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F A Macrae

Publications and source records attributed to F A Macrae.

At least 19 recordsLinked to original sources
PubMed2002

The founder mutation MSH2*1906G-->C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population.

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in the mismatch-repair genes. We report here the identification and characterization of a founder mutation in MSH2 in the Ashkenazi Jewish population. We identified a nucleotide substitution, MSH2*1906G-->C, which results in a substitution of proline for alanine at codon 636 in the MSH2 protein. This allele was identified in 15 unrelated Ashkenazi Jewish families with HNPCC, most of which meet the Amsterdam criteria. Genotype analysis of 18 polymorphic loci within and flanking MSH2 suggested a single origin for the mutation. All colorectal cancers tested showed microsatellite instability and absence of MSH2 protein, by immunohistochemical analysis. In an analysis of a population-based incident series of 686 Ashkenazi Jews from Israel who have colorectal cancer, we identified 3 (0.44%) mutation carriers. Persons with a family history of colorectal or endometrial cancer were more likely to carry the mutation than were those without such a family history (P=.042), and those with colorectal cancer who carried the mutation were, on average, younger than affected individuals who did not carry it (P=.033). The mutation was not detected in either 566 unaffected Ashkenazi Jews from Israel or 1,022 control individuals from New York. In hospital-based series, the 1906C allele was identified in 5/463 Ashkenazi Jews with colorectal cancer, in 2/197 with endometrial cancer, and in 0/83 with ovarian cancer. When families identified by family history and in case series are included, 25 apparently unrelated Ashkenazi Jewish families have been found to harbor this mutation. Although this pathogenic mutation is not frequent in the Ashkenazi Jewish population (accounting for 2%-3% of colorectal cancer in those whose age at diagnosis is <60 years), it is highly penetrant and accounts for approximately one-third of HNPCC in Ashkenazi Jewish families that fulfill the Amsterdam criteria.

Alanine↗
PubMed2001

Cancer risk in young women at risk of hereditary nonpolyposis colorectal cancer: implications for gynecologic surveillance.

OBJECTIVES: The lifetime risk of endometrial and ovarian cancers in hereditary nonpolyposis colorectal cancer (HNPCC) is up to 60 and 12%, respectively, in addition to the high risk of colorectal cancer. International guidelines recommend surveillance of those at risk with colonoscopy every 1--2 years from age 20--25 years and annual gynecologic surveillance from 25--35 years for women. We reviewed our own experience to see whether these recommendations were appropriate. METHODS: Pedigrees of 120 HNPCC families registered with the Familial Bowel Cancer Service at The Royal Melbourne Hospital were reviewed. Ninety families met our criteria for HNPCC and were included in the study. Pedigrees were analyzed to identify early-age onset colorectal and gynecologic cancers and to calculate cumulative incidence of both cancer types for at-risk women (HNPCC-affected and first-degree female relatives of affected family members) for comparison with the general population. RESULTS: Colorectal cancer occurred in 434 individuals, endometrial cancer in 43, and ovarian cancer in 24. Gynecologic and colorectal cancers were diagnosed at similar ages (mean 49.3 versus 51.8 years; P = 0.25), with 5 (7.1%) gynecologic cancers diagnosed by 35 years. Cumulative incidences of gynecologic and colorectal cancers to ages 25, 30, 35, and 40 years were substantially higher among at-risk women than in the general population. CONCLUSIONS: Consideration should be given to offering gynecologic cancer surveillance from the age of 25 years, as for colorectal cancer. However, this approach should be individualized as it has yet to be demonstrated that surveillance reduces the mortality of gynecologic cancer in HNPCC.

Adult↗
PubMed2000

Value of predictive genetic testing in management of hereditary non-polyposis colorectal cancer (HNPCC)

