Polyketide synthase positive Escherichia coli one-time measurement in stool is not informative of colorectal cancer risk in a screening setting.

Environmental factors like the pathogenicity island polyketide synthase positive (pks+) Escherichia coli (E. coli) could have potential for risk stratification in colorectal cancer (CRC) screening. The association between pks+ E. coli measured in fecal immunochemical test (FIT) samples and the detection of advanced neoplasia (AN) at colonoscopy was investigated. Biobanked FIT samples were analyzed for both presence of E. coli and pks+ E. coli and correlated with colonoscopy findings; 5020 CRC screening participants were included. Controls were participants in which no relevant lesion was detected because of FIT-negative results (cut-off ≥15 µg Hb/g feces), a negative colonoscopy, or a colonoscopy during which only a nonadvanced polyp was detected. Cases were participants with AN [CRC, advanced adenoma (AA), or advanced serrated polyp (ASP)]. Existing DNA isolation and quantitative polymerase chain reaction (qPCR) procedures were used for the detection of E. coli and pks+ E. coli in stool. A total of 4542 (90.2%) individuals were E. coli positive, and 1322 (26.2%) were pks+ E. coli positive. The prevalence of E. coli in FIT samples from individuals with AN was 92.9% compared to 89.7% in FIT samples of controls (p = 0.010). The prevalence of pks+ E. coli in FIT samples from individuals with AN (28.6%) and controls (25.9%) was not significantly different (p = 0.13). The prevalences of pks+ E. coli in FIT samples from individuals with CRC, AA, or ASP were 29.6%, 28.3%, and 32.1%, respectively. In conclusion, the prevalence of pks+ E. coli in a screening population was 26.2% and did not differ significantly between individuals with AN and controls. These findings disqualify the straightforward option of using a snapshot measurement of pks+ E. coli in FIT samples as a stratification biomarker for CRC risk. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Guaiac-based faecal occult blood tests versus faecal immunochemical tests for colorectal cancer screening in average-risk individuals.

