Introduction

In this induction period analysis of the FilgoColitis study, we report on clinical effectiveness and psychosocial outcomes in ulcerative colitis (UC) patients newly initiated on filgotinib (FIL) therapy in a real-world setting. In addition, this study attempts to define novel patient-based outcomes monitored by wearable devices.

Aims & Methods

FilgoColitis is a prospective, multi-centre, non-interventional, 24-month observational study in patients with active UC newly initiated on FIL therapy. The study evaluates patients with active UC receiving FIL in terms of disease activity (pMayo score), quality of life (QoL), and - in a subset - physical activity using two different wearable devices (Garmin® smartwatch and SensMotion® accelerometer). pMayo-defined clinical remission was related to physical activity (steps), mean heart rate, and stress levels in UC patients with complete wearable data available for the four days immediately following both baseline and week 10 (n=32). Data were considered complete if more than 50% of daily data were recorded from 6 am to 10 pm on at least 3 out of 4 days.

Results

The study enrolled 202 patients with UC who were newly treated with FIL. Six patients were excluded due to incomplete baseline data. Out of the participants with complete baseline data (n=196), 106 (54.1%) used at least one wearable device during the study. To validate the smartwatch, all steps measured in parallel by both the smartwatch and the conventional accelerometer system were compared halfway through the recruitment period and showed good agreement with a positive correlation of 0.88 (p<0.001). 168 patients with complete baseline and week 10 data were available for the induction period (week 10) analysis. Of these, 61.3% were male, and the median time since diagnosis was 8.0 years. Prior to treatment with FIL, 85.1% of patients had received biologic or small molecule therapies, and 54.8% had used immunosuppressants. After 10 weeks of induction therapy with FIL, a clinical response rate of 50.9% and a clinical remission rate of 29.2% were observed (Tab. 1). Clinical remission was 36.0% in biologic-naïve (n=25) and 28.0% in biologic-experienced patients (n=143) (p=0.564). The median baseline score on the EQ-VAS was 60, which increased to 75 by week 10, reflecting a significant improvement in QoL (p<0.001). There was no association between general biometric stress readings or step counts and clinical remission at week 10. However, heart rate at week 10 was significantly associated with clinical remission status, with a mean heart rate of 71.5 beats per minute (bpm) observed in patients in remission and 85.4 bpm in those not in remission (p=0.005). Sensitivity analysis identified a threshold of 80 bpm as optimal for discriminating clinical remission status, yielding a specificity of 0.778 and a sensitivity of 0.857.

Conclusion

In this real-world study, filgotinib demonstrated a response rate of 51% and a clinical remission rate of 29% in active UC at week 10. Using wearable device data, heart rate was identified as a suitable discriminator for categorising remission status. Subsequent analyses over the maintenance period will evaluate the utility of heart rate and additional wearable parameters in assessing clinical remission.

References

1. Plachta-Danielzik S, Grasskemper L, Schmidt K, Schreiber S, Bokemeyer B; Health Status, Quality of Life, Psychosocial Well-being, and Wearables Data of Patients With Active Ulcerative Colitis Receiving Filgotinib Therapy (FilgoColitis Study): Protocol for a Real-world Observational Study; JMIR Res Protoc 2023;12:e42574

Disclosure

Conflicts of Interest
BB has received consulting fees from AbbVie, MSD, Shire, Ferring, Hospira, Takeda, Movetis, Shield Therapeutics, Pfizer, Biogen, Janssen, Hexal, and Celgene; received financial support for lectures and teaching from AbbVie, Ferring, MSD, Merckle, Falk, HLR, Shield Therapeutics, Pfizer, Celltrion, Takeda, Janssen, and Mundipharma; and received grant and financial support for research from AbbVie and Ferring. SS has received personal fees from Abbvie, Arena, BMS, Biogen, Celltrion, Celgene, IMAB, Gilead, MSD, Mylan, Pfizer, Fresenius, Janssen, Takeda, Theravance, ProventionBio, Protagonist, and Falk.

Introduction

Colonoscopic surveillance reduces colorectal cancer (CRC) incidence and mortality in Lynch syndrome (LS) carriers. Still, its invasiveness and high costs highlight the need for a non-invasive approach to predict the presence of neoplastic lesions.