OBJECTIVE: To investigate the impact of predictive genetic testing on colonoscopic surveillance in an extended family with hereditary non-polyposis colorectal cancer (HNPCC). SETTING: Familial Bowel Cancer Service, The Royal Melbourne Hospital, Victoria. SUBJECTS: 96 people registered with the Service who were apparently unaffected members of an extended family that met the classic Amsterdam criteria for HNPCC and carried an MLH1 gene mutation (IVS9 + 3insT). INTERVENTION: Predictive genetic testing was offered in a cascade manner to at-risk family members; mutation-positive individuals were advised to have annual colonoscopic surveillance, while mutation-negative individuals were withdrawn from surveillance. MAIN OUTCOME MEASURES: Previous compliance with recommended colonoscopic surveillance; uptake and results of genetic testing; expected effect of genetic test results on number of colonoscopies over five years. RESULTS: 22 of the 96 family members (23%) were not complying with recommended surveillance. Of 48 individuals offered predictive genetic testing, 41 (85%) responded and 39 (81%) underwent testing. Seven of the 39 (18%) were positive for the family-specific mutation, and 32 (82%) were negative. The 39 tested individuals and 37 of their descendants who were registered with the screening program had undergone 70 colonoscopies in the five years before genetic testing. In the five years after testing, only 37 surveillance colonoscopies were planned (annual or two-yearly colonoscopies for the six mutation-positive individuals and five-yearly colonoscopies for four mutation-negative individuals with previously identified adenoma), an almost 50% reduction in colonoscopies. CONCLUSION: Predictive genetic testing in HNPCC families allows many individuals to be withdrawn from regular colonoscopic surveillance. It may therefore reduce costs, as well as have emotional benefits for many individuals.

Adult↗
PubMed2000

Yield from colonoscopic screening in people with a strong family history of common colorectal cancer.

BACKGROUND AND AIMS: People with a strong family history of common (so-called 'sporadic') colorectal cancer are generally advised to undergo colonoscopic screening, but the starting age for this is unclear. An audit was performed to study the age-related yield of screening colonoscopy in this risk group. METHODS: A prospective audit of the outcome of screening colonoscopy was performed on a cohort of 232 people with a strong family history of common colorectal cancer. All were registrants in a familial bowel cancer service solely because of their family medical history. They had no bowel symptoms and no prior endoscopic investigation of the large bowel. RESULTS: Neoplastic lesions were detected by using colonoscopy in 33 participants. In 27 participants, the major lesion was a small tubular adenoma, four had an advanced adenoma and two had cancer. More neoplastic (P= 0.02) and advanced neoplastic (P= 0.03) lesions were found in those patients aged > or = 50 years. Only one advanced adenoma was detected in a participant below the age of 50 years. CONCLUSION: The yield from screening colonoscopy in young people (< 50 years) with a strong family history of common colorectal cancer is low, placing doubt on the need for colonoscopic screening before the age of 50 years.

Adult↗
PubMed1997

The clinical correlates of a 3' truncating mutation (codons 1982-1983) in the adenomatous polyposis coli gene.

Familial adenomatous polyposis (FAP) is caused by mutations in the adenomatous polyposis coli (APC) gene, and different mutations may produce different clinical pictures. Most mutations occur in the 5' half of the gene, and mutations toward the 3' end are rare. The aim of this study was to document the phenotypes in a family with a truncating mutation at codons 1982-1983, one of the most 3' mutations on record. Colonic polyps in this family were much less numerous, and their growth was delayed compared with the classical FAP picture, and malignant degeneration occurred considerably later. Two individuals had sparse colonic but profuse gastric fundic gland polyposis. Gardner's syndrome stigmata were variable, and a desmoid tumor was recorded in 1 person.

Adenomatous Polyposis Coli↗
PubMed1997

Colonoscopy and biopsy.

The place of colonoscopy in the management of ulcerative colitis is restricted to clinical situations where the information provided will change clinical management. The information provided will be answers to the questions?inflammatory bowel disease, o r, in the patient with known colitis: inflammatory bowel disease?type?activity extent?dysplasia. Biopsy is pivotal to the diagnosis and provides the certainty of tissue diagnosis, assessment of activity and detection of dysplasia. Sigmoidoscopy is sufficient for providing information for clinical management in most circumstances, but colonoscopy is important where clinical features are disproportionate to sigmoidoscopic findings and systemic parameters of inflammatory activity; to determine type and extent of inflammatory bowel disease and when surveillance needs to start; and for biopsy to detect dysplasia. Ileoscopy is an important aspect of colonoscopy for differential diagnosis, and is the unique definer of total colonoscopy.

Biopsy↗
PubMed1997

Effect of cereal fibre source and processing on rectal epithelial cell proliferation.

