Mark Thompson-Fawcett

Multiple Gene Expression Classifiers from Different Array Platforms Predict Poor Prognosis of Colorectal Cancer

Purpose: This study aimed to develop gene classifiers to predict colorectal cancer recurrence. We investigated whether gene classifiers derived from two tumor series using different array platforms could be independently validated by application to the alternate series of patients. Experimental Design: Colorectal tumors from New Zealand (n = 149) and Germany (n = 55) patients had a minimum follow-up of 5 years. RNA was profiled using oligonucleotide printed microarrays (New Zealand samples) and Affymetrix arrays (German samples). Classifiers based on clinical data, gene expression data, and a combination of the two were produced and used to predict recurrence. The use of gene expression information was found to improve the predictive ability in both data sets. The New Zealand and German gene classifiers were cross-validated on the German and New Zealand data sets, respectively, to validate their predictive power. Survival analyses were done to evaluate the ability of the classifiers to predict patient survival. Results: The prediction rates for the New Zealand and German gene-based classifiers were 77% and 84%, respectively. Despite significant differences in study design and technologies used, both classifiers retained prognostic power when applied to the alternate series of patients. Survival analyses showed that both classifiers gave a better stratification of patients than the traditional clinical staging. One classifier contained genes associated with cancer progression, whereas the other had a large immune response gene cluster concordant with the role of a host immune response in modulating colorectal cancer outcome. Conclusions: The successful reciprocal validation of gene-based classifiers on different patient cohorts and technology platforms supports the power of microarray technology for individualized outcome prediction of colorectal cancer patients. Furthermore, many of the genes identified have known biological functions congruent with the predicted outcomes.

Clinical trial: alvimopan for the management of post-operative ileus after abdominal surgery: results of an international randomized, double-blind, multicentre, placebo-controlled clinical study.

Aliment Pharmacol Ther 28, 312–325

“cuffitis” and inflammatory changes in the columnar cuff, anal transitional zone, and ileal reservoir after stapled pouch-anal anastomosis

PURPOSE: During the past eight to ten years most surgeons have adopted the double-stapled technique to accomplish the pouch-anal anastomosis in restorative proctocolectomy for ulcerative colitis. Little attention has been focused on the functional implications of retaining a segment of diseased columnar mucosa in the upper anal canal. The aim of this study was to investigate clinically significant inflammation in the columnar cuff. METHOD: In all, 113 patients were studied and 715 biopsies were performed during a 2.5-year period. Biopsy specimens were taken from two or three sites, including the columnar cuff, ileal pouch, and anal transitional zone. Acute and chronic inflammation was scored for biopsy specimens from all three sites and compared with endoscopic assessment and pouch function. RESULTS: In the columnar cuff acute histologic inflammation was found in 13 percent of patients, and in 9 percent this was symptomatic during follow-up and was accompanied by evidence of endoscopic inflammation. Most patients had mild inflammation in the cuff that persisted over time. Inflammation in the pouch, pouch frequency, and anastomotic height were not related to columnar cuff inflammation. CONCLUSIONS: Cuffitis is a cause of pouch dysfunction after a double-stapled restorative proctocolectomy. We propose a triad of diagnostic criteria, including symptoms and endoscopic and histologic inflammation.

Six years of experience with sacral nerve stimulation for fecal incontinence.

PURPOSE: Sacral nerve stimulation is one of many new surgical modalities for fecal incontinence. Short-term results from sacral nerve stimulation have been more encouraging than those from other modalities. The aim of this study was to report the outcome of percutaneous nerve evaluation tests and sacral nerve stimulation for the treatment of fecal incontinence from a single center covering a period of 6 years since the procedure was introduced. METHODS: All of the candidates for a percutaneous nerve evaluation test and sacral nerve stimulation seen at our anal physiology unit between March 2001 and March 2007 were included in the study. RESULTS: A total of 177 patients with fecal incontinence (160 females), median age 59.5 (range, 27-88) years, underwent a percutaneous nerve evaluation test. Of these patients, 142 (80%) had a positive test, including 21 of 25 (84%) patients who required a repeat percutaneous nerve evaluation test. Because of a functional failure, 16 patients underwent a revision of the permanent electrode, 7 of whom (44%) were satisfied with the functional result after the revision. Of 126 patients, 15 (12%) have undergone an explantation, with an infection rate of only 1.6%. Overall, after a median follow-up of 24 (range, 3-72) months, the median Wexner incontinence score decreased from 16 (range, 6-20) to 10 (range, 0-20) (P < .0001). In the 10 patients who underwent at least 6 years of treatment, the effect was sustained, as the median Wexner incontinence score decreased from 20 (range, 12-20) to 7 (range, 2-11) (P < .0001). CONCLUSION: Sacral nerve stimulation is a simple, safe, and minimally invasive technique with low morbidity and excellent results, which appear to be maintained for the first 6 years after the procedure. For patients who underwent the treatment, median Wexner incontinence score decreased significantly after a median follow-up of 24 (range, 3-72) months. Twelve percent were explanted. The infection rate was 1.6%.

