e15643 Background: Colorectal cancer (CRC) is a major global health concern as it is the second most fatal cancer worldwide. While incidence in average onset colorectal cancer (AOCRC, > 50 years) is declining, early onset colorectal cancer (EOCRC, < 50 years) is rising globally. The reasons for this phenomenon are poorly understood. Multiomic profiling holds promise for determining aetiology and guiding treatment strategies. Methods: Patients diagnosed with CRC were enrolled in this pilot translational study with acquisition of tumour, adjacent normal tissue, blood and faeces. Here we present the data from tumour samples. Seventy-nine patients were included, comprising 38 patients with EOCRC, and 41 with AOCRC. Tumour tissue was obtained from fresh frozen specimens. Targeted genomic, proteomic and transcriptomic analyses were performed, through targeted panel sequencing, LC/MS and RNAseq respectively. Data integration strategies included pathway enrichment analysis, immune cell deconvolution, metabolic reaction enrichment analysis (MaREA), and cross-omics correlation. Clinical, molecular and survival outcomes were compared between EOCRC and AOCRC groups. Results: Integrated multiomic profiling identified 6,726 transcripts and 5,957 proteins. Targeted genomic sequencing detected somatic mutations in 50% of tumours. Tumour sidedness was prognostically relevant, with right sided tumours enriched for KRAS (G12V) and PIK3CA (E545K) mutations and associated with inferior overall survival (p = 0.007). Proteomic and transcriptomic analyses demonstrated that EOCRC exhibits a molecular profile distinct from AOCRC, characterised by enrichment of immunosuppressive processes and activation of sirtuin (SIRT1) and RHO GTPase signalling. Metabolic reaction enrichment analysis identified EOCRC specific vulnerabilities, including reduced glutathione biosynthesis, impaired pyruvate dehydrogenase activity, and altered nucleotide synthesis, consistent with increased oxidative stress sensitivity and glycolytic reliance. NQO1 emerged as a candidate biomarker with concordant transcriptomic and proteomic upregulation. Clinically, EOCRC patients presented with more advanced disease yet demonstrated improved overall survival compared with AOCRC (p = 0.02). Targeted genomic profiling had potential clinical utility, with 20% of patients demonstrating actionable changes in management and 45% harbouring alterations relevant at relapse. Conclusions: EOCRC represents a biologically distinct subtype of MSS colorectal cancer, defined by immunosuppressive signalling and altered metabolic dependencies not observed in AOCRC. These findings support age informed molecular stratification and identify candidate biomarkers and metabolic vulnerabilities that may inform targeted therapeutic strategies for this rapidly rising patient population.

Introduction:Predatory journals threaten academic integrity, highlighting the need to educate young researchers on identifying and avoiding them. This study aims to develop and validate an educational video to raise awareness of predatory journals and equip future scholars with essential publishing skills. Methodology:Between August and November 2024, two Delphi processes were carried out. The first involved validation of the video script, incorporating feedback from 10 experts in academia and publishing. The second focused on refining the audiovisual components with input from two graphic and communication designers. Consensus was established at a threshold of 100% agreement. Additionally, 15 young researchers participated to ensure the video was tailored to the target audience. Results:The final video was produced following a three-round Delphi process to validate the script and a two-round process to finalize the audiovisual features. Validation by the target audience contributed to enhancing the video's quality and ensuring it was well-tailored to the end users. The final video has a duration of 10 minutes and 42 seconds. Conclusion:This study developed and validated an educational video to raise awareness of predatory journals. Refined through a rigorous Delphi process and audience feedback, the video meets high standards of clarity and usability, offering a valuable tool for young researchers. Future evaluations will assess its effectiveness.

