Prevalence and long-term outcome of sub-clinical primary sclerosing cholangitis in patients with ulcerative colitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is closely associated with inflammatory bowel disease, particularly ulcerative colitis (UC), with an increased risk of biliary and colorectal malignancy. We sought to clarify the prevalence, characteristics and long-term outcome of sub-clinical PSC diagnosed by magnetic resonance cholangiogram (MRC) in patients with UC and normal liver biochemistry, with or without colorectal dysplasia (CRD). METHODS: In this prospective case-control study, 70 patients with UC and normal liver function (51 extensive UC, 19 CRD), 28 healthy volunteers (negative controls) and 28 patients with PSC and cholestasis (positive controls) underwent MRC and blood evaluation. MRC scans were interpreted blindly by two radiologists who graded individually, the scans as definitive for PSC, possible for PSC or normal. Clinical outcome was assessed by blood monitoring, abdominal imaging and endoscopic surveillance. RESULTS: 7/51 (14%) with extensive UC and 4/19 (21%) with CRD had biliary abnormalities on MRC consistent with PSC. 7/11 (64%) with sub-clinical PSC had isolated intrahepatic duct involvement. Sub-clinical PSC was associated with advanced age (P = .04), non-smoking (P = .03), pANCA (P = .04), quiescent colitis (P = .02), absence of azathioprine (P = .04) and high-grade CRD (P = .03). Inter-observer (kappa = 0.88) and intra-observer (kappa = 0.96) agreement for MRC interpretation was high. No negative controls were assessed as definite PSC, 4/28 were considered on blinding as possible PSC. During follow-up of sub-clinical PSC (median 10.1(3.1-11.9) years), four patients developed abnormal liver biochemistry, two had radiological progression of PSC and seven developed malignancy, including two biliary and one colorectal carcinoma. CONCLUSIONS: Prevalence of sub-clinical PSC appears high in patients with extensive UC and normal liver biochemistry, with or without CRD. Disease progression and malignancy were identified on long-term follow-up. MRC should be considered for all patients with extensive UC or CRD to stratify surveillance.

Challenging diagnostic issues in adenomatous polyps with epithelial misplacement in bowel cancer screening: 5 years' experience of the Bowel Cancer Screening Programme Expert Board.

The diagnostic difficulties of differentiating epithelial misplacement from invasive cancer in colorectal adenomatous polyps have been recognised for many years. Nevertheless, the introduction of population screening in the UK has resulted in extraordinary diagnostic problems. Larger sigmoid colonic adenomatous polyps, which are those most likely to show epithelial misplacement, are specifically selected into such screening programmes, because these polyps are likely to bleed and screening is based on the detection of occult blood. The diagnostic challenges associated with this particular phenomenon have necessitated the institution of an 'Expert Board': this is a review of the first five years of its practice, during which time 256 polyps from 249 patients have been assessed. Indeed, the Expert Board contains three pathologists, because those pathologists do not necessarily agree, and a consensus diagnosis is required to drive appropriate patient management. However, this study has shown substantial levels of agreement between the three Expert Board pathologists, whereby the ultimate diagnosis has been changed, from that of the original referral diagnosis, by the Expert Board for half of all the polyps, in the substantial majority from malignant to benign. In 3% of polyp cases, the Expert Board consensus has been the dual diagnosis of both epithelial misplacement and adenocarcinoma, further illustrating the diagnostic difficulties. The Expert Board of the Bowel Cancer Screening Programme in the UK represents a unique and successful development in response to an extraordinary diagnostic conundrum created by the particular characteristics of bowel cancer screening.

Beyond endoscopic mucosal healing in UC: histological remission better predicts corticosteroid use and hospitalisation over 6†years of follow-up.

