Failure Of Therapy Research Articles

Long-term survival of an ALK fusion lung adenocarcinoma patient with high mutation burden and microsatellite instability high: a case report.

Immune checkpoint blockage (ICB) therapy has shown minimal effectiveness in anaplastic lymphoma kinase (ALK)-positive nonsmall cell lung cancer (NSCLC) regardless of Programmed death-ligand 1 expression. ALK fusion accompanied by mismatch repair deficiency or microsatellite instability-high (MMRd/MSI-H) and high tumor mutation burden (TMB-H) are extremely rare in NSCLC, and the efficacy of ALK inhibitors or ICB-based therapies is unclear. Here, we report the case of a 60-year-old female patient with metastatic lung adenocarcinoma accompanied by EML4-ALK fusion, TMB-H, MMRd/MSI-H, and pathogenic mutations in TP53, MLH1, and STK11. The patient experienced progression on initial iruplinalkib and subsequent alectinib therapy within 5 months. After the failure of third-line therapy with cisplatin-pemetrexed combined with bevacizumab, she received sintilimab plus anlotinib which led to a progression-free survival of 6.5 months. She received sintilimab combined with albumin-paclitaxel plus carboplatin and achieved partial response after 6 months. She developed adverse events after one cycle of sintilimab plus albumin-paclitaxel treatment. Then she was continued with sintilimab plus anlotinib as a maintenance therapy due to intolerance to chemotherapy. After progression on ICB-based therapy, the patient was treated with lorlatinib and still under follow-up with overall survival of more than 3 years. Our findings highlight the therapeutic potential of ICB-based regimens in patients with MSI-H and ALK-rearranged NSCLC.

Development of HIV Drug-Resistance Mutations and Antiretroviral Efficacy Among Vietnamese Patients After Failure of 5-Year First-Line Therapy.

The emergence of drug-resistant mutations in human immunodeficiency virus (HIV) over time presents a challenge to treatment. We describe the development of drug-resistance mutations and ART efficacy reduction in Vietnamese patients with failure of first-line ART during a 5-year period. This is a 5-year observational cohort study with HIV viral loads of patients evaluated annually for 5 years (2017-2022) at the hospitals in Vietnam. Patients with a viral load ≥ 1000 copies/mL were subjected to identifying mutations in reverse transcriptase, protease, and integrase to evaluate HIV resistance and the efficacy of ART. After 5 years of monitoring the HIV load of 2932 patients on ART, 75 (2.56%) patients had concurrent virological failure at all 5 years. In 2017, only 2/75 HIV strains possessed Protease Inhibitor (PI) resistance mutations, while 75/75 HIV strains had both Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) resistance mutations. Only four PI resistance variants were found, while 40 and 32 mutations were resistant to NRTIs and NNRTIs. After 5 years, the number of HIV PI resistance mutations had increased to 14, with 13 new mutations emerging. There were six novel mutations associated with resistance to NRTIs, NNRTIs, and the proportion of preexisting mutations increased from 1.3% to 13.3%. Furthermore, HIV sensitivity to ART decreased from 2.7% to 18.6%. After 5 years, HIV had increased resistance mutations to PIs, NRTIs, and NNRTIs, with PI resistance mutations increasing the most rapidly, and the decrease in HIV sensitivity to PIs was higher than that to NRTIs and NNRTIs.

Photobiomodulation mitigates doxorubicin resistance in MDA-MB-231 breast cancer cells: a promising avenue for overcoming chemoresistance.

One of the formidable challenges that may emerge in patients with breast cancer is drug resistance which is highly correlated with failure in cancer therapy and, as a result, poorer prognosis. Thus, developing novel approaches to overcome this undesirable event has always been a hot topic in the field of cancer. Photobiomodulation (PBM), also known as low-level laser therapy, is one such approach that has recently been introduced as a promising modality in clinical settings with interesting anti-tumor properties. Moreover, PBM has been considered a possible candidate to be employed in conjunction with conventional modalities such as chemotherapy. The present study investigated the potential effects of PBM at two wavelengths of 630nm and 980nm on chemoresistance in breast cancer MDA-MB-231 cells, which previously acquired resistance to doxorubicin (DOX) through 12 passages. Findings proposed that PBM, in conjunction with DOX, led to a reduction in the viability of resistant MDA-MB 231 cells as was evidenced by decreased IC50 values of DOX across different groups. Furthermore, gene expression studies demonstrated that PBM inhibited the overexpression of some of the important resistance-related genes, including SOX9, MDR1, NRF2, TGF-β, and ABCC1. Although both wavelengths had considerable efficiency, at 630nm, PBM performed better in overcoming DOX resistance. Overall, the present study suggests that PBM might play a promising role against breast cancer via reducing chemoresistance which, indeed, necessitates further research to better understand its mechanisms and clinical potential for translation.

CD19.CAR-T cell-derived extracellular vesicles express CAR and kill leukemic cells, contributing to antineoplastic therapy.

