Lancet Oncol Research Articles

CLARITY-Gastric 01: A randomized phase 3 study of AZD0901, a Claudin18.2 (CLDN18.2)-targeted antibody-drug conjugate, in second- or later-line (2L+) advanced gastric or gastroesophageal junction cancer (GC/GEJC).

TPS507 Background: GC/GEJC is the fifth most commonly diagnosed cancer and the fourth leading cause of cancer-related death worldwide (Sung H, et al. CA Cancer J Clin 2021). Prognosis is poor in GC/GEJC; median overall survival (OS) is less than 10 months in the 2L setting and less than 6 months in the 3L+ setting (Wilke H, et al. Lancet Oncol 2014; Shitara K, et al. Lancet Oncol 2018). New treatment options are needed. CLDN18.2 has emerged as a new therapeutic target in GC/GEJC. AZD0901, a potential first-in-class CLDN18.2-targeted antibody conjugated to monomethyl auristatin E via a protease cleavable linker, has demonstrated clinical activity in a Phase 1 study in advanced GC/GEJC (Xu R-H, et al, J Clin Oncol 2023). CLARITY-Gastric 01 (NCT06346392) is a randomized, open-label, sponsor-blinded, global Phase 3 study that will assess the efficacy and safety of AZD0901 versus investigator’s (INV) choice of therapy after ≥1 prior therapy for advanced GC/GEJC expressing CLDN18.2. Methods: Participants (pts) will be randomized 1:1:1 to AZD0901 dose level 1 intravenous (IV) every three weeks (Q3W; Arm 1), AZD0901 dose level 2 IV Q3W (Arm 2), or INV choice of therapy (2L: ramucirumab [ram] + paclitaxel [PTX], PTX, or docetaxel [for pts with contraindication to ram only]; 3L+: irinotecan, TAS-102 [excluding China], or apatinib [China only]; Arm 3). One AZD0901 arm (Arm 1 or Arm 2) will stop enrollment after a pre-planned dose selection decision. Randomization will continue in a 1:1 ratio to the two remaining arms (selected AZD0901 dose arm and Arm 3). Eligible pts must have histologically confirmed, unresectable, locally advanced or metastatic GC/GEJC (non-HER2+, CLDN18.2 expression). Pts must have disease progression on/after ≥1 prior regimen (including platinum-fluoropyrimidine) and have an ECOG performance status of 0 or 1. Pts previously treated with CLDN18.2-targeting therapy (other than naked monoclonal antibody) are excluded. Recruitment has begun and pts are planned to be enrolled across 16 countries in Asia, Europe, and North America. Dual primary endpoints are progression-free survival (PFS; intent-to-treat [ITT] pts) and OS (3L+ pts). The secondary endpoints include OS (ITT pts), PFS (3L+ pts), objective response rate and duration of response (ITT and 3L+ pts), and safety/tolerability. Efficacy data will be summarized and analyzed in the ITT population. All efficacy endpoints will assess the selected AZD0901 dose arm versus Arm 3. Safety and tolerability will be assessed in all pts who receive ≥1 dose of study treatment. Previously presented at European Society for Medical Oncology - Gastrointestinal Cancers Congress 2024, Final Publication Number: 495TiP, Kohei Shitara et al. Reused with permission. Clinical trial information: NCT06346392 .

Thank you to The Lancet Respiratory Medicine's clinical and statistical peer reviewers in 2024.

Thank you to The Lancet Respiratory Medicine's clinical and statistical peer reviewers in 2024.

Correction to Lancet Public Health 2024; 9: e684–99

Correction to Lancet Public Health 2024; 9: e684–99

Thank you to The Lancet Public Health's reviewers in 2024.

Thank you to The Lancet Public Health's reviewers in 2024.

Intra-tumoral CD40 antibody with irreversible electroporation (IRE) in locally advanced pancreas cancer.

TPS787 Background: Irreversible electroporation (IRE) is a form of non-thermal tumor ablation that is currently in clinical use for selected patients with locally advanced pancreatic cancer (LAPC). Preclinical and clinical studies have suggested that IRE generates an in situ vaccination effect by releasing tumor neoantigens in the setting of inflammation. Our published data from syngeneic, orthotopic mouse models demonstrate that combination of IRE with local CD40 agonism induces systemic anti-tumor immune effects, including neoantigen-specific T-cell responses and inhibition of liver metastases (1). Mitazalimab, a second-generation CD40 agonistic IgG1 mAb, has demonstrated promising clinical antitumor activity when delivered systemically in combination with modified FOLFIRINOX in metastatic pancreatic cancer (2). Methods: This clinical trial (NCT06205849) is a phase I dose-escalation study of an agonistic CD40 antibody (mitazalimab) injected intratumorally at the time of surgical IRE in patients with LAPC who have not demonstrated distant disease progression after a minimum of 4 months of optimal standard of care (SOC) chemotherapy (modified FOLFIRINOX). The doses investigated are 25, 75 (starting dose), and 200 µg/kg, in an interval 3+3 design, with a maximum of 18 subjects. The primary endpoints are the rates of dose limiting toxicities (DLTs) and treatment-emergent adverse events (AEs). The secondary endpoints are progression-free survival (PFS) and overall survival (OS). At a liberal alpha of 25%, appropriate for this proof-of-concept early phase study, we have 80% power to detect an improvement in PFS from 12 months (based on prior studies of IRE alone) to 18 months, with an expected 16 evaluable subjects and an anticipated 11 observed events, using a one-sided log-rank test. Candidate neoantigens will be identified by profiling nucleic acids derived from tumor biopsies obtained intraoperatively prior to IRE using our Identification-Prioritization-Validation (IPV) bioinformatic pipeline (3). Blood samples will be collected pre-operatively and 12-weeks post-operatively to evaluate for evidence of neoantigen-specific T-cell reactivity and other neoantigen-independent analyses of immune response. We have enrolled two patients since the study opened in September 2024. 1. J. Shankara Narayanan et al., JITC 2023. 2. J. Van Laethem et al., Lancet Oncol 2024. 3. A. Miller et al., Sci Transl Med. 2024. Clinical trial information: NCT06205849 .

