Dynamic Prediction of Advanced Colorectal Neoplasia in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Colonoscopic surveillance is recommended in patients with colonic inflammatory bowel disease (IBD) given their increased risk of colorectal cancer (CRC). We aimed to develop and validate a dynamic prediction model for the occurrence of advanced colorectal neoplasia (aCRN, including high-grade dysplasia and CRC) in IBD. METHODS: We pooled data from 6 existing cohort studies from Canada, The Netherlands, the United Kingdom, and the United States. Patients with IBD and an indication for CRC surveillance were included if they underwent at least 1 follow-up procedure. Exclusion criteria included prior aCRN, prior colectomy, or an unclear indication for surveillance. Predictor variables were selected based on the literature. A dynamic prediction model was developed using a landmarking approach based on Cox proportional hazard modeling. Model performance was assessed with Harrell's concordance-statistic (discrimination) and by calibration curves. Generalizability across surveillance cohorts was evaluated by internal-external cross-validation. RESULTS: The surveillance cohorts comprised 3731 patients, enrolled and followed-up in the time period from 1973 to 2021, with a median follow-up period of 5.7 years (26,336 patient-years of follow-up evaluation); 146 individuals were diagnosed with aCRN. The model contained 8 predictors, with a cross-validation median concordance statistic of 0.74 and 0.75 for a 5- and 10-year prediction window, respectively. Calibration plots showed good calibration. Internal-external cross-validation results showed medium discrimination and reasonable to good calibration. CONCLUSIONS: The new prediction model showed good discrimination and calibration, however, generalizability results varied. Future research should focus on formal external validation and relate predicted aCRN risks to surveillance intervals before clinical application.

Smoking and colorectal neoplasia in patients with inflammatory bowel disease: Dose-effect relationship.

BACKGROUND AND AIMS: Prior studies on the effect of smoking on the risk of colitis-associated colorectal neoplasia (CRN) have reported conflicting results. We aimed to further elucidate the association between smoking, including possible dose-effects, and the development of colorectal neoplasia in patients with inflammatory bowel disease (IBD). METHODS: We performed a prospective multicenter cohort study including patients with colonic IBD enrolled in a surveillance program in four academic hospitals between 2011 and 2021. The effects of smoking status and pack-years at study entry on subsequent recurrent events of CRN (including indefinite, low- and high-grade dysplasia, and colorectal cancer [CRC]) were evaluated using uni- and multivariable Prentice, Williams, and Peterson total-time Cox proportional hazard models. Adjustment was performed for extensive disease, prior/index dysplasia, sex, age, first-degree relative with CRC, primary sclerosing cholangitis, and endoscopic inflammation. RESULTS: In 501 of the enrolled 576 patients, at least one follow-up surveillance was performed after the study index (median follow-up 5 years). CRN occurred at least once in 105 patients. Ever smoking was not associated with recurrent CRN risk (adjusted hazard ratio [aHR] 1.04, 95% confidence interval [CI] 0.75-1.44), but an increasing number of pack-years was associated with an increased risk of recurrent CRN (aHR per 10 pack-years 1.17, 95% CI 1.03-1.32; p < 0.05). Separate analyses per IBD type did not reveal differences. CONCLUSIONS: This study found that an increase in pack-years is associated with a higher risk of recurrent CRN in patients with IBD, independent of established CRN risk factors (NCT01464151).

Consecutive negative findings on colonoscopy during surveillance predict a low risk of advanced neoplasia in patients with inflammatory bowel disease with long-standing colitis: results of a 15-year multicentre, multinational cohort study.

