Long-term oncological outcomes of endoscopic full-thickness resection after previous incomplete resection of low-risk T1 CRC (LOCAL-study): study protocol of a national prospective cohort study.

BACKGROUND: T1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly lower morbidity, mortality and costs compared to radical surgery. An important prerequisite for endoscopic resection as definite treatment is the histological confirmation of tumour-free resection margins. Incomplete resection with involved (R1) or indeterminate (Rx) margins is considered a strong risk factor for residual disease and local recurrence. Therefore, international guidelines recommend additional surgery in case of R1/Rx resection, even in absence of high-risk factors for LNM. Endoscopic full-thickness resection (eFTR) is a relatively new technique that allows transmural resection of colorectal lesions. Local scar excision after prior R1/Rx resection of low-risk T1 CRC could offer an attractive minimal invasive strategy to achieve confirmation about radicality of the previous resection or a second attempt for radical resection of residual luminal cancer. However, oncologic safety has not been established and long-term data are lacking. Besides, surveillance varies widely and requires standardization. METHODS/DESIGN: In this nationwide, multicenter, prospective cohort study we aim to assess feasibility and oncological safety of completion eFTR following incomplete resection of low-risk T1 CRC. The primary endpoint is to assess the 2 and 5 year luminal local tumor recurrence rate. Secondary study endpoints are to assess feasibility, percentage of curative eFTR-resections, presence of scar tissue and/or complete scar excision at histopathology, safety of eFTR compared to surgery, 2 and 5 year nodal and/or distant tumor recurrence rate and 5-year disease-specific and overall-survival rate. DISCUSSION: Since the implementation of CRC screening programs, the diagnostic rate of T1 CRC is steadily increasing. A significant proportion is not recognized as cancer before endoscopic resection and is therefore resected through conventional techniques primarily reserved for benign polyps. As such, precise histological assessment is often hampered due to cauterization and fragmentation and frequently leads to treatment dilemmas. This first prospective trial will potentially demonstrate the effectiveness and oncological safety of completion eFTR for patients who have undergone a previous incomplete T1 CRC resection. Hereby, substantial surgical overtreatment may be avoided, leading to treatment optimization and organ preservation. Trial registration Nederlands Trial Register, NL 7879, 16 July 2019 ( https://trialregister.nl/trial/7879 ).

Chronic use of metamizole: not so safe after all?

Metamizole can be used in both short- and long-term pain relief therapies and has a relatively favourable safety profile compared with classic NSAIDs. Metamizole is also infamous because of its potential fatal adverse drug reaction, agranulocytosis. Although this risk varies, it is estimated to occur in less than one million metamizole prescriptions. We describe a case of a 68-year-old patient who developed leukopenia after using metamizole.

Colonic work-up after incomplete colonoscopy: significant new findings during follow-up.

BACKGROUND AND STUDY AIMS: Cecal intubation is not achieved in 2 - 23 % of colonoscopies. The efforts made by physicians to visualize the remaining colon and the number of missed significant lesions are unknown. This study evaluates 1) the reasons for incomplete colonoscopy, 2) the rates of complete colonic evaluation after incomplete colonoscopy, and 3) the number of (pre-) malignant lesions missed by incomplete colonoscopy. PATIENTS AND METHODS: In this population-based cohort study index colonoscopies were performed between September and December 2005. Prospectively collected data from consecutive patients with an incomplete colonoscopy were analyzed. For up to 18 months after the index colonoscopy, any further examinations performed in these patients were identified retrospectively. These secondary examinations included: repeat colonoscopy, computed tomography (CT) colonography, barium enema, abdominal CT scan, and surgery involving the colorectum. RESULTS: Of 5278 colonoscopies, 511 were incomplete (9.7 %). The most frequent causes of incomplete colonoscopy were looping of the scope (20.4 %), patient discomfort (15.3 %), and obstructing tumor (13.9 %). Secondary examination was performed in 278 patients (54.4 %) after incomplete colonoscopy. Patients undergoing surveillance after colorectal cancer (CRC) (78.9 %) and those with anemia (73.1 %) most frequently received a secondary examination. Incomplete colonoscopies due to stenosis (78.9 %), severe inflammation (77.8 %) or an obstructing tumor (74.6 %) were most frequently followed by a secondary examination. In all of the follow-up examinations, CRC was diagnosed in 18 patients (3.5 %) and advanced adenoma in four patients (0.8 %). CONCLUSIONS: In 4.3 % of the patients, advanced neoplasia was missed by incomplete colonoscopy. Our data therefore suggest that additional imaging is obligatory to visualize the remaining colon adequately.