BACKGROUND: Worldwide, many countries have adopted colorectal cancer (CRC) screening programmes, often based on faecal occult blood tests (FOBTs). CRC screening aims to detect advanced neoplasia (AN), which is defined as CRC or advanced adenomas. FOBTs fall into two categories based on detection technique and the detected blood component: qualitative guaiac-based FOBTs (gFOBTs) and faecal immunochemical tests (FITs), which can be qualitative and quantitative. Screening with gFOBTs reduces CRC-related mortality. OBJECTIVES: To compare the diagnostic test accuracy of gFOBT and FIT screening for detecting advanced colorectal neoplasia in average-risk individuals. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, BIOSIS Citation Index, Science Citation Index Expanded, and Google Scholar. We searched the reference lists and PubMed-related articles of included studies to identify additional studies. SELECTION CRITERIA: We included prospective and retrospective studies that provided the number of true positives, false positives, false negatives, and true negatives for gFOBTs, FITs, or both, with colonoscopy as reference standard. We excluded case-control studies. We included studies in which all participants underwent both index test and reference standard ("reference standard: all"), and studies in which only participants with a positive index test underwent the reference standard while participants with a negative test were followed for at least one year for development of interval carcinomas ("reference standard: positive"). The target population consisted of asymptomatic, average-risk individuals undergoing CRC screening. The target conditions were CRC and advanced neoplasia (advanced adenomas and CRC combined). DATA COLLECTION AND ANALYSIS: Two review authors independently screened and selected studies for inclusion. In case of disagreement, a third review author made the final decision. We used the Rutter and Gatsonis hierarchical summary receiver operating characteristic model to explore differences between tests and identify potential sources of heterogeneity, and the bivariate hierarchical model to estimate sensitivity and specificity at common thresholds: 10 µg haemoglobin (Hb)/g faeces and 20 µg Hb/g faeces. We performed indirect comparisons of the accuracy of the two tests and direct comparisons when both index tests were evaluated in the same population. MAIN RESULTS: We ran the initial search on 25 June 2019, which yielded 63 studies for inclusion. We ran a top-up search on 14 September 2021, which yielded one potentially eligible study, currently awaiting classification. We included a total of 33 "reference standard: all" published articles involving 104,640 participants. Six studies evaluated only gFOBTs, 23 studies evaluated only FITs, and four studies included both gFOBTs and FITs. The cut-off for positivity of FITs varied between 2.4 µg and 50 µg Hb/g faeces. For each Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 domain, we assessed risk of bias as high in less than 20% of studies. The summary curve showed that FITs had a higher discriminative ability than gFOBTs for AN (P < 0.001) and CRC (P = 0.004). For the detection of AN, the summary sensitivity of gFOBTs was 15% (95% confidence interval (CI) 12% to 20%), which was significantly lower than FITs at both 10 µg and 20 µg Hb/g cut-offs with summary sensitivities of 33% (95% CI 27% to 40%; P < 0.001) and 26% (95% CI 21% to 31%, P = 0.002), respectively. Results were simulated in a hypothetical cohort of 10,000 screening participants with 1% CRC prevalence and 10% AN prevalence. Out of 1000 participants with AN, gFOBTs missed 850, while FITs missed 670 (10 µg Hb/g cut-off) and 740 (20 µg Hb/g cut-off). No significant differences in summary specificity for AN detection were found between gFOBTs (94%; 95% CI 92% to 96%), and FITs at 10 µg Hb/g cut-off (93%; 95% CI 90% to 95%) and at 20 µg Hb/g cut-off (97%; 95% CI 95% to 98%). So, among 9000 participants without AN, 540 were offered (unnecessary) colonoscopy with gFOBTs compared to 630 (10 µg Hb/g) and 270 (20 µg Hb/g) with FITs. Similarly, for the detection of CRC, the summary sensitivity of gFOBTs, 39% (95% CI 25% to 55%), was significantly lower than FITs at 10 µg and 20 µg Hb/g cut-offs: 76% (95% CI 57% to 88%: P = 0.001) and 65% (95% CI 46% to 80%; P = 0.035), respectively. So, out of 100 participants with CRC, gFOBTs missed 61, and FITs missed 24 (10 µg Hb/g) and 35 (20 µg Hb/g). No significant differences in summary specificity for CRC were found between gFOBTs (94%; 95% CI 91% to 96%), and FITs at the 10 µg Hb/g cut-off (94%; 95% CI 87% to 97%) and 20 µg Hb/g cut-off (96%; 95% CI 91% to 98%). So, out of 9900 participants without CRC, 594 were offered (unnecessary) colonoscopy with gFOBTs versus 594 (10 µg Hb/g) and 396 (20 µg Hb/g) with FITs. In five studies that compared FITs and gFOBTs in the same population, FITs showed a higher discriminative ability for AN than gFOBTs (P = 0.003). We included a total of 30 "reference standard: positive" studies involving 3,664,934 participants. Of these, eight were gFOBT-only studies, 18 were FIT-only studies, and four studies combined both gFOBTs and FITs. The cut-off for positivity of FITs varied between 5 µg to 250 µg Hb/g faeces. For each QUADAS-2 domain, we assessed risk of bias as high in less than 20% of studies. The summary curve showed that FITs had a higher discriminative ability for detecting CRC than gFOBTs (P < 0.001). The summary sensitivity for CRC of gFOBTs, 59% (95% CI 55% to 64%), was significantly lower than FITs at the 10 µg Hb/g cut-off, 89% (95% CI 80% to 95%; P < 0.001) and the 20 µg Hb/g cut-off, 89% (95% CI 85% to 92%; P < 0.001). So, in the hypothetical cohort with 100 participants with CRC, gFOBTs missed 41, while FITs missed 11 (10 µg Hb/g) and 11 (20 µg Hb/g). The summary specificity of gFOBTs was 98% (95% CI 98% to 99%), which was higher than FITs at both 10 µg and 20 µg Hb/g cut-offs: 94% (95% CI 92% to 95%; P < 0.001) and 95% (95% CI 94% to 96%; P < 0.001), respectively. So, out of 9900 participants without CRC, 198 were offered (unnecessary) colonoscopy with gFOBTs compared to 594 (10 µg Hb/g) and 495 (20 µg Hb/g) with FITs. At a specificity of 90% and 95%, FITs had a higher sensitivity than gFOBTs. AUTHORS' CONCLUSIONS: FITs are superior to gFOBTs in detecting AN and CRC in average-risk individuals. Specificity of both tests was similar in "reference standard: all" studies, whereas specificity was significantly higher for gFOBTs than FITs in "reference standard: positive" studies. However, at pre-specified specificities, the sensitivity of FITs was significantly higher than gFOBTs.

Imaging alternatives to colonoscopy: CT colonography and colon capsule. European Society of Gastrointestinal Endoscopy (ESGE) and European Society of Gastrointestinal and Abdominal Radiology (ESGAR) Guideline - Update 2020.

