Introduction

Colorectal malignancy ranks third in global cancer incidence, with 1.9 million cases and nearly 1 million deaths reported in 2020. Total mesorectal excision (TME) is the gold-standard treatment for rectal cancer. Our meta-analysis evaluated surgical and functional outcomes of various anastomoses types, comparing end-to-end (EEA) to either side-to-end (SEA) or colonic J pouch (CJP).

Aims & Methods

Our protocol was registered on PROSPERO (CRD42022368907) beforehand. The systematic search was conducted on the 8th of November, 2022 in three major databases (Pubmed, Embase and CENTRAL). Randomized controlled trials (RCT) assessing adult patients following TME, where EEA was compared to another type of anastomosis were included. For data synthesis a random-effects model was used. In the case of categorical outcomes such as anastomotic leakage (AL) and mortality, the effect size was risk ratio (RR) with a 95% confidence interval (CI), whereas in the case of bowel movement mean difference (MD) with a 95% CI was used. The Risk of bias was evaluated using the Revised Cochrane risk-of-bias tool for randomized trials (ROB-2). The certainty of evidence level of the included studies was performed using GRADE-Pro.

Results

Following a careful search and selection process, 29 studies out of 4459 were included in our analysis. Comparing EEA to CJP, in terms of early (30 days) morbidity, we have found no difference in either AL (RR: 1.03; CI: 0.84;1.26) or mortality (RR: 0.77; CI: 0.30; 1.98). The functional outcome of patients was evaluated, and daily bowel movement was assessed at two-time points. At 6 months postoperatively, the EEA group had a slightly higher number of stools per day (MD: 1.89; CI: 0.39; 3.39), however at one year the MD dropped down to 1.59 (CI: -0.66; 3.84), reaching a statistically non-significant result. Because of limited data, only AL was assessed for the comparison with SEA, where no difference was found (RR: 1.19; CI= 0.60; 2.35). Twelve RCTs showed a high risk of bias due to unblinded surgeons, intervention deviations, and loss of follow-up data. According to the GRADE approach, the quality of evidence was moderate (AL, mortality) to low (bowel movement) because of the high risk of bias and imprecision.

Conclusion

In terms of early postoperative morbidity, EEA is not inferior to other types of reconstruction techniques. Regarding bowel movement, the slightly impaired intestinal function will resolve within one year following surgery. EEA should be used routinely following TME.

Introduction

The comparable efficacy and safety of both IV and SC induction with guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor, in pts with moderately to severely active CD has been established in the phase 3 GALAXI and GRAVITI studies.^1,2,3 To determine whether pts with higher baseline disease severity respond differently to IV or SC induction, we compared the efficacy of GUS IV and SC induction in subgroups based on baseline disease characteristics.

Aims & Methods

Pts had moderately to severely active CD (CDAI 220-450 and SES-CD≥6 or if ileal disease only, SES-CD≥4), and a history of inadequate response/intolerance to oral corticosteroids, AZA/6-MP/MTX, or biologics. GUS induction regimen was 200mg IV q4w in GALAXI 2 & 3 (N=582) and 400mg SC q4w in GRAVITI (N=230), while matching IV/SC PBO q4w (N=148 and N=117, respectively) was the comparator regimen. Clinical remission (CDAI<150) and endoscopic response (≥50% improvement from baseline SES-CD) were evaluated at Wk12 for predefined subgroups based on baseline involved disease location, CDAI, SES-CD, C-reactive protein (CRP), and fecal calprotectin (FeCal). Abnormal CRP was defined as >3 mg/L and >5 mg/L for GALAXI and GRAVITI, respectively.

Results

GALAXI and GRAVITI had similar entry criteria, and baseline disease characteristics of the randomized study populations were also similar. Pts treated with IV or SC GUS induction achieved clinical remission at Wk12 in greater proportions than those who received PBO across subgroups of disease location (ileal only [IV: GUS=44%, PBO=13%; SC: GUS=56%, PBO=27%], colon only [IV: GUS=44% vs PBO=18%; SC: GUS=56% vs PBO=18%], and both ileum and colon [IV: GUS=52% vs PBO=24%; SC: GUS=57% vs PBO=22%]), baseline CDAI (≤300 [IV: GUS=52%, PBO=25%; SC: GUS=66%, PBO=26%] and >300 [IV: GUS=40% vs PBO=10%; SC: GUS=41% vs PBO=14%]), baseline SES-CD (≤12 [IV: GUS=43%, PBO=21%; SC: GUS=52%, PBO=24%] and >12 [IV: GUS=53% vs PBO=16%; SC: GUS=62% vs PBO=18%]), baseline CRP (≤3mg/L or ≤5mg/L in GALAXI and GRAVITI, respectively, [IV: GUS=45%, PBO=17%; SC: GUS=53%, PBO=28%] and >3mg/L or >5mg/L [IV: GUS=48% vs PBO=20%; SC: GUS=59% vs PBO=17%]), and baseline FeCal (≤250μg/g [IV: GUS=49%, PBO=25%; SC: GUS=60%, PBO=26%] and >250μg/g [IV: GUS=46% vs PBO=16%; SC: GUS=54% vs PBO=20%]). Endoscopic response at Wk12 was also achieved by greater proportions of GUS- than PBO-induced pts across all subgroups with either IV or SC induction (Table).

