Clinical Validation of a Multitarget Fecal Immunochemical Test for Colorectal Cancer Screening : A Diagnostic Test Accuracy Study.

BACKGROUND: The fecal immunochemical test (FIT) is used in colorectal cancer (CRC) screening, yet it leaves room for improvement. OBJECTIVE: To develop a multitarget FIT (mtFIT) with better diagnostic performance than FIT. DESIGN: Diagnostic test accuracy study. SETTING: Colonoscopy-controlled series. PARTICIPANTS: Persons (n = 1284) from a screening (n = 1038) and referral (n = 246) population were classified by their most advanced lesion (CRC [n = 47], advanced adenoma [n = 135], advanced serrated polyp [n = 30], nonadvanced adenoma [n = 250], and nonadvanced serrated polyp [n = 53]), along with control participants (n = 769). MEASUREMENTS: Antibody-based assays were developed and applied to leftover FIT material. Classification and regression tree (CART) analysis was applied to biomarker concentrations to identify the optimal combination for detecting advanced neoplasia. Performance of this combination, the mtFIT, was cross-validated using a leave-one-out approach and compared with FIT at equal specificity. RESULTS: The CART analysis showed a combination of hemoglobin, calprotectin, and serpin family F member 2-the mtFIT-to have a cross-validated sensitivity for advanced neoplasia of 42.9% (95% CI, 36.2% to 49.9%) versus 37.3% (CI, 30.7% to 44.2%) for FIT (P = 0.025), with equal specificity of 96.6%. In particular, cross-validated sensitivity for advanced adenomas increased from 28.1% (CI, 20.8% to 36.5%) to 37.8% (CI, 29.6% to 46.5%) (P = 0.006). On the basis of these results, early health technology assessment indicated that mtFIT-based screening could be cost-effective compared with FIT. LIMITATION: Study population is enriched with persons from a referral population. CONCLUSION: Compared with FIT, the mtFIT showed better diagnostic accuracy in detecting advanced neoplasia because of an increased detection of advanced adenomas. Moreover, early health technology assessment indicated that these results provide a sound basis to pursue further development of mtFIT as a future test for population-based CRC screening. A prospective screening trial is in preparation. PRIMARY FUNDING SOURCE: Stand Up to Cancer/Dutch Cancer Society, Dutch Digestive Foundation, and HealthHolland.

Urgent endoscopic retrograde cholangiopancreatography with sphincterotomy versus conservative treatment in predicted severe acute gallstone pancreatitis (APEC): a multicentre randomised controlled trial.

BACKGROUND: It remains unclear whether urgent endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy improves the outcome of patients with gallstone pancreatitis without concomitant cholangitis. We did a randomised trial to compare urgent ERCP with sphincterotomy versus conservative treatment in patients with predicted severe acute gallstone pancreatitis. METHODS: In this multicentre, parallel-group, assessor-masked, randomised controlled superiority trial, patients with predicted severe (Acute Physiology and Chronic Health Evaluation II score ≥8, Imrie score ≥3, or C-reactive protein concentration >150 mg/L) gallstone pancreatitis without cholangitis were assessed for eligibility in 26 hospitals in the Netherlands. Patients were randomly assigned (1:1) by a web-based randomisation module with randomly varying block sizes to urgent ERCP with sphincterotomy (within 24 h after hospital presentation) or conservative treatment. The primary endpoint was a composite of mortality or major complications (new-onset persistent organ failure, cholangitis, bacteraemia, pneumonia, pancreatic necrosis, or pancreatic insufficiency) within 6 months of randomisation. Analysis was by intention to treat. This trial is registered with the ISRCTN registry, ISRCTN97372133. FINDINGS: Between Feb 28, 2013, and March 1, 2017, 232 patients were randomly assigned to urgent ERCP with sphincterotomy (n=118) or conservative treatment (n=114). One patient from each group was excluded from the final analysis because of cholangitis (urgent ERCP group) and chronic pancreatitis (conservative treatment group) at admission. The primary endpoint occurred in 45 (38%) of 117 patients in the urgent ERCP group and in 50 (44%) of 113 patients in the conservative treatment group (risk ratio [RR] 0·87, 95% CI 0·64-1·18; p=0·37). No relevant differences in the individual components of the primary endpoint were recorded between groups, apart from the occurrence of cholangitis (two [2%] of 117 in the urgent ERCP group vs 11 [10%] of 113 in the conservative treatment group; RR 0·18, 95% CI 0·04-0·78; p=0·010). Adverse events were reported in 87 (74%) of 118 patients in the urgent ERCP group versus 91 (80%) of 114 patients in the conservative treatment group. INTERPRETATION: In patients with predicted severe gallstone pancreatitis but without cholangitis, urgent ERCP with sphincterotomy did not reduce the composite endpoint of major complications or mortality, compared with conservative treatment. Our findings support a conservative strategy in patients with predicted severe acute gallstone pancreatitis with an ERCP indicated only in patients with cholangitis or persistent cholestasis. FUNDING: The Netherlands Organization for Health Research and Development, Fonds NutsOhra, and the Dutch Patient Organization for Pancreatic Diseases.