BACKGROUND: Endoscopic mucosal healing is an established treatment target for UC, yet the value of achieving histological remission remains unclear. AIMS: To evaluate histological remission compared to endoscopic mucosal healing for predicting patient outcomes in UC. METHODS: Blinded assessment of endoscopic and histological measures of disease activity was performed on patients with established UC at baseline. Concordance and prognostic values of endoscopic mucosal healing (defined by Baron score ≤1) and histological remission (defined by Truelove and Richards' index) for predicting outcomes of corticosteroid use, hospitalisation and colectomy were determined over a median 6 years follow-up, including κ statistics and Cox regression multivariate analysis. RESULTS: 91 patients with UC were followed up for a median 72 months (IQR 54-75 months). Overall, concordance between endoscopic and histological remission was moderate (κ=0.56, 95% CI 0.36 to 0.77); 24% patients had persistent inflammation despite endoscopic remission. Histological remission predicted corticosteroid use and acute severe colitis requiring hospitalisation over the follow-up period (HR 0.42 (0.2 to 0.9), p=0.02; HR 0.21 (0.1 to 0.7), p=0.02; respectively), whereas endoscopic mucosal healing did not (HR 0.86, 95% CI 0.5 to 1.7, p0.65; HR 0.83 95% CI 0.3 to 2.4, p0.74; respectively). CONCLUSIONS: Histological remission is a target distinct from endoscopic mucosal healing in UC and better predicts lower rates of corticosteroid use and acute severe colitis requiring hospitalisation, over a median of 6 years of follow-up. Our findings support the inclusion of histological indices in both UC clinical trials and practice, towards a target of 'complete remission'.

Risk for colorectal neoplasia in patients with colonic Crohn's disease and concomitant primary sclerosing cholangitis.

BACKGROUND & AIMS: Patients with ulcerative colitis and concomitant primary sclerosing cholangitis (PSC) have a greater risk of developing colorectal dysplasia or invasive cancer than patients with only ulcerative colitis. Therefore, annual surveillance colonoscopies are recommended. We investigated whether primary sclerosing cholangitis is also a risk factor for colorectal dysplasia or cancer in patients with Crohn's disease of the colon. METHODS: We performed a retrospective review of data from a tertiary care hospital on 166 patients with PSC and inflammatory bowel disease; 120 had concomitant ulcerative colitis, 35 had Crohn's disease, and 11 had indeterminate colitis. The controls comprised 114 patients with colonic involvement of Crohn's disease and 102 patients with ulcerative colitis. The main outcome parameter was the development of colorectal cancer or intraepithelial neoplasia. RESULTS: Only 1 patient with colonic Crohn's disease and concomitant PSC developed dysplasia in an adenomatous polyp during a median follow-up of 10 years (range, 7-16 years). In contrast, 2 cancers and 8 cases of colorectal dysplasia were diagnosed in patients with ulcerative colitis and PSC during a median follow up of 11 years (range, 8-16 years); the crude annual incidence of dysplasia or colorectal cancer was 1 in 150 patients with ulcerative colitis. Among patients with colonic Crohn's disease without PSC, 2 developed colorectal cancer during follow-up. The presence of PSC did not increase the risk of developing colorectal dysplasia in patients with Crohn's disease (P = 1.00). CONCLUSIONS: PSC does not seem to increase the risk for dysplasia of the colon in patients with colonic Crohn's disease.

The connective tissue changes of Crohn's disease.

Although the inflammatory pathology of Crohn's disease is manifestly its most important attribute, the connective tissue changes are important in the genesis of the more chronic features of the disease, and yet these have received little attention from clinicians, pathologists, and scientists. Fat-wrapping appears to be pathognomonic of Crohn's disease, and is an important marker of disease for surgeons. There is evidence of a complex interplay between the effector inflammatory cells of Crohn's disease and adipocytes, hyperplasia of which results in fat-wrapping. Pathologically, this is exhibited in the close relationship between the transmural inflammation that is so characteristic of Crohn's disease and fat-wrapping. Fibrosis and muscularization are also important components of the chronic changes of intestinal Crohn's disease. Neuronal and vascular changes make up the remaining connective tissue changes: these constitute a distinctive feature, and are even specific for Crohn's disease. For pathologists, the combination of these connective changes will allow a diagnosis of chronic 'burnt-out' Crohn's disease, even in the absence of its highly characteristic inflammatory features. The connective tissue changes of Crohn's disease form an important part of its long-term pathology. They deserve more attention from clinicians, diagnostic pathologists and researchers alike.