MAIN RECOMMENDATIONS: 1. ESGE/ESGAR recommend computed tomographic colonography (CTC) as the radiological examination of choice for the diagnosis of colorectal neoplasia. Strong recommendation, high quality evidence. ESGE/ESGAR do not recommend barium enema in this setting. Strong recommendation, high quality evidence.2. ESGE/ESGAR recommend CTC, preferably the same or next day, if colonoscopy is incomplete. The timing depends on an interdisciplinary decision including endoscopic and radiological factors. Strong recommendation, low quality evidence. ESGE/ESGAR suggests that, in centers with expertise in and availability of colon capsule endoscopy (CCE), CCE preferably the same or the next day may be considered if colonoscopy is incomplete. Weak recommendation, low quality evidence.3. When colonoscopy is contraindicated or not possible, ESGE/ESGAR recommend CTC as an acceptable and equally sensitive alternative for patients with alarm symptoms. Strong recommendation, high quality evidence. Because of lack of direct evidence, ESGE/ESGAR do not recommend CCE in this situation. Very low quality evidence. ESGE/ESGAR recommend CTC as an acceptable alternative to colonoscopy for patients with non-alarm symptoms. Strong recommendation, high quality evidence. In centers with availability, ESGE/ESGAR suggests that CCE may be considered in patients with non-alarm symptoms. Weak recommendation, low quality evidence.4. Where there is no organized fecal immunochemical test (FIT)-based population colorectal screening program, ESGE/ESGAR recommend CTC as an option for colorectal cancer screening, providing the screenee is adequately informed about test characteristics, benefits, and risks, and depending on local service- and patient-related factors. Strong recommendation, high quality evidence. ESGE/ESGAR do not suggest CCE as a first-line screening test for colorectal cancer. Weak recommendation, low quality evidence.5. ESGE/ESGAR recommend CTC in the case of a positive fecal occult blood test (FOBT) or FIT with incomplete or unfeasible colonoscopy, within organized population screening programs. Strong recommendation, moderate quality evidence. ESGE/ESGAR also suggest the use of CCE in this setting based on availability. Weak recommendation, moderate quality evidence.6. ESGE/ESGAR suggest CTC with intravenous contrast medium injection for surveillance after curative-intent resection of colorectal cancer only in patients in whom colonoscopy is contraindicated or unfeasible. Weak recommendation, low quality evidence. There is insufficient evidence to recommend CCE in this setting. Very low quality evidence.7. ESGE/ESGAR suggest CTC in patients with high risk polyps undergoing surveillance after polypectomy only when colonoscopy is unfeasible. Weak recommendation, low quality evidence. There is insufficient evidence to recommend CCE in post-polypectomy surveillance. Very low quality evidence.8. ESGE/ESGAR recommend against CTC in patients with acute colonic inflammation and in those who have recently undergone colorectal surgery, pending a multidisciplinary evaluation. Strong recommendation, low quality evidence.9. ESGE/ESGAR recommend referral for endoscopic polypectomy in patients with at least one polyp ≥6 mm detected at CTC or CCE. Follow-up CTC may be clinically considered for 6-9-mm CTC-detected lesions if patients do not undergo polypectomy because of patient choice, comorbidity, and/or low risk profile for advanced neoplasia. Strong recommendation, moderate quality evidence. Source and scope This is an update of the 2014-15 Guideline of the European Society of Gastrointestinal Endoscopy (ESGE) and the European Society of Gastrointestinal and Abdominal Radiology (ESGAR). It addresses the clinical indications for the use of imaging alternatives to standard colonoscopy. A targeted literature search was performed to evaluate the evidence supporting the use of computed tomographic colonography (CTC) or colon capsule endoscopy (CCE). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was adopted to define the strength of recommendations and the quality of evidence.

Imaging alternatives to colonoscopy: CT colonography and colon capsule. European Society of Gastrointestinal Endoscopy (ESGE) and European Society of Gastrointestinal and Abdominal Radiology (ESGAR) Guideline - Update 2020.

1: ESGE/ESGAR recommend computed tomographic colonography (CTC) as the radiological examination of choice for the diagnosis of colorectal neoplasia.Strong recommendation, high quality evidence.ESGE/ESGAR do not recommend barium enema in this setting.Strong recommendation, high quality evidence. 2: ESGE/ESGAR recommend CTC, preferably the same or next day, if colonoscopy is incomplete. The timing depends on an interdisciplinary decision including endoscopic and radiological factors.Strong recommendation, low quality evidence.ESGE/ESGAR suggests that, in centers with expertise in and availability of colon capsule endoscopy (CCE), CCE preferably the same or the next day may be considered if colonoscopy is incomplete.Weak recommendation, low quality evidence. 3: When colonoscopy is contraindicated or not possible, ESGE/ESGAR recommend CTC as an acceptable and equally sensitive alternative for patients with alarm symptoms.Strong recommendation, high quality evidence.Because of lack of direct evidence, ESGE/ESGAR do not recommend CCE in this situation.Very low quality evidence.ESGE/ESGAR recommend CTC as an acceptable alternative to colonoscopy for patients with non-alarm symptoms.Strong recommendation, high quality evidence.In centers with availability, ESGE/ESGAR suggests that CCE may be considered in patients with non-alarm symptoms.Weak recommendation, low quality evidence. 4: Where there is no organized fecal immunochemical test (FIT)-based population colorectal screening program, ESGE/ESGAR recommend CTC as an option for colorectal cancer screening, providing the screenee is adequately informed about test characteristics, benefits, and risks, and depending on local service- and patient-related factors.Strong recommendation, high quality evidence.ESGE/ESGAR do not suggest CCE as a first-line screening test for colorectal cancer.Weak recommendation, low quality evidence. 5: ESGE/ESGAR recommend CTC in the case of a positive fecal occult blood test (FOBT) or FIT with incomplete or unfeasible colonoscopy, within organized population screening programs.Strong recommendation, moderate quality evidence.ESGE/ESGAR also suggest the use of CCE in this setting based on availability.Weak recommendation, moderate quality evidence. 6: ESGE/ESGAR suggest CTC with intravenous contrast medium injection for surveillance after curative-intent resection of colorectal cancer only in patients in whom colonoscopy is contraindicated or unfeasibleWeak recommendation, low quality evidence.There is insufficient evidence to recommend CCE in this setting.Very low quality evidence. 7: ESGE/ESGAR suggest CTC in patients with high risk polyps undergoing surveillance after polypectomy only when colonoscopy is unfeasible.Weak recommendation, low quality evidence.There is insufficient evidence to recommend CCE in post-polypectomy surveillance.Very low quality evidence. 8: ESGE/ESGAR recommend against CTC in patients with acute colonic inflammation and in those who have recently undergone colorectal surgery, pending a multidisciplinary evaluation.Strong recommendation, low quality evidence. 9: ESGE/ESGAR recommend referral for endoscopic polypectomy in patients with at least one polyp ≥ 6 mm detected at CTC or CCE.Follow-up CTC may be clinically considered for 6 - 9-mm CTC-detected lesions if patients do not undergo polypectomy because of patient choice, comorbidity, and/or low risk profile for advanced neoplasia.Strong recommendation, moderate quality evidence.