Colonoscopy-controlled intra-individual comparisons to screen relevant neoplasia: faecal immunochemical test vs. guaiac-based faecal occult blood test.

BACKGROUND: Guaiac-based faecal occult blood tests (g-FOBTs) are most commonly used in colorectal cancer (CRC) screening programmes. Faecal immunochemical tests (FITs) are thought to be superior. AIM: To compare performance of a g-FOBT and a quantitative FIT for detection of CRCs and advanced adenomas in a colonoscopy-controlled population. METHODS: We assessed sensitivity and specificity of both FIT (OC-sensor) and g-FOBT (Hemoccult-II) prior to patients' scheduled colonoscopies. RESULTS: Of the 62 invasive cancers detected in 1821 individuals, g-FOBT was positive in 46 and FIT in 54 (74.2% vs. 87.1%, P = 0.02). Among 194 patients with advanced adenomas, g-FOBT was positive in 35 and FIT in 69 (18.0% vs. 35.6%, P < 0.001). Sensitivity for screen relevant tumours (197 advanced adenomas and 28 stage I or II cancers) was 23.0% for g-FOBT and 40.5% for FIT (P < 0.001). Specificity of g-FOBT compared to FIT for the detection of cancer was 95.7% vs. 91.0%, P < 0.001) and for advanced adenomas (97.4% vs. 94.2%, P < 0.001). CONCLUSIONS: Faecal immunochemical test is more sensitive for CRC and advanced adenomas. Sensitivity of FIT for screen relevant tumours, early-stage cancers and advanced adenomas, is significantly higher. Specificity of g-FOBT is higher compared with FIT.

MiR-17-92 cluster is associated with 13q gain and c-myc expression during colorectal adenoma to adenocarcinoma progression.

BACKGROUND: MicroRNAs are small non-coding RNA molecules, which regulate central mechanisms of tumorigenesis. In colorectal tumours, the combination of gain of 8q and 13q is one of the major factors associated with colorectal adenoma to adenocarcinoma progression. Functional studies on the miR-17-92 cluster localised on 13q31 have shown that its transcription is activated by c-myc, located on 8q, and that it has oncogenic activities. We investigated the contribution of the miR-17-92 cluster during colorectal adenoma to adenocarcinoma progression. METHODS: Expression levels of the miR-17-92 cluster were determined in 55 colorectal tumours and in 10 controls by real-time RT-PCR. Messenger RNA c-myc expression was also determined by real-time RT-PCR in 48 tumours with array comparative genomic hybridisation (aCGH) data available. RESULTS: From the six members of the miR-17-92 cluster, all except miR-18a, showed significant increased expression in colorectal tumours with miR-17-92 locus gain compared with tumours without miR-17-92 locus gain. Unsupervised cluster analysis clustered the tumours based on the presence of miR-17-92 locus gain. Significant correlation between the expression of c-myc and the six miRNAs was also found. CONCLUSION: Increased expression of miR-17-92 cluster during colorectal adenoma to adenocarcinoma progression is associated to DNA copy number gain of miR17-92 locus on 13q31 and c-myc expression.

Multiple putative oncogenes at the chromosome 20q amplicon contribute to colorectal adenoma to carcinoma progression.

