Individuals with unilateral transtibial amputation exhibit reduced accuracy and precision during a targeted stepping task.

Accurate foot placement is important for dynamic balance during activities of daily living. Disruption of sensory information and prosthetic componentry characteristics may result in increased locomotor task difficulty for individuals with lower limb amputation. This study investigated the accuracy and precision of prosthetic and intact foot placement during a targeted stepping task in individuals with unilateral transtibial amputation (IUTAs; N = 8, 47 ± 13 yrs), compared to the preferred foot of control participant's (N = 8, 33 ± 15 yrs). Participants walked along a 10-metre walkway, placing their foot into a rectangular floor-based target with dimensions normalised to a percentage of participant's foot length and width; 'standard' = 150% x 150%, 'wide' = 150% x 200%, 'long' = 200% x 150%. Foot placement accuracy (relative distance between foot and target centre), precision (between-trial variability), and foot-reach kinematics were determined for each limb and target, using three-dimensional motion capture. A significant foot-by-target interaction revealed less mediolateral foot placement accuracy for IUTAs in the wide target, which was significantly less accurate for the intact (28 ± 12 mm) compared to prosthetic foot (16 ± 14 mm). Intact peak foot velocity (4.6 ± 0.8 m.s-1) was greater than the prosthetic foot (4.5 ± 0.8 m.s-1) for all targets. Controls were more accurate and precise than IUTAs, regardless of target size. Less accurate and precise intact foot placement in IUTAs, coupled with a faster moving intact limb, is likely due to several factors including reduced proprioceptive feedback and active control during prosthetic limb single stance. This could affect activities of daily living where foot placement is critical, such as negotiating cluttered travel paths or obstacles whilst maintaining balance.

Hypoxia-inducible factor-1alpha and -2alpha are expressed in most rectal cancers but only hypoxia-inducible factor-1alpha is associated with prognosis.

The hypoxia-mediated response of tumours is a major determining factor in growth and metastasis. Understanding tumour biology under hypoxic conditions is crucial for the development of antiangiogenic therapy. Using one of the largest cohorts of rectal adenocarcinomas to date, this study investigated hypoxia-inducible factor-1alpha (HIF-1alpha) and HIF-2alpha protein expression in relation to rectal cancer recurrence and cancer-specific survival. Patients (n=90) who had undergone surgery for rectal adenocarcinoma, with no prior neoadjuvant therapy or metastatic disease, and for whom adequate follow-up data were available were selected. Microvessel density (MVD), HIF-1alpha and HIF-2alpha expressions were assessed immunohistologically with the CD34 antibody for vessel identification and the NB100-131B and NB100-132D3 antibodies for HIF-1alpha and HIF-2alpha, respectively. In a multifactorial analysis, results were correlated with tumour stage, recurrence rate and long-term survival. Microvessel density was higher across T and N stages (P<0.001) and associated with poor survival (hazard ratio (HR)=8.7, P<0.005) and decreased disease-free survival (HR=4.7, P<0.005). hypoxia-inducible factor-1alpha and -2alpha were expressed in >50% of rectal cancers (HIF-1alpha, 54%, 48/90; HIF-2alpha, 64%, 58/90). HIF-1alpha positivity was associated with both TNM stage (P<0.05) and vascular invasion (P<0.005). In contrast, no associations were demonstrated [corrected] between HIF-2alpha [corrected] and any pathological features or [corrected] outcome. The study showed an independent association between HIF-1alpha expression and advanced TNM stage with poor outcome. Our results indicate that HIF-1alpha, but not HIF-2alpha, might be used as a marker of prognosis, in addition to methods currently used, to enhance patient management.

Assessment of microvessel density and carbonic anhydrase-9 (CA-9) expression in rectal cancer.