Yield of Surveillance Colonoscopies 1 Year After Curative Surgical Colorectal Cancer Resections.

BACKGROUND & AIMS: Endoscopic surveillance after curative colorectal cancer (CRC) resection is routine. However, there is controversy whether the 1-year interval between preoperative and postoperative colonoscopy is justified owing to improved colonoscopy standards. We aimed to assess the yield of surveillance colonoscopies 1 year after CRC surgery. METHODS: We performed a retrospective cohort study of 572 patients (54.9% male; mean age, 66.2 ± 9.9 y), who underwent curative surgical resection of a first CRC from June 2013 through April 2016 in the Northwest region of The Netherlands. Patients were included if a complete clearing colonoscopy was performed before surgery and the interval between the preoperative and postoperative colonoscopy was 12 months (range, 6-20 mo), conforming to Dutch guidelines. The primary outcome of the study was the yield of CRC at the surveillance colonoscopy performed 1 year after curative resection. A secondary outcome was the yield of advanced neoplasia. RESULTS: After a mean surveillance interval of 13.7 months (±2.8 mo), 10 of 572 patients (1.7%; 95% CI, 0.7%-2.8%) received a diagnosis of CRC. Of these, 5 CRCs were apparently metachronous cancers (3 were stage III or IV) and 5 were recurrences at the anastomosis (1 was stage IV). In 11.4% of patients (95% CI, 8.9%-13.8%), advanced neoplasia was detected at the 1-year follow-up colonoscopy. Synchronous advanced neoplasia at baseline colonoscopy was a risk factor for detection of advanced neoplasia at the follow-up colonoscopy (odds ratio, 2.2; 95% CI, 1.3-3.8; P ≤ .01). CONCLUSIONS: Despite high colonoscopy quality, the yield of CRC at surveillance colonoscopy 1 year after CRC resection was 1.7%. These were metachronous CRCs and recurrences, often of advanced stage. The high yield justifies the recommendation of a 1-year surveillance interval after surgical CRC resection.

Fluid hydration to prevent post-ERCP pancreatitis in average- to high-risk patients receiving prophylactic rectal NSAIDs (FLUYT trial): study protocol for a randomized controlled trial.

BACKGROUND: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most common complication of ERCP and may run a severe course. Evidence suggests that vigorous periprocedural hydration can prevent PEP, but studies to date have significant methodological drawbacks. Importantly, evidence for its added value in patients already receiving prophylactic rectal non-steroidal anti-inflammatory drugs (NSAIDs) is lacking and the cost-effectiveness of the approach has not been investigated. We hypothesize that combination therapy of rectal NSAIDs and periprocedural hydration would significantly lower the incidence of post-ERCP pancreatitis compared to rectal NSAIDs alone in moderate- to high-risk patients undergoing ERCP. METHODS: The FLUYT trial is a multicenter, parallel group, open label, superiority randomized controlled trial. A total of 826 moderate- to high-risk patients undergoing ERCP that receive prophylactic rectal NSAIDs will be randomized to a control group (no fluids or normal saline with a maximum of 1.5 mL/kg/h and 3 L/24 h) or intervention group (lactated Ringer's solution with 20 mL/kg over 60 min at start of ERCP, followed by 3 mL/kg/h for 8 h thereafter). The primary endpoint is the incidence of post-ERCP pancreatitis. Secondary endpoints include PEP severity, hydration-related complications, and cost-effectiveness. DISCUSSION: The FLUYT trial design, including hydration schedule, fluid type, and sample size, maximize its power of identifying a potential difference in post-ERCP pancreatitis incidence in patients receiving prophylactic rectal NSAIDs. TRIAL REGISTRATION: EudraCT: 2015-000829-37 . Registered on 18 February 2015. ISRCTN: 13659155 . Registered on 18 May 2015.

