Introduction

IL-6 is implicated in the pathogenesis of ulcerative colitis (UC), however no IL-6 inhibitor has been approved for UC to date. Selective inhibition of IL-6 trans-signaling could ameliorate the deleterious, pro-inflammatory effects of IL-6¹,while preserving the homeostatic, tissue reparative activity of classical IL-6 signaling. Olamkicept ², a fusion protein consisting of two complete extracellular domains of gp130 attached to the Fc-region of an IgG₁ antibody, neutralizes IL-6 trans-signaling in vitro and has shown promising clinical effects in a recent randomized, double-blind, placebo-controlled phase II trial in moderate to severe UC (NCT03235752)³.

Aims & Methods

The objective of this study was to characterize the biological effects resulting from selective inhibition of IL-6 trans-signaling using an in silico model of colonic inflammation.
A hybrid mechanistic-statistical computational model of colonic inflammation in UC was developed using published pre-clinical and clinical studies as well as internally generated in vitro pharmacology data^2-4. The output of the model included changes in IL-6 signaling pathway components (IL-6, soluble IL-6 receptor, membrane-bound IL-6 receptor, soluble gp130, and STAT-3 phosphorylation), C-reactive protein (CRP), fecal calprotectin, adaptive immune cell (CD4+ T lymphocyte) sub-populations, cytokines, and chemokines. States of tissue damage and repair (healing) were estimated.
The performance of the model was tested against clinical data generated in NCT03235752³ in which patients had been allocated to receive intravenous (IV) administration of 300 mg or 600 mg olamkicept or placebo every two weeks for 12 weeks.
Simulations assessing the differential effects of modulating trans- and cis-signaling were probed using pharmacological inhibitors of trans- (olamkicept, 300-1800 mg administered IV every 2 weeks) and pan-IL-6 signaling (IL-6 receptor inhibitor and a STAT-3 phosphorylation inhibitor). Changes in concentrations of IL-6 signaling species and down-stream effects on immune cell sub-population levels were compared both in the systemic circulation and locally in the gut tissue. The initial concentrations of the signaling species were based on those typically observed in UC patients⁵.

Results

Based on the simulations, concentrations of free IL-6 in the systemic circulation were minimally impacted by exposure to olamkicept. In gut tissue, IL-6 concentrations decreased by approximately 10% at the highest olamkicept dose tested, returning to pre-treatment levels within a day post dose.
Suppression of IL-6 trans-signaling by olamkicept caused a transition away from aT_h17-rich state in gut tissue and attenuated inflammatory chemotactic signals in a dose-dependent manner. In comparison, the pan-inhibition of IL-6 signaling reduced T_h17 mediated inflammatory activity, however tissue healing pathways dependent on IL-6 cis-signaling were also suppressed.

Conclusion

In the developed in silico model of colonic inflammation, inhibition of IL-6 signaling was associated with attenuation of T_h17 mediated inflammation in the gut. Pan-inhibition of IL-6 signaling was associated with impaired tissue healing, however this was not observed for olamkicept, where homeostatic, classical IL-6 signaling was preserved.
This study provides quantitative support to therapeutic strategies targeting IL-6 trans-signaling in UC to reduce the cytokine’s undesirable effects while preserving its beneficial functions.

References

1. Garbers C. et al., The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition. Curr Opin Immunol. 2015 Jun;34:75-82. doi: 10.1016/j.coi.2015.02.008.
2. Schreiber S. et al., Therapeutic Interleukin-6 Trans-signaling Inhibition by Olamkicept (sgp130Fc) in Patients With Active Inflammatory Bowel Disease. Gastroenterology. 2021 Jun;160(7):2354-2366.e11. doi: 10.1053/j.gastro.2021.02.062.
3. Zhang S, et al., Effect of Induction Therapy With Olamkicept vs Placebo on Clinical Response in Patients With Active Ulcerative Colitis: A Randomized Clinical Trial. JAMA. 2023 Mar 7;329(9):725-734. doi: 10.1001/jama.2023.1084.
4. Reeh H. et al. Response to IL-6 trans- and IL-6 classic signalling is determined by the ratio of the IL-6 receptor α to gp130 expression: fusing experimental insights and dynamic modelling. Cell Commun Signal. 2019 May 17;17(1):46. doi: 10.1186/s12964-019-0356-0.
5. Nikolaus S et al. Evaluation of interleukin-6 and its soluble receptor components sIL-6R and sgp130 as markers of inflammation in inflammatory bowel diseases. Int J Colorectal dis. 2018 Jul;33(7):927-936. Doi: 10.1007/s00384-018-3069-8