AIM: The mechanism by which neoplasias respond to hypoxia determines their biological behavior and prognosis. Understanding the biology of tumors under hypoxic conditions is crucial for the development of anti-angiogenic therapy. Using the largest cohort of rectal adenocarcinomas to date, this study aimed to assess microvessel density (MVD) and carbonic anhydrase-9 (CA-9) expression and to correlate the results with recurrence and cancer-specific survival. MATERIALS AND METHODS: Patients (n=101) who underwent surgery for rectal adenocarcinoma without previous neoadjuvant therapy or metastatic disease were selected. MVD and CA-9 expression were assessed immunohistologically by using the CD34 antibody and the MN/CA9 M75 antibody, respectively. In a multifactorial analysis, the results were correlated with tumor stage, recurrence rate, and long-term survival. RESULTS: MVD was higher with increased T- and N-stages (p<0.01) and associated positively with poor survival (hazard ratio (HR) 1.3 per 10 vessel increase, p<0.01). CA-9 was expressed in 73% of cancers. Negative lymph node status correlated with CA-9 positivity (p<0.05), reflected in a higher rate of CA-9 positivity in earlier Dukes' stages (p<0.05). CA-9 positivity across tumor node metastasis (TNM) stages approached significance (Stage I/II: 80% CA-9 positive vs. 20% CA-9 negative; Stage III: 63% CA-9 positive vs. 37% negative, p=0.051). A trend was seen towards better cancer-specific survival in patients with CA-9 positive carcinomas (HR 0.51, p=0.07) on univariate analysis. DISCUSSION: MVD was higher in more advanced T- and N-stages and may be used as a determinant of survival in patients with rectal adenocarcinomas. CA-9 expression was seen more often in earlier Dukes' stages, possibly representing an early tumor hypoxic response. CA-9 expression by adenocarcinoma cells may confer long-term survival advantage in surgically treated rectal cancer.

Can depth of tumour invasion predict lymph node positivity in patients undergoing resection for early rectal cancer? A comparative study between T1 and T2 cancers.

OBJECTIVE: The present study investigated the risk of lymph node metastasis according to the depth of tumour invasion in patients undergoing resection for rectal cancer. METHOD: The histology of patients undergoing oncological resection with regional lymphadenectomy for rectal cancer at St Marks Hospital from 1971 to 1996 was reviewed. Of the total number of 1549 patients, 303 patients with T(1) or T(2) rectal cancers were selected. The tumour type, grade, evidence of vascular invasion, depth of submucosal invasion (classed into 'sm1-3') were evaluated as potential predictors of lymph node positivity using univariate and multi-level logistic regression analysis. RESULTS: Tumour stage was classified as T(1) in 55 (18.2%) and T(2) in 248 (81.2%) patients. The incidence of lymph node metastasis in the T(1) group was 12.7% (7/55), compared to 19% (47/247) in the T(2) group. The node positive and negative groups were similar with regard to patient demographics, although the former contained a significantly higher number of poorly differentiated (P = 0.001) and extramural vascular invasion tumours (P = 0.002). There was no significant difference in the number of patients with sm1-3, or T(2) tumour depths within the lymph node positive and negative groups. On multivariate analysis the presence of extramural vascular invasion (odds ratio = 10.0) and tumour grade (odds ratio for poorly vs well-differentiated = 11.7) were independent predictors of lymph node metastasis. CONCLUSION: Whilst the degree of vascular invasion and poor differentiation of rectal tumours were significant risk factors for lymph node metastasis, depth of submucosal invasion was not. This has important implications for patients with superficial early rectal cancers in whom local excision is being considered.

Ischaemia: a pathogenetic clue in diversion colitis?

OBJECTIVE: It is not common that, after diversion of the faecal stream by a colostomy, the defunctioned colon develops colitis. The pathogenesis of this colitis is still unclear and it has been proposed that ischaemia may play a major role. Our aim is to look for signs of ischaemia in a group of patients developing colitis after diversion colostomy for various causes. METHOD: Surgical specimens from 32 patients resected for colitis developed after diverting colostomy were examined with routine (haematoxylin-eosin) and Elastic-Van Gieson and Perls' stains. RESULTS: The histological features related to mucosal crypt architecture, crypt epithelium and inflammation were mild, non specific or related to the underlying disease. Fibrosis was present in 21 (65.6%) patients, superficial coagulative necrosis was found in 18 (56%) patients, splitting and/or thickening of muscularis mucosae was present in 20 (62%) patients. The vessels were substantially normal or ectasic without thrombi or alterations in the wall. Evident ischaemia with coagulative necrosis, submucosal oedema and focal fibrosis was detected in only two (6%) patients and an intermediate picture between acute and chronic ischaemia was present in 16 (50%) patients. CONCLUSION: It is possible that ischaemia plays some role in the pathogenesis of diversion colitis; however, further studies are needed to firmly establish its role.

