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A D Spigelman

Publications and source records attributed to A D Spigelman.

At least 73 records · Page 4Linked to original sources
PubMed1994

Bile acids do not form adducts when incubated with DNA in vitro.

Bile acids have been implicated in the aetiology of colon cancer. We have previously found, using 32P-postlabelling, that bile from control patients and from patients with familial adenomatous polyposis (FAP) produces DNA adducts when incubated with salmon sperm DNA in vitro. In the present study we have incubated the common primary and secondary, conjugated and unconjugated bile acids with salmon sperm DNA in vitro, in both the presence and absence of metabolic activation (Aroclor-induced rat liver S9). The DNA was then purified and assayed for the formation of DNA adducts using the nuclease P1 method of 32P-postlabelling. Under the conditions of the assay none of the bile acids tested with or without metabolic activation produced any evidence of DNA adduct formation. It is therefore unlikely that the adduct-forming ability of human bile can be attributed to bile acids or their metabolites.

Adenomatous Polyposis Coli↗
PubMed1994

Evidence for adenoma-carcinoma sequence in the duodenum of patients with familial adenomatous polyposis. The Leeds Castle Polyposis Group (Upper Gastrointestinal Committee).

AIMS: To explore the association between duodenal adenoma and carcinoma in patients with familial adenomatous polyposis (FAP). METHODS: A multicentre survey of 1262 patients with FAP yielded 47 cases of duodenal cancer. The association between adenoma and cancer was assessed in these cases. RESULTS: Adenomatous tissue was found within duodenal cancer in 29 of 44 (66%) patients with FAP and in mucosa adjacent to duodenal cancer in 31 of 42 (73%) such patients. Adenomas were found as a component of, or adjacent to, duodenal cancer in 38 of 45 (84%) patients. CONCLUSIONS: These observations support the existence of the adenomacarcinoma sequence in the duodenum of patients with FAP. Factors associated with malignant change included villous histology, moderate or severe dysplasia, and the presence of stage IV duodenal polyposis.

Adenoma↗
PubMed1994

Surveillance of duodenal polyps in familial adenomatous polyposis: progress report.

Familial adenomatous polyposis (FAP) is characterized by the presence of premalignant adenomas of the large and small bowel. Prophylactic colectomy deals with the risk for colon cancer, leaving duodenal cancer as the leading cause of death. Although most FAP patients have duodenal adenomas, only approximately 5% develop duodenal cancer. This study looks at progression of duodenal polyps with time. The outcome of endoscopic surveillance in the duodenum of 70 patients with familial adenomatous polyposis was determined. A mean of 40 months elapsed between endoscopies. Outcome was measured using video comparison and a staging system that includes histological assessment. Duodenal cancer developed in one patient, and was suspected in two others. The stage of duodenal polyposis worsened in another seven patients. When histology was ignored, comparison of video recordings in 52 patients showed a worsening in 21 (40%). In conclusion, further surveillance appears warranted so that patients at high risk for duodenal cancer might receive early treatment. Should slow progression of duodenal polyposis be shown to be associated with low risk, then most patients can be safely offered less frequent endoscopies than hitherto.

Adenomatous Polyposis Coli↗
PubMed1994

Glutathione S-transferase Mu phenotype in patients with familial adenomatous polyposis and in unaffected controls.

Patients with familial adenomatous polyposis (FAP) are at high risk for duodenal tumors, the distribution of which suggests that bile is important in their development. Studies of the bile of FAP patients suggest that it contains an excess of active carcinogens. Defective hepatic metabolism of carcinogens might account for these findings. The isozyme glutathione S-transferase mu (GST-mu) plays a major role in the hepatic metabolism of carcinogens. Peripheral blood GST-mu status reflects hepatic GST-mu status. The concentration of GST-mu was therefore measured by enzyme-linked immunosorbent assay of heparinized peripheral blood samples taken from 31 unrelated patients with FAP and from 38 unrelated control patients. FAP and control patients were matched for age, sex, diet, and smoking status. The median GST-mu concentration (micrograms per milliliter) was 0.5 (interquartile range, 0 to 11.6) in the FAP group and 8.85 (0.9 to 29.4, p = 0.0013) in the control group. Of the 31 FAP patients, ten had no detectable GST-mu activity compared with only one of the 38 controls (p = 0.002), while 71% of FAP patients had GST-mu concentrations less than a supplied positive control, compared with 50% of control patients (p = 0.064). Abnormal hepatic metabolism of carcinogens by GST-mu might contribute to the development of intestinal tumors in patients with FAP.