The routine use of histochemical stains in gastrointestinal pathology: a UK-wide survey.

AIMS: A survey was conducted into the routine use of special stains on gastrointestinal (GI) biopsy specimens in histopathology departments within the National Health Service. The aim was to compare the sole use of haematoxylin and eosin (H&E) staining with the use of H&E and special stains, according to the biopsy site. METHODS AND RESULTS: One hundred and sixty-seven histopathology departments in the UK were contacted using an e-mail questionnaire. Valid return rate was 55%. Sixty-eight percent of departments employ H&E only for oesophageal biopsy specimens. Gastric specimens are stained using only H&E in 47% of departments and 53% use H&E combined with special stains. Duodenal, small and large bowel biopsy specimens are mostly stained with H&E. CONCLUSIONS: The results show that the routine use of special stains in GI pathology in the UK is highly variable, especially for oesophageal and gastric biopsy specimens. The literature indicates that special stains in GI specimens can enhance sensitivity and specificity for the detection of pathological abnormalities, especially metaplasia and infections. The diversity of staining practice highlights the need to provide robust and evidence-based guidelines for the routine use of special stains to ensure universal best practice.

Observer agreement in the diagnosis of serrated polyps of the large bowel.

AIMS: To assess observer agreement in the diagnosis of colorectal serrated polyps, in particular, serrated adenomas and admixed polyps (i.e. 'polyps with admixed hyperplastic and adenomatous glands'). METHODS AND RESULTS: Sixty cases of large bowel polyps were assessed by four specialist gastrointestinal histopathologists and allocated into one of five categories: serrated adenoma, hyperplastic polyp, conventional adenoma, admixed polyp, and other polyps with serration. Complete agreement amongst all four assessors was seen with only two-fifths of the cases. The overall kappa value for all the assessors distinguishing between all five categories was 0.49. The kappa values for diagnosing serrated adenoma versus all other polyps, and admixed polyp versus all other polyps were 0.38 and 0.3, respectively. CONCLUSIONS: Specialist gastrointestinal histopathologists show only moderate concordance when distinguishing between serrated colorectal polyps. There is only fair interobserver agreement in the diagnosis of serrated adenomas and admixed polyps of the large bowel.

Contribution of histological, serological, and genetic factors to the clinical heterogeneity of adult-onset coeliac disease.

OBJECTIVE: Although the factors predisposing to coeliac disease (CD) are largely understood, it remains unclear what determines the clinical heterogeneity of the disease. The aim of this study was to explore the contribution of histological, serological, and genetic factors to disease presentation. MATERIAL AND METHODS: The study was designed as a retrospective chart review of 384 unrelated Caucasian patients diagnosed with CD after the age of 16 at a single UK centre. RESULTS: We found that 8.8% of IgA-competent CD patients were endomysial antibody (EMA)-negative. Compared with the EMA-positive group, EMA-negative CD patients had a lower prevalence of iron deficiency (52.0% versus 72.6%, p=0.03) and Marsh IIIb-c lesions (66.7% versus 85.3%, p=0.03). Histological severity at diagnosis correlated with anaemia (p<0.01), folate deficiency (p<0.01), and iron deficiency (p=0.05), but no other laboratory or clinical features. Compared with human leucocyte antigen (HLA)-DQ2.5-positive patients, those carrying HLA-DQ2.2 were similar in terms of all the characteristics we considered, whereas those carrying HLA-DQ8 had a lower frequency of EMA positivity (62.5% versus 92.6%, p<0.01). The proportion of EMA-positive patients increased with frequency of the HLA-DQB1*0201 allele (76.7% versus 92.3% versus 96.4% for 0 versus 1 versus 2 alleles, p<0.01); no other evidence of a gene-dose effect of HLA-DQB1*0201 was observed. CONCLUSIONS: Histological severity at diagnosis of CD is associated with anaemia and some micronutrient deficiencies, but no other clinical features. The proportion of EMA-positive patients is higher amongst those carrying HLA-DQ2 than in those carrying HLA-DQ8, and is highest in HLA-DQ2 homozygotes. We found no correlation between frequency of the HLA-DQ alleles encoding HLA-DQ2.5 and CD severity.

