International Multicenter Study Research Articles

Rectal neuroendocrine tumors: Can we predict their behavior?

Rectal neuroendocrine tumors (r-NETs) are the second most common type of neuroendocrine tumor in the gastrointestinal tract, with an increase in incidence in the last decades. They are low-grade tumors and, given their low risk of metastasis, current guidelines recommend endoscopic resection for small lesions. The GATIS predicting score, proposed by Zeng et al , represents an innovative model designed to predict individualized survival outcomes for patients with r-NETs, analyzing the relationship between clinicopathological features and patient prognoses. The authors identified tumor grade, T stage, tumor size, age, and prognostic nutritional index as key prognostic factors, demonstrating that the GATIS Score provides a more accurate prognosis assessment compared to the World Health Organization classification or the tumor-node-metastasis staging system. Nevertheless, further larger prospective studies are necessary, and the scientific community's efforts in this context should be directed toward developing international multicentric prospective studies, with the ultimate aim of accurately defining and understanding the behavior of these conditions.

Predicting futile outcomes following deceased donor liver transplantation in non-Hcc patients with MELD-Na score above 30: a retrospective international multicenter cohort study.

In the current "sickest first" allocation policy for limited deceased liver grafts, identifying patients "too sick to transplant" before transplantation is crucial to optimize outcomes. This study aimed to predict futile outcomes following deceased donor liver transplantation (DDLT) in patients with Model for End-Stage Liver Disease-Sodium (MELD-Na) scores ≥30. This international multicenter study was conducted as part of the International Society of Liver Surgeons. We collected data from patients with a MELD-Na score ≥30 who underwent DDLT. A total of 994 patients were enrolled between 2010-2021, including 654 from the Republic of Korea, 224 from the US, and 116 from other regions. Futility was defined as death within three months or during the hospital stay following a DDLT. After exclusion, 160 (16.6%) patients were classified into a futile group and 803 (83.4%) into a non-futile group. The MELD-Na scores collected at three time points (listing, matching, and transplantation) were comparable between the groups (P=0.442, P=0.180, and P=0.554, respectively). Regarding concomitant organ failure factors, the futile group showed a higher incidence of organ dysfunction across all measured parameters, including the use of mechanical ventilators, continuous renal replacement therapy (CRRT), pneumonia, bacteremia, and vasopressor use (all P<0.01). Independent risk factors for futile outcome were recipient age (≥65years), body mass index (<18.5kg/m2), mechanical ventilator use, CRRT (≥1week), and prolonged ICU stay before transplantation (≥2weeks). The futility rate was 53.3% in patients with ≥3 risk factors (P<0.001). We developed a nomogram to predict futility after DDLT based on multivariate regression analysis, which showed a better predictive power than previous models. The risk factors and new nomogram, which adequately reflect concomitant organ failure before liver transplantation, could effectively predict the risk of futile outcomes after DDLT and contribute to decision-making regarding transplantation eligibility in clinical practice.

FIB-4plus Score: A novel machine learning-based tool for screening high-risk varices in compensated cirrhosis (CHESS2004): An international multicenter study.

A large percentage of patients undergoing esophagogastroduodenoscopy (EGD) screening do not have esophageal varices (EV) or have only small EV. We evaluated a large, international, multicenter cohort to develop a novel score, termed FIB-4plus, by combining the fibrosis-4 (FIB-4) score, liver stiffness measurement (LSM), and spleen stiffness measurement (SSM) to identify high-risk EV (HRV) in compensated cirrhosis. This international cohort study involved patients with compensated cirrhosis from 17 Chinese hospitals and one Croatian institution (NCT04546360). Two-dimensional shear wave elastography-derived LSM and SSM values, and components of the FIB-4 score (i.e., age, aspartate aminotransferase, alanine aminotransferase, and platelet count [PLT]) were combined using machine learning algorithms (logistic regression [LR] and extreme gradient boosting [XGBoost]) to develop the LR-FIB-4plus and XGBoost-FIB-4plus models, respectively. Shapley Additive exPlanations method was used to interpret the model predictions. We analyzed data from 502 patients with compensated cirrhosis who underwent EGD screening. The XGBoost-FIB-4plus score demonstrated superior predictive performance for HRV, with an area under the receiver operating characteristic curve (AUROC) of 0.927 (95% CI: 0.897-0.957) in the training cohort (n=268), and 0.919 (95% CI: 0.843-0.995) and 0.902 (95% CI: 0.820-0.984) in the first (n=118) and second (n=82) external validation cohorts, respectively. Additionally, the XGBoost-FIB-4plus score exhibited high AUROC values for predicting EV across all cohorts. The FIB-4plus score outperformed the individual parameters (LSM, SSM, PLT, and FIB-4). The FIB-4plus score effectively predicted EV and HRV in patients with compensated cirrhosis, providing clinicians with a valuable tool for optimizing patient management and outcomes.

Detection of Echinococcus spp. and other taeniid species in lettuces and berries: Two international multicenter studies from the MEmE project.

