Introduction

Completion surgery aims to lower the risk of pT1 colorectal cancer (CRC) related mortality, and thereby overall survival (OS). However, the true effect of declining CRC-related mortality on OS depends on the risk of competing mortality. This study aimed to evaluate the impact of non-CRC related mortality among patients with T1 CRC and to compare their mortality risk to that of the general Dutch population. Additionally, the discriminative performance of the ASA score and Charlson comorbidity index (CCI) to predict mortality was evaluated.

Aims & Methods

The Dutch T1 CRC Working Group cohort, which included patients diagnosed with a T1 CRC between 2000 and 2022 in 23 Dutch hospitals, was used for this study. Causes of death were categorized in accordance with Statistics Netherlands. The 5-year OS was calculated by the Kaplan-Meier method. Standardized Mortality Ratios (SMR) were calculated for comparison of mortality with the general Dutch population stratified for age and gender. Univariate Cox regression was used to assess associations between clinical and tumor specific variables, and mortality. C-statistics were used to evaluate the predictive value of ASA and CCI in predicting all-cause mortality.

Results

A total of 4,331 patients were included (median follow-up of 4.02 years [IQR 1.92-5.33], median age 69 years [IQR 63-75], 40.8% female). The 5-year OS of the cohort was 83.0% [95%CI 81.5-84.4]. CRC related death accounted for 3.1% (N=135), while non-CRC related death accounted for 9.7% (N=422). For 3.2% (N=139) cause of death could not be retrieved. Univariate Cox regression identified age [HR 1.11; 95%CI 1.10-1.12], ASA score [ASA I versus III HR 7.37; 95%CI 5.70-9.52], CCI [HR 1.35; 95%CI 1.32-1.39], and detection through population-based screening [HR 0.49; 95%CI 0.40-0.60] as significant predictors for all-cause mortality, while tumor specifications were not. The total SMR was 0.97 [95%CI 0.90-1.05], and for patients aged younger than 70 1.41 [95%CI 1.19-1.67], indicating that mortality rates of the cohort were similar to those of the general Dutch population, except in the younger population. Median CCI score was 4 [IQR 2-5], and ASA scores III and IV were present in 15.9% and 0.8% of all patients, respectively. The C-statistics of the ASA score and CCI for all-cause mortality were 0.67 [95%CI 0.66-0.71] and 0.76 [95%CI 0.74-0.78] respectively. Table 1 shows the decline in survival for every point increase in CCI.

Table 1: Overall 5-year survival estimate for every CCI score.

Conclusion

Non-CRC related mortality is an important determinant of OS in pT1 CRCs, and mortality rates among elderly T1 CRC patients are similar to those of the general Dutch population. The CCI can make a good prediction of all-cause mortality among patients with T1 CRC. Using CCI in clinical practice can help to estimate survival in individual patients and guide treatment decisions, especially when completion surgery is considered.

Introduction

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, predominantly diagnosed in patients with chronic liver diseases. The absence of specific biomarkers and the typically asymptomatic progression of the disease lead to delayed diagnosis. Patients with liver disease, including HCC, exhibit alterations in the gut microbiome and increased bacterial permeability, factors that may influence disease progression and patient outcomes. In recent years, there has been a growing interest in exploring circulating microbiome signatures as potential indicators of liver disease stutus, providing a new avenue for understanding HCC.

Aims & Methods

Aims: To identify the signatures of the circulating blood microbiome associated with hepatocellular carcinoma, response to treatment and disease prognosis.
Methods: This study conducted a post-hoc analysis of the SORAMIC clinical trial utilizing peripheral blood plasma samples. For this analysis, blood plasma samples from a cohort of 71 patients with HCC were examined (25 treated with Sorafenib and 46 with SIRT/Sorafenib). Peripheral blood samples were collected at two time points: baseline (prior to the initiation of anti-tumor therapy) with all 71 patients included, and post-therapy (7 to 9 weeks after treatment) with 39 patients included. Additionally, peripheral blood samples were obtained from 52 control subjects, who were endoscopically diagnosed with colonic diverticulosis, to compare against the patient group. The composition of the circulating blood microbiome was assessed through 16S rRNA gene sequencing, targeting the V1-V2 hypervariable regions. Subsequent analyses focused on identifying associations with potential novel biomarkers for diagnosis, prognosis, and response to treatment.

