Histopathological audit of positive circumferential resection margins (CRMs) can be used as a surrogate measure of the success of rectal cancer treatment. We audited CRM involvement in rectal cancer patients and the impact of the multidisciplinary team (MDT) on implementing a magnetic resonance imaging (MRI)-based preoperative treatment strategy. Data were collected on all newly diagnosed rectal cancer patients treated in our network between January 1999 and December 2002. Data were analysed for MRI prediction and histopathological assessment of CRM together with the MDT meeting treatment decisions. The CRM þ ve rate of those discussed at MDT vs those not discussed were compared. We re-audited the CRM þ ve rates 1 year after introducing a policy of mandatory preoperative MRI-based MDT discussion. Of the 298 patients diagnosed with rectal cancer, 39 (13%) were deemed palliative, 178 underwent surgery alone and 81 underwent neoadjuvant therapy. Of these, 62 out of 178 patients underwent surgery alone without MRI-based MDT discussion resulting in positive CRM in 16 cases (26%) as compared to 1 out of 116 (1%) in those patients with MDT discussion of MRI. Overall CRM þ ve rate in all nonpalliative patients with or without MDT discussion was 12.5% (32 out of 256), significantly lower than the o20% rate (Po0.001) quoted in national guidelines. Re-audit in 98 consecutive patients following a change of policy produced a lower CRM þ ve rate of 3% (1 out of 37) for all surgery alone patients and an overall CRM þ ve rate of 7% (5 out of 70). In conclusion, MDT discussion of MRI and implementation of a preoperative treatment strategy results in significantly reduced positive CRM in rectal cancer patients.

Mutation screening of the major autosomal dominant polycystic kidney disease (ADPKD) locus, PKD1, has proved difficult because of the large transcript and complex reiterated gene region. We have developed methods, employing long polymerase chain reaction (PCR) and specific reverse transcription-PCR, to amplify all of the PKD1 coding area. The gene was screened for mutations in 131 unrelated patients with ADPKD, using the protein-truncation test and direct sequencing. Mutations were identified in 57 families, and, including 24 previously characterized changes from this cohort, a detection rate of 52.3% was achieved in 155 families. Mutations were found in all areas of the gene, from exons 1 to 46, with no clear hotspot identified. There was no significant difference in mutation frequency between the single-copy and duplicated areas, but mutations were more than twice as frequent in the 3' half of the gene, compared with the 5' half. The majority of changes were predicted to truncate the protein through nonsense mutations (32%), insertions or deletions (29.6%), or splicing changes (6.2%), although the figures were biased by the methods employed, and, in sequenced areas, approximately 50% of all mutations were missense or in-frame. Studies elsewhere have suggested that gene conversion may be a significant cause of mutation at PKD1, but only 3 of 69 different mutations matched PKD1-like HG sequence. A relatively high rate of new PKD1 mutation was calculated, 1.8x10-5 mutations per generation, consistent with the many different mutations identified (69 in 81 pedigrees) and suggesting significant selection against mutant alleles. The mutation detection rate, in this study, of>50% is comparable to that achieved for other large multiexon genes and shows the feasibility of genetic diagnosis in this disorder.

Abstract. The severity of renal cystic disease in the major form of autosomal dominant polycystic kidney disease (PKD1) is highly variable. Clinical data was analyzed from 324 mutation-characterized PKD1 patients (80 families) to document factors associated with the renal outcome. The mean age to end-stage renal disease (ESRD) was 54 yr, with no significant difference between men and women and no association with the angiotensin-converting enzyme polymorphism. Considerable intrafamilial variability was observed, reflecting the influences of genetic modifiers and environmental factors. However, significant differences in outcome were also found among families, with rare examples of unusually late-onset PKD1. Possible phenotype/genotype correlations were evaluated by estimating the effects of covariants on the time to ESRD using proportional hazards models. In the total population, the location of the mutation (in relation to the median position; nucleotide 7812), but not the type, was associated with the age at onset of ESRD. Patients with mutations in the 5' region had significantly more severe disease than the 3' group; median time to ESRD was 53 and 56 yr, respectively (P ϭ 0.025), with less than half the chance of adequate renal function at 60 yr (18.9% and 39.7%, respectively). This study has shown that the position of the PKD1 mutation is significantly associated with earlier ESRD and questions whether PKD1 mutations simply inactivate all products of the gene.

