Enrichment of colibactin-associated mutational signatures in unexplained colorectal polyposis patients.

BACKGROUND: Colibactin, a genotoxin produced by polyketide synthase harboring (pks+) bacteria, induces double-strand breaks and chromosome aberrations. Consequently, enrichment of pks+Escherichia coli in colorectal cancer and polyposis suggests a possible carcinogenic effect in the large intestine. Additionally, specific colibactin-associated mutational signatures; SBS88 and ID18 in the Catalogue of Somatic Mutations in Cancer database, are detected in colorectal carcinomas. Previous research showed that a recurrent APC splice variant perfectly fits SBS88. METHODS: In this study, we explore the presence of colibactin-associated signatures and fecal pks in an unexplained polyposis cohort. Somatic targeted Next-Generation Sequencing (NGS) was performed for 379 patients. Additionally, for a subset of 29 patients, metagenomics was performed on feces and mutational signature analyses using Whole-Genome Sequencing (WGS) on Formalin-Fixed Paraffin Embedded (FFPE) colorectal tissue blocks. RESULTS: NGS showed somatic APC variants fitting SBS88 or ID18 in at least one colorectal adenoma or carcinoma in 29% of patients. Fecal metagenomic analyses revealed enriched presence of pks genes in patients with somatic variants fitting colibactin-associated signatures compared to patients without variants fitting colibactin-associated signatures. Also, mutational signature analyses showed enrichment of SBS88 and ID18 in patients with variants fitting these signatures in NGS compared to patients without. CONCLUSIONS: These findings further support colibactins ability to mutagenize colorectal mucosa and contribute to the development of colorectal adenomas and carcinomas explaining a relevant part of patients with unexplained polyposis.

Understanding students' feedback use in medical progress testing: A qualitative interview study.

BACKGROUND: Active engagement with feedback is crucial for feedback to be effective and improve students' learning and achievement. Medical students are provided feedback on their development in the progress test (PT), which has been implemented in various medical curricula, although its format, integration and feedback differ across institutions. Existing research on engagement with feedback in the context of PT is not sufficient to make a definitive judgement on what works and which barriers exist. Therefore, we conducted an interview study to explore students' feedback use in medical progress testing. METHODS: All Dutch medical students participate in a national, curriculum-independent PT four times a year. This mandatory test, composed of multiple-choice questions, provides students with written feedback on their scores. Furthermore, an answer key is available to review their answers. Semi-structured interviews were conducted with 21 preclinical and clinical medical students who participated in the PT. Template analysis was performed on the qualitative data using a priori themes based on previous research on feedback use. RESULTS: Template analysis revealed that students faced challenges in crucial internal psychological processes that impact feedback use, including 'awareness', 'cognizance', 'agency' and 'volition'. Factors such as stakes, available time, feedback timing and feedback presentation contributed to these difficulties, ultimately hindering feedback use. Notably, feedback engagement was higher during clinical rotations, and students were interested in the feedback when seeking insights into their performance level and career perspectives. CONCLUSION: Our study enhanced the understanding of students' feedback utilisation in medical progress testing by identifying key processes and factors that impact feedback use. By recognising and addressing barriers in feedback use, we can improve both student and teacher feedback literacy, thereby transforming the PT into a more valuable learning tool.

Does 'summative' count? The influence of the awarding of study credits on feedback use and test-taking motivation in medical progress testing.

Despite the increasing implementation of formative assessment in medical education, its' effect on learning behaviour remains questionable. This effect may depend on how students value formative, and summative assessments differently. Informed by Expectancy Value Theory, we compared test preparation, feedback use, and test-taking motivation of medical students who either took a purely formative progress test (formative PT-group) or a progress test that yielded study credits (summative PT-group). In a mixed-methods study design, we triangulated quantitative questionnaire data (n = 264), logging data of an online PT feedback system (n = 618), and qualitative interview data (n = 21) to compare feedback use, and test-taking motivation between the formative PT-group (n = 316), and the summative PT-group (n = 302). Self-reported, and actual feedback consultation was higher in the summative PT-group. Test preparation, and active feedback use were relatively low and similar in both groups. Both quantitative, and qualitative results showed that the motivation to prepare and consult feedback relates to how students value the assessment. In the interview data, a link could be made with goal orientation theory, as performance-oriented students perceived the formative PT as not important due to the lack of study credits. This led to low test-taking effort, and feedback consultation after the formative PT. In contrast, learning-oriented students valued the formative PT, and used it for self-study or self-assessment to gain feedback. Our results indicate that most students are less motivated to put effort in the test, and use feedback when there are no direct consequences. A supportive assessment environment that emphasizes recognition of the value of formative testing is required to motivate students to use feedback for learning.

