Rectal Bleeding Research Articles

Clinical outcomes of hypofractionated radiotherapy (5x5 Gy) with a simultaneous integrated boost (5x6 Gy) in locally advanced rectal cancer.

60 Background: Hypofractionated RT (5x5 Gy) with or without subsequent chemotherapy is a standard of care used at the National Institute of Oncology, Warsaw, Poland, as a preoperative treatment for locally advanced rectal cancer. To maximize the chance of achieving a complete response (CR), when surgery is not planned or when there are clinically involved lymph nodes located outside the standard TME field, RT can be augmented with a simultaneous integrated boost (SIB) delivering 5x6 Gy. This report aims to evaluate the clinical outcomes of hypofractionated RT with a SIB in rectal cancer. Methods: From Dec 2018 to Sep 2022, 78 consecutive pts with a median age of 67 years (range 36–89 years), received hypofractionated RT utilizing the SIB-VMAT technique. The radiation dose fractionation was 5x5 Gy to the rectum, mesorectum and elective lymph nodes and a SIB to the GTV for a total dose of 30 Gy. Results: 30 pts (38.5%) received a SIB for the rectal tumor, of which 15 pts (19.2%) were deemed unfit for surgery, 10 pts (12.8%) refused surgical treatment, 3 pts (3.8%) had an oligometastatic disease, and 2 pts (2.6%) had an advanced primary tumor. 48 pts (61.5%) received a SIB to the clinically involved lymph nodes located outside the standard TME field. All 78 pts completed RT as planned without interruptions or dose modifications and with an acceptable toxicity profile. There was a 26.9% (n = 21) incidence of G2 toxicities (diarrhea, proctitis, skin toxicity, cystitis or lumbosacral plexus neuropathy) and a 3.8% (n = 3) incidence of G3 toxicities (diarrhea or proctitis). After a median follow-up of 917 days (range 33–1927 days), an assessment of response was conducted in 68 cases. In 94.1% (n = 64) there was no progression at the site irradiated to a dose of 30 Gy. After completion of RT, mr-TRG was evaluated in 28 pts. In 46.4% (n = 13) mr-TRG 1-2 (cCR) was achieved. Of the 24 pts qualified for the watch and wait strategy, 17 had follow-up. Of this group, 64.7% (n = 11) remained progression-free, and 11 pts had an adequate evaluation for cCR (imaging and endoscopy), resulting in a 63.6% (n = 7) rate of cCR. 43 pts underwent surgery, of which 97.7% (n = 42) had R0 resection. In 41 cases pathological TRG was assessed according to AJCC or Ryan, of which 41.4% (n = 17) achieved TRG 0-1 (pCR). In 40 cases the operated pts had no initial metastatic spread, among them 67.5% (n = 27) remain disease-free. 67 pts reported disease-related symptoms before RT. After treatment, 89.6% (n = 60) of those pts achieved symptomatic improvement in either rectal bleeding, bowel frequency, or pain control. Conclusions: Hypofractionated RT with SIB-VMAT delivering a dose of 30 Gy/25 Gy/5 fractions provides good local control and is a safe and viable option for both young and elderly patients who will not undergo surgery and for patients with involved lymph nodes located outside the standard TME field to maximize the chance of achieving CR.

Utilization of SDC2 gene in conjunction with SEPTIN9 gene methylation analysis for the diagnosis and efficacy assessment of colorectal cancer.

240 Background: SDC2 gene encodes the transmembrane proteoglycan molecule Syndecan-2. Syndecan-2 protein affects the proliferation, migration and invasion of colorectal cancer cells by participating in the regulation of cell adhesion, tissue differentiation and angiogenesis. Plasma methylated SEPTIN9 gene has been shown to be a sensitive and specific biomarker for the detection of CRC, which is involved in apoptosis, pseudopod projection, tumor cell migration and invasion. The aim of this study is to validate the value of SDC2 and S9 gene methylation detection in the diagnosis and efficacy evaluation of CRC. Methods: A total of 102 patients were enrolled in the study. The methylation levels of fecal SDC2 gene and blood SEPTIN9 gene were detected by fluorescence PCR. The clinical diagnostic accuracy of SDC2 kit was evaluated by patients with benign gastrointestinal lesions, gastrointestinal tumors and healthy subjects. Combined detection of SDC2 and S9 to improve the detection rate of CRC. SDC2m levels were analyzed in 26 patients with partial remission or stable disease after palliative treatment and 32 patients with complete remission after radical surgery. Results: The detection rate of SDC2 in patients was 0.0% for UC and CD, 66.7% for AA and 60.0% for NA, 25.0% for HOP. For 8 healthy subjects with negative colonoscopies, the true negative rate was 100%. The detection rates of GC and EC were 50.0% and 0.0%, respectively. Data from 72 patients with CRC were evaluated, with a sensitivity of 89.1% (41/46,95%CI 0.798-0.985) for patients with untreated CRC. The sensitivity of SDC2 was 46.2% (12/26,95%CI 0.256-0.667) in patients with partial response or stable disease after palliative treatment. The difference was statistically significant (P < 0.001). The sensitivity of S9 for CRC detection was 88.2% (15/17, 95%CI 0.712-1.053). By two tests, 94.1%(16/17, 95%CI 0.816-1.066) of CRC cases could be detected.The sensitivity was 89.1% (41/46 95%CI 0.798-0.985) in untreated CRC and 46.2% (12/26 95%CI 0.256-0.667) in patients with PR and SD after chemotherapy/radiotherapy/targeted/immunotherapy. The difference rate of SDC2m between two groups was statistically significant (P < 0.001). Among 46 untreated patients with CRC, 32 patients with positive SDC2m underwent radical surgery, of which 30 CR patients turned SDC2m test negative after surgery. We found reduced SDC2m in stool from patients with clinical benefit (CR+PR+SD). Conclusions: Detection of SDC2m in untreated CRC patients has high sensitivity and has the potential to become a non-invasive diagnostic tool for CRC. Combination of S9 and fecal SDC2 could improve the detection rate of SDC2 in non-dominant population. The methylation level of SDC2 may be helpful for postoperative follow-up of CRC after radical surgery, prediction of recurrence, and monitoring the efficacy of a series of palliative treatments for CRC.