BACKGROUND: Low fat and wheat bran interventions significantly reduced the growth of small to large adenomas and modestly suppressed rectal epithelial cell proliferation in the Australian Polyp Prevention Project. AIM: To study the effect of unprocessed wheat bran, unprocessed oat bran and processed wheat bran (Kellogg's All Bran) on rectal epithelial cell proliferation. PATIENTS: Twenty subjects with recent adenomas and a high fat background diet were recruited. METHODS: Rectal biopsy specimens were taken at entry and at the end of three six-week periods of oat bran (64 g/day), wheat bran (25 g/day) and All Bran (38 g/day), all in association with a diet < 25% energy as fat, in a randomised cross-over trial. Each of the bran supplements had a total of 11 g dietary fibre. The biopsy specimens were fixed in methacarn and stained immunohistochemically for presence of the proliferating cell nuclear antigen (PCNA). The kinetics used to measure proliferation were labelling index, whole distribution of labelled cells, and labelled cells in the top two-fifths of crypts using analysis of variance. RESULTS: There were no significant differences in mean labelling indexes between the four diets or in the percentage of labelled cells in the top two-fifths (p = 0.59), but activity in the top two-fifths of crypts was lowest with wheat bran. The mean (SD) labelling indexes were 2.23 (0.11)% for control, 2.13 (0.08)% for wheat bran, 2.19 (0.09)% for oat bran, and 2.12 (0.08)% for All Bran. The proportion in the top two-fifths of the crypts was 2.6 (0.6)% for control, 2.15 (0.5)% for wheat bran, 3.3 (0.9)% for oat bran, and 3.1 (0.9)% for All Bran. On analysis of whole distribution, there was no significant overall effect of diets but there was a difference between subjects. Analysis including total fibre intake also did not identify effects on proliferation. CONCLUSION: In this study of high risk subjects with initial high fat diets, dietary fibre in association with a low fat diet had no effect on rectal epithelial cell proliferation, although wheat bran had the greatest effect on percentage of labelled cells in the top two-fifths of crypts.

Adenoma↗
PubMed1997

The effect of incubation of rectal biopsies on measures of proliferation using proliferating cell nuclear antigen in comparison with 5-bromo-2-deoxyuridine.

Rectal epithelial cell kinetics are used as intermediate markers for colorectal cancer and relate to risk. In this study, measures of proliferation using direct immunohistochemistry for proliferating cell nuclear antigen (PCNA) were compared to in vitro labeling by bromodeoxyuridine (BrdUrd) and incubated biopsies that were later stained for PCNA (PCNA-I) in human rectal biopsies. The study group consisted of 20 sets of biopsies from 12 subjects participating in an intervention trial. Fresh nonincubated biopsies were fixed in methacarn and stained immunohistochemically for PCNA (clone 19A2). In parallel biopsies, BrdUrd was incorporated into the DNA of S-phase cells during a 2-h incubation at 37 degrees C under hyperbaric conditions and localized by immunohistochemistry. Additionally, biopsies were incubated under hyperbaric conditions for 2 h at 37 degrees C, fixed in methacarn, and stained for PCNA (PCNA-I). There was a highly significant difference in the labeling index between the three methods (P < 0.01), but there was no significant difference between subjects (P = 0.439). The mean labeling index was 2.3 +/- 0.1% for PCNA, 2.9 +/- 0.1% for PCNA-I, and 4.1 +/- 0.1% for BrdUrd. The proportion of labeled cells in the top two-fifths was significantly higher (P = 0.01) for BrdUrd (5.5 +/- 0.8%) and PCNA-I (6.4 +/- 1.1%) compared to PCNA (3.1 +/- 0.6%), and a significant difference was seen between subjects (P = 0.038). PCNA-I and BrdUrd methods had similar crypt heights with 73.5 +/- 1.8 and 71.2 +/- 1.3 cells/crypt column, respectively, but were significantly shorter (P < 0.001) than PCNA with 83.4 +/- 1.5 cells/crypt column, indicating a loss of cells during organ culture. The simplicity of the PCNA technique, which avoids potential perturbations occurring during organ culture, has considerable appeal as a marker for colorectal cancer risk, but additional studies are needed to correlate PCNA with neoplastic risk.

Adult↗
PubMed1996

Screening for colorectal cancer, 1996.

Screening average-risk people aged 55 to 70 years for colorectal cancer is now a public health priority in Australia. Pilot studies of faecal occult blood testing are required to find ways of achieving optimal compliance and cost efficiency in the Australian health care setting. Flexible sigmoidoscopy probably should be used as complementary screening but further trials are needed. High-risk groups (family history of colorectal cancer, or previous ulcerative colitis, adenomas or cancer) should already be in surveillance programs.

Adenomatous Polyposis Coli↗
PubMed1994

Changes in serum carotenoids in subjects with colorectal adenomas after 24 mo of beta-carotene supplementation. Australian Polyp Prevention Project Investigators.