OBJECTIVES: Surveillance colonoscopy is thought to prevent colorectal cancer (CRC) in patients with long-standing colonic IBD, but data regarding the frequency of surveillance and the findings thereof are lacking. Our aim was to determine whether consecutive negative surveillance colonoscopies adequately predict low neoplastic risk. DESIGN: A multicentre, multinational database of patients with long-standing IBD colitis without high-risk features and undergoing regular CRC surveillance was constructed. A 'negative' surveillance colonoscopy was predefined as a technically adequate procedure having no postinflammatory polyps, no strictures, no endoscopic disease activity and no evidence of neoplasia; a 'positive' colonoscopy was a technically adequate procedure that included at least one of these criteria. The primary endpoint was advanced colorectal neoplasia (aCRN), defined as high-grade dysplasia or CRC. RESULTS: Of 775 patients with long-standing IBD colitis, 44% (n=340) had >1 negative colonoscopy. Patients with consecutive negative surveillance colonoscopies were compared with those who had at least one positive colonoscopy. Both groups had similar demographics, disease-related characteristics, number of surveillance colonoscopies and time intervals between colonoscopies. No aCRN occurred in those with consecutive negative surveillance, compared with an incidence rate of 0.29 to 0.76/100 patient-years (P=0.02) in those having >1 positive colonoscopy on follow-up of 6.1 (P25-P75: 4.6-8.2) years after the index procedure. CONCLUSION: Within this large surveillance cohort of patients with colonic IBD and no additional high-risk features, having two consecutive negative colonoscopies predicted a very low risk of aCRN occurrence on follow-up. Our findings suggest that longer surveillance intervals in this selected population may be safe.

Malignant and Nonmalignant Complications of the Rectal Stump in Patients with Inflammatory Bowel Disease.

Background: Patients with refractory inflammatory bowel disease (IBD) might require a subtotal colectomy with construction of an ileostomy. Due to the risk of nerve damage and pelvic sepsis, the diverted rectum is often left in situ. Evidence on long-term complications of this rectal stump is limited, particularly in patients with Crohn's disease (CD). In addition to the risk of development of neoplasia, diversion proctitis is a frequently reported rectal stump associated complication. Surprisingly, clear recommendations concerning rectal stump surveillance and timing of proctectomy are lacking. Methods: Through the use of a pathology database and a review of medical records, we established a cohort of IBD patients with a diverted rectum. Among these patients, long-term complications of the rectal stump were identified. Main endpoint was advanced neoplasia (carcinoma or high-grade dysplasia [HGD]) in the rectal stump. Risk factors for advanced neoplasia were identified using Cox regression modeling. In the second, prospective part of the study, a questionnaire was sent out to 165 patients with either a rectal stump in situ or who had undergone a proctectomy, in order to identify differences in patient-reported outcome measures associated with the excision of the rectal stump. Results: From 530 patients with IBD and a (temporal) diversion of the rectum, we included 250 patients in whom the rectal stump was left in situ for more than 12 months. The majority of patients was female (61%) and had Crohn's disease (67%). On follow-up (median 8 years), 8 carcinomas, 2 cases of high-grade dysplasia, and 7 cases of low-grade dysplasia were found with incidence rates of 3.9 and 8.5 per 1000 patient-years of follow-up for cancer and all neoplasia, respectively. The 8 cases of rectal stump cancer (RSC) were diagnosed after a median of 15 years after colectomy. A history of colorectal neoplasia was associated with advanced rectal stump neoplasia. Out of 191 patients with endoscopic follow-up, rectal stump inflammation occurred in 161 (88.5%) patients. Results of the questionnaire did not show a significant difference in quality of life between patients with and patients without a rectal stump, although the latter group reported significantly more sexual and urinary symptoms than patients with a rectal stump in situ. The majority of rectal stump patients reported rectal blood loss, but 65.5% of them were not or barely limited in daily life by their rectal stumprelated problems. Conclusion: Rectal stump cancer has a low incidence rate, with patients with a history of colonic neoplasia carrying the highest risk of developing this severe complication. We observed no significant differences in quality of life between rectal stump and postproctectomy patients, but proctectomy surgery is associated with sexual and urinary complications.