Selective embolization can effectively alleviate bleeding symptoms in patients with anorectal hemangioma.

In this manuscript, I comment on the article by Pospisilova et al published in the recent issue of the journal, in which selective embolization was used to treat anorectal hemangioma, a rare disease causing lower gastrointestinal bleeding. Anorectal hemangioma can easily be mistaken; for example, the patient in this case was previously misdiagnosed with ulcerative colitis. Choosing the appropriate tests and understanding the typical manifestations of anorectal hemangioma under colonoscopy, computerized tomography, magnetic resonance imaging and other tests are beneficial for diagnosis. The patient presented with intermittent rectal bleeding despite treatment with azathioprine and mesalazine and required blood transfusions since the degree of rectal bleeding worsened. Selective embolization successfully alleviated the patient's bleeding symptoms and avoided the need for repeated blood transfusions. Tranexamic acid may be useful, considering that the patient still has bleeding symptoms and requires parenteral iron supplementation.

Lactobacillus fermentum 016 Alleviates Mice Colitis by Modulating Oxidative Stress, Gut Microbiota, and Microbial Metabolism

Ulcerative colitis (UC) is a chronic and progressive inflammatory gastrointestinal disease closely associated with gut microbiota dysbiosis and metabolic homeostasis disruption. Although targeted microbial therapies are an emerging intervention strategy for inflammatory bowel disease (IBD), the mechanisms by which specific probiotics, such as Lactobacillus fermentum 016 (LF), alleviate UC remain unclear. The current study evaluated the effects of LF supplementation on gut health in a basal model using C57BL/6 mice. Subsequently, the preventive effects and mechanisms of LF supplementation on DSS-induced UC were systematically investigated. According to our findings, LF supplementation revealed immunoregulatory capabilities with significantly altered gut the composition of microbiota and metabolic activities, particularly enhancing tryptophan metabolism. In the UC model, LF supplementation effectively mitigated weight loss, increased the disease activity index (DAI), and alleviated diarrhea, rectal bleeding, and colon shortening. Moreover, it reduced colonic pathological damage and histological injury scores. LF intervention improved antioxidant markers and intestinal mucosal barrier function with the activation of the Nrf2–Keap1 signaling pathway and regulation of systemic inflammatory markers, i.e., IL-1β, IL-6, TNF-α, IFN-γ, IL-4, and IL-10. Importantly, LF supplementation reversed metabolic disturbances by significantly increasing the abundance of beneficial genera (e.g., g_Dubosiella, g_Faecalibaculum, g_Odoribacter, g_Candidatus_saccharimonas, g_Roseburia, and g_Eubacterium_xylanophilum_group) and elevating tryptophan metabolites (e.g., melatonin, kynurenic acid, 3-indoleacetic acid, 5-methoxytryptophan, and 5-hydroxyindoleacetic acid). In conclusion, Lactobacillus fermentum 016 exhibits potential for regulating gut microbiota homeostasis, enhancing tryptophan metabolism, and alleviating UC, providing critical insights for developing probiotic-based precision therapeutic strategies for IBD.

Practitioner perspectives on symptomatic faecal immunochemical testing: a qualitative interview study.

Faecal Immunochemical Testing (FIT) is now core to the management of patients presenting in primary care with symptoms of possible colorectal cancer. Patients with a positive FIT (≥10μg Hb/g faeces) qualify for an urgent suspected cancer referral. FIT negative patients are typically managed in primary care or referred through routine pathways. To examine practitioners' experiences of delivering symptomatic FIT, identifying perceived benefits, disbenefits and implementation issues, to inform potential future service improvements. Qualitative interview study with primary and secondary care health professionals, from across the UK, involved in delivering symptomatic FIT pathways. 30 semi-structured interviews with professionals from a range of specialties. An iterative topic guide informed interviews while allowing freedom to explore novel lines of inquiry. Pseudo-anonymised transcripts were coded and themes identified and developed. Symptomatic FIT was seen to be beneficial for increasing confidence in clinical decision-making and enriching the pool of patients being definitively investigated for colorectal neoplasia. There were varying views on the impact of symptomatic FIT on workload with the burden of additional workload generally seen to be located in primary care. Concerns about current practice included over-use of FIT, burden of investigations in patients with false-positive results and diagnostic delays, for both cancer and benign disease. Uncertainties existed around management of patients with rectal bleeding, appropriate strategies for safety-netting, and the value of repeat FIT. Symptomatic FIT is largely seen as beneficial; however, health professionals would welcome further evidence and guidance around optimal application.

Small Bowel Leiomyoma Mimics Neuroendocrine Tumor on 68Ga-DOTATATE PET/CT.

A 57-year-old man with a 3-month history of lower abdominal pain and rectal bleeding with black stools underwent urgent abdominal CT, which revealed an ovoid hyperdense lesion in the ileum in the right iliac fossa. The prime differential was a midgut neuroendocrine tumor. Thus, the patient was referred for a 68Ga-DOTATATE PET/CT scan, which demonstrated intense activity in this lesion with no evidence of somatostatin receptor expression elsewhere. Surgical small bowel resection later revealed a small bowel leiomyoma, which was confirmed on immunohistochemistry analysis. This case demonstrates that leiomyomas can express somatostatin receptors and can be a false-positive on 68Ga-DOTATATE PET/CT scan.