Risk and Time Pattern of Recurrences After Local Endoscopic Resection of T1 Colorectal Cancer: A Meta-analysis.

BACKGROUND & AIMS: Growing numbers of patients with T1 CRC are being treated with local endoscopic resection only and as a result, the need for optimization of surveillance strategies for these patients also increases. We aimed to estimate the cumulative incidence and time pattern of CRC recurrences for endoscopically treated patients with T1 CRC. METHODS: Using a systematic literature search in PubMed, EMBASE, Web of Science and Cochrane Library (from inception till 15 May 2020), we identified and extracted data from studies describing the cumulative incidence of local or distant CRC recurrence for patients with T1 CRC treated with local endoscopic resection only. Pooled estimates were calculated using mixed-effect logistic regression models. RESULTS: Seventy-one studies with 5167 unique, endoscopically treated patients with T1 CRC were included. The pooled cumulative incidence of any CRC recurrence was 3.3% (209 events; 95% CI, 2.6%-4.3%; I2 = 54.9%), with local and distant recurrences being found at comparable rates (pooled incidences 1.9% and 1.6%, respectively). CRC-related mortality was observed in 42 out of 2519 patients (35 studies; pooled incidence 1.7%, 95% CI, 1.2%-2.2%; I2 = 0%), and the CRC-related mortality rate among patients with recurrence was 40.8% (42/103 patients). The vast majority of recurrences (95.6%) occurred within 72 months of follow-up. Pooled incidences of any CRC recurrence were 7.0% for high-risk T1 CRCs (28 studies; 95% CI, 4.9%-9.9%; I2 = 48.1%) and 0.7% (36 studies; 95% CI, 0.4%-1.2%; I2 = 0%) for low-risk T1 CRCs. CONCLUSIONS: Our meta-analysis provides quantitative outcome measures which are relevant to guidelines on surveillance after local endoscopic resection of T1 CRC.

Geriatric assessment and treatment outcomes in a Dutch cohort of older patients with potentially curable esophageal cancer.

BACKGROUND: Patients with potentially curable esophageal cancer can be treated with neo-adjuvant chemoradiotherapy followed by surgery or definitive chemoradiotherapy with curative intent. For frail older patients choosing the appropriate oncological treatment can be difficult, and data on geriatric deficits as determinants of treatment outcomes are not yet available. OBJECTIVES: To describe the prevalence of geriatric deficits and to study their association with treatment discontinuation and mortality in older patients with potentially curable esophageal cancer. MATERIAL AND METHODS: A cohort study was conducted in a Dutch tertiary care hospital including patients aged ≥70 years with primary stage I-IVA esophageal cancer. Geriatric screening and assessment data were collected. Outcomes were treatment discontinuation and one year all-cause mortality. RESULTS: In total, 138 patients with curable esophageal cancer were included. Mean age was 76.1 years (standard deviation 4.7), 54% had clinical stage III and 24% stage IVA disease. Most patients received neo-adjuvant chemoradiotherapy and surgery (41%), 32% definitive chemoradiotherapy and 22% palliative radiotherapy. Overall, one year all-cause mortality was 36%. Geriatric screening and assessment was performed in 94 out of 138 patients, of which 60% was malnourished, 20% dependent in Instrumental Activities of Daily Living (IADL) and 52% was frail. Malnutrition was associated with higher mortality risk (Hazard Ratio, 3.2; 95% Confidence Interval, 1.3-7.7)) independent of age, sex and tumor stage. Seventy-six out of 94 patients were treated with chemoradiotherapy, of which 23% discontinued treatment. Patients with IADL dependency and Charlson Comorbidity Index ≥1 discontinued treatment more often. CONCLUSION: All-cause mortality within one year was high, irrespective of treatment modality. Treatment discontinuation rate was high, especially in patients treated with definitive chemoradiotherapy. Geriatric assessment associates with outcomes in older patients with esophageal cancer and may inform treatment decisions and optimization in future patients, but more research is needed to establish its predictive value. Trial registration: The study is retrospectively registered at the Netherlands Trial Register (NTR), trial number NL8107. Date of registration: 22-10-2019.

