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Biomedical subjects

N A Shepherd

Publications and source records attributed to N A Shepherd.

At least 19 recordsLinked to original sources
PubMed2007

Indeterminate colitis: definition, diagnosis, implications and a plea for nosological sanity.

In 1978, Price introduced the concept of indeterminate colitis to describe cases in which colonic resections had been undertaken for chronic inflammatory bowel disease (CIBD), but a definitive diagnosis of either of the classical types of CIBD, ulcerative colitis and Crohn's disease, was not possible. This was especially apposite in cases of acute fulminant disease of the colorectum. More recently, the term indeterminate colitis has been applied to biopsy material, when it has not been possible to differentiate between ulcerative colitis and Crohn's disease. In our opinion, and in those of other workers in this field, the term should be restricted to that originally suggested by Price. This then provides a relatively well-defined group of patients in whom the implications and management of the disease are becoming much clearer. Cases where there are only biopsies with CIBD, but equivocal features for ulcerative colitis and Crohn's disease, should be termed 'CIBD, unclassified', 'equivocal/non-specific CIBD' or IBD unclassified (IBDU), in line with recent recommendations. When the diagnosis is correctly restricted to colectomy specimens, there is now good evidence that the majority of cases will behave like ulcerative colitis. Furthermore, the diagnosis should not be a contraindication to subsequent pouch surgery. When the latter is undertaken, surgeons and patients can expect an increased complication rate, compared with classical ulcerative colitis, especially of pelvic sepsis, but most patients fare well. Only very occasional patients, around 10%, will eventually be shown to have Crohn's disease. This review describes the pathology of cases appropriately classified as indeterminate colitis and the implications of that diagnosis. It also highlights recent advances in its pathological features, clinical management and its immunological and genetic associations.

Biopsy↗
PubMed2006

Basiliximab for the treatment of steroid-resistant ulcerative colitis: further experience in moderate and severe disease.

BACKGROUND: Preliminary data have suggested that interleukin-2 receptor blockade with basiliximab may increase steroid sensitivity. We have previously reported a small case series demonstrating the potential of basiliximab as a novel agent for the treatment of steroid-resistant ulcerative colitis. AIM: To report further experience of the efficacy and safety of treatment with the interleukin-2 receptor blocking monoclonal antibody basiliximab, in addition to steroids, for the treatment of severe and moderate steroid-resistant ulcerative colitis. METHODS: Twenty patients were enrolled - 13 patients with moderate steroid-resistant ulcerative colitis (Ulcerative Colitis Symptom Score: >or=6) and seven patients with severe steroid-resistant ulcerative colitis. All were given a single dose of 40 mg basiliximab plus standard steroid therapy in an open-label, uncontrolled trial. Primary end point was clinical remission within 8 weeks (Ulcerative Colitis Symptom Score: <or=2). RESULTS: Within 8 weeks, 10 of 20 (50%) patients achieved clinical remission (seven of 13 moderate, and three of seven severe). At 24 weeks, 13 of 20 (65%) patients were in clinical remission. Five patients required colectomy (four severe, one moderate ulcerative colitis) and one required rescue ciclosporin (moderate ulcerative colitis). Two patients developed herpes zoster, but treatment was generally well tolerated. CONCLUSIONS: Basiliximab appears to promote prolonged remission after a single treatment. Taken in combination with previously reported data, basiliximab shows particular promise in moderate steroid-resistant ulcerative colitis.

Adolescent↗
PubMed2005

Serosal involvement in gastrointestinal cancer: its assessment and significance.

There is an increasing burden upon diagnostic histopathologists to identify accurately factors of prognostic and therapeutic implication in gastrointestinal cancer. It is perhaps partly because of the use of rigid sequential staging systems, such as the Dukes' classification, that some factors, perhaps most notably involvement of surgical margins (especially in rectal cancer) and serosal involvement (particularly in oesophageal, colonic and rectal cancer), have been relatively neglected until more recently. This is surprising and concerning because both of these pathologically derived parameters strongly correlate with subsequent locoregional recurrence and, ultimately, with prognosis. Whilst the occurrence and significance of serosal involvement have been well recognized in gastric cancer for many years, relatively little attention has been paid to the phenomenon in oesophageal cancer and yet both pleural and peritoneal involvement may be comparatively commonly identified in oesophageal cancer. Serosal involvement and transperitoneal spread are also of considerable prognostic importance in primary appendiceal carcinoma. Only more recently has the significance of serosal involvement been appreciated in colonic and rectal cancer. In the colon, the phenomenon is now recognized to be one of the most important factors in predicting transperitoneal spread and overall prognosis. Furthermore, there is increasing interest in alternative novel strategies, including intraperitoneal chemotherapy and radical peritoneal surgery, as legitimate therapeutic options in many gastrointestinal cancers.

