The "frost sign": an inadvertent minor complication of endoscopic mucosal resection.
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Aged↗
Biomedical subjects
I C Talbot
Publications and source records attributed to I C Talbot.
The prevalence of small, flat colorectal cancers in a western population.
OBJECTIVE: Small, flat colorectal cancers have been widely reported in the Japanese literature but are thought to occur rarely outside Japan. The aim of this retrospective cohort study was to clarify the prevalence of flat colorectal cancer in a Western population. METHODS: One thousand and twenty-six consecutive colonoscopies performed by a single experienced endoscopist were retrospectively analysed over a two-year period. The morphology, site and histological appearance of all documented colorectal cancers (CRC) were recorded. RESULTS: Forty-seven cases of CRC were detected, five of which (10%) demonstrated flat configuration. Flat cancers varied between 8 and 15 mm in diameter (mean 11 mm). Histologically, all flat lesions were moderately differentiated Dukes A adenocarcinomas. Two of these cancers contained no adenomatous component. CONCLUSION: This study confirms that small, flat colorectal cancers are not an uncommon finding at colonoscopy in Western patients. Compared to polypoid neoplastic lesions, flat cancers appear to undergo malignant change at a smaller size.
Adenocarcinoma↗
Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis.
BACKGROUND AND AIMS: Colonoscopic surveillance for cancer in longstanding extensive ulcerative colitis relies heavily on non-targeted mucosal biopsies. Chromoendoscopy can aid detection of subtle mucosal abnormalities. We hypothesised that routine pancolonic indigo carmine dye spraying would improve the macroscopic detection of dysplasia and reduce the dependence on non-targeted biopsies. PATIENTS AND METHODS: One hundred patients with longstanding extensive ulcerative colitis attending for colonoscopic surveillance underwent "back to back" colonoscopies. During the first examination, visible abnormalities were biopsied, and quadrantic non-targeted biopsies were taken every 10 cm. Pancolonic indigo carmine (0.1%) was used during the second colonoscopic examination, and any additional visible abnormalities were biopsied. RESULTS: Median extubation times for the first and second colonoscopies were 11 and 10 minutes, respectively. The non-targeted biopsy protocol detected no dysplasia in 2904 biopsies. Forty three mucosal abnormalities (20 patients) were detected during the pre-dye spray colonoscopy of which two (two patients) were dysplastic: both were considered to be dysplasia associated lesions/masses. A total of 114 additional abnormalities (55 patients) were detected following dye spraying, of which seven (five patients) were dysplastic: all were considered to be adenomas. There was a strong trend towards statistically increased dysplasia detection following dye spraying (p = 0.06, paired exact test). The targeted biopsy protocol detected dysplasia in significantly more patients than the non-targeted protocol (p = 0.02, paired exact test). CONCLUSIONS: No dysplasia was detected in 2904 non-targeted biopsies. In comparison, a targeted biopsy protocol with pancolonic chromoendoscopy required fewer biopsies (157) yet detected nine dysplastic lesions, seven of which were only visible after indigo carmine application. Careful mucosal examination aided by pancolonic chromoendoscopy and targeted biopsies of suspicious lesions may be a more effective surveillance methodology than taking multiple non-targeted biopsies.
Adult↗
Histological categorisation of fibrotic cancer stroma in advanced rectal cancer.
BACKGROUND AND AIMS: Based on conflicting reports regarding the role of the fibrotic stromal response in cancer development--namely, that a desmoplastic reaction can favour either the host or the tumour--it is clear that the role of the stromal response is varied. We have classified the fibrotic stroma of rectal adenocarcinoma penetrating the muscularis propria, based on histologically identified stromal components. METHODS: Three categories of stroma were used: mature-when the stroma was composed of mature collagen fibres (fine and elongated fibres into multiple layers); intermediate-when keloid-like collagen was intermingled with mature fibres; and immature-consisting of a myxoid stroma in which no mature fibres were included. RESULTS: In a data set of 862 patients, 53% of patients had mature fibrotic cancer stroma, 33% had intermediate stroma, and 15% had immature stroma. Five year survival rates decreased as follows: mature stroma (80%), intermediate stroma (55%), and immature stroma (27%). The adverse tumour phenotype, tumour cell budding (conspicuous isolated cells or small clusters of cancer cells), was observed in the cancer fronts in tumours with unfavourable fibrotic stroma (p<0.0001). Based on multivariate analysis, categorised fibrotic stroma was selected as an independent prognostic parameter (hazard ratio 1.39; 95% confidence interval 1.17-1.64) together with tumour differentiation. By immunohistochemical examination, as maturation of the fibrotic stroma decreased, stromal T cells became significantly sparser. Furthermore, myofibroblasts were distributed extensively in immature fibrotic stroma compared with mature and intermediate fibrotic stroma. CONCLUSION: The morphological categorisation of fibrotic cancer stroma highlights the role of the stromal response in relation to the behaviour and host immune reactions of rectal adenocarcinoma and would be a useful tool for predicting patient prognostic outcome.