Results

Patients with HCC had significantly diminished α-diversity of the circulating blood microbiome as compared to controls. Significant differences were also observed in between microbial communities of these two cohorts based on Bray-Curtis dissimilarity index. Patients with HCC had significantly higher levels of Proteobacteria and Bacteroidetes and lower levels of Firmicutes and Campylobacterota. Differential abundance analysis revealed that families of Gordoniaceae, Cryomorphaceae, Burkholderiaceae, Comamonadaceae, Enterobacteriaceae were significantly enriched in patients with HCC. At the genus level, patients with HCC had higher levels of Gordonia, Fluviicola, Burholderia, Limnohabitans and Escherichia/Shigella and lower levels of Corynebacterium. HCC patients, who responded to treatment with SIRT/Sorafenib showed an increase in blood bacterial diversity, enrichment of families Burkholderiales incertae sedis, Arcobacteraceae, Peptostreptococcaceae, Moraxellaceae, genera Sphaerotilus, Aliacrobacter, Rhodoluna, Giesbergeria, Microbacterium, Romboutsia, Arcicella, Pseudorhodoferax and depletion in families Gordoniaceae, Cryomorphaceae and genera Cloacibacterium, Gordonia, Limnohabitans, Fluviicola after the treatment. Levels of Acinetobacter, Enhydrobacter and Micrococcus in the blood before the HCC treatment were associated with patient prognosis.

Conclusion

Patients with HCC exhibit a unique circulating blood microbiome profile characterized by reduced bacterial diversity. Response to treatment is linked to an increase in α-diversity and changes in the circulating microbiome profile. Specific members of the circulating microbiome show potential prognostic capabilities, suggesting their utility as biomarkers for predicting disease progression and treatment outcomes in HCC.

Introduction

Until a few years ago, there existed only off-label medical treatment options for eosinophilic esophagitis (EoE) such as proton pump inhibitors (PPI) or swallowed topical corticosteroids (STC) with various formulations and ingredients. Since the approval of a budesonide orodispersible tablet (BOT), the first biological agent (Dupilumab) has been approved by the EMA and FDA, and another budesonide oral suspension has been received approval by the FDA recently. Currently, many phase 3 trials with different drugs are running, resulting in various treatment options in the next years. However, data about patients’ perspectives are lacking. We therefore aimed to assess patients’ awareness, beliefs and restrictions to medical treatment options in EoE

Aims & Methods

We developed a web-based survey using SurveyMonkey and sent a questionnaire comprised of 47 questions about patients’ preferences regarding medical treatment options to patients with established EoE in Switzerland, Austria and Germany.

Results

A total of 56 patients (64% male, 66% with other atopic diseases) from Switzerland (64%), Austria (34%) and Germany (2%) answered the questionnaire. A swallowed topical therapy was ranked first (71% of patients) in terms of patient’s preference followed by a subcutaneous therapy every 4 weeks (21.4%) and by an oral therapy with systemic effect (7%). Although one third do not have reservations against long-term medical therapy, nearly half of patients (42%) are skeptical about long-term treatment and 65% are afraid of adverse events. However, a third of patients are not aware that STC are locally effective medications with nearly no systemic effect. Furthermore, 48% of patients believe that physicians underemphasize adverse events of medication. Nearly all patients understand the importance of not only treating symptoms but also inflammation (85%).

Conclusion

Patients with EoE prefer topical agents over other available routes of administration. Patient education should be carried out to address reservations about long-term treatment.

Disclosure

Falk Pharma, Sanofi (both consultency meetings)

Introduction

A good bowel preparation for colonoscopy is fundamental to improve the quality of the examination, reduce procedural complications and achieve optimal polyp detection. Among possible strategies to enhance bowel preparation, visual booklets have been proposed with conflicting results. Therefore we aimed to perform a systematic review with meta-analysis of randomized controlled studies (RCT) to ascertain whether booklets may be useful in this setting.