Gastrointestinal Neoplasms↗
PubMed2004

Lymph node harvests directly influence the staging of colorectal cancer: evidence from a regional audit.

AIMS: To assess the quality of histopathology reporting and accuracy of Dukes's staging of colorectal cancers in the former South Western Health region and to determine the impact of numbers of lymph nodes examined on stage ascription. METHODS: Histopathology reports of colorectal cancer for 1993-7 were analysed. Completeness was assessed regarding reported numbers of lymph nodes examined, numbers found positive, Dukes's stage, and ICD9 code. Numbers of lymph nodes examined, numbers found positive, and Dukes's stage were recorded. Results from one hospital known to have high standards of reporting were compared with those from elsewhere. RESULTS: In total, 629 reports were examined from the reference hospital and 918 from elsewhere. Fewer than one in 20 (4.3%) reports from the reference hospital were incomplete, compared with a third (36.1%) elsewhere. The average number of nodes examined for each case at the reference hospital was 18.81 and 6.41 elsewhere. The average number of positive nodes for each case was 2.47 at the reference hospital and 1.15 elsewhere. The proportion of Dukes's stage C cases was significantly higher at the reference hospital than elsewhere. Ascertainment of Dukes's stage C cases was related to number of lymph nodes examined, with optimal ascertainment levels when at least 10 and fewer than 15 nodes were examined. CONCLUSIONS: Standards of histopathology reporting, and ascertainment of Dukes's stage C, were significantly higher at the reference hospital. Variations in ascertainment levels of Dukes's stage C disease mainly resulted from variations in the numbers of lymph nodes examined.

Colorectal Neoplasms↗
PubMed2003

Basiliximab (anti-CD25) in combination with steroids may be an effective new treatment for steroid-resistant ulcerative colitis.

BACKGROUND: Steroid resistance represents a major clinical problem in the treatment of ulcerative colitis. In vitro, interleukin-2 renders lymphocytes steroid resistant. AIM: To explore the therapeutic potential of interleukin-2 receptor blockade in steroid-resistant ulcerative colitis with both in vitro measures and a pilot in vivo study. METHODS: Ten patients with steroid-resistant ulcerative colitis received a single bolus of 40 mg of intravenous basiliximab plus steroid treatment in an open-label, uncontrolled, 24-week study. The outcome was assessed using the Ulcerative Colitis Symptom Score, rectal biopsy and Inflammatory Bowel Disease Questionnaire. Lymphocyte steroid sensitivity was measured in vitro in 39 subjects in the presence or absence of basiliximab. RESULTS: Nine of the 10 patients achieved clinical remission within 8 weeks. At 24 weeks, seven patients were in clinical remission. Marked improvement in the Ulcerative Colitis Symptom Score was seen by 1 week (P = 0.004) and on rectal biopsy and Inflammatory Bowel Disease Questionnaire by 2 weeks (both P < 0.05). Improvements persisted to 24 weeks (Ulcerative Colitis Symptom Score, Inflammatory Bowel Disease Questionnaire, both P < 0.005). Eight of the nine responders relapsed (median, 9 weeks), but remission was re-achieved with further corticosteroids and the addition of azathioprine. At 24 weeks, seven patients were in full clinical remission, five off all steroid therapy. In vitro measurement of lymphocyte steroid sensitivity demonstrated steroid resistance in 22% of subjects. All were rendered steroid sensitive in the presence of basiliximab. CONCLUSIONS: Basiliximab appears to be effective at inducing remission in steroid-resistant ulcerative colitis. In vitro, basiliximab also produced a dramatic increase in lymphocyte steroid sensitivity in healthy subjects. Confirmation in randomized controlled studies is required.

Adult↗
PubMed2003

Epstein-Barr virus infection in colorectal neoplasms associated with inflammatory bowel disease: detection of the virus in lymphomas but not in adenocarcinomas.

