[Show abstract][Hide abstract] ABSTRACT: The relevance of spatial composition in the microbial changes associated with UC is unclear. We coupled luminal brush samples, mucosal biopsies and laser capture microdissection with deep sequencing of the gut microbiota to develop an integrated spatial assessment of the microbial community in controls and UC.
A total of 98 samples were sequenced to a mean depth of 31 642 reads from nine individuals, four control volunteers undergoing routine colonoscopy and five patients undergoing surgical colectomy for medically-refractory UC. Samples were retrieved at four colorectal locations, incorporating the luminal microbiota, mucus gel layer and whole mucosal biopsies.
Interpersonal variability accounted for approximately half of the total variance. Surprisingly, within individuals, asymmetric Eigenvector map analysis demonstrated differentiation between the luminal and mucus gel microbiota, in both controls and UC, with no differentiation between colorectal regions. At a taxonomic level, differentiation was evident between both cohorts, as well as between the luminal and mucosal compartments, with a small group of taxa uniquely discriminating the luminal and mucosal microbiota in colitis. There was no correlation between regional inflammation and a breakdown in this spatial differentiation or bacterial diversity.
Our study demonstrates a conserved spatial structure to the colonic microbiota, differentiating the luminal and mucosal communities, within the context of marked interpersonal variability. While elements of this structure overlap between UC and control volunteers, there are differences between the two groups, both in terms of the overall taxonomic composition and how spatial structure is ascribable to distinct taxa.
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[Show abstract][Hide abstract] ABSTRACT: Background
Tumour microenvironment (TME) of advanced colorectal cancer (CRC) suppresses dendritic cell (DC) maturation. Here, our aim was to determine how the microenvironment of early-stage tumours influences DCs.Methods:Tumour-conditioned media (TCM) was generated by culturing explant tumour tissue in vitro (n=50). Monocyte-derived DCs (MDDCs) of healthy donors or cancer patients were pretreated with TCM and stimulated with lipopolysaccharide (LPS). DC maturation was assessed by flow cytometry and cytokine production measured by ELISA.Results:TCM from both early- and late-staged tumours abrogated LPS-induction of IL-12p70 secretion, while increasing IL-10. The profile of inflammatory mediators in TCM was similar across stages, and all increased pSTAT3 expression by DCs.CRC patient DCs (n=31) secreted low levels of IL-12p70 and failed to upregulate expression of maturation markers in response to LPS. Furthermore, in vitro culture of autologous DCs with TCM did not change the hypo-responsiveness of patient DCs.Conclusion:Our data demonstrates that the TME of all stages of CRC contains inflammatory mediators capable of suppressing local DCs. MDDCs obtained from CRC patients are hyporesponsive to stimuli such as LPS. Measures to reverse the negative influence of the TME on DCs will optimise cancer vaccines in both early- and late-stage CRC.British Journal of Cancer advance online publication, 24 July 2014; doi:10.1038/bjc.2014.367 www.bjcancer.com.
British Journal of Cancer 07/2014; · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Surgery remains the mainstay of treatment for malignant melanoma. Despite previous studies examining the surgical interval (SI) between the diagnostic excision biopsy (DEB) and definitive surgical management there remains few guidelines regarding an optimal time interval. The aim of this study was to determine the SI between DEB and definitive surgery and elucidate factors associated with delays in management of malignant melanoma.
Irish Journal of Medical Science 06/2014; · 0.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Debate exists as to whether the traditional three-tiered grading of anal intraepithelial neoplasia (AIN) should be replaced by a more reproducible two-tiered system. In this study, we review our experience with AIN to determine the most suitable classification system.
[Show abstract][Hide abstract] ABSTRACT: The colonic mucus gel layer is composed of mucins that may be sulphated or sialyated. Sulphated mucins predominate in health while in ulcerative colitis(UC) sulphation is reduced. These differences result directly from inflammatory events. It may also be hypothesised that they arise in part from alterations in the colonic microbiota, particularly changes in the burden of sulphated mucin metabolising species such as desulfovibrio(DSV). The aim of this study was to correlate colonic mucin chemotypes and inflammatory scores in health and UC and relate these changes to changes in DSV colonisation of colonic crypts.