No Association Between Pseudopolyps and Colorectal Neoplasia in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Patients with inflammatory bowel diseases who have postinflammatory polyps (PIPs) have an increased risk of colorectal neoplasia (CRN). European guidelines propose that patients with PIPs receive more frequent surveillance colonoscopies, despite limited evidence of this increased risk. We aimed to define the risk of CRN and colectomy in patients with inflammatory bowel diseases and PIPs. METHODS: We conducted a multicenter retrospective cohort study of patients with inflammatory bowel diseases who underwent colonoscopic surveillance for CRN, from January 1997 through January 2017, at 5 academic hospitals and 2 large nonacademic hospitals in New York or the Netherlands. Eligible patients had confirmed colonic disease with duration of at least 8 years (or any duration, if they also had primary sclerosing cholangitis) and no history of advanced CRN (high-grade dysplasia or colorectal cancer) or colectomy. The primary outcome was occurrence of advanced CRN according to PIP status; secondary outcomes were occurrence of CRN (inclusive of low-grade dysplasia) and colectomy. RESULTS: Of 1582 eligible patients, 462 (29.2%) had PIPs. PIPs were associated with more severe inflammation (adjusted odds ratio 1.32; 95% confidence interval [CI] 1.13-1.55), greater disease extent (adjusted odds ratio 1.92; 95% CI 1.34-2.74), and lower likelihood of primary sclerosing cholangitis (adjusted odds ratio 0.38; 95% CI 0.26-0.55). During a median follow-up period of 4.8 years, the time until development of advanced CRN did not differ significantly between patients with and those without PIPs. PIPs did not independently increase the risk of advanced CRN (adjusted hazard ratio 1.17; 95% CI 0.59-2.31). The colectomy rate was significantly higher in patients with PIPs (P = .01). CONCLUSIONS: In a retrospective analysis of data from 2 large independent surveillance cohorts, PIPs were associated with greater severity and extent of colon inflammation and higher rates of colectomy, but were not associated with development of any degree of CRN. Therefore, intervals for surveillance should not be shortened based solely on the presence of PIPs.

Sample size of surgical randomized controlled trials: a lack of improvement over time.

BACKGROUND: Interpretation of randomized controlled trials (RCTs) without a significant difference regarding the primary outcome (negative RCTs) is frequently challenging, due to concerns about sample size and thus sufficient statistical power. We aimed to assess the adequacy of sample size and corresponding power of surgical RCTs. METHODS: We previously identified all surgical RCTs available in PubMed in two distinct years a decade apart (1999 and 2009). For all "negative" trials, we estimated whether the sample size of the trial was appropriate to detect a difference in the primary outcome measure. The main outcome measure was a sufficient sample size to detect large, medium, and small treatment effects. We also performed a post hoc power analysis based on the actual observed effect difference. RESULTS: A total of 228 negative RCTs (74 in 1999 and 121 in 2009) were included. The median sample size was 76 (± 222) and 80 (± 163) in 1999 and 2009, respectively. Sample size calculation was increasingly reported from 40% in 1999 to 54% in 2009 (P = 0.02). The proportion of studies adequately powered to detect large (57% versus 68%), medium (26% versus 25%), or small (8% versus 7%) differences did not differ significantly between 1999 and 2009, respectively. To reach sufficient power, the required increases in sample size were 130%, 240%, and 1032% for large, medium, and small differences, respectively. Reporting a sample size calculation was the only independent predictor for adequate power. CONCLUSIONS: Despite slight improvement in the reporting of a sample size calculation, about a third of surgical trials remains underpowered to demonstrate differences that are likely to be clinically significant. Increased attention of researchers, medical ethical boards, and journal editors is required to reduce potentially wasted resources on underpowered trials.

