Introduction

Adenomas per Colonoscopy (APC) might serve as an adjuvant quality metric to the Adenoma Detection Rate (ADR). This indicator is calculated by dividing the total number of detected adenomas by the number of colonoscopies performed. It motivates the operator to maximize adenoma identification and removal during screening procedures and allows a more comprehensive assessment of the colonoscopy's quality.

Aims & Methods

The aims of this study were to assess the association between the ADR and the APC metrics in colorectal cancer screening and to explore factors influenciating each of these indicators. This retrospective, single-center study analyzed total screening colonoscopies conducted on 50 years old or more patients, over a period of 18 months (from April 2022 to September 2023) and their corresponding histological reports. Colonoscopies with at least one colonic segment with less than 2 points on the Boston Bowel Preparation Scale (BBPs) were excluded. Statistical analysis was performed using SPSS v29.0.

Results

502 total colonoscopies were included. ADR was 41.7% and APC was 76.5%. The number of adenomas per colonoscopy ranged from 0 to 11 adenomas. There was a positive statistically significant association between the ADR and the APC (β=0.6, p<0.001). No statistically significant difference was found in the average age between patients with and without adenomas (p>0.05), nor a correlation between age and the number of APC (p>0.05). Men were 2.1 times more likely to have at least one adenoma (p<0.05) and the average number of adenomas per colonoscopy was statistically significant higher in men (p<0.05). The BBPS score was not associated with the detection of at least one adenoma or to the total number of adenomas per colonoscopy (p>0.05). The average withdrawal time was higher in patients with adenomas (p<0.05), and there was a positive, statistically significant, moderate correlation between withdrawal time and the number of APC (r=0.5; p<0.001). No association was found between the colonoscopy schedule, endoscopist fatigue or experience and the presence of at least one adenoma (p>0.05). The average number of adenomas per colonoscopy was also not statistically significantly different among the previously mentioned groups (p>0.05).

Conclusion

Our study confirmed a significant association between the ADR and the APC, encouraging the use of APC as a complementary metric in colorectal cancer screening. Influencing factors were similar between the two indicators. While gender and withdrawal time significantly influenced adenoma detection and the number of adenomas detected per colonoscopy, with men and longer procedures showing higher ADR and APC rates, other factors such as age, bowel preparation quality, and procedural variables showed no significant impact.

Introduction

Selecting the right treatment in the early stages of inflammatory bowel disease (IBD) is essential for preventing disease progression and modifying disease course. Intestinal ultrasound (IUS) is a promising tool in predicting early treatment response. We aimed to systematically review current literature on the predictive value of IUS for treatment response.

Aims & Methods

A literature search was performed on the 24^th of October and updated on the 26^th of March 2024 using PubMed, Medline, Embase, Cochrane Library and Cinahl. We included articles in paediatric and adult IBD patients where IUS was used for the assessment of treatment. Studies were grouped based on timing of IUS after start of treatment. In acute severe ulcerative colitis (ASUC) timing included within 5 days or between 6-14 days. In ulcerative colitis (UC) or Crohn’s disease (CD) baseline, 0-3 weeks, 4-8 weeks, 12-16 weeks and >16 weeks were used. Additional response assessments included clinical or endoscopic disease activity scores and adverse events (e.g. surgery, hospitalization, treatment escalation).

