Article

Risk stratification of Symptomatic Patients Suspected of Colorectal Cancer using Faecal and Urinary Markers

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Abstract

Background Faecal markers such as faecal immunochemical test for haemoglobin (FIT) and faecal calprotectin (FCP) have been increasingly used to exclude colorectal cancer (CRC) and colonic inflammation. However, in those with lower gastrointestinal symptoms, there are considerable numbers with cancer but have a negative FIT test (false negative), which, has impeded its use in clinical practice. Aims We undertook a diagnostic accuracy study of CRC using faecal immunochemical test for haemoglobin (FIT), faecal calprotectin (FCP) and urinary volatile organic compounds (VOCs) in patients with lower gastrointestinal symptoms. Methods 1016 symptomatic patients with suspected CRC referred by family physicians were recruited prospectively in accordance with national referring protocol. A total of 562 patients, who completed colonic investigations, in addition to providing stool for FIT, FCP as well as urine samples for urinary VOC measurements, were included in the final outcome measures. Results The sensitivity and specificity for CRC using FIT was 0.80 (95% confidence interval (CI): 0.66 – 0.93) and 0.93 (CI: 0.91 – 0.95) respectively. For urinary VOCs, the sensitivity and specificity for CRC was 0.63 (CI:0.46 – 0.79) and 0.63 (CI:0.59 – 0.67) respectively. However, for those who were FIT negative CRC (false negatives), adding urinary VOCs resulted in sensitivity of 0.97 (CI: 0.90 – 1.0) and specificity of 0.72 (CI: 0.68 ‐ 0.76). Conclusions When applied to FIT negative group, urinary VOCs improves CRC detection (sensitivity rises from 0.80 to 0.97) thus showing promise as a second stage test to complement FIT in CRC detection. This article is protected by copyright. All rights reserved.

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... A meta-analysis study reports that FITs could detect CRC with a pooled sensitivity of 79% and specificity of 94% [7], leading to a reduction of mortality of 22% in areas where FIT screening programmes were active [8]. In practice, there is a wide variation in sensitivity, and FITs can still miss more than 10% of cancers [9,10]. In screening for cancers, the falsenegative rate can vary by 66% depending on the cut-off thresholds used [5,6,11]. ...
... A previous observational case cohort study [9,10] The previously published data provided a reference for establishing a sensitivity cut-off threshold for this study's VOC analysis, suggesting it should be set at 0.63. ...
... Initial analysis of data [9,10] was based on calibration of the instrument on a subset of urine samples taken from a previous research project-the FAMISHED study-that had been retained in storage at −80 • C. Unfortunately, this calibration was limited by differences between study population groups. Here, we document the steps taken to unravel the data acquired from the RECEDE study and summarise the results obtained for VOC measurements of urine samples. ...
Article
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The profile of Volatile Organic Compounds (VOCs) may help prioritise at-risk groups for early cancer detection. Urine sampling has been shown to provide good disease accuracy whilst being patient acceptable compared to faecal analysis. Thus, in this study, urine samples were examined using an electronic nose with metal oxide gas sensors and a solid-phase microextraction sampling system. A calibration dataset (derived from a previous study) with CRC-positive patients and healthy controls was used to train a radial basis function neural network. However, a blinded analysis failed to detect CRC accurately, necessitating an enhanced data-processing strategy. This new approach categorised samples by significant bowel diseases, including CRC and high-risk polyps. Retraining the neural network showed an area under the ROC curve of 0.88 for distinguishing CRC versus non-significant bowel disease (without CRC, polyps or inflammation). These findings suggest that, with appropriate training sets, urine VOC analysis could be a rapid, low-cost method for early detection of precancerous colorectal polyps and CRC.
... The study selection process and reasons for exclusions are shown in Fig. 1 29,32,[36][37][38][39][41][42][43][44]46,48,55,57,58,61,62,69,70,[74][75][76]79,82 secondary and tertiary care (n = 3), 27,28,40 and tertiary care (n = 1). 45 One study was unclear regarding the setting. 81 Databases or registries were used in 17 studies. ...
... One study examined patients from two different countries: Scotland and Spain. 18 A further 24 studies assessed patients from the UK, 30,31,38,41,[43][44][45][46][47]51,56,57,[59][60][61][62]66,70,71,77,80,81 eight from Denmark, 35,39,48,69,74,76,79,82 seven from Spain, 19,30,34,40,49,63,65 five from the Netherlands, 50,[52][53][54]64 five from Sweden, 67,68,78,83,84 four from Australia, 27,28,37,72 two from China, 32,55 one from the USA, 73 one from Canada, 42 one from New Zealand, 58 one from Egypt, 75 one from Italy, 36 one from Malaysia 33 and one from Nigeria. 29 For further demographic information see Table 1. ...
... Twenty-three of the studies included FIT (n = 22) or gFOBT (n = 1) combined with one or more other variables (Table 2) only, 30,34,40,[43][44][45]60,65,70,81 four studies presented validations of models, 30,46,49 three studies presented both development and validation, 18,19,63 and six were classed as PPV only studies (i.e. they reported PPVs for FIT in combination with at least one other factor). 32,36,51,67,68,71 The cut-off considered positive for FIT varied between studies (Table 2). ...
Article
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Background Colorectal cancer (CRC) incidence and mortality are increasing internationally. Endoscopy services are under significant pressure with many overwhelmed. Faecal immunochemical testing (FIT) has been advocated to identify a high-risk population of symptomatic patients requiring definitive investigation by colonoscopy. Combining FIT with other factors in a risk prediction model could further improve performance in identifying those requiring investigation most urgently. We systematically reviewed performance of models predicting risk of CRC and/or advanced colorectal polyps (ACP) in symptomatic patients, with a particular focus on those models including FIT. Methods The review protocol was published on PROSPERO (CRD42022314710). Searches were conducted from database inception to April 2023 in MEDLINE, EMBASE, Cochrane libraries, SCOPUS and CINAHL. Risk of bias of each study was assessed using The Prediction study Risk Of Bias Assessment Tool. A narrative synthesis based on the guidelines for Synthesis Without Meta-Analysis was performed due to study heterogeneity. Findings We included 62 studies; 23 included FIT (n = 22) or guaiac Faecal Occult Blood Testing (n = 1) combined with one or more other variables. Twenty-one studies were conducted solely in primary care. Generally, prediction models including FIT consistently had good discriminatory ability for CRC/ACP (i.e. AUC >0.8) and performed better than models without FIT although some models without FIT also performed well. However, many studies did not present calibration and internal and external validation were limited. Two studies were rated as low risk of bias; neither model included FIT. Interpretation Risk prediction models, including and not including FIT, show promise for identifying those most at risk of colorectal neoplasia. Substantial limitations in evidence remain, including heterogeneity, high risk of bias, and lack of external validation. Further evaluation in studies adhering to gold standard methodology, in appropriate populations, is required before widespread adoption in clinical practice. Funding 10.13039/501100000272National Institute for Health and Care Research (NIHR) [10.13039/501100000664Health Technology Assessment Programme (HTA) Programme (Project number 133852).
... Sixteen studies -involving 2721 participants; 837 CRCs, 266 adenomas and 1618 controlsmet the inclusion criteria (Appendix Figure 1) 22,23,[30][31][32][33][34][35][36][37][38][39][40][41][42][43] . Eight records performed untargeted chemical identification using gas chromatography-mass spectrometry (GC-MS) 23,31,[33][34][35][36][37][38][41][42][43] , three targeted chemical identification using GC-MS and seven chemical fingerprinting using an electronic nose, field asymmetric ion mobility spectrometry (FAIMS) or gas chromatography-ion mobility spectrometry (GC-IMS) 22,23,30,32,39,40,42 . ...
... Sixteen studies -involving 2721 participants; 837 CRCs, 266 adenomas and 1618 controlsmet the inclusion criteria (Appendix Figure 1) 22,23,[30][31][32][33][34][35][36][37][38][39][40][41][42][43] . Eight records performed untargeted chemical identification using gas chromatography-mass spectrometry (GC-MS) 23,31,[33][34][35][36][37][38][41][42][43] , three targeted chemical identification using GC-MS and seven chemical fingerprinting using an electronic nose, field asymmetric ion mobility spectrometry (FAIMS) or gas chromatography-ion mobility spectrometry (GC-IMS) 22,23,30,32,39,40,42 . Study characteristics, identified neoplasm-associated VOCs and performance outcomes are summarized in Table 1. ...
... The studies performing chemical fingerprinting were deemed at lower risk of bias, yet some failed to report whether colonic assessment was of high-quality. Fifteen studies did not match the review question as these included patients once diagnosis had been established 22,30,31,[33][34][35][36][37][38][41][42][43] or patients with a higher pre-test probability of CRC compared to the screening population 23,32,40 . ...
Article
Background: The faecal immunochemical test (FIT) suffers from suboptimal performance and participation in colorectal cancer (CRC) screening. Urinary volatile organic compounds (VOCs) may be a useful alternative. We aimed to determine the diagnostic potential of urinary VOCs for CRC/adenomas. By relating VOCs to known pathways, we aimed to gain insight into the pathophysiology of colorectal neoplasia. Methods: A systematic search was performed in PubMed, EMBASE and Web of Science. Original studies on urinary VOCs for CRC/adenoma detection with a control group were included. QUADAS-2 tool was used for quality assessment. Meta-analysis was performed by adopting a bivariate model for sensitivity/specificity. Fagan's nomogram estimated the performance of combined FIT-VOC. Neoplasm-associated VOCs were linked to pathways using the KEGG database. Results: Sixteen studies-involving 837 CRC patients and 1618 controls-were included; 11 performed chemical identification and 7 chemical fingerprinting. In all studies, urinary VOCs discriminated CRC from controls. Pooled sensitivity and specificity for CRC based on chemical fingerprinting were 84% (95% CI 73-91%) and 70% (95% CI 63-77%), respectively. The most distinctive individual VOC was butanal (AUC 0.98). The estimated probability of having CRC following negative FIT was 0.38%, whereas 0.09% following negative FIT-VOC. Combined FIT-VOC would detect 33% more CRCs. In total 100 CRC-associated urinary VOCs were identified; particularly hydrocarbons, carboxylic acids, aldehydes/ketones and amino acids, and predominantly involved in TCA-cycle or alanine/aspartate/glutamine/glutamate/phenylalanine/tyrosine/tryptophan metabolism, which is supported by previous research on (colorectal)cancer biology. The potential of urinary VOCs to detect precancerous adenomas or gain insight into their pathophysiology appeared understudied. Conclusion: Urinary VOCs hold potential for non-invasive CRC screening. Multicentre validation studies are needed, especially focusing on adenoma detection. Urinary VOCs elucidate underlying pathophysiologic processes.
... There are a growing number of studies that report using FIT in symptomatic patients as a means to identify advanced colorectal neoplasia [21][22][23][24][25][26][27][28], and the diagnostic accuracy of FIT at a threshold of 10 µg Hb/g faeces in this setting is becoming clear ( Table 2). A prediction model for CRC detection in symptomatic patients based on FIT concentration, age and sex may further aid diagnosis [29]. ...
... Neutrophils play a major role in the release of calprotectin at sites of inflammation, and faecal calprotectin (FC) has long been considered a potential biomarker of colorectal polyps and cancer [33]. However, FC is shown to have limited diagnostic accuracy for identifying patients with CRC, irrespective of stage [33][34][35][36][37] and this is reinforced by studies that have compared the sensitivity and specificity of FC to quantitative FIT in this setting [21,23,30,38,39]. ...