Cystic and alveolar echinococcosis are severe zoonotic diseases characterized by long asymptomatic periods lasting months or years. Viable Echinococcus spp. eggs released into the environment through the feces of canids can infect humans through accidental ingestion via hand-to-mouth contact or consumption of contaminated food or water. Both Echinococcus multilocularis and Echinococcus granulosus sensu lato are considered as foodborne parasites. However, when considering possible pathways of human infection, it appears that food and water-borne related variables do not significantly increase the risk of infection. Providing evidence-based data for the presence of DNA and, potentially, eggs in fresh produce is crucial in understanding foodborne transmission of Echinococcus spp. to humans. Two multicenter and multicountry studies were conducted within the One Health EJP framework to estimate the proportion of lettuces and berries contaminated by E. multilocularis, E. granulosus sensu lato, and other taeniid DNAs from a total of 12 European countries, Tunisia and Pakistan. A total of 1117 lettuces, 71 others vegetables, 300 strawberries, 130 blueberries and 50 others berries samples were collected and analysed by washing, sequential sieving and real-time PCRs. E. multilocularis DNA was detected in 1.2% (7/570) of lettuce samples tested from the seven European endemic countries (Denmark, France, Germany, Latvia, the Netherlands, Poland and Switzerland) and in 2% (2/100) from Pakistan. E. granulosus sensu lato DNA was identified in 1.3% of lettuces (9/695) collected in five European endemic countries (France, Italy, Latvia, Poland and Portugal) and in 12% (9/75) and 4% (4/100) from Tunisia and Pakistan, respectively. All E. granulosus sensu lato samples were identified as E. granulosus sensu stricto (20/22), except for two identified as E. canadensis (2/22) from Latvia and Pakistan. Regarding berries, E. multilocularis DNA was detected in 5.4% (n=11/202) of strawberries, 7.3% (6/82) of blueberries from the seven European endemic countries and 56% (14/25) of blueberries from Pakistan. High contamination rates of E. granulosus sensu stricto were found outside of Europe, with 12.0% (3/25) in blueberries from Pakistan and 81.3%. (13/16) in strawberries from Tunisia. The total contamination rate of all taeniid species DNA in lettuces (5.3%; 59/1117), others vegetables (5.6%; 4/71) and berries (12.1%; 58/480) suggests that the transfer of taeniid eggs from carnivore feces to food is not uncommon. Although we assume that eggs are the source of the DNA detected in this study, the viability of such eggs is unknown. The detection of Echinococcus species in lettuces and berries suggests a potential risk of foodborne human infection. The relative contribution of this risk remains to be estimated. Further studies on food and environmental contamination are necessary to cover different epidemiological contexts and social habits, leading to a better understanding of human infections by Echinococcus spp. eggs.

Diagnostic and prognostic relevance of inflammatory markers in surgically treated thymic epithelial tumors: An international multicenter study.

Complementary prognostic markers are needed in thymic epithelial tumors (TETs) to aid patient stratification and determine the most appropriate follow-up strategies. This study aimed to assess the diagnostic and prognostic relevance of blood-based inflammatory markers in a large cohort of surgically treated TET patients. A total of 743 TET patients who underwent surgical resection between 1999-2021 were included in this multicenter study. Inflammatory markers were recorded from the most recent preoperative blood cell count prior to surgery. Measured variables were rescaled and harmonized to obtain comparable values across the participating centers. Preoperative CRP was significantly higher in TET patients with increased tumor size (vs. those with T1 tumors, p=0.035). Likewise, neutrophil-to-lymphocyte ratio (NLR) (p=0.002) and platelet-to-lymphocyte ratio (PLR) (p<0.001) were both significantly higher in thymic carcinomas than in thymomas. Notably, increased NLR and PLR were mainly attributed to significantly decreased lymphocyte levels in thymic carcinoma patients. Concerning survival outcomes, we found that elevated PLR and fibrinogen influenced overall survival (OS) (p=0.002 and p=0.018, respectively) and cause-specific survival (CSS) (p=0.002 and p=0.009, respectively) independently of other variables in our multivariate models, and they constituted negative prognosticators in TETs. Elevated CRP had an independent negative impact only on OS. Although elevated NLR was linked with impaired prognosis in our univariate model (p=0.008), its independent prognostic significance could not be validated. Using the so-far largest cohort of surgically treated TET patients, our study demonstrates that CRP, PLR, and NLR have diagnostic significance in TETs, while elevated PLR and fibrinogen constitute independent negative prognosticators for OS and CSS. Accordingly, the current multicenter study offers additional guidance in developing personalized surveillance protocols in thymoma and thymic carcinoma.

Clinical outcomes and management following progressive disease with anti-PD-(L)1 therapy in patients with advanced Merkel Cell Carcinoma.

Merkel Cell Carcinoma (MCC) is a rare skin cancer with a rising incidence worldwide. Anti-programmed death-1/ligand-1 (anti-PD-(L)1) therapies are effective for the treatment of advanced MCC. This study examines patterns of response / progression of advanced MCC to anti-PD-(L)1 therapies and describes subsequent management. This is a multi-centre international retrospective cohort study with data collected up to May 2023 from 17 centres across 6 countries. Outcomes included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) for anti-PD-(L)1 and subsequent therapy. One-hundred and eighty-five advanced MCC patients received anti-PD-(L)1 therapy. At median follow-up of 28.7 months (95 % CI: 21.4-38.3), ORR was 57.3 %, median DOR was 42.8 months (95 % CI, 25.8 - not reached (NR)), median PFS was 14 months (95 % CI, 8.1- 19.8), and median OS was 42.8 months (95 % CI, 30.3 - NR). One-hundred and eight patients (59 %) experienced progressive disease; 50 % (n = 54/108) with primary resistance and 26 % (n = 28/108) with secondary resistance. Fifty patients (27 %; n = 50/185) received subsequent systemic therapies (+/- local therapy) with response data; 18 (36 %; n = 18/50) received doublet platinum chemotherapy (ORR 67 %, DOR 5.0 months [95 % CI; 3.7 - NR]) and 16 (32 %; n = 16/50) were rechallenged with anti-PD-(L)1 (ORR 56 %, DOR 20.2 months [95 % CI; 8.3 - NR]). The most common subsequent treatment for patients with primary resistance was chemotherapy, while those with secondary resistance most frequently underwent further anti-PD-(L)1 therapy in combination with other therapies. Despite both therapies demonstrating promising ORR, doublet platinum chemotherapy had a poorer DOR compared to anti-PD-(L)1 rechallenge.