Results

Out of 1739 unique articles, 27 were included with 17 in CD, 6 in UC and 4 in ASUC.
Baseline IUS parameters were not predictive of treatment response in CD, UC or ASUC.
In CD, most studies investigated response to anti-TNF (n=12), though multiple therapies were evaluated (n=5). For anti-TNF, IUS was predictive of response to therapy at all time points from 2 weeks onward. IUS at week 4 to 8 showed conflicting results in studies using multiple treatments. After 12 weeks, IUS predicted clinical and endoscopic outcomes as well as adverse events in all studies regardless of treatment. Lastly, an IUS several months after starting treatment predicted clinical response, adverse events and endoscopic response in the follow years.
A variety of medical treatments were included in most UC studies (n=3). IUS within 3 weeks of treatment initiation was able to predict both short- and long-term clinical response in UC. Endoscopic response could be predicted by IUS after 6 weeks. The combination of BWT and colour Doppler signal (CDS) measured at 3 and 9 months of therapy predicted endoscopic activity after 9 and 15 months, respectively.
In ASUC, bowel wall thickness (BWT) significantly differed between responders and non-responders of intravenous steroid treatment when measured 1-3 days after treatment initiation.

Conclusion

IUS performed at 1-3 days, 2 weeks and 6 weeks was predictive of treatment response in ASUC, CD and UC, respectively. Further data is needed to characterize IUS response kinetics of the individual therapies.

Disclosure

J.M.B.W. Vos: None
C. Teichert: None
F.A.E. De Voogd: received speaker or honoraria fees from AbbVie, Janssen, Galapagos, Pfizer and Takeda
G.R.A.M. D’Haens: received research grants from Abbvie, Alimentiv, BMS, J&J, Pfizer, Takeda; consulting fees from Abbvie, Agomab, Alimentiv, AstraZeneca, AMT, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Galapagos, Index Pharmaceuticals, Kaleido, Glaxo Smith Kline, Gossamerbio, Pfizer, Immunic, Johnson and Johnson, Polpharma, Procise Diagnostics, Prometheus laboratories, Prometheus Biosciences, Progenity, Protagonist, and Ventyx; speaker’s fees from Abbvie, Arena, Boehringer Ingelheim, Celltrion, Galapagos, Gilead, Pfizer, BMS, and Takeda; data monitoring board: Galapagos, AstraZeneca, Seres Health.
B.G.P. Koot: None
K.B. Gecse: received grants from Pfizer Inc, Celltrion, and Galapagos; consultancy fees from AbbVie, Arena Pharmaceuticals, Galapagos, Gilead, ImmunicTherapeutics, Janssen Pharmaceuticals, Novartis, Pfizer Inc., Samsung Bioepis, and Takeda; and speaker’s honoraria from Celltrion, Ferring, Janssen Pharmaceuticals, Novartis, Pfizer Inc, Samsung Bioepis, Takeda, and Tillotts.

Introduction

It is widely acknowledged that postoperative complications after colon cancer resection are associated with postoperative mortality, but the association with long-term outcomes is controversial. This study examined the impact of postoperative complications on locoregional recurrence, defined as any intra-abdominal recurrence including peritoneal metastases, and overall survival.

Aims & Methods

This national, population-based cross-sectional cohort study was carried out in 46 Dutch hospitals. Patients who underwent colon cancer resection between January 2014 and December 2015 were eligible. Long-term outcomes were assessed in patients without synchronous metastases and a minimum follow-up of 6 months using logistic regression, Kaplan-Meier, log-rank test, and Cox regression analyses.

Results

A total of 8936 patients were included with a median follow-up of 59.6 months (IQR 28.0-65.6). Any complication occurred in 2649 (29.6%) patients, of whom 1576 had surgical complications (806 requiring reintervention) and 1791 non-surgical complications. When looking into patients with stage 1 to 3 colon cancer with a minimum follow-up time of 6 months, 7.5% of the cohort without any complication versus 9.2% with a complication develop a locoregional recurrence (p=0.023). Independent risk factors for locoregional recurrence were surgical approach, emergency setting, tumour location, pT, pN and resection margin status. Five-year overall survival probability was 86.7% versus 76.1% for patients with or without complications respectively (p<0.001), which remained significant in multivariable analysis (HR 1.43, 95CI% 1.29-1.59).

Conclusion

This study showed worse overall survival after a complicated postoperative course in stage I-III colon cancer patients, but no independent association with locoregional recurrence was found.