Chimeric Antigen Receptor (CAR) T cell-derived Extracellular Vesicles (EVs) might represent a new therapeutic tool for boosting CAR-T cell antileukemic effects. Here, a cohort of 22 patients infused with CD19.CAR-T cells was monitored for the presence of circulating CD19.CAR+-T cell-derived EVs (CD19.CAR+EVs), which were then separated and functionally characterized for their killing abilities. A GMP-compliant separation method was also developed. Results demonstrated that CD19.CAR+EVs were detectable in peripheral blood up to 2 years after infusion indicating long-lasting persistence of their parental cells. Notably, early decreases of circulating CD19.CAR+EVs concentrations correlated with failure of CAR-T therapy. Circulating CD19.CAR+EVs displayed a median size (SD) of 133.1±65.5 nm and carried a pro-apoptotic protein cargo. These EVs expressed higher CAR levels than their parental cells. Furthermore, CD19.CAR+EVs did not activate heterologous T cells and produced significant, specific and dose-dependent cytotoxic effects on CD19+ cell lines and on primary cells. The new GMP-compliant EV isolation method allowed a recovery of 63±5.7 % of CD19.CAR+EVs. A deeper analysis of the different protein cargoes carried by EVs derived from different CAR-T cell subpopulations identified a pro-apoptotic functional pathway linked to CD8+LAG-3+ EVs. Overall, our data indicate that CD19.CAR+EVs may be proposed as promising dynamic new biomarkers of CAR-T cell activity and, contributing to the direct killing of the leukemic target, represent a new product with a strong therapeutic potential that could be infused independently from CAR-T cells.

Left atrial appendage closure in patients with failure of anticoagulation therapy: A multicenter comparative study on the hybrid strategy using DOACs and VKAs.

Patients with non-valvular atrial fibrillation (nvAF) who experienced a cardioembolic (CE) event despite adequate oral anticoagulation (OAC) are at high risk of recurrence and the combination between percutaneous left atrial appendage closure (LAAC) and long-term OAC may be a valuable option. The aim of this study was to compare the safety and the efficacy of post-LAAC long-term assumption of direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKAs) in this population. Consecutive nvAF patients who experienced OAC failure despite adequate OAC therapy and underwent LAAC were retrospectively enrolled from three Italian centers. Patients were divided according to the anticoagulation strategy following LAAC: DOAC group and VKA group. The primary endpoint was a composite of all-cause death, CE event, and major bleeding, while secondary endpoint was a composite of CE event and major bleeding. Overall, 132 patients (39% females; mean age 69±11years), including 73 patients on DOAC and 59 patients on VKA, were enrolled. At a median follow up of 61±23months, the DOAC group reported lower rate of primary endpoint (HR 0.42, 95%CI 0.18-0.99, p=0.038) and lower rate of secondary endpoint (HR 0.28, 95%CI 0.09-0.89, p=0.02). No significant differences were detected regarding the type of DOAC assumed. Previous cerebrovascular events, CHA2DS2-VASc, CHADS2, HAS-BLED, and renal dysfunction were predictors of the primary endpoint. Long-term DOAC assumption was associated with higher free from primary and secondary endpoint with respect to VKA in nvAF patients undergoing LAAC for OAC failure.

GOBLET platform study: Preliminary safety and tumor response results for the relapsed anal carcinoma cohort in patients treated with pelareorep and atezolizumab.

6 Background: Patients with relapsed unresectable squamous cell carcinoma of the anal canal (SCCA) have limited treatment options after failure of standard first-line therapy. While checkpoint inhibitor monotherapy is possible, response rates are low (10-24%). Therapies that induce an inflammatory tumor microenvironment may improve the susceptibility of SCCA to immunotherapy. Pelareorep (pela) is a non-genetically modified, intravenously administered reovirus that stimulates the expansion of tumor-infiltrating lymphocyte (TIL) clones and simultaneously makes tumors visible to the immune system by upregulating interferon-induced gene expression. Pela-based combination therapies have demonstrated activity in metastatic breast and pancreatic cancer. In the GOBLET platform study, the efficacy of pela plus atezolizumab (atezo) in SCCA is being evaluated. Methods: GOBLET is a phase 1/2, open-label, non-randomized, Simon two-stage platform study in patients with advanced or metastatic GI cancers. SCCA patients in the trial are treated with pela plus atezo. Ten evaluable patients will be enrolled in Stage 1 and an additional 18 evaluable patients will be enrolled in Stage 2 if the prespecified Stage 1 success criterion is met (≥2 responses). The coprimary endpoints are tolerability of the treatment regimen and objective response rate (based on RECIST v1.1). Safety data are reviewed in an ongoing manner by an independent Data Safety Monitoring Board (DSMB). In addition, tumor and blood samples are being collected to assess TIL clonal expansion and other biomarkers. Results: Twelve patients are currently evaluable for tumor response in the SCCA cohort. Four out of 12 patients have achieved an objective response to therapy including 1 prolonged complete response (>15 months) and 3 partial responses- resulting in an ORR of 33.3%. Final ORR, progression-free survival, and overall survival results are pending. The DSMB has identified no safety signals and has recommended that enrollment continues without modification. TIL clonal expansion in the blood has been observed at treatment cycle 4 in all 3 responding patients for whom data are available. Conclusions: Twelve patients are currently evaluable for tumor response in the SCCA cohort. Four out of 12 patients have achieved an objective response to therapy including 1 prolonged complete response (>15 months) and 3 partial responses resulting in an ORR of 33.3%. Final ORR, progression-free survival, and overall survival results are pending. The DSMB has identified no safety signals and has recommended that enrollment continues without modification. TIL clonal expansion in the blood has been observed at treatment cycle 4 in all 3 responding patients for whom data are available. Clinical trial information: 2020-003996-16.

Beamion BCGC-1: A phase Ib/II trial of the HER2-selective tyrosine kinase inhibitor (TKI) zongertinib (BI 1810631) + trastuzumab deruxtecan (T-DXd) or trastuzumab emtansine (T-DM1) for patients with metastatic breast cancer (mBC) and metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma (mGEAC).