OBJECTIVE: This study aimed to identify the oncogenes at 20q involved in colorectal adenoma to carcinoma progression by measuring the effect of 20q gain on mRNA expression of genes in this amplicon. METHODS: Segmentation of DNA copy number changes on 20q was performed by array CGH (comparative genomic hybridisation) in 34 non-progressed colorectal adenomas, 41 progressed adenomas (ie, adenomas that present a focus of cancer) and 33 adenocarcinomas. Moreover, a robust analysis of altered expression of genes in these segments was performed by microarray analysis in 37 adenomas and 31 adenocarcinomas. Protein expression was evaluated by immunohistochemistry on tissue microarrays. RESULTS: The genes C20orf24, AURKA, RNPC1, TH1L, ADRM1, C20orf20 and TCFL5, mapping at 20q, were significantly overexpressed in carcinomas compared with adenomas as a consequence of copy number gain of 20q. CONCLUSION: This approach revealed C20orf24, AURKA, RNPC1, TH1L, ADRM1, C20orf20 and TCFL5 genes to be important in chromosomal instability-related adenoma to carcinoma progression. These genes therefore may serve as highly specific biomarkers for colorectal cancer with potential clinical applications.

Diverticulosis and diverticulitis form no risk for polyps and colorectal neoplasia in 4,241 colonoscopies.

BACKGROUND AND AIMS: There are conflicting data concerning the association between diverticular disease and colorectal carcinoma (CRC). This study was performed to determine the prevalence and association of diverticulosis, diverticulitis, polyps, and CRC. MATERIALS AND METHODS: In a cross-sectional, retrospective study, we analyzed the colonoscopy reports of complete colonoscopies and patho-histological results of all patients referred for colonoscopy in a period of 3 months in 18 hospitals in The Netherlands. Diverticulosis was defined as three or more diverticula present and diverticulitis as diverticulosis with inflammation. Polyps were also coded according to localization and size. Advanced neoplastic lesions were defined as polyps >or=10 mm in diameter and/or villous architecture and/or adenomas with high grade dysplasia and/or invasive cancer. Actual and previous described CRC were registered. RESULTS: A total of 4,241 patients were included in the study [1,996 (47%) male], mean age of 59 and range 18-95. Diverticula, diverticulitis, and polyps were seen in 1,052 (25%), 75 (2%), and 1,282 (30%) patients, respectively. No association was found between patients with polyps and those with and without diverticulosis (p=0.478). Invasive adenocarcinoma and adenomas >or=10 mm were most frequently observed. CRC was present in 372 (9%) patients. Negative relation between diverticulosis and CRC and invasive adenocarcinoma was observed. No association was found between polyps and CRC and patients with diverticulitis and CRC. In conclusion, there is no relation between patients with diverticulosis and higher incidence of polyps or CRC when using age-stratified analysis. No increased risk for polyps or CRC was found in patients with diverticulitis.

Dutch endoscopic capacity in the era of colorectal cancer screening.

BACKGROUND: Future colorectal cancer (CRC) screening programmes should not (greatly) interfere with regular health care. Hence, we analysed the Dutch endoscopic practice to provide a clear insight into endoscopic workload and manpower with a special emphasis on the current ability to facilitate a successful implementation of a faecal occult blood test (FOBT)-based nationwide CRC screening programme. METHODS: A questionnaire was sent to all Dutch endoscopy units (n = 100) in the spring of 2005. The questionnaire included topics ranging from the numbers and specifications of endoscopies performed in 2004 and the numbers of endoscopists per unit to expected vacancies for gastroenterologists and waiting times. RESULTS: The response rate was 98%, representing a total of 49,253 hospital beds. overall, a 26% increase in the number of endoscopies from 325,000 in 1999 to almost 410,000 in 2004 was found, accompanied by a 25% increase in manpower. The total number of endoscopists was 598. regional differences were observed in the number of endoscopists, the total number of endoscopies and colonoscopies, and the number of endoscopies per endoscopist. A biannual FOBT-based screening programme would yield an additional workload of 25,385 colonoscopies a year amounting to a 22% increase in the total number of colonoscopies performed. However, the workload per unit would only have to increase by five extra colonoscopies a week. CONCLUSION: Whereas an FOBT-based CRC screening programme is currently feasible without strongly interfering with regular health care, future plans regarding the scale and preferred mode of screening should incorporate solid data on the (regional) endoscopic capacity and manpower needed for a successful implementation.