Introduction

Resection of large non-pedunculated colorectal polyps (LNPCP) located in the rectum varies by institution and region with some, particularly colorectal surgeons, favouring TEM and others endoscopic resection (ER). There is a paucity of data directly comparing these strategies and the procedure of choice remains under debate. Our unit is a tertiary referral centre for complex polyps and early colorectal cancer. All rectal LNPCP were treated by TEM until a change in practice from 2011 when the first-line therapeutic strategy for rectal LNPCP changed to ER.

Aims & Methods

We aimed to report the outcomes of TEM and ER of rectal LNPCP from a large tertiary cohort. Large (≥20mm) rectal adenomas resected by TEM or ER (2009 – 2023) were analysed. From 2009-2011 all rectal adenomas were treated by TEM, after which the primary resection strategy changed to ER. Outcomes were compared between techniques. Given the difference in resection strategy, a composite outcome of septic complications included clinically significant perforation for ER (early or delayed perforation requiring any form of unplanned medical or surgical treatment) and septic complications for TEM (peritonitis or pelvic/anorectal sepsis).

Results

704 rectal adenomas were resected by TEM (n=71), EMR (n=145) and ESD/Hybrid ESD (n=488) with a mean size of 45mm for TEM vs 55mm for ER (p<0.001). 100% of patients undergoing TEM required hospital admission vs 15% for ER (p<0.001), and 100% required general anaesthesia (GA) for TEM vs 26%% for ER (GA or propofol sedation, p<0.001). En bloc resection was achieved for 96% of ESD resections, 54% of TEMS, 28% of EMR and 14% of hybrid ESD (p<0.001). The incidence of complications were similar (9.9% for TEM versus 5.0% for ER, p=0.10). Recurrence occurred in 2.7% after ESD, 21.1% after EMR, 23.6% after Hybrid ESD and 36.4% after TEM (p<0.001). No patients undergoing ER or TEM required surgery as a result of a complication.

Conclusion

Despite significantly larger lesion sizes, ER in our institution provides far superior results for patients than TEM with relatively fewer patients requiring hospital admission and lower recurrence rates, especially with ESD. En bloc resection was more likely with ER as a result of the difficulty achieving en bloc resection for extremely large lesions with TEM, which can invariably be resected en bloc by ESD. These results have led to a policy of ER for all apparently benign rectal tumours regardless of size and, in recent years, ESD as the primary approach for all rectal lesions.

Introduction

The detection of microsatellite instability (MSI) in tumor tissue is of high relevance for (1) identifying patients eligible for immune checkpoint blockade and (2) Lynch syndrome carriers. Gold standard for MSI analysis are DNA-based methods that are encompassing PCR-based amplification of short repetitive sequence stretches (microsatellites) and assessing length variations in the respective amplicons.
However, diagnostic complications can arise due to potential artifacts known as stutter bands, which are erroneous insertions or deletions occurring in PCR amplification that make it difficult to detect the true length of the microsatellite fragment. Correctly distinguishing these artifacts from true genetic insertion/deletion (indel) mutations in microsatellites in vivo is crucial for accurate MSI fragment length assessment. Factors such as PCR cycle number, laboratory conditions, and DNA quality can influence the occurrence of stutter bands. A thorough understanding of these factors is vital for preventing diagnostic errors. Moreover, improving our knowledge of changes during PCR amplification can advance our understanding of the evolvement of these mutations in microsatellites in vivo.

Aims & Methods

Fluorescent multiplex PCR for the BAT25, BAT26, BAT40, and CAT25 microsatellite fragments was performed on multiple microsatellite stable and microsatellite instable samples across different PCR cycle counts. Peak distribution was assessed for each reaction, and peak profiles were evaluated in relation to cycle numbers for different template DNA samples analyzed. In addition, we analyzed peak profiles to infer the potential fragment lengths prior to amplification, i.e. closest to the original sample.

