Najib Haboubi

Lifestyle factors and colorectal cancer risk (2): a systematic review and meta-analysis of associations with leisure-time physical activity

Objective Increased physical activity may decrease the risk of colorectal cancer. As a prerequisite to the determination of lifestyle attributable risks, we performed a systematic review and meta‐analysis of prospective observational studies to quantify gender‐specific risk associated with increased leisure‐time physical activity (LT‐PA).

Lifestyle factors and colorectal cancer risk (1): systematic review and meta‐analysis of associations with body mass index

Objective  Excess body weight, defined by body mass index (BMI), may increase the risk of colorectal cancer. As a prerequisite to the determination of lifestyle attributable risks, we undertook a systematic review and meta‐analysis of prospective observational studies to quantify colorectal cancer risk associated with increased BMI and explore for differences by gender, sub‐site and study characteristics.

The risk of dysplasia and cancer in the ileal pouch mucosa after restorative proctocolectomy for ulcerative proctocolitis is low: a long-term term follow-up study.

Aim  Some of the rare complications reported in patients with an ileopouch anal anastomosis (IPAA) after coloectomy for chronic ulcerative colitis are dysplasia and carcinoma. The supposed pathway is for the ileal pouch mucosa to go through adaptational changes then is to progress through the phases of chronic pouchitis, dysplasia and subsequently to adenocarcinoma. In many of these studies however, the dysplasia – cancer sequence is inconclusive since the carcinoma might have developed from the ileal mucosa itself or from residual viable rectal mucosa left behind. The purpose of this study was therefore to study the long‐term ileal mucosal adaptation patterns and the incidence and grading of dysplasia in the ileal pouch mucosa in patients previously operated on for ulcerative proctocolitis.

Distribution and activation of eosinophils in inflammatory bowel disease using an improved immunohistochemical technique

Eosinophils are a recognized feature of inflammatory bowel disease (IBD), but their tissue distribution and functional importance in Crohns disease (CD) and ulcerative colitis (UC) remain obscure. This study describes an improved immunohistochemical protocol to identify eosinophils in full thickness bowel wall specimens of IBD (n=40) and their in situ relationships with the chemoattractants eotaxin and RANTES. Eosinophils were identified using immunohistochemistry with a combination of monoclonal antibodies (EG1+EG2+MBP), an ultrasensitive technique superior to other methodologies, and their tissue distributions were related to those for eotaxin, RANTES, mast cells and neutrophils. Increased numbers of eosinophils (up to 400 cells/mm2) were observed in active, fulminant inflammation in both CD and UC, this being related to the severity of inflammation and not the diagnosis of the two disorders. The chemoattractants eotaxin (CCL11) and RANTES (CCL5) were upregulated in IBD tissues showing eosinophilia. Neutrophils and mast cells were commonly associated with eosinophil accumulations. Eosinophil numbers and their in situ activation are increased in active rather than chronic IBD. The observations strongly suggest a pivotal role for the eosinophil and its potent mediators in many pathophysiological symptoms of CD and UC, where it represents the major proportion of all granulocytic cells in active inflammatory bowel disease. Copyright

Early cellular events in colorectal carcinogenesis

Colorectal cancer develops through a multistage process recognizable at a histopathological level by progression from normal mucosa to invasive carcinoma (the adenoma‐carcinoma sequence). For many years, it has been hypothesized that increased cell proliferation in the colonic crypt represents the earliest recognizable stage in this sequence. This perspective is now changing. While several human studies have reported increased crypt cell proliferation in samples from at‐risk patients, there are many inconsistencies and paradoxes in their conclusions. In addition, it is appreciated that the process of apoptosis (programmed cell death) is vital for normal crypt homeostasis and its impairment may be an early event in the neoplastic process. It is now believed that aberrant crypt foci (ACFs) represent the earliest step in colorectal carcinogenesis. Two ACF types are identifiable: hypercellular and dysplastic. Increased proliferative activity may be seen in both, but the dysplastic entity is most relevant to carcinogenesis. Animal and human studies support the notion that ACFs grow by crypt fission leading to the formation of microadenomas. Adenomas are monoclonal expansions of an altered cell, but very early lesions may be polyclonal. There are outward and inward theories of polypoid growth, and evidence to support both mechanisms. The ACF assay has become a useful tool to detect carcinogens in animal studies but has been less frequently used in human studies. For future cancer chemopreventive and risk assessment studies in humans, the identification and quantification of ACFs should be considered a more effective intermediate marker of risk than the determination of crypt cell proliferation alone.

Lymphatic vessel density, microvessel density and lymphangiogenic growth factor expression in colorectal cancer.

Objective  Microvessel density (MVD) has been studied as a prognostic marker in human cancers. Quantification of lymphatic vessel density (LVD) is now possible by using new antibodies. Expression of the lymphangiogenic growth factors, VEGF‐C and VEGF‐D, is associated with poorer clinicopathological outcomes in various tumours. The aim of this study was to quantify LVD and MVD in colorectal cancer, determine the relationship between LVD, MVD and clinicopathological variables and examine the relationship between LVD and tumour expression of VEGF‐C and VEGF‐D.