The difference in endoscopic yield in patients with either iron-deficiency anemia or anemia with normal ferritin.

OBJECTIVE: Current guidelines recommend a gastroduodenoscopy (GDS) and colonoscopy in patients with iron-deficiency anemia (IDA). However, in daily practice, patients with nonferriprive anemia are also referred for endoscopy. The aim of this study is to compare the diagnostic yield of colonoscopy and GDS in patients with IDA and non-IDA. PATIENTS AND METHODS: A retrospective single-center cohort study was carried out from January 2013 till February 2016 that included 917 patients with anemia. We compared the endoscopic yield in patients with IDA versus patients with anemia otherwise. Multivariate regression analyses were carried out to identify predictive factors for the diagnostic yield of GDS and colonoscopy. RESULTS: The yield of both GDS (25%) and colonoscopy (30%) was comparable in IDA and non-IDA patients. However, in patients without known gastrointestinal medical history and without concomitant indications for endoscopy (N=373), the diagnostic yield of GDS was three times higher in IDA patients compared with non-IDA patients (P<0.01). The diagnostic yield for colonoscopy was not significantly different between the two groups. Age and sex were recurrent predictive variables in the outcome of both GDS and colonoscopies. CONCLUSION: We recommend IDA as well as non-IDA as indications for GDS and colonoscopy. Only in patients without gastrointestinal history or localizing complaints a significant difference in the diagnostic yield is found between IDA and non-IDA patients. In this group, upper endoscopy can be omitted in non-IDA patients as they were three times less likely to have a bleeding source found on GDS compared with IDA patients.

Novel Stool-Based Protein Biomarkers for Improved Colorectal Cancer Screening: A Case-Control Study.

BACKGROUND: The fecal immunochemical test (FIT) for detecting hemoglobin is used widely for noninvasive colorectal cancer (CRC) screening, but its sensitivity leaves room for improvement. OBJECTIVE: To identify novel protein biomarkers in stool that outperform or complement hemoglobin in detecting CRC and advanced adenomas. DESIGN: Case-control study. SETTING: Colonoscopy-controlled referral population from several centers. PARTICIPANTS: 315 stool samples from one series of 12 patients with CRC and 10 persons without colorectal neoplasia (control samples) and a second series of 81 patients with CRC, 40 with advanced adenomas, and 43 with nonadvanced adenomas, as well as 129 persons without colorectal neoplasia (control samples); 72 FIT samples from a third independent series of 14 patients with CRC, 16 with advanced adenomas, and 18 with nonadvanced adenomas, as well as 24 persons without colorectal neoplasia (control samples). MEASUREMENTS: Stool samples were analyzed by mass spectrometry. Classification and regression tree (CART) analysis and logistic regression analyses were performed to identify protein combinations that differentiated CRC or advanced adenoma from control samples. Antibody-based assays for 4 selected proteins were done on FIT samples. RESULTS: In total, 834 human proteins were identified, 29 of which were statistically significantly enriched in CRC versus control stool samples in both series. Combinations of 4 proteins reached sensitivities of 80% and 45% for detecting CRC and advanced adenomas, respectively, at 95% specificity, which was higher than that of hemoglobin alone (P < 0.001 and P = 0.003, respectively). Selected proteins could be measured in small sample volumes used in FIT-based screening programs and discriminated between CRC and control samples (P < 0.001). LIMITATION: Lack of availability of antibodies prohibited validation of the top protein combinations in FIT samples. CONCLUSION: Mass spectrometry of stool samples identified novel candidate protein biomarkers for CRC screening. Several protein combinations outperformed hemoglobin in discriminating CRC or advanced adenoma from control samples. Proof of concept that such proteins can be detected with antibody-based assays in small sample volumes indicates the potential of these biomarkers to be applied in population screening. PRIMARY FUNDING SOURCE: Center for Translational Molecular Medicine, International Translational Cancer Research Dream Team, Stand Up to Cancer (American Association for Cancer Research and the Dutch Cancer Society), Dutch Digestive Foundation, and VU University Medical Center.