Results

We analyzed the formation of stutter bands during PCR analysis in microsatellite fragments and were able to highlight a shift in the distributions of PCR peaks with increasing cycle count. Amplified fragment sizes tended to be of shorter length with higher numbers of cycles. This was paralleled by an increase of stutter bands in high compared to low cycle reactions. Additionally, in silico modeling of our peak data demonstrates how the length of microsatellite markers, the read depth and the number of PCR cycles affect the reliability and interpretability of MSI detection PCR.

Conclusion

Our results indicate that optimizing reaction conditions is a critical step to standardizing MSI detection by PCR. This may have important implications in MSI diagnostic procedures, particularly when assessing small samples with low DNA template concentration or tumors with borderline MSI status. Our observations suggest that a comprehensive understanding of the peak data produced in fluorescent multiplex PCR can significantly improve diagnostic capability in detecting MSI status in tumor samples and can further insight into the development of MSI mutations in vivo. Developing mathematical models that describe cycle-wise changes of peak distributions is the next step to improve the accuracy of PCR-based MSI testing.

Introduction

The United Kingdom National Institute for Health and Care Excellence recommends Faecal Immunochemical Testing (FIT) for all patients presenting to primary care with symptoms suggestive of colorectal cancer. How use of this test varies across England is unknown, which this study aimed to quantify.

Aims & Methods

Routinely-collected primary care records (Clinical Practice Research Datalink Aurum) were used to assess variations in symptomatic FIT use in adults (≥18 years) between regions and over time in England from 2019 to 2023. Rates were calculated using the population registered to each primary care practice as the denominator, with analysis split by calendar year.
The first coded FIT test with a numerical result per patient each year was extracted from the primary care records. Rates of testing were calculated using Poisson regression, adjusted for other confounders. Results were described between groups, regions and years at the recommended threshold of ≥10 µgHb/g faeces (results above this threshold henceforth referred to as FIT10), describing the proportions likely to have a secondary care referral based on national guidance. Logistic regression was used to compare the impact of year, region, gender and age on the differences in FIT10.

Results

Between 01/01/2019 and 05/06/2023 there were 531,735 FIT results among 495,121 patients and a denominator population of 17,910,681. The number of completed FITs increased from 8,395 in 2019 to 237,708 in 2022 (the last complete year within the study), with a corresponding ~thirty-fold increase from 0.69 tests per 1000 person-years in 2019 (95%CI 0.68-0.71) to 19.57 per thousand person-years in 2022 (95%CI 19.50-19.65). There was large variation in testing between regions, with rates 3.6 times higher in the North East compared to the West Midlands (17.05 per thousand person-years, 95%CI 16.87-17.23 versus 4.72 per thousand person-years, 95%CI 4.67-4.76). These differences persisted to 2022, with less than half the rate in the West Midlands (11.32) compared to the North East (31.85 per thousand person-years).
20.4% of results were FIT10. Despite increased testing, the overall proportion FIT10 did not change over time. 51.7% of all tests FIT10 were in those over 70 years of age. The percentage FIT10 was lower in regions with higher rates of FIT testing, for example FIT10 ranged from 16.7% in the South West (rate of testing 14.62 per thousand person-years) to 25.3% in the South East (rate of testing 8.00 per thousand person-years). After adjusting for year, region, gender and age, this difference persisted (adjusted OR 0.57, 95%CI 0.55-0.58) comparing FIT10 in the South West to the South East. The difference in proportions FIT10 between regions showed some convergence over time, from a range of 16.6%-26.7% (10.1%) in 2021 to 15.8%-23.7% (7.9%) in 2023.

Conclusion

There has been a marked increase over time in the use of FIT for patients with symptoms in primary care, with large and persistent variations between regions of England. The overall proportion FIT10 has not decreased over time with increasing use, however there were large differences in FIT10 between regions that correlated with rates of testing. These regional differences persisted but reduced over time as testing rates increased nationally. It is likely that clinical pathway differences in the implementation of FIT over time and between regions explain the variations we have observed. If used as a guide to referral, such variation could lead to inequalities in colorectal investigation and diagnosis.