Aims & Methods

Literature search was performed in July 2022, in main databases (PUBMED, SCOPUS, ScienceDirect, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov). only RCTs were selected. The primary outcome was the quality of bowel preparation. Further outcomes were the adenoma detection rate (ADR), number of polyps detected per patient, rate of cecal intubation, time of insertion and withdrawal, adverse events, willingness to repeat preparation and colonoscopy. We estimated odd ratios (OR) for dichotomous outcomes. mean differences (MD) or standardized mean differences (SMD) were used for continuous outcomes. We estimated heterogeneity among studies with the Chi2 (Cochran Q) and the I2 statistics. In case of high heterogeneity, a random effect model was used, otherwise a fixed effects model was preferred. All analyses were performed using RevMan version 5.4.1.

Results

Six studies were selected, enrolling overall 1755 patients (857 in the booklet and 898 in the control group). Adequate bowel preparation was achieved in the 86.7% (743 out of 857) of booklet preparation versus the 77.5% (696 out of 898) in the control group, with an OR of 2.31 in favour of booklet (95% CI 1.20-4.45, p = 0.01). Booklet was more effective than control in the transverse colon (MD = 0.37, 95% CI 0.01-0.72, p = 0.03), while no differences were found in right colon and left colon. In four studies a 4-L PEG-based preparation was used and the pooled analysis did not find any difference compared to controls, while when sodium phosphate and magnesium citrate or sodium phosphate or PEG were used, preparation with booklet was better than in controls (OR = 5.10, 95% CI 1.82-14.27, p = 0.002). Two studies were performed in inpatient setting, without difference between booklet and controls while in outpatients patients receiving booklets were better prepared than controls (OR = 7.13, 95% CI 5.39-9.45, p < 0.001). ADR was similar between the two groups, with an OR = 0.93 (95% CI 0.75-1.16, p = 0.53). The mean number of polyps per patient did not differ between the two groups (MD = 0.22, 95% CI -0.14-0.58, p = 0.23).

Conclusion

The present meta-analysis demonstrated that booklets are useful to enhance bowel preparation. Outpatients and non PEG-based preparations seem to benefit more from booklets, while no effect on ADR has been observed.

Introduction

Endoscopic submucosal dissection (ESD) is an advanced technique that can provide a successful ‘en-bloc’ and R0 resection rate for large gastrointestinal (GI) lesions. To date, several ESD techniques have been proposed, but their comparative efficacy is still unclear.

Aims & Methods

This network meta-analysis aims to investigate and compare the efficacy and safety of different ESD techniques for resection of colonic lesions. MEDLINE, Embase, Scopus, and the Cochrane Library were systematically searched for randomized controlled trials (RCTs) comparing different ESD techniques through March 2024. The primary outcomes were ‘en-bloc’ and R0 resection rates. The secondary outcome was the incidence of procedure-related AEs. Direct and indirect comparisons were performed among different ESD techniques. Results were expressed as risk ratio (RR) and 95% confidence interval (CI), using the DerSimonian and Laird random-effects model. The relative ranking of the interventions for achieving the aforementioned outcomes was calculated as their surface under the cumulative ranking curve (SUCRA). The study quality was evaluated using the revised Cochrane risk-of-bias (RoB2) tool for randomized trials.

Results

After selection of studies, 9 RCTs were included in the systematic review.
On network meta-analysis for ‘en-bloc’ resection (9 RCTs, 872 patients, 5 techniques assessed), pocked with traction ESD (PT-ESD) (RR=1.02 - 95%CI=0.96-1.07) and pocket ESD (P-ESD) (RR=1.02 - 95%CI=0.98-1.05) showed higher efficacy, whereas hybrid ESD (H-ESD) (RR=0.94 - 95%CI=0.87-1.02) lower efficacy compared to conventional ESD (C-ESD).
On network meta-analysis for R0 resection (7 RCTs, 732 patients, 4 techniques assessed), PT-ESD (RR=1.05 - 95%CI=0.96-1.16) showed higher efficacy, and H-ESD (RR=0.97 - 95%CI=0.84-1.13) lower efficacy compared to C-ESD. Overall, P-ESD resulted the best technique for ‘en-bloc’ resection (SUCRA 0.70) and PT-ESD for R0 (SUCRA 0.83), while H-ESD showed the poorest performance for both outcomes (SUCRA 0.06 and 0.30, respectively) (Table 1).
On network meta-analysis for AEs (9 RCTs, 872 patients, 5 techniques assessed), PT-ESD (RR=0.35 - 95%CI=0.05-2.48) was associated with a lower incidence of AEs, and H-ESD (RR=1.22 - 95%CI=0.30-5.01) with higher incidence of AEs, compared to C-ESD. Overall, PT-ESD resulted as the safest technique (SUCRA 0.83), followed by T-ESD (SUCRA 0.60), whereas H-ESD showed the poorest performance (SUCRA 0.28).
According to the RoB2 tool, none of the studies included was of poor methodological quality except for one.