Hemophagocytic lymphohistiocytosis in early pregnancy: A rare and fatal diagnostic challenge.

This report details the complexities of diagnosing and treating rapid-onset multisystemic hemophagocytic lymphohistiocytosis (HLH) during pregnancy, as evidenced by a fatal case in early pregnancy with severe hematological and obstetric complications. A 20-year-old pregnant woman in her second pregnancy presented at 8 weeks of gestation with abdominal pain, fever, and rectal bleeding. Laboratory tests revealed leukopenia, thrombocytopenia, and anemia, leading to immediate transfusion and intensive care unit admission. Despite intensive interventions, including vasopressors and antibiotics, the patient developed progressive organ failure, with disseminated intravascular coagulation, and suffered a fatal stroke. This critical case with severe complications demonstrates the diagnostic and treatment challenges of rapid-onset HLH in early pregnancy. Early and accurate differential diagnosis in obstetric emergencies is vital for conditions such as HLH. This case highlights the importance of multifaceted care in managing pregnant patients with complex, atypical presentations.

P0655 VTE thromboprophylaxis in patients with inflammatory bowel disease admitted to hospital; can we increase adherence with guidelines?

Abstract Background Incidence of venous thromboembolism (VTE) increases two to three folds in patients with inflammatory bowel disease (IBD), with hospitalisation, active disease and surgery as the major risk factors. VTE risk assessment and low molecular weight Heparin (LMWH) is recommended in all patients with IBD admitted to hospital1,2. The aim of the quality improvement project was to look at our practice, audit our adherence with guidance and where possible improve practice. Methods A tertiary centre audit was conducted from 1 September 2023 to 30 November 2023, to include all IBD patients ≥ 18 years, admitted for one day or more. Relevant data on VTE risk assessment, prescribing VTE prophylaxis, any missed doses and reasons were collected from electronic patient records. Patient identifiable details were omitted, and the audit was registered with institutional audit department. Audit outcomes were identified, interventions were implemented and a re-audit was conducted from 1 June 2024 to 30 June 2024. Results Out of 107 patients, VTE risk assessment was done in 61(57%) and LMWH was started in 79 (74%). Among 45 patients admitted with IBD flare, LMWH was started in 36 (80%). Among 28 patients where LMWH was not started, rectal bleeding(n=6) and ‘declined by patients’ (n=5) were the most common reasons. Other reasons highlighted included subdural haematoma (2), fall and suspected brain haemorrhage (1), major trauma (1), razor blade ingestion (1), diverticular bleed (1), lymphoma and low platelets (1), metastatic cancer and end of life (1). In patients started on LMWH (n=79), 76 (96%) received the first dose on Day 1, while 47 (59%) received all the recommended doses. ‘Declined by the patient’ was the most common reason for any missed dose (47%). The findings were disseminated with the relevant medical teams at team education sessions with opportunities to discuss the guidelines, wider issues including importance of giving LMWH despite rectal bleeding, and any concerns explored. After these initiatives, a re-audit was conducted. Out of 51 admissions, 45 (88.2%) had VTE risk assessments, and 44 (86.25%) started on LMWH, showing improvement in practice. Among 16 patients admitted with IBD flare, all had VTE risk assessment and started on LMWH. No thromboembolic events were identified during either of the audit periods. Conclusion Low compliance with thromboprophylaxis in IBD inpatients is commonly driven by fear of aggravating rectal bleeding and patient’s declining administration. Communication and raising awareness by education with relevant medical & nursing teams and patients can improve practice and thus prevent thromboembolic events.

P0748 Characterisation of Remission Levels in Patients with Ulcerative Colitis Treated with 5-Aminosalicylates: Results of the CARUC-ASA Prospective Multicentre Study

Abstract Background The treatment goals for chronic inflammatory bowel diseases are increasingly ambitious, targeting steroid-free remission, mucosal healing, and biomarker normalisation. In ulcerative colitis (UC), histological remission lowers risks of hospitalisation, cancer, and relapse. This study aims to describe remission levels in UC patients in symptomatic remission on first-line 5-aminosalicylic acid (5-ASA) and factors associated with remission. Methods This national, multicentre, prospective, phase 4 interventional study (ClinicalTrials.gov: NCT05992142) included UC patients in symptomatic remission, defined by a stool frequency score ≤ 1 and no rectal bleeding, on 5-ASA monotherapy (oral and/or rectal) for at least 6 months. Patients on corticosteroids, immunomodulators, biologics, or small molecules were excluded. Assessments included stool frequency, rectal bleeding, urgency, rectosigmoidoscopy (Mayo score, UCEIS), biopsies with the Geboes score assessed by central reading, faecal calprotectin (FCP), and MARS (Medication Adherence Report Scale) questionnaire. The different levels of remission were defined as followed: Complete Symptomatic Remission (CSR: PRO-2 = 0, no urgency), Endoscopic Remission (ER: Mayo 0–1, UCEIS 0–1), Complete Endoscopic Remission (CER: Mayo 0, UCEIS 0–1), Histological Remission (HR: Geboes 0–1), and FCP <150 μg/g; and Deep Remission as combined CCR, CER, and HR. In the absence of CER, physicians completed a questionnaire to investigate the reasons for not altering therapy. Results From December 2022 to February 2024, 198 UC patients (median age 50, 41% female) were enrolled from 14 centres. Montreal classifications were E1 (37%), E2 (44%), and E3 (18%). Treatment included oral 5-ASA (n=134, 68%), rectal 5-ASA (n=19, 9%), and a combination (n=45, 23%) with a median duration of 2.0 years (1.0 - 4.0). The median MARS-5 score was 24. ER was observed in 172/198 patients (87%), CER in 138/198 (70%), and HR in 156/196 (80%). Among those in ER and CER, 151/172 (88%) and 127/137 (93%) also had HR, respectively. Normal FCP was seen in 152/194 (78%) and in 128/153 (83%) of the HR subgroup. Deep remission was achieved in 47/197 (24%) of patients. The main reason for absence of deep remission was the absence of CSR (63%). The main reason for not altering treatment, despite the absence of CER, was physician reluctance in 37% of cases. 5-ASA administration form was significantly associated with ER (p=0.5, OR=2.9, 95%CI 1.1-7.3) for oral against combined. Conclusion In UC patients in clinical remission on 5-ASA, the majority achieved endoscopic and/or histological remission, suggesting that higher remission levels beyond clinical remission alone are attainable in selected, highly adherent patients on first-line therapy.