191 Background: Early onset colorectal cancer (EOCRC), diagnosed in patients under 50 years, is rising globally. The underlying biological mechanisms of EOCRC, compared with late-onset CRC (LOCRC), remain to be elucidated. Transcriptomic profiling enables a comprehensive exploration of regulatory networks, molecular subtypes, immune landscape, and metabolic rewiring across age-defined CRC cohorts. Methods: Bulk RNA sequencing was performed on matched tumour and adjacent normal tissues from microsatellite stable EOCRC (n=19) and LOCRC (n=28) patients. Genes with FPKM ≥1 in ≥50% of samples were retained (n=6,726). Principal component analysis (PCA) and clustering were used to assess global expression patterns. Further, consensus molecular subtypes (CMS) were assigned using the classifieRc application. Immune cell composition was inferred using the MCP-counter deconvolution framework. Metabolic reprogramming was assessed by projecting transcriptomic data onto metabolic networks using Metabolic Reaction Enrichment Analysis (MaREA). Results: Principal component analysis showed clear separation of tumour and adjacent normal tissue. CMS distribution was similar between EOCRC and LOCRC, with CMS1 the most frequent in both cohorts. Notably, all CMS1 cases were microsatellite stable (MSS), highlighting a potential therapeutic gap as this immune active subtype is currently excluded from immunotherapy eligibility. Immune deconvolution confirmed greater infiltration in CMS1 but revealed no significant difference between the two cohorts. Metabolic profiling identified EOCRC specific vulnerabilities, including reduced glutamate cysteine ligase activity and cystine uptake, decreased nucleotide synthesis, and reduced pyruvate dehydrogenase complex function, consistent with glycolytic dependence. These features suggest heightened EOCRC sensitivity to oxidative stress and potential metabolic intervention opportunities. Conclusions: Transcriptomic profiling reveals both shared and unique features of EOCRC and LOCRC. While CMS distribution and immune landscapes are broadly conserved, EOCRC demonstrates unique metabolic vulnerabilities and transcriptomic separation from normal tissue. These findings underscore the need for refined molecular stratification, particularly for MSS CMS1 patients, and highlight metabolic interventions as an underexplored avenue in CRC treatment.

Introduction Cancer recurrence is a pivotal outcome after treatment with curative intent for colon cancer patients, as it is related to worse survival, the subsequent need for further treatment and the associated use of healthcare resources. However, at present there is no consensus regarding the definition of locoregional recurrence of colon cancer. This contributes to variability in reporting outcomes and clinical management, limiting comparability across registries and clinical studies. This study aims to establish a consensus definition of locoregional recurrence using the Delphi method. Methods and analysis We will conduct a worldwide Delphi consensus study among international experts involved in the treatment of colon cancer and recurrence (surgeons, medical oncologists, radiologists and pathologists). Conceptual elements of the survey were identified through literature exploration and concern: (i) anatomical locations, (ii) diagnostic criteria, (iii) resection margins and (iv) disease-free interval. Participants will be asked to rate their agreement on statements regarding the definition of locoregional recurrence of colon cancer. After the first round, we will analyse the data to determine which items have reached consensus for inclusion/exclusion and develop a second survey including items that did not reach consensus and any new items suggested by participants. Ethics and dissemination The Dutch Medical Research Involving Human Subjects Act (WMO) does not apply to this study, as it does not involve patient participation. Participation is restricted to clinical health professionals. Results will be disseminated via communication to relevant societies in this field, presentations on (inter)national meetings and peer-reviewed publication.

PURPOSE:The incidence of early-onset colorectal cancer (EOCRC; CRC diagnosed before age 50 years) is increasing globally. This study analyses the trend in the Republic of Ireland over a 28-year period. METHODS:Epidemiologic data on CRC incidence were obtained from the National Cancer Registry of Ireland (NCRI) from January 1994 until December 2021. Additional information on age of diagnosis and tumor sidedness for the entire period was obtained, while data relating to stage and sex were available for the study period 1999-2018. Incidence rates were stratified by sex, age group (20-34, 35-49, and ≥ 50 years), and tumor location. RESULTS:Between 1994 and 2021, there were 61,180 cases of CRC among adults older than 20 years in the Republic of Ireland. The age-specific rate (ASPR) annual percentage change (APC) in patients younger than 50 years was 0.97 (95% CI, 0.30 to 1.76) in females and 0.57 (95% CI, 0.08 to 1.30) in males, while in patients age 50 years or older, it was -0.60 (95% CI, -1.03 to -0.15) in females and -0.70 in males (95% CI, -1.18 to -0.16), respectively. CONCLUSION:In line with global trends, the incidence of EOCRC is increasing in Ireland. Further studies investigating the etiology and optimal treatment strategies for this cohort are necessary.

