Rory Kennelly

Oestrogen and the colon: potential mechanisms for cancer prevention

The role of oestrogen in oncogenesis has been examined extensively, especially in the context of breast cancer, and receptor modulators are an integral part of targeted treatment in this disease. The role of oestrogen signalling in colonic carcinoma is poorly understood. Men are more susceptible than women to colon cancer. Furthermore, hormone-replacement therapy affords an additive protective effect for postmenopausal women, and when these women do develop cancer, they typically have less aggressive disease. The discovery of a second oestrogen receptor (ERbeta) and its over expression in healthy human colon coupled with reduced expression in colon cancer suggests that this receptor might be involved. The underlying mechanism, however, remains largely unknown. In this Review, we discuss the various hypotheses presented in the published literature. We examine the cellular and molecular mechanisms through which oestrogen is purported to exert its protective influence, and we review the evidence available to support these claims.

Multicentre study of circumferential margin positivity and outcomes following abdominoperineal excision for rectal cancer

Rectal cancer outcomes following abdominoperineal excision (APE) have been inferior to those for anterior resection, including more positive circumferential resection margins (CRMs). An erroneously conservative interpretation of APE (rather than a radical resection termed ‘extralevator’) has been proposed as the cause. In this multicentre study, factors contributing to CRM positivity were examined following APE according to its original description.

Evaluation of intestinal absorption enhancement and local mucosal toxicity of two promoters. I. Studies in isolated rat and human colonic mucosae

The effects of two absorption promoters, (sodium caprate (C(10)) and melittin), on intestinal permeability and viability were measured in intact rat and human colonic epithelia mounted in Ussing chambers. Apical-side addition of C(10) (10 mM) and melittin (10-50 microM) rapidly reduced the transepithelial electrical resistance (TEER) and increased the apparent permeability coefficient (Papp) of [(14)C]-mannitol and FITC-dextran-4 kDa (FD4) across colonic mucosae from both species. Effects of C(10) on flux were greater than those of melittin at the concentrations selected. C(10) irreversibly decreased TEER, but the effects of melittin were partially reversible. Enhanced permeability of polar sugars (0.18-70 kDa) in colonic mucosae with C(10) was accompanied by significant release of lactate dehydrogenase (LDH) from the luminal surface as well as by inhibition of electrogenic chloride secretion induced by the muscarinic agonist, carbachol (0.1-10 microM). Although melittin did not alter electrogenic chloride secretion in rat or human colonic mucosae, it caused leakage of LDH from rat tissue. Gross histology and electron microscopy of rat and human colonic mucosae demonstrated that each permeation enhancer can induce colonic epithelial damage at concentrations required to increase marker fluxes. C(10) led to more significant mucosal damage than melittin, characterised by sloughing and mucosal erosion. Overall, these results indicate that while C(10) and melittin increase transport of paracellular flux markers across isolated human and rat colonic mucosae in vitro, these effects are associated with some cytotoxicity.

Oestrogen inhibits human colonic motility by a non-genomic cell membrane receptor-dependent mechanism

Classical effects of oestrogen involve activation of target genes after binding nuclear receptors. Oestrogenic effects too rapid for DNA transcription (non‐genomic) are known to occur. The effect of oestrogen on colonic motility is unknown despite the prevalence of gastrointestinal symptoms in pregnant and premenopausal women.

Multimodal treatment of perianal fistulas in Crohn’s disease: seton versus anti-TNF versus advancement plasty (PISA): study protocol for a randomized controlled trial

BackgroundCurrently there is no guideline for the treatment of patients with Crohn’s disease and high perianal fistulas. Most patients receive anti-TNF medication, but no long-term results of this expensive medication have been described, nor has its efficiency been compared to surgical strategies. With this study, we hope to provide treatment consensus for daily clinical practice with reduction in costs.Methods/DesignThis is a multicentre, randomized controlled trial. Patients with Crohn’s disease who are over 18 years of age, with newly diagnosed or recurrent active high perianal fistulas, with one internal opening and no anti-TNF usage in the past three months will be considered. Patients with proctitis, recto-vaginal fistulas or anal stenosis will be excluded. Prior to randomisation, an MRI and ileocolonoscopy are required. All treatment will start with seton placement and a course of antibiotics. Patients will then be randomised to: (1) chronic seton drainage (with oral 6-mercaptopurine (6MP)) for one year, (2) anti-TNF medication (with 6MP) for one year (seton removal after six weeks) or (3) advancement plasty after eight weeks of seton drainage (under four months anti-TNF and 6MP for one year). The primary outcome parameter is the number of patients needing fistula-related re-intervention(s). Secondary outcomes are the number of patients with closed fistulas (based on an evaluated MRI score) after 18 months, disease activity, quality of life and costs.DiscussionThe PISA trial is a multicentre, randomised controlled trial of patients with Crohn’s disease and high perianal fistulas. With the comparison of three generally accepted treatment strategies, we will be able to comment on the efficiency of the various treatment strategies, with respect to several long-term outcome parameters.Trial registrationNederlands Trial Register identifier: NTR4137 (registered on 23 August 2013).

Mast Cells in Tissue Healing: From Skin to the Gastrointestinal Tract

Mast cells are largely found at interfaces between the environment and the internal milieu. Early knowledge of the mast cell suggested a role predominantly associated with allergy and pathologic response to antigens, but more recent research has shown a myriad of functions is likely. Wound healing is a complex process of lysis and reconstitution controlled by a series of cell signalling proteins. Mast cells have been shown to play a significant role in the early inflammatory stage of wound healing and also influence proliferation and tissue remodelling in skin. Emerging work implicates the mast cell as a modulator of intestinal healing particularly following surgical anastomosis. The study of mast cells and wound healing involves the use of cell studies and animal models through the use of mast cell inhibitors, promoters and mast cell deficient rodent strains. This review addresses wound healing in skin and the gastrointestinal tract and specifically identifies data pertaining to the role of the mast cell in the process of cell breakdown, repair and regeneration.

