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Biomedical subjects

Robert J C Steele

Publications and source records attributed to Robert J C Steele.

10 recordsLinked to original sources
PubMed2006

Chromosomal changes in colorectal adenomas: relationship to gene mutations and potential for clinical utility.

Although the occurrence of both chromosomal aberrations and specific gene mutations in colorectal tumorigenesis is firmly established, the relationship between these different forms of genetic abnormality remains poorly understood. We have previously demonstrated, in colorectal adenocarcinomas, that mutations of APC, KRAS, and TP53 are each specifically associated with certain chromosomal aberrations. Using comparative genomic hybridization and mutational analysis of APC, KRAS, and TP53 to evaluate 78 colorectal adenomas, we have shown that several of the significant relationships between gene mutations and chromosomal abnormalities reported in colorectal adenocarcinomas also exist at the adenomatous stage. KRAS mutation correlated with 12p gain (P < 0.001) and TP53 mutation with both 20q gain and 18q loss (P = 0.03 for both). In addition, we have identified two chromosomal aberrations, gain of 13q and loss of 11q, that correlate with the presence of synchronous adenomas (P = 0.049 and P = 0.03, respectively) and several chromosomal changes (20p+, 20q+, 17p-, and 18q-) that are related to the onset of high-grade dysplasia. These data strengthen our previous contention that the co-occurrence of specific gene mutations and chromosomal changes is not random and significant relationships do exist. Our findings also raise the possibility that certain chromosomal aberrations may act as important clinical biomarkers.

Adenoma↗
PubMed2006

Effective screening for bowel cancer: a United kingdom perspective.

Bowel cancer is a major cause of morbidity and death and is a high cost to health care systems. Screening currently offers the best chance of improving outcomes from bowel cancer. When introducing screening, the problems encountered in other cancers need to be avoided to maximize benefits and minimize harms.

Adenomatous Polyps↗
PubMed2006

Immunochemical testing of individuals positive for guaiac faecal occult blood test in a screening programme for colorectal cancer: an observational study.

BACKGROUND: Screening for colorectal cancer by use of guaiac-based faecal occult blood tests (FOBT) reduces disease-specific mortality. However, due to imperfect specificity, about half of individuals positive for guaiac FOBT are negative for neoplasia on colonoscopy. We aimed to assess whether the testing of individuals positive for guaiac FOBT in a screening programme for colorectal cancer by use of a sensitive immunochemical FOBT could select more appropriately those who should receive colonoscopy. METHODS: We invited individuals who were guaiac FOBT positive in the second screening round of a pilot study in Scotland, UK, to give two samples, each from separate stools, for immunochemical FOBT while awaiting colonoscopy. Results were classed as: both samples negative (N/N), one sample negative and one positive (N/P), and both samples positive (P/P); data were assessed for sampling bias. We compared immunochemical findings with those from colonoscopy using odds ratios of positive samples (P/P) versus negative (N/N and N/P). Sensitivity, specificity, and positive and negative likelihood ratios for cancer, and for cancer and high-risk adenomatous polyps were also calculated. FINDINGS: 1486 participants were invited and 801 (54%) sets of duplicate samples were returned. We found no evidence of sampling bias with regard to sex, age, or degree of positivity on guaiac FOBT. Of 800 sets returned with consent and analysed, 173 (22%) were N/N, 129 (16%) were N/P, and 498 (62%) were P/P. Chi2 test showed a highly significant positive correlation between degree of positivity on guaiac FOBT and on immunochemical FOBT (p<0.003). 795 individuals had data for colonoscopy: one (<1%) of 171 N/N participants and one (<1%) of 127 N/P participants had colorectal cancer, compared with 38 (8%) of 497 P/P participants; adenomatous polyps were found in 28 (16%) N/N individuals, 24 (19%) N/P individuals, and 193 (39%) P/P individuals. Normal colonoscopy was less common in the P/P group (85 [17%]) than in the N/N (67 [39%]) and N/P (49 [39%]) groups. The odds ratio for P/P being associated with cancer was 7.57 (95% CI 1.84-31.4) and with high-risk adenomatous polyps was 3.11 (1.86-5.18). Sensitivity of a P/P result for cancer was 95.0% (81.8-99.1), and for cancer and high-risk adenomatous polyps was 90.1% (84.4-94.0); specificity was 39.5% (36.0-43.1) and 47.8% (43.9-51.8), respectively. INTERPRETATION: Immunochemical FOBT for individuals with positive guaiac FOBT could decrease substantially the number of false positives in a screening programme for colorectal cancer.

Aged↗
PubMed2003

Mutations of APC, K-ras, and p53 are associated with specific chromosomal aberrations in colorectal adenocarcinomas.

It is widely accepted that both large-scale chromosomal abnormalities and mutation of specific genes, such as APC, K-ras, and/or p53, occur in the majority of colorectal adenocarcinomas. Whether or not a relationship exists between these different forms of genetic abnormalities was previously unknown. Using comparative genomic hybridization and mutational analysis of APC, K-ras, and p53 to evaluate 50 colorectal adenocarcinomas, we have shown that mutation of p53 is significantly associated with gain of 20q, 13q, and 8q and loss of 18q (P = 0.000, 0.02, 0.044, and 0.001, respectively). Conversely, APC mutation did not associate with any of the above-mentioned aberrations but did associate significantly with gain of 7p (P = 0.01). Gain of chromosomal arm 12p, although a less common aberration, was significantly associated with K-ras mutation (P = 0.011). The associations we have described should refine the search for candidate genes underlying chromosomal aberrations and assist in the definition of distinct pathways in colorectal tumorigenesis.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Patient generated index: new instrument for measuring quality of life in patients with rectal cancer.