Adenocarcinoma↗
Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk.
BACKGROUND AND AIMS: The risk of colorectal cancer is increased in ulcerative colitis (UC). Patients with UC have diverse colonoscopic appearances. Determining colonoscopic markers for cancer risk could allow patient risk stratification. PATIENTS AND METHODS: Following on from an earlier study which demonstrated a correlation between inflammation severity and neoplasia risk, a case control study was performed to look for colonoscopic markers of colorectal neoplasia risk in UC. Each patient with neoplasia detected between 1988 and 2002 was matched with two non-dysplastic colitic controls. Data were collected on post-inflammatory polyps, scarring, strictures, backwash ileitis, a shortened, tubular, or featureless colon, severe inflammation, and normal looking surveillance colonoscopies. RESULTS: Cases (n = 68) and controls (n = 136) were well matched. On univariate analysis, cases were significantly more likely to have post-inflammatory polyps (odds ratio (OR) 2.14 (95% confidence interval 1.24-3.70)), strictures (OR 4.22; 1.08-15.54), shortened colons (OR 10.0; 1.17-85.6), tubular colons (OR 2.03; 1.00-4.08), or segments of severe inflammation (OR 3.38; 1.41-10.13), and less likely to have had a macroscopically normal looking colonoscopy (OR 0.40; 0.21-0.74). After multivariate analysis, a macroscopically normal looking colonoscopy (OR 0.38; 0.19-0.73), post-inflammatory polyps (2.29; 1.28-4.11), and strictures (4.62; 1.03-20.8) remained significant. The five year risk of colorectal cancer following a normal looking colonoscopy was no different from that of matched general population controls. CONCLUSIONS: Macroscopic colonoscopic features help predict neoplasia risk in UC. Features of previous/ongoing inflammation signify an increased risk. A macroscopically normal looking colonoscopy returns the cancer risk to that of the general population: it should be possible to reduce surveillance frequency to five years in this cohort.
Adolescent↗
Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis.
BACKGROUND: Ten to 15% of patients with pouchitis experience refractory or recurrent disease. The aim of this study was to evaluate the effectiveness of a single daily high dose probiotic preparation (VSL#3) in maintaining antibiotic induced remission, and quality of life (QOL), for one year in such patients. METHODS: Patients with pouchitis at least twice in the previous year or requiring continuous antibiotics, associated with a pouchitis disease activity index (PDAI) > or =7 (0 = perfect; 18 = worst), in whom remission was induced by four weeks of combined metronidazole and ciprofloxacin, were randomised to receive VSL#3 6 g or placebo once daily for one year or until relapse. Symptomatic, endoscopic, and histological evaluations were made before, and two and 12 months after randomisation or at the time of relapse. Remission was defined as a clinical PDAI < or =2 and endoscopic PDAI < or =1. Relapse was defined as an increased clinical PDAI score > or =2 and increased endoscopic PDAI score > or =3. QOL was assessed using the inflammatory bowel disease questionnaire (IBDQ). RESULTS: Thirty six patients were randomised: 20 to VSL#3 and 16 to placebo. Remission was maintained at one year in 17 patients (85%) on VSL#3 and in one patient (6%) on placebo (p<0.0001). The IBDQ score remained high in the VSL#3 group (p = 0.3) but deteriorated in the placebo group (p = 0.0005). CONCLUSION: The once daily high dose probiotic VSL#3 is effective in maintaining antibiotic introduced remission for at least a year in patients with recurrent or refractory pouchitis. This is associated with a high level of quality of life.