High Risk of Advanced Colorectal Neoplasia in Patients With Primary Sclerosing Cholangitis Associated With Inflammatory Bowel Disease.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC, termed PSC-IBD) are at increased risk for colorectal cancer, but their risk following a diagnosis of low-grade dysplasia (LGD) is not well described. We aimed to determine the rate of advanced colorectal neoplasia (aCRN), defined as high-grade dysplasia and/or colorectal cancer, following a diagnosis of indefinite dysplasia or LGD in this population. METHODS: We performed a retrospective, longitudinal study of 1911 patients with colonic IBD (293 with PSC and 1618 without PSC) who underwent more than 2 surveillance colonoscopies from 2000 through 2015 in The Netherlands or the United States (9265 patient-years of follow-up evaluation). We collected data on clinical and demographic features of patients, as well as data from each surveillance colonoscopy and histologic report. For each surveillance colonoscopy, the severity of active inflammation was documented. The primary outcome was a diagnosis of aCRN during follow-up evaluation. We also investigated factors associated with aCRN in patients with or without a prior diagnosis of indefinite dysplasia or LGD. RESULTS: Patients with PSC-IBD had a 2-fold higher risk of developing aCRN than patients with non-PSC IBD. Mean inflammation scores did not differ significantly between patients with PSC-IBD (0.55) vs patients with non-PSC IBD (0.56) (P = .89), nor did proportions of patients with LGD (21% of patients with PSC-IBD vs 18% of patients with non-PSC IBD) differ significantly (P = .37). However, the rate of aCRN following a diagnosis of LGD was significantly higher in patients with PSC-IBD (8.4 per 100 patient-years) than patients with non-PSC IBD (3.0 per 100 patient-years; P = .01). PSC (adjusted hazard ratio [aHR], 2.01; 95% CI, 1.09-3.71), increasing age (aHR 1.03; 95% CI, 1.01-1.05), and active inflammation (aHR, 2.39; 95% CI, 1.63-3.49) were independent risk factors for aCRN. Dysplasia was more often endoscopically invisible in patients with PSC-IBD than in patients with non-PSC IBD. CONCLUSIONS: In a longitudinal study of almost 2000 patients with colonic IBD, PSC remained a strong independent risk factor for aCRN. Once LGD is detected, aCRN develops at a higher rate in patients with PSC and is more often endoscopically invisible than in patients with only IBD. Our findings support recommendations for careful annual colonoscopic surveillance for patients with IBD and PSC, and consideration of colectomy once LGD is detected.

Journal impact factor and methodological quality of surgical randomized controlled trials: an empirical study.

PURPOSE: The journal impact factor (IF) is often used as a surrogate marker for methodological quality. The objective of this study is to evaluate the relation between the journal IF and methodological quality of surgical randomized controlled trials (RCTs). METHODS: Surgical RCTs published in PubMed in 1999 and 2009 were identified. According to IF, RCTs were divided into groups of low (<2), median (2-3) and high IF (>3), as well as into top-10 vs all other journals. Methodological quality characteristics and factors concerning funding, ethical approval and statistical significance of outcomes were extracted and compared between the IF groups. Additionally, a multivariate regression was performed. RESULTS: The median IF was 2.2 (IQR 2.37). The percentage of 'low-risk of bias' RCTs was 13% for top-10 journals vs 4% for other journals in 1999 (P < 0.02), and 30 vs 12% in 2009 (P < 0.02). Similar results were observed for high vs low IF groups. The presence of sample-size calculation, adequate generation of allocation and intention-to-treat analysis were independently associated with publication in higher IF journals; as were multicentre trials and multiple authors. CONCLUSION: Publication of RCTs in high IF journals is associated with moderate improvement in methodological quality compared to RCTs published in lower IF journals. RCTs with adequate sample-size calculation, generation of allocation or intention-to-treat analysis were associated with publication in a high IF journal. On the other hand, reporting a statistically significant outcome and being industry funded were not independently associated with publication in a higher IF journal.

Clinical implications of low grade dysplasia found during inflammatory bowel disease surveillance: a retrospective study comparing chromoendoscopy and white-light endoscopy.