Comparative restricted mean survival time (RMST) analysis of survival in advanced hepatocellular carcinoma (aHCC) from pivotal phase III trials: IMbrave-150, ORIENT-32, CARES-310, HIMALAYA, and CM-9DW.

597 Background: In advanced hepatocellular carcinoma (aHCC), the evaluation of overall survival (OS) and progression-free survival (PFS) through restricted mean survival time (RMST) provides a nuanced understanding of treatment efficacy. The RMST analysis serves as a valuable complement to the hazard ratio (HR) analysis, offering insights into the average survival time over a specified period. This study compares RMST analyses of OS at 24 and 36 months, and PFS at 12 and 18 months, across five pivotal phase III trials: IMbrave-150, ORIENT-32, CARES-310, HIMALAYA, and CM-9DW. Methods: Data from the experimental arms of the five phase III trials were analyzed. The RMST was calculated using the area under the Kaplan-Meier survival curves up to the specified time points. Specifically, OS was evaluated at 24 and 36 months, and PFS at 12 and 18 months. The RMST provides an estimate of the average time that patients survive (for OS) or remain progression-free (for PFS) within a specific timeframe. Kaplan-Meier survival curves were digitized if not available in raw form, and the area under the curve (AUC) was computed using numerical integration methods. RMST values were extracted from the AUC for the specified periods. This approach accounts for censored data and provides a robust comparison of survival times across different treatment groups. Results: The results for OS RMST at 24 and 36 months and PFS RMST at 12 and 18 months are summarized in the table. Conclusions: Angiogenesis inhibitor + immune checkpoint inhibitor combinations (Atezolizumab + Bevacizumab; Sintilimab + IBI305) provide the most favorable RMST outcomes in terms of OS and PFS. Restricted mean survival time (RMST) comparison of OS and PFS (months). aHCC 1L Phase III Trials Treatment Arm OS 24m OS 36m PFS 12m PFS 18m IMbrave-150 1, 2 Atezolizumab + Bevacizumab 17.50 22.79 9.69 13.29 ORIENT-32 3 Sinitilimab + IBI305 17.01 21.09 9.18 12.54 CARES-310 4 Camrelizumab + Rivoracenib 16.34 19.75 9.29 12.14 HIMALAYA 5, 6 Tremelimumab + Durvalumab 15.36 18.76 8.95 12.02 CM-9DW 7, 8 Nivolumab + Ipilimumab 15.87 20.08 8.74 11.78 1 Finn et al. N Engl J Med 2020;382:1894-905; 2 Cheng et al. J Hepatol 2022;76:862-873; 3 Ren et al. Lancet Oncol 2021;22:977–90; 4 Qin et al. Lancet 2023;402:1133–46; 5 Abou-Alfa et al. NEJM Evid 2022;1(8):EVIDoa2100070; 6 Sangro et al. Ann Oncol 2024;35:448-457; 7 Galle et al. J Clin Oncol 2024;42(suppl 17):abstr LBA4008; 8 Decaens et al. Ann Oncol 2024;35:S657.

Thank you to The Lancet Oncology's reviewers in 2024.

Thank you to The Lancet Oncology's reviewers in 2024.

Thank you to The Lancet HIV's statistical and peer reviewers in 2024.

Thank you to The Lancet HIV's statistical and peer reviewers in 2024.

Performance of the 2023 diagnostic criteria for MOGAD: real-world application in a Chinese multicenter cohort of pediatric and adult patients