Table 1. SUCRA score ranking of different interventions in terms of ‘en-bloc’ resection rate, R0 resection rate and incidence of AEs.

Conclusion

The results of this network meta-analysis show a trend towards greater effectiveness and safety of PT-ESD for the removal of colonic lesions. H-ESD was associated with worse results and should be avoided, preferring other techniques.

Introduction

The outcome of ESD in early gastrointestinal neoplasia in Japan is well established. However, in the west, ESD practice is variable given different disease prevalence in UGI tract and also the volume and experience of each centre.

Aims & Methods

We aim to evaluate ESD practice and outcomes in the UK and hence, multi centre registry was set up. This is a prospective observational study for patients undergoing ESD for early GI neoplasia. All technical and outcomes data was prospectively collected onto REDCap.

Results

There were 451 UGI ESD cases recruited between August 2016 to August 2023 from 6 large tertiary referral centres in the UK. Mean age of the patients was 70.8 years (range: 24-94 years) with male preponderance (318 males vs. 133 females). Majority were in oesophagus: 282 (62.53%), stomach: 159 (35.25%) and duodenum: 10 (2.22%).
Of 282 oesophageal ESDs, 277 (98.23%) were technically successful with en-bloc resection rate of 96%. There were 3 intraprocedural complications (2 oesophageal perforations and 1 oral laceration from overtube). All of them were managed endoscopically. There were 29 (10.28%) post ESD strictures requiring endoscopic dilatations. 3 (1.06%) delayed bleeding were noted and 3 were readmitted for decompensation of underlying co-morbidities.
There were 204/282 (72.34%) Barrett’s cases with average length of C3 M5 and mean size 34.5mm. 34 cases (16.67%) had previous ESD or ablation at the same site. Post ESD resection showed deep submucosal (SM) invasion in 21 patients (deep R0 achieved in 42.9% and lateral R0 in 76.2%), 23 pT1bSM1 (deep R0 in 87.0% and lateral R0 in 87%), 107 pT1a (deep R0 in 89.7% and lateral R0 in 85.1%), 31 high grade dysplasia (HGD) (R0 in 97%) and 9 low grade dysplasia (LGD) (R0 in 78%) as shown in Table 1.
There were 44 squamous cell carcinoma (SCC), 26 gastro-oesophageal junctional neoplasia and 8 others (submucosal lesion and granular cell tumours). Of 44 SCC, there were 8 pT1b (5 achieved deep R0, 7 achieved lateral R0), 10 pT1a (all achieved both deep and lateral R0), 22 HGD (81.8% achieved R0), 3 LGD (all achieved R0) as shown in Table 1.
There were 160 gastric ESDs with completion rate of 96.25% and en-bloc rate of 95.5%. There were 8 (5%) intra-procedural perforation which required endoscopic clippings. There were 7 (4.36%) delayed bleeds which were managed endoscopically. Of 160 cases, 138 were epithelial neoplasia, 11 were submucosal lesions while 4 were large hyperplastic polyps. As shown in Table 1, of 138 epithelial neoplasia, 10 had deep SM invasion (7 achieved deep R0, 8 lateral R0), 14 pT1bSM1 (7 achieved deep R0, 10 lateral R0), 50 pT1a (90% achieved deep R0, 80% lateral R0), 35 HGD (94.3% R0) and 27 LGD (77.8% R0).

