Introduction

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide and is being increasingly diagnosed at younger ages¹. Pregnancy-related and early life factors have been shown to have a long-lasting influence on an individual’s future health. While low birthweight and preterm birth have been associated with future development of the metabolic syndrome^{2 3} and cardiovascular disease⁴, associations with NAFLD have been conflicting^{5 6}.

Aims & Methods

This nationwide case-control study involving all Swedish children, adolescents, and young adults (≤25 years) who were diagnosed with biopsy-proven NAFLD between 1 January 1992 and 30 April 2017 (n=165) aimed to investigate the relationship between perinatal characteristics with later development of NAFLD. Individuals were matched to up to 5 matched general population comparators (n=717) on age, sex, calendar year, and county of residence. Data on maternal and perinatal characteristics were retrieved from the population-based Swedish Medical Birth Register. We used conditional multivariable-adjusted logistic regression, adjusted for several maternal health- and socioeconomic factors.

Results

Among individuals with biopsy-proven NAFLD, median age at time of diagnosis was 12.0 years (interquartile range 4.4-16.9) and the majority of cases were male (60.6%). There was a strong association between birth weight and future development of NAFLD: low birthweight (<2500g; aOR 4.24; 95% CI 1.03-17.53), normal birthweight (2500-4000g; reference, aOR 1.0), and high birthweight (>4000g; aOR 0.62; 0.27-1.40). A positve association with later NAFLD was also seen for individuals born small for gestational age (SGA, <10^th percentile; aOR 3.12; 95% CI 1.84-5.29), when compared to adequate for gestational age (AGA, 10-90^th percentile; reference aOR 1.0), and large for gestational age (LGA, >90^th percentile; aOR 0.55; 95% CI 0.26-1.18). Severe NAFLD (biopsy-proven fibrosis or cirrhosis) was significantly more common among individuals born with low birthweight (aOR 4.24; 95% CI 1.03-17.53) or SGA (aOR 4.33; 95% CI 1.85-10.10).

Table: Risk of NAFLD According to Perinatal Characteristics

Conclusion

This nationwide study involving all children, adolescents, and young adults with biopsy-proven NAFLD compared to matched general population comparators shows a strong association between low birthweight, being born small for gestational age and future NAFLD as well as severe course of disease with development of NAFLD-associated fibrosis or cirrhosis. The findings were independent from maternal metabolic and socioeconomic factors.

References

1. Quek, J., et al. Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 8, 20-30 (2023).
2. Sipola-Leppanen, M., et al. Cardiometabolic Risk Factors in Young Adults Who Were Born Preterm. American Journal of Epidemiology 181, 861-873 (2015).
3. Van Hulst, A., et al. Birth Weight, Postnatal Weight Gain, and Childhood Adiposity in Relation to Lipid Profile and Blood Pressure During Early Adolescence. J Am Heart Assoc 6, e006302 (2017).
4. Barker, D.J., Osmond, C., Forsen, T.J., Kajantie, E. & Eriksson, J.G. Trajectories of growth among children who have coronary events as adults. N Engl J Med 353, 1802-1809 (2005).
5. Querter, I., et al. Maternal and Perinatal Risk Factors for Pediatric Nonalcoholic Fatty Liver Disease: A Systematic Review. Clinical Gastroenterology and Hepatology 20, 740-755 (2022).
6. Wesolowski, S.R., Kasmi, K.C., Jonscher, K.R. & Friedman, J.E. Developmental origins of NAFLD: a womb with a clue. Nat Rev Gastroenterol Hepatol 14, 81-96 (2017).

Disclosure

FE has served as advisory board member for Boehringer Ingelheim.
JS has no conflicts of interest.
JFL has coordinated an unrelated study on behalf of the Swedish IBD quality register (SWIBREG). This study received funding from Janssen corporation. He has also received financial support from MSD to develop a paper reviewing national healthcare registers in China and has ongoing discussions with Takeda about a celiac disease project.