Table. Endoscopic Response at Week 12 by Baseline Disease Characteristics

Conclusion

Both IV and SC induction with GUS were similarly effective in pts with moderately to severely active CD across predefined subgroups of disease location and baseline clinical, endoscopic, and inflammatory biomarker disease activity. The treatment effects were consistent in the subgroups following IV and SC induction, particularly in those that represent high disease severity.

References

1. Sachen K, Hammaker D, Sarabia I, et al. Frontiers in Immunology. 2025: doi:10.3389/fimmu.2025.1532852.
2. Panaccione R, Danese S, Feagan BG, et al. Gastroenterology. 2024; 166(5): S1057b.
3. Hart A, Panaccione R, Steinwurz F, et al. Gastroenterology. 2025: doi:10.1053/j.gastro.2025.02.033.

Disclosure

BES reports consulting fees from Abbvie, Adiso Therapeutics, Agomab, Alimentiv , Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Fresenius Kabi, Fzatat, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Microba, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Spyre Therapeutics, Sun Pharma, Surrozen, Target RWE,Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Lilly; research grants, consulting and speaking fees and other support from Bristol Myers Squibb, Janssen, Pfizer, Takeda; research grants and consulting fees from Theravance Biopharma; and stock/stock options from Ventyx Biopharma.
TH received grant support from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., Boston Scientific Corporation, Kissei Pharmaceutical Co. Ltd., consulting fees from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, Janssen Pharmaceutical K.K., Pfizer Inc., Nichi-Iko Pharmaceutical Co. Ltd., Eli Lilly, Gilead Sciences, Bristol Myers Squibb, and lecture fee from Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc. Kissei Pharmaceutical Co. Ltd.
AA reports potential conflicts of interest with AbbVie, Bristol Myers Squibb/Celgene, DiaSorin, Eli Lilly, Gilead, IBD Horizons, Janssen, Pfizer, Takeda, and TLL Pharmaceuticals.
NAT, MO, RVR, JY, and WvD are employees of Johnson & Johnson and own company stock/stock options.
AH served as a clinical investigator and consultant for Janssen.
SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB and Vifor; and reports lecture fees from AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer and Takeda.
RP reports having received consulting fees from Abbivax, Abbott, AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring,Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, Ventyx, UCB; Speaker’s Fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, Takeda Pharmaceuticals and served on Advisory Boards for: AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, and Ventyx.

Introduction

Vedolizumab (VDZ) is approved in Europe and the USA for the treatment of moderately to severely active ulcerative colitis (UC). Real-world evidence is needed to assess the effectiveness and benefit–risk profile of VDZ for UC outside clinical trial settings. A systematic literature review (SLR) and meta-analysis published in 2018 confirmed the real-world effectiveness and positive benefit–risk profile of VDZ treatment for up to 1 year in patients with inflammatory bowel disease.¹ Further real-world evidence is required to support the long-term (> 1 year) effectiveness of VDZ in patients with UC.

Aims & Methods

The aims of the current meta-analysis based on the SLR were to evaluate the rates of treatment persistence at 1 and at 2 years and of mucosal healing and corticosteroid-free clinical remission at 1 year (overall and stratified by biologic-naive versus biologic-experienced patients). Literature searches identified studies published from 2014 to 2022. For the SLR overall, outcomes of interest included clinical remission, mucosal healing, treatment patterns (including treatment persistence) and safety. Data on adults with UC treated with vedolizumab in a real-world setting were extracted for meta-analysis if there were at least 2 studies for each timepoint and population. Weighted proportions and corresponding 95% confidence intervals (CIs) were calculated using the DerSimonian-Laird random-effects model to account for between-study heterogeneity.

