Evaluating colonoscopy screening intervals in patients with Lynch syndrome from a large Canadian registry.

Background: Lynch syndrome (LS) screening guidelines originally recommended colonoscopy every 1 to 2 years, beginning between the ages of 20 and 25 years. Recent studies have questioned the benefits of these short screening intervals in preventing colorectal cancer (CRC). Our goal is to determine how colonoscopy screening intervals impact CRC in patients with LS.

Anal Adenocarcinoma: A Rare Entity in Need of Multidisciplinary Management.

Background: Anal adenocarcinoma is a rare clinical entity for which the optimal management is not defined.

Objective: This study aimed to describe the multidisciplinary management and outcomes of patients with anal adenocarcinoma.

Design: This is a retrospective cohort study.

Eflornithine plus Sulindac for Prevention of Progression in Familial Adenomatous Polyposis.

Background: The efficacy and safety of combination therapy with eflornithine and sulindac, as compared with either drug alone, in delaying disease progression in patients with familial adenomatous polyposis are unknown.

Methods: We evaluated the efficacy and safety of the combination of eflornithine and sulindac, as compared with either drug alone, in adults with familial adenomatous polyposis. The patients were stratified on the basis of anatomical site with the highest polyp burden and surgical status; the strata were precolectomy (shortest projected time to disease progression), rectal or ileal pouch polyposis after colectomy (longest projected time), and duodenal polyposis (intermediate projected time).

Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer.

Inflammatory bowel disease patients have a greatly increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Using three models of CAC, we find that sustained inflammation triggers 8-oxoguanine DNA lesions. Strikingly, antioxidants or iNOS inhibitors reduce 8-oxoguanine and polyps in CAC models.

Cost-effectiveness of Active Identification and Subsequent Colonoscopy Surveillance of Lynch Syndrome Cases.

Background & Aims: The province of Ontario, Canada is considering immunohistochemical followed by cascade analyses of all patients who received a diagnosis of colorectal cancer (CRC) at an age younger than 70 years to identify individuals with Lynch syndrome. We evaluated the costs and benefits of testing for Lynch syndrome and determined the optimal surveillance interval for first-degree relatives (FDRs) found to have Lynch syndrome.

Methods: We developed a patient flow diagram to determine costs and yield of immunohistochemical testing for Lynch syndrome in CRC cases and, for those found to have Lynch syndrome, their FDRs, accounting for realistic uptake.

High prevalence of adenomatous colorectal polyps in young cancer survivors treated with abdominal radiation therapy: results of a prospective trial.

Objective: Cancer survivors treated with abdominal/pelvic radiation therapy (ART) have increased the risks of colorectal cancer (CRC), although evidence supporting early CRC screening for these patients is lacking. We sought to determine whether there is an elevated prevalence of adenomatous colorectal polyps in young survivors prior to the age when screening would be routinely recommended.

Design: We conducted a prospective study of early colonoscopic screening in cancer survivors aged 35-49 who had received ART ≥10 years previously.

DNA Mismatch Repair Status Predicts Need for Future Colorectal Surgery for Metachronous Neoplasms in Young Individuals Undergoing Colorectal Cancer Resection.

Background: The treatment of colorectal cancer in young patients involves both management of the incident cancer and consideration of the possibility of Lynch syndrome and the development of metachronous colorectal cancers.

Objective: This study aims to assess the prognostic role of DNA mismatch repair deficiency and extended colorectal resection for metachronous colorectal neoplasia risk in young patients with colorectal cancer.

Design, Setting, And Patients: This is a retrospective review of 285 patients identified in our GI cancer registry with colorectal cancer diagnosed at 35 years or younger in the absence of polyposis.

Proctocolectomy for colorectal cancer--is the ileal pouch anal anastomosis a safe alternative to permanent ileostomy?

Purpose: Ileal pouch anal anastomosis (IPAA) is the procedure of choice in patients requiring surgery for ulcerative colitis (UC) and familial adenomatous polyposis (FAP). There are few data on reconstruction with the IPAA in patients with colorectal cancer (CRC). This study assessed the outcomes of the IPAA compared to proctocolectomy and permanent ileostomy (PI) on these patients.