Reappraising prediction of surgical complexity of non-functioning pituitary adenomas after transsphenoidal surgery: the modified TRANSSPHER grade

PurposePrognostication of surgical complexity is crucial for optimizing decision-making and patient counseling in pituitary surgery. This study aimed to develop a clinical score to predict gross-total resection (GTR) in non-functioning pituitary adenomas (NFPAs) using externally validated machine-learning (ML) models.MethodsClinical and radiological data were collected from two tertiary medical centers. Patients had pre- and postoperative structural T1-weighted MRI with gadolinium and T2-weighted preoperative scans. Three ML classifiers were trained on the National Hospital for Neurology and Neurosurgery dataset and tested on the Foundation IRCCS Ca’ Granda Polyclinic of Milan dataset. Feature importance analyses and hierarchical-tree inspection identified predictors of surgical complexity, which were used to create the grading score. The prognostic performance of the proposed score was compared to that of the state-of-the art TRANSSPHER grade in the external dataset. Surgical morbidity was also analyzed.ResultsAll ML models accurately predicted GTR, with the random forest classifier achieving the best performance (weighted-F1 score of 0.87; CIs: 0.71, 0.97). Key predictors—Knosp grade, tumor maximum diameter, consistency, and supra-sellar nodular extension—were included in the modified (m)-TRANSSPHER grade. The ROC analysis showed superior performance of the m-TRANSSPHER grade over the TRANSSPHER grade for predicting GTR in NFPAs (AUC 0.85 vs. 0.79).ConclusionsThis international multi-center study used validated ML algorithms to refine predictors of surgical complexity in NFPAs, yielding the m-TRANSSPHER grade, which demonstrated enhanced prognostic accuracy for surgical complexity prediction compared to existing scales.

Impact of baseline alterations in HER2-pathway oncogenic drivers on response to anti-HER2 therapy in patients (pts) with HER2-amplified advanced colorectal cancer (aCRC).

243 Background: HER2-amplified aCRC is associated with poor prognosis despite new anti-HER2 regimens. Insight on biomarkers that predict response to these therapies is limited. This study aims to evaluate whether baseline alterations in oncogenic drivers along the HER2 pathway predict response to anti-HER2 therapy in HER2-amplified aCRC. Methods: In this international multi-center study involving Mayo Clinic, Duke Cancer Institute and National Cancer Center Hospital East (Japan), we collected baseline genomic alterations from tissue or blood samples using next-generation sequencing (NGS) prior to anti-HER2 therapy initiation. We defined PIK3CA, RAS, RAF, MAP2K, and MET as oncogenic drivers of resistance within the HER2 pathway. Overall survival (OS) was evaluated with the Kaplan-Meier method and a log-rank test was used to compare median OS (mOS) between pts with and without alterations in the above genes. A chi-square test (significance level 0.05) was performed to compare overall response rate (ORR) and disease control rate (DCR). Results: We identified 39 pts with HER2-amplified aCRC and baseline NGS. Median age was 57 (range 30-77), 54% were male. Baseline alterations in HER2 pathway oncogenic drivers were identified in 17 pts (43.5%). 18 (46%) received monoclonal antibodies (mAbs) plus tyrosine kinase inhibitors, 12 (30%) received dual mAbs and 7 (18%) received trastuzumab deruxtecan. The mOS was 41.9 months (mos) (95%CI 23.7-60.1) for other alterations vs 24.2 mos (95%CI 14.1-34.3) in pts with HER2 pathway alterations (p = 0.1). ORR was 47% vs 41% (p = 0.7) and DCR 82% vs 73% (p = 0.4), for pts with HER2 pathway alterations and without HER2 pathway alterations, respectively. 4 pts receiving trastuzumab/tucatinib had complete response, none of which had HER2 pathway alterations. Conclusions: Pts with baseline alterations in oncogenic drivers of the HER2 pathway had clinically worse outcomes compared to pts without such alterations despite receiving HER2-targeted therapy, though results lacked statistical significance. Larger studies are needed to confirm the lack of benefit from anti-HER2 therapy in this subgroup.

Validation of the PANAMA-Score for Survival and Benefit of Adjuvant Therapy in Patients with Resected Pancreatic Cancer After Neoadjuvant FOLFIRINOX.

To validate the prognostic value of the PAncreatic NeoAdjuvant MAssachusetts (PANAMA)-score and to determine its predictive ability for survival benefit derived from adjuvant treatment in patients after resection of pancreatic ductal adenocarcinoma (PDAC) following neoadjuvant FOLFIRINOX. The PANAMA-score was developed to guide prognostication in patients after neoadjuvant therapy and resection for PDAC. As this score focuses on the risk for residual disease after resection, it might also be able to select patients who benefit from adjuvant after neoadjuvant therapy. This retrospective international multicenter study is endorsed by the European-African Hepato-Pancreato-Biliary Association (E-AHPBA). Patients with PDAC who underwent resection after neoadjuvant FOLFIRINOX were included. Mantel-Cox regression with interaction analysis was performed to assess the impact of adjuvant chemotherapy. Overall, 383 patients after resection of PDAC following neoadjuvant FOLFIRINOX were included of whom 187 (49%), 137 (36%), and 59 (15%) had a low-risk, intermediate-risk, and high-risk PANAMA-score, respectively. A discrimination in median OS was observed stratified by risk groups (48.5, 27.6, and 22.3 months, Log-Rank-Plow-intermediate=0.004, Log-Rank-Pintermediate-high=0.027). Adjuvant therapy was not associated with an OS difference in the low-risk group (HR 1.50, 95%CI:0.92-2.50), whereas improved OS was observed in the intermediate (HR 0.58, 95%CI:0.34-0.97) and high-risk groups (HR 0.47, 95%CI:0.24-0.94) (p-interaction=0.008). The PANAMA 3-tier risk groups (low-risk, intermediate-risk, and high-risk, available via pancreascalculator.com) correspond with differential survival in patients with resected PDAC following neoadjuvant FOLFIRINOX. The risk groups also differentiate between survival benefit associated with adjuvant treatment, with only the intermediate- and high-risk groups associated with improved OS.