Results

Data from 68 studies of 21 774 patients with UC had at least one outcome of interest for analysis. The mean age ranged from 34.0–53.0 years (16 studies), the mean disease duration ranged from 4.9–10.4 years (5 studies) and the mean partial Mayo score ranged from 4.1–6.1 (6 studies). In the 28 and 9 studies that assessed treatment persistence at 1 and at 2 years, the rates of treatment persistence were 72.4% (95% CI 68.7–75.8) and 64.2% (95% CI 55.3–72.2), respectively. Similar treatment persistence rates at 1 year were observed among biologic-naive vs biologic-experienced patients, but at 2 years higher rates were observed for biologic-naive patients vs overall (Table). The overall mucosal healing rate at 1 year (assessed in 29 studies) was 42.6% (95% CI 37.0–48.3), and similar rates were observed in biologic-naive vs biologic-experienced patients (Table). The corticosteroid-free clinical remission rates at 1 year were 42.7% (95% CI 38.4–47.1; 22 studies) and at 2 years 43.4% (95% CI 27.9–60.2; 5 studies); higher rates were observed among biologic-naive vs biologic-experienced patients at 1 year (Table).

Conclusion

This meta-analysis of real-world studies of VDZ demonstrated high rates of long-term treatment persistence, mucosal healing and corticosteroid-free clinical remission in patients with UC, indicating effective disease management for these outcomes. However, the assessment of mucosal healing rates may not have been systematically conducted across all studies.
This study was funded by Takeda Pharmaceuticals International AG, Zurich, Switzerland.
Writing assistance provided by E Sugrue, PhD, of Oxford PharmaGenesis.

References

Schreiber S et al. J Gastroenterol. 2018;53:1048–64.

Disclosure

MC has served as a speaker or consultant, or has received funding for research or education, from AbbVie, Biogen, Dr Falk Pharma, Eli Lilly, Ferring, Gilead, Hospira, Janssen, MSD, Pfizer, Shire Pharmaceuticals, Takeda and Tillotts Pharma.
AA has received advisory board/lecture fees from AbbVie, Amgen, Arena, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr Falk Pharma, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, Lion Health, MSD, Nestlé, Novartis, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda, Teva Pharmaceuticals and Tillots Pharma.
PB is an employee and stockholder of Takeda Pharmaceuticals International AG, Zurich, Switzerland.
MM is an employee and stockholder of Takeda Pharma AG, Zurich, Switzerland.
ER is an employee of Putnam Associates, which received funding for this study from Takeda Pharmaceuticals International AG, Zurich, Switzerland.
CS is an employee of Putnam Associates, which received funding for this study from Takeda Pharmaceuticals International AG, Zurich, Switzerland.
SS has received personal fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr Falk Pharma, Fresenius, Galapagos/Gilead, Hikma, I-Mab, Janssen, MSD, Mylan, Pfizer, Protagonist Therapeutics, ProventionBio, Takeda, Theravance Biopharma and Ventyx.
SV has received financial support for research from AbbVie, Galapagos, J&J, Pfizer and Takeda, and speakers’ and/or consultancy fees from AbbVie, Abivax, AbolerISPharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Cytoki Pharma, Dr Falk Pharma, Eli Lilly, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Materia Prima, Mestag Therapeutics, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Surrozen, Takeda, Theravance Biopharma, Tillots Pharma AG, VectivBio, Ventyx and Zealand Pharma.

Introduction

Vedolizumab (VDZ) is approved in Europe and the USA for the treatment of moderately to severely active ulcerative colitis (UC). A previous systematic literature review (SLR) and meta-analysis published in 2018 demonstrated the real-world effectiveness and positive benefit–risk profile of VDZ treatment for up to 1 year in patients with inflammatory bowel disease.¹ There is limited real-world evidence on the long-term (> 1 year) treatment persistence and safety of VDZ compared with anti-tumour necrosis factor-alpha (TNFα) treatment in biologic-naive patients with UC.

Aims & Methods

The aims of this meta-analysis were to assess the real-world effectiveness and treatment persistence of VDZ in patients with UC. We report an exploratory analysis of treatment persistence and serious adverse events (SAEs) among biologic-naive patients with UC treated with VDZ compared with anti-TNFα treatment at 1 and at 2 years. Literature searches were conducted to identify studies published from 2014 to 2022. For the primary analysis, outcomes of interest included clinical remission, mucosal healing, treatment patterns (including treatment persistence) and safety. Data on adults with UC treated with VDZ or anti-TNFα treatment in a real-world setting were extracted if there were at least 2 studies for each timepoint and population. Weighted proportions and corresponding 95% confidence intervals (CIs) were calculated using the DerSimonian-Laird random-effects model to account for between-study heterogeneity. No formal statistical significance testing between treatments was applied.