P1139 A real-world, observational study comparing the side effects of budesonide MMX with prednisolone and the resolution of symptoms in patients with mild to moderate ulcerative colitis

Abstract Background Budesonide MMX is indicated for the induction of remission in mild to moderate Ulcerative Colitis (UC) patients when 5-ASA treatment is not sufficient. There is limited real-world evidence of the relative side effects following budesonide MMX treatment using prednisolone as a benchmark and the time to resolution of symptoms following initiation of budesonide MMX exists. Methods Between July 2022 and August 2024, 27 patients with mild to moderate UC, based on clinical assessment, received the treatment. Patients initially completed a nurse-led questionnaire regarding their experiences with prior prednisolone treatment. Following subsequent flare therapy with budesonide MMX, patients completed a nurse-led follow-up questionnaire. Results A comparison of the patient-reported side effects is shown in Figure 1. Following prednisolone treatment, side effects were reported in 26% (n=7) of patients compared to 7% (n=2) following treatment with budesonide MMX. Mood disturbance was reported in 11% of patients following prednisolone and 4% following budesonide MMX. Sleep disturbance was reported in 7% of patients following both treatments. Moon face, weight gain, insomnia and acne were reported following prednisolone but not budesonide treatment. The time to resolution of symptoms following treatment with budesonide MMX is shown in Figure 2. Following 1 week of budesonide MMX flare therapy, rectal bleeding was resolved in 37% of patients rising to 67% by week 4. Stool frequency was resolved in 33% of patients in week 1 and 78% by week 4. Conclusion The overall incidence of patient-reported side effects was significantly higher (P<0.001) following prednisolone treatment compared with budesonide MMX. This suggests that budesonide MMX may be a better tolerated treatment option for patients with mild to moderate UC. Some prednisolone-related side effects were not reported following treatment with budesonide MMX. Of those that were, only 1 patient reported that they affected daily life, indicating that budesonide MMX may have a lower impact on patients’ daily activities.Either rectal bleeding or stool frequency was resolved in over three quarters of patients by week 4 of flare therapy with budesonide MMX.

P1065 Rapid onset of action of ustekinumab in patients with moderate to severe Ulcerative Colitis (RAUCU Study)

Abstract Background Real-world data on the speed of onset of ustekinumab (UST) in patients with ulcerative colitis (UC) are limited. Current information regarding early response in these patients comes from the UNIFI trial. The primary outcome of this study was to evaluate the response to UST in patients with moderate-to-severe UC by assessing PRO2 at 14 days after the first intravenous dose (6mg/kg). Methods A multicenter, prospective observational study was designed in patients ≥18 years old with moderate-to-severe UC (partial Mayo score ≥6) who initiated UST 6mg/kg between June 2023 and September 2024. Patients received a diary to record the stool frecuency and rectal bleeding during first 14 days after first dose of induction. The proportion of patients achieving the combined outcome of rectal bleeding score = 0 and stool frequency score ≤ 1 (PRO-2: patient-reported outcome 2 remission) was assessed. FC was measured at baseline and at day 7 and 14. Health-Related Quality of Life was evaluated using the disease-specific shortened Spanish version of the IBDQ (SIBDQ-9) at baseline and at 4 weeks. Patients with previous panproctocolectomy with ileostomy or pouch and those who had received cyclosporine within one month prior to starting UST were excluded. Descriptive statistics are presented as frequencies with percentages for categorical variables. Results A total of 54 patients were included across 14 hospitals in Spain. Of these, 29 (53.7%) were men, with a mean age of 54 (± SD 16.1) years. Thirty (55.6%) patients had pancolitis, 20 (37%) had left-sided colitis, and 4 (7.4%) had proctitis. Five (9.3%) patients were bio-naïve, 32 (59.3%) had previously received one biological therapy, 10 (18.5%) had received two, and 7 (13%) had received three biologics prior to starting UST. Mean decreases in stool frequency and rectal bleeding are shown in Figure 1. By day 14, 26% of patients had achieved clinical remission. No significant differences in clinical remission were observed based on disease extent (p = 0.11) or the number of prior biologics (p = 0.39). By day 7, 12/31 (38.7%) patients with baseline bloody stools had achieved a rectal bleeding score = 0. A reduction in FC >50% was observed in 14/48 (29%) patients by day 7 and in 20/47 (43%) patients by day 14. The SIBDQ9 average score was 54.9 (± SD 6.2) at baseline and 61.3 (± SD 7.4) at week 4. Conclusion One-quarter of patients with moderate-to-severe UC achieved clinical remission by day 14 following the first induction dose of UST. Nearly 40% of patients achieved a rectal bleeding score = 0 (PRO2) by day 7. A reduction in FC >50% was observed in 43% of patients by day 14.