SELective defunctioning Stoma Approach in low anterior resection for rectal cancer (SELSA): Protocol for a prospective study with a nested randomized clinical trial investigating stoma-free survival without major LARS following total mesorectal excision.

Accumulated data suggest that routine use of defunctioning stoma in low anterior resection for rectal cancer may cause kidney injury, bowel dysfunction and a higher risk of permanent stomas. We aim to study whether avoidance of a diverting stoma in selected patients is safe and reduces adverse consequences. SELSA is a multicentre international prospective observational study nesting an open-label randomized clinical trial. All patients with primary rectal cancer planned for low anterior resection are eligible. Patients operated with curative intent, aged <80 years, with an American Society of Anaesthesiologists' fitness grade I or II, and a low predicted risk of anastomotic leakage are eligible to 1:1 randomization between no defunctioning stoma (experimental arm) or a defunctioning stoma (control arm). The primary outcome is the composite measure of 2-year stoma-free survival without major low anterior resection syndrome (LARS). Secondary outcomes include anastomotic leakage, postoperative mortality, reinterventions, stoma-related complications, quality of life measures, LARS score, and permanent stoma rate. To be able to state superiority of any study arm regarding the main outcome, with 90% statistical power and assuming 25% attrition, we aim to enrol 212 patients. Patient inclusion will commence in the autumn of 2024. The SELSA study is investigating a tailored approach to defunctioning stoma use in low anterior resection for rectal cancer in relation to the risk of anastomotic leakage. Our hypothesis is that long-term effects will favour the selective approach, enabling some patients to avoid a defunctioning stoma. Swedish Ethical Review Authority approval (2023-04347-01, 2024-02418-02 and 2024-03622-02), Regional Ethics Committee Denmark (H-24014463), and ClinicalTrials.gov (NCT06214988).

P-1920. The influence of comorbidity, age, sex, and immunosuppression on COVID-19 mortality throughout the course of the SARS-CoV-2 pandemic in Europe: Data from the LEOSS study

