Colon cancer prevention currently relies on colonoscopy using white light to detect and remove polyps, but small and flat polyps are difficult to detect and frequently missed when using this technique. Fluorescence colonoscopy combined with a fluorescent probe specific for a polyp biomarker may improve polyp detection. Here we describe GE-137, a water-soluble probe consisting of a 26-amino acid cyclic peptide that binds the human tyrosine kinase c-Met conjugated to a fluorescent cyanine dye. Intravenous administration of GE-137 leads to its accumulation specifically in c-Met-expressing tumors in mice, and it is safe and well tolerated in humans. Fluorescence colonoscopy in patients receiving intravenous GE-137 enabled visualization of all neoplastic polyps that were visible with white light (38), as well as an additional nine polyps that were not visible with white light. This first-in-human pilot study shows that molecular imaging using an intravenous fluorescent agent specific for c-Met is feasible and safe, and that it may enable the detection of polyps missed by other techniques.

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We did not find a significant reduction in CRC incidence or stage of detection in Germany (annual colonoscopic surveillance) than in countries with longer surveillance intervals (the Netherlands, with 1-2-year intervals, and Finland, with 2-3-year intervals). Overall, we did not find a significant association of the interval with CRC risk, although age, sex, mutation, and prior neoplasia were used to individually modify colonoscopy intervals. Studies are needed to develop and validate risk-adapted surveillance strategies and to identify patients who benefit from shorter surveillance intervals.

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In gastric cancer, a new epigenetic mechanism of tumour suppressor loss has been suggested where the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is responsible for loss of expression of RUNX3. This is consistent with EZH2 upregulation in multiple cancer types being associated with poor prognosis. We investigated whether EZH2 influences the expression of RUNX3 in colorectal cancer (CRC) and whether this is independent of methylation. We determined protein and messenger RNA (mRNA) levels of EZH2 and RUNX3 and assessed RUNX3 methylation with methylation-specific polymerase chain reaction using 72 human CRCs and 8 CRC cell lines. We assessed the effect of efficient RNA interference-mediated knockdown of EZH2 on RUNX3 levels, cell viability and H3K27 trimethylation of the RUNX3 promoter using chromatin immunoprecipitation. Despite higher levels of EZH2 and lower levels of RUNX3 in CRC specimens in general, no inverse correlation between EZH2 and RUNX3 in paired samples was found arguing against a major role for histone methylation in silencing RUNX3 in CRC. Conversely, downregulation of RUNX3 mRNA in the same tumours was associated with RUNX3 DNA methylation (P < 0.05). In cell lines, knockdown of EZH2 removed the repressive chromatin marks from RUNX3 but did not result in RUNX3 re-expression. However, it prevented the re-silencing of RUNX3 after the removal of demethylating agents. In conclusion, DNA methylation is primarily responsible for the transcriptional silencing of RUNX3 in CRC, but EZH2 and histone methylation are necessary for its methylation-dependent re-silencing after the removal of demethylating agents. These results would predict that inhibitors of EZH2 and histone methylation would enhance the effects of demethylating agents in cancer therapy.

Background:The optimal treatment of desmoid tumours is controversial. We evaluated desmoid management in Dutch familial adenomatous polyposis (FAP) patients.Methods:Seventy-eight FAP patients with desmoids were identified from the Dutch Polyposis Registry. Data on desmoid morphology, management, and outcome were analysed retrospectively. Progression-free survival (PFS) rates and final outcome were compared for surgical vs non-surgical treatment, for intra-abdominal and extra-abdominal desmoids separately. Also, pharmacological treatment was evaluated for all desmoids.Results:Median follow-up was 8 years. For intra-abdominal desmoids (n=62), PFS rates at 10 years of follow-up were comparable after surgical and non-surgical treatment (33% and 49%, respectively, P=0.163). None of these desmoids could be removed entirely. Eventually, one fifth died from desmoid disease. Most extra-abdominal and abdominal wall desmoids were treated surgically with a PFS rate of 63% and no deaths from desmoid disease. Comparison between NSAID and anti-estrogen treatment showed comparable outcomes. Four of the 10 patients who received chemotherapy had stabilisation of tumour growth, all after doxorubicin combination therapy.Conclusion:For intra-abdominal desmoids, a conservative approach and surgery showed comparable outcomes. For extra-abdominal and abdominal wall desmoids, surgery seemed appropriate. Different pharmacological therapies showed comparable outcomes. If chemotherapy was given for progressively growing intra-abdominal desmoids, most favourable outcomes occurred after combinations including doxorubicin.

Background:Upregulation of the matrix metalloproteinases MMP-2 and MMP-9 in various cancers has been associated with worse survival of the patients.Methods:We assessed MMP-2 and MMP-9 levels in normal colorectal mucosa from colorectal cancer patients in relation to the course of the disease.Results:A high protein expression of MMP-2 as well as MMP-9 in normal mucosa was found to be correlated with worse 5-year survival. The combination of both parameters was an even stronger prognostic factor. These protein levels were found not to be related to the corresponding single nucleotide polymorphisms of MMP-2 (−1306C>T) and MMP-9 (−1562C>T). Multivariate analyses indicated that the MMP-2 and MMP-9 levels in normal mucosa are prognostic for survival, independent of TNM classification.Conclusion:MMP-2 and MMP-9 levels in normal mucosa are indicative of the course of disease in colorectal cancer patients.

High-risk: 7.0% Low-risk: 0.7% 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%; I 2 [ 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%; I 2 [ 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%; I 2 [ 48.1%) and 0.7% (36 studies; 95% CI, 0.4%-1.2%; I 2 [ 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.