Investigation of pathogenic mechanisms in multiple colorectal adenoma patients without germline APC or MYH/MUTYH mutations.

Patients with multiple (5-100) colorectal adenomas (MCRAs) often have no germline mutation in known predisposition genes, but probably have a genetic origin. We collected a set of 25 MCRA patients with no detectable germline mutation in APC, MYH/MUTYH or the mismatch repair genes. Extracolonic tumours were absent in these cases. No vertical transmission of the MCRA phenotype was found. Based on the precedent of MYH-associated polyposis (MAP), we searched for a mutational signature in 241 adenomatous polyps from our MCRA cases. Somatic mutation frequencies and spectra at APC, K-ras and BRAF were, however, similar to those in sporadic colorectal adenomas. Our data suggest that the genetic pathway of tumorigenesis in the MCRA patients' tumours is very similar to the classical pathway in sporadic adenomas. In sharp contrast to MAP tumours, we did not find evidence of a specific mutational signature in any individual patient or in the overall set of MCRA cases. These results suggest that hypermutation of APC does not cause our patients' disease and strongly suggests that MAP is not a paradigm for the remaining MCRA patients. Our MCRA patients' colons showed no evidence of microadenomas, unlike in MAP and familial adenomatous polyposis (FAP). However, nuclear beta-catenin expression was significantly greater in MCRA patients' tumours than in sporadic adenomas. We suggest that, at least in some cases, the MCRA phenotype results from germline variation that acts subsequent to tumour initiation, perhaps by causing more rapid or more likely progression from microadenoma to macroadenoma.

The reliability of lymph-node staging in rectal cancer after preoperative chemoradiotherapy.

AIMS: To determine the prognostic significance of the nodal stage and number of nodes recovered in the surgical specimen after preoperative synchronous chemoradiation (SCRT) and surgery for locally advanced or unresectable rectal cancer. MATERIALS AND METHODS: One hundred and eighty-two consecutive patients with locally advanced or unresectable (T3/T4) rectal carcinomas were entered on a prospective database and treated in this department with preoperative chemoradiation, followed 6-12 weeks later by surgical resection. Most patients received chemotherapy in the form of low-dose folinic acid and 5-fluorouracil (5-FU) 350 mg/m2 via a 60-min infusion on days 1-5 and 29-33 of a course of pelvic radiotherapy delivered at a dose of 45 Gy in 25 fractions over 33 days to a planned volume. After resection, patients with a positive circumferential margin (< or = 1 mm), extranodal deposits or Dukes' C histology received adjuvant 5-FU-based-chemotherapy (n = 40). RESULTS: After SCRT, 161 patients underwent resection. Twenty-one patients remained unresectable or refused an exenterative operation. Median follow-up is 36 months. Down-staging was achieved in most patients, with 19 having a complete pathological response (pT0). The median number of lymph nodes recovered for all patients was five (range 0-21). The 3-year survival rate for node-positive patients is 47%, for node-negative patients with less than three lymph nodes recovered is 62% and for node-negative patients with three or more lymph nodes recovered is 70%. Compared with node-positive patients, simple regression models revealed a reduced hazard ratio (HR) of 0.72 (0.36-1.43) for node-negative patients with less than three nodes recovered and 0.48 (0.26-0.89) for node-negative patients with three or more lymph nodes recovered. In a multivariate model, including nodal status, excision status, age and sex only positive excision margins significantly predicted a poor outcome: HR = 3.05 (1.55-5.97). CONCLUSIONS: The number of nodes found after preoperative chemoradiation is a significant prognostic factor by univariate analysis. In this study, patients with node-negative histology, and at least three nodes recovered, had better long-term survival than patients in whom two or less nodes were recovered or with positive nodes. This effect was attenuated by the inclusion of excision status in multivariate models.