Adult↗
An ancestral Ashkenazi haplotype at the HMPS/CRAC1 locus on 15q13-q14 is associated with hereditary mixed polyposis syndrome.
The putative locus for hereditary mixed polyposis syndrome (HMPS) in a large family of Ashkenazi descent (SM96) was previously reported to map to chromosome sub-bands 6q16-q21. However, new clinical data, together with molecular data from additional family members, have shown 6q linkage to be incorrect. A high-density genomewide screen for the HMPS gene was therefore performed on SM96, using stringent criteria for assignment of affection status to minimize phenocopy rates. Significant evidence of linkage was found only on a region on chromosome 15q13-q14. Since this region encompassed CRAC1, a locus involved in inherited susceptibility to colorectal adenomas and carcinomas in another Ashkenazi family (SM1311), we determined whether HMPS and CRAC1 might be the same. We found that affected individuals from both families shared a haplotype between D15S1031 and D15S118; the haplotype was rare in the general Ashkenazi population. A third informative family, SM2952, showed linkage of disease to HMPS/CRAC1 and shared the putative ancestral haplotype, as did a further two families, SMU and RF. Although there are probably multiple causes of the multiple colorectal adenoma and cancer phenotype in Ashkenazim, an important one is the HMPS/CRAC1 locus on 15q13-q14.
Adenomatous Polyposis Coli↗
Pathological staging of epidermoid anal carcinoma for the new era.
Chemoradiotherapy is the standard treatment for most patients with epidermoid anal cancer. Pre-treatment staging is based on size for T1-T3 lesions and clinical and radiological assessment of adjacent organ invasion for T4 lesions. For patients with residual or recurrent carcinoma, anorectal excision offers the best chance of oncological salvage. Pathological staging systems for anorectal excision specimens were validated at the time when surgical treatment was first line therapy. A validated staging system is necessary for salvage surgical excision specimens following an attempt to cure by radiotherapy and chemotherapy for the purpose of prognosis and further treatment planning.
Anus Neoplasms↗
Influence of pathological tumour variables on long-term survival in resectable gastric cancer.
Although tumour stage and nodal status are established prognostic factors for resectable gastric cancer, the relative importance of other pathological characteristics remains unclear. This study reports univariate and multivariate analyses of the prognostic value of various pathological and staging factors based on 324 patients entered into the MRC randomised surgical trial for gastric cancer. In the univariate analysis tumour stage, nodal status, UICC clinical stage, number of involved nodes, WHO predominant type, mixed Lauren type, Ming type, tumour differentiation, lymphocytic and tumour stromal eosinophilic infiltration were all found to have a significant impact on survival (logrank test, 5% level). In the multivariate analysis, UICC clinical stage and eosinophilic infiltration were found to have a significant influence. Risk of death increased for UICC stage II and III patients (Hazard Ratio for stage II compared to stage I=2.0, 95% Confidence Interval (CI) 1.4-2.9; Hazard Ratio for stage III compared to stage I=3.5, 95% CI 2.5-4.8). Patients with numerous eosinophils had a lower risk of death than those with none (Hazard Ratio=0.5, 95% CI 0.3-0.8). This association between survival and eosinophilic infiltration merits further study.
Aged↗
Four-week open-label trial of metronidazole and ciprofloxacin for the treatment of recurrent or refractory pouchitis.
