J Hill

Central Manchester University Hospitals NHS Foundation Trust, Manchester, England, United Kingdom

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Publications (20)70.36 Total impact

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    ABSTRACT: Lynch syndrome (LS) patients have DNA mismatch repair deficiency and up to 80% lifetime risk of colorectal cancer (CRC). Screening of mutation carriers reduces CRC incidence and mortality. Selection for constitutional mutation testing relies on family history (Amsterdam and Bethesda Guidelines) and tumour-derived biomarkers. Initial biomarker analysis uses mismatch repair protein immunohistochemistry and microsatellite instability. Abnormalities in either identify mismatch repair deficiency but do not differentiate sporadic epigenetic defects, due to MLH1 promoter region methylation (13% of CRCs) from LS (4% of CRCs). A diagnostic biomarker capable of making this distinction would be valuable. This study compared two biomarkers in tumours with mismatch repair deficiency; quantification of methylation of the MLH1 promoter region using a novel assay and BRAF c.1799T>A, p.(Val600Glu) mutation status in the identification of constitutional mutations.
    Journal of medical genetics. 10/2014;
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    ABSTRACT: AimColonic surveillance reduces life time risk of colorectal cancer from 60-80% to 10% and confers a seven-year survival advantage in patients with Lynch syndrome (HNPCC). The British Society of Gastroenterologists recommends colonoscopy at least every two years from age 25. Currently in the UK, genetic diagnosis is made by a regional genetics service and screening recommendations are made to the referring clinician. The aim of this study was to investigate compliance with and the effectiveness of large bowel surveillance in Lynch syndrome.MethodA retrospective longitudinal study of Lynch syndrome mutation carriers on the Regional Familial Colorectal Cancer Registry under and not under screening was conducted. To investigate screening compliance, patients were included if alive at the start of the study. Data were gathered on timeliness, quality and outcome of screening. To examine the effectiveness of screening, the cumulative incidence of colorectal cancer was estimated using Kaplan-Meier and the screened population compared to that in patients not being screened.Results227 Lynch Syndrome mutation carriers were under screening at 26 hospitals. 439 colonoscopies were assessed for timeliness of which 68% were compliant (interval <27 months). Compliance on 01/11/2011 was 87%. Cumulative incidence of colorectal cancer to age 70 was 25% (95% CI 17-32%) in the surveillance population and 81% (95% CI 78-84%) in 689 mutation positive patients not being screened (p<0.0001).Conclusion Overall 68% of colonoscopies were on time. The incidence of colorectal cancer was greatly reduced by screening but remained significant. Lynch syndrome patients need pro-active surveillance management.This article is protected by copyright. All rights reserved.
    Colorectal Disease 09/2014; · 2.08 Impact Factor
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    ABSTRACT: The British Society of Gastroenterology recommends that all familial adenomatous polyposis (FAP) and Lynch syndrome (LS) families are screened in the context of a registry. This systematic review was performed to appraise the published evidence for registration and screening in relation to colorectal cancer (CRC) incidence and mortality. Five electronic databases were searched using a combination of medical subject heading terms and free-text keywords. Titles and abstracts were scrutinized by two independent reviewers. Inclusion criteria were English-language studies describing CRC incidence and/or mortality in patients with FAP or LS, with comparison of either: screened and unscreened patients, or time periods before and after establishment of the registry. Of 4668 abstracts identified, 185 full-text articles were selected; 43 studies fulfilled the inclusion criteria. No randomized clinical trial evidence was identified. For FAP, 33 of 33 studies described a significant reduction of CRC incidence and mortality with registration and screening. For LS, nine of ten studies described a reduction of CRC incidence and mortality with registration and screening. Five studies (FAP, 2; LS, 3) provided evidence for complete prevention of CRC-related deaths during surveillance. Clinical and statistical heterogeneity prevented pooling of data for meta-analysis. Studies consistently report that registration and screening result in a reduction of CRC incidence and mortality in patients with FAP and LS (level 2a evidence, grade B recommendation). Funding and managerial support for hereditary CRC registries should be made available. Presented to the Association of Surgeons of Great Britain and Ireland 2013 Congress, Glasgow, UK, May 2013, and to the Annual Meeting of the Association of Coloproctology of Great Britain and Ireland, Liverpool, UK, July 2013; published in abstract form as Br J Surg 2013; 100(Suppl 7): 123-124 and as Colorectal Dis 2013; 15(Suppl 1): 4.
