Michael Thomas

Coordinated localisation of mucins and trefoil peptides in the ulcer associated cell lineage and the gastrointestinal mucosa

BACKGROUND AND AIMS Trefoil factor family (TFF) peptides and the chromosome 11p15.5 mucin glycoproteins are expressed and secreted in a site specific fashion along the length of the gastrointestinal tract. Evidence for coexpression of mucins and trefoil peptides has been suggested in numerous gastrointestinal mucosal pathologies. The ulcer associated cell lineage (UACL) occurs at sites of chronic ulceration in Crohns disease, expresses all three trefoil peptides, and is implicated in mucosal restitution. We tested the hypothesis that individual trefoil peptides are uniquely localised with specific mucins in the UACL and normal gastrointestinal epithelia. METHODS Expression of mucin genes in the UACL from small bowel tissue of patients with Crohns disease was detected by in situ hybridisation, and localisation of the products by immunohistochemistry. Colocalisation of mucins and trefoil peptides was demonstrated by immunofluorescent colabelling in UACL and normal gastrointestinal epithelia. RESULTS MUC5AC and TFF1 were colocalised in distal ductular and surface elements of the UACL and in foveolar cells of the stomach, whereas MUC6 and TFF2 were colocalised to acinar and proximal ductular structures in the UACL, in the fundus and deep antral glands of the stomach, and in Brunners glands of the duodenum. MUC5B was found sporadically throughout the UACL and gastric body. MUC2 was absent from the UACL, Brunners glands, and stomach. MUC2 and TFF3 were colocalised throughout the large and small bowel mucosa. CONCLUSIONS The UACL has a unique profile of mucin gene expression. Coordinated localisation of trefoil peptides and mucins in UACL and normal gastrointestinal epithelia suggests they may assist each others functions in protection and repair of gastrointestinal mucosa.

An evaluation of treatment decisions at a colorectal cancer multi-disciplinary team

Objectiveu2002 It is mandatory for treatment decisions for patients with colorectal cancer to be made within the context of a multi‐disciplinary team (MDT) meeting. It is currently uncertain, however, how to best evaluate the quality of MDT decision‐making. This study examined MDT decision‐making by studying whether MDT treatment decisions were implemented and investigated the reasons why some decisions changed after the meeting.

Differential expression of the chromosome 11 mucin genes in colorectal cancer

The four secretory mucin genes clustered on chromosome 11, MUC2, MUC5AC, MUC5B and MUC6, were screened in 37 patients with cancers in the left hemi‐colon or rectum and 10 normal rectal controls. The mucin genes were detected by in situ hybridization using oligonucleotide probes to the variable number tandem repeat (VNTR) sequences, while the proteins were stained with non‐VNTR (MUC2, MUC5AC and MUC5B) or VNTR (MUC6) antibodies. Low levels of MUC2u2009mRNA were detected in non‐mucinous adenocarcinomas (5/27) while a higher proportion of mucinous carcinomas (4/9) was positive. All 25 cases of adjacent normal tissue expressed MUC2u2009mRNA. No transcripts for MUC5AC, MUC5B or MUC 6 were detected in any of these specimens. MUC2 protein product was detected immunohistochemically in 34/36 carcinoma specimens, with no change from normal controls. There was de novo expression of MUC5AC in 23/36 carcinomas. No MUC5B or MUC6 protein was detected. No difference in MUC2 and MUC5AC protein was found between mucinous and non‐mucinous carcinomas. The level of MUC2 was increased in moderately differentiated cancers compared with normal controls and decreased in the poorly differentiated group. Decreased MUC2 was found in poorly differentiated compared with moderately differentiated tumours. More MUC5AC protein was detected in well and moderately differentiated tumours than in poorly differentiated tumours and in all tumours relative to controls. The pattern of MUC2 staining in cancers was different from control tissue, with strong staining in the perinuclear region and none in goblet cell vesicles. MUC5AC staining was mainly detected in the cytoplasm. Poor detection of MUC2 and MUC5AC mRNA and associated strong staining for the total protein suggests altered biosynthesis and processing, leading to the characteristic subcellular distribution. Hence, change in the synthesis of MUC2 and the de novo appearance of MUC5AC in colorectal carcinomas may be significant events in the adenoma‐carcinoma sequence, with possible implications for tumour prognosis. Copyright

Alterations in the Composition of the Supramucosal Defense Barrier in Relation to Disease Severity of Ulcerative Colitis

Mucin glycoproteins and trefoil peptides play an important role in protection and repair of the gastrointestinal epithelium. This study investigates alterations in mucin and trefoil peptide gene expression and product localization in ulcerative colitis (UC). Product localization and message expression of mucin MUC1 to 6 and trefoil peptide TFF1 to 3 genes was analyzed in rectosigmoid tissue from a cohort of patients with active UC and compared with that of normal colorectal mucosa. MUC1 expression was upregulated in severe UC at the site of rupture of crypt abscesses. Reduction in MUC2 expression occurred in UC adjacent to ulceration. No alteration in MUC3 or MUC4 gene expression was detectable in UC compared with normal colorectal mucosa. No ectopic expression of MUC5AC, MUC5B, or MUC6 was identified in UC. Ectopic TFF1 expression was identified in tissues eliciting histological features of severe disease. Decreased TFF3 localization was demonstrated in UC tissues, but no TFF2 expression was detected in any colorectal specimens. Subtle alterations in composition of the supramucosal defense barrier exist in UC and vary in relation to clinical severity of disease. There is upregulation in mucin MUC1 at crypt abscesses and neo-expression of TFF1 trefoil peptide in severe disease.