Results

Among comparative studies of VDZ and anti-TNFα treatment, 8 studies were identified (10 486 biologic-naive patients with UC). Of these, 5 and 2 studies, respectively, reported the rates of treatment persistence in biologic-naive patients at 1 and at 2 years. The rate of treatment persistence at 1 year was 74.9% with VDZ (95% CI 64.3–83.3) and 59.0% with anti-TNFα treatment (47.2–69.8). Similarly, the rate of treatment persistence at 2 years was 77.6% with VDZ (70.8–83.2) and 60.0% with anti-TNFα treatment (48.3–70.7). Three retrospective cohort studies of 775 biologic-naive patients with UC treated with VDZ (n=465) versus anti-TNFα treatment (n=310) reported SAEs. In the first study, safety outcomes were followed from treatment initiation up to five half-lives after treatment discontinuation; 6.8% treated with VDZ experienced SAEs compared with 19.2% with anti-TNFα treatment.² In the second study, the rate of SAEs was similar between patients treated with VDZ (4.5%) and anti-TNFα treatment (5.0%).³ In the third study that reported SAEs within the first year of treatment; the rates of SAEs were 14.3% and 10.9% among patients who received VDZ and anti-TNFα treatment, respectively.⁴

Conclusion

This analysis of comparative studies in biologic-naive patients with UC suggested that treatment persistence rates were higher with VDZ than with anti-TNFα treatment both at 1 and at 2 years. In addition, these data support a comparable safety profile, with similar rates of SAEs between VDZ and anti-TNFα treatment.
This study was funded by Takeda Pharmaceuticals International AG, Zurich, Switzerland.
Writing assistance provided by E Sugrue, PhD, of Oxford PharmaGenesis.

References

1. Schreiber S et al. J Gastroenterol. 2018;53:1048–64.
2. Bressler B et al. J Crohn's Colitis. 2021;15:1694–706.
3. Helwig et al. BMC Gastroenterol. 2020;20:211.
4. Moens et al. Inflamm Bowel Dis. 2022;28:1135–1142.

Disclosure

SV has received financial support for research from AbbVie, Galapagos, J&J, Pfizer and Takeda, and speakers’ and/or consultancy fees from AbbVie, Abivax, AbolerISPharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Cytoki Pharma, Dr Falk Pharma, Eli Lilly, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Materia Prima, Mestag Therapeutics, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Surrozen, Takeda, Theravance Biopharma, Tillots Pharma AG, VectivBio, Ventyx and Zealand Pharma.
SS has received personal fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr Falk Pharma, Fresenius, Galapagos/Gilead, Hikma, I-Mab, Janssen, MSD, Mylan, Pfizer, Protagonist Therapeutics, ProventionBio, Takeda, Theravance Biopharma and Ventyx.
PB is an employee and stockholder of Takeda Pharmaceuticals International AG, Zurich, Switzerland.
MM is an employee and stockholder of Takeda Pharma AG, Zurich, Switzerland.
ER is an employee of Putnam Associates, which received funding for this study from Takeda Pharmaceuticals International AG, Zurich, Switzerland.
CS is an employee of Putnam Associates, which received funding for this study from Takeda Pharmaceuticals International AG, Zurich, Switzerland.
AA has received advisory board/lecture fees from AbbVie, Amgen, Arena, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr Falk Pharma, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, Lion Health, MSD, Nestlé, Novartis, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda, Teva Pharmaceutical and Tillots Pharma.
MC has served as a speaker or consultant, or has received funding for research or education, from AbbVie, Biogen, Dr Falk Pharma, Eli Lilly, Ferring, Gilead, Hospira, Janssen, MSD, Pfizer, Shire Pharmaceuticals, Takeda and Tillotts Pharma.

Introduction

Micronutrient deficiency of amino acids display a hitherto underappreciated role in the pathophysiology of IBD. Serine is a nonessential amino acid and directly involved in the cellular redox balance. In the absence of sufficient external supply, serine can be synthesized via glycolysis through the rate-limiting enzyme phosphoglycerate dehydrogenase (PHGDH). Serine metabolism is upregulated in cancer and immune cells, maintaining survival and growth. However, its role in coordinating cellular function in the context of IBD is not known.