BackgroundThe clinical phenotypes of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) have been found to overlap with several other diseases. The new criteria proposed in 2023 were designed to better identify the disease but require validation across various populations to ascertain its clinical utility. We aimed to investigate the diagnostic performance in phenotypically diverse patients.MethodsThis multicenter study retrospectively included adult and pediatric patients who were hospitalized for a first suspected demyelinating event and tested positive for MOG immunoglobulin G (IgG) during the acute phase. The 2023 Lancet Neurology criteria were assessed against the benchmark of empirical clinical diagnosis, and the 2018 JAMA Neurology and Journal of Neuroinflammation criteria were also evaluated for comparative analysis.ResultsAmong the 291 eligible patients (82 adults, 209 children), 282 (96.9%) were clinically diagnosed as definite MOGAD (77 adults, 205 children), while 262 (90.0%) fulfilled the 2023 diagnostic criteria (78 adults, 184 children). A total of 265 patients met the criteria for core clinical demyelinating events, and 76 (26.1%) had serum clear positive MOG-IgG (≥ 1:100). The sensitivity of the 2023 criteria was 0.91 (adults vs. children = 0.97 vs. 0.89), the specificity was 0.56 (adults vs. children = 0.40 vs. 0.75), positive likelihood ratio was 2.06 (adults vs. children = 1.62 vs. 3.57), and negative likelihood ratio (NLR) was 0.15 (adults vs. children = 0.06 vs. 0.14). Additionally, 264 and 256 cases were classified as definite MOGAD by the 2018 JAMA Neurology and Journal of Neuroinflammation criteria, respectively. Compared to the 2023 diagnostic criteria, the 2018 JAMA Neurology criteria demonstrated similar diagnostic performance. However, the 2018 Journal of Neuroinflammation criteria exhibited comparable sensitivity (0.92, adults vs. children = 0.96 vs. 0.89), higher specificity (1.00, adults vs. children = 1.00 vs. 1.00) and better NLR (0.09, adults vs. children = 0.04 vs. 0.11).ConclusionsThe 2023 criteria demonstrated good sensitivity in adult and pediatric patients in China yet modest specificity. Close follow-up is needed for patients with atypical phenotypes but high-titer MOG-IgG to avoid underdiagnosis.

P0975 Cost-effectiveness analysis of anti-TNF treatment from diagnosis for patients with moderate and severe Crohn’s disease: an analysis using data from the PROFILE trial

Abstract Background The PROFILE trial in patients with newly-diagnosed Crohn’s disease demonstrated that “top-down” therapy, with combination infliximab and immunomodulator from diagnosis, provided superior efficacy and a better safety profile over a one-year follow-up period compared to an “accelerated step-up” approach. The current study aims to evaluate cost-effectiveness by assessing the healthcare cost and health outcomes associated with starting anti-TNF medication as soon as possible after diagnosis. Methods A de novo Markov model was developed to model the cost-effectiveness of using a “top-down” compared to “accelerated step-up” strategy in adults newly-diagnosed with moderate and severe Crohn’s disease. The model structure included three possible mutually exclusive health states (active disease, inactive disease and death). Use of infliximab and adalimumab from diagnosis was modelled with biosimilar costs based on average real-world UK contract drug costs ascertained from 20 PROFILE trial sites in 2024. Parameters were informed by individual patient data from PROFILE and data from the published literature. Key model outcomes included healthcare costs (drug acquisition, drug administration, surgery, hospitalisation, disease management) and health outcomes (quality-adjusted life years gained [QALYs]) measured over a 5-year time horizon. Results The base case cost-effectiveness analysis indicates that a “top-down” strategy dominates over an “accelerated step-up” approach. Initiating infliximab from the point of diagnosis yields greater clinical benefits, with an incremental gain of 0.17 QALYs per patient over a 5-year period, and is less costly, saving £1034 per patient over the same time frame. Similar clinical benefits were obtained when modelling use of adalimumab treatment from diagnosis, with even greater cost savings, totalling £9412 per patient over 5 years. Sensitivity analysis further supports robustness of the “top-down” approach, showing it to be the most cost-effective option in 97.6% of model simulations, based on a commonly applied UK decision-maker willingness-to-pay threshold of £30000 per QALY. Conclusion This health economic analysis demonstrates that “top-down” treatment with anti-TNF therapy from diagnosis results in lower healthcare resource use compared to an “accelerated step-up” strategy. The economic benefits align with improved clinical outcomes, as early, effective treatment better controls inflammation. Patients experience longer periods in remission, fewer disease-related flares, and enhanced quality of life. In newly-diagnosed patients with moderate and severe Crohn’s disease, “top-down” treatment with anti-TNF therapy is more efficacious, safer and cost-efficient than an “accelerated step-up” treatment strategy. References Noor NM et al. A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn’s disease (PROFILE): a multicentre, open-label randomised controlled trial. Lancet Gastroenterol Hepatol. 2024 May;9(5):415-427.

P1120 ‘Early’ surgery for ileocaecal Crohn’s disease: a study of the patient perspective