BACKGROUND: Preliminary data suggest that short-term antibiotic therapy with a single drug is effective for the treatment of patients with pouchitis. However, some patients are resistant to treatment. AIM: To evaluate the therapeutic efficacy of a prolonged course of a combination of two antibiotics in patients with refractory or recurrent pouchitis, as well as its impact on their quality of life. METHODS: Patients with active refractory or recurrent pouchitis were recruited. This was defined as both: (i) a history of pouchitis at least twice in the last 12 months or persistent pouchitis requiring continual intake of antibiotics; and (ii) a Pouchitis Disease Activity Index score 3 7 (best to worst pouchitis=0-18) at the beginning of therapy. Treatment consisted of a combination of metronidazole, 400 or 500 mg twice daily, and ciprofloxacin, 500 mg twice daily, for 28 days. Symptomatic, endoscopic and histological evaluations were undertaken before and after antibiotic therapy using the Pouchitis Disease Activity Index score. Remission was defined as a combination of a Pouchitis Disease Activity Index clinical score of <or= 2, endoscopic score of <or= 1 and total score of <or= 4. The quality of life was assessed with the Inflammatory Bowel Disease Questionnaire, which encompasses bowel, systemic and emotional symptoms as well as social function (worst to best=32-224). RESULTS: Forty-four patients (24 male, 20 female; median age, 37.5 years) entered the trial and completed treatment. Thirty-six (82%) went into remission. The median Pouchitis Disease Activity Index scores before and after therapy were 12 (range, 8-17) and 3 (range, 1-10), respectively (P < 0.0001). The median Inflammatory Bowel Disease Questionnaire score also significantly improved from 96.5 (range, 74-183) to 175 (range, 76-215) with this therapy (P < 0.0001). The eight patients (five male, three female) who did not go into remission were significantly older (median 47.5 vs. 35 years; P=0.007), had a longer history of pouchitis (95.5 vs. 26 months; P=0.0008), had a greater proportion with chronic pouchitis (chronic/relapsing: 6/2 vs. 9/27; relative risk, 1.6; 95% confidence interval, 1.0-2.4) and tended to have a higher Pouchitis Disease Activity Index score before treatment (median 14.5 vs. 12; P=0.13) than those who went into remission. Even in these eight patients, the median Pouchitis Disease Activity Index score significantly improved from 14.5 (range, 8-16) to 9.5 (range, 7-10) (P=0.0078), as did the Inflammatory Bowel Disease Questionnaire score from 95.5 (range, 74-134) to 127 (range, 76-187) (P=0.039). The Inflammatory Bowel Disease Questionnaire score strongly correlated with the Pouchitis Disease Activity Index score (r=0.79, P < 0.0001), and was significantly related to the patients' overall assessment of satisfaction (P < 0.0001). No serious side-effects were noted. CONCLUSIONS: Four-week treatment with a combination of metronidazole and ciprofloxacin is highly effective in patients with active recurrent or refractory pouchitis, objectively improving the inflammation and quality of life. The Inflammatory Bowel Disease Questionnaire is a sensitive tool for evaluating patients with pouchitis, and correlates well with disease activity.
Adult↗
Gut mucosal response to food antigens in Crohn's disease.
BACKGROUND: Food antigens may contribute to gut inflammation in Crohn's disease. AIM: To assess in vivo sensitization to food antigens, ascertain whether sensitivity is gut specific, assess food sensitization in vitro, and correlate in vivo changes with histological and blood changes. METHODS: Skin testing and rectal exposure to six food antigens (cereal, cabbage, citrus, milk, yeast and peanut) and control saline were assessed double-blind by immediate and 3.5-h laser Doppler blood flowmetry, and rectal biopsies were taken. Peripheral blood lymphocyte proliferation was measured in response to the same antigens. RESULTS: Ten patients with Crohn's disease and 10 healthy controls were studied. Blood flow increased in 24 of 60 antigen sites in Crohn's disease patients and six of 60 antigen sites in controls (P < 0.0001) after 3.5 h. The Crohn's disease group demonstrated higher rectal blood flow than controls in response to all food antigens, and this was significantly different for the responses to yeast (P = 0.036) and citrus fruits (P = 0.038). Lymphocyte proliferation occurred in 32 of 60 tests in Crohn's disease patients and eight of 60 tests in controls (P < 0.0001). There were no skin responses. Submucosal oedema corresponded to increased mucosal flow. CONCLUSIONS: Crohn's disease patients demonstrate in vivo and in vitro sensitization to food antigens, which is gut specific. Mucosal flowmetry allows the identification of sensitization to gut antigens.
Adult↗
Tumour 'budding' as an index to estimate the potential of aggressiveness in rectal cancer.