Factors associated with anxiety and depressive symptoms in colorectal cancer survivors.

BACKGROUND: Up to 37% of colorectal cancer (CRC) survivors report depressive and anxiety symptoms. The identification of risk factors for depressive or anxiety symptoms might help focus supportive care resources on those patients most in need. The present study aims to explore which factors are associated with heightened anxiety or depression symptom severity. METHODS: In this cross-sectional study, individuals diagnosed with CRC 3.5 to 6 years ago completed questionnaires on sociodemographic information, medical comorbidities, anxiety symptoms (Beck Anxiety Inventory), and depressive symptoms (Inventory of Depressive Symptomatology). The general linear model analysis of covariance was used to identify factors associated with heightened anxiety or depressive symptom severity. RESULTS: The sample included 91 CRC survivors, 40.7% women, mean age 69.1 years. A minority of CRC survivors had moderate (3.4%) or severe (2.3%) anxiety symptoms, and moderate (7.7%) or severe (0%) depressive symptoms. Shorter time since diagnosis and higher number of comorbid diseases were associated with higher anxiety symptom severity. Female sex and higher number of comorbid diseases were associated with higher depressive symptom severity. CONCLUSION: From this explorative study, it follows that survivors with multiple comorbid diseases, shorter time since diagnosis, and female survivors might be at risk for higher anxiety and/or depressive symptom severity. Survivors with these characteristics might need extra monitoring.

Early biliary decompression versus conservative treatment in acute biliary pancreatitis (APEC trial): study protocol for a randomized controlled trial.

BACKGROUND: Acute pancreatitis is mostly caused by gallstones or sludge. Early decompression of the biliary tree by endoscopic retrograde cholangiography (ERC) with sphincterotomy may improve outcome in these patients. Whereas current guidelines recommend early ERC in patients with concomitant cholangitis, early ERC is not recommended in patients with mild biliary pancreatitis. Evidence on the role of routine early ERC with endoscopic sphincterotomy in patients without cholangitis but with biliary pancreatitis at high risk for complications is lacking. We hypothesize that early ERC with sphincterotomy improves outcome in these patients. METHODS/DESIGN: The APEC trial is a randomized controlled, parallel group, superiority multicenter trial. Within 24 hours after presentation to the emergency department, patients with biliary pancreatitis without cholangitis and at high risk for complications, based on an Acute Physiology and Chronic Health Evaluation (APACHE-II) score of 8 or greater, Modified Glasgow score of 3 or greater, or serum C-reactive protein above 150 mg/L, will be randomized. In 27 hospitals of the Dutch Pancreatitis Study Group, 232 patients will be allocated to early ERC with sphincterotomy or to conservative treatment. The primary endpoint is a composite of major complications (that is, organ failure, pancreatic necrosis, pneumonia, bacteremia, cholangitis, pancreatic endocrine, or exocrine insufficiency) or death within 180 days after randomization. Secondary endpoints include ERC-related complications, infected necrotizing pancreatitis, length of hospital stay and an economical evaluation. DISCUSSION: The APEC trial investigates whether an early ERC with sphincterotomy reduces the composite endpoint of major complications or death compared with conservative treatment in patients with biliary pancreatitis at high risk of complications. TRIAL REGISTRATION: Current Controlled Trials ISRCTN97372133 (date registration: 17-12-2012).

Prospective cross-sectional study on faecal immunochemical tests: sex specific cut-off values to obtain equal sensitivity for colorectal cancer?