DOP061 RO7790121 shows early and rapid symptomatic remission in the treatment of moderately to severely active ulcerative colitis – Findings from the phase IIb TUSCANY-2 trial

Abstract Background Tumor necrosis factor-like ligand 1A (TL1A) is upregulated in inflammatory bowel disease and believed to promote inflammation and intestinal fibrosis. RO7790121, an anti-TL1A antibody, showed promising results in the phase IIa TUSCANY trial.1 Here we report post-hoc analyses of patient-reported outcomes from the TUSCANY-2 trial. Methods This phase IIb, multicenter, randomized, double-blind, treat-through, dose-ranging study evaluated RO7790121 in patients (pts) aged 18–75 years with moderately to severely active ulcerative colitis (UC) (total Mayo score [MS] ≥6, endoscopic subscore ≥2). Pts were randomized to receive subcutaneous (SC) RO7790121 50mg, 150mg, 450mg or matched placebo (PBO) monthly during the 12-week induction period, and SC RO7790121 50mg, 150mg or 450mg monthly during the 40-week treat-through maintenance period. To assess efficacy of RO7790121 in supporting pts achieving early symptomatic improvement, rectal bleeding (RB), stool frequency (SF) and partial modified MS (RB+SF) were evaluated at baseline and Weeks 2, 4, 8, 12 and 14. The exploratory endpoint of symptomatic remission, defined as a RB subscore of 0 and a SF subscore of 0 or 1, was assessed throughout induction. Safety was assessed throughout the study. Results Overall, 245 pts received ≥1 dose of RO7790121 or PBO. At Week 2, pts receiving RO7790121 were more likely to report a RB subscore of 0 (34% RO7790121; 20% PBO) and less likely to report a RB subscore of 2 or 3 (25% RO7790121; 40% PBO) (Figure). Improvements in SF increased from Week 2 and throughout induction, with ~60% of pts receiving RO7790121 reporting a SF subscore of 0 or 1 at Weeks 12 and 14, vs ~40% for PBO. Greater rates of symptomatic remission were observed in pts receiving RO7790121 vs PBO throughout induction and from Week 2 (17.5% RO7790121; 8.9% PBO) (Table). Treatment-emergent adverse events (TEAEs) were reported during induction in 117/245 pts, the most common (reported in ≥5% of pts in any treatment group) were nausea, urinary tract infection and UC (highest in the 50mg arm), anemia (highest in the placebo arm) and fatigue, headache and pyrexia (highest in the 450mg arm). Serious TEAEs were reported in ten pts during induction (PBO=4; 50mg=3; 450mg=3); two were treatment related (PBO=1; 450mg=1). There were six treatment discontinuations due to TEAEs and a generally similar safety profile was observed during the maintenance period. Conclusion Greater and earlier improvements in RB and SF were observed in pts receiving RO7790121 vs PBO. These results indicate early symptom relief and a favorable safety profile for pts treated with RO7790121, supporting its further clinical development. RO7790121 is currently being evaluated in phase III studies (NCT06589986 and NCT06588855).

P0163 Novel IBD treatment: Small molecule oral GPRx agonists for Treg cell therapy

Abstract Background Our study has revealed that GPRx regulates gut DC migration to local draining lymph node to induce iTreg (Fig 1).1 To fulfil our drive to drug discovery and development for IBD (and other autoimmune diseases) program, we’ve rationally designed small molecule oral GPRx agonists that can induce gut antigen specific iTreg and intended to examine their efficacy utilizing TNBS induced acute IBD model.2-4 Methods C57/BL6 8-10 weeks old female mouse was intrarectally administered with 2,4,6-trinitrobenzene sulfonic acid (TNBS) in 30% ethanol solution through a special catheter to induce colitis, from day 0 to day 4. The tested drug was given via PO, from day 0 to day 4. The experiment ended on day 5. DAI (disease activity index) on weight loss, diarrhea, and rectal bleeding, was recorded daily, to determine disease severity. Colon was taken at the end of experiment for measurement and photography. Results A series of compounds have been tested using this in vivo TNBS induced acute IBD mouse model and some of them have shown excellent activity (Fig 2). Conclusion With this new MOA and first-in-class approach using small molecule oral GPRx agonists for Treg cell therapy, we could develop a different treatment for IBD (and other autoimmune diseases in general) patients than JAK inhibition or a4b7 inhibition or S1P1 activation, etc. The outstanding efficacy data described here together with their safety profile and acute/sub-acute toxicity results have provided us the confidence to a successful IND late-2025.

Effect of a high dose atorvastatin as adjuvant therapy to mesalamine in attenuating inflammation and symptoms in patients with ulcerative colitis: a randomized controlled pilot study

BackgroundUlcerative colitis (UC) is a chronic inflammatory disorder of the colon. Several preclinical studies investigated the beneficial effects of atorvastatin in colitis. Activation of sphingosine 1 phosphate (S1P)/ tumor necrosis factor-alpha (TNF-α)/ interleukin-6 (IL-6) pathways has been confirmed in the pathogenesis of UC and preclinical studies proved the efficacy of atorvastatin on these pathways.AimTo investigate the role of atorvastatin on S1P/TNF-α/IL-6 pathway in UC.MethodsPatients with mild to moderate UC were allocated into two groups in this pilot study. For 6 months, Group 1 (placebo group) received both a placebo and 1 g of mesalamine three times daily (t.i.d.). Group 2, (the atorvastatin group) received atorvastatin 80 mg once daily and 1 g of mesalamine t.i.d. A gastroenterologist evaluated the patients’ colitis severity by partial Mayo score index (PMS). Serum IL-6, S1P, TNF-α, nitric oxide (NO), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and fecal calprotectin were measured before and after treatment. Short Form 36 questionnaire (SF-36) was also assessed. A clinical response was defined as a decline in the rectal bleeding sub score of at least one point, and a decrease in PMS of at least two points. Clinical remission was defined as a PMS of less than 2 and the absence of any single sub score greater than 1.Primary outcomeDecreased PMS and improved quality of life.Secondary outcomeChange in the level of measured biomarkers.ResultsCompared to the placebo group (n = 24), the atorvastatin group (n = 23) exhibited a significant decrease in the level of IL-6 (p = 0.001), S1P (p = 0.0001), TNF-α (p = 0.003), NO (p = 0.0001), CRP (p = 0.015), ESR (p = 0.012), PMS (p = 0.013), and fecal calprotectin (p = 0.0003), and improved SF-36 (p = 0.006). In placebo group, the response rate was 83.33% (n = 20/24) for PMS, and the remission rate was 45.83% (n = 11/24). In the atorvastatin group, the response rate was 91.3% (n = 21/23), and the remission rate was 60.8% (n = 14/23) for PMS.ConclusionAtorvastatin could be an adjunctive therapy for patients with UC.Clinical trial registrationhttps://www.clinicaltrials.gov/, Identifier NCT05561062.