Disclosure

O. Sternebring, A. Ravi, A. Rivollier, S. Read, R. Szabady and P. Pinton are employees of Ferring Pharmaceuticals. P. Pinton owns stocks of Takeda Pharmaceutical Company Limited. N. Patidar, R. Carcillo, M. Behar, Jørgen Sørensen and P. D’Alessandroare employees of PriceWaterhouseCoopers.

Introduction

Volatile organic compounds (VOCs) form a specific chemical profile that can be used to detect the colorectal cancer-related changes in human metabolism and thereby, to diagnose this type of cancer even at an early stage.

Aims & Methods

The aim of this study was to characterize the volatile chemical patterns associated with cancer and normal tissues obtained from colorectal cancer patients and identify potential volatile biomarkers of colorectal cancer. In total 50 paired tissue samples were analyzed. Volatiles released by the tissue samples were captured using solid phase microextraction (HS-SPME) and next identified and quantified using gas chromatography with mass spectrometric detection (GC-MS). A Wilcoxon signed-rank test was used to compare the emissions of VOCs from cancer and non-cancerous tissues and p<0.05 was taken as significant threshold.

Results

A total of 163 compounds were found in the headspace of the tissue samples. Amongst these, 149 VOCs were identified in cancer tissues and 147 in non-cancerous ones. 138 volatiles were found in both types of tissues. The predominant chemical classes in both tissues are hydrocarbons (25%) and alcohols (15%). These are followed by aldehydes, ketones and aromatics. Only 40 VOCs (27%) exhibited incidence higher than 50% in cancerous tissues. In case of healthy tissue this number amounted to 44 (30%). 11 volatiles occurred in at least 90% of both types of samples and thereby can be considered as omnipresent. 15 VOCs showed consistent differences in their headspace concentrations above samples under study. Of these, 4 compounds were found to have increased emissions from the cancer tissue, and the other 11 showed the reduced release from this type of samples. The species emitted in higher amounts by cancerous tissue comprised 1-propanol, pyridine, isoprene and methyl thiolacetate (p<0.05).

Conclusion

The results of this study confirm that the chemical fingerprint formed by volatiles in colorectal tissue is altered by colorectal cancer. These VOCs - 1-propanol, pyridine, isoprene, methyl thiolacetate were found to be the most promising biomarker candidates for detecting colorectal cancer.

Introduction

Post-colonoscopy colorectal cancer (PCCRC) is that diagnosed after a colonoscopy in which no cancer is found. PCCRC has become an important quality indicator. We aimed to determine its rates, characteristics, and index colonoscopy-related predictive factors.

Aims & Methods

Multicenter, observational, retrospective study between 2015 and 2018. We considered as PCCRC those developing up to 10 years after colonoscopy. PCCRC rates were calculated and PCCRC were categorized according to their most plausible explanation using the World Endoscopy Organization (WEO) methodology. Our PCCRC population was compared to a control cohort without CRC matched 1:4 by sex, age, index colonoscopy date and indication, endoscopist, and hospital.

Results

107 PCCRC were detected, of 101,524 colonoscopies (0.1%) and 2,508 CRC (4.3%), leading to rates of 0.4% (1-year), 2.2% (3-year), 3.1% (5-year), 4.1% (10-year). PCCRCs were in right (42.4%), left (41.4%), transverse (16.4%) colon with 31.5% at stage I, 24.7% stage II, 32.6% stage III, 11.2% stage IV. 20.3% of PCCRCs were classified as incomplete resection, 5.4% as unresected detected lesions, 48.6% as missed lesions with adequate colonoscopy, and 25.7% as missed lesions with inadequate colonoscopy. Mean time from previous colonoscopy to PCCRC was 42 months. Previous inadequate preparation (OR 3.05, 95%CI 1.73-5.36) and piecemeal polypectomy (OR 19.89, 95%CI 8.67-45.61) were independently associated with PCCRC.