Abstract Background Population immunity against SARS-CoV-2 has increased, resulting in a decline of COVID-19 mortality. The aim of the study was to analyse the COVID-19-related mortality over the pandemic, stratified by a model of groups at risk of severe COVID-19. Predicted probability of COVID-19-related death in dependence of age and SARS-CoV-2 variant. Methods COVID-19-related patients were included from January 2020 to November 2022 using the international multicentric cohort study Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS). Predicted probability of COVID-19-related death was calculated using a multivariate logistic regression model adjusted to age, gender and vaccination status.Figure 2:Predicted probability of COVID-19-related death in dependence of gender and SARS-CoV-2 variant. Results In total, 12,096 patients were included. The overall mortality was 13% (n=1546), decreasing from 14% during the wildtype (wt) period (01/2020-12/2020), to 13%, 10%, and 6% in the alpha (α) (01/2021-06/2021), delta (δ) (07/2021-12/2021), and omicron (Ω) (01/2022-11/2022) periods, respectively. Patients aged 66-75, 76-85, and &amp;gt;85 years (y) had a 13.3-, 22.5-, and 40.4-fold higher odds of mortality compared to 26-35y old patients (p&amp;lt; 0.001 in all listed comparisons). This increase in mortality between younger (age: 26-35y, mortality: wt 2%, Ω 1%) and older patients (age: &amp;gt;85y, mortality: wt 41%, Ω 23%) decreased with the shift from wt (increase of 39 percentage points) to Ω (increase of 22 percentage points) (Fig. 1). The overall mortality in males (m) (15%) was higher than in females (f) (10%), but this gender-specific difference leveled off with the shift from wt (m: 19%, f: 10%) to Ω (m: 9%, f: 9%) (Fig. 2). Referring to the difference in mortality between patients with zero and four comorbidities, the predicted increase in mortality during the periods wt, α, δ, and Ω was 14, 14, 1, and 0 percentage points, respectively (Fig. 3). Concerning severely immunosuppressed patients, mortality significantly decreased throughout the pandemic (wt: 15%, Ω: 4%, p=0.031) (Fig. 4).Figure 3:Predicted probability of COVID-19-related death in dependence of number of comorbidities and SARS-CoV-2 variant.Comorbidities include cardiovascular diseases, renal diseases, diabetes, pulmonary diseases, liver diseases, rheumatic diseases, haemato-oncological diseases, neurological diseases, autoimmune diseases and HIV/AIDS. Conclusion Overall mortality decreased during the pandemic. This change was observed even among severely immunosuppressed patients. Age, gender, and the number of comorbidities were identified as relevant mortality risk factors, with decreasing importance as the pandemic progressed.Figure 4:Subgroup analysis for severely immunosuppressed patients.Severely immunosuppressed group, including: stem cell transplant, organ transplant, b-cell depletion, autoimmune disease, immunosuppressive therapy (corticosteroids, methotrexate, azathioprine, ciclosporin, calcineurin-inhibitors, mTOR-inhibitors). Disclosures Jochen Schneider, n/a, AbbVie: Grant/Research Support|AbbVie: Honoraria|AbbVie: non-financial support|Central Innovation Program for small and medium-sized enterprises: Grant/Research Support|Central Innovation Program for small and medium-sized enterprises: Honoraria|Central Innovation Program for small and medium-sized enterprises: Central Innovation Program for small and medium-sized enterprises|Deutsche Forschungsgemeinschaft: Grant/Research Support|Deutsche Forschungsgemeinschaft: Honoraria|Deutsche Forschungsgemeinschaft: non-financial support|Diasorin: Grant/Research Support|Diasorin: Honoraria|Diasorin: non-financial support|Dr. Falk Pharma GmbH: Grant/Research Support|Dr. Falk Pharma GmbH: Honoraria|Dr. Falk Pharma GmbH: non-financial support|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|Gilead Sciences: non-financial support|GSK/ViiV Healthcare: Grant/Research Support|GSK/ViiV Healthcare: Honoraria|GSK/ViiV Healthcare: non-financial support|Janssen-Cilag: Grant/Research Support|Janssen-Cilag: Honoraria|Janssen-Cilag: non-financial support|MSD: Grant/Research Support|MSD: Honoraria|MSD: non-financial support|Takeda Pharmaceutical: Grant/Research Support|Takeda Pharmaceutical: Honoraria|Takeda Pharmaceutical: non-financial support Christoph Spinner, MD, AbbVie: Honoraria|Apeiron: Honoraria|AstraZeneca: Grant/Research Support|AstraZeneca: Honoraria|BBraun Melsungen: Honoraria|BBraun Melsungen: non-financial support|BioNTech: Honoraria|Cepheid: Grant/Research Support|Eli Lilly: Honoraria|Formycon: Honoraria|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|Gilead Sciences: non-financial support|GSK: Honoraria|Janssen-Cilag: Grant/Research Support|Janssen-Cilag: Honoraria|Molecular partners: Honoraria|MSD: Grant/Research Support|MSD: Honoraria|Pfizer: Honoraria|Roche: Honoraria|Shionogi: Honoraria|SOBI: Honoraria|Synairgen: Honoraria|ViiV Healthcare: Grant/Research Support|ViiV Healthcare: Honoraria Maria JGT Vehreschild, Prof. Dr. med., 3M: Honoraria|Ärztekammer Niedersachsen: Honoraria|ADKA: Honoraria|Akademie für Infektionsmedizin: Honoraria|Astellas: Honoraria|Berliner Dialy Seminar: Honoraria|Biontech: Grant/Research Support|CED Service: Honoraria|DiaLog Service: Honoraria|EUMEDICA: Advisor/Consultant|EUMEDICA: Honoraria|Falk Foundation: Honoraria|Ferring: Honoraria|Forum für medizinische Fortbildung Gmbh: Honoraria|GILEAD: Honoraria|Heel: Grant/Research Support|Helios Kliniken: Honoraria|Institute Merieux: Honoraria|Janssen: Honoraria|Kit Kongress: Honoraria|Klinikum Essen: Honoraria|Klinikum Leverkusen: Honoraria|Lahn-Dill-Kliniken: Honoraria|Landesärztekammer Hessen: Honoraria|Limbach Gruppe SE: Honoraria|MaaT: Advisor/Consultant|MSD: Advisor/Consultant|MSD: Grant/Research Support|MSD: Honoraria|Pfizer: Honoraria|Roche: Advisor/Consultant|Roche: Grant/Research Support|SD Biosensor: Grant/Research Support|St. Johannes Hospital: Honoraria|St. Josef Hospital: Honoraria|SUMIT OXFORD Ltd.: Honoraria|Tillotts: Advisor/Consultant|Tillotts: Honoraria|Uniklinik Frankfurt: Honoraria|Uniklinik Köln: Honoraria|Uniklinik Karlsruhe: Honoraria|Universitätsklinikum Freiburg: Honoraria|Universitätsklinikum Heidelberg: Honoraria Floran Voit, MD, Gilead Sciences: Honoraria|Gilead Sciences: non-financial support|MSD: Grant/Research Support|Pfizer: non-financial support|ViiV Healthcare: non-financial support Johanna Erber, Dr. med., Gilead Sciences: non-financial support|Pfizer: non-financial support|Tillotts Pharma AG: non-financial support|ViiV Healthcare: non-financial support

Rational and design of EACVI-MMVD study: an international registry on multimodality imaging for mixed and multiple valvular heart disease

Abstract Background Despite the high frequency of multiple (combination of stenotic or regurgitant lesions occurring on ≥2 cardiac valves) and mixed (combination of stenotic and regurgitant lesions on the same valve) valvular heart disease (MMVD) in clinical practice, comprehensive insights into its clinical presentation, management strategies, impact of multimodality imaging, and outcomes are not well established. Objective The "EACVI-MMVD Study" will be the first prospective international study assessing all consecutive patients with MMVD to assess its proportion, and describe baseline epidemiological, cardiovascular imaging, management, and prognosis data. Methods International prospective, multicentre, observational study led by the Heart Imagers of Tomorrow (HIT) of the European Association of Cardiovascular Imaging (EACVI) to include all consecutive patients with at least 2 moderate-to-severe VHD involving ≥2 different valves, according to the current ESC guidelines, and/or mixed VHD, defined as at least moderate stenosis and at least moderate regurgitation of a single valve, according to the current ESC guidelines. The recruitment is ongoing over 6 months, involving more than 100 centres across 30 countries. Inclusion and exclusion criteria are provided in Table 1. Results The primary outcome will be the proportion of MMVD cases assessed in echocardiographic labs over 6 months. We will then describe the clinical presentation, management strategies, cardiovascular imaging data, and 1-year prognosis of these MMVD patients (Figure 1). Physicians will determine baseline evaluation, which may include the full spectrum of multimodality imaging, such as transthoracic and transoesophageal echocardiography, stress echocardiography, computed tomography, and cardiovascular magnetic resonance. Optionally, three dedicated core laboratories will analyse cardiovascular imaging data from participating centres. Conclusion The EACVI-MMVD study will be the first and largest international multicentre study evaluating the prevalence of MMVD in clinical practice and determining the impact of multimodality imaging in MMVD patients. Table1 Inclusion and exclusion criteria Figure 1 Overview of the study

DOP044 Active disease on intestinal ultrasound in pregnancy is associated with an increased risk of adverse obstetric and neonatal outcomes: an international multi-centre prospective cohort study.