Effect of neoadjuvant chemoradiotherapy on p53 and SOX2 protein expression in esophageal adenocarcinoma.

Aim: To determine if neoadjuvant chemoradiotherapy (nCRT) affects p53 and SOX2 expression in esophageal adenocarcinoma (EAC). Materials & methods: Comparison of p53 and SOX2 expression in 100 paired pre- and post-nCRT EAC samples. Results: Aberrant p53 was largely concordant (75/83, 90%), while 13/18 (72%) pre-nCRT samples with wild-type (WT) p53 staining, showed aberrant staining in paired post-nCRT samples. Similarly, 31/45 (69%) with previous WT SOX2 showed SOX2 loss in paired post-nCRT samples, whereas aberrant SOX2 loss was concordant in 50/55 (91%) cases. The prognostic values of both markers regarding survival differ before and after nCRT. Conclusion: Aberrant expression of p53 and SOX2 staining in EAC tissue is unaffected by nCRT. Conversely, the WT-staining pattern frequently changed to aberrant expression.

Can a biomarker triage test reduce colonoscopy burden in fecal immunochemical test screening?

Aim: To assess the potential of biomarker triage testing (BM-TT) in the Dutch colorectal cancer (CRC) screening program. Materials & methods: Using the Adenoma and Serrated pathway to Colorectal CAncer model, we simulated fecal immunochemical test (FIT)47-screening and various FIT plus BM-TT screening scenarios in which only individuals with both a positive FIT and BM-TT are referred to colonoscopy. Results: Adding a low polyp sensitivity BM-TT to FIT-screening reduced colonoscopy burden (89-100%) while increasing CRC mortality (27-41%) compared with FIT47-screening only. The FIT plus high polyp sensitivity BM-TT scenarios also decreased colonoscopy burden (71-89%) while hardly affecting CRC mortality (FIT47 0-4% increase, FIT15 2-7% decrease). Conclusion: Adding a BM-TT to FIT-screening considerably reduces colonoscopy burden, but could also decrease screening effectiveness. Combining FIT15 with a high polyp sensitivity BM-TT seems most promising.

First steps towards combining faecal immunochemical testing with the gut microbiome in colorectal cancer screening.

OBJECTIVES: Many countries use faecal immunochemical testing (FIT) to screen for colorectal cancer. There is increasing evidence that faecal microbiota play a crucial role in colorectal cancer carcinogenesis. We assessed the possibility of measuring faecal microbial features in FIT as potential future biomarkers in colorectal cancer screening. METHODS: Bacterial stability over time and the possibility of bacterial contamination were evaluated using quantitative polymerase chain reaction analysis. Positive FIT samples (n = 200) of an average-risk screening cohort were subsequently analysed for universal 16S, and bacteria. Escherichia coli (E. coli), Fusobacterium nucleatum (F. nucleatum), Bacteroidetes and Faecalibacterium prausnitzii (F. prausnitzii) by qPCR. The results were compared with colonoscopy findings. RESULTS: Faecal microbiota in FIT were stably measured up to six days for E. coli (p = 0.53), F. nucleatum (p = 0.30), Bacteroidetes (p = 0.05) and F. prausnitzii (p = 0.62). Overall presence of bacterial contamination in FIT controls was low. Total bacterial load (i.e. 16S) was significantly higher in patients with colorectal cancer and high-grade dysplasia (p = 0.006). For the individual bacteria tested, no association was found with colonic lesions. CONCLUSIONS: These results show that the faecal microbial content can be measured in FIT samples and remains stable for six days. Total bacterial load was higher in colorectal cancer and high-grade dysplasia. These results pave the way for further research to determine the potential role of microbiota assessment in FIT screening.

Substantial and sustained improvement of serrated polyp detection after a simple educational intervention: results from a prospective controlled trial.

OBJECTIVE: Serrated polyps (SPs) are an important cause of postcolonoscopy colorectal cancers (PCCRCs), which is likely the result of suboptimal SP detection during colonoscopy. We assessed the long-term effect of a simple educational intervention focusing on optimising SP detection. DESIGN: An educational intervention, consisting of two 45 min training sessions (held 3 years apart) on serrated polyp detection, was given to endoscopists from 9 Dutch hospitals. Hundred randomly selected and untrained endoscopists from other hospitals were selected as control group. Our primary outcome measure was the proximal SP detection rate (PSPDR) in trained versus untrained endoscopists who participated in our faecal immunochemical test (FIT)-based population screening programme. RESULTS: Seventeen trained and 100 untrained endoscopists were included, who performed 11 305 and 51 039 colonoscopies, respectively. At baseline, PSPDR was equal between the groups (9.3% vs 9.3%). After training, the PSPDR of trained endoscopists gradually increased to 15.6% in 2018. This was significantly higher than the PSPDR of untrained endoscopists, which remained stable around 10% (p=0.018). All below-average (ie, PSPDR ≤6%) endoscopists at baseline improved their PSPDR after training session 1, as did 57% of endoscopists with average PSPDR (6%-12%) at baseline. The second training session further improved the PSPDR in 44% of endoscopists with average PSPDR after the first training. CONCLUSION: A simple educational intervention was associated with substantial long-term improvement of PSPDR in a prospective controlled trial within FIT-based population screening. Widespread implementation of such interventions might be an easy way to improve SP detection, which may ultimately result in fewer PCCRCs. TRIAL REGISTRATION NUMBER: NCT03902899.