Volume-outcome analysis in rectal cancer: A plea for enquiry, evidence and evolution

In the last three decades, since Luft suggested a link between hospital volume and patient outcome, little has changed. Despite great efforts to formally quantify the relationship between volume and cancer survival, much uncertainty remains. It is intuitive that increased experience (of the surgeon, the hospital or the ancillary staff) translates to better patient care but closer analysis of the literature uncovers widespread inconsistency in study design questioning validity of conclusions. Although centralisation of cancer services would seem beneficial, definitive evidence is only available regarding pancreatic and oesophageal disease and that pertaining to rectal cancer is heterogeneous and often flawed. A majority of evidence suggests better outcome for patients with rectal cancer managed in high volume centres. There are, however, many variables in data collection and interpretation rendering comparison between studies challenging. Definitions of the rectum range from distance from the anal verge (inherent disagreement e range 10e16 cm), to relationship to sacral promontory (subject to interpreter variation), and location of peritoneal reflection (cannot be interpreted endoscopically). Many authors fail to differentiate between sigmoid colon and rectum 3 and, those that do demonstrate wide variation. One of the largest studies, (more than 7000 patients) from the Californian Cancer Registry offered no description of tumour location. It concluded that patients undergoing surgery at high volume hospitals were less likely to have permanent colostomies and had better survival rates. The diagnosis of rectal cancer was, however, questionable as it was based only on a discharge letter, often written by the most junior team member with no reference to true anatomical location. Most US studies are published from a few high volume institutions with a select patient cohort and are based on retrospective analysis of large databases which, themselves are notoriously inaccurate. The European experience was recently explored by Ptok in a prospective trial of almost 7000 patients undergoing resection for rectal cancer. This is arguably the most complete data set available to date and great effort was made to overcome common biases. A clear definition of the rectum was provided, hospital volume was classified

Adjuvant therapies in the treatment of stage II and III malignant melanoma

BACKGROUND The incidence of cutaneous melanoma has increased during the past three decades. The development of sentinel lymph node biopsy has facilitated better staging. Despite these improvements, 5-year survival rates for American Joint Committee on Cancer stage II and III disease range from 50%-90%. METHODS A review of the current literature concerning adjuvant therapies in patients with stage II and III malignant melanomas was undertaken. RESULTS The focus of adjuvant therapies has shifted from radiotherapy, BCG and levamisole to newer biological agents. Interferon, interleukin and vaccines have been evaluated but none of these agents have demonstrated an increase in overall survival in patients with stage II and III melanoma. Interferon can prolong disease-free interval. CONCLUSION At present, no adjuvant therapy improves overall survival in patients with stage II and III melanoma. New staging allows more accurate stratification of patients for clinical trials.

Mast cell degranulation is essential for anastomotic healing in well perfused and poorly perfused rat colon.

BACKGROUND Mast cell degranulation is an important step in early wound healing in the skin however the role of the mast cell in anastomotic healing is less clear. The aim of this study was to investigate the importance of mast cell degranulation in anastomotic healing and to assess whether a promoter of mast cell degranulation could increase anastomotic healing in poorly perfused bowel. METHODS Fifty Wistar rats were divided into five groups: control, normally perfused bowel with mast cell stabilisation, normally perfused bowel with mast cell degranulation, hypoperfused bowel, and hypoperfused bowel with mast cell degranulation. A colo-colonic anastomosis was formed in each animal. Four d later, following sacrifice, the strength of the anastomosis was assessed in each animal. RESULTS Mast cell stabilisation reduced anastomotic healing in normally perfused bowel (P < 0.001). Hypoperfused bowel resulted in reduced anastomotic strength (P < 0.001) however the addition of a mast cell degranulating agent increased healing in hypoperfused bowel to levels comparable with control. CONCLUSIONS Mast cell degranulation is essential for early anastomotic healing. Healing is reduced in hypoperfused bowel but the administration of a mast cell degranulation agent can compensate for the adverse effects of a poor blood supply on anastomotic healing.

Electrical field stimulation promotes anastomotic healing in poorly perfused rat colon

IntroductionHypoperfusion of the bowel is a risk factor for anastomotic failure. Electrical field stimulation has been shown to improve repair in ischemic tissue, but its influence in hypoperfused colon has not been investigated. The hypothesis of this experimental animal study was that electrical field stimulation improves anastomotic healing in ischemic bowel.Materials and methodsThirty rats were divided evenly into three groups: control, ischemia/placebo, and ischemia/test group. Ischemia was induced by ligation of the arterial supply to the proximal colon. The watershed area was identified and transected. Field stimulation was achieved by application of negatively charged diethylaminoethyl Sephadex beads in methylcellulose gel to the colonic epithelium prior to anastomosis. The placebo group had methylcellulose gel only applied and control animals had anastomosis only. Anastomotic strength was measured using anastomotic bursting pressure and hydroxyproline content. Systemic effect was investigated via interleukin-6 and vascular endothelial growth factor assay.ResultsThe ischemia/electrical field stimulation (EFS) group had significantly increased bursting pressure and hydroxyproline content in comparison with the placebo group (P < 0.001). Serum cytokine levels were unaffected.ConclusionNegatively charged EFS improves anastomotic healing in hypoperfused colon without induction of systemic cytokines and has potential as a local treatment in high-risk bowel anastomosis.