Adenomatous Polyposis Coli↗
PubMed1993

Surgical polypectomy of duodenal adenomas in familial adenomatous polyposis: experience of two European centres.

Between 1978 and 1988, 12 patients with familial adenomatous polyposis (FAP) and severe duodenal polyposis underwent duodenotomy and duodenal polypectomy. The patients were from two separate institutions; all were women, with a mean age of 45.6 (range 25-62) years at the time of duodenotomy. Recurrent duodenal polyposis was detected at endoscopy in all 12 patients, at a mean of 13.3 (range 5-36) months after duodenotomy. All patients had moderate to severe duodenal polyposis at the time of the last endoscopic examination. Local excision of duodenal adenomas is an unsatisfactory treatment option in those with FAP. The ideal management of patients with FAP who have severe duodenal polyposis remains uncertain.

Adenoma↗
PubMed1993

Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis.

Twenty-four patients with familial adenomatous polyposis who had previously undergone prophylactic colectomy and had advanced duodenal polyposis were entered into a randomized trial to assess the effect of the non-steroidal anti-inflammatory drug sulindac on duodenal and rectal polyps. Polyp size and number were assessed by videotaped duodenoscopy (and rectoscopy in 14 patients) at entry and after 6 months of treatment; the tapes were compared by two assessors who were unaware of the randomization and the shuffled chronological order of the recordings. Mucosal cell proliferation was measured by in vitro incorporation of 5-bromo-2'-deoxyuridine. Sulindac therapy was associated with a reduction in epithelial cell proliferation in the duodenum (median labelling index (LI) 15.8 versus 14.4 per cent, P = 0.003) and a trend towards duodenal polyp regression (P = 0.12). In the rectum, cell proliferation showed a marked reduction (median LI 8.5 versus 7.4 per cent, P = 0.018), and significant (P = 0.01) polyp regression was seen. Rectal polyposis was less severe than that in the duodenum and responded more dramatically. Sulindac is a possible treatment for patients in whom rectal polyps have failed to show significant regression after ileorectal anastomosis and who are unsuitable for pouch surgery; it may be useful in early duodenal polyposis or as an adjunct after duodenal clearance.

Adenomatous Polyposis Coli↗
PubMed1993

Life expectancy after colectomy and ileorectal anastomosis for familial adenomatous polyposis.

PURPOSE: Despite the introduction of screening, surveillance, and prophylactic colectomy surgery, patients with familial adenomatous polyposis (FAP) are at risk of dying from other malignancies. METHODS: In order to quantify this risk and identify the causes of mortality, a retrospective life table analysis was performed on 222 patients with familial adenomatous polyposis who had undergone a total colectomy and ileorectal anastomosis between 1948 and 1990. These FAP patients were compared with an age- and sex-matched group of the general population and a relative risk of dying was calculated. RESULTS: Of 222 patients, 53 have died. In a matched group of the general population the expected number of deaths would be 15.8. The relative risk of dying is therefore 3.35. There has been no significant improvement with time and the relative risk is greatest for female patients. CONCLUSION: The three main causes of mortality are upper gastrointestinal malignancy, desmoid disease, and perioperative complications. Further research should therefore be aimed at prevention and improved treatment of these in order to improve survival.

Adenomatous Polyposis Coli↗
PubMed1993

DNA adducts, detected by 32P-postlabelling, in DNA treated in vitro with bile from patients with familial adenomatous polyposis and from unaffected controls.