... VOCs are also detected in exhaled breath [14,82]. The potential diagnostic accuracy of VOCs for early detection of CRC, exemplified by the sensitivity and specificity of canine scent detection [83], is now reflected in studies that report VOCs in the headspace of urine [23,84,85], breath [86][87][88][89], blood [90] and faeces [91][92][93][94] (Table 3). There is also evidence that detection of urinary VOCs can improve CRC detection in FIT-negative patients [23]. ...
Article
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Colorectal cancer is a leading cause of mortality worldwide. The high incidence and the acceleration of incidence in younger people reinforces the need for better techniques of early detection. The use of noninvasive biomarkers has potential to more accurately inform how patients are prioritised for clinical investigation, which, in turn, may ultimately translate into improved survival for those subsequently found to have curable-stage CRC. This review surveys a wide range of CRC biomarkers that may (alone or in combination) identify symptomatic patients presenting in primary care who should be progressed for clinical investigation.
... The included studies involved 2312 individuals with the number of disease patients ranging from 6 to 127 in each study (table 1). Diagnostic performance was assessed for a range of medical conditions: inflammatory bowel disease (n = 5) [27,33,[36][37][38]; colorectal cancer (n = 3) [29,42,44]; various infections (i.e. C. difficile, Escherichia coli, and sepsis) (n = 3) [32,43,48]; liver disease (n = 2) [31,34]; diabetes (n = 2) [39,40]; anastomotic leakage (n = 2) [46,47]; bile acid diarrhoea (n = 1) [28]; coeliac disease (n = 1) [30]; gastrointestinal toxicity (n = 1) [26]; tuberculosis (n = 1) [35]; ovarian cancer (n = 1) [41]; and pancreatic cancer (n = 1) [45]. Most of the studies involved the analysis of urine (n = 13) [27-31, 39-42, 44-47], followed by faeces (n = 6) [26,32,[36][37][38]43] and breath (n = 3) [33][34][35]. ...
... One study involved the analysis of muscle or tissue excisions and secretions during surgery or postoperative care [48]. The majority of studies reported the use of the random forest algorithm (n = 7) [31,32,36,38,43,46,47] to give the best diagnostic performance, followed by sparse logistic (n = 6) [30,33,34,37,40,44], fisher discriminant (n = 3) [26,27,29], Gaussian process (n = 2) [35,39], linear discriminant (n = 2) [28,45], quadratic discriminant (n = 1) [41], logistic regression (n = 1) [42], and other (n = 1) [48]. ...
... 41 Algorithm based on local warning integrated with global feature. 42 Following pancreatic surgery. 43 Non-postoperative leakage observed. ...
Article
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Non-invasive medical diagnosis by analysing volatile organic compounds (VOCs) at the point-of-care is becoming feasible owing to recent advances in portable instrumentation. A number of studies have assessed the performance of a state-of-the-art VOC analyser (micro-chip high-field asymmetric waveform ion mobility spectrometry, FAIMS) for medical diagnosis. However, a comprehensive meta-analysis is needed to investigate the overall diagnostic performance of these novel methods across different medical conditions. An electronic search was performed using the CAplus and MEDLINE database through the SciFinder platform. The review identified a total of 23 studies and 2312 individuals. Eighteen studies were used for meta-analysis. A pooled analysis found an overall sensitivity of 80% (95% CI, 74%–85%, I ² = 62%), and specificity of 78% (95% CI, 70%–84%, I ² = 80%), which corresponds to the overall diagnostic performance of micro-chip FAIMS across many different medical conditions. The diagnostic accuracy was particularly high for coeliac and inflammatory bowel disease (sensitivity and specificity from 74% to 97%). The overall diagnostic performance was similar across breath, urine, and faecal matrices with sparse logistic regression and random forests algorithms resulting in higher diagnostic accuracy. Sources of variability likely arise from differences in sample storage, sampling protocol, method of data analysis, type of disease, sample matrix, and potentially to clinical and disease factors. The results of this meta-analysis indicate that micro-chip FAIMS is a promising candidate for disease screening at the point-of-care, particularly for gastroenterology diseases. This review provides recommendations that should improve the techniques relevant to diagnostic accuracy of future VOC and point-of-care studies.
... However, the diagnostic accuracy of FAIMS-detected urinary VOCs, in a larger cohort including 562 patients, was lower than FIT (63% sensitivity and 63% specificity vs. 80% sensitivity and 93% specificity, respectively) [57]. Unsatisfactory results were observed in high-risk adenomas (specificity of 16%). ...
... Unsatisfactory results were observed in high-risk adenomas (specificity of 16%). Combined urinary VOCs and FIT did not provide a significant advantage (80% sensitivity and 89% specificity) [57]. ...
... Indeed, this novel diagnostic approach is relatively unexpansive, as fecal VOC profiling costs approximately €11 [35], 30% less than fecal occult blood testing [72]. Urinary VOC evaluation cost is slightly more expensive, twice as much as a fecal immunochemical test (28 vs. 18 £/test) [55,57]. ...
Article
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Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the Western world. Early detection decreases incidence and mortality. Screening programs based on fecal occult blood testing help identify patients requiring endoscopic examination, but accuracy is far from optimal. Among the alternative strategies, volatile organic compounds (VOCs) represent novel potentially useful biomarkers of colorectal cancer. They also represent a promising tool for the screening of both intestinal inflammation and related CRC. The review is focused on the diagnostic potential of VOCs in sporadic CRC and in inflammatory bowel diseases (IBD), which increase the risk of CRC, analyzing future clinical applications. Despite limitations related to inadequate strength of evidence, differing analytical platforms identify different VOCs, and this unconventional approach for diagnosing colorectal cancer is promising. Some VOC profiles, besides identifying inflammation, seem disease-specific in inflammatory bowel diseases. Thus, breath, urine, and fecal VOCs provide a new and promising clinical approach to differential diagnosis, evaluation of the inflammatory status, and possibly the assessment of treatment efficacy in IBD. Conversely, specific VOC patterns correlating inflammatory bowel disease and cancer risk are still lacking, and studies focused on this issue are strongly encouraged. No prospective studies have assessed the risk of CRC development by using VOCs in samples collected before the onset of disease, both in the general population and in patients with IBD.
... Earlier studies did not report influence of IDA on diagnostic accuracy of FIT. 82 84 The prevalence of CRC in this cohort with IDA, as expected increased with bands of fHb levels; 1.2% in those with fHb under 9 ug/g, 13.5% in the band 10-200 ug/g and 38.9% in those with cut-offs >200 ug/g. Another study in abstract form, suggested that fHb offered similar discriminatory values to symptoms and even younger patients. ...
... Volatile organic compounds (biomarkers of cellular inflammation and/or cancer) 108 have shown some promise with Widlak et al 82 showing improved CRC detection in those who are tested negative with fHb (<10 ug/g faeces) in terms of improving its sensitivity from 80% to 97%. A recent network meta-analysis of both fHb and volatile organic compounds for CRC detection demonstrated the probability of CRC detection improving from 0.5% to 0.1% when both tests were negative. ...
Article
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Faecal immunochemical testing (FIT) has a high sensitivity for the detection of colorectal cancer (CRC). In a symptomatic population FIT may identify those patients who require colorectal investigation with the highest priority. FIT offers considerable advantages over the use of symptoms alone, as an objective measure of risk with a vastly superior positive predictive value for CRC, while conversely identifying a truly low risk cohort of patients. The aim of this guideline was to provide a clear strategy for the use of FIT in the diagnostic pathway of people with signs or symptoms of a suspected diagnosis of CRC. The guideline was jointly developed by the Association of Coloproctology of Great Britain and Ireland/British Society of Gastroenterology, specifically by a 21-member multidisciplinary guideline development group (GDG). A systematic review of 13 535 publications was undertaken to develop 23 evidence and expert opinion-based recommendations for the triage of people with symptoms of a suspected CRC diagnosis in primary care. In order to achieve consensus among a broad group of key stakeholders, we completed an extended Delphi of the GDG, and also 61 other individuals across the UK and Ireland, including by members of the public, charities and primary and secondary care. Seventeen research recommendations were also prioritised to inform clinical management.
... The VOCs were detected from samples of both cancer and noncancer tissue, 11,12 urine, 13 plasma, 14 saliva, 15 bacteria culture, 16 and breath [17][18][19][20][21][22] and achieved more than 0.9 AUC of SROC to [28][29][30][31][32][33][34][35][36][37][38][39][40] The pooled sensitivity of VOCs differentiating GI cancer from precancerous lesions is 0.84 (95% CI: 0.67-0.92), the pooled specificity is 0.74 (95% CI: 0.43-0.91), and the AUC of SROC is 0.87 (95% CI: 0.84-0.89). ...
... and the AUC of SROC is 0.87 (95% CI: 0.84-0.89). 20,28,29,31,33,37 It was found that VOC combinations detected from different samples were different. We took VOCs for esophagogastric cancer as an example. ...
Article
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Background Volatile organic compounds (VOCs) have been involved in cancer diagnosis via breath, urine, and feces. We aimed to assess the diagnostic ability of VOCs on digestive cancers. Methods We systematically reviewed prospective clinical trials evaluating VOCs’ diagnostic ability on esophageal, gastric, colorectal, hepatic, and pancreatic cancer (PC). Databases including PubMed and Ovid-Medline were searched. Results A total of 35 trials with 5314 patient-times qualified for inclusion. The pooled sensitivity of VOCs diagnosing gastroesophageal cancer from healthy controls is 0.89 (95% confidence interval [CI]: 0.82-0.94), the pooled specificity is 0.890 (95% CI: 0.84-0.93), and area under the curve (AUC) of the summary receiver operating characteristic curve is 0.95 (95% CI: 0.93-0.95). The pooled sensitivity of VOCs diagnosing colorectal cancer from heathy controls is 0.92 (95% CI: 0.85-0.96), the pooled specificity is 0.88 (95% CI: 0.77-0.94), and the AUC is 0.96 (95% CI: 0.94-0.97). The pooled sensitivity of VOCs distinguishing gastrointestinal (GI) cancer from precancerous lesions is 0.84 (95% CI: 0.67-0.92), the pooled specificity is 0.74 (95% CI: 0.43-0.91), and the AUC is 0.87 (95% CI: 0.84-0.89). The pooled sensitivity of VOCs diagnosing hepatocellular carcinoma is 0.68 (95% CI: 0.52-0.81), the pooled specificity is 0.81 (95% CI: 0.47-0.96), and the AUC is 0.78 (95% CI: 0.74-0.81). The pooled sensitivity of VOCs diagnosing PC is 0.88 (95% CI: 0.80-0.93), the pooled specificity is 0.82 (95% CI: 0.62-0.93), and the AUC is 0.92 (95% CI: 0.89-0.94). Conclusions Volatile organic compounds have potential role in diagnosing GI cancer with comparatively high sensitivity, specificity, and AUC (PROSPERO registration number: CRD42021260039).
... The required number of participants with SBD to achieve this sensitivity is 200. Figure 2 shows CIs for different observed sensitivity cases of SBD (150, 200, 250). Figure 3 shows the widths of the CI limits are narrower and wider when the observed sensitivity is above or below 97%, 13 respectively. This sample size is also robust to negative predictive value (NPV), an outcome that is of interest as a high NPV suggests that participants without SBD would avoid having colonoscopy examination. ...