BACKGROUND: Faecal immunochemical tests (FITs) are commonly used in colorectal cancer (CRC) screening. Diagnostic accuracy of FIT differs between males and females. This so far unexplained difference could result in a dissimilarity in screening outcome between both sexes. The aim of this study is to compare sensitivity and specificity of a FIT between males and females, and study potential explanatory variables. METHODS: In this cross-sectional study, data were prospectively collected. 3,022 subjects performed a FIT prior to complete colonoscopy. Sensitivity, specificity, and ROC curves were compared for both sexes. Potential explanatory variables of the relation between sensitivity and sex were explored. RESULTS: At all cut-off values, FIT sensitivity for CRC was higher (range 13-23%) and specificity was lower (range 2-4%) in males compared to females. At 75 ng/ml, sensitivity for CRC was 93% in males compared to 71% in females (p = 0.03), and specificity was 90% in males compared to 93% in females (p = <0.05). For advanced adenomas, males had a slightly higher sensitivity and lower specificity (not significant). At 75 ng/ml, sensitivity for advanced adenomas was 33% in males compared to 29% in females (p = 0.46), and specificity was 93% in males compared to 95% in females (p = 0.22). ROC curves were similar for both sexes, and equal combinations of sensitivity and specificity could be achieved by adjusting the cut-off values. For CRC, the difference in sensitivity could not be explained by age or location of the tumour. CONCLUSIONS: FIT has a higher sensitivity and a lower specificity for CRC in males than in females. Equal test characteristics can be achieved by allowing separate cut-off values for both sexes. Location and age do not explain the observed differences in sensitivity.

Similar fecal immunochemical test results in screening and referral colorectal cancer.

AIM: To improve the interpretation of fecal immunochemical test (FIT) results in colorectal cancer (CRC) cases from screening and referral cohorts. METHODS: In this comparative observational study, two prospective cohorts of CRC cases were compared. The first cohort was obtained from 10 322 average risk subjects invited for CRC screening with FIT, of which, only subjects with a positive FIT were referred for colonoscopy. The second cohort was obtained from 3637 subjects scheduled for elective colonoscopy with a positive FIT result. The same FIT and positivity threshold (OC sensor; ≥ 50 ng/mL) was used in both cohorts. Colonoscopy was performed in all referral subjects and in FIT positive screening subjects. All CRC cases were selected from both cohorts. Outcome measurements were mean FIT results and FIT scores per tissue tumor stage (T stage). RESULTS: One hundred and eighteen patients with CRC were included in the present study: 28 cases obtained from the screening cohort (64% male; mean age 65 years, SD 6.5) and 90 cases obtained from the referral cohort (58% male; mean age 69 years, SD 9.8). The mean FIT results found were higher in the referral cohort (829 ± 302 ng/mL vs 613 ± 368 ng/mL, P = 0.02). Tissue tumor stage (T stage) distribution was different between both populations [screening population: 13 (46%) T1, eight (29%) T2, six (21%) T3, one (4%) T4 carcinoma; referral population: 12 (13%) T1, 22 (24%) T2, 52 (58%) T3, four (4%) T4 carcinoma], and higher T stage was significantly associated with higher FIT results (P < 0.001). Per tumor stage, no significant difference in mean FIT results was observed (screening vs referral: T1 498 ± 382 ng/mL vs 725 ± 374 ng/mL, P = 0.22; T2 787 ± 303 ng/mL vs 794 ± 341 ng/mL, P = 0.79; T3 563 ± 368 ng/mL vs 870 ± 258 ng/mL, P = 0.13; T4 not available). After correction for T stage in logistic regression analysis, no significant differences in mean FIT results were observed between both types of cohorts (P = 0.10). CONCLUSION: Differences in T stage distribution largely explain differences in FIT results between screening and referral cohorts. Therefore, FIT results should be reported according to T stage.

Faecal immunochemical test accuracy in patients referred for surveillance colonoscopy: a multi-centre cohort study.

