J. Calvin Coffey

Pathogenesis of and unifying hypothesis for idiopathic pouchitis.

Ileal pouch-anal anastomosis is the procedure of choice in the surgical management of refractory ulcerative colitis. Pouchitis affects up to 60% of patients following ileal pouch-anal anastomosis for ulcerative colitis. It overlaps significantly with ulcerative colitis such that improvements in our understanding of one will impact considerably on the other. The symptoms are distressing and impinge significantly on patients’ quality of life. Despite 30 years of scientific and clinical investigation, the pathogenesis of pouchitis is unknown; however, recent advances in molecular and cell biology make a synergistic hypothesis possible. This hypothesis links interaction between epithelial metaplasia, changes in luminal bacteria (in particular sulfate-reducing bacteria), and altered mucosal immunity. Specifically, colonic metaplasia supports colonization by sulfate-reducing bacteria that produce hydrogen sulfide. This causes mucosal depletion and subsequent inflammation. Although in most cases antibiotics lead to bacterial clearance and symptom resolution, immunogenetic subpopulations can develop a chronic refractory variant of pouchitis. The aims of this paper are to discuss proposed pathogenic mechanisms and to describe a novel mechanism that combines many hypotheses and explains several aspects of pouchitis. The implications for the management of both pouchitis and ulcerative colitis are discussed.

The mesentery: structure, function, and role in disease

Systematic study of the mesentery is now possible because of clarification of its structure. Although this area of science is in an early phase, important advances have already been made and opportunities uncovered. For example, distinctive anatomical and functional features have been revealed that justify designation of the mesentery as an organ. Accordingly, the mesentery should be subjected to the same investigatory focus that is applied to other organs and systems. In this Review, we summarise the findings of scientific investigations of the mesentery so far and explore its role in human disease. We aim to provide a platform from which to direct future scientific investigation of the human mesentery in health and disease.

A systematic review of spinal cord injury and cerebrospinal fluid drainage after thoracic aortic endografting

BACKGROUND The use of thoracic endovascular aneurysm repair (TEVAR) is increasing. Similar to open repair, TEVAR carries a risk of spinal cord ischemia (SCI). We undertook a systematic review to determine whether preoperative cerebrospinal fluid (CSF) drainage reduces SCI. METHODS PubMed, the Cochrane Library, and conference abstracts were searched using the keywords thoracic endovascular aortic repair, cerebrospinal fluid, spinal cord ischaemia, TEVAR, and aneurysm. Studies reporting SCI rates and CSF drain rates for TEVAR patients were eligible for inclusion. SCI rates across studies were pooled using random-effects modeling. Study quality was evaluated using the Downs and Black score. RESULTS Study quality was generally poor to moderate (median Downs and Black score, 9). The systematic review identified 46 eligible studies comprising 4936 patients; overall, SCI affected 3.89% (95% confidence interval, 2.95.05%-4.95%). Series reporting routine prophylactic drain placement or no prophylactic drain placement reported pooled SCI rates of 3.2% and 3.47%, respectively. The pooled SCI rate from 24 series stating that prophylactic drainage was used selectively was 5.6%. CONCLUSIONS Spinal chord injury is uncommon after TEVAR. The role of prophylactic CSF drainage is difficult to establish from the available literature. High-quality studies are required to determine the role of prophylactic CSF drainage in TEVAR.

The mesocolon: a histological and electron microscopic characterization of the mesenteric attachment of the colon prior to and after surgical mobilization.

Background:Colonic mobilization requires separation of mesocolon from underlying fascia. Despite the surgical importance of planes formed by these structures, no study has formally characterized their microscopic features. The aim of this study was to determine the histological and electron microscopic appearance of mesocolon, fascia, and retroperitoneum, prior to and after colonic mobilization. Methods:In 24 cadavers, samples were taken from right, transverse, descending, and sigmoid mesocolon. In 12 cadavers, specimens were stained with hematoxylin and eosin (3 sections) or Masson trichrome (3 sections). In the second 12 cadavers, lymphatic channels were identified by staining immunohistochemically for podoplanin. The ascending mesocolon was assessed with scanning electron microscopy. The above process was first conducted with the mesocolon in situ. The mesocolon was then surgically mobilized, and the process was repeated on remaining structures. Results:The microscopic structure of mesocolon and associated fascia was consistent from ileocecal to mesorectal level. A surface mesothelium and underlying connective tissue were evident throughout. Fibrous septae separated adipocyte lobules. Where apposed to retroperitoneum, 2 mesothelial layers separated mesocolon and underlying retroperitoneum. A connective tissue layer occurred between these (ie, Toldts fascia). Lymphatic channels were evident both in mesocolic connective tissue and Toldts fascia. After surgical separation of mesocolon and fascia both remained contiguous, the fascia remained in situ and the retroperitoneum undisturbed. Conclusions:The findings demonstrate that the contiguous mesocolon and retroperitoneum are separated by mesothelial and connective tissue layers. These properties generate the surgical planes (ie, meso- and retrofascial planes) exploited in colonic and mesocolic mobilization.