Abstract Background Surgery for Crohn’s disease (CD) is considered when medical therapy is unsuccessful. However earlier bowel resection may offer more stable remission for localised luminal ileocaecal disease. The adoption of earlier surgery into practice comes with challenges, reflected by the difficulty in recruiting participants into trials of surgical treatment. We aimed to establish the acceptability of, and potential barriers to, early surgery from a patient perspective through a multicentre qualitative study. Methods Patients with ileocaecal CD from 8 centres across the United Kingdom (including both specialist IBD centres and non-specialist hospitals) were recruited, using purposive sampling, to participate in semi-structured interviews. Interviews were audio-recorded and transcribed. Recruitment continued until data saturation was achieved. Data were analysed thematically; 50% of the data were coded independently by two researchers. Results Twenty-nine participants were interviewed (14 males, 17 with a previous bowel resection, median time since diagnosis 6 years (8 months – 10 years), median age 34 years (22-71), 4 non-white patients). The themes and subthemes identified are summarised in Table 1. Participants with a previous bowel resection reported that surgery was not offered to them until they had tried several drugs or until disease complications had ensued; they described a poor quality of life prior to their operation. Surgery-naïve patients viewed a bowel resection as a last resort measure. There were many accounts of surgery being framed negatively by clinicians when offering treatment. Only one patient was aware of the benefits of early surgery. However, even participants with a good surgical outcome viewed surgery negatively; patients generally wanted to avoid an operation because of the risk of a stoma and the potential for complications. Conclusion This is the first study investigating the gap between the evidence-base and clinical practice around the management of luminal ileocaecal CD. Patients’ views of treatment are influenced by their clinicians’. In our previous study investigating the clinician perspective on early surgery, clinician-participants were proponents of early surgery. This is in contrast with the findings of this study where patients reported being offered a resection late in the pathway. Surgery should be discussed sooner with patients, ideally as part of a multidisciplinary team consultation. It is possible that patients will still prefer medical therapy to surgery. This has implications for the design of future trials comparing surgery to medical therapy for ileocaecal CD – recruitment into randomised trials may remain difficult in the face of strong patient (and/or clinician) preferences. References Ponsioen CY, de Groof EJ, Eshuis EJ, Gardenbroek TJ, Bossuyt PMM, Hart A, et al. Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn’s disease: a randomised controlled, open-label, multicentre trial. Lancet Gastroenterol Hepatol. 2017;2(11):785-92. Husnoo N, Gana, T, Hague AG, Khan Z, Morgan JL, Wyld L, Brown SR. Is early bowel resection better than medical therapy for ileocolonic Crohn’s disease? A systematic review and meta-analysis. Colorectal Dis. 2023; 25(6): 1090-1101. Husnoo N, Morgan JL, Wyld L, Brown SR, P230: The challenges of implementing early surgery for terminal ileal Crohn’s disease – a qualitative study of the clinician perspective, British Journal of Surgery, Volume 111, Issue Supplement_2, March 2024, znae046.119,

P0391 The impact of point of care ultrasound on time to initiating advanced therapy in IBD (GUIDE-IBD): A randomised controlled trial

Abstract Background Intestinal ultrasound is an accurate tool for assessing inflammatory bowel disease activity1. Previous studies showed point-of-care ultrasound (POCUS) can impact treatment decisions in 48% of appointments2. Early diagnosis and treatment improves outcomes in Crohn’s disease (CD). We aimed to investigate if POCUS in the IBD clinic led to earlier initiation of advanced therapies using a randomised controlled trial. Methods Patients attending an IBD clinic at a UK tertiary referral centre with known or suspected IBD (with a high likelihood) were eligible. During the primary clinic appointment clinicians’ investigation and treatment decisions were recorded. Immediately following this they were randomised 1:1 to POCUS or standard of care (SOC). The POCUS group then had further review with an option to alter treatment decisions. The primary end-point was time to initiating definitive therapy (in days) (new/changed immunomodulator, advanced therapy or surgery only). Secondary end-points included clinical score (HBI, SCCAI), calprotectin and patient tolerability. Patients were followed for 12 months. Results 122 patients were enrolled between 1st June and 1st November 2023. Median age was 25 years (16-79) and 50% male with a final diagnosis of 87 CD, 23 UC, 4 IBD-U and 8 non IBD (new referrals). 63 had POCUS and 59 SOC. POCUS was performed by one of two sonographers (one gastroenterologist and one radiologist). 65 (53%) were on advanced therapy or immunomodulators at baseline. 99 (81%) had advanced therapy, immunomodulators or surgery during the study period. Mean time to definitive treatment decision was 43 days with POCUS compared to 92 days in SOC (p<0.01). 65 (53%) patients had a change of, or started a new therapy and mean time to treatment initiation was also significantly shorter in the POCUS group, 75 days, compared to SOC, 131 days (p=0.033). In a sub-group of 20 new referrals, 12 were diagnosed with IBD. Mean time to treatment initiation was shorter with POCUS (82 vs 151 days). Steroid prescriptions at the baseline appointment were significantly higher in the POCUS group, 11/63 vs 2/59 (p = 0.012). Any change to treatment in the POCUS group occurred in 29/63 (46%) patients. Scans took an average of 7.5 minutes with 100% patient acceptability. Conclusion POCUS leads to earlier IBD-related decision making which translates into earlier initiation of effective therapy. This should, in turn, lead to improved care with shorter time to remission and reduced complications. Pathways to incorporate POCUS into routine clinical practice to optimise its effectiveness need further evaluation. This will require collaborative training and working across multiple specialties to effectively deliver this service. References (1)Taylor SA, Mallett S, Bhatnagar G, et al. Diagnostic accuracy of magnetic resonance enterography and small bowel ultrasound for the extent and activity of newly diagnosed and relapsed Crohn’s disease (METRIC): a multicentre trial. Lancet Gastroenterol Hepatol. 2018;3(8):548-558. doi:10.1016/S2468-1253(18)30161-4 (2)Bots S, De Voogd F, De Jong M, et al. Point-of-care Intestinal Ultrasound in IBD Patients: Disease Management and Diagnostic Yield in a Real-world Cohort and Proposal of a Point-of-care Algorithm. J Crohns Colitis. 2022;16(4):606-615. doi:10.1093/ecco-jcc/jjab175

P0962 Relationship between Total Corticosteroid Dose Prior to Advanced Therapy Induction and Primary Non-Response