Abstract Background Clinically active inflammatory bowel disease (IBD) impacts 30-50% of women antenatally1,2. Such clinically active disease is associated with an increased risk of adverse pregnancy outcomes, including preterm delivery2. However, the validity of clinical scores to assess antenatal disease activity has been questioned, whilst both faecal calprotectin (FCP) and intestinal ultrasound (IUS) are feasible and accurate in pregnancy3,4. We aimed to assess whether active disease defined by IUS may predict adverse obstetric outcomes in pregnant women with IBD. Methods This international multi-centre prospective cohort study recruited both preconception and pregnant individuals with IBD in Australia and the USA from 2017-2023. Participants underwent clinical assessments and FCP testing six months before conception, in each trimester (T1, T2, and T3), and, when feasible, six weeks postpartum. IUS was performed preconception and in T1 and T2. Clinically active disease in pregnancy was defined by a PGA&amp;gt;1, or a HBI&amp;gt;5 or SCCAI &amp;gt;3. A FCP&amp;gt;100μg/g was considered elevated, and IUS remission was defined as a bowel wall thickness of &amp;lt;3mm in all bowel segments, with normal bowel wall stratification, a lack of extra-mural complications, and an absence of mesenteric fat hypertrophy or hyperaemia. Univariable and multivariable binary logistic regression analyses including relevant confounders were used to determine the independent impact of IUS disease activity on obstetric outcomes. Cohen κ coefficients were used to determine agreement between FCP, IUS and clinical disease activity. Results 379 participants, 200 with Crohn’s Disease (CD), were recruited. Overall, rates of adverse obstetric outcomes were comparable to the general population (Figure 1). Maximal bowel wall thickness (BWT) &amp;gt;6mm in T1 was associated with a three-fold increased risk of neonatal intensive or special care unit admission (RR 3.10;1.27-7.54, p=0.013) and in T2 was associated with a four-fold increased risk of prematurity (4.51; 1.45-14.04, p=0.009). IUS hyperaemia in T2 was associated with a three-fold increase in preeclampsia risk (3.61; 1.07-12.15, p=0.038). FCP &amp;gt;100μg/g in T2 was associated with an increased risk of preterm delivery after adjusting for clinical disease activity (RR 2.90; 1.22-7.50, p=0.028). Agreement between clinical (HBI or SCCAI) and IUS/FCP activity during pregnancy was weak (Figure 2). Conclusion Sub-clinical disease activity identified on IUS in pregnancy is associated with an increased risk of pre-term delivery, with poor agreement between clinical symptoms and objective biomarkers of disease activity during pregnancy. IUS monitoring should be performed as part of routine antenatal IBD care and IUS remission targeted.

OP05 Efficacy and safety of autologous hematopoietic stem cell transplantation in refractory Crohn’s disease: outcomes from the international stem cell transplant consortium

Abstract Background Autologous hematopoietic stem cell transplant (HSCT) emerged as a treatment for refractory CD after several clinical studies including a randomized clinical trial (ASTIC).1,2 In CD patients at risk for bowel failure these studies demonstrated an endoscopic response in over 80% of patients with two transplant related deaths. A recent randomized trial using an alternative fludarabine-based conditioning regimen had unexpected safety outcomes with 2 deaths and renal failure secondary to thrombotic microangiopathy.3 Here we report recent long-term clinical and safety outcomes of HSCT for refractory CD using a cyclophosphamide-ATG conditioning regimen from 3 international centers. Methods Data from 100 patients was reviewed from 3 international centers (Barts Health, UK; Hospital Clinic Barcelona, Spain and Mount Sinai, US) for subjects with medically refractory CD that underwent HSCT. We compiled clinical (CDAI) and endoscopic (SES-CD) evaluations at baseline and the last documented follow-up after HSCT for 68 patients that underwent HSCT since the ASTIC trial. We further compiled additional outcomes including new initiation of advanced therapy, IBD-related surgery, need for parental nutrition, hospitalizations and death. Results As of the last follow-up (median 2 years) post-HSCT, 75% of patients had endoscopic improvement (SES CD↓50%) and 53% endoscopic remission (SESCD&amp;lt;4 ulcer sub-score&amp;lt;1) (N = 56)(Figure 1). 65% of patients were in clinical remission. 46% did not require advanced therapy following HSCT and of patients that started an advanced therapy 84% required a single therapy over 120 patient-years of follow-up (Figure 2). After HSCT there were 7 CD-related surgeries of which 2 were ileostomy reversals. No patients progressed to bowel failure and there were no long-term (&amp;gt;100 days post-HSCT) complications related to transplant including hospitalization, renal failure, death or malignancy. Conclusion In this multicenter international study, the majority of patients demonstrated sustained endoscopic and clinical improvement without progression to bowel failure or with long-term transplant related adverse events over 120 patient-years of follow up. These results support HSCT as a therapy for highly refractory CD patients and the need to refer these patients to international centers of expertise to prevent CD-related morbidity and mortality.

