In primary care, assessing which patients with bowel symptoms harbour significant disease (cancer, higher-risk adenoma or IBD) is difficult. We studied the diagnostic accuracies of faecal haemoglobin ...(FHb) and faecal calprotectin (FC) in a cohort of symptomatic patients.
From October 2013 to March 2014, general practitioners were prompted to request FHb and FC when referring patients with bowel symptoms to secondary care. Faecal samples were analysed for haemoglobin (EIKEN OC-Sensor io) and calprotectin (BÜHLMANN Calprotectin ELISA). Patients triaged to endoscopy were investigated within 6 weeks. All clinicians and endoscopists were blind to the faecal test results. The diagnostic accuracies of FHb and FC for identification of significant bowel disease were assessed.
1043 patients returned samples. FHb was detectable in 57.6% (median 0.4 µg/g, 95% CI 0.4 to 0.8; range 0-200). FC at 50 µg/g or above was present in 60.0%. 755 patients (54.6% women, median age 64 years (range 16-90, IQR 52-73)) returned samples and completed colonic investigations. 103 patients had significant bowel disease; the negative predictive values of FHb for colorectal cancer, higher-risk adenoma and IBD were 100%, 97.8% and 98.4%, respectively. Using cut-offs of detectable FHb and/or 200 µg/g FC detected two further cases of IBD, one higher-risk adenoma and no additional cancers.
In primary care, undetectable FHb is a good 'rule-out' test for significant bowel disease and could guide who requires investigation.
The importance of asymmetric divisions for stem cell function and maintenance is well established in the developing nervous system and the skin; however, its role in gut epithelium and its importance ...for tumorigenesis is still debated. We demonstrate alignment of mitotic spindles perpendicular to the apical surface specifically in the stem cell compartments of mouse and human intestine and colon. This orientation correlates with the asymmetric retention of label-retaining DNA. Both the preference for perpendicular spindle alignment and asymmetric label retention are lost in precancerous tissue heterozygous for the adenomatous polyposis coli tumor suppressor (
Apc). This loss correlates with cell shape changes specifically in the stem cell compartment. Our data suggest that loss of asymmetric division in stem cells might contribute to the oncogenic effect of
Apc mutations in gut epithelium.
► Mitotic spindles in intestinal stem cells align perpendicularly ► In precancerous tissue, this spindle orientation bias is lost ► Spindle alignment correlates with segregation of unreplicated DNA ► Loss of unreplicated DNA occurs more quickly in precancerous tissue
Cancers exhibit abnormal molecular signatures associated with disease initiation and progression. Molecular signatures could improve cancer screening, detection, drug development and selection of ...appropriate drug therapies for individual patients. Typically only very small amounts of tissue are available from patients for analysis and biopsy samples exhibit broad heterogeneity that cannot be captured using a single marker. This report details application of an in-house custom designed GenomeLab System multiplex gene expression assay, the hCellMarkerPlex, to assess predictive gene signatures of normal, adenomatous polyp and carcinoma colon tissue using archived tissue bank material. The hCellMarkerPlex incorporates twenty-one gene markers: epithelial (EZR, KRT18, NOX1, SLC9A2), proliferation (PCNA, CCND1, MS4A12), differentiation (B4GANLT2, CDX1, CDX2), apoptotic (CASP3, NOX1, NTN1), fibroblast (FSP1, COL1A1), structural (ACTG2, CNN1, DES), gene transcription (HDAC1), stem cell (LGR5), endothelial (VWF) and mucin production (MUC2). Gene signatures distinguished normal, adenomatous polyp and carcinoma. Individual gene targets significantly contributing to molecular tissue types, classifier genes, were further characterised using real-time PCR, in-situ hybridisation and immunohistochemistry revealing aberrant epithelial expression of MS4A12, LGR5 CDX2, NOX1 and SLC9A2 prior to development of carcinoma. Identified gene signatures identify aberrant epithelial expression of genes prior to cancer development using in-house custom designed gene expression multiplex assays. This approach may be used to assist in objective classification of disease initiation, staging, progression and therapeutic responses using biopsy material.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Faecal haemoglobin concentration (f-Hb), estimated using a faecal immunochemical test, can be safely implemented in primary care to assess risk of colorectal cancer (CRC). Clinical ...outcomes of patients presenting with symptoms of lower gastrointestinal disease were examined using an extensive range of f-Hb thresholds to decide on reassurance or referral for further investigation.
Methods
All patients who attended primary care and submitted a single faecal specimen faecal immunochemical test in the first year of the routine service had f-Hb estimated using HM-JACKarc: f-Hb thresholds from <2 to ≥ 400 µg Hb/g faeces (µg/g) were examined.