BACKGROUND: Given the increasing burden on colonoscopy capacity, it has been suggested that faecal immunochemical test (FIT) results could guide surveillance colonoscopy intervals. Against this background, we have evaluated the test accuracy of single and double FIT sampling to detect colorectal cancer (CRC) and/or advanced adenomas in an asymptomatic colonoscopy-controlled high-risk population. METHODS: Cohort study of asymptomatic high-risk patients (personal history of adenomas/CRC or family history of CRC), who provided one or two FITs before elective colonoscopy. Test accuracy of FIT for detection of CRC and advanced adenomas was determined (cut-off level 50 ng/ml). RESULTS: 1,041 patients provided a FIT (516 personal history of adenomas, 172 personal history of CRC and 353 family history of CRC). Five CRCs (0.5%) and 101 advanced adenomas (9.7%) were detected by colonoscopy. Single FIT sampling resulted in a sensitivity, specificity, PPV and NPV for CRC of 80%, 89%, 3% and 99.9%, respectively, and for advanced adenoma of 28%, 91%, 24% and 92%, respectively. Double FIT sampling did not result in a significantly higher sensitivity for advanced neoplasia. Simulation of multiple screening rounds indicated that sensitivity of FIT for advanced adenoma could reach 81% after 5 screening rounds. CONCLUSIONS: In once-only FIT sampling before surveillance colonoscopy, 70% of advanced neoplasia were missed. A simulation approach indicates that multiple screening rounds may be more promising in detecting advanced neoplasia and could potentially alleviate endoscopic burden.

Double sampling of a faecal immunochemical test is not superior to single sampling for detection of colorectal neoplasia: a colonoscopy controlled prospective cohort study.

BACKGROUND: A single sampled faecal immunochemical test (FIT) has moderate sensitivity for colorectal cancer and advanced adenomas. Repeated FIT sampling could improve test sensitivity. The aim of the present study is to determine whether any of three different strategies of double FIT sampling has a better combination of sensitivity and specificity than single FIT sampling. METHODS: Test performance of single FIT sampling in subjects scheduled for colonoscopy was compared to double FIT sampling intra-individually. Test positivity of double FIT sampling was evaluated in three different ways: 1) "one of two FITs+" when at least one out of two measurements exceeded the cut-off value, 2) "two of two FITs+" when both measurements exceeded the cut-off value, 3) "mean of two FITs+" when the geometric mean of two FITs exceeded the cut-off value. Receiver operator curves were calculated and sensitivity of single and the three strategies of double FIT sampling were compared at a fixed level of specificity. RESULTS: In 124 of 1096 subjects, screen relevant neoplasia (SRN) were found (i.e. early stage CRC or advanced adenomas). At any cut-off, "two of two FITs+" resulted in the lowest and "one of two FITs+" in the highest sensitivity for SRN (range 35-44% and 42%-54% respectively). ROC's of double FIT sampling were similar to single FIT sampling. At specificities of 85/90/95%, sensitivity of any double FIT sampling strategy did not differ significantly from single FIT (p-values 0.07-1). CONCLUSION: At any cut off, "one of two FITs+" is the most sensitive double FIT sampling strategy. However, at a given specificity level, sensitivity of any double FIT sampling strategy for SRN is comparable to single FIT sampling at a different cut-off value. None of the double FIT strategies has a superior combination of sensitivity and specificity over single FIT.

Acute pancreatitis and concomitant use of pancreatitis-associated drugs.

OBJECTIVES: Drug-induced pancreatitis (DIP) is considered a relative rare disease entity, perhaps due to lack of recognition. The objective of this study was to evaluate the prevalence of pancreatitis-associated drugs in a Dutch cohort of patients admitted for acute pancreatitis (AP) and to identify the proportion AP possibly attributable to the use of drugs. METHODS: This was a multicenter observational study (EARL study). Etiology, disease course, use of pancreatitis-associated drugs at hospital admittance, and discontinuation of these drugs were evaluated. Drugs were scored by means of an evidence-based DIP classification system. RESULTS: The first documented hospital admissions of 168 patients were analyzed. In all, 70 out of 168 (41.6%; 95% confidence interval (CI): 34.5-49.2%) patients used pancreatitis-associated drugs at admission. In 26.2% (44/168; 95% CI: 20.1-33.3%) of cases, at least one class I pancreatitis-associated drug was used. Possibly DIP was present in 12.5% (21/168; 95% CI: 8.3-18.4%); in less than half of these patients (9/21 or 42.9%; 95% CI: 24.5-63.5%), the prescribed drugs were actually discontinued, with no recurrence of AP later on. Among the remaining 12 patients without discontinuation of their drugs use and in absence of an alternative etiologic cause of AP, 8 patients used a class I pancreatitis-associated drug, representing 4.8% (8/168, 95% CI: 2.4-9.1%) of the total study population. CONCLUSIONS: In this series, a remarkably high percentage of patients who were admitted because of an attack of AP used pancreatitis-associated drugs. Physicians should be more aware of the possibility of DIP in patients with otherwise unexplained AP and act appropriately by discontinuation of the drug.