Epstein-Barr virus (EBV) is associated with several lymphoid and epithelial human malignancies. The latter include gastric adenocarcinomas, while sporadic colorectal adenocarcinomas (CRCs) have been reported to be EBV-negative. Recently, increased numbers of EBV-infected B lymphocytes have been detected in intestinal mucosal samples affected by ulcerative colitis (UC) and, to a lesser extent, Crohn's disease (CD). Both CRC and colorectal non-Hodgkin's lymphoma (NHL) are recognized complications of inflammatory bowel disease (IBD), but it is unclear to what extent EBV contributes to the development of these neoplasms. Seventeen cases of IBD-associated CRC and nine cases of IBD-associated colorectal NHL were therefore studied for the presence of EBV by in situ hybridization. EBV-positive cases were further studied for the expression of the EBV-encoded nuclear antigen (EBNA) 2 and the latent membrane protein (LMP) 1 of EBV by immunohistochemistry. Four out of seven cases of colorectal NHL associated with UC were shown to be EBV-positive. In addition, two of two colorectal NHLs developing in patients with CD were EBV-positive. Of the EBV-positive lymphomas, three displayed a pattern of EBV latent gene expression consistent with type I latency (EBNA2(-)/LMP1(-)), two a type II pattern (EBNA2(-)/LMP1(+)), and one a type III pattern (EBNA2(+)/LMP1(+)). These findings suggest that EBV infection is involved in the pathogenesis of a proportion of colorectal NHLs developing in IBD. Iatrogenic immunosuppression may contribute to the development of these lymphomas. By contrast, all 17 IBD-associated CRCs were EBV-negative, including a case of CRC occurring synchronously with an EBV-positive NHL. In conjunction with previous reports on sporadic CRCs, this suggests that EBV is not involved in the pathogenesis of CRC.

Adenocarcinoma↗
PubMed2003

Colorectal mass lesions masquerading as chronic inflammatory bowel disease on mucosal biopsy.

AIMS: We bring to the attention of diagnostic pathologists a further cause of mimicry of chronic inflammatory bowel disease on mucosal biopsy, namely intramural and subserosal colorectal mass lesions. METHODS AND RESULTS: In a 10-year prospective study in one centre, we describe 26 cases in which the initial colonoscopic biopsies suggested a diagnosis of chronic inflammatory bowel disease, whereas subsequent information indicated that the mucosal changes were due to underlying mass lesions, without evidence of chronic inflammatory bowel disease. These mass lesions included underlying primary adenocarcinoma, metastatic carcinoma, pneumatosis, endometriosis and complicated diverticular disease. CONCLUSIONS: In the colon and rectum, intramural and subserosal mass lesions are a significant cause of chronic inflammatory bowel disease mimicry. Possible pathogenic mechanisms include mechanical effects, lymphatic obstruction by underlying tumour, relative mucosal ischaemia and mucosal prolapse. Since the changes seen on mucosal biopsies are a secondary phenomenon, we tentatively suggest that 'secondary colitis' may be an appropriate appellation.

Adenocarcinoma↗
PubMed2002

Primary endometrioid adenocarcinoma of the large intestine arising in colorectal endometriosis.

AIMS: Three cases of endometrioid adenocarcinoma arising in colorectal endometriosis are described with discussion of their macroscopic and microscopic pathology and diagnosis, using immunohistochemistry. METHODS AND RESULTS: Three middle-aged women presented with symptoms and signs of colorectal mass effect. Two had a preceding history of gynaecological endometriosis and all three had either been on hormone replacement therapy or had functioning ovaries prior to presentation with colorectal disease. Each underwent resection of tumours of the distal large intestine. The definitive diagnosis was dependent on histological examination and immunohistochemistry, which was used to demonstrate an origin in endometriotic tissue. CONCLUSIONS: Endometrioid adenocarcinoma is a rare complication of colorectal endometriosis, this report contributing to a total of 25 cases in the literature. Definitive diagnosis, aided by immunohistochemical studies, is important to enable the identification of the optimal management for this uncommon condition.

Biomarkers, Tumor↗
PubMed2002

What is diverticular colitis?