... Assuming the prevalence of SBD in the study population is 19%, then 1053 participants are required. Based on our previous study, 13 the return rate of both stool and urine samples that are eligible for analysis is about 55% resulting in a total required sample size of 1915 participants across multiple UK sites within a 24-month period. ...
Article
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Introduction Demand for colonoscopies and CT colonography (CTC) is exceeding capacity in National Health Service Trusts. In many patients colonoscopies and CTCs show no significant bowel disease (SBD). Faecal Immunochemical Testing (FIT) is being introduced to prioritise patients for colonoscopies but is insufficient to identify non-SBD patients meaning colonoscopy and CTC demand remains high. The REducing Colonoscopies in patients without significant bowEl DiseasE (RECEDE) study aims to test urine volatile organic compound (VOC) analysis alongside FIT to improve detection of SBD and to reduce the number of colonoscopies and CTCs. Methods and analysis This is a multicentre, prospective diagnostic accuracy study evaluating whether stool FIT plus urine VOC compared with stool FIT alone improves detection of SBD in patients referred for colonoscopy or CTC due to persistent lower gastrointestinal symptoms. To ensure SBD is not missed, the dual test requires a high sensitivity, set at 97% with 95% CI width of 5%. Our assumption is that to achieve this sensitivity requires 200 participants with SBD. Further assuming 19% of all participants will have SBD and 55% of all participants will return both stool and urine samples we will recruit 1915 participants. The thresholds for FIT and VOC results diagnosing SBD have been pre-set. If either FIT or VOC exceeds the respective threshold, the participant will be classed as having suspected SBD. As an exploratory analysis we will be testing different thresholds. The reference comparator will be a complete colonoscopy or CTC. Secondary outcomes will look at optimising the FIT and VOC thresholds for SBD detection. An economic evaluation, using a denovo decision analytic model, will be carried out determine the costs, benefits and overall cost-effectiveness of FIT +VOC vs FIT followed by colonoscopy. Ethics and dissemination Ethical approval was obtained by Liverpool Central Research Ethics Committee (20/NW/0346). Trial registration number RECEDE is registered on Clinicaltrials.gov NCT04516785 & ISRCTN14982373 . This protocol was written and published before results of the trial were available.
... All assay methods are recommended by NICE and because these UK studies recruited from patients on the NG12 referral pathway, it is unexpected that they would be fundamentally different. Among the four studies that reported data for f-Hb <4 µg/g including our own [8,26,39], patient characteristics were similar (Supplementary Table 6), and although the percentage of CRC cases found varied between 2.5 and 6.2%, these are consistent with the expected 2-8% using symptoms alone in the United Kingdom [46,47]. The study by D'Souza et al. [26] was based on patients who had a colonoscopy, whereas our study included patients who had any investigation as part of the referral, which might partly explain the difference in the CRC miss rates and specificity. ...
... Chapman et al. [8] D'Souza et al. [26] McSorley et al. [34] Nicholson et al. [17] Our study Turvill et al. [28] Khan et al. [25] Widlak et al. [22] Widlak et al. [39] Overall Heterogeneity = 72%, p < 0.001 Nicholson et al. [17] Turvill et al. [28] Khan et al. [25] D'Souza et al. [26] Chapman et al. [8] McSorley et al. [34] Our study Fig. 2 Nine studies were conducted in the United Kingdom (patients recruited between 2015 and 2020), in which all patients were referred using the NICE NG12 pathway. CRC miss rate (100 minus sensitivity), and specificity using the lowest limit of detection for f-Hb in each study. ...
Article
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Background We evaluated whether faecal immunochemical testing (FIT) can rule out colorectal cancer (CRC) among patients presenting with ‘high-risk’ symptoms requiring definitive investigation. Methods Three thousand five hundred and ninety-six symptomatic patients referred to the standard urgent CRC pathway were recruited in a multi-centre observational study. They completed FIT in addition to standard investigations. CRC miss rate (percentage of CRC cases with low quantitative faecal haemoglobin [f-Hb] measurement) and specificity (percentage of patients without cancer with low f-Hb) were calculated. We also provided an updated literature review. Results Ninety patients had CRC. At f-Hb < 10 µg/g, the miss rate was 16.7% (specificity 80.1%). At f-Hb < 4 µg/g, the miss rate was 12.2% (specificity 73%), which became 3.3% if low FIT plus the absence of anaemia and abdominal pain were considered (specificity 51%). Within meta-analyses of 9 UK studies, the pooled miss rate was 7.2% (specificity 74%) for f-Hb < 4 µg/g. Discussion FIT alone as a triage tool would miss an estimated 1 in 8 cases in our study (1 in 14 from meta-analysis), while many people without CRC could avoid investigations. FIT can focus secondary care diagnostic capacity on patients most at risk of CRC, but more work on safety netting is required before incorporating FIT triage into the urgent diagnostic pathway.
... As in patients with confirmed cancer, FIT was superior (80% sensitivity) to VOC analysis alone (63% sensitivity). However, when applied to a FIT-negative CRC cohort, the two-step combination of FIT testing and urinary VOC detection increased the sensitivity to 97% 74 . This dual testing platform is comparable to the performance of colonoscopy but with a vast reduction in cost and improved patient experience supporting the use of VOC biomarker in the diagnosis of CRC. ...
... ,73 emphasising the requirement for non-stool methods. Several studies have aimed to characterise microbial-related biomarkers from urine64,74,75 , blood62,75 and oral samples 61 .2.1.2.1 Oral BiomarkersZhang et al., (2020) investigated the association between the oral microbiome and CRC by carrying out 16s rRNA sequencing on oral swab samples from CRC patients, CRA patients and healthy controls. Notably, the oral microbial alpha diversity was higher in the CRA and CRC cohorts compared to control patients, possibly underpinned by translocation of oral bacteria to the GI tract. ...
Article
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Over the last few decades it has been established that the complex interaction between the host and the multitude of organisms that compose the intestinal microbiota plays an important role in human metabolic health and disease. Whilst there is no defined consensus on the composition of a healthy microbiome due to confounding factors such as ethnicity, geographical locations, age and sex, there are undoubtedly populations of microbes that are consistently dysregulated in gut diseases including colorectal cancer (CRC). In this review, we discuss the most recent advances in the application of the gut microbiota, not just bacteria, and derived microbial compounds in the diagnosis of CRC and the potential to exploit microbes as novel agents in the management and treatment of CRC. We highlight examples of the microbiota, and their derivatives, that have the potential to become standalone diagnostic tools or be used in combination with current screening techniques to improve sensitivity and specificity for earlier CRC diagnoses and provide a perspective on their potential as biotherapeutics with translatability to clinical trials.
... The detection of volatile organic compounds (VOC) emanating from bodily fluids has been shown to have a good diagnostic performance for CRC. [10][11][12][13] A recent meta-analysis by Zhou et al 14 showed that VOC had an overall sensitivity of 0.82 and specificity of 0.79 for the detection of CRC. This suggests that VOC has potential to be used as a complementary test to FIT, in particular in, the FITnegative group. ...
... Overall, the search had identified 121 articles for FIT and 133 articles for VOC. Among them, 15 studies 20-34 were included for FIT meta-analysis and 14 studies[10][11][12][13][35][36][37][38][39][40][41][42][43][44] for VOC meta-analysis. The selection process of the studies, for both meta-analyses, ...
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Background Faecal immunochemical test (FIT) is emerging as a valid test to rule‐out the presence of colorectal cancer (CRC). However, the accuracy of FIT is dependent on the cut‐off applied. An additional low‐cost test could improve further detection of CRC. Aims To evaluate the efficacy of combined FIT and volatile organic compounds (VOC) in the detection of CRC within symptomatic populations. Methods Systematic reviews on the diagnostic accuracy of FIT and VOC, for the detection of CRC, were updated. Meta‐analyses were performed adopting a bivariate model for sensitivity and specificity. Clinical utility of combined FIT and VOC was estimated using Fagan's nomogram. Post‐test probability of FIT negatives was used as a pre‐test probability for VOC. Results The pooled sensitivity and specificity of FIT at 10 µg/g faeces, for the detection of CRC, were 0.914 (95% confidence interval [CI] = 0.894‐0.936) and 0.783 (CI = 0.850‐0.696), respectively. For VOC, the sensitivity was 0.837 (CI = 0.781‐0.881) and the specificity was 0.803 (CI = 0.870‐0.712). The area under the curve for FIT and VOC were 0.926 and 0.885, respectively. In a population with 5% CRC prevalence, the estimated probability of having CRC following a negative FIT was 0.5% and following both negative FIT and VOC was 0.1%. Conclusions In a FIT‐negative symptomatic population, VOC can be a good test to rule‐out the presence of CRC. The estimated probability reduction by 0.4% when both tests being negative offers adequate safety netting in primary care for the exclusion of CRC. The number needed to colonoscope to identify one CRC is eight if either FIT or VOC positive. Cost‐effectiveness and clinical accuracy of this approach will need further evaluation.
... accuracy for detection of advanced adenomas, with AUCs ranging between 0.73-0.96 [19,[36][37][38] (for urine data were scarce and more conflicting [40,41]). The higher AUCs for CRC and advanced adenomas observed in other studies compared to ours might be attributed to a type II error stemming from the small number of advanced neoplasia assessed in our study, as our study population was already under strict colonoscopy surveillance. ...
Article
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Background Non‐invasive biomarkers may reduce post‐colonoscopy colorectal cancer (CRC) rates and colonoscopy overuse in Lynch syndrome. Unlike faecal immunochemical test (FIT), faecal volatile organic compounds (VOCs) may accurately detect both advanced and non‐advanced colorectal neoplasia. Aim The aim of this study was to evaluate the potential of faecal VOCs—separately and with FIT—to guide optimal colonoscopy intervals in Lynch syndrome. Methods Prospective longitudinal multicentre study in which individuals with Lynch syndrome collected faeces before and after high‐quality surveillance colonoscopy. VOC‐patterns were analysed using field asymmetric ion mobility spectrometry (FAIMS) and gas chromatography‐ion mobility spectrometry (GC‐IMS) followed by machine learning pipelines, and combined with FIT at 2.55 μg Hb/g faeces. Gas chromatography time‐of‐flight mass spectrometry analysed individual VOC abundance. Results Among 200 included individuals (57% female, median 51 years), 62 had relevant neoplasia at colonoscopy: 3 CRC, 6 advanced adenoma (AA), 3 advanced serrated lesion (ASL), and 50 non‐advanced adenoma (NAA). Respective sensitivity and negative predictive value for CRC and AA (and also ASL in case of FAIMS) were 100% and 100% using FAIMS (54% specificity), and 89% and 99% using GC‐IMS (58% specificity). Respective sensitivity and specificity for any relevant neoplasia were 88% and 44% (FAIMS) and 84% and 28% (GC‐IMS); accuracy did not significantly improve upon VOC‐FIT. VOC‐patterns differed before and after polypectomy (AUC 0.70). NAA showed decreased faecal abundance of butanal, 2‐oxohexane, dimethyldisulphide and dimethyltrisulphide. Conclusions In Lynch syndrome, faecal VOCs may be a promising strategy for postponing colonoscopy and for follow‐up after polypectomy. Our results serve as a stepping stone for large validation studies. Trial Registration NL8749
... В целом полученные результаты позволяют заключить, что для КРР характерны метаболические сдвиги в виде усиления протеолитической и ослабления сахаролитической ферментации [44]. В настоящее время основным методом скрининга КРР является иммунохимическое тестирование кала, чья чувствительность и специфичность составили 80 и 93% [45]. При комбинировании этой методики с анализом ЛОС в моче специфичность выросла до 97%. ...