Abstract Background The PROFILE study1) highlighted the importance of top-down treatment with Advanced Therapy (AT) in Crohn’s disease. In ulcerative colitis (UC), the corticosteroid (CS) treatment cascade remains crucial for selecting AT candidates. CS treatment efficacy decreases with repeated use, affecting therapeutic outcomes of GMA and carotegrast. We hypothesized that total CS dose impacts subsequent AT efficacy and examined this relationship to optimize AT induction timing. Methods We retrospectively reviewed medical records of UC patients diagnosed after January 2010, analyzing the correlation between total CS dose prior to initial AT administration and AT response. Patients using steroids for other diseases or with incomplete CS dose information were excluded. Variables assessed included onset age, sex, disease extent, activity (PRO2), treatment details, and treatment failure rates. Nominal variables were analyzed using Fisher’s exact test and logistic regression analysis. Results Data from 92 UC patients (44 males) were analyzed. Median onset age was 41.5 years, with median AT induction age of 46.5 years. Disease extent: total colitis/left-sided/rectum = 57/33/2. Mean total CS dose before AT initiation was 1,743.2 mg, with a mean 479.1 days between CS initiation and AT start. AT breakdown: IFX/ADA/GLM/VDZ/UST/UPA/TOF/FIL = 37/19/13/13/6/2/1/1. Median PRO2 at AT initiation was 4. (TABLE 1) Primary non-response (PNR) occurred in 23 cases (24.0%), and loss of response (LOR) in 18 cases (18.8%). Multivariate analysis identified total CS dose ≥3,000 mg as a significant risk factor for PNR (OR 4.21, 95%CI 1.32-13.5, p=0.02). (TABLE 2) No risk factors were identified for LOR. Conclusion As previously reported, elderly-onset UC requires careful management due to potentially poor treatment response. The total CS dose appears to significantly impact primary non-response, suggesting that early transition to Advanced Therapy may be crucial for optimal patient outcomes. References 1)Nurulamin MN. A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn’s disease (PROFILE). Lancet Gastroenterol Hepatol. 2024;9(5):415-427 doi:10.1016/S2468-1253(24)00034-7

P0607 Opportunistic infections in patients with inflammatory bowel disease under advanced drug therapy. Real-word experience of 8 years from a medium-volume center in Cordoba, Argentina

Abstract Background The frequency of inflammatory bowel disease (IBD) has been rising in Latin American countries. Opportunistic infections (OIs) are a potential complication in patients receiving advanced drug therapy (ADT), particularly when combined with corticosteroids and immunosuppressants. Our objective was to evaluate the frequency of OIs in patients with IBD undergoing ADT in a real-world setting. Methods An observational study was conducted using data from the registry (n=395) of a private center in Córdoba, Argentina. We included adult patients (pts) diagnosed with IBD [ulcerative colitis (UC) or Crohn’s disease (CD)] who had at least one prescribed ATD. We analyzed the presence of OI after starting ADT and the use of concomitant treatments (corticosteroids and immunosuppressants) during follow-up. Qualitative variables were described as percentages and quantitative variables were described as medians and interquartile ranges (IQR 25-75). Variables were compared using the chi-square and Mann-Whitney U tests. Results We included 118 pts (58.5% UC, 41.5% CD) who received 180 ATDs during follow-up (2017-2024). Median age was 44.5 years (IQR 25-75: 32-55.5), and 54.2% were female. A total of 24 (20.3%) pts presented OI during follow-up and 35 episodes of OI were observed out of 180 ADTs prescribed. Two patients (8.3%) presented a fatal outcome. OI episodes were skin and soft tissue infections (n=10, 28.6%), cytomegalovirus colitis (n=7, 20%), Clostridium difficile colitis (n=6, 17.1%), herpes zoster virus infection (n=3, 8.6%), complex herpes simplex infection (n=3, 8.6%), fungal infection (n=3, 8.6%), severe pneumonia (n=2, 5.7%), and intestinal tuberculosis (n=1, 2.9%). OI episodes distribution according to drug class was: Anti-TNF (n=21, 60%), anti-IL 12-23/IL-23 (n=9, 25.7%), vedolizumab (n=4, 11.4%), and JAK inhibitors (n=1, 2,9%). The proportion of OI episodes was similar according to the use of anti-TNF (19.8%) vs. non-anti-TNF drugs (17.7%), p=0.6. In 26 (74.3%) of the OI episodes patients were receiving corticosteroids simultaneously. The simultaneous use of corticosteroids was associated with a higher number (>1 episodes) of OI episodes per patient (100% vs 50%, p=0.04). Within patients with concurrent corticosteroid use, there was a similar number of episodes if the ADT was anti-TNF compared to another class (50% vs. 67% respectively, p=0.7). Conclusion The concurrent use of corticosteroids was a risk factor for OI in patients with IBD receiving ATDs. No higher frequency of OIs was observed in patients receiving anti-TNF agents compared to those receiving ATDs of other classes. Further studies are needed to evaluate OIs in regions with limited access to ATDs. References Balderramo D, Quaresma AB, Olivera PA, Savio MC, Villamil MPG, Panaccione R, Ng SC, Kaplan GG, Kotze PG. Challenges in the diagnosis and treatment of inflammatory bowel disease in Latin America. Lancet Gastroenterol Hepatol. 2024 Mar;9(3):263-272. doi: 10.1016/S2468-1253(23)00284-4. PMID: 38340754.