    British Journal of Surgery 12/2013; 100(13):1719-31. · 4.84 Impact Factor
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    ABSTRACT: Urological tumours are the third most frequent malignancy in Lynch syndrome after colonic and endometrial cancer. Upper urinary tract tumours are well recognised in Lynch syndrome, but the association with prostate and bladder cancer is controversial. We determined the incidence and cumulative and relative risks of prostate and bladder cancer in a cohort of Lynch syndrome families. Male Lynch syndrome mutation carriers and their genetically untested male first degree relatives (FDR) were identified from the Manchester Regional Lynch syndrome database (n = 821). Time to the development of urological cancer was identified for each urological site (renal pelvis, ureter, bladder and prostate). Cumulative and relative risks were calculated, with results classified by mutation carrier status and specific causative genetic mutations. Eight prostate cancers were identified, only one occurring before the age of 60. Analysis of person-years at risk of prostate cancer by Lynch syndrome mutation carrier status suggests a correlation between MSH2 mutation carriers and a tenfold increased risk of prostate cancer (RR 10.41; 95 % CI 2.80, 26.65). No such association was found with bladder cancer (RR 1.88; 95 % CI 0.21, 6.79). The association of upper urinary tract tumours with MSH2 and MLH1 mutations was confirmed. We have carried out the largest study of male Lynch syndrome mutation carriers to establish the risks of urological malignancy. A tenfold increased risk of prostate cancer is supported in MSH2 with mutation carriers having roughly double the risk of prostate cancer to FDRs. A trial of PSA testing in MSH2 carriers from 40 to 50 years may be justifiable.
    Familial Cancer 10/2012; · 1.94 Impact Factor
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    ABSTRACT: Aim:  Life-time risk of a metachronous colorectal cancer (CRC) is 0.6%-3% following sporadic CRC and 15-26% in Lynch syndrome (LS). The life-time incidence of CRC in individuals with moderate familial risk is 8-17%. Risk of metachronous CRC (mCRC) is unknown. Method:  A retrospective longitudinal study of the Regional Familial CRC Registry was performed. Patients who had at least one CRC were categorised as follows: moderate risk (n=383), LS (n=528) and population risk (n=409). Kaplan-Meier estimate (1-KM) and cumulative incidence function (CI) were used to calculate the risk of mCRC. 1-KM gives the risk for individuals remaining at risk (alive) at a given time point thus is useful for counselling. CI gives the risk for the whole population. Results:  1-KM and CI demonstrated that the risk of mCRC was significantly higher in moderate risk patients compared with population risk (1-KM p= 0.008, CI p= 0.00097). Both were lower than LS. Moderate risk 1-KM was 2.7%, 6.3% and 23.5% at 5,10 and 20 years. Population risk 1-KM was 1.3%, 3.1% and 7.0% at 5, 10 and 20 years and CI was 0.3%, 0.6% and 2.4%. Conclusion:  These data indicate that the risk of mCRC is significantly higher in patients with a moderate family history than in those at population risk. This justifies pro-active life-long surveillance. © 2012 The Authors Colorectal Disease © 2012 The Association of Coloproctology of Great Britain and Ireland.