O(6)-methylguanine methyltransferase in colorectal cancers: detection of mutations, loss of expression, and weak association with G:C>A:T transitions.

BACKGROUND AND AIMS: O(6)-methylguanine methyltransferase (MGMT) repairs inappropriately methylated guanine in DNA. MGMT mutations have not previously been reported in cancers, but in colorectal tumours MGMT promoter methylation is common and has been associated with increased G:C>A:T transitions, a high frequency of K-ras mutations, and low level microsatellite instability (MSI low). However, some have suggested that MGMT changes are background or secondary events, with little importance for tumorigenesis. METHODS: We have analysed fresh frozen colorectal cancers and colorectal cancer cell lines for MGMT changes: mutations, allelic loss, and protein expression. RESULTS: Six of 113 cancers harboured somatic missense MGMT mutations, at least three of which probably caused reduced MGMT function and were accompanied by silencing or loss of the wild-type allele. Cancers with pathogenic MGMT mutations tended to harbour G:C>A:T somatic mutations at other loci. Overall, MGMT expression was reduced or lost in more than half of the cancers. We found no association between MGMT expression and the somatic mutation spectrum at APC, beta-catenin, K-ras, or p53, but decreased MGMT expression was weakly associated with the presence of a G:C>A:T change at any one of these loci. Reduced MGMT expression was not however associated with an increased frequency of K-ras mutations or with MSI low. CONCLUSION: In summary, we found that mutation of MGMT contributes to decreased protein function. Our findings provide good evidence to show that MGMT changes, including methylation, are selected rather than background events, at least in some cases. Decreased MGMT expression or function probably has a weak or moderate effect on the mutation spectrum in colorectal cancers.

Indeterminate colitis: a pathologist's view.

Indeterminate colitis is only a partial diagnosis, which is provisional until sufficient information becomes available for a more precise diagnosis of either ulcerative colitis or Crohn's disease. As originally defined, i.e. based only on the pathological features in the colon resected for fulminant colitis, a few patients eventually developed Crohn's disease. If the term is used only after all available clinical and investigative evidence is considered, 'indeterminate colitis' behaves clinically like ulcerative colitis. This has important implications for pouch surgery.

Analysis of somatic molecular changes, clinicopathological features, family history, and germline mutations in colorectal cancer families: evidence for efficient diagnosis of HNPCC and for the existence of distinct groups of non-HNPCC families.

OBJECTIVE: To analyse somatic molecular changes, clinicopathological features, family history, and germline mutations in families with colorectal cancer (CRC). METHODS: Molecular changes (K-ras and beta-catenin mutations, chromosome 18q allele loss (LOH), APC LOH, microsatellite instability (MSI), and expression of beta-catenin and p53) were examined in four series of CRC patients with proven or probable hereditary disease: hereditary non-polyposis colon cancer (HNPCC); MYH associated polyposis (MAP); multiple (>5) colorectal adenomas without familial adenomatous polyposis (FAP); and other families/cases referred to family cancer clinics (FCC series). HNPCC was diagnosed using a combination of germline mutation screening and tumour studies. A series of unselected CRC patients was also studied. RESULTS: There was overlap between genetic pathways followed by each type of CRC, but significant differences included: increased frequency of K-ras mutation and reduced frequency of APC LOH in cancers from MAP, but not from multiple adenoma patients; reduced frequency of LOH in HNPCC CRCs; and increased MSI in CRCs from HNPCC, but not from FCC or multiple adenoma patients. HNPCC was apparently detected efficiently by combined germline and somatic analysis. Cancers from the FCC, unselected, and multiple adenoma series shared similar molecular characteristics. In the FCC and multiple adenoma series, hierarchical cluster analysis using the molecular features of the cancers consistently identified two distinct groups, distinguished by presence or absence of K-ras mutation. CONCLUSIONS: While K-ras mutation status is known to differentiate hereditary bowel cancer syndromes such as MAP and FAP, it may also distinguish groups of non-HNPCC, FCC patients whose disease has different, as yet unknown, genetic origins.