Article
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Diseases of the digestive system are very common among the population around the world. Diagnosis of the diseases of this group is expensive and often invasive, which greatly limits its accessibility to the population. Increasing the time of disease development before diagnosis increases the risk of complications and adverse outcomes. The use of volatile organic compounds (VOC) as a biomarker is becoming increasingly popular due to the accuracy and ease of use. The article examines the available analytical platforms of VOCs for detecting changes in the state of the digestive system, assesses their strengths and weaknesses, provides examples of VOC assessment tool for the diagnosis of certain diseases of the digestive system – inflammatory bowel diseases, colorectal cancer, infectious diarrhea and celiac disease.
... Sensitivity can range from a little over 60% to 100%. Widlak et al. demonstrated that the sensitivity and specificity of FAIMS analysis of urinary VOCs can be improved when combined with FIT [73]. The diagnostic ability of urinary VOC analysis with the FAIMS method has not been comprehensively and systematically reviewed. ...
Article
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Volatile organic compounds have drawn significant attention in recent years as a novel tool for non-invasive detection of a wide range of diseases, including gastrointestinal cancers, for which the need for effective, affordable, and non-invasive screening methods is substantial. Sample preparation is a fundamental step that greatly influences the quality of results and the feasibility of wide-range applications. This review summarizes sampling methods used in studies aiming at testing the diagnostic value of volatile organic compounds in gastrointestinal cancers, discussing in detail some of the recent advancements in automated sampling techniques. Finally, we propose some directions in which sample collection and processing can improve for VOC analysis to be popularized in clinical settings.
... У дуже цікавому дослідженні Widlak et al. спостерігали, що додаткове виявлення ЛОС у сечі в хибно-негативному FIT (тобто не вдалося виявити рак) збільшило виявлення КРР. Використання виявлення ЛОС у фекаліях (FIT і фекальний кальпротектин) і в сечі підвищило точність діагностики КРР з 80 % до 97 % і специфічність до 72 % у пацієнтів із симптомами нижнього відділу шлунковокишкового тракту [16]. ...
Article
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Introduction. The work considers new approaches to the development of modern alternative methods of detecting colorectal cancer (CRC), which are based on the recommendations of the European Society of Medical Oncology (ESMO) at the current stage. The purpose review of modern foreign sources of literature with laboratory achievements regarding the development of new alternative diagnostic methods of screening CRC.
... Among them, 22 studies employed VOC analysis for the diagnosis of colorectal cancer (7, 28-46, 48, 49), 9 studies utilized e-nose technology (25, 26, [50][51][52][53][54][55]58), and one study used both VOC analysis and e-nose (47). In the VOC studies, 10 studies used breath samples (7, 28-30, 38, 39, 41-43, 49), 6 studies used urine samples (32, 37,[44][45][46]48), 5 studies used fecal samples (31,33,35,36,40), and one study used salivary sample (34). Most studies used MS-based techniques, principally GC-MS (n=7), TD-GC-MS (n=4), FAIM (n=4), and SIFT-MS (n=2). ...
Article
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Introduction The detection of Volatile Organic Compounds (VOCs) could provide a potential diagnostic modality for the early detection and surveillance of colorectal cancers. However, the overall diagnostic accuracy of the proposed tests remains uncertain. Objective This systematic review is to ascertain the diagnostic accuracy of using VOC analysis techniques and electronic noses (e-noses) as noninvasive diagnostic methods for colorectal cancer within the realm of clinical practice. Methods A systematic search was undertaken on PubMed, EMBASE, Web of Science, and the Cochrane Library to scrutinize pertinent studies published from their inception to September 1, 2023. Only studies conducted on human subjects were included. Meta-analysis was performed using a bivariate model to obtain summary estimates of sensitivity, specificity, and positive and negative likelihood ratios. The Quality Assessment of Diagnostic Accuracy Studies 2 tool was deployed for quality assessment. The protocol for this systematic review was registered in PROSPERO, and PRISMA guidelines were used for the identification, screening, eligibility, and selection process. Results This review encompassed 32 studies, 22 studies for VOC analysis and 9 studies for e-nose, one for both, with a total of 4688 subjects in the analysis. The pooled sensitivity and specificity of VOC analysis for CRC detection were 0.88 (95% CI, 0.83-0.92) and 0.85 (95% CI, 0.78-0.90), respectively. In the case of e-nose, the pooled sensitivity was 0.87 (95% CI, 0.83-0.90), and the pooled specificity was 0.78 (95% CI, 0.62-0.88). The area under the receiver operating characteristic analysis (ROC) curve for VOC analysis and e-noses were 0.93 (95% CI, 0.90-0.95) and 0.90 (95% CI, 0.87-0.92), respectively. Conclusion The outcomes of this review substantiate the commendable accuracy of VOC analysis and e-nose technology in detecting CRC. VOC analysis has a higher specificity than e-nose for the diagnosis of CRC and a sensitivity comparable to that of e-nose. However, numerous limitations, including a modest sample size, absence of standardized collection methods, lack of external validation, and a notable risk of bias, were identified. Consequently, there exists an imperative need for expansive, multi-center clinical studies to elucidate the applicability and reproducibility of VOC analysis or e-nose in the noninvasive diagnosis of colorectal cancer. Systematic review registration https://www.crd.york.ac.uk/prospero/#recordDetails, identifier CRD42023398465.
... [6][7][8] Recently, there has been increased interest in improving the efficacy of non-invasive CRC screenings, including exploration of the use of biomarkers for CRC screening. [9][10][11][12][13][14][15][16][17] While existing biomarkerbased CRC screening tests offer promise in enhancing sensitivity, they often require a separate stool, blood, or urine sample to perform the test. This requirement for additional sample collection can reduce adherence, arguably the most important factor in the success of screening. ...
Article
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Background The faecal immunochemical test (FIT) is an inexpensive and convenient modality to screen for colorectal cancer. However, its one‐time sensitivity for detecting colorectal cancer and cancer precursors is limited. There is growing interest in using the non‐haemoglobin contents of FIT residual buffer to enhance colonic neoplasia detection. Aim To establish from the literature a framework to catalogue candidate biomarkers within FIT residual buffer for non‐invasive colorectal cancer screening. Methods The search strategy evaluated PubMed, Scopus, Web of Science, Embase, and Google Scholar for publications through 25 October 2023, with search terms including FIT, buffer, OC‐sensor, biomarkers, microbiome, microRNA (miR), colon, rectum, screening, neoplasm, and early detection. Studies employing home‐based collection samples using quantitative FIT first processed for haemoglobin were included. One author reviewed all articles; a second author completed a 20% full‐text audit to ensure adherence to eligibility criteria. Results A broad search yielded 1669 studies and application of eligibility criteria identified 18 relevant studies. Multiple protein, DNA/RNA, and microbiome biomarkers (notably haptoglobin, miR‐16, miR‐27a‐3p, miR‐92a, miR‐148a‐3p, miR‐223, miR‐421, let‐7b‐5p, and Tyzzerella 4) were associated with colorectal neoplasia. Furthermore, studies highlighted the short‐term stability of biomarkers for clinical use and long‐term stability for research purposes. Conclusions This scoping review summarises the framework and progress of research on stability of biomarkers in FIT residual buffer and their associations with colorectal neoplasia to guide opportunities for further confirmatory studies to enhance colorectal cancer screening.
... Furthermore-rather than purely acting as surrogate markers of inflammation-VOCs could give more information and distinguish between certain diseases, for example between infective gastroenteritis, UC, CD, or cancer, as VOC patterns are disparate based on the underlying disease. [51][52][53] There is more scope to evolve and observe different patterns of recognition. ...
Article
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Background: Volatile organic compounds (VOCs) show promise as potential biomarkers of for ulcerative colitis and Crohn's disease, two chronic idiopathic gastrointestinal disorders with diagnostic and management challenges. Non-invasive biomarkers aid early diagnosis and management. In this study we review studies of diagnostic accuracy of VOCs in inflammatory bowel disease. Methods: A systematic search was carried out on the Pubmed and Scopus databases; with sixteen studies reviewed and meta-analysis carried out on ten. Results: Meta analysis of 696 IBD cases against 605 controls revealed a pooled sensitivity and specificity of 87% (95% CI, 0.79 - 0.92) and 83% (95% CI, 0.73 - 0.90) respectively. AUC was 0.92. Conclusion: VOCs perform very well as non-invasive biomarkers of IBD; with much scope for future improvement and research.
... Future clinical applications will likely utilize both FITs and VOC analysis for cancer screening [99]. For example, Widlak et al. [100] found a sensitivity and specificity of 80% and 93%, respectively, for detecting CRC using FITs. However, when paired with urinary VOC analysis, a new sensitivity and specificity of 97% and 72% was achieved. ...
Article
Full-text available
Gastrointestinal (GI) diseases have a high prevalence throughout the United States. Screening and diagnostic modalities are often expensive and invasive, and therefore, people do not utilize them effectively. Lack of proper screening and diagnostic assessment may lead to delays in diagnosis, more advanced disease at the time of diagnosis, and higher morbidity and mortality rates. Research on the intestinal microbiome has demonstrated that dysbiosis, or unfavorable alteration of organismal composition, precedes the onset of clinical symptoms for various GI diseases. GI disease diagnostic research has led to a shift towards non-invasive methods for GI screening, including chemical-detection tests that measure changes in volatile organic compounds (VOCs), which are the byproducts of bacterial metabolism that result in the distinct smell of stool. Many of these tools are expensive, immobile benchtop instruments that require highly trained individuals to interpret the results. These attributes make them difficult to implement in clinical settings. Alternatively, electronic noses (E-noses) are relatively cheaper, handheld devices that utilize multi-sensor arrays and pattern recognition technology to analyze VOCs. The purpose of this review is to (1) highlight how dysbiosis impacts intestinal diseases and how VOC metabolites can be utilized to detect alterations in the microbiome, (2) summarize the available VOC analytical platforms that can be used to detect aberrancies in intestinal health, (3) define the current technological advancements and limitations of E-nose technology, and finally, (4) review the literature surrounding several intestinal diseases in which headspace VOCs can be used to detect or predict disease.
... The use of FIT has likely diverted more patients onto more CRC-focused pathways, however presently there is no consensus for the use of FIT in detecting adenomas in these patient groups. Use of novel biomarkers, such as urinary volatile organic compounds, to help improve FIT sensitivity remains in its infancy 33 and whether such adjuncts with FIT would change adenoma detection remains to be determined. At present the role of FIT in the follow-up of patients who have undergone recent polyp removal is controversial, as current miss rates for CRC and advanced adenomas at 3 years post-endoscopy are 30-40 per cent and 40-70 per cent respectively 34 . ...
Article
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Background: Measurement of faecal haemoglobin using faecal immunochemistry testing is recommended in patients presenting with symptoms suspicious for colorectal cancer, to aid in triage and prioritization of definitive investigations. While its role in colorectal cancer has been extensively investigated, the ability of faecal immunochemistry testing to detect adenomas in symptomatic patients is unclear. Methods: A multicentre prospective observational study was conducted between April 2017 and March 2019, recruiting adults from 24 hospitals across England and 59 general practices in London who had been urgently referred with suspected colorectal cancer symptoms. Each patient provided a stool sample for faecal immunochemistry testing, in parallel with definitive investigation. A final diagnosis for each patient was recorded, including the presence, size, histology, and risk type of colonic polyps. The outcome of interest was the sensitivity of faecal immunochemistry testing in detecting the presence of adenomas. Results: Of 3496 patients included in the analysis, 553 (15.8 per cent) had polyps diagnosed. Sensitivity of faecal immunochemistry testing for polyp detection was low across all ranges; with a cut-off for faecal haemoglobin of 4 µg/g or lower, sensitivity was 34.9 per cent and 46.8 per cent for all polyp types and high-risk polyps respectively. The area under the receiver operating characteristic curve in detection probability was relatively low for both intermediate-risk (0.63) and high-risk polyps (0.63). Conclusion: While faecal immunochemistry testing may be useful in prioritizing investigations to diagnose colorectal cancer, if used as a sole test, the majority of polyps would be missed and the opportunity to prevent progression to colorectal cancer may be lost.