    Colorectal Disease 09/2012; · 2.08 Impact Factor
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    ABSTRACT: Familial adenomatous polyposis (FAP) has been divided into three clinical subtypes: mild, classical and severe. This study aimed to investigate for a correlation between genotype and phenotype. A codon-specific survival difference is unknown. A retrospective longitudinal study of 492 patients on the Manchester Polyposis Registry was conducted. Patients were grouped according to genotypes: 0, unknown mutation; 1, adenomatous polyposis coli (APC) 0-178 (and 312-412 of exon 9); 2, APC >1550; 3, APC 179-1249; 4, APC 1250-1549; and 5, MutYH. Date of onset of polyposis, incidence of colorectal cancer (CRC), survival and actuarial time to surgery were calculated. Median age of onset of polyposis for genotype 0 was 20.3 years, genotype 1 35.6 years, genotype 2 32.2, genotype 3 15.9 years, and genotype 4 14.8 years (p < 0.0001). Age of onset of CRC was similar between genotypes. Median survival for genotype 0 was 56.6 years, genotype 1 74.9 years, genotype 2 61.0 years, genotype 3 63.0 years, genotype 4 48.1 years, and genotype 5 69.7 years (p = 0.003). This survival difference was also seen when patients who underwent screening and those who did not were analysed separately. Survival in the screened population was 53.9 years in genotype 4 and 72.9 years in genotype 3. Patients with genotype 4 (APC 1249-1549) have a significantly worse survival despite screening and early prophylactic surgery. This analysis supports a genotype-phenotype correlation. Patients with a mutation APC 1249-1549 develop polyposis at an early age and have a worse survival. Patients with a mutation APC 0-178 or 312-412 develop polyposis later and have an improved survival. This survival difference has not previously been documented.
    Clinical Genetics 06/2011; 81(6):521-31. · 4.25 Impact Factor
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    ABSTRACT: Aims. To compare methylation profiles, protein expression, and microsatellite instability (MSI) of sporadic, HNPCC, and familial hyperplastic polyps (HPs). Methods. Methylation-specific PCR (MSP) and pyrosequencing assessed p16, MGMT, hMLH-1, MINT 1, and MINT 31 methylation. IHC (Immunohistochemistry) assessed Ki67, CK20, hMLH-1, hMSH-2, and hMSH-6 protein expression. MSI analysis was performed on those polyps with adequate DNA remaining. Results. 124 HPs were identified 78 sporadic, 21 HNPCC, 25 familial, and the HNPCC group demonstrated no significant differences in overall methylation (P = .186 Chi(2)). The familial group demonstrated significantly less over all methylation levels (P = .004 Chi(2)). Conclusions. HPs that occur in HNPCC have no more worrying features at a molecular level than those patients with HPs in a sporadic setting.
    International journal of surgical oncology. 01/2011; 2011:653163.
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    ABSTRACT: Regular colonic surveillance of familial adenomatous polyposis (FAP) patients is necessary to ensure appropriate prophylactic surgery is performed before colorectal cancer (CRC) develops. Polyposis Registries have been established to coordinate screening programmes. The aim of this study was to assess the effect of screening and of the formation of the Registry on survival, incidence of CRC and age at onset of CRC, in FAP patients. Patients on the Manchester Polyposis Registry were categorised according to their mode of presentation; screening or symptomatic, and survival time from birth was calculated for each patient (n=353). The effect of the formation of the Registry was assessed by comparing survival times from birth for patients diagnosed in the 20 years before the establishment of the Registry, to patients diagnosed in the 20 years since the formation of the Registry (n=273). This study demonstrated that survival was increased from 57.8 years to 70.4 years (p<0.001) by screening, and from 58.1 years to 69.6 years (p=0.007) following establishment of the Polyposis Registry. The incidence of CRC was reduced from 43.5% to 3.8% by screening, and from 28.7% to 14.0% following establishment of the Polyposis Registry. Although direct causation between improved survival and reduced CRC incidence, and establishment of the Registry cannot be proven, an association has been demonstrated. Colorectal cancer was found to develop, on average, 16 years later in the screening population. A regular systematic large bowel screening programme, managed by a Polyposis Registry, significantly improves the prognosis of FAP.