The effect of beta-carotene supplementation on major serum carotenoid fractions (lutein/zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, and beta-carotene) was investigated in 224 people with colorectal adenomas (139 men, 85 women) recruited for the Australian Polyp Prevention Project (APPP). Each subject was randomly assigned to take either 20 mg beta-carotene/d or placebo over 24 mo. Besides the expected increase in serum concentration of beta-carotene (1073% in men, 839% in women), lycopene (176% in men) and alpha-carotene (211% in men and 166% in women) concentrations were also increased after body mass index, baseline concentration, change in respective carotenoid intake, and other confounding factors were adjusted for. The increase in serum concentrations of these carotenoids after beta-carotene supplementation suggests that beta-carotene may interact biologically with other carotenoids and such interaction would need to be taken into consideration when the protective effect of beta-carotene supplementation for cancer or other diseases is examined.

Adenoma↗
PubMed1994

Rectal epithelial cell proliferation: comparison of errors of measurement with inter-subject variance. Australian Polyp Prevention Project Investigators.

If measures of rectal epithelial kinetics are to be used on a large scale, or as part of multicenter studies, the variance of repeated measures must be sufficiently small to detect the effect of clinical status and dietary, or chemoprevention interventions. Errors in measurement can be categorized as intra-reader (sigma 2I), inter-biopsy (sigma 2B), inter-laboratory (sigma 2L), and inter-reader (sigma 2R); the sum of these (sigma 2T) when compared to inter-subject variance (sigma 2S) is a measure of the precision with which cell kinetics can be estimated for a given subject. We estimated the variances of the component errors in four separate experiments, each involving 6 to 10 subjects, using the proliferating cell nuclear antigen (PCNA) technique. PCNA labeling index variances for a single laboratory study were sigma 2I = 0.02-0.07 and sigma 2B = 0.08-0.15. Inter-laboratory and inter-reader variances were sigma 2L = 0.08 and sigma 2R = 0.03. Summing the errors applicable within a laboratory gives a rounded estimate of 0.15. For inter-laboratory studies the total error (sigma 2T) is greater, estimated in our two-laboratory study as 0.3. In a separate study, the variation between biopsies (sigma 2B) could be accounted for by the variation between crypts within biopsies; an acceptable level of accuracy is achieved after counting 20-30 crypts. In contrast to the measurement errors, the variance between subjects, which includes a treatment effect of diet, was larger, estimated to be between 0.75 and 1.30.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma↗
PubMed1993

Fat and calories in colon and breast cancer: from animal studies to controlled clinical trials.

BACKGROUND: Fat and total calories are closely correlated in the diet. Because of this correlation, studies of dietary fat and breast and colorectal cancer incidence have been peculiarly difficult to interpret. METHODS: This article reviews the information from rodent models of breast and colorectal cancer and epidemiological studies addressing the separate effects of calories and fat in the diet. Various statistical approaches described for separating the effects of calories and fat are outlined, with a review of epidemiological case-control, cohort, and prospective controlled clinical studies of diet and breast and colorectal neoplasia. RESULTS: Animal studies provide convincing evidence for a dominant effect of calorie restriction over fat modification in tumorigenesis. Individual case-control studies show no effect or are inconsistent in distinguishing calories from fat in colorectal carcinogenesis, and are largely null in breast cancer. However, a meta-analysis of these studies in breast cancer defines a relative risk (P < 0.05) of 1.40 for calories "solely" due to fat (1.48; P < 0.05). Cohort studies for colorectal cancer have reported variable results, but a recent large study of women implicates animal fats, particularly from red meat, as a risk for colon cancer, independently of calories. For breast cancer, a marginally significant effect of fat independent of calories was found in one recent cohort study, but earlier large cohort studies could not identify calories or fat as risk factors. CONCLUSION: Caloric restriction is likely to be important in inhibiting tumorigenesis based on animal studies. However, the influence of animal fats is seen both in animal studies and epidemiological studies of breast and bowel cancer. The differential effect of fats from different dietary sources in both colon and breast cancer points to a qualitative effect separate from calories in tumorigenesis. Extrapolation of significant analyses of trend to very low-fat diets should be interpreted cautiously without further information on concurrent nutrient deficiencies and competing illnesses. Randomized controlled trials of dietary intervention to prevent neoplasia are feasible and will enhance the quality of information available about diet and tumorigenesis.

Animals↗
PubMed1993

Evaluation of new occult blood tests for detection of colorectal neoplasia.