... The prevalence of adenoma in the polyp surveillance population was considered as 40% [13]. A previous Cancers 2022, 14, 4951 6 of 16 study by Widlak et al. [24] showed that the sensitivity of FIT for the detection of adenoma was 0.53. The specificity was 0.68. ...
Article
Full-text available
(1) Background: The service capacity for colonoscopy remains constrained, and while efforts are being made to recover elective services, polyp surveillance remains a challenge. (2) Methods: This is a multi-centre study recruiting patients already on polyp surveillance. Stool and urine samples were collected for the faecal immunochemical test (FIT) and volatile organic compounds (VOC) analysis, and all participants then underwent surveillance colonoscopy. (3) Results: The sensitivity and specificity of VOC for the detection of a high-risk finding ((≥2 premalignant polyps including ≥1 advanced polyp or ≥5 premalignant polyps) were 0.94 (95% CI, 0.88 to 0.98) and 0.69 (95% CI, 0.64 to 0.75) respectively. For FIT, the sensitivity was (≥10 µg of haemoglobin (Hb) / g faeces) 0.54 (95% CI, 0.43 to 0.65) and the specificity was 0.79 (95% CI, 0.73 to 0.84). The probability reduction for having a high-risk finding following both negative VOC and FIT will be 24% if both tests are applied sequentially. (4) Conclusion: The diagnostic performance of VOC is superior to FIT for the detection of a high-risk finding. The performance further improves when VOC is applied together with FIT sequentially (VOC first and then FIT). VOC alone or the combination of VOC and FIT can be used as a triage tool for patients awaiting colonoscopy within a polyp surveillance population, especially in resource-constrained healthcare systems.
... Relevant studies have shown that FC combined with other stool tests has more diagnostic value. One study showed that FC combined with FIT had a sensitivity of 80% and a specificity of 93% in the diagnosis of CRC (9). At present, because FC detection still has many shortcomings, such as low specificity, high detection cost, and complicated detection steps and operations, it is not listed as a routine CRC detection method. ...
Article
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Colorectal cancer (CRC) is the third most common cancer in the world in terms of morbidity and mortality, which brings great health hazards and economic burdens to patients and society. A fecal examination is an effective method for clinical examination and the most commonly used method for the census. It is simple, non-invasive, and suitable for large-scale population screening. With the development of molecular biology, lots of efforts have been made to discover new fecal biomarkers for the early screening of colorectal cancer. In this review, we summarize and discuss the recent advances of fecal biomarkers for CRC screening or diagnosis, including DNA biomarkers, RNA biomarkers, protein biomarkers, gut microbes and volatile organic compounds focusing on their diagnostic evaluation for CRC, which can provide a basis for the further development of new and effective CRC fecal screening and early diagnosis techniques.
... It has been suggested that the addition of another biomarker, such as urinary volatile organic compounds (VOC), might offer a better strategy. 34 Widlak et al. 35 suggest a two-stage process using VOC testing in patients with negative FIT results may be superior to repeat FIT results since sensitivity for CRC is improved. ...
Article
Background: Faecal Immunochemical tests (FITs) in the assessment of patients presenting with symptoms have generally used a single sample. Little evidence pertains to the use of replicate, where a number of tests are done prior to decision-making or repeat FIT, where additional FIT are performed following clinical decision-making. Overwhelmingly, research has focused on FIT to help identify colorectal cancer (CRC). The aim of this review is to assess the available literature concerning replicate and repeat FIT in symptomatic patients to help generate consensus and guide future research. Methods: The terms 'faecal immunochemical test' or 'FIT' were combined with 'multiple' or 'repeat'. EMBASE, Medline and PubMed database and other searches were conducted. All papers published in English were included with no exclusion date limits until November 2021. Results: Of the 161 initial papers screened, seven were included for review. Qualitative and quantitative FIT outcomes were assessed in the studies. The primary aims of most related to whether replicate FIT increased diagnostic yield of CRC, with colonoscopy used as the reference standard. One publication assessed the impact of a new COVID-adapted pathway on CRC detection. No consensus on replicate FIT was apparent. Some concluded that FITs may help minimise missed CRC diagnoses: others showed no increase in diagnostic yield of CRC. Conclusions: Current evidence on replicate and repeat FIT is both minimal and conflicting. FIT is a superb clinical tool, but significant gaps surrounding application remain. Further studies relating to replicate and repeat FIT are required.
... However, it remains worthwhile to investigate strategies to further enhance the sensitivity and specificity of FIT and guide prioritisation of FIT-positive patients for immediate colonoscopy. Risk stratification tools that have been developed in the screening setting incorporating polygenic risk scores [29][30][31], urinary volatile organic compounds [10,32], and circulating and/or faecal tumour DNA [33] could be explored to complement FIT for triage of primary care patients. ...
Article
Full-text available
Background Faecal immunochemical tests (FITs) are used to triage primary care patients with symptoms that could be caused by colorectal cancer for referral to colonoscopy. The aim of this study was to determine whether combining FIT with routine blood test results could improve the performance of FIT in the primary care setting. Methods Results of all consecutive FITs requested by primary care providers between March 2017 and December 2020 were retrieved from the Oxford University Hospitals NHS Foundation Trust. Demographic factors (age, sex), reason for referral, and results of blood tests within 90 days were also retrieved. Patients were followed up for incident colorectal cancer in linked hospital records. The sensitivity, specificity, positive and negative predictive values of FIT alone, FIT paired with blood test results, and several multivariable FIT models, were compared. Results One hundred thirty-nine colorectal cancers were diagnosed (0.8%). Sensitivity and specificity of FIT alone at a threshold of 10 μg Hb/g were 92.1 and 91.5% respectively. Compared to FIT alone, blood test results did not improve the performance of FIT. Pairing blood test results with FIT increased specificity but decreased sensitivity. Multivariable models including blood tests performed similarly to FIT alone. Conclusions FIT is a highly sensitive tool for identifying higher risk individuals presenting to primary care with lower risk symptoms. Combining blood test results with FIT does not appear to lead to better discrimination for colorectal cancer than using FIT alone.
... In a very interesting study, Widlak et al. observed that the additional detection of urinary VOCs in the FIT false-negative (i.e., failed to detect cancer) increased the detection of CRC. Using both faecal (FIT and faecal calprotectin) and urinary VOC detection increased diagnostic accuracy for CRC from 80% to 97% and specificity to 72% in patients with lower gastrointestinal symptoms [435]. ...
Article
Full-text available
Colorectal cancer (CRC) is still a leading cause of cancer death worldwide. Less than half of cases are diagnosed when the cancer is locally advanced. CRC is a heterogenous disease associated with a number of genetic or somatic mutations. Diagnostic markers are used for risk stratification and early detection, which might prolong overall survival. Nowadays, the widespread use of semi-invasive endoscopic methods and feacal blood tests characterised by suboptimal accuracy of diagnostic results has led to the detection of cases at later stages. New molecular noninvasive tests based on the detection of CRC alterations seem to be more sensitive and specific then the current methods. Therefore, research aiming at identifying molecular markers, such as DNA, RNA and proteins, would improve survival rates and contribute to the development of personalized medicine. The identification of “ideal” diagnostic biomarkers, having high sensitivity and specificity, being safe, cheap and easy to measure, remains a challenge. The purpose of this review is to discuss recent advances in novel diagnostic biomarkers for tumor tissue, blood and stool samples in CRC patients.
... Colorectal cancer (CRC) is the second leading cause of the cancer-related deaths and third leading cause of cancer-related deaths among men and women, respectively, in Europe [8]. As such, screening using faecal immunochemical testing for haemoglobin (FIT) has been introduced but still can miss up to 10% of cancers [9][10][11]. More recently, there is evidence to suggest addition of VOC to FIT can further improve diagnosis of CRC [12]. ...
Article
Full-text available
Electronic noses (e-nose) offer potential for the detection of cancer in its early stages. The ability to analyse samples in real time, at a low cost, applying easy–to-use and portable equipment, gives e-noses advantages over other technologies, such as Gas Chromatography-Mass Spectrometry (GC-MS). For diseases such as cancer with a high mortality, a technology that can provide fast results for use in routine clinical applications is important. Colorectal cancer (CRC) is among the highest occurring cancers and has high mortality rates, if diagnosed late. In our study, we investigated the use of portable electronic nose (PEN3), with further analysis using GC-TOF-MS, for the analysis of gases and volatile organic compounds (VOCs) to profile the urinary metabolome of colorectal cancer. We also compared the different cancer stages with non-cancers using the PEN3 and GC-TOF-MS. Results obtained from PEN3, and GC-TOF-MS demonstrated high accuracy for the separation of CRC and non-cancer. PEN3 separated CRC from non-cancerous group with 0.81 AUC (Area Under the Curve). We used data from GC-TOF-MS to obtain a VOC profile for CRC, which identified 23 potential biomarker VOCs for CRC. Thus, the PEN3 and GC-TOF-MS were found to successfully separate the cancer group from the non-cancer group.
... More objective measures alongside FIT, such as anaemia or thrombocytosis, may help to determine risk of EOCRC. 31,32 Further research into further non-invasive biomarkers for CRC such as breath 33 or urinary volatile organic compounds, 34 or faecal/serum DNA samples, may help to identify patients at higher risk of CRC. Adding in ...
Article
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Introduction Detection of early onset colorectal cancer is challenging, and remains a rare diagnosis amongst younger people with gastrointestinal symptoms. We investigated whether the faecal immunochemical test (FIT) could identify younger patients at higher risk of colorectal cancer or serious bowel disease including colorectal cancer, inflammatory bowel disease or advanced adenomas. Methods A subgroup analysis was performed of symptomatic patients under 50 years of age (<50) from the NICE FIT study, a multicentre, prospective diagnostic accuracy study of FIT conducted between October 2017 and December 2019. The diagnostic accuracy of FIT for colorectal cancer and serious bowel disease was investigated in younger patients at different faecal haemoglobin (f-Hb) cut-offs of 2, 10 and 150 µg blood/g faeces (µg/g). Results Early onset colorectal cancer was diagnosed in 1.5% (16/1103) of younger symptomatic patients. The sensitivity of FIT for younger patients aged <50 was 87.5% (95% confidence interval 61.7-98.4%), 81.3% (54.4-96.0%) and 68.8% (41.3-89.0%) at f-Hb cut-offs of 2, 10 and 150 µg/g, respectively. The positive predictive value for colorectal cancer increased from 4.2% (2.3-6.9%), to 11.5% (5.9-19.6%) at cut-offs of 2 and 150 µg/g, while the positive predictive value for serious bowel disease increased from 31.3% (26.3-36.5%) to 65.6% (55.2-75.0%) at the same cut-offs. The negative predictive value of FIT for colorectal cancer remained above 99.5% at all cut-offs. Conclusion Detectable f-Hb on FIT in symptomatic younger patients may indicate referral for investigation of colorectal cancer and serious bowel disease.