TPS509 Background: Approximately 15% of mGEAC tumors overexpress HER2. Currently, the HER2-targeted antibody-drug conjugate (ADC), T-DXd, is approved in mGEAC as a second-line or later-line treatment option following the failure of prior trastuzumab-containing therapy. Zongertinib (BI 1810631) is a novel, orally administered HER2-selective TKI that spares EGFR. In a Phase I trial (NCT04886804), zongertinib showed encouraging tolerability and efficacy in patients with HER2 aberration-positive advanced solid tumors, including mGEAC. Beamion BCGC-1 (NCT06324357) is a Phase Ib/II dose escalation/optimization trial investigating zongertinib plus T-DXd or T-DM1 in patients with HER2+ mGEAC or mBC. Here we focus on the mGEAC cohorts, in which patients will receive zongertinib in combination with T-DXd. Methods: Across the whole trial, approximately 240 patients will be enrolled from approximately 48 sites in 6 countries. In the mGEAC cohorts, approximately 80 patients with histologically/cytologically confirmed locally advanced/metastatic, unresectable, HER2-positive, pre-treated mGEAC will be enrolled. All patients must have investigator-assessed progression and documented HER2-positive disease (overexpressed and/or amplified; confirmed by immunohistochemistry and in situ hybridization). In Phase Ib, approximately 20 patients will receive escalating doses of zongertinib plus a fixed approved dose of T-DXd (6.4 mg/kg, once every 21 days). Dose escalation will be guided by a Bayesian Logistic Regression Model, with overdose control. In Phase Ib, the primary endpoint is the occurrence of dose-limiting toxicities (DLTs) during the maximum tolerated dose evaluation period (first 21-day cycle); secondary endpoints include objective response (RECIST v1.1), DLTs during the on-treatment period and pharmacokinetics. In Phase II, up to 60 patients with mGEAC will be randomized 1:1 to receive one of two zongertinib dose levels (dose levels informed by Phase Ib), plus a fixed approved dose of T-DXd. In Phase II, the primary endpoint is objective response; secondary endpoints include progression-free survival, disease control, treatment-emergent adverse events leading to dose reduction, pharmacokinetics and patient-reported outcomes. Patients will remain on treatment until disease progression, undue toxicity or any other protocol-defined stopping criterion. Enrollment is ongoing. Clinical trial information: NCT06324357 .

Predictive Factors for Failed Nonsurgical Management of Long Bone Metastasis and Myeloma.

Understanding the risk factors for failing nonsurgical management of metastatic bone disease is necessary to determine those patients who will benefit from prophylactic stabilization; however, standard predictive models do not include several clinically relevant factors. The primary and secondary objectives of this study were to evaluate comprehensive patient- and disease-related factors as potential predictors of failure of radiation therapy alone for long bone lesions and overall survival in metastatic disease and myeloma. All patients who underwent radiation therapy for long bone metastases at our tertiary care institution from May 2011 to February 2020 were retrospectively reviewed. Of 475 lesions, we excluded those with prophylactic fixation or fracture before radiation therapy, and those <0.5 cm on plain radiographs. Outcomes of the 186 lesions were classified as no progression, progression requiring prophylactic fixation, or progression to pathologic fracture. Blinded radiograph review was done by two orthopaedic oncology surgeons and two musculoskeletal radiologists. Demographic, socioeconomic, lesion, cancer severity, and patient-specific risk factors were identified, and potential predictors were analyzed using backwards stepwise regression. Following radiation therapy, 8.6% lesions underwent prophylactic fixation and 14.0% fractured. Prophylactic fixation was associated with Mirels' score (OR = 1.98, P = 0.025), lesion cortical involvement (OR = 16.96, P = 0.010), and younger patient age (OR = 0.93, P = 0.024). Fracture was associated with lesion cortical involvement (OR = 10.16, P = 0.003) and "low risk" histology (OR = 9.01, P = 0.057). Orthopaedic treatment (either prophylactic surgery or pathologic fracture management) was associated with Mirels' score (OR = 1.62, P = 0.015), lesion cortical involvement (OR = 8.94, P = 0.002), humerus location (OR = 4.19, P = 0.042), and Medicare (OR = 4.12, P = 0.062) or private insurance (OR = 5.69, P = 0.022) compared with Medicaid. ECOG score (OR = 1.28, P = 0.003) was found to be a risk factor for increased mortality after radiotherapy, while "low risk" histology (OR = 0.51, P = 0.029), mixed lesion type (OR = 0.34, P = 0.006), and increased body mass index (OR = 0.95, P = 0.001) were protective factors. Radiograph measurements of cortical involvement were the most clinically relevant for determination of metastatic lesion fracture risk; however, predictors of local failure not addressed in Mirels' score should be considered in clinical decisions about prophylactic fixation. Surgery may be underperformed for histologies commonly considered to be "low risk" for local progression after radiation therapy.

Lubricating Copolymer Brushes Achieving Excellent Antiadhesion and Antibacterial Performance through Hydration and Electrostatic Repulsion Effects.

Interventional catheters have been widely applied in diagnostics, therapeutics, and other biomedical areas. The complications caused by catheter-related bacterial infection, venous thrombosis, and vascular abrasion have become the main reasons for the failure of interventional therapy. In this study, polyacrylamide/poly(acrylic acid) lubricating copolymer brushes were constructed on the surface of catheters and efficiently resisted the adhesion of blood components and bacteria through hydration and electrostatic repulsion effects. The copolymer brushes are surface-independently constructed on various substrates through a three-step method. The brushes achieve effective lubricating, antiadhesion, and antibacterial properties. Particularly, the 2PAM/6PAA brushes exhibited the most excellent overall performance with a 94% reduction in coefficient of friction, 87.2 and 78.3% reduction in adhesion levels of bovine serum albumin and bovine blood fibrin, and 92.3, 97.1, and 93.5% reduction in adhesion levels of Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. The 2PAM/6PAA brushes significantly reduced the adhesion of blood components in the in vitro blood circulation test, demonstrating its practical application efficacy. Additionally, experiments and molecular dynamics simulations were used to reveal the antiadhesion mechanism of the brushes. Thus, the copolymer brushes in this work show great potential in the antithrombotic, antibacterial, and lubrication modification for medical devices contacting with blood.