Higher fecal immunochemical test cutoff levels: lower positivity rates but still acceptable detection rates for early-stage colorectal cancers.

BACKGROUND: Adjusting the threshold for positivity of quantitative fecal immunochemical tests (FIT) allows for controlling the number of follow-up colonoscopies in a screening program. However, it is unknown to what extent higher cutoff levels affect detection rates of screen-relevant neoplasia. This study aimed to assess the effect of higher cutoff levels of a quantitative FIT on test positivity rate and detection rate of early-stage colorectal cancers (CRC). METHODS: Subjects above 40 years old scheduled for colonoscopy in 5 hospitals were asked to sample a single FIT (OC sensor) before colonoscopy. Screen-relevant neoplasia were defined as advanced adenoma or early-stage cancer (stage I and II). Positivity rate, sensitivity, and specificity were evaluated at increasing cutoff levels of 50 to 200 ng/mL. RESULTS: In 2,145 individuals who underwent total colonoscopy, 79 patients were diagnosed with CRC, 38 of which were with early-stage disease. Advanced adenomas were found in 236 patients. When varying cutoff levels from ≥ 50 to ≥ 200 ng/mL, positivity rates ranged from 16.5% to 10.2%. With increasing cutoff levels, sensitivity for early-stage CRCs and for screen-relevant neoplasia ranged from 84.2% to 78.9% and 47.1% to 37.2%, respectively. CONCLUSIONS: Higher FIT cutoff levels substantially decrease test positivity rates with only limited effects on detection rates of early-stage CRCs. However, spectrum bias resulting in higher estimates of sensitivity than would be expected in a screening population may be present. IMPACT: Higher cutoff levels can reduce strain on colonoscopy capacity with only a modest decrease in sensitivity for curable cancers.

Does delay in diagnosing colorectal cancer in symptomatic patients affect tumor stage and survival? A population-based observational study.

BACKGROUND: Diagnosing colorectal cancer (CRC) at an early stage improves survival. To what extent any delay affects outcome once patients are symptomatic is still unclear.Our objectives were to evaluate the association between diagnostic delay and survival in symptomatic patients with early stage CRC and late stage CRC. METHODS: Prospective population-based observational study evaluating daily clinical practice in Northern Holland. Diagnostic delay was determined through questionnaire-interviews. Dukes' stage was classified into two groups: early stage (Dukes A or B) and late stage (Dukes C or D) cancer. Patients were followed up for 3.5 years after diagnosis. RESULTS: In total, 272 patients were available for analysis. Early stage CRC was present in 136 patients while 136 patients had late stage CRC. The mean total diagnostic delay (SE) was 31 (1.5) weeks in all CRC patients. No significant difference was observed in the mean total diagnostic delay in early versus late stage CRC (p = 0.27).In early stage CRC, no difference in survival was observed between patients with total diagnostic delay shorter and longer than the median (Kaplan-Meier, log-rank p = 0.93).In late stage CRC, patients with a diagnostic delay shorter than the median had a shorter survival than patients with a diagnostic delay longer than the median (log-rank p = 0.01). In the multivariate Cox regression model with survival as dependent variable and median delay, age, open access endoscopy, number and type of symptoms as independent variables, the odd's ratio for survival in patients with long delay (>median) versus short delay (

[Diagnosis of colorectal tumours in daily clinical practice: comparison of colonoscopy and sigmoidoscopy]. / Diagnostiek van colorectale tumoren in de dagelijkse praktijk. Vergelijking van coloscopie en sigmoïdoscopie.