Risk of recurrence after local resection of T1 rectal cancer: a meta-analysis with meta-regression.

BACKGROUND: T1 rectal cancer (RC) patients are increasingly being treated by local resection alone but uniform surveillance strategies thereafter are lacking. To determine whether different local resection techniques influence the risk of recurrence and cancer-related mortality, a meta-analysis was performed. METHODS: A systematic search was conducted for T1RC patients treated with local surgical resection. The primary outcome was the risk of RC recurrence and RC-related mortality. Pooled estimates were calculated using mixed-effect logistic regression. We also systematically searched and evaluated endoscopically treated T1RC patients in a similar manner. RESULTS: In 2585 unique T1RC patients (86 studies) undergoing local surgical resection, the overall pooled cumulative incidence of recurrence was 9.1% (302 events, 95% CI 7.3-11.4%; I2 = 68.3%). In meta-regression, the recurrence risk was associated with histological risk status (p < 0.005; low-risk 6.6%, 95% CI 4.4-9.7% vs. high-risk 28.2%, 95% CI 19-39.7%) and local surgical resection technique (p < 0.005; TEM/TAMIS 7.7%, 95% CI 5.3-11.0% vs. other local surgical excisions 10.8%, 95% CI 6.7-16.8%). In 641 unique T1RC patients treated with flexible endoscopic excision (16 studies), the risk of recurrence (7.7%, 95% CI 5.2-11.2%), cancer-related mortality (2.3%, 95% CI 1.1-4.9), and cancer-related mortality among patients with recurrence (30.0%, 95% CI 14.7-49.4%) were comparable to outcomes after TEM/TAMIS (risk of recurrence 7.7%, 95% CI 5.3-11.0%, cancer-related mortality 2.8%, 95% CI 1.2-6.2% and among patients with recurrence 35.6%, 95% CI 21.9-51.2%). CONCLUSIONS: Patients with T1 rectal cancer may have a significantly lower recurrence risk after TEM/TAMIS compared to other local surgical resection techniques. After TEM/TAMIS and endoscopic resection the recurrence risk, cancer-related mortality and cancer-related mortality among patients with recurrence were comparable. Recurrence was mainly dependent on histological risk status.

Neoadjuvant chemoradiotherapy followed by resection for esophageal cancer: clinical outcomes with the 'CROSS-regimen' in daily practice.

BACKGROUND AND OBJECTIVES: Since the first results of the Dutch randomized CROSS-trial, neoadjuvant chemoradiotherapy (CRT) using carboplatin and paclitaxel followed by resection for primary resectable nonmetastatic esophageal cancer (EC) has been implemented as standard curative treatment in the Netherlands. The purpose of this retrospective study is to evaluate the clinical outcomes of this treatment in daily practice in a large academic hospital. METHODS: Medical records of patients treated for primary resectable nonmetastatic EC between May 2010 and December 2015 at our institution were reviewed. Treatment consisted of five weekly courses of carboplatin (area under the curve 2) and paclitaxel (50 mg/m2) with concurrent external beam radiotherapy (23 fractions of 1.8 Gy), followed by transthoracic or transhiatal resection. Data on survival, progression, acute and late toxicity were recorded. RESULTS: A total of 145 patients were included. Median follow-up was 43 months. Median overall survival (OS) and progression-free survival (PFS) were 35 (95% confidence interval [CI] 29.8-40.2) and 30 (95% CI 19.7-40.3) months, respectively, with corresponding 3-year OS and PFS of 49.6% (95% CI 40.4-58.8) and 45.6% (95% CI 36.6-54.6). Acute toxicity grade ≥3 was observed in 25.5% of patients. Late adverse events grade ≥3 were seen in 24.8%, mostly esophageal stenosis. CONCLUSION: Neoadjuvant CRT followed by resection for primary resectable nonmetastatic EC in daily practice results in a 3-year OS of 49.6% (95% CI 40.4-58.8) and PFS of 45.6% (95% CI 36.6-54.6), compared with 58% (51-65%) and 51% (43-58%) within the CROSS-trial. The slightly poorer survival in our daily practice group might be due to the presence of less favorable patient and tumor characteristics in daily practice, as is to be expected in daily practice. Toxicity was comparable with that in the CROSS-trial and considered acceptable.