Prevalence and clinical implications of anti-drug antibody formation and serum drug levels among patients with IBD receiving anti-TNF therapy: A cross-sectional study.

The emergence of tumor necrosis factor inhibitors (anti-TNF) has considerably changed the management of inflammatory bowel disease (IBD) in patients who do not respond to traditional therapies. This study assesses the prevalence of anti-TNF drug levels (DLs) and antibodies (ATAbs) in patients with IBD in Saudi Arabia and explores their associations with IBD type and prior anti-TNF failure. This cross-sectional study included patients aged 14-75 years diagnosed with Crohn's disease (CD) or ulcerative colitis (UC), treated with anti-TNF medications at King Fahad Medical City over January 2016 to December 2022. Data were analyzed using descriptive statistics, Mann-Whitney U test, Kruskal-Wallis test, Pearson's Chi-squared test, and multinomial logistic regression. Among 392 patients with IBD (median age, 31 years), 75.8% were diagnosed with CD and 24.2% with UC. Anti-TNF levels were subtherapeutic in 27.0% patients, therapeutic in 21.5%, and supratherapeutic in 51.5%. ATAbs were negative in 73.1% patients, weakly positive in 9.8%, and positive in 17.1%. Subtherapeutic anti-TNF levels were significantly associated with positive ATAbs (P < 0.001). Prior anti-TNF therapy failure was observed in 37.2% cases, with 15.3% showing immunogenicity. No significant demographic differences were noted across ATAbs groups. We highlight the prevalence of subtherapeutic and supratherapeutic anti-TNF levels among patients with IBD in Saudi Arabia and their association with ATAbs. The findings underscore the importance of monitoring anti-TNF DLs and ATAbs to optimize treatment outcomes in IBD management. Future research should focus on the longitudinal impact of these factors and explore genetic predictors of treatment response.

DOP053 Efficacy of appendectomy in inducing remission in moderate-to-severe ulcerative colitis: preliminary one year results of a multicentre prospective cohort study (COSTA)

Abstract Background This study aimed to evaluate the efficacy of appendectomy in inducing remission in patients with moderately to severely active ulcerative colitis (UC), despite biological or small molecule therapy. Methods This multicentre, prospective cohort study included patients aged ≥16 years with moderately to severely active UC (total Mayo score [TMS] ≥5; endoscopic subscore of ≥2) despite optimised prior treatment with advanced medical therapy (i.e. biological/small molecule exposed). Eligible patients where those for whom the next treatment step was considered to be switching to a Janus kinase (JAK) inhibitor or undergoing (procto)colectomy. Enrolled patients were counselled (patient-preference model) to either undergo laparoscopic appendectomy (study intervention) or continue standard step-up therapy, which included: 1) switching to a JAK inhibitor or 2) undergoing staged restorative proctocolectomy with ileoanal pouch. The primary outcome was the proportion of patients achieving clinical remission (TMS≤2 with no subscore &amp;gt;1) at 12 months without therapy failure. Therapy failure was defined as (re)start of oral corticosteroids, switch of advanced therapy, start trial medication or proctocolectomy. Patients without therapy failure and pMS≤2 at 12 months without endoscopic follow-up were considered failures for the primary outcome. Primary analyses will be conducted based on a modified intention-to-treat (mITT) principle. Patients who received the assigned intervention (appendectomy in the intervention group, proctocolectomy in the control group) or at least one dose of the assigned medication (JAK-inhibitor in the control group) will be analysed. The last patient 12-month follow-up visit was completed in September 2024. Results A total of 120 patients were included in the mITT analysis (appendectomy group: n=65, JAK-inhibitor group: n=50, proctocolectomy group: n=5). Numerical baseline differences across groups (appendectomy vs JAK-i vs proctocolectomy) were: male gender (35.4% vs 54.0% vs 20.0%, p=0.08), family history of IBD (33.8% vs 12.0% vs 0%, p=0.02), current smoking (13.8% vs 2.0% vs 0%, p=0.22), disease extent (E3: 41.5% vs 60.0% vs 80.0%, p=0.18), TMS (median 9 [IQR, 7-10] vs 9 [IQR, 8-10] vs 10 [0-.], p=0.16) and concomitant oral corticosteroids (26.2% vs 46.0% vs 80.0%, p=0.01). The appendectomy group had a significantly higher proportion of patients in clinical remission at 12 months without therapy failure after appendectomy, compared to the JAK inhibitor group (33.8% vs 12.0%, p=0.007, Figure 1.). Final analysis are scheduled for Q4 2024 and Q1 2025. Conclusion Appendectomy may be an effective treatment option for inducing clinical remission in moderately to severely active UC. Final analyses are expected in Q1 2025.