AIMS: Although the characteristic of invasive pattern which contributes to Jass's classification is a sensitive prognostic marker in rectal cancer, reproducibility of its assessment has been shown to be problematic. As another histological parameter of invasive margin, we examined the prognostic significance of tumour 'budding' and attempted to establish its appropriate criteria. METHODS AND RESULTS: A total of 638 rectal cancer specimens was examined. We defined tumour 'budding' as an isolated single cancer cell or a cluster composed of fewer than five cancer cells. We divided these into two groups by their intensity, i.e. the number of 'budding' foci within a microscopic field of x 250. Rectal cancer with high-grade 'budding' (>or= 10 foci in a field) was observed in 30.1% of patients, and was associated with lower 5-year survival rates (40.7%) than patients with low-grade 'budding' (84.0%) (P < 0.0001). Based on multivariate analysis, tumour 'budding' was selected as the significant independent variable, together with the number of nodes involved, extramural spread, lymphocytic infiltration, apical nodal involvement and tumour differentiation. Kappa coefficient of two-graded tumour 'budding' in the intraobserver study was 0.84. CONCLUSIONS: Because of its value as a prognostic indicator and its reproducibility, tumour 'budding' would be a good index to estimate the aggressiveness of rectal cancer.
Adult↗
Clinicopathological significance of the 'keloid-like' collagen and myxoid stroma in advanced rectal cancer.
AIM: To establish the histological categorization of fibrotic stroma which reflects the biological behaviour of advanced rectal cancer. METHODS AND RESULTS: Six hundred and twenty-seven surgically resected cases of advanced rectal carcinoma were examined. We histologically categorized fibrotic stroma in the invasive frontal region into three groups: type A, multiple fine and mature fibres were stratified into layers; type B, broad bands of eosinophilic hyalinized collagen ('keloid-like' collagen) were intermingled; type C, myxoid stroma. Type A stroma was observed in 63% of patients, type B stroma in 25%, type C stroma in 12%. The incidence of type A stroma decreased in accordance with Dukes stage (98% in Dukes A; 73% in B; 41% in C1; 29% in C2) and conversely, there was an increase of C type (0% in Dukes A; 4% in B; 20% in C1; 54% in C2). Stroma type had a significant correlation with long-term survival (80% of 5-year survival in type A stroma; 54% in type B; 26% in type C). Based on multivariate analysis, it was found that the stromal pattern had independent prognostic value, together with nodal involvement, growth pattern, and lymphocyte infiltration. CONCLUSIONS: Tumour fibrotic stroma may play an important role as a regulator of neoplastic behaviour. Pathological categorization of the fibrotic stroma is helpful for predicting the prognostic outcome of patients with rectal carcinoma.
Adult↗
The spectrum of p53 mutations in colorectal adenomas differs from that in colorectal carcinomas.
BACKGROUND: p53 mutations are frequently observed in colorectal carcinomas but they have also been found in colorectal adenomas, although considerably less frequently. AIMS: To explore p53 mutations in benign tumours, we have screened 70 colorectal adenomas for allelic loss at, and point mutations in, TP53 by analysis of selected microdissected cell populations. RESULTS: Sixteen (22.8%) adenomas were found to have allelic loss, of which 11 (15.7%) had p53 mutations. In adenomas with mild, moderate, or severe dysplasia, mutation or allelic loss occurred in 4.8%, 16.7%, and 52.6%, respectively (p<0.001). Seven different mutations were found, all missense changes or inframe deletions: one (Thr150Arg) has not been found before while three (Gln144His, Gly245Arg, and Glu285Gln) have not been described previously in colorectal tumours. The other three mutations (Arg175Gly, DeltaPro190, and Gly245Ser) have been found in colorectal carcinomas, the last commonly. Adenomas harboured a spectrum of p53 mutations which was significantly different from cancers as regards the position in the gene and a higher frequency of G-->C/C-->G changes. CONCLUSIONS: Combining our data on adenomas with data already published and in comparison with the spectrum of mutations in colorectal carcinomas, it is suggested that some p53 mutations have a weaker effect than others and are therefore more likely to be found in adenomas which have not progressed to carcinomas.
Adenoma↗
Molecular characteristics of serrated adenomas of the colorectum.