Transanal minimally invasive surgery (TAMIS) versus endoscopic submucosal dissection (ESD) for resection of non-pedunculated rectal lesions (TRIASSIC study): study protocol of a European multicenter randomised controlled trial.

BACKGROUND: In the recent years two innovative approaches have become available for minimally invasive en bloc resections of large non-pedunculated rectal lesions (polyps and early cancers). One is Transanal Minimally Invasive Surgery (TAMIS), the other is Endoscopic Submucosal Dissection (ESD). Both techniques are standard of care, but a direct randomised comparison is lacking. The choice between either of these procedures is dependent on local expertise or availability rather than evidence-based. The European Society for Endoscopy has recommended that a comparison between ESD and local surgical resection is needed to guide decision making for the optimal approach for the removal of large rectal lesions in Western countries. The aim of this study is to directly compare both procedures in a randomised setting with regard to effectiveness, safety and perceived patient burden. METHODS: Multicenter randomised trial in 15 hospitals in the Netherlands. Patients with non-pedunculated lesions > 2 cm, where the bulk of the lesion is below 15 cm from the anal verge, will be randomised between either a TAMIS or an ESD procedure. Lesions judged to be deeply invasive by an expert panel will be excluded. The primary endpoint is the cumulative local recurrence rate at follow-up rectoscopy at 12 months. Secondary endpoints are: 1) Radical (R0-) resection rate; 2) Perceived burden and quality of life; 3) Cost effectiveness at 12 months; 4) Surgical referral rate at 12 months; 5) Complication rate; 6) Local recurrence rate at 6 months. For this non-inferiority trial, the total sample size of 198 is based on an expected local recurrence rate of 3% in the ESD group, 6% in the TAMIS group and considering a difference of less than 6% to be non-inferior. DISCUSSION: This is the first European randomised controlled trial comparing the effectiveness and safety of TAMIS and ESD for the en bloc resection of large non-pedunculated rectal lesions. This is important as the detection rate of these adenomas is expected to further increase with the introduction of colorectal screening programs throughout Europe. This study will therefore support an optimal use of healthcare resources in the future. TRIAL REGISTRATION: Netherlands Trial Register, NL7083 , 06 July 2018.

Quality of life and fear of cancer recurrence in T1 colorectal cancer patients treated with endoscopic or surgical tumor resection.

BACKGROUND AND AIMS: To optimize therapeutic decision-making in early invasive colorectal cancer (T1 CRC) patients, it is important to elicit the patient's perspective next to considering medical outcome. Because empirical data on patient-reported impact of different treatment options are lacking, we evaluated patients' quality of life, perceived time to recovery, and fear of cancer recurrence after endoscopic or surgical treatment for T1 CRC. METHODS: In this cross-sectional study, we selected patients with histologically confirmed T1 CRC who participated in the Dutch Bowel Cancer Screening Programme and received endoscopic or surgical treatment between January 2014 and July 2017. Quality of life was measured using the European Organization for Research and Treatment 30-item Core Quality of Life Questionnaire and the 5-level EuroQoL 5-dimension questionnaire. We used the Cancer Worry Scale (CWS) to evaluate patients' fear of cancer recurrence. A question on perceived time to recovery after treatment was also included in the set of questionnaires sent to patients. RESULTS: Of all 119 eligible patients, 92.4% responded to the questionnaire (endoscopy group, 55/62; surgery group, 55/57). Compared with the surgery group, perceived time to recovery was on average 3 months shorter in endoscopically treated patients after adjustment for confounders (19.9 days vs 111.3 days; P = .001). The 2 treatment groups were comparable with regard to global quality of life, functioning domains, and symptom severity scores. Moreover, patients in the endoscopy group did not report more fear of cancer recurrence than those in the surgery group (CWS score, 0-40; endoscopy 7.6 vs surgery 9.7; P = .140). CONCLUSIONS: From the patient's perspective, endoscopic treatment provides a quicker recovery than surgery, without provoking more fear of cancer recurrence or any deterioration in quality of life. These results contribute to the shared therapeutic decision-making process of clinicians and T1 CRC patients.