Increased frequency of regulatory T cells in peripheral blood and tumour infiltrating lymphocytes in colorectal cancer patients.

Recent results have shown a correlation between survival and frequency of tumour infiltrating T lymphocytes in colorectal cancer patients. However, it remains unclear whether the frequency of regulatory T cells is higher in colorectal cancer as compared to normal colon. To address this question we analysed the frequency and function of regulatory T cells in the peripheral blood and tumour infiltrating lymphocytes of colorectal cancer patients. The proportion of regulatory T cells in the peripheral blood of colorectal cancer patients (mean 8%) was significantly higher than that in normal controls (mean 2.2%). There were significantly more regulatory T cells in tumour infiltrating lymphocytes (mean 19.2%) compared to lymphocytes from an autologous non-malignant portion of the colon (mean 9%). Regulatory T cells from colorectal cancer patients were FOXP3 positive and suppressed the proliferation of autologous CD4+ CD25- cells. A higher density of tumour infiltrating regulatory T cells was found in patients with advanced as compared to early disease. These results support the hypothesis that increased numbers of regulatory T cells in the blood and tumours of colorectal cancer patients may influence the immune response against cancer and suggest that strategies to overcome regulatory T cell activity may be beneficial in the treatment of human colorectal cancer.

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.

The pathology of diverticular disease.

Diverticular disease is common in the elderly Western population and its complications are frequent clinical presentations. Despite this, the pathogenesis of the condition remains relatively poorly understood. Several theories have been developed, the most acceptable suggesting elastosis of the taeniae coli as the primary event, causing shortening of the sigmoid colon, with relative mucosal excess and subsequent mucosal herniations. A Western-type diet is implicated in the increased uptake of proline from the gut, leading to elastosis of the sigmoid colon. For pathologists, in clinical practice, the disease is most commonly seen in sigmoid colonic resection specimens, usually performed for complications of the disease. It is now realised that mucosal biopsies of the luminal mucosa, in the sigmoid colon affected by diverticular disease, can produce perplexing pathological changes. In particular diverticular colitis can mimic both ulcerative colitis and Crohn's disease: care should be taken when diagnosing chronic inflammatory bowel disease on a background of diverticular disease. For pathologists, diverticular disease remains something of an enigma: although common, its pathogenesis remains ill-defined and its complications can provide diagnostic difficulties, which require precise clinical and radiological correlation.

The pattern and outcome of acute severe colitis.