Family history of colorectal cancer is not associated with colorectal cancer survival regardless of microsatellite instability status.

Background: Individuals with a family history of colorectal cancer in first-degree relatives have an elevated risk of developing colorectal cancer themselves, particularly colorectal cancer exhibiting high microsatellite instability (MSI-high). Given that MSI-high colorectal cancer is associated with a favorable prognosis, it is plausible that having a family history of colorectal cancer could, in turn, be favorably associated with colorectal cancer survival.

Methods: This study comprised N = 4,284 incident colorectal cancer cases enrolled in the Colon Cancer Family Registry via population-based cancer registries.

Identification of genes expressed by immune cells of the colon that are regulated by colorectal cancer-associated variants.

A locus on human chromosome 11q23 tagged by marker rs3802842 was associated with colorectal cancer (CRC) in a genome-wide association study; this finding has been replicated in case-control studies worldwide. In order to identify biologic factors at this locus that are related to the etiopathology of CRC, we used microarray-based target selection methods, coupled to next-generation sequencing, to study 103 kb at the 11q23 locus. We genotyped 369 putative variants from 1,030 patients with CRC (cases) and 1,061 individuals without CRC (controls) from the Ontario Familial Colorectal Cancer Registry.

Colon and rectal cancer survival by tumor location and microsatellite instability: the Colon Cancer Family Registry.

Background: Cancers in the proximal colon, distal colon, and rectum are frequently studied together; however, there are biological differences in cancers across these sites, particularly in the prevalence of microsatellite instability.

Objective: We assessed the differences in survival by colon or rectal cancer site, considering the contribution of microsatellite instability to such differences.

Design: This is a population-based prospective cohort study for cancer survival.

Integrated analysis of genome-wide copy number alterations and gene expression in microsatellite stable, CpG island methylator phenotype-negative colon cancer.

Microsatellite stable (MSS), CpG island methylator phenotype (CIMP)-negative colorectal tumors, the most prevalent molecular subtype of colorectal cancer, are associated with extensive copy number alteration (CNA) events and aneuploidy. We report on the identification of characteristic recurrent CNA (with frequency >25%) events and associated gene expression profiles for a total of 40 paired tumor and adjacent normal colon tissues using genome-wide microarrays. We observed recurrent CNAs, namely gains at 1q, 7p, 7q, 8p12-11, 8q, 12p13, 13q, 20p, 20q, Xp, and Xq and losses at 1p36, 1p31, 1p21, 4p15-12, 4q12-35, 5q21-22, 6q26, 8p, 14q, 15q11-12, 17p, 18p, 18q, 21q21-22, and 22q.

cis-Expression QTL analysis of established colorectal cancer risk variants in colon tumors and adjacent normal tissue.

Genome-wide association studies (GWAS) have identified 19 risk variants associated with colorectal cancer. As most of these risk variants reside outside the coding regions of genes, we conducted cis-expression quantitative trait loci (cis-eQTL) analyses to investigate possible regulatory functions on the expression of neighboring genes. Forty microsatellite stable and CpG island methylator phenotype-negative colorectal tumors and paired adjacent normal colon tissues were used for genome-wide SNP and gene expression profiling.

Juvenile polyposis, hereditary hemorrhagic telangiectasia, and early onset colorectal cancer in patients with SMAD4 mutation.

Background: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder most often caused by mutation in the endoglin or ALK1 genes. A distinct syndrome combines the clinical features of HHT and juvenile polyposis (JP) and has been associated with SMAD4 mutation. The aim of this study was to describe the phenotype of patients with JP-HHT and SMAD4 mutations and to compare this phenotype with HHT or JP patients with mutations other than SMAD4.

Inherited colorectal cancer syndromes.

Colorectal cancer is common in the Western world; ~5% of individuals diagnosed with colorectal cancer have an identifiable inherited genetic predisposition to this malignancy. Genetic testing and rational clinical management recommendations currently exist for the management of individuals with a variety of colorectal cancer syndromes, including hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome), familial adenomatous polyposis (FAP), MYH-associated polyposis (MAP), and the hamartomatous polyposis syndromes (Peutz-Jeghers, juvenile polyposis, and Cowden disease). In addition to colorectal neoplasia, these syndromes frequently predispose carriers to a variety of extracolonic cancers.