Diverticular colitis is the term used to describe a particular pattern of active chronic inflammation in the sigmoid colon affected by diverticular disease, namely the occurrence of luminal mucosal inflammation, whether or not there is evidence of inflammation within and/or around the diverticula themselves. The pathogenesis remains uncertain but is almost certainly multifactorial. In some cases mucosal prolapse, faecal stasis and relative mucosal ischaemia have been implicated as important pathogenetic factors, whilst other cases are clearly the result of a mass effect caused by subserosal peridiverticulitis and suppuration. Symptoms and endoscopic findings are diverse. Histologically, the disease may vary from modest inflammatory changes with vascular ectasia, through classical mucosal prolapse changes, to florid active chronic inflammation, closely mimicking chronic inflammatory bowel disease, especially ulcerative colitis. Thus, accurate clinical and endoscopic correlation is vital for the attainment of the correct diagnosis. Diverticular colitis may respond well to treatment similar to that used for chronic inflammatory bowel disease, adding to the similarities of this disease, notably localised to the sigmoid colon, and ulcerative colitis. Indeed, in a few cases described in the literature, diverticular colitis may 'progress' to otherwise classical ulcerative colitis, suggesting, in some cases at least, a similar pathogenesis.

Chronic Disease↗
PubMed2002

An insight into the genetic pathway of adenocarcinoma of the small intestine.

BACKGROUND: Although the adenoma to carcinoma pathway in colorectal cancer is well described, the mechanisms of carcinogenesis in the small intestine remain unclear. AIMS: The aim of this study was to investigate candidate genes in the genetic pathway of adenocarcinoma of the small intestine. SUBJECTS AND METHODS: A total of 21 non-familial, non-ampullary adenocarcinomas of the small intestine were analysed. DNA was extracted from formalin fixed paraffin wax embedded tissue using standard techniques. The replication error (RER) status was determined by amplification of BAT26. The mutation cluster region (MCR) of the adenomatous polyposis coli (APC) gene was screened using polymerase chain reaction single strand conformational polymorphism and direct sequencing. Immunohistochemistry was performed on formalin fixed paraffin wax embedded tissue using monoclonal antibodies for hMLH1, hMSH2, beta-catenin, E-cadherin, and p53. RESULTS: Fourteen male and seven female patients with a median age of 64 years (range 21-85) presented with adenocarcinoma of the duodenum (10), jejunum (7), and ileum (4). One cancer (5%) was found to be RER+, and all tumours stained positive for hMLH1 and hMSH2. No mutations were detected in the MCR of the APC gene. beta-Catenin showed increased nuclear expression with loss of membranous staining in 10 cancers (48%). Absent or decreased membrane expression of E-cadherin was found in eight cancers (38%). Strong staining of p53 was found in the nucleus of five cancers (24%). CONCLUSION: We did not detect mutations in the MCR of the APC gene, and this suggests that adenocarcinoma of the small intestine may follow a different genetic pathway to colorectal cancer. Abnormal expression of E-cadherin and beta-catenin was common and reflects an early alternative to APC in this pathway in which mutations may be found in adenocarcinoma of the small intestine.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Identification of objective pathological prognostic determinants and models of prognosis in Dukes' B colon cancer.

BACKGROUND AND AIMS: There is a need for objective easily determined pathological prognostic parameters in Dukes' B colon carcinoma to allow selection of such patients for further treatment as the role of adjuvant chemotherapy for these patients remains unclear. This study was initiated to assess the influence of pathological factors on prognosis in an unselected prospective series of Dukes' B colonic cancer. METHODS: The Gloucester Colorectal Cancer study, established in 1988, recruited more than 1000 cases. Meticulous pathological assessment of the 268 Dukes' B colonic cancer resections in this series included evaluation of all pathological factors that could influence staging and prognosis. All patients entered a comprehensive follow up system. RESULTS: Four pathologically determined factors--peritoneal involvement, venous spread (both submucosal and extramural), spread to involve a surgical margin, and perforation through the tumour-were independent prognostic factors in multivariate analysis. Combining these four factors into a simple cumulative scoring system generated clinically useful prognostic groups. CONCLUSIONS: The cumulative prognostic index allows apportionment of patients with Dukes' B colon cancer into defined prognostic groups, which in turn could allow more objective selection of patients for adjuvant therapy, especially as part of clinical trials.

Adult↗
PubMed2001

The significance of cagA(+) Helicobacter pylori in reflux oesophagitis.