Personalised surveillance for serrated polyposis syndrome: results from a prospective 5-year international cohort study.

BACKGROUND AND AIMS: Serrated polyposis syndrome (SPS) is associated with an increased risk of colorectal cancer (CRC). International guidelines recommend surveillance intervals of 1-2 years. However, yearly surveillance likely leads to overtreatment for many. We prospectively assessed a surveillance protocol aiming to safely reduce the burden of colonoscopies. METHODS: Between 2013 and 2018, we enrolled SPS patients from nine Dutch and Spanish hospitals. Patients were surveilled using a protocol appointing either a 1-year or 2-year interval after each surveillance colonoscopy, based on polyp burden. Primary endpoint was the 5-year cumulative incidence of CRC and advanced neoplasia (AN) during surveillance. RESULTS: We followed 271 SPS patients for a median of 3.6 years. During surveillance, two patients developed CRC (cumulative 5-year incidence 1.3%[95% CI 0% to 3.2%]). The 5-year AN incidence was 44% (95% CI 37% to 52%), and was lower for patients with SPS type III (26%) than for patients diagnosed with type I (53%) or type I and III (59%, p<0.001). Most patients were recommended a 2-year interval, and those recommended a 2-year interval were not at increased risk of AN: AN incidence after a 2-year recommendation was 15.6% compared with 24.4% after a 1-year recommendation (OR 0.57, p=0.08). CONCLUSION: Risk stratification substantially reduced colonoscopy burden while achieving CRC incidence similar to previous studies. AN incidence is considerable in SPS patients, but extension of surveillance intervals was not associated with increased AN in those identified as low-risk by the protocol. We identified SPS type III patients as low-risk group that might benefit from even less frequent surveillance. TRIAL REGISTRATION NUMBER: The study was registered on http://www.trialregister.nl; trial-ID NTR4609.

Increasing incidence of colorectal cancer in young adults in Europe over the last 25 years.

OBJECTIVE: The incidence of colorectal cancer (CRC) declines among subjects aged 50 years and above. An opposite trend appears among younger adults. In Europe, data on CRC incidence among younger adults are lacking. We therefore aimed to analyse European trends in CRC incidence and mortality in subjects younger than 50 years. DESIGN: Data on age-related CRC incidence and mortality between 1990 and 2016 were retrieved from national and regional cancer registries. Trends were analysed by Joinpoint regression and expressed as annual percent change. RESULTS: We retrieved data on 143.7 million people aged 20-49 years from 20 European countries. Of them, 187 918 (0.13%) were diagnosed with CRC. On average, CRC incidence increased with 7.9% per year among subjects aged 20-29 years from 2004 to 2016. The increase in the age group of 30-39 years was 4.9% per year from 2005 to 2016, the increase in the age group of 40-49 years was 1.6% per year from 2004 to 2016. This increase started earliest in subjects aged 20-29 years, and 10-20 years later in those aged 30-39 and 40-49 years. This is consistent with an age-cohort phenomenon. Although in most European countries the CRC incidence had risen, some heterogeneity was found between countries. CRC mortality did not significantly change among the youngest adults, but decreased with 1.1%per year between 1990 and 2016 and 2.4% per year between 1990 and 2009 among those aged 30-39 years and 40-49 years, respectively. CONCLUSION: CRC incidence rises among young adults in Europe. The cause for this trend needs to be elucidated. Clinicians should be aware of this trend. If the trend continues, screening guidelines may need to be reconsidered.

Performance of two faecal immunochemical tests for the detection of advanced neoplasia at different positivity thresholds: a cross-sectional study of the Dutch national colorectal cancer screening programme.