Adenomatous polyps develop commonly in the ileal pouch of patients with familial adenomatous polyposis

PURPOSE: The aim of this study was to establish the prevalence of adenomatous polyps in the ileal pouch of patients with familial adenomatous polyposis. METHOD: Forty-three patients who had an ileal pouch for familial adenomatous polyposis were invited to have a careful endoscopic examination of their pouch, including dye spraying. The number of polyps was recorded, and up to ten were biopsied. In addition, four random biopsy specimens were taken from the proximal and four from the distal pouch. RESULTS: Thirty-three patients with a median age of 36 (range, 14–63) years who had a pouch (5 Kock and 28 pelvic) for a median of 7 (range, 1–19) years accepted the invitation. Twenty-one patients (64 percent) had endoscopically identified polyps, the number of polyps ranging from 1 to 100 (median, 10) and varying in size from 1 to 3 mm. Fourteen patients (42 percent) had adenomatous polyps and 4 of these also had microadenomas on random biopsies. Nine of the 14 patients with adenomas also had lymphoid polyps. Seven patients had lymphoid polyps only and two of these patients had a microadenoma on random biopsy. Four of 12 patients with no visible polyps had microadenomas in their random biopsies. The presence of adenomatous polyps (Pearsons correlation;P < 0.01) increased with the age of the pouch. In total, 20 of 33 (60 percent) patients had adenomas and or microadenomas. CONCLUSION: Adenomatous polyps occur frequently in ileal pouches. These findings are of concern, and therefore, regular surveillance seems warranted until the natural history of these adenomatous polyps is determined.

Fibre supplementation in addition to loperamide for faecal incontinence in adults: a randomized trial.

Background and aims  Many patients with faecal incontinence (FI) are prescribed a constipating agent concurrently with either fibre supplementation or a low‐residue diet. Clinician opinion varies as to which initial approach is best. This study compared these treatments in routine clinical practice.

Comprehensive analysis of the bacterial content of stool from patients with chronic pouchitis, normal pouches, or familial adenomatous polyposis pouches.

Background: Chronic pouchitis is an important long‐term complication following ileal pouch–anal anastomosis for ulcerative colitis. Antibiotic administration reduces symptoms of pouchitis, indicating that bacteria have a role in pathogenesis. The aim of the research was to investigate the bacterial content of pouches using nucleic acid‐based methods. Methods: Stool microbiota of 17 patients with normal pouches (NP), 17 patients with pouchitis (CP) utilizing samples collected from each patient when antibiotic‐treated (CP‐on, asymptomatic) and when untreated (CP‐off, symptomatic), and 14 familial adenomatous polyposis (FAP) patients were analyzed by high‐throughput sequencing, fluorescence in situ hybridization technologies, and quantitative polymerase chain reaction (qPCR). Results: Fluorescence in situ hybridization analysis revealed an expanded phylogenetic gap in NP and CP‐off patients relative to FAP. Antibiotic treatment reduced the gap in CP stool. The phylogenetic gap of CP‐off patients was due to members of the bacterial families Caulobacteriaceae, Sphingomonadaceae, Comamonadaceae, Peptostreptococcaceae, and Clostridiaceae. There was a greater diversity of phylotypes of Clostridiaceae in CP‐off subjects. The phylogenetic gap of NP stool was enriched by Ruminococcaceae and Bifidobacteriaceae. CP stool microbiota had reduced diversity relative to NP and FAP stool due largely to a reduction in Lachnospiraceae/Insertae Sedis XIV/clostridial cluster IV groups. Conclusions: Bacterial groups within the expanded phylogenetic gap of pouch patients may have roles in the pathogenesis of pouchitis. Further research concerning the physiology of cultured members of these groups will be necessary to explain their specific roles. Members of the Lachnospiraceae, Incertae Sedis XIV, and clostridial cluster IV could be useful biomarkers of pouch health. (Inflamm Bowel Dis 2011;)

