[Show abstract][Hide abstract] ABSTRACT: Patients with metastatic colorectal cancer have a very poor prognosis. Incorporation of targeted molecular therapies, such as the anti-EGFR receptor monoclonal antibodies cetuximab and panitumumab, into treatment regimens has improved outcomes for patients with wild-type RAS tumors. Yet, response rates remain low and overall survival times are short. Increased understanding of oncogenic signaling pathways within the tumor, and how these are regulated by the inflammatory tumor microenvironment, is a priority to facilitate the development of biomarkers to better guide the use of existing therapies and to develop new ones. Here, we review recent preclinical and clinical progress in the development of biomarkers for predicting response to anti-EGFR therapy in metastatic colorectal cancer.
Biomarkers in Medicine 03/2015; 9(4):363-75. DOI:10.2217/bmm.15.5. · 2.65 Impact Factor
[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.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Gut 01/2015; 64(10). DOI:10.1136/gutjnl-2014-307873 · 14.66 Impact Factor
[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; DOI:10.1038/bjc.2014.367 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
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.
A retrospective study of 107 consecutive patients who had a DEB and subsequent wide local excision between January 2011 and June 2012 was performed. Mode of referral and dates of diagnostic biopsy/definitive surgery were documented. Patient demographics and tumour characteristics were reviewed.
The mean age was 59.6 years, and male:female ratio was 1:1.3. Median duration of the SI was 41 ± 27 days (range 6-137 days). The SI was increased when dermatologists performed the DEB as opposed to general surgeons (p = 0.035). The anatomic location of the lesion predicted the SI, with lesions of the head/neck undergoing definitive excision 48 ± 32.3 days after DEB vs. 37.5 ± 22.6 days for all other sites (p = 0.001). Neither demographic factors nor histopathological prognostic features affected the SI. Reasons for a prolonged SI included referrals to different services and time for pre-operative planning.
Significant variations were noted in the SI predominantly accounted for by mode of referral and location of the malignant melanoma. Further investigation is required to elucidate factors affecting the SI and its subsequent effect on patient outcomes.
Irish Journal of Medical Science 06/2014; 184(2). DOI:10.1007/s11845-014-1157-5 · 0.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AimThere is debate about 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. Method
We performed a retrospective review of all histological reports over a 19year period. All specimens were graded on haemataloxin and eosin appearance and those with dysplasia had immunohistochemistry for p16 and Ki67 performed. ResultsCases included 25 condyloma acuminata, 11 dysplastic cases and 24 invasive squamous cell carcinomas. On review, 18 were classified as condyloma acuminata without dysplasia. Seven had AIN I, five had AIN II and six had AIN III when using a three-tiered system. All cases classified as dysplastic (n=18) showed an increased proliferation index as measured by Ki67. p16 positivity was seen in all AIN III, two AIN II and none of the AIN I cases. Recurrence was not observed in any of the AIN I cases. Five of eleven AIN II and AIN III cases recurred or persisted at a similar, higher or lower grade. Both of the AIN II cases which recurred or persisted were p16 positive. None of the AIN II cases that were p16 negative recurred. Three of the p16-positive AIN III cases did not recur. None of the 18 AIN cases progressed to carcinoma. Conclusion
The findings support the slow progression of AIN as described in the literature. In our small series, a two-tiered system with further subclassification of the traditional AIN II group using p16 appears to be clinically useful.
[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).
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.
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.
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; 18(1). DOI:10.1007/s10151-013-0981-3 · 2.04 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.
[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.
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.
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. DOI:10.1016/j.ijscr.2012.11.024
[Show abstract][Hide abstract] ABSTRACT: The Editors welcome topical correspondence from readers relating to articles published in the Journal. Responses should be sent electronically via the BJS website (http://www.bjs.co.uk). All letters will be reviewed and, if approved, appear on the website. A selection of these will be edited and published in the Journal. Letters must be no more than 250 words in length. Copyright (c) 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
British Journal of Surgery 11/2012; 99(11):1601-2. DOI:10.1002/bjs.8947 · 5.54 Impact Factor
[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 07/2012; 99(7):993-1001. DOI:10.1002/bjs.8700 · 5.54 Impact Factor