Aims & Methods

This study aimed to identify faecal bacterial biomarkers to discern between carriers with colorectal lesions and those with normal colon.
Two independent Spanish cohorts (a training and a validation cohort) were recruited through two multicenter studies (Table 1). Participants provided a faecal sample before surveillance colonoscopy to quantify the abundance of F. prausnitzii (FPRA) and its phylogroups I and II (PHGI and PHGII), P. stomatis (PTST), B. fragilis (BCTF), B. thetaiotaomicron (BCTT), B46 (best BLAST match S. variabile), G. morbillorum (GMLL), B48 (best BLAST match R. faecis), and E. coli (ECO) through qPCR. Eubacteria (EUB) was quantified as the total bacterial load. Participants were classified based on colonoscopy findings as normal colonoscopy (NC), non-advanced adenoma (NAA), and advanced neoplasia (AN, including advanced adenoma and CRC). A bacterial signature for neoplasia prediction was defined and validated in the training and validation cohorts, respectively.

Table 1. Main characteristics of the study participants. NC, normal colonoscopy; NAA, non-advanced adenoma; AA, advanced adenoma; CRC, colorectal cancer.

Results

The bacterial abundances were analysed in the training cohort according to age, sex, body mass index (BMI), germline mutation, and colonoscopy findings. Significant moderate positive correlations were identified between the abundances of BCTF and age (r=0.325, p=0.040), and PHGII and BMI (r=0.399, p=0.010). A significant negative correlation was identified between GMLL abundance and BMI (r=-0.331, p=0.036). Patients harbouring MLH1 mutations exhibited a significantly higher abundance of FPRA compared to PMS2 carriers (p=0.048). Patients with neoplasia (NAA+AN) presented significantly lower abundances of BCTF (p=0.027) and B48 (p=0.038) than patients with NC. Patients with AN presented a significantly lower abundance of PTST compared to patients with NC or NAA (p=0.032).
Although all the bacterial markers achieved a sensitivity of 100% to predict the presence of neoplasia, none of them presented a specificity higher than 25% by itself. To maintain sensitivity and increase specificity a bacterial signature was defined including ECO, BCTF, GMLL, FPRA, PHGI, PHGII, and B46 combined with the inherited mutation. The signature showed 100% sensitivity (SS), 52.50% specificity (SP), 34.48% positive predictive value (PPV), and 100% negative predictive value (NPV). This signature was subsequently validated demonstrating 100% SS, 56.45% SP, 53.44% PPV, and 100% NPV.

Conclusion

A new faecal bacterial signature to predict the presence of colorectal neoplasia in LS carriers has been identified, showcasing its potential usefulness to improve and personalise LS surveillance, optimising endoscopic resources, and providing a less invasive and cost-effective approach.

Disclosure

S. Taboada-López, M. Malagón, S. Ramió-Pujol and M. Serra-Pagès are employees of GoodGut.

Introduction

Organoid models simulate organ function and structure, offering a physiologically relevant platform for studying organ development, disease mechanisms, and drug responses. Mouse pancreatic ductal organoids serve as valuable models for pancreatic research, yet their long-term viability remains uncertain. Simultaneously, pancreatic cancer, predominantly pancreatic ductal adenocarcinoma (PDAC), poses significant clinical challenges globally. Despite its prevalence and lethality, the genetic alterations driving PDAC progression remain largely elusive. Thus, understanding the gene expression changes in PDAC is crucial for therapeutic advancements.

Aims & Methods

Our study aimed to sustain mouse pancreatic ductal organoids long-term and explore associated gene expression changes, focusing on cancer-related markers. Ductal organoid cultures from wild-type FVB/N mice (N=3) were propagated for 40 passages (p40). RNA was isolated at various time points (p3/5/10/20/30/40) for transcriptomic analysis, with p3 serving as the starting time point. Passaging frequency and organoid morphology were monitored. Transcriptomic data underwent Ingenuity Pathway Analysis (IPA) to elucidate changes over passages in the organoids.

Results

The passaging frequency subsequently declined with time. The morphology of the organoids underwent noticeable changes starting from p20, characterized by the emergence of outgrowths surrounding the domes and the presence of adhesions in the organoids. The preliminary findings from the transcriptome data indicate that the markers associated with ductal cell fate and brush border development exhibit the greatest transcripts per million (TPM) values at p10. The expression of Cftr, Ano1, and Adcy8, which play a crucial role in maintaining the balance of ions in ductal cells, exhibited a notable decline starting at p20. Similarly, starting from p20, the TPM values of cancer-related markers exhibited an unregulated escalation, and there was a notable alteration in the expression of genes that govern the G1/S checkpoint regulation in the cell cycle.

Conclusion

Our research shows that mouse organoid cultures are sustainable for studying ductal cell functionality up to p10. Additionally, we observed potential signs of spontaneous carcinogenesis making suggesting that this model could be utilized for in vitro tumorigenesis studies. These findings have the potential to enhance comprehension of the mechanisms involved in the progression of PDAC.

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

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

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.