... The sensitivity of the qFIT for detecting cancer at the threshold of 10 mg/g was set as 82.5 per cent for the decision-tree model based on the authors' local audit data of symptomatic patients over the previous year, which fluctuated between 80 and 85 per cent, in keeping with published data of qFIT sensitivity for symptomatic people 24,25 . The incremental diagnostic yield was 6-8 per cent based on the authors' current pathway operation, which possibly offers 'enrichment' for pathology, that is, enhances the chance of finding a pathology. ...
Article
Full-text available
Background: COVID-19 has brought an unprecedented challenge to healthcare services. The authors' COVID-adapted pathway for suspected bowel cancer combines two quantitative faecal immunochemical tests (qFITs) with a standard CT scan with oral preparation (CT mini-prep). The aim of this study was to estimate the degree of risk mitigation and residual risk of undiagnosed colorectal cancer. Method: Decision-tree models were developed using a combination of data from the COVID-adapted pathway (April-May 2020), a local audit of qFIT for symptomatic patients performed since 2018, relevant data (prevalence of colorectal cancer and sensitivity and specificity of diagnostic tools) obtained from literature and a local cancer data set, and expert opinion for any missing data. The considered diagnostic scenarios included: single qFIT; two qFITs; single qFIT and CT mini-prep; two qFITs and CT mini-prep (enriched pathway). These were compared to the standard diagnostic pathway (colonoscopy or CT virtual colonoscopy (CTVC)). Results: The COVID-adapted pathway included 422 patients, whereas the audit of qFIT included more than 5000 patients. The risk of missing a colorectal cancer, if present, was estimated as high as 20.2 per cent with use of a single qFIT as a triage test. Using both a second qFIT and a CT mini-prep as add-on tests reduced the risk of missed cancer to 6.49 per cent. The trade-off was an increased rate of colonoscopy or CTVC, from 287 for a single qFIT to 418 for the double qFIT and CT mini-prep combination, per 1000 patients. Conclusion: Triage using qFIT alone could lead to a high rate of missed cancers. This may be reduced using CT mini-prep as an add-on test for triage to colonoscopy or CTVC.
... In 2018, Widlak et al. [61] conducted a large single-center, prospective, and blinded study on a subset of 562 patients with matching urine and stool samples (FIT and faecal calprotectin) who were included for final statistical analysis from an initial population of 1850 patients meeting criteria for inclusion. They used a commercial gas analysis instrument based on ion mobility spectroscopy (FAIMS) to analyze VOCs emanating from the urine samples. ...
Article
Full-text available
Colorectal cancer (CRC) is one of the leading cancer-related causes of death in the world. Since the 70s, many countries have adopted different CRC screening programs, which has resulted in a decrease in mortality. However, current screening test options still present downsides. The commercialized stool-based tests present high false-positive rates and low sensitivity, which negatively affects the detection of early stage carcinogenesis. The gold standard colonoscopy has low uptake due to its invasiveness and the perception of discomfort and embarrassment that the procedure may bring. In this review, we collected and described the latest data about alternative CRC screening techniques that can overcome these disadvantages. Web of Science and PubMed were employed as search engines for studies reporting on CRC screening tests and future perspectives. The searches generated 555 articles, of which 93 titles were selected. Finally, a total of 50 studies, describing 14 different CRC alternative tests, were included. Among the investigated techniques, the main feature that could have an impact on CRC screening perception and uptake was the ease of sample collection. Urine, exhaled breath, and blood-based tests promise to achieve good diagnostic performance (sensitivity of 63–100%, 90–95%, and 47–97%, respectively) while minimizing stress and discomfort for the patient.
... Among the protein markers, combining transferrin or calgranulin C tests to FIT yielded a slight increase in sensitivity [58,59]. However, calprotectin led to a significant increase in sensitivity for all adenomas, from 53 to 86%, but the specificity decreased from 68 to 26% [58,60]. ...
Article
Full-text available
Colorectal cancer (CRC) is the third most common form of cancer in terms of incidence and the second in terms of mortality worldwide. CRC develops over several years, thus highlighting the importance of early diagnosis. National screening programs based on fecal occult blood tests and subsequent colonoscopy have reduced the incidence and mortality, however improvements are needed since the participation rate remains low and the tests present a high number of false positive results. This review provides an overview of the CRC screening globally and the state of the art in approaches aimed at improving accuracy and participation in CRC screening, also considering the need for gender and age differentiation. New fecal tests and biomarkers such as DNA methylation, mutation or integrity, proteins and microRNAs are explored, including recent investigations into fecal microbiota. Liquid biopsy approaches, involving novel biomarkers and panels, such as circulating mRNA, micro- and long-non-coding RNA, DNA, proteins and extracellular vesicles are discussed. The approaches reported are based on quantitative PCR methods that could be easily applied to routine screening, or arrays and sequencing assays that should be better exploited to describe and identify candidate biomarkers in blood samples.
... 22 These include undetectable, 20 2, 11 4, 12,28 and 7 mg/g. 29,30 CRC detection did improve at lower f-Hb thresholds with higher clinical sensitivity, but at the expense of higher positivity and colonoscopy demand, and lower positive predictive value (PPV). In contrast, few have studied higher f-Hb thresholds but, because of the imperative to prioritize patients for further investigation in the current COVID-19 pandemic, a f-Hb threshold of 100 mg/g has been suggested for England despite the clinical characteristics being unknown at present. ...
Article
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Background Faecal haemoglobin concentration (f-Hb), estimated using a faecal immunochemical test (FIT), 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 FIT 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 (NNS) 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.
... A pilot study of 137 individuals found that a faecal VOC profile could be a potential biomarker for CRC 56 . Urinary VOCs have also been studied as an alternative noninvasive biomarker for CRC, although the evidence is limited at present 57,58 . One study has suggested that urinary VOCs could be used in combination with FIT, on the basis that it improves the diagnostic performance for CRC detection (sensitivity 0.97, specificity 0.77, negative predictive value (NPV) 1.0) compared with FIT alone (sensitivity 0.80, specificity 0.93, positive predictive value 0.44, NPV 0.9) 56 . ...
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Population screening and endoscopic surveillance are used widely to prevent the development of and death from colorectal cancer (CRC). However, CRC remains a major cause of cancer mortality and the increasing burden of endoscopic investigations threatens to overwhelm some health services. This Perspective describes the rationale for and approach to improved risk stratification and decision-making for CRC prevention and diagnosis. Limitations of current approaches will be discussed using the UK as an example of the challenges faced by a particular health-care system, followed by discussion of novel risk biomarker utilization. We explore how risk stratification will be advantageous to current health-care providers and users, enabling more efficient use of limited colonoscopy resources. We discuss risk stratification in the setting of population screening as well as the surveillance of high-risk groups and investigation of symptomatic patients. We also address challenges in the development and validation of risk stratification tools and identify key research priorities.
... When cancer metabolites appear in the systemic circulation, they reach the kidneys and following filtration, the cancer metabolic by-products are eventually then excreted in the urine. The VOCs have distinctive bio-signatures or smell prints and hence their detection can lead to the differentiation between normal and malignant tissues [11][12][13][14][15]. The metabolomics profile describes the health and disease status of an individual and this approach is becoming an attractive tool for the development of precision medicine. ...
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(1) Background: Colorectal cancer is one of the leading causes of cancer-related death, while early detection decreases incidence and mortality. Current screening programs involving fecal immunological testing and colonoscopy commonly bring about unnecessary colonoscopies, which adds burden to healthcare systems. The objective of this study was to provide an assessment of the diagnostic performance of an electronic nose serving as a complementary screening tool to improve current screening programs in clinical settings. (2) Methods: We conducted a case–control study that included patients from a medical center with colorectal cancer and non-colorectal cancer controls. We analyzed the composition of volatile organic compounds in their exhaled breath using the electronic nose. We then used machine learning algorithms to develop predictive models and provided the estimated accuracy and reliability of the breath testing. (3) Results: We enrolled 77 patients, with 40 cases and 37 controls. The area under the curve, Kappa coefficient, sensitivity, and specificity of the selected model were 0.87 (95% CI 0.76–0.95), 0.66 (95% CI 0.49–0.83), 0.81, and 0.85. For subjects at an early stage of disease, the sensitivity and specificity were 0.90 and 0.85. Excluding smokers, the sensitivity and specificity were 0.88 and 0.92. (4) Conclusions: This study highlights the promising potential of breath testing using an electronic nose for enabling early detection and reducing unnecessary treatments. However, more independent data for external validation are required to ensure applicability and generalizability.
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Background Cancer is a significant public health problem, causing dozens of millions of deaths annually. New cancer screening programs are urgently needed for early cancer detection, as this approach can improve treatment outcomes and increase patient survival. The search for affordable, noninvasive, and highly accurate cancer detection methods revealed a valuable source of tumor-derived metabolites in the human metabolome through the exploration of volatile organic compounds (VOCs) in noninvasive biofluids. Aim of review This review discusses volatilomics-based approaches for cancer detection using noninvasive biomatrices (breath, saliva, skin secretions, urine, feces, and earwax). We presented the historical background, the latest approaches, and the required stages for clinical validation of volatilomics-based methods, which are still lacking in terms of making noninvasive methods available and widespread to the population. Furthermore, insights into the usefulness and challenges of volatilomics in clinical implementation steps for each biofluid are highlighted. Key scientific concepts of review We outline the methodologies for using noninvasive biomatrices with up-and-coming clinical applications in cancer diagnostics. Several challenges and advantages associated with the use of each biomatrix are discussed, aiming at encouraging the scientific community to strengthen efforts toward the necessary steps to speed up the clinical translation of volatile-based cancer detection methods, as well as discussing in favor of (i) hybrid applications (i.e., using more than one biomatrix) to describe metabolite modulations that can be “cancer volatile fingerprints” and (ii) in multi-omics approaches integrating genomics, transcriptomics, and proteomics into the volatilomic data, which might be a breakthrough for diagnostic purposes, onco-pathway assessment, and biomarker validations. Graphical abstract
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Tumorigenesis is a multistep process, with oncogenic mutations in a normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic mutations and clonal expansion in normal tissues, their transformation into cancer remains a rare event, indicating the presence of additional driver events for progression to an irreversible, highly heterogeneous, and invasive lesion. Recently, researchers are emphasizing the mechanisms of environmental tumor risk factors and epigenetic alterations that are profoundly influencing early clonal expansion and malignant evolution, independently of inducing mutations. Additionally, clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into tumors. However, the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully understood. In this review, we summarize the genetic, epigenetic, and external driver events, and their effects on the co-evolution of the transformed cells and their ecosystem during tumor initiation and early malignant evolution. A deeper understanding of the earliest molecular events holds promise for translational applications, predicting individuals at high-risk of tumor and developing strategies to intercept malignant transformation.
Chapter
Despite the advent of screening programmes, diagnosis for the majority of colorectal cancers (CRC) still follows a symptomatic presentation. Current approaches to assessment of patients with symptoms suspicious of CRC rely on subjective symptoms which are poor predictors of CRC diagnosis. Multiple practical challenges have also arisen as a result of excessive reliance on symptoms for diagnosis and triage. Current approaches have also overwhelmed health care resources without producing the expected benefits. Better ways of triaging patients with symptoms suspicious of CRC are needed. The principles of triaging are explored followed by an overview of the advantages and limitations of a number of current triaging approaches. The faecal immunochemical test (FIT) is a prime candidate to bring major practice change in how these patients are triaged. FIT offers practical solutions that address many of the challenges faced by current triaging methods. The role and evidence supporting the use of FIT in symptomatic patients is explored in detail, with further discussion about unresolved considerations such as safety netting for patients with low FIT results, equity concerns, and future directions for improving FIT implementation.