BACKGROUND: Hemoccult II, the guaiac-based fecal occult blood test used in most colorectal cancer screening programs, has an unsatisfactory sensitivity for asymptomatic colorectal neoplasms. We evaluated the relative performance of four fecal occult blood tests, directed against various components of the hemoglobin molecule. METHODS: All tests, Hemoccult II, HemoccultSENSA (a more sensitive guaiac test), HemeSelect (an immunochemical test specific for human hemoglobin), and HemoQuant (the heme-porphyrin assay), were performed by 107 patients with symptomatic colorectal cancer and 81 patients with predominantly asymptomatic adenoma. Hemoccult-SENSA and HemeSelect were performed by 1,355 screenees. RESULTS: HemeSelect and Hemoccult-SENSA had significantly higher sensitivity for colorectal cancer (97% and 94%, respectively) than the other tests. HemeSelect had the highest sensitivity for adenomas; in 45 patients with large (> or = 10 mm) adenomas, sensitivity was 76% for HemeSelect, 60% for HemoccultSENSA, and 42% for both Hemoccult and HemoQuant. In the screenees, estimated specificity was 97.8% for HemeSelect and 96.1% for Hemoccult-SENSA. CONCLUSIONS: HemeSelect and Hemoccult-SENSA have the highest levels of sensitivity for detection of colorectal neoplasia, but the immunochemical test HemeSelect provides the best combination of specificity and sensitivity.

Adenoma↗
PubMed1992

Gastrointestinal endoscopy: an accurate and safe primary diagnostic and therapeutic modality.

OBJECTIVE: To review the place of gastrointestinal endoscopy in the management of upper and lower gastrointestinal disorders. DATA SOURCES: We reviewed articles on endoscopy reported over two decades. A Medline search complementing our experience and knowledge of the literature was used to identify the articles. STUDY SELECTION: Papers were selected which focused on indications, comparison with radiology, including clinical outcome measures, and complications. One hundred papers, including those from radiology journals, were reviewed. DATA EXTRACTION: Results of studies are referenced as appropriate. DATA SYNTHESIS AND CONCLUSIONS: Endoscopy allows direct visualisation of the mucosa of the upper gastrointestinal tract, colon and terminal ileum. Subtleties of colour change, vascular pattern abnormalities and scarring are easily detected at endoscopy and are often of diagnostic importance. Endoscopy also provides access for tissue biopsy and allows a wide variety of therapeutic interventions. Traditionally barium studies have been the first step in the evaluation of many gastrointestinal symptoms and still retain cost advantages over endoscopy. However, endoscopy is frequently more sensitive and specific than barium studies. Costs associated with incorrect diagnoses may undermine the apparent cost benefits of barium studies. Advances in endoscopic design have allowed wider therapeutic options and increased safety. Gastrointestinal endoscopy should now be the first line of investigation where diagnostic precision is required or where therapeutic intervention is likely.

Barium Sulfate↗
PubMed1992

Collagenous colitis: jejunal and colorectal pathology.

AIMS: To determine: (1) whether there is an association between collagenous colitis and coeliac disease or lymphocytic colitis; (2) the distribution of lymphocyte subsets and macrophages in the lamina propria and surface epithelial layer in collagenous colitis; and (3) the colorectal distribution of the disease and whether a mucosal biopsy specimen, using a flexible sigmoidoscope, is sufficient to diagnose it. METHODS: The clinical data and colorectal biopsy specimens from 38 patients with collagenous colitis were studied. In 10, small bowel biopsy specimens were also available for review. Immunostaining of the mucosal lymphoid infiltrate with a panel of relevant antibodies was carried out on formalin fixed tissue in seven cases; in three the phenotyping was performed on fresh biopsy specimens separately frozen or fixed in B5 solution. RESULTS: Coeliac disease was found in four out of the 10 patients with collagenous colitis who had had a small bowel biopsy, in contrast to the prevalence of the disease in Australia of 1 in 3000. Collagenous colitis did not respond to gluten withdrawal. Five of 29 (17%) of the patients had a mixed pattern of lymphocytic and collagenous colitis. Immunostaining of the lymphoid infiltrate showed that the striking increase in intraepithelial lymphocytes in collagenous colitis was due to an influx of CD8 positive cells. The occurrence and severity of collagenous colitis along the large bowel were independent of the anatomical site, and in more than 90% of cases biopsy specimens from the sigmoid colon or rectum were diagnostic. CONCLUSIONS: There is a very high incidence of coeliac disease among patients with collagenous colitis so that jejunal biopsy should be an essential part of their investigations, especially if symptoms persist. However, only a minority showed a mixed pattern of lymphocytic and collagenous colitis. The intraepithelial lymphocytes in collagenous colitis are CD8 positive cells. Collagenous colitis can be diagnosed from rectal or sigmoid colon biopsy specimens in more than 90% of cases.

Adult↗