BACKGROUND: Faecal immunochemical tests (FITs) are recommended for colorectal cancer screening. Two frequently used FIT methods (FOB-Gold, Sentinel Diagnostics, Milan, Italy and OC-Sensor, Eiken Chemical, Tokyo, Japan) perform similarly in detecting advanced neoplasia (ie, colorectal cancer and advanced adenoma) at a fixed positivity cutoff for faecal haemoglobin concentration. It is unclear whether the performance of the two methods is also comparable at other thresholds. We compared the accuracy of the two assays in detecting advanced neoplasia across various thresholds. METHODS: In a cross-sectional study in the Dutch national screening programme, individuals who were screening naive in 2016 (aged 55-75 years) living in the southwest region of the Netherlands were invited to use two different FIT assays on the same bowel movement. Eligible participants were randomly selected from municipal registers. Participants were referred for colonoscopy if either FIT assay result met the predefined positivity threshold (≥15 µg haemoglobin per g faeces). We compared the respective distributions of reported haemoglobin concentration and positivity rates with various FIT positivity thresholds. The performance of each FIT for identifying advanced neoplasia at colonoscopy in FIT-positive assays was compared with the area under the receiver operating characteristic curve. FINDINGS: 21 078 (50·0%) of 42 179 invitees completed both FIT assays. The distribution of haemoglobin concentrations differed significantly between the two FITs (p<0·0001), with higher positivity rates for OC-Sensor at FIT thresholds of 5 and 10 µg haemoglobin per g faeces, similar positivity rates at 15 and 20 µg haemoglobin per g faeces, and higher rates for FOB-Gold at FIT thresholds of 25-150 µg haemoglobin per g faeces. 2046 (9·7%) of 21 078 participants had at least one FIT assay that was positive and of these, 1724 (84·3%) attended colonoscopy. The accuracy of results in individuals undergoing colonoscopy did not significantly differ between the FITs, with an area under the receiver operating characteristic curve of 0·675 (95% CI 0·649 to 0·702) for FOB-Gold and 0·686 (0·661 to 0·712) for OC-Sensor (p=0·40). At identical positivity rates, the positive predictive value of the two FIT assays was similar (difference varying from 0·5% [95% CI -2·6 to 3·7] at a positivity rate of 3·5% to 2·4% [-2·5 to 7·3] at a positivity rate of 2·0%). INTERPRETATION: The two widely used FITs have significantly different distributions of reported haemoglobin concentration and yield different positivity rates at equal thresholds. However, they perform similarly in detecting advanced neoplasia at a preset positivity rate. When implementing either FIT in a screening programme, the desired positivity rate that identifies participants to be referred for colonoscopy should first be set, guided by available resources and feasibility. FUNDING: The Netherlands Organisation for Health Research and Development.

Four cancer cases after esophageal atresia repair: Time to start screening the upper gastrointestinal tract.

Esophageal atresia (EA) is one of the most common congenital digestive malformations and requires surgical correction early in life. Dedicated centers have reported survival rates up to 95%. The most frequent comorbidities after EA repair are dysphagia (72%) and gastroesophageal reflux (GER) (67%). Chronic GER after EA repair might lead to mucosal damage, esophageal stricturing, Barrett's esophagus and eventually esophageal adenocarcinoma. Several long-term follow-up studies found an increased risk of Barrett's esophagus and esophageal carcinoma in EA patients, both at a relatively young age. Given these findings, the recent ESPGHAN-NASPGHAN guideline recommends routine endoscopy in adults born with EA. We report a series of four EA patients who developed a carcinoma of the gastrointestinal tract: three esophageal carcinoma and one colorectal carcinoma in a colonic interposition. These cases emphasize the importance of lifelong screening of the upper gastrointestinal tract in EA patients.

Endoscopic screening for gastric cancer: A cost-utility analysis for countries with an intermediate gastric cancer risk.

BACKGROUND: Endoscopic screening for gastric cancer is debatable in countries with an intermediate risk. OBJECTIVE: The objective of this article is to determine the cost-utility of screening strategies for gastric cancer in a European country. METHODS: We conducted a cost-utility analysis using a Markov model comparing three screening strategies versus no screening: stand-alone upper endoscopy, endoscopy combined with a colorectal cancer screening colonoscopy after a positive faecal occult blood test or pepsinogens serologic screening. Clinical data were collected from systematic reviews, costs from published national data and utilities as quality-adjusted life years (QALY). The primary outcome was the incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were performed. The threshold was set at €37,000 (2016 prices). RESULTS: Upper endoscopy combined with screening colonoscopy (every 10 or 5 years) had an ICER of 15,407/QALY and €30,908/QALY respectively, stand-alone endoscopic screening (every five years) an ICER of €70,693/QALY and pepsinogens screening an ICER of €143,344/QALY. Sensitivity analyses revealed that only endoscopic costs <€75, a provision of only three endoscopies per patient or a gastric cancer risk >25/100,000 would make stand-alone endoscopic screening cost-effective. CONCLUSION: Endoscopic gastric cancer screening in Europe can be cost-effective if combined with a screening colonoscopy in countries with a gastric cancer risk ≥10 per 100,000.

Palliative chemotherapy and targeted therapies for esophageal and gastroesophageal junction cancer.