BACKGROUND: The prognosis of acute severe ulcerative colitis (ASC) influences therapeutic decisions, but data on prevalence or long-term outcome are few. METHODS: A systematic review of all patients with UC diagnosed in Oxford was performed to assess the prevalence of ASC defined by Truelove and Witts' (TW) criteria and determine whether outcome is related to disease activity on admission, likelihood of recurrence and long-term prognosis. RESULTS: 750 patients (median follow up 12.7 yr, range 0-648 mo) met inclusion criteria out of a total cohort of 1853 patients. 24.8% (186/750) had at least one admission for ASC (294 admissions in 186 patients). Overall, 12% (93/750) had a colectomy, compared to 39.8% (74/186) of patients with one or more episodes of ASC (p<0.0001) and 3.4% (19/564) in those with no admission. The colectomy rate on first admission (37/186, 19.9%) was lower than on the second or subsequent admissions (OR 2.35, 95% CI 1.33-4.14, p=0.003), being 29.0%, 36.6%, 38.2% after two, three, or subsequent episodes respectively. It was 8.5% (11/129) if patients had one TW criterion in addition to ≥6 bloody bowel motions/day, compared to 31% (29/94) if two additional criteria were present and 48% (34/71) if three or more additional criteria were present (p=1.4 × 10⁻5; OR 4.35, 95% CI 2.20-8.56 one criterion vs two or more). CONCLUSIONS: A quarter of all patients with ulcerative colitis experience at least one episode of ASC; 20% come to colectomy on first admission, but 40% after two admissions. The likelihood of colectomy is related to biological severity on admission.

The role of CMV in steroid-resistant ulcerative colitis: A systematic review.

BACKGROUND AND AIMS: Steroid-resistance presents a management challenge in ulcerative colitis. How steroid-resistance occurs is unknown, but cytomegalovirus infection, often unrecognised, may be the cause in some patients. Current evidence and therapeutic recommendations are examined. METHODS: A systematic review of PubMed and EMBASE databases was performed. Search and exclusion criteria are defined in the text. RESULTS: Heterogeneity of experimental design and definitions of key terms were notable. Criteria for cytomegalovirus disease, infection or detection varied, as did definitions of steroid-resistance. CMV infection defined by antigenaemia or serology was common in patients on steroids and associated with a higher rate of steroid-resistance (41.66-61% versus 0-68% in steroid-responsive patients). Colonic mucosal cytomegalovirus disease detected by histopathology was associated with intravenous steroid-resistance in 5-36%, compared to 0-10% of steroid-responsive patients. CMV colitis has rarely been reported in association with ulcerative colitis without steroids or other immunomodulators. CMV colitis in healthy individuals is so exceptional as to be the topic of case reports. CONCLUSION: Ulcerative colitis and its treatment put patients at risk of CMV infection or reactivation. A distinction is necessary between CMV disease (colitis) and CMV infection. Only colonic mucosal CMV infection detected by histopathology appears clinically relevant and appropriate for antiviral therapy. CMV antigenaemia may be associated with steroid-resistance, but may also be a self-limiting marker of viral reactivation. The impact of CMV on steroid-resistance is complicated by inconsistencies in the literature. Coherent definitions of clinically relevant CMV infection and steroid-resistance are needed.

Obstructing giant post-inflammatory polyposis in ulcerative colitis: Case report and review of the literature.

BACKGROUND: Post-inflammatory polyps >15 mm in diameter or length are termed "giant". This benign and rare sequel of ulcerative colitis or colonic Crohn's disease can mimic colorectal carcinoma. OBJECTIVE: To illustrate this rare complication of inflammatory bowel disease and outline the characteristic radiological, endoscopic and histopathological features, by reviewing all previously published cases of giant post-inflammatory polyps in the English literature. RESULTS: Reports of 81 giant post-inflammatory polyps in 78 patients were identified by systematic review of the literature. The incidence of giant post-inflammatory polyps is related to the extent of ulcerative colitis (incidence: 0%, 30%, and 70%, in proctitis, left-sided, and extensive disease, respectively). These lesions are typically located in the transverse or descending colon. Giant post-inflammatory polyps are as common in Crohn's disease (n=36) as in ulcerative colitis (n=42, 54%). Clinical presentations varies, including pain (n=29), rectal bleeding (n=20), diarrhoea (n=19), luminal obstruction (n=15), or a palpable mass (n=11). Symptomatic presentation results in surgical resection. Clinical details and outcomes are comprehensively tabulated. CONCLUSION: Recognition of this rare entity will prevent unnecessary radical surgical resection for presumed carcinoma. It highlights the need for clinical, radiological, endoscopic and histopathological correlation.