P0419 Impact of psychopathology and gut-microbiota on disease progression in Ulcerative Colitis: a five-year follow-up study

Abstract Background Psychological distress and gut dysbiosis are key factors in patients with IBD. This study aimed to assess whether specific psychopathological and gut microbiota features could predict adverse outcomes in patients with UC. Methods In this prospective longitudinal cohort study, we enrolled 35 adult patients with UC. At baseline, patients completed a psychometric evaluation and provided a stool sample for gut microbiota analysis. For the purposes of this study, only trait-focused scales (MMPI-2, TAS-20, CD-RISC, STAI-Y2) were considered, while state-focused assessments were excluded. Five years later we reconstructed each patient’s clinical history, focusing on adverse outcomes including failure of biological therapy, UC-related hospitalizations, and UC-related surgeries. Results Patients with failure of biological therapy exhibited increased levels of Proteobacteria (p = 0.006), Fusobacteria (p = 0.042), Enterobacteriaceae (p = 0.025), and Trabulsiella (p = 0.011), while Firmicutes were found to be less abundant (p = 0.036). UC-related hospitalized patients presented lower levels of Rikenellaceae (p = 0.011), Ruminococcaceae (p = 0.004), Faecalibacterium (p = 0.004), Lachnospira (p = 0.005), Methanobrevibacter (p = 0.036) and Phascolarctobacterium (p = 0.011), compared to non-hospitalized patients. Considering the psychometric scales, UC-related hospitalized patients had higher scores on the Sc clinical scale (p = 0.032) and higher scores on the OBS (p = 0.044) and HEA (p = 0.026) content scales. Acidaminococcus (p = 0.023) and Bilophila (p = 0.045) were significantly more abundant in patients that underwent UC-related surgery compared to patients who do not. A PCA analysis, specifically conducted on the phyla, revealed differences only between patients who experienced at least one biological failure and those without therapy failure (PERMANOVA: F = 24.2, p = 0.049, explained variance = 48.89%). Other PCA analyses did not show significant differences between the various groups. At the binary logistic regression, Fusobacteria was negatively correlated with the failure of three or more biologics (OR = 0.000; B = -10,584.860, p = 0.028). Hy and Pd were positively correlated with the failure of three or more biologics (OR = 2.167; B = 0.773, p = 0.044) and 2.639 (B = 0.971, p = 0.024). Conversely, Pa and Pt were negatively correlated with multifailure, associated with odds ratios of OR = 0.622, B = -0.476, p = 0.041 and OR = 0.152, B = -1.886, p = 0.021 respectively. Conclusion Psychopathological features related to obsessiveness, health concerns, and somatization, along with specific microbiota characteristics (a lower abundance of SCFA-producing bacteria), may act as predictive factors for UC-related adverse outcomes.

P1029 Janus Kinase Inhibitors for the Management of Acute Severe Ulcerative Colitis: A Multicentre Study

Abstract Background Acute Severe Ulcerative Colitis (ASUC) is a medical emergency, with limited therapeutic options available for medical management. Tofacitinib and Upadacitinib are novel Janus Kinase inhibitors (JAKi), with proven efficacy for ulcerative colitis (UC). This study aimed to examine the outcomes of patients treated with JAKi for ASUC in a real-world population. Methods A retrospective multi-centre study was conducted including patients (≥18 years) with ASUC commenced on Tofacitinib or Upadacitinib from April 2021 to April 2024. ASUC was defined according to Truelove and Witt’s criteria. Demographic and clinical data were recorded at admission, JAK induction, discharge, week 8, week 16 and 1 year post-induction. The primary outcome was need for colectomy. We further evaluated adverse events and drug-specific response. Results A total of 124 patients were included from 11 Australian Inflammatory Bowel Disease (IBD) centers. Tofacitinib was used in 49%, while Upadacitnib was used in the remainder. 58% of patients received JAKi as first line salvage therapy, while the remainder received JAKi sequentially after failure of first line infliximab therapy. The rate of colectomy during admission was 17% and 40% by 1 year. There was no significant difference between rate of colectomy during index admission (p=0.38), or 1 year post induction (p=0.24) between Tofacitinib and Upadacitinib. There was a significantly increased risk of inpatient colectomy for those receiving sequential salvage compared to initial JAKi salvage (p=&amp;lt;0.01). However, there was no significant difference in the rate of colectomy in either cohort up to 1 year post induction (p=0.19). Clinical response was observed in 45% of patients by day 3 of induction and 65% by day 7. Clinical remission rates were 40% by week 8 and 65% by week 16. Biochemical remission was achieved in 51% by week 16. Mucosal healing was achieved in 47% of patients who underwent repeat endoscopy within 16 weeks of induction. Adverse events occurred in 16% of patients, all of which were minor and did not require hospitalisation. The most common events noted were acne (7%) and nasopharyngitis (6%). Conclusion Jaki demonstrate effectiveness and safety for the management of ASUC. There was no significant difference in the inpatient colectomy rate between Tofacitinib and Upadacitinib. There was a significantly higher rate of inpatient colectomy for patients requiring sequential salvage therapy, but no significance when patients were followed up to 1 year. There is variability in prescribing practice between dosage of Tofacitinib and Upadacitinib, duration and dosage of corticosteroid wean, and the use of prophylactic PJP and VTE prophylaxis.

P1304 High prevalence of HLA DRB1*01:03 in Australian Inflammatory Bowel Disease patients without prediction of refractory disease

Abstract Background Crohn’s disease (CD) and ulcerative colitis (UC) have been associated with the major histocompatibility complex in genome wide association studies (1) and subsequently this area is the most widely studied genetic region. HLA-DRB1*01:03 has been associated with susceptibility to both CD and UC (2), and with severe ulcerative colitis (3). However, the frequency of this allele is known to vary by ethnicity. We aimed to determine the frequency of HLA DRB1*01:03 in a multi-ethnic Australian population and determine its association with refractory disease. Methods At a single centre, tertiary Inflammatory Bowel Disease (IBD) service patients with either CD or UC underwent blood collection at the time of clinic appointment, endoscopy or medication infusion and their HLA DRB1 genotype was determined. Demographic and clinic data was retrospectively collected from the electronic medical record (EMR). Refractory disease was determined by failure of 1 or more advanced therapies including biologics and small molecules, as well as the use of steroids within the last 12 months. Descriptive statistics were used and a Chi Square test (IBM SPSS Version 29) used to assess the relationship between HLA DRB1*01:03 and refractory disease. Results 123 patients were enrolled and HLA DRB1 genotypes identified. 10 patients were excluded from further analysis due to an absence of clinical data or a diagnosis of IBD-U. 113 patients were included for final analysis of which 57.5% were male, the mean age was 40.2 (+/- 16.3). 39.8% had UC and 60.2% had CD, and of those 45.5% had fistulising disease. 35.4% had previously undergone surgery and 77% of the cohort were prescribed an advanced therapy. 11.5% of patients had either heterogenous or homogenous HLA DRB1*01:03. There was no significant association between HLA DRB1*01:03 and failure of advanced therapy (P=0.88) or steroid use (P=0.88). Conclusion We identified a high proportion of IBD patients with HLA DRB1*01:03 compared with previous reports (4). High rates of advanced therapy use, and previous surgery indicate that the cohort has a high proportion of severe disease that could account for this finding. However, no association was found between HLA DRB1*01:03 and our measures of refractory disease possibly due to inadequate numbers in our cohort at present. Further investigation of the utility of HLA DRB1*01:03 is warranted in multi-ethnic populations.