P0193 Oral administration of Sophora Flavescens-derived exosomes-like nanovesicles carrying CX5461 ameliorates DSS-induced colitis in mice

Abstract Background Ulcerative colitis (UC) belongs inflammatory disease with chronic and relapsing characterizations and increased-cancer risk. CX5461 has been demonstrated the important roles in autoimmune disease, immunological rejection, and macrophage-mediated vascular inflammation. However, whether CX5461 can serve as UC therapeutic drug remains unclear. The objective of this study is to investigate the therapeutic effect of oral administration of SFELNVs@CX5461 on DSS-induced colitis and its possible molecular mechanism. Methods SFELNVs were extracted and the morphology were charactered. The preparation of SFELNVs@CX5461 were electroporated and the loading efficiency of SFELNVs@CX5461 were calculated. We conducted the experiments using SFELNV, CX5461 and SFELNVs@CX5461 respectively. Proliferation and apoptosis of RAW264.7 cells were detected by flow cytometry according to the kits. C57BL/6 mice (8 weeks, 18-20g) were induced by 3% DSS in drinking water for a week to establish the colitis model. Then, DSS-induced C57BL/6 colitis mice models were orally administrated with SFELNVs@CX5461 (n=5, 80mg/kg) and SFELNVs (n=5, 80mg/kg) for 5 days. The body weight, consistency of stool, and rectal bleeding were measured each day. Finally, after sacrificing the mice, colons and main organs were obtained for the qPCR, HE, and IHC. Results Cellular uptake has shown that SFELNVs were targeted uptake by macrophages, thus increasing drug concentration. Additionally, Oral SFELNVs@CX5461 exhibited good safety and stability, as well as inflammation-targeting ability in the gastrointestinal tract of dextran sodium sulfate (DSS)-induced colitis mice. In vivo, Oral administration of SFELNVs and CX5461 could relieve mice colitis. More importantly, combined SFELNVs and CX5461 enhanced the treatment efficacy of mice colitis by inhibiting pro-inflammatory factors (TNF-α, IL-1β, and IL-6) expression and promoting M2 macrophage infiltration. Furthermore, SFELNVs promoted M2 polarization by miR4371c using miRNA sequencing. Our results suggest that SFELNVs@CX5461 represents a novel orally therapeutic drug that can ameliorate colitis, and a promising targeting strategy for safe and effective UC therapy. Conclusion In summary, SFELNVs@CX5461 represents a therapeutic strategy to UC with excellent biocompatibility due to the ability to enhance anti-inflammatory effects in vitro and in vivo to alleviate UC.

DOP091 Early serum infliximab levels predict outcomes in Acute Severe Ulcerative Colitis: results from PREDICT-UC

Abstract Background The utility of infliximab (IFX) therapeutic drug monitoring (TDM) in acute severe ulcerative colitis (ASUC) is unclear. We aimed to assess whether IFX levels are associated with outcomes in ASUC. Methods PREDICT-UC (NCT02770040) was a randomised controlled trial that compared dosing strategies in 138 steroid-refractory ASUC patients.1 Serum and faecal IFX levels were quantified by ELISA (MabTrack level infliximab, Essange Reagents, Netherlands) after conclusion of the trial and correlated with outcomes: IFX response by day 7 (Lichtiger score [LS]<10, with ≥3-point reduction and decrease in rectal bleeding and stool frequency ≤4/day); eventual response by day 14 (LS<10); and colectomy by month 3. Individual IFX clearance was estimated using a two-compartment pharmacokinetic model with fixed V1, V2 and Q. Results 681 serum IFX levels were available across 135 patients; 91 received an initial 5mg/kg and 44 an initial 10mg/kg IFX dose. 85 responded by day 7 and 17 required colectomy by month 3. Post-IFX serum levels were higher on days 1 and 3 (median ug/mL, IQR) in the 10mg/kg group (175.4, 137.2-202.7 and 116.3, 83.4-132.9) compared to the 5mg/kg group (91.8, 77.2-109.4 and 56.0, 46.0-67.0; each P<0.001). Day 1 and day 3 serum IFX levels were not significantly different in responders and non-responders. A higher day 3:day 1 serum IFX ratio predicted response (63.1%, IQR 56.0-72.1 vs 58.1%, IQR 51.6-62.8, P=0.006; AUC 0.67). A lower day 3 serum IFX level predicted colectomy (51.0, IQR 39.2-57.4 vs 69.0, IQR 51.1-101.7, P=0.003; AUC 0.23). IFX clearance using serum levels between days 1-7 was higher in non-responders compared to responders (0.72L/day, IQR 0.55-0.89 vs 0.56L/day, IQR 0.39-0.72, P<0.001) and in patients who had colectomy (P=0.011). Patients with high clearance (≥0.62L/day) were more likely to respond to an initial 10mg/kg vs 5mg/kg IFX dose (RR 1.50, 95%CI 1.01-2.23, P=0.046), and more likely to require colectomy if they received an initial 5mg/kg vs 10mg/kg dose (HR 4.81, 95%CI 1.09-21.37, P=0.039). In patients with high clearance who did not respond initially, response by day 14 was higher in those receiving a second 10mg/kg dose compared to 5mg/kg (10/26 [38%] vs 1/9 [11%]; RR 3.43, 95%CI 1.05-11.19, P=0.041). Day 1 and 3 faecal IFX correlated with IFX clearance (both rho=0.36, both P<0.001), CRP and the UCEIS (including bleeding and erosion/ulcer sub-scores). Conclusion Elevated day 3:day 1 serum IFX ratio was associated with IFX response by day 7. Early IFX clearance predicted IFX response and month 3 colectomy. High IFX clearance may be overcome by higher IFX dosing, resulting in improved response and reduced colectomy rates. Early IFX level quantification can help predict outcomes in ASUC.