e15696 Background: The incidence of early onset colorectal cancer (EOCRC; ≤50 years) is increasing globally, while the incidence of average onset colorectal cancer (AOCRC; colorectal cancer ≥ 50years) is stabilising and beginning to decline with increased screening uptake. In Ireland screening begins at 59 years. We analysed trends in incidence of colorectal cancer (CRC) in the Republic of Ireland over a twenty-eight year period. Methods: Epidemiological data pertaining to the incidence of CRC (ICD-10 C18-C20), was obtained from the National Cancer Registry of Ireland (NCRI) from January 1994 until December 2021. Additional information on age of diagnosis and tumour sidedness for the entire period was obtained, while data relating to stage and gender was available for the study period 1999 - 2018. Incidence rates were stratified by sex, age group (20-34, 35-49, and greater than 50 years), and tumour sidedness (right versus left side). Results: Between 1994 to 2021, there were 61,180 cases of colorectal cancer among adults ≥20 years in the Republic of Ireland. During that time, the incidence of EOCRC increased by 34%, while the incidence of AOCRC decreased by 12.2%. The age specific rate (ASPR) annual percentage change (APC) amongst those with EOCRC was 0.97 (CI 0.30 - 1.76) in females and 0.57 (CI 0.08 - 1.30) in males. The age specific rate (ASPR) APC in those with AOCRC was -0.60 (CI -1.03 - -0.15) in females and -0.70 in males (CI -1.18 - -0.16). There were significantly higher rates of stage III and stage IV disease at diagnosis in the EOCRC group compared to the AOCRC group. For instance, in the 20-34 age group, 64% of individuals in the EOCRC group presented with stage III or IV disease, compared to 49% in the AOCRC group. A higher percentage of left-sided colorectal cancers compared to right-sided ones was observed across all age groups across the entire study period. The proportion of males diagnosed was higher than females in all groups except in the 20-34 age group, where there was a higher percentage of females than males. The 5-year net survival rate increased for both sexes across all age groups during the study period. Conclusions: In line with global trends, the incidence of EOCRC across both sexes is increasing in Ireland, and such patients are diagnosed at a later stage than their AOCRC counterparts. Public health initiatives must focus on screening age and public and healthcare practitioner awareness of this concerning trend. In addition, undertaking large-scale epidemiological and genomic studies will be essential to improve understanding of this disease and inform new treatment strategies for this patient group with unique needs.

212 Background: Early onset colorectal cancer (EOCRC) is defined as colorectal cancer (CRC) in those under the age of 50. It has been hypothesized that the molecular signatures of EOCRC could differ from those of late onset CRC (LOCRC). Next Generation Sequencing (NGS) using the Oncomine Precision Assay is a useful tool to guide treatment decisions based on the presence or absence of oncogene drivers. While not all of these mutations currently influence the clinical management of CRC patients, ongoing research on the function of these genes and the development of new drugs could offer insights into patient prognosis, treatment choices and prediction of therapy resistance. Methods: Of >1500 CRC identified between 2010 and 2024, we investigated the clinical and genetic characteristics of 38 EOCRC and 41 LOCRC cases. All cases were microsatellite stable and staged I-III. NGS was performed with the Ion Torrent Genexus integrated platform using the Oncomine 45-gene Precision Assay panel. DNA hotspot mutations and copy number variations (CNVs) were assessed, followed by the classification of clinically relevant mutations using the genetic variant OncoKB database. Results: There were 38 EOCRC and 41 LOCRC cases. The age range was 27 to 49 and 50 to 91, with median ages of 44 and 72, in the EOCRC and LOCRC groups, respectively. Based on the stratification of NGS mutation levels as per the OncoKB classification, all patients in both groups (100%) had level 1 actionable mutations. NRAS wild type (WT) status was present in 100% of patients in both groups. However, differences were observed in KRAS status: 84% (32/38) of EOCRC were KRAS WT, while only 65% (27/41) of LOCRC were KRAS WT. While 3 % (n=1) of the EOCRC cohort had an ERBB2 amplification, none were detected in the LOCRC group. BRAF V600E mutations were present in 11% (4/38) of EOCRC and 12% (5/41) of LOCRC. Level 4 mutations were detected in 18% (n=7) of EOCRC, all of which were PIK3CA mutations, while these were seen in 24% (n=10) of the LOCRC group, including 9 PIK3CA mutations and 1 FGFR1 mutation. Regarding concurrent mutations, 2 patients in the EOCRC group had two mutations each: one with concurrent KRAS and PIK3CA mutations, and another with concurrent JAK2 and KRAS mutations. The LOCRC group had a higher incidence of concurrent mutations, with 8 patients affected: 6 had concurrent KRAS and PIK3CA mutations, and 2 had concurrent BRAF and PIK3CA mutations. Conclusions: Our study demonstrates that EOCRC have higher KRAS WT status and fewer concurrent mutations compared to LOCRC, who exhibit more frequent KRAS non-G12C oncogenic mutations. It also underscores the importance of routine NGS mutation panel analysis in CRC management. Additionally, identifying specific mutations in patients that relapse can guide targeted therapies, potentially improving outcomes and offering personalized treatment options.