P1039 An Evaluation of Anti-IL23 Therapy in Primary Sclerosing Cholangitis Associated Inflammatory Bowel Disease

Abstract Background The majority of patients with primary sclerosing cholangitis (PSC) have inflammatory bowel disease (IBD). This association has fostered several pathogenic hypotheses linking mucosal immunity to hepatobiliary inflammation. A putative therapeutic target along this axis centres on gut-derived IL-17 secretor cell subtypes, which are activated by interleukin (IL)23. Notably, emergent forms of IBD treatment host several anti-IL23 agents, however safety and efficacy data in PSC patients is limited. Methods We conducted a multi-centre study, evaluating treatment experiences with Ustekinumab (a dual anti-IL12/23 agent), Risankizumab, and Mirikizumab (anti-IL23 alone). Data was analysed to determine treatment impact on liver biochemistry; IBD response defined by serial Mayo colitis scores or faecal calprotectin (FCP) values; and treatment-emergent adverse events. Results Data was accrued across eight centres from 66 pts (Ustekinumab, 62; Risankizumab, 4 [n=1 escalated from Ustekinumab] and Mirikizumab, 1) with median treatment time of 9 months (IQR 5-24). The majority of patients were men (63%; n=42) with a median age at PSC diagnosis of 24y (IQR 17-36). The predominant PSC phenotype was large duct (73%; n=49), with two patients having cirrhosis, 13% (n=7) being transplant recipients, and 66% (n=44) having an IBD phenotype consistent with ulcerative colitis. At baseline, the median FCP and Mayo colitis scores were 810ug/L (IQR 369-1727; n=33/66) and 5 (IQR3-8; n=31/66), respectively. 60 patients were commenced on these agents as 2nd-4th line, after failure of prior biologic therapy. In all, IBD response was observed in 15% (n=8/52) at 6 months, 20% (n=7/35) at 12 months and 21% (n=4/19) at 24 months. Remission was achieved in 3 pts (4.5%) at 18 months. Among non-transplant patients, the median change in ALP from baseline to 6 months was not significant (ALP x upper limit of normal [ULN] 1.4 vs. 1.2; p=0.67), nor from baseline to 12 (ULN 1.1 vs. 1.1; p=0.161) or 24 months (ULN 1.6 vs. 1.0; p=0.074) (Figure 1). No significant differences in serum ALT or bilirubin were observed from baseline to 6, 12 or 24 months. Treatment was discontinued in 37% (n=25/67) due to lack of efficacy and in one patient due to an adverse event. Conclusion Anti-IL23 agents are safe and well-tolerated in PSC-IBD. However, IBD response and remission rates appear to dwarf those seen in IBD alone, with no significant effects on liver biochemistry.

P0914 Clinical outcomes of dose-escalated adalimumab in Inflammatory Bowel Disease: A retrospective tertiary centre experience

Abstract Background Despite anti-tumour necrosis factor-α agents (anti-TNF-α) – infliximab (IFX) and adalimumab (ADA) changing the landscape of inflammatory bowel disease (IBD) treatments over the last decade, their use is limited by secondary loss of response (SLOR).1 Anti-TNF-α dose escalation is frequently employed in patients with SLOR and/or low drug levels.2-3 The long-term effectiveness and safety of dose-escalated ADA remains unclear. Hence, we evaluated clinical outcomes following ADA dose escalation in a tertiary centre IBD cohort. We aimed to determine the effectiveness and safety of dose-escalated ADA in IBD patients who had inadequate response to standard dosing ADA after initial response and in patients undergoing escalated induction. Methods We conducted a retrospective analysis of IBD patients who underwent ADA dose escalation between 2018-2024 at a tertiary IBD centre. Dose escalation was defined as an increase in dose (&amp;gt; 40 mg) and/or frequency [&amp;gt; every 2 weeks (Q2W)]. Primary outcomes included clinical improvement (HBI), biochemical markers (CRP, faecal calprotectin), and treatment persistence, assessed at 3-12 months and annually up to 3 years following dose escalation. Secondary outcomes included adverse events (AE). Results A total of 50 patients (median age 35 years, 48% female) were included, of which 47 patients (94%) had Crohn’s disease (CD) and 3 patients (6%) had ulcerative colitis (UC) (Figure 1). Indications for dose escalation included SLOR (36/50; 72%), low drug levels (10/50; 20%) and escalated induction following failure of an alternative biologic therapy (4/50; 8%). Dose-escalated ADA led to a significant improvement in HBI at 3-12 months (p=0.018). This improvement was maintained at 12 months (p=0.009) and 2 years (p=0.010). Significant initial improvements in biochemical markers were reported at 3-12 months (CRP: p=0.048; faecal calprotectin: p=0.023). These improvements were not maintained at any further follow-up points (p&amp;gt;0.05). Treatment persistence was high at 3-12 months (82%), however, only 45% of patients persisted at 3 years. Persistence was higher for biologic-naïve patients (56%) compared with biologic-exposed patients (37%) at 3 years. Four patients reported AE. Urticaria around the injection site (n=2) led to discontinuation in a single patient. Other AE included rheumatological symptoms (n=1) and recurrent catheter-associated urinary tract infections (n=1), the latter prompting de-escalation. Conclusion Dose-escalated ADA appears to be an effective and safe strategy for achieving sustained clinical improvements and early biochemical improvements in IBD patients. Higher persistence in biologic-naïve patients suggests that this strategy may be more effective in this group.