P0691 Impact of Ozanimod (OZA) on Circulating Neutrophils: Results from the Phase 3 Japanese True North (J-TN) Study of Patients (Pts) With Moderately to Severely Active Ulcerative Colitis (UC)

Abstract Background OZA was approved for treatment (tx) of moderately to severely active UC in adults based on TN study results. Increases in circulating neutrophils are an indicator of systemic inflammation, and increased infiltration of activated neutrophils in intestinal mucosa contributes to mucosal inflammation in inflammatory bowel disease (IBD). Human neutrophil elastase-mediated degradation of calprotectin (CPa9-HNE) is a measure of neutrophil activity. Methods The effect of OZA on neutrophils and CPa9-HNE levels and the association of neutrophils and CPa9-HNE levels with OZA efficacy were assessed in all J-TN pts. During the 12-wk induction period, pts were randomized to OZA 0.46 mg, OZA 0.92 mg or placebo (PBO). OZA clinical responders at Week (W) 12 were continually assigned treatment to OZA or PBO for maintenance through W52. Circulating neutrophil and CPa9-HNE levels were analyzed at baseline and throughout the induction periods. Neutrophil and CPa9-HNE levels were explored by clinical response status at W12 and W52. Results Absolute neutrophil counts remained within the normal range throughout the induction and maintenance periods. Circulating neutrophil levels decreased with OZA 0.46 mg and 0.92 mg during induction and were significantly lower than those observed with PBO. Neutrophil levels significantly decreased by 2 weeks of treatment with OZA at 0.92mg dose groups compared to baseline. Circulating neutrophils remained low with continued OZA during induction period. Decreases in circulating neutrophil levels were greater in patients with clinical response starting at Week 9 (responders) than those without clinical response at Week 12 (nonresponders) in both dose Oza-treated pts groups during the induction period. CPa9-HNE levels also decreased with OZA 0.92 mg during induction period as compared with PBO and baseline. However, No significant difference of circulating Cpa9-HNE levels between responder vs nonresponser with Oza treatment at week 12. Baseline NEUT was positively associated with baseline stool frequency, 9-point Mayo and CRP. Baseline Cpa9-HNE levels was positively associate with baseline CRP. Furthermore, CfB NEUT was positively associated with CfB Physician Global Assessment, Rectal Bleeding and CRP with Oza 0.92mg treatment at week 12. CfB NEUT and Cpa9-HNE was positively associated with CfB CRP with both dose Oza treatments at week 12. Conclusion Circulating inflammatory markers of neutrophils and CPa9-HNE decreased with ozanimod use. These findings support the use of circulating neutrophils and CPa9-HNE, a measure of neutrophil activity, as pharmacodynamic markers for ozanimod treatment effect and potential disease markers in patients with UC.

P0580 Efficacy and safety results of tulisokibart re-induction treatment in participants with ulcerative colitis in the Phase 2 ARTEMIS-UC clinical trial

Abstract Background Tulisokibart is a monoclonal antibody that targets tumor necrosis factor-like cytokine 1A (TL1A), a regulator of inflammation and fibrosis in inflammatory bowel disorders such as ulcerative colitis (UC). The Phase 2 ARTEMIS-UC study demonstrated a significantly higher proportion of tulisokibart vs. placebo participants achieving clinical remission after 12 weeks of treatment1. This analysis evaluates the effects of re-induction treatment in participants who were non-responders during the initial 12-week induction period of the study. Methods Participants (≥18 years) of moderate to severe active UC, with conventional or advanced treatment failure, were randomized (1:1 ratio) to placebo or the 12-week induction treatment (intravenous tulisokibart 1000 mg, Day 1 and 500 mg, Weeks 2, 6, and 10). The study population consisted of 2 cohorts based on a genetic diagnostic test (Dx) assessing likelihood for responding to anti-TL1A treatment. Cohort 1 included participants stratified by Dx results while Cohort 2 included only Dx positive participants. Cohort 1 is the population used in these post-hoc analyses evaluating induction non-responders. Induction non-responders in either the tulisokibart or placebo groups were assigned to an open label 12-week re-induction with aforementioned induction dosing regimen (non-responders are defined as participants who did not achieve reduction of ≥2 points and ≥30% in modified Mayo score from baseline, accompanied by a reduction ≥1 in rectal bleeding sub score or absolute rectal bleeding sub score ≤1 at week 12). Efficacy and safety were assessed following the re-induction treatment at Week 26. Results In Cohort 1, 67 and 68 participants were randomized to receive placebo or tulisokibart induction treatment, respectively. At Week 14, 41 (placebo) and 21 (tulisokibart) induction non-responders entered re-induction and received 12-week open label tulisokibart treatment. At Week 26, 48% and 63% of participants who received initial 12-week of tulisokibart treatment (total 24-week tulisokibart treatment) and 63% and 76% of participants who received initial 12-week placebo treatment (total 12-week tulisokibart treatment) achieved symptomatic improvement and symptomatic response, respectively (Table). Re-induction with tulisokibart was well tolerated with no serious AEs or discontinuations due to AEs and no new safety signals (Table). Conclusion Re-induction treatment with tulisokibart is effective in participants who did not respond to initial induction treatment. Additionally, up to two tulisokibart induction regimens totaling 24 weeks is well tolerated with no new safety signals identified.