BACKGROUND: Helicobacter pylori is a gastroduodenal pathogen associated with ulceration, dyspepsia, and adenocarcinoma. Recent preliminary studies have suggested that H pylori may be protective for oesophageal adenocarcinoma. In addition, strains of H pylori identified by the presence of the cytotoxin associated gene A (cagA) are shown to have a significant inverse association with oesophageal adenocarcinoma. Given that cagA(+) H pylori may protect against oesophageal carcinoma, these strains may be protective for oesophagitis, a precursor of oesophageal carcinoma. AIMS: The aim of this study was to investigate the association between cagA(+) H pylori and endoscopically proved oesophagitis. PATIENTS: The study group included 1486 patients attending for routine upper gastrointestinal tract endoscopy. METHODS: At endoscopy the oesophagus was assessed for evidence of reflux disease and graded according to standard protocols. Culture and histology of gastric biopsy specimens determined H pylori status. The prevalence of cagA was identified by an antibody specific ELISA (Viva Diagnostika, Germany). RESULTS: H pylori was present in 663/1485 (45%) patients and in 120/312 (38%) patients with oesophagitis. Anti-CagA antibody was found in 499/640 (78%) H pylori positive patients. Similarly, anti-CagA antibody was found in 422/521 (81%) patients with a normal oesophagus and in 42/60 (70%) with mild, 24/35 (69%) with moderate, and 11/24 (46%) with severe oesophagitis. The risk of severe oesophagitis was significantly decreased for patients infected with cagA(+) H pylori after correction for confounding variables (odds ratio 0.57, 95% confidence interval 0.41-0.80; p=0.001). CONCLUSIONS: These results suggest that infection by cagA(+) H pylori may be protective for oesophageal disease.

Adult↗
PubMed2001

Expression of the p53 homologue p63alpha and DeltaNp63alpha in the neoplastic sequence of Barrett's oesophagus: correlation with morphology and p53 protein.

BACKGROUND: While loss of p53 function is a key oncogenic step in human tumorigenesis, mutations of p53 are generally viewed as late events in the metaplasia-dysplasia-adenocarcinoma sequence of Barrett's oesophagus. Recent reports of a series of genes (p63, p73, and others) exhibiting close homology to p53 raise the possibility that abnormalities of these p53 family members may exert their influence earlier in the sequence. AIM: Following recent characterisation of expression of p63 and a major isoform DeltaNp63 by generation of an antiserum that recognises p63 isoforms, but not p53, our aim was a comparative study of expression of p63 protein and p53 protein in a morphologically well defined biopsy series representative of all stages of the metaplasia-dysplasia-carcinoma sequence in Barrett's oesophagus. METHODS: A series of 60 biopsy cases representing normal oesophagus through to invasive adenocarcinoma were stained, using immunohistochemistry, with antibodies to p63 and p53. All biopsies derived from patients with endoscopic and histopathological substantiation of a diagnosis of traditional/classical Barrett's oesophagus. RESULTS: There was exact concordance in p53 and p63 expression in more advanced forms of neoplasia, high grade dysplasia, and invasive adenocarcinoma, while p63, but not p53, was detected in the proliferative compartment of some non-neoplastic oesophageal tissue, in both squamous mucosa and in the non-neoplastic metaplastic glandular epithelium. CONCLUSIONS: In neoplastic Barrett's oesophagus there is upregulation of both p63 and p53 while p63 isoforms may well have an important role in epithelial biology in both non-metaplastic and metaplastic mucosa of the oesophagus. While abnormalities of p53 function represent an indisputable and critical element of neoplastic transformation, other closely linked genes and their proteins have a role in both the physiology and pathophysiology of the oesophageal mucosa.

Adenocarcinoma↗
PubMed2000

What is the significance of muciphages in colorectal biopsies? Muciphages and other mucosal accumulations in the colorectal mucosa.

Muciphages (mucin-containing macrophages), first described in 1966 by Azzopardi & Evans, are a common feature of biopsies of large intestinal mucosa, even in the absence of other abnormalities such as active inflammation or evidence of chronic inflammatory bowel disease. Should they be mentioned in diagnostic reports? Do muciphages reliably indicate previous mucosal disease, now quiescent? In the following articles, Salto-Tellez & Price review what is known about muciphages and conclude that they reflect previous occult and clinically unimportant mucosal damage and that, in an otherwise normal colorectal mucosa, they have no diagnostic significance; and Shepherd draws attention to a wide range of clinically much more significant mucosal infiltrates that could be mistakenly regarded as muciphages and thus overlooked.

Biopsy↗