Optimizing the timing of colorectal surgery in patients with familial adenomatous polyposis in clinical practice.

Background: Familial adenomatous polyposis (FAP) is characterized by the development of hundreds of colorectal adenomas in the second decade of life, and prophylactic colectomy is usually performed around age of 20. A common question is the appropriate timing of surgery and which endoscopic findings indicate surgery. Methods: All FAP patients known at Leiden University Medical Centre from 1985 onwards were included. The patients were then subdivided into those diagnosed before or after 2000. Patient information included age at diagnosis, colonic phenotype, age at surgery, pathological findings and the outcome of follow-up colonoscopies in whom surgery was postponed. Results: The 72 FAP patients identified consisted of 33 patients diagnosed before (group A) and 39 after (group B) 2000. The median age at diagnosis for patients with classical FAP was 18 in groups A and B. All patients diagnosed before 2000 underwent colorectal surgery versus 68% of those diagnosed >2000. The median age at surgery for classical FAP patients was 19 and 24 years in groups A and B, respectively. In patients with intact colon, the number of adenomas gradually increased over many years. Although most adenomas remained <5 mm, the proportion of 5-15 mm adenomas slowly increased. Only one patient developed a high-grade adenoma. None of the patients developed CRC. Conclusions: Surgery today in FAP is performed less often and at a more advanced age. Our experience also suggests that surgery can be safely postponed in selected patients. The most important endoscopic indication for surgery is substantial number of large adenomas of >5-10 mm.

Identification of familial colorectal cancer and hereditary colorectal cancer syndromes through the Dutch population-screening program: results ofa pilot study.

OBJECTIVES: In 2014, a population-screening program using immuno-faecal occult blood testing (I-FOBT) has started in the Netherlands. The aims of this study were to evaluate the proportion of individuals in the Dutch screening program with a positive I-FOBT that fulfill the criteria for familial colorectal cancer (FCC) and to evaluate the proportion of participants that needs genetic counseling or colonoscopic surveillance. MATERIAL AND METHODS: This retrospective observational study was performed in two large hospitals. Individuals aged between 55 and 75 years with a positive I-FOBT that underwent colonoscopy were included. A detailed family history was obtained in all individuals. RESULTS: A total of 657 individuals with a positive I-FOBT test underwent colonoscopy. A total of 120 (18.3%) participants were found to have a positive family history for CRC, 20 (3.0%) fulfilled the FCC criteria, 4 (0.6%) the Bethesda guidelines and 1 (0.2%) participant the Amsterdam criteria. Multiple adenomas (>10) were found in 21 (3.2%) participants. No cases of serrated polyposis were identified. Based on these criteria and guidelines, a total of 35 (5.3%) required referral to the clinical geneticist and the relatives of 20 (3.0%) participants should be referred for surveillance colonoscopy. CONCLUSION: Obtaining a detailed family history at the time of intake of participants with a positive I-FOBT in the Dutch surveillance program increased the identification of participants with familial CRC.

Equivalent Helicobacter pylori infection rates in Lynch syndrome mutation carriers with and without a first-degree relative with gastric cancer.

BACKGROUND: Patients with Lynch syndrome (LS) are at an increased risk of developing gastric cancer. In 2010, a guideline that recommended to screen all patients for Helicobacter pylori was implemented in the Netherlands. H. pylori is an important risk factor in the development of gastric cancer in the general population, and eradication of the bacterium reduces this risk. We aimed to assess the proportion of LS patients being tested and the yield and also addressed the question whether H. pylori infection is more prevalent in LS families with known cases of gastric cancer. METHODS: Proven mutation carriers from five different Dutch hospitals were included. The implementation of H. pylori screening and its outcome was examined. The observation period was 2008-2013. The presence of first-degree family members with gastric cancer was noted, and it was observed if H. pylori infection was more prevalent in Lynch families with known cases of gastric cancer. Obtainable endoscopy reports were reviewed. RESULTS: Four hundred forty-three (male, 184) proven mutation carriers were included. The proportion of patients screened increased after 2010, from 37 to 68%. Twenty percent of the patients were infected. The 25 patients who had a first-degree family member with gastric cancer did not have a higher infection rate. In 30% of cases, an endoscopy was performed; in four patients, intestinal metaplasia and in eight patients, gastric cancer was found. CONCLUSION: The recommendation to screen for H. pylori is increasingly followed. The prevalence of infection in this patient group does not differ from the general population. Patients who had a first-degree family member with gastric cancer did not have a higher infection rate.