Clinical and molecular characteristics of isolated colonic Crohn's disease.

BACKGROUND: Clinical, serological, and molecular data support the existence of discrete subsets of Crohn's disease (CD) defined by location of disease. Little is known about the epidemiology and natural history of isolated CD of the colon (Montreal Classification L2) because most studies have not accurately distinguished it from ileocolonic disease. Our objectives were to describe the clinical features and natural history of isolated colonic CD in a rigorously characterized patient cohort and to investigate the association of polymorphisms in a number of genes with colonic location of disease and disease behavior. METHODS: Patients with L2 disease were identified from a database of 675 CD patients. Only patients with a normal small bowel enema (70%), ileoscopy alone (30%), or both (20%) were included. Genotyping was performed using PCR-SSP or the iPLEX platform. RESULTS: In all, 135 patients were classified with L2 disease. L2 disease was more common in women (74.0% versus 58.0%; P = 0.0004; odds ratio [OR] = 2.11, 95% confidence interval [CI] 1.36-3.26) and in never smokers (48.9% versus 36.9%; P = 0.008; OR = 1.64, 95% CI 1.09-2.45); 20.7% underwent colonic resection for severe disease. We confirmed that carriage of the HLA-DRB1*0103 allele is strongly associated with isolated colonic CD (14.9% versus 4.0%; P = 0.000016; OR 4.6, 95% CI 2.25-9.47) and report the novel association of this allele with time to first surgical event (log rank P = 0.001). There was no association with any of the known CD susceptibility loci (NOD2, IBD5, NOD1, IL23R, ATG16L1) and isolated colonic CD. A nonsynonymous polymorphism in MEKK1 (rs832582) was associated with CD susceptibility overall (15% versus 19%; P = 0.0083; OR = 1.28, 95% CI 1.07-1.54). The association was strongest in those patients not carrying a NOD2 mutation and had no effect on disease location. CONCLUSIONS: This study describes the clinical features of isolated colonic CD and demonstrates the importance of the HLA region in determining the molecular basis of colonic inflammation.

Outcome measurement in clinical trials for Ulcerative Colitis: towards standardisation.

Clinical trials on novel drug therapies require clear criteria for patient selection and agreed definitions of disease remission. This principle has been successfully applied in the field of rheumatology where agreed disease scoring systems have allowed multi-centre collaborations and facilitated audit across treatment centres. Unfortunately in ulcerative colitis this consensus is lacking. Thirteen scoring systems have been developed but none have been properly validated. Most trials choose different endpoints and activity indices, making comparison of results from different trials extremely difficult. International consensus on endoscopic, clinical and histological scoring systems is essential as these are the key components used to determine entry criteria and outcome measurements in clinical trials on ulcerative colitis. With multiple new therapies under development, there is a pressing need for consensus to be reached.

Use of a monoclonal antibody to sucrase-isomaltase for evaluation of the columnar cuff after stapled restorative proctocolectomy.

PURPOSE: Restorative proctocolectomy with a double-stapled pouch-anal anastomosis retains a cuff of diseased columnar mucosa (columnar cuff) in the upper anal canal that may require biopsy. Biopsying this can be difficult and colonic phenotypic change in the pouch can lead to errors interpreting the histology. This study was designed to investigate the use of a monoclonal antibody to sucrase-isomaltase for differentiating ileal pouch from columnar cuff mucosa. Then, by using this antibody, the ability to accurately take and report biopsies from the anal canal was examined. METHODS: The technique of staining for sucrase-isomaltase was developed. From 113 patients who had a double-stapled pouch-anal anastomosis, 467 formalin-fixed biopsies and 177 fresh-frozen biopsies were taken from the ileal pouch, columnar cuff, or anal transitional zone. Biopsies were stained with a monoclonal antibody to sucrase-isomaltase, and fixed biopsies were routinely reported after staining with hematoxylin and eosin. RESULTS: A monoclonal antibody to sucrase-isomaltase reliably discriminated between ileal from rectal mucosa. A biopsy of columnar cuff mucosa as reported by routine histology was obtained during 72 percent of attempted outpatient examinations. Sucrase-isomaltase staining of reported columnar cuff biopsies showed that biopsies were of pouch rather than columnar cuff in 4.4 percent (95 percent confidence interval, 2-8) of outpatient examinations. CONCLUSIONS: The monoclonal antibody to sucrase-isomaltase used in this study may have a clinical role when interpreting columnar cuff biopsies from patients being investigated for pouch dysfunction, or in patients having surveillance biopsies to exclude neoplasia in the columnar cuff.