Overview of colorectal cancer genetics.

Cancer is a genetic disease in which the clonal accumulation of genetic alterations confers a cell with the malignant characteristics of uncontrolled growth, local invasiveness, and metastastic potential. Studies of colorectal cancer and its precursor lesion, the adenomatous polyp, have served as the cornerstone in advancing knowledge of cancer molecular genetics. The past 30 years have ushered in an era of revolutionary increases in understanding colorectal cancer genetics.

Concordance with clinical practice guidelines for adjuvant chemotherapy in patients with stage I-III colon cancer: experience in 2 Canadian provinces.

Background: Clinical practice guidelines (CPGs) for the adjuvant treatment of colorectal cancer were published by the National Institutes of Health in 1991. The American Society of Clinical Oncology and Cancer Care Ontario have recommended adjuvant chemotherapy for patients with high-risk stage II colon cancer. We evaluated differences in concordance with guidelines in the treatment of patients with stage I-III colon cancer in the Canadian provinces of Newfoundland and Labrador and Ontario.

Missense polymorphisms in the adenomatous polyposis coli gene and colorectal cancer risk.

Purpose: Whereas truncating germline mutations of the adenomatous polyposis coli (APC) gene give rise to familial adenomatous polyposis, missense polymorphisms of APC may confer a weaker risk for colorectal cancer.

Methods: We sequenced the entire open reading frame of the APC gene and tested for two common MYH mutations in a population-based series of patients with colorectal cancer and 5 to 99 adenomas. Missense adenomatous polyposis coli alterations identified in this colorectal cancer multiple-polyp population were analyzed in a population-based series of patients with colorectal cancer and healthy control subjects.

Complications and sexual function after vaginectomy for anorectal tumors.

Purpose: The objective of this study was to determine complication rates and functional outcomes of females who underwent vaginectomy during anorectal tumor resection and to determine whether flap reconstruction of the vagina improves sexual function.

Methods: A retrospective review was performed of all females who underwent multivisceral resections involving the vagina for anorectal tumors at two academic hospitals from 1985 to 2004. Living patients were contacted, and a 25-question telephone questionnaire was administered.

Transcriptional cooperation between the transforming growth factor-beta and Wnt pathways in mammary and intestinal tumorigenesis.

Transforming growth factor-beta (TGF-beta) and Wnt ligands function in numerous developmental processes, and alterations of both signaling pathways are associated with common pathologic conditions, including cancer. To obtain insight into the extent of interdependence of the two signaling cascades in regulating biological responses, we used an oligonucleotide microarray approach to identify Wnt and TGF-beta target genes using normal murine mammary gland epithelial cells as a model. Combination treatment of TGF-beta and Wnt revealed a novel transcriptional program that could not have been predicted from single ligand treatments and included a cohort of genes that were cooperatively induced by both pathways.

Clinical implications of our advancing knowledge of colorectal cancer genetics: inherited syndromes, prognosis, prevention, screening and therapeutics.

Recent genetic advances in our knowledge of colorectal cancer genetics are beginning to pay translational dividends in the management of this common clinical problem. We are now able to accurately screen and counsel individuals at risk of rare inherited cancer syndromes. We have recently introduced two of what are sure to be numerous biologic-based therapies, and have shown that colorectal neoplasia risk can be modestly reduced by various chemopreventative agents.

Prevalence of male and female sexual dysfunction is high following surgery for rectal cancer.

Objective: To measure sexual function and quality of life (QOL) after rectal cancer treatment.

Summary Background Data: Previous studies on sexual function after rectal cancer treatment have focused on males and have not used validated instruments.

Methods: Patients undergoing curative rectal cancer surgery from 1980 to 2003 were administered a questionnaire, including the Female Sexual Function Index (FSFI) or International Index of Erectile Function (IIEF), and the EORTC QLQ-C30/CR-38.

Robotic-assisted laparoscopic colorectal surgery.

Robotic assistance provides a number of potential benefits for laparoscopic surgery by addressing several inherent limitations. However, its utility in colorectal surgery has not been determined. This is a report of our initial experience with robot-assisted colon resections.