DOP055 Upadacitinib for induction of remission in pediatric Crohn’s disease: An international multicenter study

Abstract Background Data on upadacitinib therapy in children with Crohn’s disease (CD) are scarce. We aimed to evaluate the effectiveness and safety of upadacitinib as an induction therapy in pediatric CD. Methods A multicenter retrospective study of children treated with upadacitinib for the induction of remission of active CD from 30 centers worldwide affiliated with the IBD Interest and Porto group of the ESPGHAN between 2022 and 2024. Demographic, clinical, laboratory, and imaging data as well as adverse events (AEs) were recorded at week 8 post induction. The analysis of the primary outcome was based upon the intention-to-treat (ITT) principle. Results One-hundred children (median age 15.8 [interquartile range 14.3–17.2] years) were included. All children were previously treated with biologic therapies and 89 with ≥2 biologics. At the end of the 8-week induction period, clinical response, clinical remission and corticosteroid- and exclusive enteral nutrition-free clinical remission (CFR) were observed in 75%, 56% and 52% of the children, respectively. Normal C-reactive protein was achieved in 68% of the children and fecal calprotectin (FC) &amp;lt;150 mcg/g in 58%. Combined CFR and FC remission was observed in 13/31 (42%) children with available data at 8 weeks [13% of the ITT population]. AEs were recorded in 24 children, the most frequent was acne (n=12). Two AEs (severe acne and hypertriglyceridemia) led to discontinuation of therapy. Conclusion Upadacitinib is an effective induction therapy for refractory pediatric CD. Efficacy should be weighed against the potential risks of AEs.

DOP051 Upadacitinib for induction of remission in pediatric Ulcerative Colitis: An international multicenter study

Abstract Background Data on upadacitinib therapy in children with ulcerative colitis (UC) or unclassified inflammatory bowel disease (IBD-U) are scarce. We aimed to evaluate the effectiveness and safety of upadacitinib as an induction therapy in pediatric UC or IBD-U. Methods In this multicenter retrospective study, children treated with upadacitinib for induction of remission of active UC or IBD-U from 30 centers worldwide were enrolled. Demographic, clinical and laboratory data as well as adverse events (AEs) were recorded at week 8 post induction. Results One hundred children were included (90 UC and 10 IBD-U, median age 15.6 [interquartile range 13.3–17.1] years). Ninety-eight were previously treated with biologic therapies, and 76 were treated with ≥2 biologics. At the end of the 8-week induction period, clinical response, clinical remission, and corticosteroid-free clinical remission (CFR) were observed in 84%, 62%, and 56% of the children, respectively. The median pediatric ulcerative colitis activity index (PUCAI) decreased from 45 [33-60] to 0 [0-20] at week 8 (p &amp;lt; 0.001; Figure 1). Normal C-reactive protein and fecal calprotectin (FC) &amp;lt;150 mcg/g were achieved in 75% and 50%, respectively. The median FC level declined from 1645 [628-2263] mcg/g at baseline to 140 [33-669] mcg/g at week 8 (p &amp;lt; 0.001) (Figure 1).Combined CFR and FC remission was observed in 18/46 (39%) children with available data at 8 weeks. AEs were recorded in 37 children, including one serious AE of an appendiceal neuroendocrine tumor. The most frequent AEs were hyperlipidemia (n=13), acne (n=12), and infections (n=10, five of whom with herpes viruses). Conclusion In this largest and first multicenter study on a cohort of children with UC treated with upadacitinib, upadacitinib was an effective induction therapy for refractory pediatric UC and IBD-U. Efficacy should be weighed against the potential risks of AEs.

P1064 Association of subcutaneous infliximab CT-P13 serum levels and therapeutic outcomes in patients affected by Inflammatory Bowel Disease: A retrospective international multicentric study

Abstract Background The association between therapeutic outcomes and serum levels associated with the use of subcutaneous (SC) IFX CT-P13 in patients with inflammatory bowel disease [IBD] has been poorly studied. We aimed to define SC-IFX thresholds associated with therapeutic outcomes. Methods Patients receiving SC-IFX who had at least one therapeutic drug monitoring [TDM] were enrolled. Therapeutic outcomes were assessed as follows: clinical remission [HBI &amp;lt;5, SCCAI ≤2]; fecal calprotectin [FCAL] remission [&amp;lt;250 mg/g]; C-reactive protein [CRP] remission [CRP &amp;lt;5 mg/L]; deep remission [clinical + biomarker remission]. Chi-squared test for trend was used to analyze serum levels quartile data. Results 177 patients [54% male; 67% Crohn’s disease; Weight ≥ 80 kg 51%; 7% active smoker; 39% on immunosuppressants [IMM]; 9% on steroids; 26% with previous biologic exposure] from 4 centres had a total of 263 TDM measurements. Of these, were available 242 concurrent clinical measurement, 244 CRP and 152 FCAL.Median duration of SC treatment at time of TDM was 24 months (4-135). Proportion of patients achieving outcomes is described in table 1. The median IFX serum level was significantly higher in patients with clinical remission as well as in those with clinical and CRP remission (Figure 1), compared with patients who did not reach these targets. Conversely, there was no significant difference for the FCAL, clinical and FCAL, clinical and CRP and FCAL outcomes. In univariate analysis of factors associated with clinical remission (p&amp;lt;0.1) were sex, concomitant IMM, concomitant steroids, and previous biologic exposure and were included in a multivariate analysis in which only concomitant IMM showed remained significant [OR 0,1796 CI 95% 0,028-0,633]. Quartile analysis showed better outcome on higher drug levels for clinical remission, but not for other outcomes. Based on the ROC analysis and the Youden index, the cut-off levels for the therapeutic outcomes were respectively: clinical remission 12.85 mg/ml [sensitivity 0.85, specificity 0.5]; FCAL remission 11.8 mg/ml [sensitivity 0.82, specificity 0.32]; clinical and CRP remission 14.55 mg/ml [sensitivity 0.77, specificity 0.44]; clinical and FCAL remission 12.05 mg/ml [sensitivity 0.85, specificity 0.35]; clinical, CRP and FCAL remission12.05 mg/ml [sensitivity 0.85, specificity 0.33]. Conclusion An association between drug levels and clinical outcomes was identified in patients with IBD treated with SC IFX. Clinical remission was associated with a level of 12.8 mg/ml but the association between higher drug levels and deeper remission that has been described previously was not seen. References Roblin X, Nancey S, Papamichael K, et al. Higher Serum Infliximab Concentrations Following Subcutaneous Dosing are Associated with Deep Remission in Patients with Inflammatory Bowel Disease. J Crohns Colitis. 2024;18(5):679-685. doi:10.1093/ecco-jcc/jjad188 Iborra M, Caballol B, Garrido A, et al. Subcutaneous infliximab cut-off points in patients with inflammatory bowel disease. Data from the ENEIDA registry. J Crohns Colitis. Published online August 22, 2024. doi:10.1093/ecco-jcc/jjae127