Paired colonic biopsies from 34 healthy controls (HC) and 19 patients with active UC were collected for the purpose of parallel histological and microbiological assessment. High-Iron Diamine and Alcian-Blue staining and H&E staining of mucosal biopsy specimens were used to assess histological changes within the clinical spectrum of UC. Quantitative Real-Time PCR analysis was employed to determine the total and DSV copy number within the colonic crypts.
Compared with HC, mucin chemotype in UC was less sulphated and inversely correlated with the degree of mucosal inflammation. A weak but significant negative correlation was found between abundance of sulphated mucins and DSV burden.
Mucin composition strongly correlates with the degree of mucosal inflammation, and to a lesser extent with DSV burden. These data suggest that mucin chemotype and DSV burden are linked phenomena and highlight the need to consider changes in mucin chemotype in the setting of microbial dysbiosis occurring within the colitic colon. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: We report a case of Castleman's Disease (CD), hyaline vascular subtype involving the biliary tract with obstruction. A 43 year old man presented with a 5 week history of abdominal and back pain with biliary obstructive symptoms. He was jaundiced with persistently high LFTs. Radiological investigation revealed a stricture in the extrahepatic biliary tract. The clinical impression at the time was of sclerosing cholangitis with bile duct cholangiocarcinoma. A Whipple's procedure was performed. Histology and immunohistochemistry supported the histologic diagnosis of CD of hyaline vascular subtype. There was no evidence of disease elsewhere and the patient was disease free after a 6 year follow-up. Our case describes the hyaline vascular subtype of CD, a relatively rare disease occurring in a previously undescribed location.
Irish medical journal 03/2013; 106(3):86. · 0.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: This study evaluated the clinicopathological features and survival rates of patients with inflammatory bowel disease who developed colorectal cancer (CRC). METHODS: A retrospective review was performed on a prospectively maintained institutional database (1981-2011) to identify patients with inflammatory bowel disease who developed CRC. Clinicopathological parameters, management and outcomes were analysed. RESULTS: A total of 2,843 patients with inflammatory bowel disease were identified. One thousand six hundred and forty-two had ulcerative colitis (UC) and 1,201 had Crohn's disease (CD). Following exclusion criteria, there were 29 patients with biopsy-proven colorectal carcinoma, 22 of whom had UC and 7 had CD. Twenty-six patients had a preoperative diagnosis of malignancy/dysplasia; 16 of these were diagnosed at surveillance endoscopy. Nodal/distant metastasis was identified at presentation in 47 and 71 % of the UC and CD group, respectively. Operative morbidity for UC and CD was 33 and 17 %, respectively. Despite the less favourable operative outcomes following surgery management of UC-related CRC, overall 5-year survival was significantly better in the UC group compared to the CD group (41 vs. 29 %; p = 0.04) reflecting the difference in stage at presentation between the two groups. CONCLUSIONS: Patients who undergo surgery for UC-related CRC have less favourable short-term outcomes but present at a less advanced stage and have a more favourable long-term prognosis than similar patients with CRC and CD.
Techniques in Coloproctology 02/2013; · 1.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BRAF is an oncogene encoding a serine-threonine protein kinase involved in the MAPK signalling cascade. BRAF acts as direct effector of RAS and through the activation of MEK, promotes tumour growth and survival. Approximately, 8% of cancers carry a BRAF mutation. However, the prevalence of this mutation varies significantly across different tumour types. There has been increasing interest in the specific role of BRAF mutations in cancer growth and progression over the last few years, especially since the clinical introduction of therapeutic BRAF inhibitors. In this paper we review the published literature on the role of BRAF mutations in melanoma and colorectal cancer, focusing on similarities and differences of BRAF mutations with respect to frequency, demographics, risk factors, mutation-associated clinico-pathologic and molecular features and clinical implications between these two diseases.
