosomal defects in colorectal cancer. This study sought to clarify the relationships between chromosomal abnormalities and defects of both p53 and mismatch repair. Extensive chromosomal analysis was undertaken, using¯ow cytometry and comparative genomic hybridization, of a series of sporadic colorectal cancers which had been grown to early passage as subcutaneous xenografts in SCID mice. Overall levels of chromosomal defects were observed to be low in RER+ cancers compared with RERx and distinctive patterns of chromosomal anomalies were found to be associated with both the RER+ and RERx phenotype. No particular level or pattern of chromosomal anomalies appeared to be associated with p53 status, supporting recent observations that abnormal p53 function is not suf®cient to cause chromosomal anomalies in colorectal tumours.

Background Most medical liver biopsies in the UK are now taken in radiology departments using 18 g biopsy needles. Subjectively, the resulting biopsies are narrow and fragile. Aim To compare the quality of liver biopsy tissue sections obtained from 16 and 18 g biopsy needles. Method Fifty consecutive routine medical liver biopsies obtained with 16 and 18 g needles, processed identically in the same laboratory, were measured using digital pathology software. We recorded their fragmentation, length, width, area and number of portal tracts. Results Biopsies obtained with 16 g needles more often resulted in an intact core in tissue sections than those with 18 g needles (71% vs 24%, p<0.001) and were significantly wider (average width of tissue 0.88 vs 0.53 mm, p<0.001). The average total area of tissue per pass was 11.38 mm2 compared with 8.34 mm2 (p<0.001). The number of complete portal tracts per length of biopsy was very variable, but double for 16 vs 18 g biopsies. Routinely taking two passes with the 18 g needle compensated for the reduced area, but the resulting liver in tissue sections was fragmented and distorted. Conclusions Our results support the routine use of 16 g rather than 18 g biopsy needles for routine ultrasound-guided medical liver biopsies. A second pass should be considered if the first biopsy core is short, especially for investigation of disease stage.

Current opinion of the genetic events driving colorectal tumourigenesis focuses on genomic instability. At least two apparently independent mechanisms are recognized, microsatellite instability and chromosomal instability. The genetic defects underlying each type of instability are only partially understood and controversy remains as to the role of p53 in the generation of chromosomal defects in colorectal cancer. This study sought to clarify the relationships between chromosomal abnormalities and defects of both p53 and mismatch repair. Extensive chromosomal analysis was undertaken, using flow cytometry and comparative genomic hybridization, of a series of sporadic colorectal cancers which had been grown to early passage as subcutaneous xenografts in SCID mice. Overall levels of chromosomal defects were observed to be low in RER+ cancers compared with RER- and distinctive patterns of chromosomal anomalies were found to be associated with both the RER+ and RER- phenotype. No particular level or pattern of chromosomal anomalies appeared to be associated with p53 status, supporting recent observations that abnormal p53 function is not sufficient to cause chromosomal anomalies in colorectal tumours.

Functional colonic obstruction is a colonic motility disorder with a number of causes. One cause is myenteric ganglionitis, which may result from paraneoplastic processes. We present the case of a previously healthy 53-year-old man who presented with a week's history of functional colonic obstruction. A transverse loop colostomy failed to resolve his symptoms and he subsequently underwent an extended right hemicolectomy. Histology demonstrated lymphocytic myenteric ganglionitis that was felt to be of paraneoplastic origin. The patient later developed bilateral ptosis and was diagnosed with ocular myasthenia gravis. Further investigation revealed the presence of a thymoma that was resected, resulting in an improvement to his symptoms. We present this case and a review of the literature to illustrate the importance of seeking out a paraneoplastic cause for functional colonic obstruction in adults as early resection of the tumour may help alleviate symptoms and avoid bowel surgery.

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