BACKGROUND: Almost half of people with esophageal or gastroesophageal junction cancer have metastatic disease at the time of diagnosis. Chemotherapy and targeted therapies are increasingly used with a palliative intent to control tumor growth, improve quality of life, and prolong survival. To date, and with the exception of ramucirumab, evidence for the efficacy of palliative treatments for esophageal and gastroesophageal cancer is lacking. OBJECTIVES: To assess the effects of cytostatic or targeted therapy for treating esophageal or gastroesophageal junction cancer with palliative intent. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Web of Science, PubMed Publisher, Google Scholar, and trial registries up to 13 May 2015, and we handsearched the reference lists of studies. We did not restrict the search to publications in English. Additional searches were run in September 2017 prior to publication, and they are listed in the 'Studies awaiting assessment' section. SELECTION CRITERIA: We included randomized controlled trials (RCTs) on palliative chemotherapy and/or targeted therapy versus best supportive care or control in people with esophageal or gastroesophageal junction cancer. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. We assessed the quality and risk of bias of eligible studies according to the Cochrane Handbook for Systematic Reviews of Interventions. We calculated pooled estimates of effect using an inverse variance random-effects model for meta-analysis. MAIN RESULTS: We identified 41 RCTs with 11,853 participants for inclusion in the review as well as 49 ongoing studies. For the main comparison of adding a cytostatic and/or targeted agent to a control arm, we included 11 studies with 1347 participants. This analysis demonstrated an increase in overall survival in favor of the arm with an additional cytostatic or targeted therapeutic agent with a hazard ratio (HR) of 0.75 (95% confidence interval (CI) 0.68 to 0.84, high-quality evidence). The median increased survival time was one month. Five studies in 750 participants contributed data to the comparison of palliative therapy versus best supportive care. We found a benefit in overall survival in favor of the group receiving palliative chemotherapy and/or targeted therapy compared to best supportive care (HR 0.81, 95% CI 0.71 to 0.92, high-quality evidence). Subcomparisons including only people receiving second-line therapies, chemotherapies, targeted therapies, adenocarcinomas, and squamous cell carcinomas all showed a similar benefit. The only individual agent that more than one study found to improve both overall survival and progression-free survival was ramucirumab. Palliative chemotherapy and/or targeted therapy increased the frequency of grade 3 or higher treatment-related toxicity. However, treatment-related deaths did not occur more frequently. Quality of life often improved in the arm with an additional agent. AUTHORS' CONCLUSIONS: People who receive more chemotherapeutic or targeted therapeutic agents have an increased overall survival compared to people who receive less. These agents, administered as both first-line or second-line treatments, also led to better overall survival than best supportive care. With the exception of ramucirumab, it remains unclear which other individual agents cause the survival benefit. Although treatment-associated toxicities of grade 3 or more occurred more frequently in arms with an additional chemotherapy or targeted therapy agent, there is no evidence that palliative chemotherapy and/or targeted therapy decrease quality of life. Based on this meta-analysis, palliative chemotherapy and/or targeted therapy can be considered standard care for esophageal and gastroesophageal junction carcinoma.

Fecal immunochemical test-based colorectal cancer screening: The gender dilemma.

BACKGROUND: Despite differences between men and women in incidence of colorectal cancer (CRC) and its precursors, screening programs consistently use the same strategy for both genders. OBJECTIVE: The objective of this article is to illustrate the effects of gender-tailored screening, including the effects on miss rates of advanced neoplasia (AN). METHODS: Participants (age 50-75 years) in a colonoscopy screening program were asked to complete a fecal immunochemical test (FIT) before colonoscopy. Positivity rates, sensitivity and specificity for detection of AN at multiple cut-offs were determined. Absolute numbers of detected and missed AN per 1000 screenees were calculated. RESULTS: In total 1,256 individuals underwent FIT and colonoscopy, 51% male (median age 61 years; IQR 56-66) and 49% female (median age 60 years; IQR 55-65). At all cut-offs men had higher positivity rates than women, ranging from 3.8% to 10.8% versus 3.2% to 4.8%. Sensitivity for AN was higher in men than women; 40%-25% and 35%-22%, respectively. More AN were found and missed in absolute numbers in men at all cut-offs. CONCLUSION: More AN were both detected and missed in men compared to women at all cut-offs. Gender-tailored cut-offs could either level sensitivity in men and women (i.e., lower cut-off in women) or level the amount of missed lesions (i.e., lower cut-off in men).

Cost-effectiveness of routine screening for Lynch syndrome in endometrial cancer patients up to 70years of age.

PURPOSE: To assess cost-effectiveness of routine screening for Lynch Syndrome (LS) in endometrial cancer (EC) patients ≤70years of age. METHODS: Consecutive EC patients ≤70years of age were screened for LS by analysis of microsatellite instability, immunohistochemistry and MLH1 hypermethylation. Costs and health benefit in life years gained (LYG) included surveillance for LS carriers among EC patients and relatives. We calculated incremental cost-effectiveness ratios (ICERs) comparing LS screening among EC patients ≤70years with ≤50years and the revised Bethesda guidelines. RESULTS: Screening for LS in 179 EC patients identified 7 LS carriers; 1 was ≤50 and 6 were 51-70years. Per age category 18 and 9 relatives were identified as LS carrier. Screening resulted in 74,7 LYG (45,4 and 29,3 LYG per age category). The ICER for LS screening in EC patients ≤70 compared with ≤50years was €5,252/LYG. The revised Bethesda guidelines missed 4/7 (57%) LS carriers among EC patients. The ICER for LS screening in EC patients ≤70years of age compared with the revised Bethesda guidelines was €6,668/LYG. Both ICERs remained <€16,000/LYG in sensitivity analyses. CONCLUSION: Routine LS screening in EC patients ≤70years is a cost-effective strategy, allowing colorectal cancer prevention in EC patients and their relatives.

Development and validation of the WASP classification system for optical diagnosis of adenomas, hyperplastic polyps and sessile serrated adenomas/polyps.