DOP083 «Sonorescue»-treatment response in acute severe Ulcerative Colitis measured with ultrasound

Abstract Background First line medical treatment in acute severe ulcerative colitis (ASUC) is intravenous corticosteroids. Patients with insufficient response receives rescue treatment. The decision is made by the treating physician and is based on disease severity and improvement in stool frequency, rectal bleeding, biochemical parameters, and general well-being. Gastrointestinal ultrasound (GIUS) can be used to find the degree of inflammation in ulcerative colitis, but can it be used to detect the lack of treatment response in ASUC? Methods Patients with ASUC were included from June 2020 to Nov 2024 at two hospitals in Bergen, Norway. They were examined with GIUS prior to treatment with iv corticosteroids and after 2-3 days of treatment. Patients with a normal GIUS, endoscopic MAYO<2 or isolated proctitis were excluded. Bowel wall thickness, bowel wall vessel density with colour Doppler, loss of haustration and fatty tissue reaction was registered for every segment of the colon as well as an activity score based on these parameters1. The two main outcomes of the study were the clinical decision to give rescue with infliximab and Lindgren’s criteria for the risk of colectomy2. Results In total 33/64 patients received rescue treatment. In the sigmoid colon the wall was 4.3±1,3 mm in patients receiving rescue treatment and 2.5±1mm in the others (p<0.001). There was also a significant difference in vessel density, haustrations, and fatty tissue reaction. Furthermore, there were significant differences for wall thickness in all the other colon segments including the sum of these measurements. The full score based on all parameters was 15.2±5,2 vs 8.3±5,3 (p<0.001). The areas under the receiver operating curve (AUROC) for wall thickness in the sigmoid colon, total bowel wall thickness and the activity score were 0.87 (0.79-0.96), 0.84 (0.75-0.94) and 0.84 (0.74-0.94), respectively. According to Lindgren’s Criteria 23/64 had a high risk for colectomy. AUROCs for the same parameters were 0.86(0.75-0.96), 0.88(0.80-0.97) and 0.85 (0.76-0.94), respectively. If a low risk of colectomy is required a total bowel wall thickness ≥ 9mm at day 2-3 predicts the risk of colectomy with 100% sensitivity and 50% specificity. For the single measurement in the sigmoid colon and a corresponding sensitivity of 96% (cut off 2.4 mm) the specificity will wall fall to 32.5%. Conclusion GIUS can be used to detect insufficient treatment response in ASUC already after 2-3 days of intravenous corticosteroids which confirms previous findings3. A single measurement in the sigmoid colon could be sufficient, but the combined sum of bowel wall thickness in all colon segments could be better for selecting patients that should get rescue treatment.

P0538 Histologic remission predicts relapse in patients with Ulcerative Colitis

Abstract Background Histologic remission is not currently established as a formal treatment target in ulcerative colitis (UC). However, growing evidence indicates that histologic activity is associated with increased rates of relapse, hospitalization, and colectomy1. We aimed to evaluate the predictive value of histologic remission in UC patients and its potential role in guiding disease management. Methods A unicentric retrospective study was conducted, including all patients with UC who achieved endoscopic remission (Mayo Endoscopic Subscore ≤1) on colonoscopy between January 2020 and June 2023. Histologic remission was defined as the absence of neutrophils in the lamina propria or epithelium. Clinical activity was assessed using patient reported outcomes (PRO-2) for stool frequency or rectal bleeding (PRO-2>0). Clinical relapse was defined as the need for therapy optimization, switching therapy, or corticosteroid use. Factors associated with relapse were assessed using chi-square tests for categorical variables and t-tests for continuous variables. A binary logistic regression model was applied to further evaluate these associations. Results A total of 90 patients were included (58% male; mean age: 55 ± 15 years), with a median disease duration of 15±9 years. Among patients in endoscopic remission, 61% had a Mayo endoscopic subscore of 0, and 39% had a score of 1. Histologic remission was observed in 74% of patients (table 1). During follow-up, 23% (n=21) of patients experienced a relapse. Histologic activity was statistically associated with a higher risk of clinical relapse (p=<0.001). No differences were found in relapse rates between patients with Endoscopic Mayo Subscores of 0 or 1 (p=0.073). Younger age (p=0.009), shorter disease duration (p=0.002), and previous failure of advanced therapies (p=0.049) were also associated with a higher risk of clinical relapse. Multivariate analysis identified histologic remission as the sole independent predictor of relapse (odds ratio: 0.173, 95% CI: 0.053–0.571, p=0.004). Conclusion These observational data suggest that histologic remission may predict clinical relapse in patients with UC. In this cohort, histologic remission was identified as the sole predictor of relapse, outperforming endoscopic remission. References Lobatón T, Bessissow T, Ruiz-Cerulla A, De Hertogh G, Bisschops R, Guardiola J, Van Assche G, Vermeire S, Ferrante M. Prognostic value of histological activity in patients with ulcerative colitis in deep remission: A prospective multicenter study. United European Gastroenterol J. 2018 Jun;6(5):765-772. doi: 10.1177/2050640617752207.