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Background The gradual evolution of the detection and quantification of volatile organic compounds (VOCs) has been instrumental in cancer diagnosis. The primary objective of this study was to assess the diagnostic potential of exhaled breath and urinary VOCs in cancer detection. As VOCs are indicative of tumor and human metabolism, our work also sought to investigate the metabolic pathways linked to the development of cancerous tumors. Materials and Methods An electronic search was performed in the PubMed database. Original studies on VOCs within exhaled breath and urine for cancer detection with a control group were included. A meta-analysis was conducted using a bivariate model to assess the sensitivity and specificity of the VOCs for cancer detection. Fagan’s nomogram was designed to leverage the findings from our diagnostic analysis for the purpose of estimating the likelihood of cancer in patients. Ultimately, MetOrigin was employed to conduct an analysis of the metabolic pathways associated with VOCs in relation to both human and/or microbiota. Results The pooled sensitivity, specificity and the area under the curve for cancer screening utilizing exhaled breath and urinary VOCs were determined to be 0.89, 0.88, and 0.95, respectively. A pretest probability of 51% can be considered as the threshold for diagnosing cancers with VOCs. As the estimated pretest probability of cancer exceeds 51%, it becomes more appropriate to emphasize the ‘ruling in’ approach. Conversely, when the estimated pretest probability of cancer falls below 51%, it is more suitable to emphasize the ‘ruling out’ approach. A total of 14, 14, 6, and 7 microbiota-related VOCs were identified in relation to lung, colorectal, breast, and liver cancers, respectively. The enrichment analysis of volatile metabolites revealed a significant enrichment of butanoate metabolism in the aforementioned tumor types. Conclusions The analysis of exhaled breath and urinary VOCs showed promise for cancer screening. In addition, the enrichment analysis of volatile metabolites revealed a significant enrichment of butanoate metabolism in four tumor types, namely lung, colorectum, breast and liver. These findings hold significant implications for the prospective clinical application of multiomics correlation in disease management and the exploration of potential therapeutic targets.
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This meta-analysis was aimed to estimate the diagnostic performance of volatile organic compounds (VOCs) as a potential novel tool to screen for the neoplasm of the digestive system. An integrated literature search was performed by two independent investigators to identify all relevant studies investigating VOCs in diagnosing neoplasm of the digestive system from inception to 7th December 2020. STATA and Revman software were used for data analysis. The methodological quality of each study was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. A bivariate mixed model was used and meta-regression and subgroup analysis were performed to identify possible sources of heterogeneity. A total of 36 studies comprised of 1712 cases of neoplasm and 3215 controls were included in our meta-analysis. Bivariate analysis showed a pooled sensitivity of 0.87 (95% confidence interval (CI) 0.83–0.90), specificity of 0.86 (95% CI 0.82–0.89), a positive likelihood ratio of 6.18 (95% CI 4.68–8.17), and a negative likelihood ratio of 0.15 (95% CI 0.12–0.20). The diagnostic odds ratio and the area under the summary ROC curve for diagnosing neoplasm of the digestive system were 40.61 (95% CI 24.77–66.57) and 0.93 (95% CI 0.90–0.95), respectively. Our analyses revealed that VOCs analysis could be considered as a potential novel tool to screen for malignant diseases of the digestive system.
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Different oncogenes that act in different phases of the epithelium–adenoma–carcinoma sequence are involved in the development of colorectal carcinoma. Although this sequence is perfectly known, so far it is only possible to act on specific points of the set of known genetic alterations. Therapies aimed at neutralizing the effects of these alterations form the basis of personalized medicine or precision medicine. In this chapter, concepts closely related to these therapeutic strategies are analyzed, bringing us closer to the necessary knowledge of different types of biomarkers, key targets that currently mark treatment options, essential information to make an adequate patient selection, and the progress and challenges that arise in the short and medium term.
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Faecal immunochemical tests (FITs) are the most widely colorectal cancer (CRC) diagnostic biomarker available. Many population screening programmes are based on this biomarker, with the goal of reducing CRC mortality. Moreover, in recent years, a large amount of evidence has been produced on the use of FIT to detect CRC in patients with abdominal symptoms in primary healthcare as well as in surveillance after adenoma resection. The aim of this review is to highlight the available evidence on these two topics. We will summarize the evidence on diagnostic yield in symptomatic patients with CRC and significant colonic lesion and the different options to use this (thresholds, brands, number of determinations, prediction models and combinations). We will include recommendations on FIT strategies in primary healthcare proposed by regulatory bodies and scientific societies and their potential effects on healthcare resources and CRC prognosis. Finally, we will show information regarding FIT-based surveillance as an alternative to endoscopic surveillance after high-risk polyp resection. To conclude, due to the coronavirus disease 2019 pandemic, FIT-based strategies have become extremely relevant since they enable a reduction of colonoscopy demand and access to the healthcare system by selecting individuals with the highest risk of CRC.
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Aim: Although the relationship between colorectal neoplasia and inflammation is well described, the role of faecal calprotectin (FC) in clinical practice to diagnose or screen patients for colorectal neoplasia is less defined. This prospective study characterizes the relationship between FC and colorectal neoplasia in patients within the faecal occult blood testing (FOBT) positive patients in the Scottish Bowel Screening Programme. Methods: All FOBT positive patients attending for colonoscopy between February 2016 and July 2017 were invited to participate. Patients provided a stool sample for FC before commencing bowel preparation. All demographics and endoscopic findings were collected prospectively. Results: In all, 352 patients were included. 210 patients had FC > 50 µg. Colorectal cancer (CRC) patients had a higher median FC (138.5 μg/g, P < 0.05), in comparison to those without CRC, and 13/14 had an FC > 50 µg/g (93%). FC had a high sensitivity (92.8%) and negative predictive value (99.3%) for CRC, but with a low specificity (41.7%) and positive predictive value (6.2%). FC sensitivity increased sequentially as neoplasms progressed from non-advanced to malignant neoplasia (48.6% non-advanced adenoma vs. 92.9% CRC). However, no significant relationship was observed between FC and non-cancer neoplasia. Conclusion: In an FOBT positive screening population, FC was strongly associated with CRC (sensitivity 92.8%, specificity 41.7% for CRC, at 50 µg/g). However, although sensitive for the detection of CRC, FC failed to show sufficient sensitivity or specificity for the detection of non-cancer neoplasia. Based on these results we cannot recommend routine use of FC in a bowel screening population to detect cancer per se, but it is apparent that, with further optimization, faecal assessments including quantification of haemoglobin and inflammation could form part of a risk assessment tool aimed at refining the selection of patients for colonoscopy in both symptomatic and screening populations.
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LINKED CONTENT This article is linked to Chandrapalan et al and Hanna & Cross papers. To view these articles, visit https://doi.org/10.1111/apt.16405 and https://doi.org/10.1111/apt.16471
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Objective Implementation of faecal immunochemical tests (FIT) as a triage test in primary healthcare may improve the efficiency of referrals without missing cases of colorectal cancer (CRC). We aim to summarise the performance characteristics of FITs for CRC in symptomatic patients presenting to primary healthcare. Design We performed a systematic literature review of Medline and EMBASE databases from May 2018 to November 2020. Previous related systematic searches were also adapted to this aim and completed with reference screening. We identified studies performed on adult patients consulting for abdominal symptoms in primary care which reported data such that the FIT diagnostic performance parameters for CRC could be obtained. Bivariate models were used to synthesise available evidence. Meta-regression analysis was performed to evaluate the causes of heterogeneity. Results Twenty-three studies (69 536 participants) were included (CRC prevalence 0.3%–6.2%). Six studies (n=34 691) assessed FIT as rule in test (threshold of ≥150 µg Hb/g faeces) showing a sensitivity of 64.1% (95% CI 57.8% to 69.9%) and a specificity of 95.0% (95% CI 91.2% to 97.2%). A threshold of 10 µg/g (15 studies; n=48 872) resulted in a sensitivity of 87.2% (95% CI 81.0% to 91.6%) and a specificity of 84.4% (95% CI 79.4% to 88.3%) for CRC. At a 20 µg Hb/g faeces threshold (five studies; n=24 187) less than one additional CRC would be missed per 1000 patients investigated compared with 10 µg Hb/g faeces threshold (CRC prevalence 2%). Conclusion FIT is the test of choice to evaluate patients with new-onset lower gastrointestinal symptoms in primary healthcare.
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To increase compliance with colorectal cancer screening programs and to reduce the recommended screening age, cheaper and easy non-invasiveness alternatives to the fecal immunochemical test should be provided. Following the PRISMA procedure of studies that evaluated the metabolome and volatilome signatures of colorectal cancer in human urine samples, an exhaustive search in PubMed, Web of Science, and Scopus found 28 studies that met the required criteria. There were no restrictions on the query for the type of study, leading to not only colorectal cancer samples versus control comparison but also polyps versus control and prospective studies of surgical effects, CRC staging and comparisons of CRC with other cancers. With this systematic review, we identified up to 244 compounds in urine samples (3 shared compounds between the volatilome and metabolome), and 10 of them were relevant in more than three articles. In the meta-analysis, nine studies met the criteria for inclusion, and the results combining the case-control and the pre-/post-surgery groups, eleven compounds were found to be relevant. Four upregulated metabolites were identified, 3-hydroxybutyric acid, L-dopa, L-histidinol, and N1, N12-diacetylspermine and seven downregulated compounds were identified, pyruvic acid, hydroquinone, tartaric acid, and hippuric acid as metabolites and butyraldehyde, ether, and 1,1,6-trimethyl-1,2-dihydronaphthalene as volatiles.
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Objective To assess whether a faecal immunochemical test (FIT) could be used to select patients with suspected colorectal cancer (CRC) symptoms for urgent investigation. Design Multicentre, double-blinded diagnostic accuracy study in 50 National Health Service (NHS) hospitals across England between October 2017 and December 2019. Patients referred to secondary care with suspected CRC symptoms meeting NHS England criteria for urgent 2 weeks wait referral and triaged to investigation with colonoscopy were invited to perform a quantitative FIT. The sensitivity of FIT for CRC, and effect of relevant variables on its diagnostic accuracy was assessed. Results 9822 patients were included in the final analysis. The prevalence of CRC at colonoscopy was 3.3%. The FIT positivity decreased from 37.2% to 19.0% and 7.6%, respectively, at cut-offs of 2, 10 and 150 µg haemoglobin/g faeces (µg/g). The positive predictive values of FIT for CRC at these cut-offs were 8.7% (95% CI, 7.8% to 9.7%), 16.1% (95% CI 14.4% to 17.8%) and 31.1% (95% CI 27.8% to 34.6%), respectively, and the negative predictive values were 99.8% (95% CI 99.7% to 99.9%), 99.6% (95% CI 99.5% to 99.7%) and 98.9% (95% CI 98.7% to 99.1%), respectively. The sensitivity of FIT for CRC decreased at the same cut-offs from 97.0% (95% CI 94.5% to 98.5%) to 90.9% (95% CI 87.2% to 93.8%) and 70.8% (95% CI 65.6% to 75.7%), respectively, while the specificity increased from 64.9% (95% CI 63.9% to 65.8%) to 83.5% (95% CI 82.8% to 84.3%) and 94.6% (95% CI 94.1% to 95.0%), respectively. The area under the receiver operating characteristic curve was 0.93 (95% CI 0.92 to 0.95). Conclusion FIT sensitivity is maximised to 97.0% at the lowest cut-off (2 µg/g); a negative FIT result at this cut-off can effectively rule out CRC and a positive FIT result is better than symptoms to select patients for urgent investigations. Trial registration number ISRCTN49676259 .