    Gut 10/2010; 59(10):1378-82. · 10.73 Impact Factor
  • K F Newton, W Newman, J Hill
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    ABSTRACT: Advances in molecular technology have resulted in the discovery of many putative biomarkers relevant to colorectal cancer (CRC). Literature searches were performed on PubMed and EMBASE using the words 'colorectal cancer', AND 'biomarkers OR markers'. Biomarkers that are either currently in clinical use or have potential clinical use were identified. Most potential markers are in the discovery phase waiting to undergo clinical validation. Hypermethylation of the plasma septin-9 gene shows promise as a nonstool-based screening tool. Hypermethylation of the DYPD gene (encodes the enzyme dihydropyrimidine dehydrogenase) and variation of the uridine diphosphate-glucuronosyltransferase 1A (UGT1A1) gene have predictive value for side effects and the efficacy of 5-fluoruracil and irinotecan, respectively. Mismatch repair protein immunohistochemistry is able to predict response to 5-fluorouracil, and the KRAS (Kirsten rat sarcoma viral oncogene) and B-RAF (v-RAF murine sarcoma viral oncogene homolog B1) somatic gene mutation status can predict the response to anti-epidermal growth factor receptor therapy. Recent advances indicate that the widespread use of biomarkers may herald the next major advance in the diagnosis and management of CRC.
    Colorectal Disease 10/2010; 14(1):3-17. · 2.08 Impact Factor
  • K Newton, J Hill
    Colorectal Disease 07/2010; 12(7):706-7. · 2.08 Impact Factor
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    ABSTRACT: Lynch syndrome or hereditary non-polyposis colorectal cancer is caused by mutations of DNA mismatch repair (MMR) genes. The extracolonic tumour spectrum includes endometrial, ovarian, gastric, small bowel, pancreatic, hepatobiliary, brain, and urothelial neoplasms. Families were referred on the basis of clinical criteria. Tumour immunohistochemistry and microsatellite testing were performed. Appropriate patients underwent sequencing of relevant exons of the MMR genes. Proven and obligate mutation carriers and first-degree relatives (FDRs) with a Lynch syndrome spectrum cancer were considered mutation carriers, as were a proportion of untested, unaffected FDRs based on the proportion of unaffected relatives testing positive in each age group. Kaplan-Meier analysis of risk to 70 years was calculated. One hundred and eighty-four Lynch syndrome spectrum extracolonic cancers in 839 proven, obligate, or assumed mutation carriers were analysed. Cumulative risk for females of an extracolonic tumour is 47.4% (95% CI 43.9-50.8). The risk to males is 26.5% (95% CI 22.6-30.4). There was no reduction in gynaecological malignancies due to gynaecological screening (examination, transvaginal ultrasound scan, hysteroscopy and endometrial biopsy). Males have a higher risk of gastric cancer than females (p = 0.0003). Gastric cancer risk in those born after 1935 does not justify surveillance. These penetrance estimates have been corrected for ascertainment bias and are appropriate for those referred to a high-risk clinic.
    Clinical Genetics 03/2009; 75(2):141-9. · 4.25 Impact Factor
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    J Hill
    British Journal of Surgery 10/2008; 95(10):1195-6. · 4.84 Impact Factor
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    ABSTRACT: Microsatellite instability (MSI) in colorectal cancer is caused by defective DNA mismatch repair (MMR). It is present in 15 per cent of sporadic colorectal cancers owing to epigenetic mutL homologue 1 (MLH1) inactivation. The evidence suggests that patients with tumours caused by defective DNA MMR do not benefit from 5-fluorouracil (5-FU)-based chemotherapy. The proportion of cancers with defective DNA MMR identified by MSI analysis or immunohistochemistry was calculated from published data. The cost of analysis was compared with the potential savings if 5-FU-based chemotherapy was not administered to these patients. Some 16.3 per cent of sporadic colorectal cancers had defective DNA MMR. Immunostaining for MLH1 and mutS homologue 2 (MSH2) had a sensitivity of 92.4 per cent and a specificity of 99.6 per cent for identifying MSI-high tumours. The strongest predictive variable was right-sidedness, with positive and negative predictive values of 0.329 and 0.948 respectively. If 5-FU-based chemotherapy were not administered, potential savings of up to pound 1.2 million per 1000 patients tested could be made. Costs would be higher if alternative chemotherapeutic regimens were substituted as a result of testing. Knowledge of MMR status may enable participation in trials of non-5-FU-based chemotherapy. The cost of MMR testing may be offset by more efficient use of chemotherapy.