Aims & Methods

We hypothesized that serine metabolism provides a novel and underappreciated metabolic switch to maintain immunological homeostasis in the intestinal epithelium of IBD patients.We assessed the gene expression of the rate-limiting enzymes of de novo serine synthesis PHGDH in two cross-sectional IBD cohorts (1. N=67, 2. N=212 patients) and linked PHGDH expression with endoscopic or clinical disease activity. We used murine small intestinal epithelial cells (Mode-K cells) and murine small intestinal and colon organoids to understand the molecular regulator of de novo serine synthesis via PHGDH. To assess the potential role of PHGDH in coordinating innate immune response, Mode-K cells were treated with LPS or tunicamycin in the presence or absence of the Phgdh inhibitor BI-4916. The impact of proinflammatory cytokines Cxcl1 and Il6 was assessed through qPCR and ELISA. Upstream activation of the NFκB signaling pathway was assessed by WB. Seahorse assay was conducted to evaluate the impact of Phgdh on mitochondrial function.

Results

Compared with healthy control, serine metabolic enzyme PHGDH was significantly increased in both UC and CD patients. PHGDH expression correlated with the degree of inflammation in tissue biopsies of IBD patients correlated with ER stress marker (HSP90B1). Chemical induction of ER stress strongly increased the expression of Phgdh, Psat1, and Psph in Mode-K cells and intestinal organoids. To assess the regulatory role of serine metabolism on innate immune function, Mode-K cells were treated in serine/glycine-deprived medium. PHGDH function was inhibited using the specific inhibitor BI-4916. Treatment with tunicamycin or LPS resulted in strong induction of the proinflammatory cytokines Cxcl1 and Il6. Parallel Seahorse assay displayed significantly disrupted mitochondrial function (basal-, ATP linked- and maximum respiration). As serine feeds into the 1C-metabolism to provide mitochondrial-derived formate, we co-treated cells with glycine and formate to overcome the functional consequences of deprived de novo serine synthesis. We show that co-treatment of glycine and formate rescued mitochondrial dysfunction and inhibited Cxcl1 overactivation in intestinal epithelial cells.

Conclusion

Our data provide a novel link on how disrupted serine metabolism directly fuels epithelial-derived proinflammatory mechanisms via disruption of mitochondrial function. Our data suggest a so far underappreciated role of cellular serine metabolism on IBD pathophysiology.

Introduction

Colorectal endoscopic submucosal dissection (ESD) is not widely performed in western countries due to technical complexity, risk of adverse events, and procedure time. Hybrid ESD (H-ESD) - partial submucosal dissection followed by snare-assisted resection – may be useful to achieved endoscopic resection in difficult situations. In our center we use H-ESD as rescue therapy during conventional ESD in case of unstable position, inability to achieving appropriate and safe knife angle, advanced submucosal fibrosis or thin submucosal layer and patient instability.

Aims & Methods

We retrospectively analyzed colorectal ESD performed in our centre between January 2014 and March 2023, colorectal lesions in inflammatory bowel diseases were excluded. Univariate and multivariate analyses were conducted to examine factors that may have influenced switch to H-ESD.

Results

A total of 281 colorectal ESDs for superficial neoplasms in 276 patients were considered. 160 patients (58%) were male with an average age of 68,9 years. In 55 (19,6%) cases ESD was switch to H-ESD.. 171 lesions were located in the colon (60.8 %) and 110 (39.1%) in the rectum; mean maximum diameter of the neoplasms was 35,9 mm (SD 18,4 mm). En bloc resection and complete resection (en bloc resection and R0) were achieved in 259 (92 %) and 245 (86 %) cases respectively.
On univariate analysis, the use of waterjet system-assisted knife (OR 0,3; 95% CI 0,17-0,57), underwater-ESD (OR 0,24; 95% CI 0,09-0,63), rectal localization (OR 0,17; 95% CI 0,07-0,40) and granular laterally spreading morphology (OR 0,40; 95% CI 0,21-0,75) were significantly associated to the achievement of complete ESD. Proximal colon localization (OR 3,9; 95% CI 2,08-7,30), severe submucosal fibrosis (OR 4,9; 95% CI 2,51-9,63), non-granular laterally spreading morphology (OR 2,31; 95% CI 1,27-4,21) and maximum diameter < 40 mm (OR 3,91; 95% CI 1,83-8,38) were related to the switch to H-ESD. On multivariate analysis only waterjet system-assisted knife use and U-ESD were significantly correlated with achievement of complete ESD; severe submucosal fibrosis and proximal colon localization resulted significantly related to the switch to H-ESD.

Conclusion

The use of waterjet system-assisted knife and underwater technique reduce the need to switch to H-ESD during endoscopic submucosal dissection of superficial colorectal lesions. Severe submucosal fibrosis and proximal location are risk factors for the need for the H-ESD switch.