Feasibility and inter-reporter variability of submaximal outcomes derived from cardiopulmonary exercise testing in people with advanced cystic fibrosis lung disease

BackgroundCardiopulmonary exercise testing (CPET) provides prognostic information in people with advanced cystic fibrosis lung disease (pwACFLD). This project aimed to ascertain feasibility and inter-reporter variability in the identification of submaximal CPET outcomes for pwACFLD as potential predictors of prognosis where no peak exercise data are available.MethodsWe utilised data from an international retrospective multicentre study involving pwACFLD, for whom raw CPET data were available. Two experienced operators independently reviewed and analysed CPET tests with a focus on three pre-defined measures: oxygen uptake (V̇O2) at the anaerobic threshold (AT), the breathing reserve index at the AT (BRIAT), and the slope of the minute ventilation to carbon dioxide production ratio (V̇E/V̇CO2-slope). We calculated intra-class correlation coefficients (ICC) with their 95% confidence intervals (CI), and limits of agreement using the Bland-Altman method.ResultsThe original cohort included 174 pwACFLD. Among those, raw CPET data were available for 101 individuals, of which 89 tests were of sufficient technical quality for submaximal analysis. In 72 out of 89 technically-acceptable tests (81%), the AT could be confidently identified by both operators. Furthermore, ICCs indicated good-to-excellent inter-reporter agreement for V̇O2at the AT [ICC (95% CI) 0.79 (0.62 to 0.88)], the V̇E/V̇CO2-slope [0.95, 0.93 to 0.97)], and BRIAT [0.76, 0.63 to 0.85].ConclusionsSubmaximal CPET data can be reliably obtained in most pwACFLD by trained CPET operators. Future studies may ascertain the prognostic value of submaximal CPET outcomes in pwACFLD.

The impact of neoadjuvant therapy in patients with left-sided resectable pancreatic cancer: an international multicenter study.

To assess the association between neoadjuvant therapy and overall survival (OS) in patients with left-sided resectable pancreatic cancer (RPC) compared to upfront surgery. Left-sided pancreatic cancer is associated with worse OS compared to right-sided pancreatic cancer. Although neoadjuvant therapy is currently seen as not effective in patients with RPC, current randomized trials included mostly patients with right-sided RPC. International multicenter retrospective study including consecutive patients after left-sided pancreatic resection for pathology-proven RPC, either after neoadjuvant therapy or upfront surgery in 76 centers from 18 countries on 4 continents (2013-2019). Primary endpoint is OS from diagnosis. Time-dependent Cox regression analysis was performed to investigate the association of neoadjuvant therapy with OS, adjusting for confounders at time of diagnosis. Adjusted OS probabilities were calculated. Overall, 2,282 patients after left-sided pancreatic resection for RPC were included of whom 290 patients (13%) received neoadjuvant therapy. The most common neoadjuvant regimens were (m)FOLFIRINOX (38%) and gemcitabine-nab-paclitaxel (22%). After upfront surgery, 72% of patients received adjuvant chemotherapy, mostly a single-agent regimen (74%). Neoadjuvant therapy was associated with prolonged OS compared to upfront surgery (adjusted HR=0.69 [95%CI 0.58-0.83]) with an adjusted median OS of 53 vs. 37 months (P=0.0003) and adjusted 5-year OS rates of 47% vs. 35% (P=0.0001) compared to upfront surgery. Interaction analysis demonstrated a stronger effect of neoadjuvant therapy in patients with a larger tumor (Pinteraction=0.003) and higher serum CA19-9 (Pinteraction=0.005). In contrast, the effect of neoadjuvant therapy was not enhanced for splenic artery (Pinteraction=0.43), splenic vein (Pinteraction=0.30), retroperitoneal (Pinteraction=0.84), and multivisceral (Pinteraction=0.96) involvement. Neoadjuvant therapy in patients with left-sided RPC was associated with improved OS compared to upfront surgery. The impact of neoadjuvant therapy increased with larger tumor size and higher serum CA19-9 at diagnosis. Randomized controlled trials on neoadjuvant therapy specifically in patients with left-sided RPC are needed.

Safe Implementation of Treatments in Stroke: a study on intravenous thrombolysis in patients over 80 years of age with acute ischaemic stroke

ObjectivesTo investigate the safety and efficacy outcomes of intravenous thrombolysis (IVT) in patients aged >80 years with acute ischaemic stroke (AIS) after IVT was approved in this patient population in...