Exon 3 beta-catenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome.

BACKGROUND AND AIMS: Activating beta-catenin mutations in exon 3 have been implicated in colorectal tumorigenesis. Although reports to the contrary exist, it has been suggested that beta-catenin mutations occur more often in microsatellite unstable (MSI+) colorectal carcinomas, including hereditary non-polyposis colorectal cancer (HNPCC), as a consequence of defective DNA mismatch repair. We have analysed 337 colorectal carcinomas and adenomas, from both sporadic cases and HNPCC families, to provide an accurate assessment of beta-catenin mutation frequency in each tumour type. METHODS: Direct sequencing of exon 3 of beta-catenin. RESULTS: Mutations were rare in sporadic (1/83, 1.2%) and HNPCC adenomas (1/37, 2.7%). Most of the sporadic adenomas analysed (80%) were small (<1 cm), and our data therefore differ from a previous report of a much higher mutation frequency in small adenomas. No oncogenic beta-catenin mutations were identified in 34 MSI+ and 78 microsatellite stable (MSI-) sporadic colorectal cancers but a raised mutation frequency (8/44, 18.2%) was found in HNPCC cancers; this frequency was significantly higher than that in HNPCC adenomas (p=0.035) and in both MSI- (p<0.0001) and MSI+ (p=0.008) sporadic cancers. Mutations were more common in higher stage (Dukes' stages C and D) cancers (p=0.001). CONCLUSION: Exon 3 beta-catenin mutations are associated specifically with malignant colorectal tumours in HNPCC; mutations appear not to result directly from deficient mismatch repair. Our data provide evidence that the genetic pathways of sporadic MSI+ and HNPCC cancers may be divergent, and indicate that mutations in the HNPCC pathway of colorectal tumorigenesis may be determined by selection, not simply by hypermutation.

Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk.

BACKGROUND AND AIMS: The risk of colorectal cancer is increased in ulcerative colitis (UC). Patients with UC have diverse colonoscopic appearances. Determining colonoscopic markers for cancer risk could allow patient risk stratification. PATIENTS AND METHODS: Following on from an earlier study which demonstrated a correlation between inflammation severity and neoplasia risk, a case control study was performed to look for colonoscopic markers of colorectal neoplasia risk in UC. Each patient with neoplasia detected between 1988 and 2002 was matched with two non-dysplastic colitic controls. Data were collected on post-inflammatory polyps, scarring, strictures, backwash ileitis, a shortened, tubular, or featureless colon, severe inflammation, and normal looking surveillance colonoscopies. RESULTS: Cases (n = 68) and controls (n = 136) were well matched. On univariate analysis, cases were significantly more likely to have post-inflammatory polyps (odds ratio (OR) 2.14 (95% confidence interval 1.24-3.70)), strictures (OR 4.22; 1.08-15.54), shortened colons (OR 10.0; 1.17-85.6), tubular colons (OR 2.03; 1.00-4.08), or segments of severe inflammation (OR 3.38; 1.41-10.13), and less likely to have had a macroscopically normal looking colonoscopy (OR 0.40; 0.21-0.74). After multivariate analysis, a macroscopically normal looking colonoscopy (OR 0.38; 0.19-0.73), post-inflammatory polyps (2.29; 1.28-4.11), and strictures (4.62; 1.03-20.8) remained significant. The five year risk of colorectal cancer following a normal looking colonoscopy was no different from that of matched general population controls. CONCLUSIONS: Macroscopic colonoscopic features help predict neoplasia risk in UC. Features of previous/ongoing inflammation signify an increased risk. A macroscopically normal looking colonoscopy returns the cancer risk to that of the general population: it should be possible to reduce surveillance frequency to five years in this cohort.

Histological categorisation of fibrotic cancer stroma in advanced rectal cancer.