    British Journal of Surgery 08/2008; 95(7):868-75. · 4.84 Impact Factor
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    ABSTRACT: Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant condition caused by inactivating mutations of DNA mismatch repair (MMR) genes. An accurate estimation of colorectal cancer risk for mutation carriers is essential for counselling and rationalizing screening programmes. Families were referred on the basis of clinical criteria. Tumour immunohistochemistry and microsatellite testing were performed. Appropriate patients underwent sequencing of all relevant exons of the MMR genes. Proven and obligate mutation carriers and first-degree relatives (FDRs) with an HNPCC spectrum cancer were considered mutation carriers, as were a proportion of untested, unaffected FDRs based on the proportion of unaffected relatives testing positive in each age group. The cumulative lifetime risk was calculated by Kaplan-Meier analysis. Three hundred and forty-one colorectal cancers in 839 proven, obligate, or assumed mutation carriers were analysed. The cumulative risk to age 70 years for all mutation carriers combined was 50.4% (95% CI 47.8-52.9). The cumulative risk in males was 54.3% (95% CI 50.7-57.8), which was significantly higher than in females (log rank p = 0.02) who had a risk of 46.3% (95% CI 42.8-49.9). These penetrance estimates from HNPCC families attending high-risk clinics have been corrected for ascertainment bias and are appropriate risks for those referred to a high-risk clinic. Current colonoscopic screening guidelines are appropriate.
    Clinical Genetics 07/2008; 74(3):233-42. · 4.25 Impact Factor
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    ABSTRACT: To determine follow-up requirements following transanal endoscopic microsurgery (TEM) for rectal tumours based on clinical and histopathological assessment of resection specimens. A consecutive series of 117 patients undergoing TEM between 1997 and 2005 was studied. The excised specimens were classified as intact with clear surgical resection margins, macroscopically intact specimens with microscopically involved resection margins or piecemeal. Recurrence rates were determined for the three groups. Of the 117 procedures performed, 80 were for benign disease and 37 for malignancy. Within the benign group 39 (49%) resections were intact with clear surgical resection margins and yielded zero recurrences; 22 (27%) resections were macroscopically intact with microscopically involved surgical resection margin and yielded two recurrences; and 19 (24%) resections were piecemeal and yielded eight recurrences. Within the malignant group all 37 patients had resection specimens which were intact with clear surgical resection margins. Two patients had immediate salvage surgery. Of the 35 who went on to long-term follow-up post-TEM (0.6-8.1 years, median 4) four developed recurrent cancer (two local with submucosal disease and two liver metastases). For benign rectal neoplasms, resection of an intact specimen with histologically clear surgical resection margins was associated with no observed mucosal recurrence. Local recurrence after TEM is significantly more frequent when histological examination reveals involved margins or when resection is piecemeal. Early endoscopic follow up is required for the latter two groups. Local recurrence for malignant cases was submucosal and detected by palpation.
    Colorectal Disease 06/2008; 10(4):330-5. · 2.08 Impact Factor
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    ABSTRACT: Screening colonoscopy has been shown to reduce mortality and cancer stage in hereditary nonpolyposis colorectal cancer (HNPCC) individuals. However, the benefit of screening in intermediate risk groups is unknown. The most recent national guidelines have recommended a reduction of screening frequency for the intermediate risk group. Therefore, this study aims to compare the results of colonoscopic screening in HNPCC and intermediate risk groups and assess the effect of the most recent screening protocol recommendations. A total of 244 individuals; 108 from HNPCC families (28 mismatch repair gene carriers) and 136 from intermediate risk families were referred for regular colonoscopic screening by the Regional Genetics Service. Findings from 417 colonoscopies performed between 1992 and 2003 were evaluated. A total of three cancers, 39 adenomas and 41 hyperplastic polyps were found in the HNPCC group compared with one cancer, 22 adenomas and 19 hyperplasic polyps in the intermediate risk group. If the recent screening guidelines for the intermediate group were applied, then 89 (44%) fewer colonoscopies would have been performed. Although no cancers would have been missed, six adenomas (mean size = 5.7 mm, range 2-10 mm) with two graded as severely dysplasic and six hyperplastic polyps would not have been detected. The detection rate and distribution of adenomas were similar in both groups. If the new colonoscopic screening recommendations for the intermediate risk group had been applied, a small number of significant lesions would have been missed.