Introduction

Canopy FGF signaling regulator 3 (CNPY3) is a protein predominantly localized in the endoplasmic reticulum. Its expression is increased in several cancers, including colorectal cancer (CRC). However, how CNPY3 affects CRC progression and the function of CNPY3 translocation to the nucleus in CRC is not clear.

Aims & Methods

This study aimed to investigate the role of CNPY3 in the development of CRC. In vitro, the impacts of CNPY3 on CRC growth were evaluated by 5-Ethynyl-2′-deoxyuridine staining, colony formation, wound healing, transwell migration, and apoptosis assay. Tumor xenograft mouse models and orthotopic mouse models of colorectal cancer metastasis were used to assess in vivo. Furthermore, the underlying mechanism of CNPY3 in CRC was revealed by RT-qPCR, western blot, LC-MS/MS analysis, immunofluorescence staining, coimmunoprecipitation, GST-pulldown, confocal microscopy, ubiquitination assays, and rescue experiments.

Results

CNPY3 was significantly upregulated in CRC tissue and cell lines, correlating with their poor prognosis. Functional experiments demonstrated that CNPY3 enhances CRC proliferation, migration, invasion, and tumor growth. Notably, our investigation reveals a nucleus translocation of cnpy3 by activation of nuclear localization sequences through protein conformational changes. Meanwhile, nuclear localization of CNPY3 promotes the binding of TRIM21 and p53 and forms a CNPY3-TRIM21-p53 complex, thereby promoting the ubiquitination-proteasomal degradation of wild-type p53 protein, inhibiting the related genes of the TP53 signaling pathway, and promoting apoptosis of tumor cells. In vivo and in vitro, inhibiting the degradation of p53 was able to suppress CNPY3 in cancer-promoting tumors, whereas the knockdown of CNPY3 in p53^-/- HCT116 cells did not significantly inhibit CRC.

Conclusion

CNPY3, after nuclear translocated, binds to TRIM21 and p53 and stabilizes the TRIM21–p53 interaction. This CNPY3–TRIM21–p53 complex facilitates TRIM21‐mediated p53 ubiquitinoylation and causes p53 proteasome degradation. Collectively, these findings support that CNPY3, an oncogene with CRC progression and poor prognosis, serves as a biomarker and therapeutic target correlated to suppress p53 function.

References

1. Wakabayashi Y, Kobayashi M, Akashi-Takamura S, et al. A protein associated with toll-like receptor 4 (PRAT4A) regulates cell surface expression of TLR4. J Immunol. 2006;177(3):1772-9.
2.
3. Xiao L, Li XX, Chung HK, Kalakonda S, et al. RNA-Binding Protein HuR Regulates Paneth Cell Function by Altering Membrane Localization of TLR2 via Post-transcriptional Control of CNPY3. Gastroenterology. 2019;157(3):731-743.
4. Ghait M, Husain RA, Duduskar SN, et al. The TLR-chaperone CNPY3 is a critical regulator of NLRP3-inflammasome activation. Eur J Immunol. 2022;52(6):907-923.
5. Zhou YQ, Bao TS, Xie JX, et al. The SLITRK4-CNPY3 axis promotes liver metastasis of gastric cancer by enhancing the endocytosis and recycling of TrkB in tumour cells. Cell Oncol (Dordr). 2023;46(4):1049-1067.
6. Reddy BA, van der Knaap JA, Bot AG, et al. Nucleotide biosynthetic enzyme GMP synthase is a TRIM21-controlled relay of p53 stabilization. Mol Cell. 2014;53(3):458-70.
7. Liu J, Zhang C, Xu D, et al. The ubiquitin ligase TRIM21 regulates mutant p53 accumulation and gain of function in cancer. J Clin Invest. 2023;133(6):e164354.