BACKGROUND AND AIMS: Based on conflicting reports regarding the role of the fibrotic stromal response in cancer development--namely, that a desmoplastic reaction can favour either the host or the tumour--it is clear that the role of the stromal response is varied. We have classified the fibrotic stroma of rectal adenocarcinoma penetrating the muscularis propria, based on histologically identified stromal components. METHODS: Three categories of stroma were used: mature-when the stroma was composed of mature collagen fibres (fine and elongated fibres into multiple layers); intermediate-when keloid-like collagen was intermingled with mature fibres; and immature-consisting of a myxoid stroma in which no mature fibres were included. RESULTS: In a data set of 862 patients, 53% of patients had mature fibrotic cancer stroma, 33% had intermediate stroma, and 15% had immature stroma. Five year survival rates decreased as follows: mature stroma (80%), intermediate stroma (55%), and immature stroma (27%). The adverse tumour phenotype, tumour cell budding (conspicuous isolated cells or small clusters of cancer cells), was observed in the cancer fronts in tumours with unfavourable fibrotic stroma (p<0.0001). Based on multivariate analysis, categorised fibrotic stroma was selected as an independent prognostic parameter (hazard ratio 1.39; 95% confidence interval 1.17-1.64) together with tumour differentiation. By immunohistochemical examination, as maturation of the fibrotic stroma decreased, stromal T cells became significantly sparser. Furthermore, myofibroblasts were distributed extensively in immature fibrotic stroma compared with mature and intermediate fibrotic stroma. CONCLUSION: The morphological categorisation of fibrotic cancer stroma highlights the role of the stromal response in relation to the behaviour and host immune reactions of rectal adenocarcinoma and would be a useful tool for predicting patient prognostic outcome.

Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis.

BACKGROUND AND AIMS: Colonoscopic surveillance for cancer in longstanding extensive ulcerative colitis relies heavily on non-targeted mucosal biopsies. Chromoendoscopy can aid detection of subtle mucosal abnormalities. We hypothesised that routine pancolonic indigo carmine dye spraying would improve the macroscopic detection of dysplasia and reduce the dependence on non-targeted biopsies. PATIENTS AND METHODS: One hundred patients with longstanding extensive ulcerative colitis attending for colonoscopic surveillance underwent "back to back" colonoscopies. During the first examination, visible abnormalities were biopsied, and quadrantic non-targeted biopsies were taken every 10 cm. Pancolonic indigo carmine (0.1%) was used during the second colonoscopic examination, and any additional visible abnormalities were biopsied. RESULTS: Median extubation times for the first and second colonoscopies were 11 and 10 minutes, respectively. The non-targeted biopsy protocol detected no dysplasia in 2904 biopsies. Forty three mucosal abnormalities (20 patients) were detected during the pre-dye spray colonoscopy of which two (two patients) were dysplastic: both were considered to be dysplasia associated lesions/masses. A total of 114 additional abnormalities (55 patients) were detected following dye spraying, of which seven (five patients) were dysplastic: all were considered to be adenomas. There was a strong trend towards statistically increased dysplasia detection following dye spraying (p = 0.06, paired exact test). The targeted biopsy protocol detected dysplasia in significantly more patients than the non-targeted protocol (p = 0.02, paired exact test). CONCLUSIONS: No dysplasia was detected in 2904 non-targeted biopsies. In comparison, a targeted biopsy protocol with pancolonic chromoendoscopy required fewer biopsies (157) yet detected nine dysplastic lesions, seven of which were only visible after indigo carmine application. Careful mucosal examination aided by pancolonic chromoendoscopy and targeted biopsies of suspicious lesions may be a more effective surveillance methodology than taking multiple non-targeted biopsies.

The prevalence of small, flat colorectal cancers in a western population.