A systematic review of outcome reporting in colorectal cancer surgery

Evaluation of surgery for colorectal cancer (CRC) is necessary to inform clinical decision‐making and healthcare policy. The standards of outcome reporting after CRC surgery have not previously been considered.

Contrast-enhanced intraoperative ultrasound improves detection of liver metastases during surgery for primary colorectal cancer

BACKGROUNDnComputed tomography (CT) is the most common staging investigation in colorectal cancer (CRC). Up to 25% of patients are found to have previously undetected hepatic lesions when intraoperative ultrasound (IOUS) of the liver is used during CRC resection. We aimed to assess the ability of IOUS to detect additional liver lesions/metastases at primary colorectal resection, and to evaluate whether contrast-enhanced IOUS (CE-IOUS) improves the detection and characterization of hepatic lesions.nnnMETHODSnWe performed a single-centre, prospective pilot study. At CRC resection, patients underwent IOUS of the liver. Contrast-enhanced IOUS of the liver was undertaken using i.v. sulphur hexafluoride micro-bubbles (SonoVue, 4.8 ml). Findings of CT, non-enhanced IOUS and CE-IOUS were compared. Changes in staging or management were noted. Additional lesions were corroborated with iron oxide magnetic resonance imaging (MRI).nnnRESULTSnAmong 21 patients, IOUS demonstrated additional lesions in seven (33%). Contrast altered the diagnosis of non-enhanced IOUS in four (20%) and changed the management strategy in three (14%) patients. Thus, IOUS in combination with the contrast agent altered the intraoperative or postoperative management plan in four patients.nnnCONCLUSIONSnIn the first study of its kind, early results suggest that the ability of IOUS to detect additional metastases is improved by CE-IOUS, and that this may impact on surgical staging and management.

The role of colonoscopic endoanal ultrasound scanning (EUS) in selecting patients suitable for resection by transanal endoscopic microsurgery (TEM).

Objectiveu2003 This study was performed to assess the accuracy of colonoscopic endoanal ultrasound scanning (EUS) in the selection of patients with rectal neoplasia suitable for local excision by transanal endoscopic microsurgery (TEM). Our policy is to offer TEM to patients with premalignant (T0) lesions or with T1 tumours that have early disease.

Core Outcomes for Colorectal Cancer Surgery: A Consensus Study.

Background Colorectal cancer (CRC) is a major cause of worldwide morbidity and mortality. Surgical treatment is common, and there is a great need to improve the delivery of such care. The gold standard for evaluating surgery is within well-designed randomized controlled trials (RCTs); however, the impact of RCTs is diminished by a lack of coordinated outcome measurement and reporting. A solution to these issues is to develop an agreed standard “core” set of outcomes to be measured in all trials to facilitate cross-study comparisons, meta-analysis, and minimize outcome reporting bias. This study defines a core outcome set for CRC surgery. Methods and Findings The scope of this COS includes clinical effectiveness trials of surgical interventions for colorectal cancer. Excluded were nonsurgical oncological interventions. Potential outcomes of importance to patients and professionals were identified through systematic literature reviews and patient interviews. All outcomes were transcribed verbatim and categorized into domains by two independent researchers. This informed a questionnaire survey that asked stakeholders (patients and professionals) from United Kingdom CRC centers to rate the importance of each domain. Respondents were resurveyed following group feedback (Delphi methods). Outcomes rated as less important were discarded after each survey round according to predefined criteria, and remaining outcomes were considered at three consensus meetings; two involving international professionals and a separate one with patients. A modified nominal group technique was used to gain the final consensus. Data sources identified 1,216 outcomes of CRC surgery that informed a 91 domain questionnaire. First round questionnaires were returned from 63 out of 81 (78%) centers, including 90 professionals, and 97 out of 267 (35%) patients. Second round response rates were high for all stakeholders (>80%). Analysis of responses lead to 45 and 23 outcome domains being retained after the first and second surveys, respectively. Consensus meetings generated agreement on a 12 domain COS. This constituted five perioperative outcome domains (including anastomotic leak), four quality of life outcome domains (including fecal urgency and incontinence), and three oncological outcome domains (including long-term survival). Conclusion This study used robust consensus methodology to develop a core outcome set for use in colorectal cancer surgical trials. It is now necessary to validate the use of this set in research practice.

The routine use of intra-operative ultrasound in patients with colorectal cancer improves the detection of hepatic metastases

Introductionu2002 Up to one fifth of patients with carcinoma of the colon have occult liver metastases at the time of presentation. Intra‐operative hepatic ultrasonography might improve disease staging. We report the use of intra‐operative ultrasonography (IOUS) in routine clinical practice over a five‐year period.

Synthesis and summary of patient‐reported outcome measures to inform the development of a core outcome set in colorectal cancer surgery

Patient‐reported outcome (PRO) measures (PROMs) are standard measures in the assessment of colorectal cancer (CRC) treatment, but the range and complexity of available PROMs may be hindering the synthesis of evidence. This systematic review aimed to: (i) summarize PROMs in studies of CRC surgery and (ii) categorize PRO content to inform the future development of an agreed minimum ‘core’ outcome set to be measured in all trials.