Background and study aims Current guidelines recommend the use of pancolonic chromoendoscopy for surveillance of patients with inflammatory bowel disease (IBD). It is currently unknown whether low grade dysplasia (LGD) found using chromoendoscopy carries a similar risk of high grade dysplasia (HGD) or colorectal cancer (CRC) compared with LGD detected using white-light endoscopy (WLE). The aim of this study was to compare the risk of advanced neoplasia, a combined endpoint of HGD and CRC, during follow-up after detection of lesions containing LGD identified with either chromoendoscopy or WLE. Patients and methods A retrospective cohort was established to identify patients who underwent IBD surveillance for ulcerative colitis or colonic Crohn's disease between 2000 and 2014. Subgroups were identified, based on the endoscopic technique (standard definition resolution WLE, high definition resolution WLE or chromoendoscopy). LGD detected in random biopsies was considered invisible LGD. Patients were followed until detection of advanced neoplasia, colectomy, death, or the last known surveillance colonoscopy. Results Of 1065 patients undergoing IBD surveillance, 159 patients underwent follow-up for LGD, which was visible in 133 cases and invisible in 26 cases. On follow-up, five cases of HGD and five cases of CRC were detected. The overall incidence rate of advanced neoplasia was 1.34 per 100 patient-years with a median follow-up of 4.7 years and a median time to advanced neoplasia of 3.3 years. There were no significant differences in the incidence of advanced neoplasia between chromoendoscopy-detected and WLE-detected LGD. Conclusion Advanced neoplasia was found to develop infrequently after detection of LGD in patients undergoing endoscopic surveillance for IBD. LGD lesions detected with either chromoendoscopy or WLE carry similar risks of advanced neoplasia over time.

Low Rate of Dysplasia Detection in Mucosa Surrounding Dysplastic Lesions in Patients Undergoing Surveillance for Inflammatory Bowel Diseases.

BACKGROUND & AIMS: When dysplastic lesions are encountered during surveillance colonoscopy of patients with inflammatory bowel disease (IBD), guidelines recommend collection of additional biopsies from the surrounding mucosa to ensure the lesion has been adequately circumscribed. We aimed to determine the rate of dysplasia in mucosa biopsies collected from tissues surrounding dysplastic lesions during IBD surveillance. METHODS: In a retrospective study, we collected endoscopy and pathology reports from 1065 patients undergoing colonoscopic surveillance for IBD from 2000 through 2015 at 3 centers in the Netherlands. We analyzed reports from all patients with dysplastic lesions from whom biopsies of surrounding mucosa were collected. Among 194 patients with 1 or more visible dysplastic lesions, mucosal biopsies were collected from tissues adjacent to 140 dysplastic lesions from 71 patients (63% male; 48% with ulcerative colitis, 42% with Crohn's disease, and 10% with indeterminate colitis). RESULTS: The mean number of surrounding mucosa biopsies collected per lesion was 3.4 (range, 1-6). Dysplasia was detected in 7 biopsies surrounding 140 areas of dysplasia (5.0%) and 5 biopsies surrounding 136 areas of low-grade dysplasia (3.7%). Dysplasia in biopsies of surrounding mucosa could be observed during 5 of 87 white light endoscopies and during 2 of 53 chromoendoscopies. In patients with dysplasia in mucosa surrounding lesions of low-grade dysplasia, post-resection surveillance did not reveal high-grade dysplasia or colorectal cancer. CONCLUSIONS: Dysplasia is detected in only 5% of biopsies collected from mucosa surrounding dysplastic lesions. This observation indicates that endoscopists accurately delineate the borders of dysplastic lesions during surveillance of patients with IBD. The lack of clinical consequences from routinely collecting biopsies from areas surrounding dysplastic lesions casts doubt on the usefulness and cost-effectiveness of this practice.

Surveillance of long-standing colitis: the role of image-enhanced endoscopy.

Patients with long-standing inflammatory bowel disease of the colon are at an increased risk of developing colorectal carcinoma. Surveillance programs have been implemented with the aim of detecting neoplastic lesions in an early stage. Due to limitations of conventional white light endoscopy, several new techniques to enhance the detection of dysplastic lesions in this setting have been explored. These advanced endoscopic techniques use a variety of methods to improve visualization, such as pancolonic dye-spraying (chromoendoscopy), optical filters (narrow-band imaging) and autofluorescence of mucosal tissue (autofluorescence imaging). At present, most guidelines have adopted chromoendoscopy as the preferred method for surveillance, based on several controlled studies. It is currently unknown if widespread implementation of chromoendoscopy will lead to an improved clinical outcome. This review explores the current evidence on image-enhanced endoscopic techniques used in the detection of neoplastic lesions in patients with long standing colitis.