Results
Low f-Hb thresholds of <2, <7, <10 and <20 µg/g gave respective CRC risks of 0.1, 0.3, 0.3 and 0.4%, numbers needed to scope for one CRC of 871, 335, 300 and 249, and ‘false negative’ rates of 2.9, 11.4, 13.3 and 17.1%. With thresholds of <2, <7, <10 and <20 µg/g, 48.6, 74.6, 78.1 and 83.2% respectively of symptomatic patients could be managed without further investigation. With reassurance thresholds of <2 µg/g, <7 µg/g and <10 µg/g, the thresholds for referral for urgent investigation would be >400 µg/g, ≥200 µg/g and ≥100 µg/g. However, patients with a f-Hb concentration of <10 or <20 µg/g with iron deficiency anaemia, or with severe or persistent symptoms, should not be denied further investigation.
Conclusions
In primary care, f-Hb, in conjunction with clinical assessment, can safely and objectively determine individual risk of CRC and decide on simple reassurance or urgent, or routine referral.
Colorectal cancer is one of the most significant causes of cancer death. A genetic model for colorectal cancer has been proposed in which the sequential accumulation of mutations in specific genes, ...including adenomatous polyposis coli (APC), Kirsten-ras (K-ras), and p53, drives the transition from healthy colonic epithelia through increasingly dysplastic adenoma to colorectal cancer. We have characterized tumor mutation spectra in a large cohort of colorectal cancer patients. In marked contrast to the predictions of the sequential model of mutation accumulation, only 6.6% of tumors were found to contain mutations in APC, K-ras, and p53, with 38.7% of tumors containing mutations in only one of these genes. The most common combination of mutations was p53 and APC (27.1%), whereas mutations in both p53 and K-ras were extremely rare. Statistical analysis (two-sided Fisher's exact test) confirmed that mutations in K-ras and p53 co-occurred less frequently than expected by chance (P < 0.01, Fisher's exact test). This finding suggests that these mutations lie on alternate pathways of colorectal tumor development. The heterogeneous pattern of tumor mutations in our patient cohort suggests that multiple alternative genetic pathways to colorectal cancer exist and that the widely accepted genetic model of cancer development is not representative of the majority of colorectal tumors.
•This ESO-ESMO ABC 5 Clinical Practice Guideline provides key recommendations for managing advanced breast cancer patients.•It provides updates on managing patients with all breast cancer subtypes, ...LABC, follow-up, palliative and supportive care.•Updated diagnostic and treatment algorithms are also provided.•All recommendations were compiled by a multidisciplinary group of international experts.•Recommendations are based on available clinical evidence and the collective expert opinion of the authors.
Prediction models for colorectal cancer (CRC) detection in symptomatic patients, based on easily obtainable variables such as fecal haemoglobin concentration (f‐Hb), age and sex, may simplify CRC ...diagnosis. We developed, and then externally validated, a multivariable prediction model, the FAST Score, with data from five diagnostic test accuracy studies that evaluated quantitative fecal immunochemical tests in symptomatic patients referred for colonoscopy. The diagnostic accuracy of the Score in derivation and validation cohorts was compared statistically with the area under the curve (AUC) and the Chi‐square test. 1,572 and 3,976 patients were examined in these cohorts, respectively. For CRC, the odds ratio (OR) of the variables included in the Score were: age (years): 1.03 (95% confidence intervals (CI): 1.02–1.05), male sex: 1.6 (95% CI: 1.1–2.3) and f‐Hb (0–<20 µg Hb/g feces): 2.0 (95% CI: 0.7–5.5), (20‐<200 µg Hb/g): 16.8 (95% CI: 6.6–42.0), ≥200 µg Hb/g: 65.7 (95% CI: 26.3–164.1). The AUC for CRC detection was 0.88 (95% CI: 0.85–0.90) in the derivation and 0.91 (95% CI: 0.90–093; p = 0.005) in the validation cohort. At the two Score thresholds with 90% (4.50) and 99% (2.12) sensitivity for CRC, the Score had equivalent sensitivity, although the specificity was higher in the validation cohort (p < 0.001). Accordingly, the validation cohort was divided into three groups: high (21.4% of the cohort, positive predictive value—PPV: 21.7%), intermediate (59.8%, PPV: 0.9%) and low (18.8%, PPV: 0.0%) risk for CRC. The FAST Score is an easy to calculate prediction tool, highly accurate for CRC detection in symptomatic patients.
What's new?
Lower gastrointestinal symptoms potentially indicative of colorectal cancer (CRC) are a common reason for physician visits. While the probability that any one of those symptoms is associated with CRC is low, identifying patients for further screening remains a challenge. Here, the possibility of improving CRC diagnostic accuracy and risk stratification was explored using a three‐variable FAST Score based on fecal hemoglobin concentration, age, and sex. Among symptomatic patients referred to colonoscopy, the FAST Score prediction model identified three risk groups, the lowest of which ruled out CRC. Threshold scores were sensitive across variables, including country, age, and sex.