Conclusion

In our population, 4.3% of CRCs were PCCRC. Most of these lesions were in the right colon and almost half attributable to lesions not visualized despite adequate bowel cleansing. Previous inadequate cleansing and piecemeal polypectomy were associated with PCCRC.

Disclosure

RJ has received research grants from MSD, and has participated as an advisor to MSD, Norgine, Alpha-Sigma, and GISupply. The rest of authors have nothing to disclose.

Introduction

Previous studies showed that adhering to high-quality screening colonoscopy leads to markedly decreased incidence and mortality of colorectal cancer. However, more is needed to know about the impact of the duration of participation on quality parameters.

Aims & Methods

This study aims to evaluate the relationship between the duration of endoscopists' participation within the Austrian quality assurance program for screening colonoscopy and their quality parameters. A generalized linear mixed model, adjusted for sex and age, was utilized to evaluate the effect of the time elapsed since participation on quality parameters, such as adenoma detection rate (ADR), advanced adenoma detection rate (AADR) and carcinoma detection rate (CDR).

Results

392 endoscopists provided data from 326,445 screening colonoscopies from 2007 to 2022. Results showed that each year of participation in the quality assurance initiative led to a 1.02% increase in ADR (95% CI [1.004-1.034], p-value = 0.013) as well as a 1.17% increase in CDR (95% CI [1.107-1.245], p-value <0.001) adjusted for patients' age and sex. The advanced adenoma detection rate increased by 1.00% each year of participation (95% CI [0.983-1.023], p-value = 0.762).

Conclusion

The participation of endoscopists in the quality assurance initiative was associated with a significant increase in ADR and CDR for each year of participation. However, the increase in AADR was not statistically significant.

Introduction

The organized, population-based National Colorectal Cancer (CRC) Screening Program in the Czech Republic is focused on asymptomatic individuals aged over 50. There are two methods available. Fecal occult blood test (FOBT) is offered by general practitioners annually at ages 50 – 54 and biennially at age ≥ 55 (followed by FOBT+ colonoscopy, if positive). And screening colonoscopy from age 50, repeated in 10 years interval, if negative. Both, FOBT+ colonoscopy and screening colonoscopy are considered preventive colonoscopies. FOBT performed in the laboratory is designated as diagnostic FOBT. Interval cancer is defined as a malignity diagnosed after an index exam (preventive, diagnostic, or therapeutic) in which no cancer is detected, and before the date of the next recommended exam.

Aims & Methods

The analysis included men and women of age ≥ 55 diagnosed with their first colorectal cancer in the period 2016-2020 (data source: National Cancer Registry). For those patients, the search of examinations in the National Registry of Reimbursed Health Services was performed focused on procedures in the period 0.5-5.5 years (depending on the type of examination; FOBT till 2.5 years, colonoscopy till 5.5 years) before the time of the cancer diagnosis: FOBT (screening and diagnostic), FOBT+colonoscopy and screening colonoscopy marked as preventive colonoscopy, diagnostic colonoscopy. As therapy, the endoscopic polypectomy, mucosal resection, and submucosal dissection performed within 6 months of the mentioned examinations were considered.

Results

There were colorectal cancers in 30,723 patients found (Table 1), with 13,816 cancers in stages III and IV (45.0%). The majority of the patients (64.4%) did not undergo any observed procedure. 20.3% of patients had negative FOBT, so, they were considered as patients with interval cancer. Preventive colonoscopies were accompanied by a low rate of interval cancers (0.9%).

Conclusion

The highest number of colorectal cancers was found in patients with no procedures related to CRC incidence and mortality reduction (preventive, diagnostic, or therapeutic). Approximately 20% of people with colorectal cancers had interval carcinoma (after negative screening FOBT) which could be caused by the inappropriate setting of FOBT examination or low sensitivity of FOBT. The higher proportion of cancers after negative screening FOBT might be also caused by the fold higher number of procedures FOBT performed.

References

Supported by the Czech Ministry of Health grants NV18-08-00246 and NU22-08-00424 and projects MO1012 and Cooperatio.