Critical reviews in oncology/hematology 12/2012; · 5.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: We report the case of a 21 year old female with underlying facial lipodystrophy who presented with left lower abdominal pain, weight gain and altered bowel habit. PRESENTATION OF CASE: Subsequent investigation showed a large (21cm×18cm×8cm) intraabdominal mass. At laparotomy, it was completely excised and was seen to arise from the transverse mesocolon and following histology revealed it to be mesenteric lipodystrophy. DISCUSSION: Mesenteric lipodystrophy is a rare clinical entity, and part of a spectrum of disorders of sclerosing mesenteritis. This is the first reported case in a patient with pre-existing facial lipodystrophy. CONCLUSION: Herein we describe a case of mesenteric lipodystrophy, discuss its management and review of the literature.
International journal of surgery case reports. 12/2012; 4(2):232-234.
[Show abstract][Hide abstract] ABSTRACT: Local excision of rectal cancer after neoadjuvant chemoradiotherapy (CRT) has been proposed as an alternative to radical surgery in selected patients. However, little is known about the significance of the morphological and histological features of residual tumour.
Patients who had undergone CRT at the authors' institution between 1997 and 2010 were identified. Multiple features were assessed as putative markers of pathological response. These included: gross residual disease, diameter of residual mucosal abnormalities, tumour differentiation, presence of lymphovascular/perineural invasion and lymph node ratio.
Data from 220 of 276 patients were suitable for analysis. Diameter of residual mucosal abnormalities correlated strongly with pathological tumour category after CRT (ypT) (P < 0·001). Forty of 42 tumours downstaged to ypT0/1 had residual mucosal abnormalities of 2·99 cm or less after CRT. Importantly, 19 of 31 patients with a complete pathological response had evidence of a residual mucosal abnormality consistent with an incomplete clinical response. The ypT category was associated with both pathological node status after CRT (P < 0·001) and lymph node ratio (P < 0·001). Positive nodes were found in only one of 42 patients downstaged to ypT0/1. The risk of nodal metastases was associated with poor differentiation (P = 0·027) and lymphovascular invasion (P < 0·001).
In this series, the majority of patients with a complete pathological response did not have a complete clinical response. In tumours downstaged to ypT0/1 after CRT, residual mucosal abnormalities were predominantly small and had a 2 per cent risk of positive nodes, thus potentially facilitating transanal excision. The presence of adverse histological characteristics risk stratified tumours for nodal metastases.
British Journal of Surgery 02/2012; 99(7):993-1001. · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The homeobox containing transcription factor MSX2 is a key regulator of embryonic development and has been implicated to have a role in breast and pancreatic cancer.
Using a selection of two- and three-dimensional in vitro assays and tissue microarrays (TMAs), the clinical and functional relevance of MSX2 in malignant melanoma was explored. A doxycyline-inducible over-expression system was applied to study the relevance of MSX2 in vitro. For TMA construction, tumour material from 218 melanoma patients was used.
Ectopic expression of MSX2 resulted in the induction of apoptosis and reduced the invasive capacity of melanoma cells in three-dimensional culture. MSX2 over-expression was shown to affect several signalling pathways associated with cell invasion and survival. Downregulation of N-Cadherin, induction of p21 and inhibition of both BCL2 and Survivin were observed. Cytoplasmic MSX2 expression was found to correlate significantly with increased recurrence-free survival (P=0.008). Nuclear expression of MSX2 did not result in significant survival correlations, suggesting that the beneficial effect of MSX2 may be independent of its DNA binding activity.
MSX2 may be an important regulator of melanoma cell invasion and survival. Cytoplasmic expression of the protein was identified as biomarker for good prognosis in malignant melanoma patients.
British Journal of Cancer 08/2011; 105(4):565-74. · 5.08 Impact Factor