P1101 Real-world effectiveness and safety of Risankizumab in Crohn’s Disease

Abstract Background Data on real-world therapy outcomes for the use of risankizumab in Crohn’s Disease (CD) remain limited. We aimed to assess the real-world effectiveness and safety of risankizumab therapy in CD. Methods A retrospective study was carried out at a tertiary referral centre on patients started on risankizumab for CD between February 2019 and November 2024. Primary outcomes included: rates of clinical response and clinical remission at weeks 12, 28, and 52, and rates of endoscopic improvement by week 52. Clinical response was defined as a treatment response recorded in the chart as “complete response” or “partial response”, clinical remission was defined as remission status recorded as “in remission”, and endoscopic improvement as an endoscopic assessment of normal, inactive or mild disease. Secondary outcomes included treatment persistence (patients who did not discontinue treatment during follow-up), changes in Harvey Bradshaw Index (HBI), SES-CD score, CRP, faecal calprotectin, and adverse events. Kaplan-Meier analysis was used for survival probabilities, and Mann-Whitney test compared group differences. Results The study cohort included 122 patients. The median duration of follow-up was 38.7 weeks (IQR 24.4-61.5). Clinical response rates at week 12, 28, and 52, were 78%, 69%, and 77% respectively. Clinical remission rates at week 12, 28, and 52 were 32%, 38%, and 37% respectively. Endoscopic improvement by week 52 was seen in 26% of patients who underwent endoscopy (n=35). There was no difference in rates of treatment persistence in the ustekinumab exposed group (n=45). In the overall cohort, there was no difference in median HBI score at baseline and the pre-defined time points. Median SES-CD score reduced from baseline (8 [IQR 6-11]) to week 12 (3 [0-3], p=0.009) and week 28 (6 [3-7], p=0.015). No differences between baseline SES-CD score and week 52 were seen. Median faecal calprotectin levels reduced from baseline (766μg/mg [IQR 318-1500]) to week 12 (427μg/mg [232-1096], p=0.04), week 28 (332μg/mg [59-1435], p=0.04), and week 52 (200μg/mg [54-900], p=0.048). There was a non-statistical trend towards reduction of CRP over the same time period. 13% (n=16) discontinued therapy in the follow-up period, 11 due to therapy failure, 3 due to adverse events and, 2 due to patient preference. There were 39 reported adverse events; 6 disease-related, 15 infectious (1 serious). There were 2 pregnancies during the follow-up period, with one early-term delivery and the second ongoing. Conclusion In a real-world setting risankizumab is an effective and safe therapeutic option in CD. Clinical effectiveness is comparable to other biologic therapies for CD. No new significant adverse events were identified.

P0463 Co-infection of Clostridium innocuum Worsens Outcomes in Inflammatory Bowel Disease Patients with Clostridioides difficile Infection

Abstract Background Clostridioides difficile infection (CDI) is known to trigger acute flare-ups and worsen clinical outcomes in patients with inflammatory bowel disease (IBD). Increasing evidence suggests that co-infection with Clostridium innocuum (CI), which is resistant to vancomycin, also contributes to negative outcomes. However, CI is often overlooked or misdiagnosed. No previous study has specifically examined the impact of CI co-infection in IBD patients with CDI. This study aims to address this gap. Methods This retrospective cohort study included 142 IBD inpatients at Linkou Chang Gung Memorial Hospital, Linkou, between January 2000 and May 2021, of whom 79 were diagnosed with CDI based on stool toxin A/B tests. Patients were classified into two groups: 50 with CDI alone and 29 with co-infection of CDI and CI, based on stool culture results. Clinical manifestations, outcomes, and between-group differences were analyzed using the Mann-Whitney U test, while independent risk factors were evaluated through multivariable analysis. Results Among the 79 IBD patients included, 50 had CDI and 29 had CDI with CI co-infection. In the co-infection group, the most common symptoms were bloody stool (69%) and diarrhea (65.5%) (Table 1). Clinically, the co-infection group experienced a higher rate of biological therapy failure (1 vs. 0, p = 0.050) and took longer to achieve clinical remission (6.5 vs. 2 months, p = 0.002) and steroid-free remission (11 vs. 6 months, p = 0.016). Multivariable analysis identified biologic use as the only independent predictor of CDI/CI co-infection (OR 5.375, 95% CI 1.822–15.857, p = 0.002). Conclusion Co-infection with Clostridioides difficile and Clostridium innocuum is associated with poorer outcomes in IBD patients, including prolonged time to remission and increased risk of biological therapy failure. Early recognition of CI, even in IBD patients with CDI, is crucial for improving clinical management and outcomes.