OBJECTIVE: To map the locations of advanced colorectal neoplasia in patients referred for colonoscopy or sigmoidoscopy and to compare the yield of advanced neoplasia and the distribution of advanced neoplasia per indication for endoscopy. DESIGN: Observational. METHOD: In a multicentre survey in North Holland, the Netherlands (n = 18 hospitals), data on all colonoscopies and sigmoidoscopies performed during a three-month period in 2005 were analyzed. The locations and the histological features of all colonic neoplasia and the indications for endoscopy were recorded. Advanced neoplasm was defined as adenoma >or=10 mm in size, an adenoma with any villous features, or high-grade dysplasia or adenocarcinoma. RESULTS: A total of 4623 patients underwent a total colonoscopy and 3004 patients underwent sigmoidoscopy. The prevalence of advanced neoplasia was 13% on colonoscopy and 6% on sigmoidoscopy. Of the advanced neoplasia found on colonoscopy, 67% were located in the distal colon and 33% in the proximal colon. Of the patients with advanced neoplasia in the proximal colon (n = 228), 51% had no abnormalities in the distal colon. The percentage of advanced neoplasia in the proximal colon varied from 23% in patients younger than 50 years to 41% in patients aged 80 years and older. Depending on the indication for endoscopy, the prevalence of advanced neoplasia in the proximal colon varied from 11-57%. CONCLUSION: Of the advanced colorectal neoplasms 33% were located in the proximal colon. With increasing age, a shift in tumour localization occurs from distal to proximal in the colon. Colonoscopy is the preferred method for the endoscopic diagnosing of colorectal neoplasia.

Colonoscopic yield of colorectal neoplasia in daily clinical practice.

AIM: To assess the prevalence and location of advanced neoplasia in patients undergoing colonoscopy, and to compare the yield per indication. METHODS: In a multicenter colonoscopy survey (n = 18 hospitals) in the Amsterdam area (Northern Holland), data of all colonoscopies performed during a three month period in 2005 were analyzed. The location and the histological features of all colonic neoplasia were recorded. The prevalence and the distribution of advanced colorectal neoplasia and differences in yield between indication clusters were evaluated. Advanced neoplasm was defined as adenoma > 10 mm in size, with > 25% villous features or with high-grade dysplasia or cancer. RESULTS: A total of 4623 eligible patients underwent a total colonoscopy. The prevalence of advanced neoplasia was 13%, with 281 (6%) adenocarcinomas and 342 (7%) advanced adenomas. Sixty-seven percent and 33% of advanced neoplasia were located in the distal and proximal colon, respectively. Of all patients with right-sided advanced neoplasia (n = 228), 51% had a normal distal colon, whereas 27% had a synchronous distal adenoma. Ten percent of all colonoscopies were performed in asymptomatic patients, 7% of whom had advanced neoplasia. In the respective procedure indication clusters, the prevalence of right-sided advanced neoplasia ranged from 11%-57%. CONCLUSION: One out of every 7-8 colonoscopies yielded an advanced colorectal neoplasm. Colonoscopy is warranted for the evaluation of both symptomatic and asymptomatic patients.

Paradoxical elevated thiopurine S-methyltransferase activity after pancytopenia during azathioprine therapy: potential influence of red blood cell age.

There is an increased risk of developing bone marrow depression and infections during azathioprine therapy for inflammatory bowel disease. Patients with low or absent thiopurine S-methyltransferase (TPMT) activity have an increased risk of developing myelotoxicity. We describe a patient who developed pancytopenia combined with cytomegalovirus pneumonia after several years of azathioprine use. The bone marrow depression was probably caused by the viral infection, as all others causative factors were unlikely. Surprisingly, we observed grossly elevated TPMT activity (182 nmol/g/h) during the recovery phase, following the pancytopenic period. After complete recovery of the bone marrow suppression, TPMT activity returned to usual reference activity (43 nmol/g/h). This remarkable change in enzymatic activity of TPMT may be explained by differences in the age of red blood cells, as younger erythrocytes have a higher TPMT activity. Determination of a patient's TPMT status by phenotyping should therefore not be performed just after bone marrow depression or in cases of activated erythropoieses.