    Colorectal Disease 10/2007; 9(7):635-40. · 2.08 Impact Factor
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    ABSTRACT: :The aim of this study was to determine the proportion of patients with familial adenomatous polyposis (FAP) who had mutations in the desmoid region of the adenomatous polyposis coli (APC) gene that phenotypically expresses desmoid disease, and to determine the role for surgery in these patients. Data from the North West Region FAP database and case notes were analysed retrospectively. Of 363 patients with FAP, 47 from ten families had APC mutations in the desmoid region 3' to codon 1399. Of 22 patients undergoing surgery, 16 developed desmoids, and of these 12 had mesenteric desmoid disease. Complications from mesenteric desmoids were death (two patients), enterectomy (three), local resection (three), fistula (one), cholangitis and local resection (one), bowel obstruction (one) and bowel and ureteric obstruction (one). Preoperative polyp burden ranged from 0 to 100 in eight patients (median age 24.5 (range 16-39) years) and more than 100 in seven (median age 39 (range 31-64) years). One patient had no record of polyp burden. In individuals with 3' APC mutations, abdominal surgery is associated with a 65 per cent risk of developing mesenteric desmoids. An alternative strategy might be to attempt to manage the polyps endoscopically.
    British Journal of Surgery 09/2007; 94(8):1009-13. · 4.84 Impact Factor
  • Seminars in Oncology 01/2007; 34(5):411. · 4.33 Impact Factor
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    ABSTRACT: We assessed the association between breast cancer (BC) and colorectal cancer (CRC) from referral pattern to the Regional Genetics Service including molecular analysis. Hospital computer records and/or department referral books were used to identify cases referred to the Regional Genetic Service during a 16-year period (1990-2005 inclusive). All files were reviewed along with associated demographic data, risk assessments, referral details and results from mutation testing. Families were assessed for hereditary breast and colorectal cancer (HBCC) criteria, and all families with eligible individuals were tested for the 1100delC mutation in CHEK2. A total of 8,612 families were identified. One hundred and sixteen of 1,631 (7.5%) families with a primary referral for CRC fulfilled the criteria for HBCC, whereas only 68/6981 (1%) BC referrals fulfilled these criteria. Blood samples were obtained from 113 individuals from 83/184 families. Only 1/113 (1%) has screened positive for the CHEK2 mutation, whereas 14 (17%) families segregate BRCA1/2 mutations and at least 7 (8.5%) carry MLH1/MSH2 mutations. HBCC syndrome, if it exists as a separate entity, is not likely to be due to CHEK2 mutations. Many families are explicable by existing high-penetrance genes, and further work is necessary to elucidate whether the remainder is due to chance or as yet undiscovered genes.
    Clinical Genetics 12/2006; 70(5):388-95. · 3.94 Impact Factor
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    ABSTRACT: Mass screening for colorectal cancer reduces mortality and, with recent advances in molecular genetics, molecular stool-based tests have produced promising results. This article reviews this innovation and discusses its clinical significance. Medline searches were used to identify recent key articles relating to stool-based testing. Further articles were obtained by manual scanning of the reference lists of identified papers. Current screening methods are based on endoscopic, radiological and stool-based testing. Recent recognition of the adenoma-carcinoma sequence and pathophysiological studies of colonic epithelium have enabled tumour markers to be used in the screening setting. Non-invasive molecular stool testing has now been shown to have a high sensitivity and specificity. Recent studies on molecular stool-based testing have shown higher sensitivity and specificity than earlier studies, but larger clinical trials are required. Laboratory methods are still undergoing research, with the aim of improving sensitivity to allow large-scale testing.
    British Journal of Surgery 08/2004; 91(7):790-800. · 4.84 Impact Factor

Publication Stats

224 Citations
70.36 Total Impact Points

Institutions

  • 2010–2014
    • Central Manchester University Hospitals NHS Foundation Trust
      • • Department of Colorectal Surgery and Stoma Care
      • • Department of Respiratory Medicine (Manchester Royal Infirmary)
      Manchester, England, United Kingdom
  • 2008–2012
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom
  • 2006–2007
    • Saint Mary's Hospital Center
      Montréal, Quebec, Canada