Matrix metalloproteinases, and notably the gelatinases MMP-2 and MMP-9, have important roles in tumour invasion, metastasis and angiogenesis. Our study investigates the distribution of MMP-2 and MMP-9 in colorectal cancer, the correlation with plasma levels, changes following surgical resection and whether plasma levels reflect clinical staging and disease course. MMP-2 and MMP-9 expression in 48 colorectal tumours and 13 adenomatous polyps was analysed by RT-PCR, immunohistochemistry, and quantified by ELISA of tumour lysates. Concentrations of MMP-2 and MMP-9 in plasma samples from these patients and 36 other patients who underwent curative resections were measured by ELISA prior to and 6 -12 months after surgery. MMP-2 expression was significantly increased in colorectal cancer tissues compared to matched normal colon as measured by ELISA. Active MMP-2 was localised by immunohistochemistry to regions where tumour cells invaded the muscularis with little staining in more superficial areas. Plasma MMP-2 levels were also significantly elevated in patients with colorectal cancer, with significant reductions following curative resections at all stages. Similarly, MMP-9 expression was significantly increased in colorectal cancer tissues, predominantly in the tumour stroma. Plasma levels of MMP-9 were significantly elevated at all stages in colorectal cancer patients and a significant reduction was seen following curative resections. With both MMP-2 and MMP-9, the strongest correlation with clinical staging in colorectal cancer was represented by the total plasma concentration of the enzymes, both falling to within the normal range following curative surgery. Plasma levels of these enzymes may therefore have potential as a noninvasive indicator of invasion or metastasis in colorectal cancer or as a marker of disease status during follow-up. © 2003 Wiley-Liss, Inc. colorectal cancer; metastasis; proteolysis; staging; plasma Matrix metalloproteinases are a closely related multigene family of zinc-dependent proteolytic enzymes. They have a role in normal physiological tissue remodelling and are capable of degrading all components of the extracellular matrix. There is increasing evidence that metalloproteinases play many important roles in cancer, for example, releasing and activating growth factors and other proteases and assisting tumour cells to invade the extracellular matrix. In addition, MMPs potentiate neovascularisation of tumour tissue, 1-4 with both MMP-2 and MMP-9 expression being correlated with angiogenesis in colorectal cancer. 5 Several previous studies have examined MMPs and also tissue inhibitors of MMPs (TIMPs) in colorectal cancer and in some cases a relationship between expression and tumour characteristics or metastasis has been found. 2,6 -9 Other studies have measured serum or plasma levels of MMPs and stated that they are raised in various cancers; 10 -14 however few studies have been reported in colorectal cancer, and it is not clear whether circulating MMP levels reflect tumour expression....

Whilst imaging of poor prognostic features in rectal cancers has assisted pre-operative treatment stratification, such features have yet to be evaluated in colonic cancers. This study aims to develop criteria for identifying poor prognostic features in colonic tumours and assess the accuracy of CT prediction against histopathology. Criteria were developed for predicting T-stage and N-stage, the presence of extramural vascular invasion and involvement of the retroperitoneal surgical margin (RSM). These criteria were tested on 33 patients with colonic cancer who underwent pre-operative high-resolution CT of their tumour. Two radiologists (Obs 1 and Obs 2) identified independently these poor prognostic features and the results were compared with the final histopathological results. Histological agreement and interobserver variation were calculated using the kappa test. Accuracy of CT prediction of tumour extension beyond muscularis propria was 82% (Obs 1) and 70% (Obs 2). Correct prediction of RSM involvement was 76% (95% confidence interval (CI): 57.8-88.9%) and 79% (95%CI: 61.1-91%) for Obs1 and Obs 2, respectively, with significant agreement between observers (kappa = 0.455, p = 0.050). Prognosis was correctly predicted using CT in 82% (95%CI: 61.5-81.2%) (Obs1) and 85% (95%CI: 68.1-94.9%) (Obs2) with moderate agreement (kappa = 0.459, kappa = 0.527, respectively) with histology. In conclusion, CT has potential as the imaging modality of choice in the pre-operative prediction of poor prognostic features in colonic cancers and could play a role in future treatment stratification.

No abstract

No abstract

The LAP-BAND system is a safe and effective bariatric procedure leading to considerable weight loss and reduction in comorbidity.