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Chronic diarrhoea is a common problem, hence clear guidance on investigations is required. This is an updated guideline from 2003 for the investigations of chronic diarrhoea commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG). This document has undergone significant revision in content through input by 13 members of the Guideline Development Group (GDG) representing various institutions. The GRADE system was used to appraise the quality of evidence and grading of recommendations.
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Background & aims: A variety of fecal immunochemical tests (FITs) for hemoglobin (Hb) are used in colorectal cancer screening. It is unclear to what extent differences in reported sensitivities and specificities reflect true heterogeneity in test performance or differences in study populations or varying pre-analytical conditions. We directly compared the sensitivity and specificity values with which 9 quantitative (laboratory-based and point-of-care) FITs detected advanced neoplasms (AN) in a single colorectal cancer screening study. Methods: Pre-colonoscopy stool samples were obtained from participants of screening colonoscopy in Germany from 2005 through 2010 and frozen at -80°C until analysis. The stool samples were thawed, homogenized, and used for 9 different quantitative FITs in parallel. Colonoscopy and histology reports were collected from all participants and evaluated by 2 independent, trained research assistants who were blinded to the test results. Comparative evaluations of diagnostic performance for AN were made at preset manufacturers' thresholds (range, 2.0-17.0 μg Hb/g feces), at a uniform threshold (15 μg Hb/g feces), and at adjusted thresholds yielding defined levels of specificity (99%, 97%, and 93%). Results: Of the 1667 participants who fulfilled the inclusion criteria, all cases with AN (n = 216) and 300 randomly selected individuals without AN were included in the analysis. Sensitivities and specificities for AN varied widely when we used the preset thresholds (21.8%-46.3% and 85.7%-97.7%, respectively) or the uniform threshold (16.2%-34.3% and 94.0%-98.0%, respectively). Adjusting thresholds to yield a specificity of 99%, 97%, or 93% resulted in almost equal sensitivities for detection of AN (14.4%-18.5%, 21.3%-23.6%, and 30.1%-35.2%, respectively) and almost equal positivity rates (2.8%-3.4%, 5.8%-6.1%, and 10.1%-10.9%, respectively). Conclusions: Apparent heterogeneity in diagnostic performance of quantitative FITs can be overcome to a large extent by adjusting thresholds to yield defined levels of specificity or positivity rates. Rather than simply using thresholds recommended by the manufacturer, screening programs should choose thresholds based on intended levels of specificity and manageable positivity rates.
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Screening of colorectal cancer is crucial for early stage diagnosis and treatment. Detection of volatile organic compounds (VOCs) of the metabolome present in exhaled breath is a promising approach to screen colorectal cancer (CRC). Various forms of volatile organic compounds (VOCs) that show the definitive signature for the different diseases including cancers are present in exhale breathe. Among all the reported CRC VOCs, cyclohexane, methylcyclohexane, 1,3-dimethyl- benzene and decanal are identified as the prominent ones that can be used as the signature for CRC screening. In the present investigation, detection of the four prominent VOCs related to CRC is explored using functionalized titania nanotubular arrays (TNAs)-based sensor. These signature biomarkers are shown to be detected using nickel-functionalized TNA as an electrochemical sensor. The sensing mechanism is based on the electrochemical interaction of nickel-functionalized nanotubes with signature biomarkers. A detailed mechanism of the sensor response is also presented.
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Background Colorectal cancer (CRC) is the third most common cancer in the UK. Presenting symptoms that can be associated with CRC usually have another explanation. Faecal immunochemical tests (FITs) detect blood that is not visible to the naked eye and may help to select patients who are likely to benefit from further investigation. Objectives To assess the effectiveness of FITs [OC-Sensor (Eiken Chemical Co./MAST Diagnostics, Tokyo, Japan), HM-JACKarc (Kyowa Medex/Alpha Laboratories Ltd, Tokyo, Japan), FOB Gold (Sentinel/Sysmex, Sentinel Diagnostics, Milan, Italy), RIDASCREEN Hb or RIDASCREEN Hb/Hp complex (R-Biopharm, Darmstadt, Germany)] for primary care triage of people with low-risk symptoms. Methods Twenty-four resources were searched to March 2016. Review methods followed published guidelines. Summary estimates were calculated using a bivariate model or a random-effects logistic regression model. The cost-effectiveness analysis considered long-term costs and quality-adjusted life-years (QALYs) that were associated with different faecal occult blood tests and direct colonoscopy referral. Modelling comprised a diagnostic decision model, a Markov model for long-term costs and QALYs that were associated with CRC treatment and progression, and a Markov model for QALYs that were associated with no CRC. Results We included 10 studies. Using a single sample and 10 µg Hb/g faeces threshold, sensitivity estimates for OC-Sensor [92.1%, 95% confidence interval (CI) 86.9% to 95.3%] and HM-JACKarc (100%, 95% CI 71.5% to 100%) indicated that both may be useful to rule out CRC. Specificity estimates were 85.8% (95% CI 78.3% to 91.0%) and 76.6% (95% CI 72.6% to 80.3%). Triage using FITs could rule out CRC and avoid colonoscopy in approximately 75% of symptomatic patients. Data from our systematic review suggest that 22.5–93% of patients with a positive FIT and no CRC have other significant bowel pathologies. The results of the base-case analysis suggested minimal difference in QALYs between all of the strategies; no triage (referral straight to colonoscopy) is the most expensive. Faecal immunochemical testing was cost-effective (cheaper and more, or only slightly less, effective) compared with no triage. Faecal immunochemical testing was more effective and costly than guaiac faecal occult blood testing, but remained cost-effective at a threshold incremental cost-effectiveness ratio of £30,000. The results of scenario analyses did not differ substantively from the base-case. Results were better for faecal immunochemical testing when accuracy of the guaiac faecal occult blood test (gFOBT) was based on studies that were more representative of the correct population. Limitations Only one included study evaluated faecal immunochemical testing in primary care; however, all of the other studies evaluated faecal immunochemical testing at the point of referral. Further, validation data for the Faecal haemoglobin, Age and Sex Test (FAST) score, which includes faecal immunochemical testing, showed no significant difference in performance between primary and secondary care. There were insufficient data to adequately assess FOB Gold, RIDASCREEN Hb or RIDASCREEN Hb/Hp complex. No study compared FIT assays, or FIT assays versus gFOBT; all of the data included in this assessment refer to the clinical effectiveness of individual FIT methods and not their comparative effectiveness. Conclusions Faecal immunochemical testing is likely to be a clinically effective and cost-effective strategy for triaging people who are presenting, in primary care settings, with lower abdominal symptoms and who are at low risk for CRC. Further research is required to confirm the effectiveness of faecal immunochemical testing in primary care practice and to compare the performance of different FIT assays. Study registration This study is registered as PROSPERO CRD42016037723. Funding The National Institute for Health Research Health Technology Assessment programme.
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Background: The diagnosis of colorectal cancer (CRC) can be difficult as symptoms are variable with poor specificity. Thus, there is a quest for simple, non-invasive testing that can help streamline those with significant colonic pathology. Aim: To assess using faecal immunochemical test for haemoglobin (FIT) or faecal calprotectin (FCP) to detect CRC and adenoma in symptomatic patients referred from primary care. Methods: A total of 799 referred for urgent lower gastrointestinal investigations were prospectively recruited. Of these, 430 completed colonic investigations and returned stool samples, and were included in the final statistical analysis. Faecal immunochemical test for haemoglobin was performed on HM-JACKarc analyser (Kyowa Medex, Tokyo, Japan), and FCP by the EliA Calprotectin immunoassay (Thermo Fisher Scientific, Waltham, United States). Results: The negative predictive value (NPV) using FIT alone or both markers (FIT and FCP) in combination was similar at 99% for CRC, with a sensitivity and specificity of 84% and 93%, respectively. FIT measurements were significantly higher in left-sided colonic lesions compared with the right side; 713 vs. 94; P = 0.0203). For adenoma, the NPV using FIT alone, or both markers (FIT and FCP) in combination, was similar at 94% with a sensitivity and specificity of 69% and 56%, respectively. Conclusions: Undetectable faecal immunochemical test for haemoglobin is sufficiently sensitive to exclude colorectal cancer, with higher values in left-sided lesions. FCP in combination does not appear to provide additional diagnostic information. Further studies to determine the health economic benefits of implementing faecal immunochemical test for haemoglobin in primary care are required.
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In the course and prognosis of colorectal cancer (CRC), early detection and treatment are essential factors. Fecal immunochemical tests (FITs) are currently the most commonly used non-invasive screening tests for CRC and pre-malignant (advanced) adenomas, however, with restricted sensitivity. We hypothesized that fecal volatile organic compounds (VOCs) may serve as a diagnostic biomarker of CRC and adenomas. In this proof of concept study, we aimed to assess disease-specific VOC smellprints in fecal gas to distinguish patients with CRC and advanced adenomas from healthy controls. Fecal samples of patients who were scheduled to undergo an elective colonoscopy were collected. An electronic nose (Cyranose 320®) was used to measure VOC patterns in fecal gas from patients with histopathologically proven CRC, with advanced adenomas and from controls (no abnormalities seen at colonoscopy). Receiver Operator Characteristic curves and corresponding sensitivity and specificity for detection of CRC and advanced adenomas were calculated. A total of 157 stool samples (40 patients with CRC, 60 patients with advanced adenomas, and 57 healthy controls) were analyzed by electronic nose. Fecal VOC profiles of patients with CRC differed significantly from controls (Area Under Curve ±95%CI, p-value, sensitivity, specificity; 0.92±0.03, <0.001, 85%, 87%). Also VOC profiles of patients with advanced adenomas could be discriminated from controls (0.79±0.04, <0.001, 62%, 86%). The results of this proof of concept study suggest that fecal gas analysis by an electronic nose seems to hold promise as a novel screening tool for the (early) detection of advanced neoplasia and CRC. © 2013 Wiley Periodicals, Inc.
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Microbial metabolism of proteins and amino acids by human gut bacteria generates a variety of compounds including phenol, indole, and sulfur compounds and branched chain fatty acids, many of which have been shown to elicit a toxic effect on the lumen. Bacterial fermentation of amino acids and proteins occurs mainly in the distal colon, a site that is often fraught with symptoms from disorders including ulcerative colitis (UC) and colorectal cancer (CRC). In contrast to carbohydrate metabolism by the gut microbiota, proteolysis is less extensively researched. Many metabolites are low molecular weight, volatile compounds. This review will summarize the use of analytical methods to detect and identify compounds in order to elucidate the relationship between specific dietary proteinaceous substrates, their corresponding metabolites, and implications for gastrointestinal health.
Electronic Nose Technology as a Point-of-Care Solution for the Detection of Colorectal Cancer
  • Westenbrinke
Westenbrink E. Electronic Nose Technology as a Point-of-Care Solution for the Detection of Colorectal Cancer. 2016;School of Engineering, University of Warwick.
Nose Technology as a Point-of-Care Solution for the Detection of Colorectal Cancer
  • E Westenbrink
  • Electronic