Conclusion

Unlike in the East, most ESDs in our study were performed in Barrett’s oesophagus rather than the stomach. Our data demonstrates the feasibility and safety of UGI ESD in Western setting with high en-bloc rate and low complication rates. We found that within indication of ESD, complete resection (R0) rate is high but lesions with deep submucosal invasion have poor R0 rate.

Disclosure

Professor Bhandari has received research grants or is the advisory board for Fujifilm, Boston, Olympus, Pentax, 3-D matrix, NEC (Japan), Medtronic.

Introduction

Ultra-Processed Foods (UPFs) have been associated with chronic diseases such as cancer, obesity and inflammatory bowel diseases (IBD). A typical feature of UPFs is the presence of Advanced Glycation End products (AGEs), including Carboxy-Methyl Lysine (CML), due to thermal treatments.

Aims & Methods

We studied to what extent different cooking methods affect cardiometabolic and inflammatory markers through differential dietary AGE intake.
In a randomized cross-over pilot trial, healthy participants sequentially consumed a diet prepared with cooking methods that generate either low or high amounts of AGEs. Recipes during both periods contained identical ingredients, but simply differed in their cooking methods (grilling and baking vs. steaming and raw foods). Daily food logs were kept using photo documentation and the smartphone application FatSecret during the one-week run-in (baseline diet) and the subsequent two-week intervention periods. Estimated AGEs levels were calculated based on the previously published database of Uribarri et al.¹ Anthropometric measurements and biological samples were taken at baseline and after each intervention period. Blood samples were collected for routine tests, Lipopolysaccharide-Binding Protein (LBP) ELISAs, serum proteomics (Olink Target 96 Inflammation and Cardiometabolic panels), and direct measurement of serum AGEs. Faecal calprotectin, 16S rRNA sequencing, and short chain fatty acids (SCFA) measurements were performed on stool samples. Small intestinal permeability was measured according to a 2-hour Lactulose Mannitol Ratio (LMR) protocol.

Results

Twenty healthy participants with a median age (IQR) of 28 (23.5-38) years, and a median BMI of 23.0 (20.9-25.4) kg/m² were included. The average estimated intake of CML during the high-AGEs diet was comparable to baseline (20,480.5 vs. 19,545 kU CML/day, Wilcoxon signed rank test, p>0.1), but significantly higher than during the low-AGEs period (10,590 kU CML/day, Wilcoxon signed rank test, p=3.8 x 10^-6). Metabolically, total cholesterol values increased (paired Wilcoxon signed rank test, p= 0.04) when changing from a low-to-high AGEs diet. After applying a linear mixed model per protein, eukaryotic initiation factor 4E-binding protein (4E-BP1), increased significantly after consumption of the low-AGEs diet (adjusted p=0.03). The gut microbiota composition was largely unaffected by the diets, as was faecal calprotectin. Importantly, faecal butyrate concentrations increased after the high-AGEs study period in the low-to-high AGEs group (paired Wilcoxon signed rank test, p=0.04). The LMR was increased throughout the study in the high-to-low AGEs group, but not in the low-to-high AGEs group. Serum LBP showed no difference.

Conclusion

By conducting the first randomized cross-over cooking methods trial that focusses on both intestinal and systemic endpoints at a proteomic, gut microbiome and permeability level, we found that cooking methods generating different AGE levels have a differential impact on human and gut microbial metabolism. More specifically, we show a beneficial effect of the low-AGEs diet on lipid profiles and the serum protein 4E-BP1, a protein known to affect lifespan, metabolism, and cancer development. In contrast, the high-AGEs diet was associated with increased faecal butyrate levels, a SCFA that is studied for its beneficial and anti-inflammatory luminal properties. These results are instructive for diet-based interventions in the prevention and treatment of chronic diseases, including the metabolic syndrome and IBD.

References

1. Uribarri J, Woodruff S, Goodman S, et al. AGE’s in Foods and practical ways to reduce them. J Am Diet Assoc. 2010;110(6):911-916.

Disclosure

The authors have no direct conflicts of interest to disclose. However the general COIs can be found below for optimal transparency.