Aneuploidy and columnar cuff surveillance after stapled ileal pouch-anal anastomosis in ulcerative colitis

PURPOSE: A stapled pouch-anal anastomosis without mucosectomy is widely used in restorative proctocolectomy. Uncertainty exists about the longer-term outcome of retaining a columnar cuff of epithelium in the anal canal and about the need for surveillance of the columnar cuff. The aim of this article was to assess the ability to obtain biopsies of the columnar cuff, to assess the risk of dysplasia, and to search for the presence of aneuploidy as an early of marker of dysplasia in nondysplastic epithelium. METHOD: A total of 457 biopsy specimens were taken during 203 examinations of 113 patients. All biopsy specimens were stained with hematoxylin and eosin and examined by microscopy. One hundred thirty-two of these biopsy specimens from 67 patients were frozen and analyzed by flow cytometry for aneuploidy. RESULTS: Mean follow-up after pouch formation was 2.5 years, and the time after diagnosis of ulcerative colitis was 10.1 years. Successful columnar cuff biopsies were done on 93 percent of patients. There was no dysplasia. Two biopsy specimens from one patient had aneuploidy. CONCLUSION: To date, neoplastic change in the columnar cuff is rare. A selective policy of surveillance biopsies is recommended that includes patients greater than ten years after the diagnosis of ulcerative colitis and patients with dysplasia or cancer in their proctocolectomy specimen, but long-term follow-up data are needed.

Reduced expression of a gene proliferation signature is associated with enhanced malignancy in colon cancer.

The association between cell proliferation and the malignant potential of colon cancer is not well understood. Here, we evaluated this association using a colon-specific gene proliferation signature (GPS). The GPS was derived by combining gene expression data obtained from the analysis of a cancer cell line model and a published colon crypt profile. The GPS was overexpressed in both actively cycling cells in vitro and the proliferate compartment of colon crypts. K-means clustering was used to independantly stratify two cohorts of colon tumours into two groups with high and low GPS expression. Notably, we observed a significant association between reduced GPS expression and an increased likelihood of recurrence (P<0.05), leading to shorter disease-free survival in both cohorts. This finding was not a result of methodological bias as we verified the well-established association between breast cancer malignancy and increased proliferation, by applying our GPS to public breast cancer data. In this study, we show that reduced proliferation is a biological feature characterizing the majority of aggressive colon cancers. This contrasts with many other carcinomas such as breast cancer. Investigating the reasons underlying this unusual observation may provide important insight into the biology of colon cancer progression and putative novel therapy options.

The impact of splenectomy on outcome after resection for colorectal cancer: a multicenter, nested, paired cohort study.

PurposeThis study was designed to determine whether incidental splenectomy for iatrogenic injury affects long-term cancer-specific survival in patients having resection of an adenocarcinoma of the sigmoid or rectum.MethodsA retrospective case-matched review of patients undergoing surgery for colorectal cancer with incidental splenectomy between January 1, 1990 and December 31, 1999 was undertaken. Data were analysed for age, American Society of Anesthesiologists physical status, gender, disease stage, operation type, and outcome. These cases were matched with patients from the same center, of the same age and gender, with the same stage of disease and operation, who did not require a splenectomy at the time of their surgery.ResultsFifty-five patients were identified who had an iatrogenic splenectomy. Matched gender, stage, and American Society of Anesthesiologists-matched controls were identified. Follow-up from time of surgery to death or last follow-up ranged from 2 to 205 (median, 43) months. A Kaplan-Meier survival analysis using the Cox proportional hazards model to define the statistical significance found a significant difference between the groups favoring those without splenectomy (hazard ratio, 1.8; 95 percent confidence interval (CI), 1–3.3; P = 0.0399). Cancer-specific survival at five years was 70 vs. 47 percent and at ten years was 55 vs. 38 percent.DiscussionPatients with colorectal cancer who had splenectomy as a result of iatrogenic damage of the spleen while undergoing resection of the sigmoid or rectum for adenocarcinoma had a significantly worse prognosis.