Early molecular and functional changes in colonic epithelium that precede increased gut permeability during colitis development in mdr1a(-/-) mice.

Background: The early molecular changes preceding the onset of mucosal inflammation in colitis and their temporal relationship with gut permeability remain poorly defined. This study investigated functional and transcriptomic changes in mdr1a(−/−) mice lacking the intestinal transporter P‐glycoprotein, which develop colitis spontaneously when exposed to normal enteric flora. Methods: Mdr1a(−/−) mice were housed in specific pathogen‐free conditions to slow colitis development and compared to congenic controls. Mucosal permeability and cytokine secretion were analyzed in ex vivo colon. Gene expression in colonic mucosal and epithelial preparations was analyzed by microarray and qPCR. Colonocyte responsiveness to bacterial antigens was measured in short‐term culture. Results: Colon from 4–5‐week‐old, disease‐free mdr1a(−/−) mice was histologically normal with no evidence of increased permeability compared to controls. However, these tissues display a distinctive pattern of gene expression involving significant changes in a small number of genes. The majority of upregulated genes were associated with bacterial recognition and the ubiquitin‐proteasome system and were gamma‐interferon (IFN‐&ggr;) responsive. Expression of the antiinflammatory factor pancreatitis‐associated protein (PAP) and the related gene RegIII&ggr; were markedly reduced. Colonocytes from 4–5‐week mdr1a(−/−) exhibit similar transcriptomic changes, accompanied by higher basal chemokine secretion and increased responsiveness to LPS. Significant increases in colonic permeability were associated with older (12–16‐week) mdr1a(−/−) mice displaying molecular and functional evidence of active inflammation. Conclusions: These studies show that early epithelial changes associated with altered responsiveness to bacteria precede increased permeability and mucosal inflammation in this model of colitis, highlighting the importance of P‐glycoprotein in regulating interactions with the commensal microflora.

Physical activity before and after diagnosis of colorectal cancer: disease risk, clinical outcomes, response pathways and biomarkers.

Physical inactivity may be responsible for 13–14% of colon cancer, an attributable risk greater than family history. Epidemiological evidence shows an association between occupational and recreational physical activity and colon cancer, but has not established whether physical activity is protective against low-risk or more advanced adenomas. The evidence is inconclusive as to whether physical activity protects against rectal cancer and is conflicting with respect to whether physical activity has equal effects on male and female risk of colorectal cancer. The effect of exercise ‘interventions’ on the risk of colorectal cancer is currently not known. Also, although inferences can be made from epidemiological studies, no optimal exercise regimen can be confidently prescribed for protection against colorectal cancer. There is little available evidence for the benefits of physical activity before diagnosis of colorectal cancer for disease-specific survival and prognosis, and the clinical effects of an exercise intervention after diagnosis have not been investigated. There is some evidence that improvements in cardiorespiratory fitness reduce adverse effects from cancer treatment when physical activity is undertaken following diagnosis of colorectal cancer. Markers/mechanisms by which physical activity may protect against colorectal cancer and/or improve disease prognosis include gastrointestinal transit-time, chronic inflammation, immune function, insulin levels, insulin-like growth factors, genetics and obesity. Research evidence is, however, limited as to whether these markers are beneficially affected by physical activity, either before or after diagnosis of colorectal cancer.

The importance of accurate pathological assessment of lymph node involvement in colorectal cancer

This review presents an up‐to‐date analysis of the importance of accurate pathological lymph node staging in colorectal cancer. Lymph node staging is reliant on the technique of the surgeon and the pathologist as well as methods employed in the histopathology laboratory, and is vital for determining appropriate therapy. The significance of micrometastatic nodal disease is evaluated and new techniques for pathological evaluation are discussed. Recommendations for evaluation of lymph node status in colorectal cancer are provided based on current scientific evidence, and standardization of pathological dissection and laboratory handling is advocated.

Dysplasia in the ileoanal pouch

Formation of an ileo‐anal pouch is an accepted technique following colectomy in the surgical management of ulcerative colitis (UC) and familial adenomatous polyposis (FAP). The configuration of pouches and anastomotic techniques has varied over the last two decades. The increased use of stapling devices in formation of the pouch‐anal anastomosis avoids the need for endoanal mucosal stripping and may contribute to improved functional results, but leaves a ‘columnar cuff’ of residual rectal mucosa in situ. Concerns regarding the long‐term safety of the ileo‐anal pouch have been raised by reports of the occurrence of dysplasia in the pouch mucosa and 15 cases of adenocarcinoma. In UC, persistence of underlying disease in the residual rectal mucosa, anal transition zone and columnar cuff provides the site for development of dysplasia and malignancy. Pouchitis is unlikely to be a major cause of dysplasia or malignancy, as long‐term follow‐up of patients with Koch pouches has demonstrated. In FAP, any persistent rectal mucosa and mucosa of the small intestine is at risk of adenomatous dysplasia due to the genetic alterations causing the disease. Long‐term surveillance should focus on all FAP pouch patients, and in UC patients should be directed towards the diagnosis of residual rectal mucosa in the area distal to the pouch anastomosis. Specialist histopathological opinion is essential in the diagnosis of dysplasia in the ileo‐anal pouch.