BACKGROUND: Serrated adenomas (SAs) of the colorectum combine architectural features of hyperplastic polyps and cytological features of classical adenomas. Molecular studies comparing SAs and classical adenomas suggest that each may be a distinct entity; in particular, it has been proposed that microsatellite instability (MSI) distinguishes SAs from classical adenomas and that SAs and the colorectal cancers arising from them develop along a pathway driven by low level microsatellite instability (MSI-L). AIMS: To define the molecular characteristics of SAs of the colorectum. MATERIALS AND METHODS: We analysed 39 SAs from 27 patients, including eight SAs from patients with familial adenomatous polyposis (FAP). We screened these polyps for selected molecular changes, including loss of heterozygosity (LOH) close to APC (5q21) and CRAC1 (15q13-q22), MSI, and mutations of K-ras, APC, p53, and beta-catenin. Expression patterns of beta-catenin, p53, MLH1, MSH2, E-cadherin, and O(6)-methylguanine DNA methyltransferase (MGMT) were assessed by immunohistochemistry. Comparative genomic hybridisation was performed on several polyps. RESULTS: MSI was rare (<5% cases) and there was no loss of expression of mismatch repair proteins. Wnt pathway abnormalities (APC mutation/LOH, beta-catenin mutation/nuclear expression) occurred in 11 SAs, including 6/31 (19%) non-FAP tumours. CRAC1 LOH occurred in 23% of tumours. K-ras mutations and p53 mutations/overexpression were found in 15% and 8% of SAs, respectively. Loss of MGMT expression occurred in 18% of polyps and showed a borderline association with K-ras mutations. Aberrant E-cadherin expression was found in seven polyps. Comparative genomic hybridisation detected no gains or deletions of chromosomal material. CONCLUSIONS: The serrated pathway of colorectal tumorigenesis appears to be heterogeneous. In common with classical adenomas, some SAs develop along pathways involving changes in APC/beta-catenin. SAs rarely show MSI or any evidence of chromosomal-scale genetic instability. K-ras mutations may however be less common in SAs than in classical adenomas. Some SAs may harbour changes in the CRAC1 gene. Changes in known genes do not account for the growth of the majority of SAs.
Adenoma↗
Further comments on fibrosing colonpathy study.
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Attitude of Health Personnel↗
Genetic alterations in gastric cancers from British patients.
Twenty-six gastric carcinoma and matching normal tissue DNAs, which had previously been analyzed for alterations of the APC (adenomatous polyposis coli) and MCC (mutated in colorectal cancer) genes were further investigated for the following genetic alterations: mutation and loss of heterozygosity (LOH) of the p53 gene, replication error (RER) and LOH at 12 microsatellite repeat loci, and mutation of the hMSH2 gene. In addition, 9 of the 26 gastric carcinomas were analyzed for genetic alterations using comparative genomic hybridization (CGH). Somatic mutations of the p53 gene were found to be frequent being detected in 31% of gastric carcinomas while LOH at the p53 locus was observed in 37.5% of informative cases. Loss of wild type p53 allele was detected in the majority (7 of 8) tumors found to be harboring a mutation. In the hMSH2 gene, an intronic 4 base pair insertion at 31 base pairs upstream of the beginning of exon 13 was detected in both tumor and normal tissue from one gastric carcinoma case. RER was detected in 11.5% of gastric carcinomas, at one or more microsatellite repeat loci. Of the 12 microsatellite repeat loci analyzed LOH was most frequently observed at D22S351 (30% informative cases) suggesting that a tumor suppressor gene on 22q may be important in gastric carcinogenesis. In support of this, CGH analysis carried out on 9 of the gastric carcinomas identified loss of chromosome 22 in 5 of these tumors.
Base Sequence↗
Molecular and cellular biology of pre-malignancy in the gastrointestinal tract.
Important pathogenic alterations within established cancers are acquired during the pre-malignant stage. These genetic alterations can be grouped into specific neoplastic pathways that differ within and between anatomical sites. By understanding the mechanisms that determine the initiation and progression of each pathway, it will be possible to develop novel approaches to the diagnosis, prevention and treatment of cancer. This chapter outlines the principles underlying the molecular characterization of pre-malignant lesions, taking colorectal neoplasia as the main model.
Colonic Polyps↗