OBJECTIVE: Accurate endoscopic differentiation would enable to resect and discard small and diminutive colonic lesions, thereby increasing cost-efficiency. Current classification systems based on narrow band imaging (NBI), however, do not include neoplastic sessile serrated adenomas/polyps (SSA/Ps). We aimed to develop and validate a new classification system for endoscopic differentiation of adenomas, hyperplastic polyps and SSA/Ps <10 mm. DESIGN: We developed the Workgroup serrAted polypS and Polyposis (WASP) classification, combining the NBI International Colorectal Endoscopic classification and criteria for differentiation of SSA/Ps in a stepwise approach. Ten consultant gastroenterologists predicted polyp histology, including levels of confidence, based on the endoscopic aspect of 45 polyps, before and after participation in training in the WASP classification. After 6 months, the same endoscopists predicted polyp histology of a new set of 50 polyps, with a ratio of lesions comparable to daily practice. RESULTS: The accuracy of optical diagnosis was 0.63 (95% CI 0.54 to 0.71) at baseline, which improved to 0.79 (95% CI 0.72 to 0.86, p<0.001) after training. For polyps diagnosed with high confidence the accuracy was 0.73 (95% CI 0.64 to 0.82), which improved to 0.87 (95% CI 0.80 to 0.95, p<0.01). The accuracy of optical diagnosis after 6 months was 0.76 (95% CI 0.72 to 0.80), increasing to 0.84 (95% CI 0.81 to 0.88) considering high confidence diagnosis. The combined negative predictive value with high confidence of diminutive neoplastic lesions (adenomas and SSA/Ps together) was 0.91 (95% CI 0.83 to 0.96). CONCLUSIONS: We developed and validated the first integrative classification method for endoscopic differentiation of small and diminutive adenomas, hyperplastic polyps and SSA/Ps. In a still image evaluation setting, introduction of the WASP classification significantly improved the accuracy of optical diagnosis overall as well as SSA/P in particular, which proved to be sustainable after 6 months.

Accuracy of Detecting Residual Disease After Cross Neoadjuvant Chemoradiotherapy for Esophageal Cancer (preSANO Trial): Rationale and Protocol.

BACKGROUND: Results from the recent CROSS trial showed that neoadjuvant chemoradiotherapy (nCRT) significantly increased survival as compared to surgery alone in patients with potentially curable esophageal cancer. Furthermore, in the nCRT arm 49% of patients with a squamous cell carcinoma (SCC) and 23% of patients with an adenocarcinoma (AC) had a pathologically complete response in the resection specimen. These results provide a rationale to reconsider and study the timing and necessity of esophagectomy in (all) patients after application of the CROSS regimen. OBJECTIVE: We propose a "surgery as needed" approach after completion of nCRT. In this approach, patients will undergo active surveillance after completion of nCRT. Surgical resection would be offered only to those patients in whom residual disease or a locoregional recurrence is highly suspected or proven. However, before a surgery as needed approach in oesophageal cancer patients (SANO) can be tested in a randomized controlled trial, we aim to determine the accuracy of detecting the presence or absence of residual disease after nCRT (preSANO trial). METHODS: This study is set up as a prospective, single arm, multicenter, diagnostic trial. Operable patients with potentially curable SCC or AC of the esophagus or esophagogastric junction will be included. Approximately 4-6 weeks after completion of nCRT all included patients will undergo a first clinical response evaluation (CRE-I) including endoscopy with (random) conventional mucosal biopsies of the primary tumor site and of any other suspected lesions in the esophagus and radial endo-ultrasonography (EUS) for measurement of tumor thickness and area. Patients in whom no locoregional or disseminated disease can be proven by cytohistology will be offered a postponed surgical resection 6-8 weeks after CRE-I (ie, approximately 12-14 weeks after completion of nCRT). In the week preceding the postponed surgical resection, a second clinical response evaluation (CRE-II) will be planned that will include a whole body PET-CT, followed again by endoscopy with (random) conventional mucosal biopsies of the primary tumor site and any other suspected lesions in the esophagus, radial EUS for measurement of tumor thickness and area, and linear EUS plus fine needle aspiration of PET-positive lesions and/or suspected lymph nodes. The main study parameter is the correlation between the clinical response assessment during CRE-I and CRE-II and the final pathological response in the resection specimen. RESULTS: The first patient was enrolled on July 23, 2013, and results are expected in January 2016. CONCLUSIONS: If this preSANO trial shows that the presence or absence of residual tumor can be predicted reliably 6 or 12 weeks after completion of nCRT, a randomized trial comparing nCRT plus standard surgery versus chemoradiotherapy plus "surgery as needed" will be conducted (SANO trial). TRIAL REGISTRATION: Netherlands Trial Register: NTR4834; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4834 (archived by Webcite at http://www.webcitation.org/6Ze7mn67B).

Non-prostatic pathology on prostate needle-biopsy - colorectal carcinoid: a case report.

INTRODUCTION: Prostate needle-biopsies are among the most common specimens in routine histopathological practice; in 15% colorectal tissue is also present. Rectal pathology is described to be found in 17% of this coincidentally obtained material. CASE PRESENTATION: We present a case in which colorectal carcinoid was found in the rectal mucosa obtained via transrectal prostate biopsies in a screening program for prostate cancer in a 71-year old Caucasian male. To the best of our knowledge, this was the first time that such a coincidental finding was discovered. Besides a colonoscopy with polypectomy, this coincidental detection remained without any further clinical consequences for this patient until today. CONCLUSION: As there is a considerable chance that abnormalities are found in the rectal tissue of prostate biopsies, it is advisable for all pathologists to include this tissue in the histology evaluation and look for potential irregularities in this simultaneously collected material.