Patients with familial adenomatous polyposis (FAP) have a high risk of developing duodenal adenomas and carcinomas. The distribution of these neoplasms resembles mucosal exposure to bile, suggesting that bile may play a role in adenoma development. Our previous results, using DNA adducts detected by 32P-postlabelling as an index of genotoxicity, have supported this hypothesis. We found significantly higher adduct labelling in the duodenum of FAP patients than in the duodenum of control patients and significantly higher labelling in the small bowel of rats gavaged with FAP bile than in rats given control bile. We have now investigated the ability of human bile to form adducts with DNA in vitro. Bile obtained from the gallbladder of 18 FAP patients immediately before colectomy, and from 18 control patients, was incubated with salmon sperm DNA in solution at 37 degrees C for 1 h, after which the purified DNA was analysed for DNA adducts, using the nuclease P1 method of 32P-postlabelling. Relative adduct labelling values (RAL, adducts per 10(9) nucleotides) produced by FAP bile samples were significantly higher than RAL values produced by control bile samples (medians 197 versus 86, P = 0.0016, Mann-Whitney test). We found a consistent pattern of adduct labelling, varying in intensity between samples. Adduct spots were eluted from TLC plates and analyzed by reverse-phase HPLC. Each major spot gave several peaks that were consistent between bile samples from different patients and were similar in FAP and control bile. These results indicate that bile from FAP and control patients contains similar, directly acting genotoxic compounds but that levels are higher in FAP than in control patients. This suggests that bile from FAP patients is more genotoxic than bile from control patients. Incubation of bile with free-radical scavengers and deconjugating enzymes failed to influence adduct labelling in this system.

Adenomatous Polyposis Coli↗
PubMed1993

32P-postlabelling studies of target tissues and bile from patients with familial adenomatous polyposis and from unaffected controls.

Patients with the inherited form of colon cancer, familial adenomatous polyposis (FAP), are at high risk of developing duodenal adenomas and carcinomas. The periampullary clustering of these neoplasms suggests that bile plays a role in their development. We investigated this theory using 32P-postlabelling to detect DNA adducts. We found significantly higher adduct levels in duodenum of FAP patients than in unaffected controls, and higher levels in duodenum than stomach. Levels of adducts were significantly higher in the small bowel of rats gavaged with FAP gallbladder bile than in the small bowel of those that received control gallbladder bile. We found that bile from FAP gallbladder produced significantly more DNA adducts than control gallbladder bile when incubated with salmon sperm DNA in vitro. These results support the hypothesis that the bile of FAP patients may be involved in the development of duodenal adenomas in these patients.

Adenomatous Polyposis Coli↗
PubMed1992

Management of familial adenomatous polyposis.

The management of FAP involves treatment of affected individuals and their families. Such an approach is best coordinated by registrars working in dedicated registries, in close collaboration with nurses, physicians, surgeons, clinical geneticists and others who become involved in the care of these patients. The large bowel of patients with FAP should be removed (totally or subtotally) by the third decade of life. Screening of other areas at risk is recommended to document the natural history of extracolonic manifestations and to allow study of the effects of intervention. Despite these other, sometimes life-threatening manifestations, a near to normal life span is possible in the majority of patients with FAP. The aims of management of the individual and of the family are to ensure that their quality of life is optimal, that support is provided in times of emotional need, that anxiety is minimized and that relatives are adequately screened and treated.

Adenomatous Polyposis Coli↗
PubMed1992

DNA adducts detected by 32P-postlabelling, in the intestine of rats given bile from patients with familial adenomatous polyposis and from unaffected controls.

Duodenal adenomas are common in patients with familial adenomatous polyposis (FAP) and cluster around the papilla, suggesting the involvement of bile in their development. Using 32P-postlabelling we determined levels of DNA adducts in the small bowel and colon of rats treated with bile from FAP and control patients. We found a significantly higher level of adducts in the small bowel of rats treated with FAP gallbladder bile compared with control gallbladder bile (P = 0.0034). This result supports the hypothesis that bile plays a role in the development of neoplasia in the foregut of FAP patients.

Adenomatous Polyposis Coli↗