P0743 Clinical impact of delayed access to advanced IBD treatment in Latin America. Experience of 8 years from a medium-volume center in Cordoba, Argentina

Abstract Background Inflammatory Bowel Disease (IBD) frequency has been increasing in Latin American countries. Argentinapresents significant heterogeneity in healthcare systems, which may delay access to advanced therapeutic drugs (ATDs) for IBD. We aimed to evaluate the delay in access to ADT and its impact on patients with IBD. Methods An observational study was conducted using data from the registry (n=395) of a private center in Córdoba, Argentina. We included adult patients diagnosed with IBD [ulcerative colitis (UC) or Crohn’s disease (CD)] who had at least one prescribed ATD. Patients who accessed ATDs through clinical trials were excluded. We defined access time as the period (in days) between the ATD request and the start of treatment. During this period, complications were assessed based on a composite endpoint including IBD flare (defined as an increase in oral corticosteroid dosage or need of hospitalization), the need for IBD-related surgery, or severe infections (requiring hospitalization and intravenous treatment). Qualitative variables were described as percentages, while quantitative variables were reported as medians and interquartile ranges (IQR 25-75). Variables were compared using the chi-square and Mann-Whitney U tests. Results We included 108 patients (58.5% UC, 41.5% CD) who received 163 ATDs across different lines of therapy during follow-up from 2017-2024 (1L: 108, 2L: 38, 3-5L: 17). The median age was 44 years (IQR 25-75: 30-55), and 55.6% were female. The median access time for all ATD lines was 31 days (IQR 25-75: 28-62), with no significant differences between therapy lines [1L: 31 days (IQR 25-75: 28-76), 2L: 32 days (IQR 25-75: 30-61), 3L-5L: 29 days (IQR 25-75: 20-38), p=NS]. 101/163 (62%) of the requested ADTs were anti-TNF. Access time was similar according to the drug class [anti-TNFs 31 days (IQR 25-75: 27-62) vs. non-anti-TNF agents 31 days (IQR 25-75: 28-63) (p=0.6)]. A total of 36 (22%) ATD indications were associated with complications while patients awaited therapy (32 flare, 3 IBD-related surgeries and one severe infection). Patients who experienced complications had a longer access time compared to those who did not experience complications [61 days (IQR 25-75: 31-122) vs. 31 days (IQR 25-75: 25-61) respectively, p<0.01]. Conclusion A delay of more than 4 weeks was observed in more than half of the patients with an indication for ADT. The delay was similar according to the type of IBD, drug class and line of treatment. A higher frequency of complications was observed in patients with a longer delay in receiving the requested ADT. Policies are needed to improve the time to access ADT, avoiding the complications associated with delayed access. References Balderramo D, Quaresma AB, Olivera PA, Savio MC, Villamil MPG, Panaccione R, Ng SC, Kaplan GG, Kotze PG. Challenges in the diagnosis and treatment of inflammatory bowel disease in Latin America. Lancet Gastroenterol Hepatol. 2024 Mar;9(3):263-272. doi: 10.1016/S2468-1253(23)00284-4. PMID: 38340754.

P0365 The evolution of Geldof fistula class in patients with Crohn’s disease perianal fistula

Abstract Background Progressing the evaluation and management of Perianal fistulizing Crohn’s disease ( CD-pAF ) , an aggressive phenotype of CD , is one of the key unmet needs in Inflammatory Bowel Disease (IBD). There is sub-optimal understanding of the behavior of CD-pAF with some patients having rapid velocity of disease progression needing radical surgery such as proctectomy or diverting stoma. More recently, a practical patient-centric classification has been developed recently by Geldof et al has been used to classify patients underpinned by the behavior of CD-pAF(1). We aimed to evaluate the fistula class trajectory using Geldof classification in a large cohort of CD-pAF patients. Methods Data for 997 patients with Crohn’s disease perianal fistula (CD-pAF) included in a cohort study of patients with existing diagnosis of CD-pAF. Data was entered to predefined time points starting at the date of diagnosis of Cd-pAF and onward until entry into the cohort. We analysed the change in fistula classification using Geldof classification over 2 years. Results Data at entry to the cohort of 997 ( Males 52% , Females 48%) patients were included in the analysis The median age at fistula diagnosis was 31 years (23, 42). Among the 997 patients 686 had their Geldof class identified at baseline and 665 at 6-12 months. Class 2a followed by class 1 were the most frequent classes reported (Class 2a at baseline 376/686(55%) and Class 1 167/686(24%), at 6-12 months class 2a were 286/665(43%) and class 1 were 252/665(38%). At 12-24 months from fistula diagnosis 599 patients’ classes were reported, the most frequent being class 1 279/599(47%). There were minimal variations in Class 2b and class 2ci over the 3 time periods. (Class 2b [112/686(16%], [92/665(14%)]and [82/549(15%)] respectively, class 2ci [21/686(3%)], [20/665(3%)] [14/549(3%)] respectively). 15/686(2.1%) had proctectomy in the first 2 years. Conclusion While there are dynamic changes in fistula classification over 2 year period from fistula diagnosis there seems to be clustering among some classes. This indicates potential opportunity for identifying distinct classes which may have refractory course and tailor therapies accordingly. References (1)Geldof J, Iqbal N, LeBlanc JF, et al. Classifying perianal fistulising Crohn’s disease: an expert consensus to guide decision-making in daily practice and clinical trials. Lancet Gastroenterol Hepatol. 2022;7(6):576-584. doi:10.1016/S2468-1253(22)00007-3