Objective
To compare interval cancer proportions (ICP) in the faecal immunochemical test (FIT)-based Scottish Bowel Screening Programme (SBoSP) with the former guaiac faecal occult blood test ...(gFOBT)-based SBoSP and investigate associations between interval cancer (IC) and faecal haemoglobin concentration (f-Hb) threshold, sex, age, deprivation, site, and stage.
Methods
The ICP data from first year of the FIT-based SBoSP and the penultimate year of the gFOBT-based SBoSP were compared in a prospective cohort design.
Results
With FIT, 801 colorectal cancers (CRCs) were screen detected (SDC), 802 were in non-participants, 548 were ICs, 39 were colonoscopy missed and 72 were diagnosed after incomplete screening; with gFOBT: 540, 904, 556, 45, and 13, respectively. FIT had a significantly higher proportion of SDC compared to IC than gFOBT. For FIT and gFOBT, ICP was significantly higher in women than men. As f-Hb threshold increased, ICP increased and, for any f-Hb threshold for men, a lower threshold was required for comparable ICP in women. In Scotland, the current threshold of ≥80 µg Hb/g faeces would have to be lowered to ≥40 µg Hb/g faeces for women to achieve sex equality for ICP. In the FIT-based SBoSP, there were four times as many stage I SDC than IC. This was reversed in advanced stages, with twice as many stage IV CRC diagnosed as IC versus SDC.
Conclusions
Reducing the numbers of IC requires lowering the f-Hb threshold. Using different f-Hb thresholds for women and men could eliminate the sex disparity, but with additional colonoscopy.
Guaiac faecal occult blood tests are being replaced by faecal immunochemical tests (FIT). We investigated whether faecal haemoglobin concentration (f-Hb) was related to stage in progression of ...colorectal neoplasia, studying cancer and adenoma characteristics in an evaluation of quantitative FIT as a first-line screening test.
We invited 66 225 individuals aged 50-74 years to provide one sample of faeces. f-Hb was measured on samples from 38 720 responders. Colonoscopy findings and pathology data were collected on the 943 with f-Hb ≥ 400 ng Hb/ml (80 µg Hb/g faeces).
Of the 814 participants with outcome data (median age: 63 years, range 50-75, 56.4% male), 39 had cancer, 190 high-risk adenoma (HRA, defined as ≥ 3 or any ≥ 10 mm) and 119 low-risk adenoma (LRA). 74.4% of those with cancer had f-Hb>1000 ng Hb/ml compared with 58.4% with HRA, and 44.1% with no pathology. Median f-Hb concentration was higher in those with cancer than those with no (p<0.002) or non-neoplastic (p<0.002) pathology, and those with LRA (p=0.0001). Polyp cancers had lower concentrations than more advanced stage cancers (p<0.04). Higher f-Hb was also found in those with HRA than with LRA (p<0.006), large (>10 mm) compared with small adenoma (p<0.0001), and also an adenoma displaying high-grade dysplasia compared with low-grade dysplasia (p<0.009).
f-Hb is related to severity of colorectal neoplastic disease. This has ramifications for the selection of the appropriate cut-off concentration adopted for bowel screening programmes.
Objectives
Quantitative faecal immunochemical tests (FIT) for faecal haemoglobin (f-Hb) in colorectal cancer (CRC) screening pose challenges when colonoscopy is limited. For low positivity rates, ...high f-Hb concentration cut-offs are required, but little is known about interval cancer (IC) proportions using FIT. We assessed IC proportions using an 80 µg Hb/g cut-off.
Methods
In two NHS Boards in the Scottish Bowel Screening Programme, f-Hb was estimated for 30,893 participants aged 50–75, of whom 753 participants with f-Hb ≥ 80 µg Hb/g were referred for colonoscopy. ICs, defined as CRC within two years of a negative result, were identified from the Scottish Cancer Registry.
Results
There were 31 ICs and 30 screen-detected (SD) CRCs, an IC proportion of 50.8% (48.4% for men, 53.3% for women). CRC site distribution was similar between ICs and SD, but ICs were later stage (46.7% and 33.3%, Dukes’ stages C and D, respectively). Of 31 ICs, 23 had f-Hb < 10 µg Hb/g, including six with undetectable f-Hb. A f-Hb cut-off of 10 µg Hb/g would have raised the positivity rate from 2.4% to 9.4%, increased colonoscopy requirement from 753 to 2147, and reduced the IC proportion to 38.3%.
Conclusions
The IC proportion was similar to that seen with guaiac-based FOBT. The later stage distribution of ICs highlights the benefits of lower f-Hb cut-offs, but with 19.4% of ICs having undetectable f-Hb, some cancers would have been missed, even with drastic reduction in the f-Hb cut-off.
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