P0527 Bowel Ultrasound Scan (BUS) in Pediatric Acute Severe Colitis (ASC): a multicenter prospective study on behalf of the IBD Porto group

Abstract Background Acute severe colitis (ASC) is a potentially life-threatening event. Optimal timing for second-line treatment in children is mainly based on the clinical score Pediatric Ulcerative Colitis Activity Index (PUCAI) score. The aim of our study was to evaluate the potential role of bowel ultrasound scan (BUS) in predicting short-term treatment outcomes in pediatric ASC. Methods This was a prospective longitudinal study, conducted across ten European centers between March 2020 and March 2024. Biologic-naïve children with Ulcerative Colitis hospitalized for ASC, either at diagnosis or at disease relapse, were included. Each patient underwent two BUS, the first one within the first 48 hours of from IVCS intravenous corticosteroids administration and the second one within 5-7 days from treatment initiation. Key metrics assessed included colonic wall thickness (CWT), colonic wall stratification (CWS) and colonic wall blood flow via power Doppler. All the above-mentioned ultrasound parameters were recorded in 4 different segments of the bowel: ascending, transverse, descending, and sigmoid colon. Furthermore, Milan ultrasound criteria (MUC) score was also calculated for each colonic quadrant. Clinical, laboratory, and treatment data were gathered during hospitalization and at 2-, 4-, and 8-weeks follow-up. Results 59 patients (61% males, median age at ASC: 14.2 years) were included. Almost 60% of patients had pancolitis, 22 (37.3%) experienced ASC at disease onset. Table 1. summarizes patients’ characteristics at ASC. 38 (64.4%) patients failed to respond intravenous corticosteroids (IVCS) and required second-line therapy with infliximab (IFX). Patients who required step-up treatment with IFX had higher colonic wall thickness (CWT) and more frequently an increased vascularization (Limberg score &amp;gt; 2) (p=0.041 and p=0.005, respectively). Furthermore, patients who failed to respond to IVCS and required escalation to IFX had a higher MUC score at firs BUS (p=0.042). Ten patients (16.9%) failed to respond to medical treatment and required short-term colectomy (within 8 weeks of follow-up). Patients who required colectomy had a higher CWT both at first and at second BUS (p=0.033 and p=0.004, respectively). Moreover, patients who responded to medical therapy had higher DeltaCWT (difference between worse CWT at first and at second BUS) compared to those who required surgery (p=0.0018). Conclusion BUS may serve as an effective noninvasive tool to predict first-line therapy failure and the need for colectomy in patients with ASC. Its implementation in clinical practice may enable physician to support clinical evaluation and tailor treatment escalation upon patient’s individual characteristics.

P1089 Efficacy and safety of mirikizumab as induction and maintenance treatment in adults 60 years or older with moderately to severely active ulcerative colitis

Abstract Background Mirikizumab (MIRI), an anti-IL-23p19 antibody, has demonstrated efficacy and safety in adults with moderately to severely active ulcerative colitis (UC) in two Phase 3 trials (LUCENT-1/-2; NCT03518086, NCT03524092). [1] As novel therapies for UC are not well studied in adults ≥60 years (older adults), we aimed to evaluate the efficacy and safety of MIRI compared to placebo (PBO) during induction and maintenance treatment among this especially vulnerable subgroup of patients with UC. [2. 3] Methods In LUCENT-1, patients with UC were randomized to receive 3 intravenous (IV) doses of 300mg MIRI or PBO every four weeks (Q4W) at W0, W4, and W8. In LUCENT-2, responders to MIRI induction at W12 were re-randomized to subcutaneous (SC) 200mg MIRI or PBO Q4W for another 40 weeks (until W52 of continuous treatment). Endpoints evaluated in this post-hoc analysis included clinical response, clinical remission, symptomatic remission, endoscopic remission, corticosteroid (CS)-free remission (W52 only), histologic-endoscopic mucosal improvement (HEMI), histologic-endoscopic mucosal remission (HEMR), and bowel urgency (clinically meaningful improvement and remission). Efficacy in the subgroup of older adults was assessed at W12 and W52 using Fisher’s Exact tests. Safety data were summarized among patients aged 60 and older who received at least one dose of study treatment. Results At LUCENT-1 baseline, 13.3% of patients (n=154/1162) were ≥60 years, with a median age of 65 [Quartile (Q)1: 62.0, Q3: 69]. Apart from higher prevalence of comorbidities, longer disease duration, older age at diagnosis, and lower frequency of concomitant treatment with thiopurines, the baseline demographics and characteristics were similar to the overall patient population, including disease activity (per modified Mayo Score and Mayo Endoscopic Subscore), disease extent, and prior advanced therapy failure. At W12 and W52, a significantly greater proportion of older adults treated with MIRI vs. PBO achieved clinical response and symptomatic remission (Table 1). While the studies were not powered to detect differences between MIRI and PBO in this subgroup, there were numerically higher response rates for MIRI vs. PBO for all other outcomes. The safety profile for MIRI in older patients was consistent with the overall study population. There were no deaths and no discontinuations due to adverse events among MIRI-treated older adults (Table 2). Conclusion Mirikizumab induced and maintained clinical response and was well tolerated in patients 60 years of age and older with moderately to severely active UC. References 1)D’Haens G, Dubinsky M, Kobayashi T, et al. Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis [published correction appears in N Engl J Med. 2023 Aug 24;389(8):772. doi: 10.1056/NEJMx230004]. N Engl J Med. 2023;388(26):2444-2455. doi:10.1056/NEJMoa2207940 2)Ananthakrishnan AN, Nguyen GC, Bernstein CN. AGA Clinical Practice Update on Management of Inflammatory Bowel Disease in Elderly Patients: Expert Review. Gastroenterology. 2021;160(1):445-451. doi:10.1053/j.gastro.2020.08.060 3)Sturm A, Maaser C, Mendall M, et al. European Crohn’s and Colitis Organisation Topical Review on IBD in the Elderly. J Crohns Colitis. 2017;11(3):263-273. doi:10.1093/ecco-jcc/jjw188