Modulation of CD103 expression on human colon carcinoma-specific CTL.

Recent results have shown a correlation between survival and frequency of tumor-infiltrating T cells in colorectal cancer patients. However, the mechanisms controlling the ability of human T lymphocytes to infiltrate colon carcinoma remain unclear. Although, it is known that expression of the integrin CD103alpha(E)/beta(7) by intraepithelial lymphocytes controls the retention of lymphocytes in epithelial layers, very little is known about the expression of intestinal homing receptors in human T lymphocytes. In particular, it remains unknown whether expression of CD103/beta(7) by human colon cancer-specific T lymphocytes is controlled by recognition of tumor Ags and is imprinted during T cell priming, facilitating its expression during memory T cell activation. In this study, we demonstrate that expression of CD103/beta(7) in human colon carcinoma-specific CTL is synergistically enhanced by the simultaneous TGF-beta1 stimulation and Ag recognition. These results were confirmed by using a panel of human CTL clones. Finally, we show that priming of naive CD8(+) T cells in the presence of TGF-beta1 ensures up-regulation of CD103/beta(7) in recall responses, at concentrations of TGF-beta1 significantly lower than those required by memory T cells primed in the absence of TGF-beta1. These results indicate a role of TGF-beta1 during T cell priming in modulating expression of CD103/beta(7) and controlling retention of human memory CD8(+) T cells into tumor epithelium.

Denonvilliers' fascia lies anterior to the fascia propria and rectal dissection plane in total mesorectal excision.

PURPOSE: Opinion is divided whether Denonvilliers' fascia lies anterior or posterior to the anatomic fascia propria plane of anterior rectal dissection in total mesorectal excision. This study was designed to evaluate this anatomic relationship by assessing the presence or absence of Denonvilliers' fascia on the anterior surface of the extraperitoneal rectum in specimens resected for both nonanterior and anterior rectal cancer in males. METHODS: Surgical specimens were collected prospectively from males undergoing total mesorectal excision for mid and low rectal cancer, with a deep dissection of the anterior extraperitoneal rectum to the pelvic floor. Specimens were histopathologically analyzed using best practice methods for rectal cancer. The anterior aspects of the extraperitoneal rectal sections were examined microscopically for the presence or absence of Denonvilliers' fascia. RESULTS: Thirty rectal specimens were examined. Denonvilliers' fascia was present in 12 (40 percent) and absent in 18 specimens (60 percent). Denonvilliers' fascia was significantly more frequently present when tumor involved (55 percent) rather than spared the anterior rectal quadrant (10 percent; difference between groups 45 percent; 95 percent confidence interval, 30-60 percent; P = 0.024, Fisher's exact test). CONCLUSIONS: When tumors were nonanterior, rectal dissection was conducted on fascia propria in the usual anatomic plane, and Denonvilliers' fascia was not present on the specimen. It was almost exclusively found in anterior tumors, deliberately taken by a radical extra-anatomic anterior dissection in the extramesorectal dissection plane. Denonvilliers' fascia lies anterior to the anatomic fascia propria plane of anterior rectal dissection and is more closely applied to the prostate than the rectum.