Helicobacter pylori infection is not correlated with subclinical thrombocytopenia: a cross-sectional study.

In a small percentage of patients with immune thrombocytopenia (ITP), H. pylori eradication has a positive effect on platelet counts. Whether H. pylori infection is associated with a lower thrombocyte count in persons without clinical ITP is unknown. We performed a cross-sectional study to compare thrombocyte count between H. pylori infected (n=108) and H. pylori non-infected patients (n=600) who underwent a diagnostic gastroscopy. The mean thrombocyte count in H. pylori negative patients was 257 × 10(9)/l, in H. pylori positive patients 252 × 10(9)/l (mean difference 5 × 10(9)/l, 95% CI: -23 to 14). Subgroup analysis did not show significant differences either. In the patient group without apparent comorbidity, there were no subjects with thrombocyte counts <120. In 36 H. pylori positive patients in whom data post-eradication was available, platelet counts pre- and post-eradication were similar. In conclusion, this study could not demonstrate a lower thrombocyte count in H. pylori infected patients or in subgroups of H. pylori infected patients compared to non-infected subjects.

[Learning from assessment: how quality questions can stimulate learning]. / Leren van toetsen.

Assessment plays a significant role in the career of medical doctors. Not only are they being assessed, many medical doctors are also involved in teaching which includes the creation of tests. Therefore, knowledge on high quality assessment questions is essential. Multiple-choice questions (MCQs) are commonly used, but allow for cueing, stimulates recognition-based learning and do not align clinical practice. The Very Short Answer Question (VSAQ), an open-ended question with a limited answer, is a good alternative which does not allow for cueing, is authentic and encourages students to study more actively. The marking time of VSAQs is relatively short and plausible alternative answer options are no longer needed. It's time to challenge the limits of our comfort zone and to dare using VSAQs in our assessments more often. This way, good and representative assessments can stimulate the learning process of medical doctors and form a strong fundament for professional practice.

MLH1 Promotor Hypermethylation in Colorectal and Endometrial Carcinomas from Patients with Lynch Syndrome.

Screening for Lynch syndrome (LS) in colorectal cancer (CRC) and endometrial cancer patients generally involves immunohistochemical staining of the mismatch repair (MMR) proteins. In case of MLH1 protein loss, MLH1 promotor hypermethylation (MLH1-PM) testing is performed to indirectly distinguish the constitutional MLH1 variants from somatic epimutations. Recently, multiple studies have reported that MLH1-PM and pathogenic constitutional MMR variants are not mutually exclusive. This study describes 6 new and 86 previously reported MLH1-PM CRCs or endometrial cancers in LS patients. Of these, methylation of the MLH1 gene promotor C region was reported in 30 MLH1, 6 MSH2, 6 MSH6, and 3 PMS2 variant carriers at a median age at diagnosis of 48.5 years [interquartile range (IQR), 39-56.75 years], 39 years (IQR, 29-51 years), 58 years (IQR, 53.5-67 years), and 68 years (IQR, 65.6-68.5 years), respectively. For 31 MLH1-PM CRCs in LS patients from the literature, only the B region of the MLH1 gene promotor was tested, whereas for 13 cases in the literature the tested region was not specified. Collectively, these data indicate that a diagnosis of LS should not be excluded when MLH1-PM is detected. Clinicians should carefully consider whether follow-up genetic MMR gene testing should be offered, with age <60 to 70 years and/or a positive family history among other factors being suggestive for a potential constitutional MMR gene defect.

Patient educational videos on T1 colorectal cancer.

Video 1Colorectal cancer: how does it develop and how can you detect it? Video 2A polyp suspected to be colorectal cancer: what now? Video 3Early-stage colon cancer with unfavorable features: what now?