OBJECTIVE: Small, flat colorectal cancers have been widely reported in the Japanese literature but are thought to occur rarely outside Japan. The aim of this retrospective cohort study was to clarify the prevalence of flat colorectal cancer in a Western population. METHODS: One thousand and twenty-six consecutive colonoscopies performed by a single experienced endoscopist were retrospectively analysed over a two-year period. The morphology, site and histological appearance of all documented colorectal cancers (CRC) were recorded. RESULTS: Forty-seven cases of CRC were detected, five of which (10%) demonstrated flat configuration. Flat cancers varied between 8 and 15 mm in diameter (mean 11 mm). Histologically, all flat lesions were moderately differentiated Dukes A adenocarcinomas. Two of these cancers contained no adenomatous component. CONCLUSION: This study confirms that small, flat colorectal cancers are not an uncommon finding at colonoscopy in Western patients. Compared to polypoid neoplastic lesions, flat cancers appear to undergo malignant change at a smaller size.

Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis.

BACKGROUND: Ten to 15% of patients with pouchitis experience refractory or recurrent disease. The aim of this study was to evaluate the effectiveness of a single daily high dose probiotic preparation (VSL#3) in maintaining antibiotic induced remission, and quality of life (QOL), for one year in such patients. METHODS: Patients with pouchitis at least twice in the previous year or requiring continuous antibiotics, associated with a pouchitis disease activity index (PDAI) > or =7 (0 = perfect; 18 = worst), in whom remission was induced by four weeks of combined metronidazole and ciprofloxacin, were randomised to receive VSL#3 6 g or placebo once daily for one year or until relapse. Symptomatic, endoscopic, and histological evaluations were made before, and two and 12 months after randomisation or at the time of relapse. Remission was defined as a clinical PDAI < or =2 and endoscopic PDAI < or =1. Relapse was defined as an increased clinical PDAI score > or =2 and increased endoscopic PDAI score > or =3. QOL was assessed using the inflammatory bowel disease questionnaire (IBDQ). RESULTS: Thirty six patients were randomised: 20 to VSL#3 and 16 to placebo. Remission was maintained at one year in 17 patients (85%) on VSL#3 and in one patient (6%) on placebo (p<0.0001). The IBDQ score remained high in the VSL#3 group (p = 0.3) but deteriorated in the placebo group (p = 0.0005). CONCLUSION: The once daily high dose probiotic VSL#3 is effective in maintaining antibiotic introduced remission for at least a year in patients with recurrent or refractory pouchitis. This is associated with a high level of quality of life.

Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome.

Germline mutations in the LKB1/STK11 tumour suppressor gene cause Peutz-Jeghers syndrome (PJS), a rare dominant disorder. In addition to typical hamartomatous gastrointestinal polyps and pigmented perioral lesions, PJS is associated with an increased risk of tumours at multiple sites. Follow-up information on carriers is limited and genetic heterogeneity makes counselling and management in PJS difficult. Here we report the analysis of the LKB1/STK11 locus in a series of 33 PJS families, and estimation of cancer risks in carriers and noncarriers. Germline mutations of LKB1/STK11 were identified in 52% of cases. This observation reinforces the hypothesis of a second PJS locus. In carriers of LKB1/STK11 mutations, the risk of cancer was markedly elevated. The risk of developing any cancer in carriers by age 65 years was 47% (95% CI: 27-73%) with elevated risks of both gastrointestinal and breast cancer. PJS with germline mutations in LKB1/STK11 are at a very high relative and absolute risk of multiple gastrointestinal and nongastrointestinal cancers. To obtain precise estimates of risk associated with PJS requires further studies of genotype-phenotype especially with respect to LKB1/STK11 negative cases, as this group is likely to be heterogeneous.

Pathological staging of epidermoid anal carcinoma for the new era.

Chemoradiotherapy is the standard treatment for most patients with epidermoid anal cancer. Pre-treatment staging is based on size for T1-T3 lesions and clinical and radiological assessment of adjacent organ invasion for T4 lesions. For patients with residual or recurrent carcinoma, anorectal excision offers the best chance of oncological salvage. Pathological staging systems for anorectal excision specimens were validated at the time when surgical treatment was first line therapy. A validated staging system is necessary for salvage surgical excision specimens following an attempt to cure by radiotherapy and chemotherapy for the purpose of prognosis and further treatment planning.