P0878 Early lymphocytosis is a novel predictor of response to rescue infliximab in acute severe ulcerative colitis: results from PREDICT-UC

Abstract Background The ability to predict failure of infliximab (IFX) in acute severe ulcerative colitis (ASUC) is crucial to identify patients who may benefit from dose-escalation, sequential rescue or early colectomy. Methods PREDICT-UC (NCT02770040) was a randomised controlled trial that compared IFX dosing strategies in ASUC.1 Clinical factors and biomarkers were collected daily between day 0 to 3 post-IFX and assessed on their ability to predict IFX failure (Lichtiger score ≥10 on day 14) and 3-month colectomy. Stepwise logistic regression was used to develop a Risk of IFX Failure (RIF) index, which was calibrated against the observed risk of IFX failure. The RIF index represents the predicted probability of IFX failure and takes on values between 0 and 1. Internal validation was performed using bootstrap validation. Results Of 138 patients, 46 received a first IFX dose of 10mg/kg and 92 received 5mg/kg; 39 (28%) experienced IFX failure and 17 (12%) required colectomy by 3 months. There was no difference in lymphocyte count (LC, ×109/L) on day 0 (prior to IFX) in patients who failed or responded to IFX (median [IQR] 1.1 [0.9–1.6] vs 1.3 [0.9–1.8], P=0.47). LC rose by day 3 in both groups, though to a lesser degree in patients who failed IFX (median [IQR] 1.9 [1.4–2.8]) compared to responders (3.3 [2.1–4.9]; P=0.004), and lower in patients requiring colectomy (median [IQR] 1.4 [1.1–1.9] vs 3.0 [2.0–4.8]; P<0.001). A lower day 3 LC was predictive of IFX failure (AUC 0.71, 95% CI 0.60–0.81) and colectomy (AUC 0.83, 95% CI 0.74–0.92). A higher CRP was predictive of both IFX failure and colectomy at all time-points from days 0 to 3 (day 3 CRP AUC 0.68, P=0.003 and 0.70, P=0.019 respectively). A lower day 3 albumin predicted IFX failure (AUC 0.63, P=0.039) while a lower day 2 albumin predicted colectomy (AUC 0.66, P=0.042). The final RIF index comprised day 3 stool frequency, rectal bleeding score, CRP and LC. The RIF index had a naïve AUC of 0.80 and an optimism-adjusted AUC of 0.73 (95% CI 0.65–0.80) for predicting IFX failure, and a naïve AUC of 0.90 and an optimism-adjusted AUC of 0.88 (95% CI 0.81–0.94) for predicting colectomy. A RIF index threshold of ≥0.15 had an 85% sensitivity and 90% negative predictive value (NPV) for IFX failure and a 94% sensitivity and 98% NPV for colectomy, while a threshold of ≥0.50 had a 92% specificity and 69% positive predictive value (PPV) for IFX failure, and an 88% specificity and 42% PPV for colectomy. Conclusion Lymphocytosis by day 3 is a novel predictor of response to IFX rescue in ASUC. The RIF index is a simple on-treatment risk index that predicts IFX failure and colectomy, and may be used to inform IFX dose-optimisation or switch to alternate therapies. References 1Choy MC, Li Wai Suen CFD, Con D, et al. Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): an open-label, multicentre, randomised controlled trial. Lancet Gastroenterol Hepatol 2024; 9(11): 981-96.