• JW reports no conflict of interest.
• EV reports no conflict of interest.
• AD reports no conflict of interest.
• SH received consultancy fees from Ferring, Takeda.
• Julie Vanderstappen received consultancy fees from Ferring, Janssen.
• Joke Verbeke reports no conflict of interest to disclose.
• RV is a clinical investigator for Bayer, Eli Lilly, Boehringer Ingelheim, Novo Nordisk; he reports speaker’s fees from Boehringer Ingelheim, Eli Lilly, Goodlife Pharma, Novo Nordisk, Prowell, Sanofi; consultancy fees from Boehringer Ingelheim, Eli Lilly, Sanofi; Financial compensation for these activities has been received by the institution (UZ/KU Leuven).
• BV reports having received Research support from AbbVie, Biora Therapeutics, Landos, Pfizer, Sossei Heptares and Takeda. Speaker’s fees from Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Janssen, Lily, MSD, Pfizer, R-Biopharm, Sandoz, Takeda, Tillots Pharma, Truvion and Viatris. Consultancy fees from Abbvie, Alimentiv, Applied Strategic, Atheneum, BenevolentAI, Biora Therapeutics, Bristol Myers Squibb, Galapagos, Guidepont, Landos, Lily, Mylan, Inotrem, Ipsos, Janssen, Pfizer, Progenity, Sandoz, Santa Ana Bio, Sosei Heptares, Takeda, Tillots Pharma and Viatris.
• MF reports to have received research grants from AbbVie, Amgen, Biogen, EG, Janssen, Pfizer, Takeda, and Viatris; consultancy fees from AbbVie, Agomab Therapeutics, Boehringer Ingelheim, Celltrion, Eli Lilly, Janssen-Cilag, Medtronic, MRM Health, MSD, Pfizer, Regeneron, Samsung Bioepis, Sandoz, Takeda, and Thermo Fisher; and speakers’ fees from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Falk, Ferring, Janssen-Cilag, Lamepro, MSD, Mylan, Pfizer, Samsung Bioepis, Sandoz, Takeda, and Truvion Healthcare.
• CM is chair of the KU Leuven Fund ‘Nutrition’, a donation-based fund to stimulate research on nutrition. Recipient of travel/accommodation expenses and small participation fee (<100€/meeting) as member of working groups of the Belgian Superior Health Council and Belgian Federal Agency of the Safety of the Food Chain. Recipient of travel/accommodation expenses as member of the scientific advisory body of the EU Joint Programme Initiative Healthy Diet, Healthy Life, as co-chair ILSI Europe Task Force Dietary Intake and Exposure, as member ILSI Europe Task Force Nutrient Intake Optimisation. Recipient of honoraria (<500€/year) as active member of the advisory board of NutriNews (Belgian Nutrition Information Center). Recipient of honoraria as jury-member of nutrition-related awards and reviewing EU-grants. Recipient of royalties form a textbook (Handboek Voeding, ACCO). Honoraria are used to support research of PhD Students.
• JR reports grants from Beneo, Cargill, Colruyt group, Danone, DSM, J&J, MRM/Prodigest, Nestle Pfizer, and Takeda; and has received consulting and/or speaking fees from Aphea, Biofortis, DSM, Ferring, GSK, Janssen Pharmaceuticals, Metagenics, MSD, MRM/Prodigest, Nutricia, Takeda, Tsumura
• KV receives travel /accommodation expenses as co-chair of the ILSI Europe Prebiotic Task Force and travel expenses and a participation fee as a member of a working group of the Belgian Superior Health Council. Recipient of honoraria and travel/accommodation expenses as a reviewer of grants (NWO (The Netherlands), ANR (France) and EU grants). Recipient of speakers’fees from Yakult and Kintu.
• SV received financial support for research from AbbVie, J&J, Pfizer, Takeda and Galapagos and receives speakers’ and/or consultancy fees from AbbVie, Abivax, AbolerISPharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, Mestag Therapeutics, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Surrozen, Takeda, Theravance, Tillots Pharma AG, VectivBio, Ventyx, Zealand Pharma.
• JS reports speaker’s fees from Pfizer, Abbvie, Ferring, Falk, Takeda, Janssen, Fresenius, and Galapagos; consultancy fees from Janssen, Ferring, Fresenius, Abbvie, Galapagos, Celltrion, Pharmacosmos, and Pharmanovia; and research support from Galapagos and Viatris.