The objective of this study was to assess the validity and responsiveness of a new quality of life instrument, the Patient Generated Index (PGI), in patients with rectal cancer. Thirty-three patients with rectal cancer were administered the PGI, the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires QLQ-C30 and QLQ-CR38, and the Medical Outcomes Study short form SF-36 questionnaire preoperatively and at 3 months postoperatively. The PGI was assessed in this group of patients for validity and responsiveness. PGI scores achieved significant correlations with a number of domains on the three quality of life (QOL) questionnaires. Stepwise regression analysis showed that 91.3% of the variation in PGI scores could be explained by three health-related QOL variables alone: pain, role limitations due to physical problems, and a global rating of health and QOL. The mean PGI score showed significant improvement 3 months following surgery. The PGI was found to be more responsive to change than the SF-36, the QLQ-C30, or the QLQ-CR38 items except the micturition item. The PGI assesses the extent to which the expectations of patients suffering from rectal cancer are matched by reality; and it satisfies the criteria of validity and responsiveness of this instrument for this cancer. Further studies are needed to determine its psychometric properties in other areas of surgery and oncology. If these studies support our findings, we believe that patient-centered measures such as the PGI may provide a meaningful assessment of the outcome of surgery for patients with cancer.

Adenocarcinoma↗
PubMed2002

Mutations in APC, Kirsten-ras, and p53--alternative genetic pathways to colorectal cancer.

Colorectal cancer is one of the most significant causes of cancer death. A genetic model for colorectal cancer has been proposed in which the sequential accumulation of mutations in specific genes, including adenomatous polyposis coli (APC), Kirsten-ras (K-ras), and p53, drives the transition from healthy colonic epithelia through increasingly dysplastic adenoma to colorectal cancer. We have characterized tumor mutation spectra in a large cohort of colorectal cancer patients. In marked contrast to the predictions of the sequential model of mutation accumulation, only 6.6% of tumors were found to contain mutations in APC, K-ras, and p53, with 38.7% of tumors containing mutations in only one of these genes. The most common combination of mutations was p53 and APC (27.1%), whereas mutations in both p53 and K-ras were extremely rare. Statistical analysis (two-sided Fisher's exact test) confirmed that mutations in K-ras and p53 co-occurred less frequently than expected by chance (P < 0.01, Fisher's exact test). This finding suggests that these mutations lie on alternate pathways of colorectal tumor development. The heterogeneous pattern of tumor mutations in our patient cohort suggests that multiple alternative genetic pathways to colorectal cancer exist and that the widely accepted genetic model of cancer development is not representative of the majority of colorectal tumors.

Aged↗
PubMed2002

Surgery for colorectal cancer.

Colorectal cancer remains the second commonest cause of cancer death in North America and Western Europe. Surgery remains the mainstay of treatment. The aim of surgery should be to achieve cure and to avoid locoregional recurrence. The fixity of the primary tumour determines resectability, and the extent of spread determines ultimate survival. Patients with rectal cancer present a particular problem. There is good evidence that lower local recurrence rates may be achieved both by improvements in surgical technique and the use of adjuvant radiotherapy. The importance of adequate treatment of the circumferential tumour margin cannot be over-emphasised; meticulous attention is required to ensure an adequate circumferential excision. The lowest incidences of locoregional recurrence are reported by surgeons who perform total mesorectal excision. Anorectal function, sexual and urinary dysfunction may occur after rectal excision. Both postoperative and pre-operative radiotherapy can reduce the incidence of local recurrence. However, in view of the low recurrence rates obtained with TME alone, the role of adjuvant radiotherapy requires further evaluation. Several aspects of the surgical management of colorectal cancer, for example, the role of transanal local excision of selected rectal cancers and laparoscopic surgery, the management of obstructed cases and the role of follow-up remain to be defined clearly.

Aged↗
PubMedDate not supplied

Does an ileoanal pouch offer a better quality of life than a permanent ileostomy for patients with ulcerative colitis?

Although an ileoanal pouch is frequently offered to patients with ulcerative colitis, it is still not clear to what extent this operation offers advantages over a permanent ileostomy. The aim of this study was to determine whether patients with a pouch have less morbidity and a better quality of life than a matched group of patients with a Brooke ileostomy. Nineteen patients (12 males and 7 females, median age 41 years) who had undergone total colectomy and ileoanal pouch formation for ulcerative colitis were individually matched with patients who had had a panproctocolectomy and ileostomy; patients were matched for disease process, sex, age, socioeconomic status, and time since surgery. Quality of life was assessed using the Short-Form 36 version 2 questionnaire, the inflammatory bowel disease questionnaire, and a few additional questions on perception of body image. The scores were compared using the nonparametric Wilcoxon signed-rank test for paired samples. The number and type of postoperative complications, as well as the number of operative stages, were recorded prospectively. Restorative proctocolectomy was associated with a significantly better perception of body image than a permanent stoma, although quality of life in general was similar in both groups. Patients with a pouch had more long-term complications than patients with an ileostomy within the same period of time (52.6% vs. 26.3%). The median number of stages for pouch construction was two, compared to a median of one stage for an ileostomy (P<0.0001). Because of the high long-term complication rate and the relatively small quality-of-life advantage associated with restorative proctocolectomy, patients need to be counseled thoroughly before agreeing to this operation.

Adult↗