Colorectal cancer (CRC) is a common cancer in Ireland. Of all CRCs, 2–4

AIM:Minimally invasive surgery has been increasingly adopted for locally advanced colon cancer. However, evidence comparing robotic (RRC) versus laparoscopic right colectomy (LRC) for nonmetastatic pT4 cancers is lacking. METHODS:This was a multicentre propensity score-matched (PSM) study of a cohort of consecutive patients with pT4 right colon cancer treated with RRC or LRC. The two surgical approaches were compared in terms of R0, number of lymph nodes harvested, intra- and postoperative complication rates, overall (OS), and disease-free survival (DFS). RESULTS:Among a total of 200 patients, 39 RRC were compared with 78 PS-matched LRC patients. The R0 rate was similar between RRC and LRC (92.3% vs. 96.2%, respectively; p = 0.399), as was the odds of retrieving 12 or more lymph nodes (97.4% vs. 96.2%; p = 1). No significant difference was noted for the mean operating time (192.9 min vs. 198.3 min; p = 0.750). However, RRC was associated with fewer conversions to laparotomy (5.1% vs. 20.5%; p = 0.032), less blood loss (36.9 vs. 95.2 mL; p < 0.0001), fewer postoperative complications (17.9% vs. 41%; p = 0.013), a shorter time to flatus (2 vs. 2.8 days; p = 0.009), and a shorter hospital stay (6.4 vs. 9.5 days; p < 0.0001) compared with LRC. These results were confirmed even when converted procedures were excluded from the analysis. The 1-, 3- and 5-year OS (p = 0.757) and DFS (p = 0.321) did not significantly differ between RRC and LRC. CONCLUSION:Adequate oncological outcomes are observed for RRC and LRC performed for pT4 right colon cancer. However, RRC is associated with lower conversion rates and improved short-term postoperative outcomes.

Early-onset colorectal cancer (EOCRC), defined as colorectal cancer in individuals under 50 years of age, has shown an alarming increase in incidence worldwide. We report a case of a twenty-four-year-old female with a strong family history of colorectal cancer (CRC) but without an identified underlying genetic predisposition syndrome. Two years after primary surgery and adjuvant chemotherapy, the patient developed new liver lesions. Extensive diagnostic imaging was conducted to investigate suspected liver metastases, ultimately leading to a diagnosis of focal nodular hyperplasia. The young age of the patient has prompted comprehensive genomic and transcriptomic profiling in order to identify potential oncogenic drivers and inform further clinical management of the patient. Besides a number of oncogenic mutations identified in the patient’s tumour sample, including KRAS G12D, TP53 R248W and TTN L28470V, we have also identified a homozygous deletion of 24.5 MB on chromosome 8. A multivariate Cox regression analysis of this patient’s mutation profile conferred a favourable prognosis when compared with the TCGA COADREAD database. Notably, the identified deletion on chromosome 8 includes the WRN gene, which could contribute to the patient’s overall positive response to chemotherapy. The complex clinical presentation, including the need for emergency surgery, early age at diagnosis, strong family history, and unexpected findings on surveillance imaging, necessitated a multidisciplinary approach involving medical, radiation, and surgical oncologists, along with psychological support and reproductive medicine specialists. Molecular profiling of the tumour strongly indicates that patients with complex mutational profile and rare genomic rearrangements require a prolonged surveillance and personalised informed interventions.