P0550 Introducing Intestinal ultrasound in the UK NHS – the first 6-months

Abstract Background Intestinal ultrasound (IUS) has been integrated into inflammatory bowel disease (IBD) practice outside of the UK for several years. The NHS has been slow to adopt this and there is ongoing scepticism with regards to its utility. Methods We performed a retrospective service evaluation to demonstrate the utility of IUS in the NHS. IUS was requested additionally to tests performed as standard of care to enable internal audit. We assessed the proportion of cases where IUS altered decision making. Secondary outcomes included the additional value of IUS to faecal calprotectin (fcal) and the accuracy of IUS in terms of the presence, activity and extent of disease. Similar to the METRIC study,1 IUS accuracy was determined after accounting for all available investigations performed in each patient and recorded as a binary outcome. Where pathology was missed, changes in management were recorded. Data collected included demographic, disease phenotype, body mass index, pregnancy, indication for IUS and scan adequacy. Results We performed 74 IUS on patients with: Crohn’s disease (53) [L1–40; L3–13; B1–11; B2–32; B3–10; p1], ulcerative colitis (17) [E1–2; E2–5; E3–10] and suspected CD (4). Mean age 45.5 years; 45 (61%) female, mean BMI 25.2, pregnant [mean 29/40 weeks] 7 (9.4%). Indications included disease flare (34, 46%), asymptomatic with raised fcal (4, 5%) or disease monitoring (36, 49%). In total, 10 (13%) were deemed inadequate due to (gravid uterus obscuring view [3, 4%), BMI >26 (4, 5%), difficult scan (3, 4%). All 10 patients had mild (6, 8%) or quiescent disease (4, 5%). Table 1 shows the outcomes of the remaining 64 scans. In 52/64 (81%) cases the IUS altered immediate treatment decisions. In 38/64 cases, the IUS added additional value compared to using the subsequently resulted fcal alone. The presence, activity and extent of disease was concordant with standard tests (92%, 92% and 62% of cases, respectively). Missed pathology requiring alternative treatment was identified in 6/63 (9.5%) cases (mild aphthous ulceration seen on VCE [normal MRE] [4], lymphoma [1] and ileorectal anastomotic stricture [1]). The latter two cases required cross-sectional imaging irrespective of the IUS result. Time to definitive treatment decision was reduced by an average of 57 (24-92) days. Conclusion Despite limited experience in IUS, our outcomes are similar to results from the METRIC trial. The NHS should expedite the adoption of IUS to avoid invasive/expensive tests, add value to the clinical consultation and streamline IBD care. References Taylor SA, Mallett S, Bhatnagar G, et al. Diagnostic accuracy of magnetic resonance enterography and small bowel ultrasound for the extent and activity of newly diagnosed and relapsed Crohn’s disease (METRIC): a multicentre trial. Lancet Gastroenterol Hepatol 2018;3(8):548-558. (In eng). DOI: 10.1016/s2468-1253(18)30161-4.

P0148 Studying the role of adipose tissue in intestinal inflammation using acquired generalized lipodystrophy

Abstract Background Crohn’s disease (CD) is associated with creeping fat, characterized by hyperplasia of mesenteric adipocytes and increased secretion of adipokines, including leptin (1). However, limited models currently exist to study the effect of adipose tissue on intestinal inflammation. Therefore, acquired generalized lipodystrophy and Crohn’s disease (AGLCD), a rare metabolic disorder characterized by the complete loss of fat tissue and intestinal inflammation, could provide a unique model to further elucidate the contribution of adipose tissue to the pathogenesis of inflammatory bowel disease. Methods To decipher the role of adipose tissue, we characterized the immune cell compartment in a patient with AGLCD using mass cytometry, whole exome sequencing and single cell sequencing. Samples collected for the analysis include lamina propria mononuclear cells (LPMCs) isolated from ileum biopsies and peripheral blood mononuclear cells (PBMCs) from blood obtained from 6 CD patients, one AGLCD patient, and 4 non-inflamed controls. Results Using mass cytometry, we were able to identify 17 intestinal immune cell clusters in the LPMCs. Namely, there was a higher frequency of CD8+ CD45RO+ T cells, CD11c+ CD11b+ myeloid cells and CD19+ CCR7+ B cells in the AGLCD sample compared to the fat-proficient CD controls. In addition, single cell sequencing of CD3+ T cells isolated from the blood of the AGLCD patient showed an expansion of CD8+ and CD4+ effector memory T cells compared to a healthy donor, suggesting that adipose tissue plays a role in T cell homeostasis in CD. To confirm that leptin plays a role in the regulation of T cells, we analyzed PBMCs from the AGLCD patient pre and post treatment with recombinant leptin. An increase in the expression of IL-17 producing CD4 T cells were present after treatment with leptin. To further investigate the expansion of CD8+ T cells, analysis of whole exome sequencing of the AGLCD showed a mutation in the NRAS gene, an essential regulator of hematopoietic development. The mutation was confirmed only in CD8 and CD4 T cells in the blood and intestinal biopsies of the AGLCD patient using Sanger sequencing. Conclusion These observations demonstrate that AGLCD is a unique model that can be used to further study the effects of adipose tissue in intestinal inflammation. References (1) Coffey JC, O'Leary DP. The mesentery: structure, function, and role in disease. Lancet Gastroenterol Hepatol 2016;1:238-247.

World Stroke Organization: Global Stroke Fact Sheet 2025.

Among non-communicable disorders (NCDs), stroke remains the second leading cause of death and the third leading cause of death and disability combined (as expressed by disability-adjusted life-years lost-DALYs) in the world. The study was aimed to estimate global, regional and nationa burden of stroke and its risk factors from 1990 to 2021. Finding presented in this paper were derived mainly from the Global Burden of Disease 2021 Study on stroke burden published in The Lancet Neurology 2024:23:973-1003. The estimated global cost of stroke is over US$890 billion (0.66% of the global GDP). From 1990 to 2021, the burden (in terms of the absolute number of cases) increased substantially (70.0% increase in incident strokes, 44.0% deaths from stroke, 86.0% prevalent strokes, and 32% DALYs), with the bulk of the global stroke burden (87.0% of deaths and 89.0% of DALYs) residing in lower-income and lower-middle-income countries (LMICs). Stroke attributable to metabolic risks constituted 69.0% of all strokes, environmental risks constituted 37.0%, and behavioral risks constituted 35.0%. This World Stroke Organization (WSO) Global Stroke Fact Sheet 2025 provides the most updated information that can be used to inform communication with all internal and external stakeholders; all statistics have been reviewed and approved for use by the WSO Executive Committee and leaders from the Global Burden of Disease research group.