KRAS mutation does not predict the efficacy of neo-adjuvant chemoradiotherapy in rectal cancer: a systematic review and meta-analysis.

INTRODUCTION The current management of locally advanced rectal cancer involves total mesorectal excision, which may be preceded by neo-adjuvant chemoradiotherapy (CRT). Individual patient response to CRT is variable and reproducible biomarkers of response are needed. The role of the V-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) in rectal cancer remains equivocal. The aim of the current study was to systematically appraise the effect of KRAS mutation on outcomes following CRT for rectal cancer. METHODS A comprehensive search for published studies examining the effect of KRAS mutation on outcome after neo-adjuvant CRT in rectal cancer was performed. Each study was reviewed and data extracted. Random-effects methods were used to combine data. RESULTS Data was retrieved from 8 series describing 696 patients. Neo-adjuvant treatment regimens varied in usage of chemotherapeutic agents and interval to surgery. KRAS mutation was present in an average of 33.2 ± 11.8% of patients with rectal cancer. KRAS mutation was not associated with decreased rates of pathological complete response (odds ratio (OR): 0.778, 95% confidence interval (CI): 0.424-1.428, P = 0.418), tumor down-staging (OR: 0.846, 95% CI: 0.331-2.162, P = 0.728) or an increase in cancer related mortality (OR: 1.239, 95% CI: 0.607-2.531, P = 0.555). CONCLUSIONS Based on these data, the presence of KRAS mutation does not affect tumor down-staging or cancer specific survival following neo-adjuvant CRT and surgery for rectal cancer.

Phosphoinositide 3-Kinase Accelerates Postoperative Tumor Growth by Inhibiting Apoptosis and Enhancing Resistance to Chemotherapy-induced Apoptosis NOVEL ROLE FOR AN OLD ENEMY

Tumor removal remains the principal treatment modality in the management of solid tumors. The process of tumor removal may potentiate the resurgent growth of residual neoplastic tissue. Herein, we describe a novel murine model in which flank tumor cytoreduction is followed by accelerated local tumor recurrence. This model held for primary and recurrent tumors generated using a panel of human and murine (LS174T, DU145, SW480, SW640, and 3LL) cell lines and replicated accelerated tumor growth following excisional surgery. In investigating this further, epithelial cells were purified from LS174T primary and corresponding recurrent tumors for comparison. Baseline as well as tumor necrosis factor apoptosis-inducing ligand (TRAIL)-induced apoptosis were significantly reduced in recurrent tumor epithelia. Primary and recurrent tumor gene expression profiles were then compared. This identified an increase and reduction in the expression of p110γ and p85α class Ia phosphoinositide 3-kinase (PI3K) subunits in recurrent tumor epithelia. These changes were further confirmed at the protein level. The targeting of PI3K ex vivo, using LY294002, restored sensitivity to TRAIL in recurrent tumor epithelia. In vivo, adjuvant LY294002 prolonged survival and significantly attenuated recurrent tumor growth by greatly enhancing apoptosis levels. Hence, PI3K plays a role in generating the antiapoptotic and chemoresistant phenotype associated with accelerated local tumor recurrence.

A detailed appraisal of mesocolic lymphangiology – an immunohistochemical and stereological analysis

Inadequate resection of the adjoining mesentery is associated with adverse outcome for colon cancer. Disruption of the integrity of the mesenteric lymphatic package has been implicated in this, though not proven. Recent studies have determined mesenteric anatomy and histology and now provide an opportunity to determine accurately the distribution of lymphatic vessels. The aim of this study was to characterise the distribution of the lymphatic vessels (LV) within the small intestinal and colonic mesentery, and in Toldts fascia, which lies between the mesocolon and underlying retroperitoneum. Mesenteric samples were harvested from 12 human cadavers. Samples were taken from the small bowel mesentery, ascending, transverse, descending mesocolon and from both apposed and non‐apposed portions of the mesosigmoid. Serial sections were stained immunohistochemically with monoclonal antibody D2‐40 (podoplanin), and Massons Trichrome. Lymphatic vessel (LV) density and radius of diffusion were determined using a stereological approach. A lymphatic network was embedded within the mesenteric connective tissue lattice throughout each mesenteric region. LV were identifiable within the submesothelial connective tissue where they measured 10.2 ± 4.1 μm in diameter and had an average radius of diffusion of 174.72 ± 97.68 μm. Unexpectedly, LV were identified in Toldts fascia, where they measured 4.3 ± 3.1 μm in diameter and had a radius of diffusion of 165.12 ± 66.26 μm. This is the first study systematically to determine and quantify the distribution of lymphatic vessels within the mesenteric organ and to demonstrate the presence of such vessels within Toldts fascia. A rich lymphatic network occupies all levels of the mesenteric connective tissue lattice. Within the latter, they are found within 0.1 mm of peritonealised mesenteric surfaces and are separated by an average distance of 0.17 mm and may be particularly vulnerable during surgery.