This study aimed to compare the short- and long-term outcomes of robotic (RRC-IA) versus laparoscopic (LRC-IA) right colectomy with intracorporeal anastomosis using a propensity score matching (PSM) analysis based on a large European multicentric cohort of patients with nonmetastatic right colon cancer. Elective curative-intent RRC-IA and LRC-IA performed between 2014 and 2020 were selected from the MERCY Study Group database. The two PSM-groups were compared for operative and postoperative outcomes, and survival rates. Initially, 596 patients were selected, including 194 RRC-IA and 402 LRC-IA patients. After PSM, 298 patients (149 per group) were compared. There was no statistically significant difference between RRC-IA and LRC-IA in terms of operative time, intraoperative complication rate, conversion to open surgery, postoperative morbidity (19.5

Background Extended right hemicolectomy (ERHC) or left hemicolectomy (LHC) are accepted as the standard-of-care for colonic tumours of the splenic flexure. Lymphatic drainage at this site is poorly defined and subject to significant heterogeneity. Nevertheless, emerging evidence demonstrates the potential oncological safety of segmental splenic flexure colectomy (SFC). Aim To perform a systematic review and network meta-analysis (NMA) to compare outcomes following ERHC, LHC and SFC for splenic flexure tumours (SFTs). Methods A systematic review was performed as per PRISMA guidelines. NMA was performed using R Shiny and Netmeta packages. Results A total of 13 studies, involving 6176 patients (ERHC n = 785; LHC n = 1527; SFC n = 3864) were included in the NMA. There was no difference in overall survival (OS) (SFC vs LHC Hazard Ratio [HR] 1.0, 95% Credible Interval [CrI] 0.76,1.34; SFC vs ERHC HR 1.18, 95% CrI 0.85,1.58) between the groups. SFC had a shorter operation time (Mean 176.37 min; Mean Difference [MD] SFC vs LHC 20.34 min 95% CrI 10.9, 29.97; SFC vs ERHC MD 22.19 95% CrI 11.09, 33.29) but also had a lower average lymph node yield (LNY) compared with ERHC (MD 7.15, 95% CrI 5.71, 8.60). ERHC had a significantly higher incidence of post-operative ileus (Odds Ratio [OR] 3.47, 95% CrI 1.11, 10.84). There was also no difference observed for minimally invasive approaches, anastomotic leak rate, perioperative mortality, reoperation rates or length of stay. Conclusions While SFC may allow for reduced operative duration and improved bowel function postoperatively. SFC, LHC, ERHC are all acceptable approaches for curative resection of cancers of the splenic flexure, with no difference in OS observed. Thus, surgeon preference and candidate-specific factors will likely determine the management of SFTs.

This Guide to Statistics and Methods describes the process for publishing about a clinical trial by planning its clinical relevance, knowing the audience, and following reporting guidelines.

NK cells and CD8 T cells use cytotoxic molecules to kill virally infected and tumor cell targets. While perforin and granzyme B (GzmB) are the most commonly studied lytic molecules, less is known about granzyme K (GzmK). However, this granzyme has been recently associated with improved prognosis in solid tumors. In this study, we show that, in humans, GzmK is predominantly expressed by innate-like lymphocytes, as well as a newly identified population of GzmK+CD8+ non- mucosal-associated invariant T cells with innate-like characteristics. We found that GzmK+ T cells are KLRG1+EOMES+IL-7R+CD62L-Tcf7int, suggesting that they are central memory T and effector memory T cells. Furthermore, GzmK+ cells are absent/low in cord blood, suggesting that GzmK is upregulated with immune experience. Surprisingly, GzmK+ cells respond to cytokine stimuli alone, whereas TCR stimulation downregulates GzmK expression, coinciding with GzmB upregulation. GzmK+ cells have reduced IFN-γ production compared with GzmB+ cells in each T cell lineage. Collectively, this suggests that GzmK+ cells are not naive, and they may be an intermediate memory-like or preterminally differentiated population. GzmK+ cells are enriched in nonlymphoid tissues such as the liver and adipose. In colorectal cancer, GzmK+ cells are enriched in the tumor and can produce IFN-γ, but GzmK+ expression is mutually exclusive with IL-17a production. Thus, in humans, GzmK+ cells are innate memory-like cells that respond to cytokine stimulation alone and may be important effector cells in the tumor.