On attitudes about colorectal cancer screening among gastrointestinal specialists and general practitioners in the Netherlands.

AIM: To find out whether there are differences in attitudes about colorectal cancer (CRC) screening among gastrointestinal (GI) specialists and general practitioners (GPs) and which method is preferred in a national screening program. METHODS: Four hundred and twenty Dutch GI specialists in the Netherlands and 400 GPs in Amsterdam were questioned in 2004. Questions included demographics, affiliation, attitude towards screening both for the general population and themselves, methods of screening, family history and individual risk. RESULTS: Eighty-four percent of the GI specialists returned the questionnaire in comparison to 32% of the GPs (P < 0.001). Among the GI specialists, 92% favoured population screening whereas 51% of GPs supported population screening (P < 0.001). Of the GI specialists 95% planned to be screened themselves, while 30% of GPs intended to do so (P < 0.001). Regarding the general population, 72% of the GI specialists preferred colonoscopy as the screening method compared to 27% of the GPs (P < 0.001). The method preferred for personal screening was colonoscopy in 97% of the GI specialists, while 29% of the GPs favoured colonoscopy (P < 0.001). CONCLUSION: Screening for CRC is strongly supported by Dutch GI specialists and less by GPs. The major health issue is possibly misjudged by GPs. Since GPs play a crucial role in a successful national screening program, CRC awareness should be realized by increasing knowledge about the incidence and mortality, thus increasing awareness of the need for screening among GPs.

Chemoprevention for colon cancer: new opportunities, fact or fiction?

Colorectal cancer (CRC) is still a disease with a high incidence and mortality. Prevention of (pre-) cancerous lesions of CRC by endoscopic screening is promising, but costs are high and identification of high-risk populations is difficult. Since screening both average-risk and high-risk populations for CRC has its logistic and financial limitations, new primary prevention strategies are sought. Substantial evidence has shown that non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors can reduce the incidence and mortality of CRC. However, long-term use of NSAIDs is associated with substantial gastrointestinal toxicity and may cause an exacerbation in IBD patients. Selective COX-2 inhibitors, with a better toxicity profile and no flare-up in IBD disease activity, are therefore attractive candidates for prevention. Chemoprevention with low-dose aspirin can be considered for individuals carrying a high risk for CRC. Folate supplementation is beneficial to the folate-depleted patients, since significant risk reductions for CRC are reported. Moreover, it might be applicable to the general population because it is safe, inexpensive and protects against vascular diseases. In line with drugs beneficial for multiple disease entities, statins have recently been proposed to reduce CRC risk. Ursodeoxycholic acid has been shown to decrease the incidence of colonic dysplasia in patients with ulcerative colitis and PSC and possibly reduces recurrence rates of polyps in general. Unfortunately, prospective randomized trials, in both high-risk and general population, are not available and the evidence is still controversial. Furthermore, cumulative epidemiological and observational data suggest the potential role of hormones as a chemoprotective agent. An increase in CRC in females with an early menopause, as well as a decrease of CRC in women with hormone replacement therapy justify further research into this issue. In IBD patients, both the severity and duration of the inflammation are the most evident risk factors for the development of dysplasia and subsequently cancer. Remission of inflammation, clinically, endoscopically and histologically, in IBD is the major goal. Long-term use of 5-aminosalicylates (5-ASA) has been shown to decrease the incidence of CRC and may hold the best promise as a chemoprotective agent in IBD. In parallel with primary prevention strategies in vascular medicine, the aim might be to postpone adenoma formation, for instance for 10 years, thereby achieving a significant risk reduction for CRC. In current practice, folate supplementation along with low-dose aspirin use in high-risk patients may be most attractive candidates, while future studies will have to clarify the role of these and other chemoprotective agents.