Postsurgical Recurrence of Ileal Crohn’s Disease: An Update on Risk Factors and Intervention Points to a Central Role for Impaired Host-Microflora Homeostasis

BackgroundA pressing need exists to identify factors that predispose to recurrence after terminal ileal resection for Crohn’s disease (CD) and to determine effective prophylactic strategies. This review presents an up-to-date summary of the literature in the field and points to a role for bacterial overproliferation in recurrence.MethodsThe literature (Medline, Embase, and the Cochrane Library, 1971–2009) on ileal CD and postoperative recurrence was searched, and 528 relevant articles were identified and reviewed.ResultsSmoking is a key independent risk factor for recurrence. NOD2/CARD15 polymorphisms and penetrating phenotype are associated with aggressive disease and higher reoperation rates. Age at diagnosis, disease duration, gender, and family history are inconsistent predictors of recurrence. Prophylactic 5-aminosalicylic acid therapy and nitromidazole antibiotics are beneficial. Combination therapies with immunosuppressants are also effective. Anti-TNFα-based regimens show benefit but the evidence base is small. Corticosteroid, interleukin-10, and probiotic therapies are not effective. Wider, stapled anastomotic configurations are associated with reduced recurrence rates. Strictureplasty and laparoscopic approaches have similar long-term recurrence rates to open resection techniques. Length of resection and presence of microscopic disease at resection margins do not influence recurrence. A lack of consensus exists regarding whether the presence of granulomas or plexitis affects outcome.ConclusionsCurrent evidence points to defects in mucosal immunity and intestinal dysbiosis of either innate (NOD2/CARD15) or induced (smoking) origin in postoperative CD recurrence. Prophylactic strategies should aim to limit dysbiosis (antibiotics, side-to-side anastomoses) or prevent downstream chronic inflammatory sequelae (anti-inflammatory, immunosuppressive, and immunomodulatory therapy).

National trends in intestinal resection for Crohn's disease in the post-biologic era

IntroductionPrior international datasets have demonstrated equivocal results in the rate of surgical procedures for the treatment of Crohn’s disease (CD) following the introduction of biologic medications. The first biologic medication licensed for use in the Republic of Ireland (ROI) was infliximab in 1999. The current study examined national trends in intestinal resection for CD in the ROI following the introduction of biologic medications.MethodsThe Irish Hospital In-Patient Enquiry database was examined for the period 2000–2010. Cases of CD and relevant surgical interventions were identified using International Classification of Diseases, ninth and tenth editions. Using Irish census data to establish population denominators, trends in population-based procedure rates were examined. Trends were tested for significance with Spearman rank tests.ResultsFrom 2000 to 2010, there were 11,796 patient admissions with a principal diagnosis of CD. The rates of admission for CD overall (r2 = −0.191, P = 0.574) and for emergencies (r2 = 0.055, P = 0.873) did not change; however, elective admissions reduced (r2 = −0.636, P = 0.035). The mean length of stay reduced (r2 = −0.783, P = 0.004). The rates of small bowel/right colon procedures (r2 = 0.282, P = 0.401) and proctectomy (r2 = −0.209, P = 0.537) did not change. Left colon procedures reduced (r2 = −0.800, P = 0.003) while the rate of total colectomy increased (r2 = 0.718, P = 0.013).ConclusionsDuring the decade following the introduction of biologic medications in the ROI, the rate of elective hospitalization and length of stay reduced. However, there has not been a dramatic reduction in the rate of intestinal resection for Crohn’s disease at a population level.

Mesenteric-Based Surgery Exploits Gastrointestinal, Peritoneal, Mesenteric and Fascial Continuity from Duodenojejunal Flexure to the Anorectal Junction--A Review.

Introduction: It is now well established that mesenteric-based colorectal surgery is associated with superior outcomes. Recent anatomic observations have demonstrated that the mesenteric organ is contiguous from the duodenojejunal to the anorectal junction. This led to similar observations in relation to associated peritoneum and fascia. The aim of this review was to demonstrate the relevance of the contiguity principle to resectional colorectal surgery. Methods: All literature in relation to mesenteric anatomy was reviewed from 1873 to the present, without language restriction. Results: Mesenteric-based surgery (i.e. complete mesocolic excision, total mesocolic and mesorectal excision) requires division of the peritoneal reflection (i.e. peritonotomy), and mesenteric mobilisation in the mesofascial plane. These are the fundamental technical elements of mesenterectomy. Mesenteric, peritoneal and fascial contiguity mean that in resectional surgery, these technical elements can be reproducibly applied at all levels from the origin at the superior mesenteric root, to the anorectal junction. Conclusions: The goals of complete mesocolic, total mesocolic and mesorectal excision can be universally achieved at any level from duodenojejunal flexure to anorectal junction, by adopting technical elements based on mesenteric, peritoneal and fascial contiguity.