Introduction

Therapeutic management of acute biliary pancreatitis (ABP) includes endoscopic sphincterotomy and cholecystectomy. However, the optimal feeding strategy prior to cholecystectomy—early oral intake or exclusive enteral nutrition—remains debated, particularly given the risk of recurrent biliary events (BEs) before surgery, especially when surgery is delayed.

Aims & Methods

The primary objective was to evaluate the likehood of BEs (biliary colic/migration, stone impaction, cholangitis, recurrent acute pancreatitis, and acute cholecystitis) prior to cholecystectomy, comparing feeding methods: oral vs. exclusive enteral nutrition. The secondary objective was to evaluate cholecystectomy rates during the initial hospitalization and the reasons for non-performance. Data were collected during hospitalization, at 3 months, and at 6 months if surgery had not been performed by month 3. BEs and feeding modalities at those times were documented. Analyses included Cox models and Chi-square tests.

Results

From October 2022 to December 2023, 1,172 patients with ABP were prospectively enrolled by 60 French hospitals, with 1,167 included in the final analysis. Sixty patients (5%) were lost to follow-up, and 34 deaths (3%) were reported. Severe ABP was observed in 27.2% (n=317) of patients. After 48–72 hours, oral feeding was resumed in 62% (n=724), enteral feeding in 16% (n=192), and fasting/parenteral feeding in 21% (n=249). During follow-up, 236 BEs occurred in 172 patients, meaning 15.5% experienced at least one event, with a median onset time of 26 days (range: 9–57 days). Specifically, 6% had at least one episode of biliary colic/migration, 2.1% experienced stone impaction, 2.3% developed cholangitis, 6.1% had recurrent AP (9% of which were severe), and 1.6% developed acute cholecystitis.
Univariate analysis identified several factors associated with a higher risk of BE recurrence (p < 0.10): age ≥52 years (p=0.093), obesity (BMI ≥30, p=0.032), ASA score >2 (p=0.097), total bilirubin ≥60 µmol/L (p=0.010), CRP >150 mg/L, diagnostic delay ≥21 days (p=0.009), and prior sphincterotomy (p=0.136). No difference in BE incidence was observed between severe and non-severe ABP (p=0.497) when analyzing the first 172 BEs.
Over the full follow-up period, despite the 87 BEs analyzed and potential biases, there remained no significant association between nutrition type (oral vs. exclusive enteral nutrition ) and the likelihood of BE occurrence (p=0.447).
In patients with non-severe ABP, cholecystectomy was performed during the initial hospitalization in only 33% of cases. The main reasons for non-performance were structural (e.g., lack of availability or surgeon refusal), accounting for 45% of cases.

Conclusion

BEs are frequent and clinically relevant: 15.5% of patients experienced at least one before surgery, with 6% developing recurrent ABP (9% of which were severe). Cholecystectomy remains underutilized; only one-third of patients with non-severe ABP underwent it during their initial stay, often due to modifiable reasons. Neither ABP severity nor nutritional type-oral vs enteral nutrition (despite potential biases, missing data, and ongoing analysis)-appeared to be associated with the occurrence of BEs prior to surgery. Early cholecystectomy, when possible, remains the only reliable strategy for preventing BEs.

Disclosure

This study received a research grant from Fresenius Kabi.

Introduction

Tumor necrosis factor–like cytokine 1A (TL1A) is a regulator of inflammation and fibrosis in inflammatory bowel disease. Tulisokibart, an anti-TL1A monoclonal antibody, demonstrated efficacy without clinically meaningful safety findings vs placebo after a 12-week induction period in adults with moderately to severely active UC in the phase 2 ARTEMIS-UC study.¹ We report long-term efficacy and safety of tulisokibart among cohort 1 induction responders from the open-label extension (OLE) period of ARTEMIS-UC.

Aims & Methods

ARTEMIS-UC was a phase 2, multicenter, double-blind, placebo-controlled study of tulisokibart in patients with moderately to severely active UC. Cohort 1 enrolled patients regardless of genetic-based diagnostic test (Dx) status whereas cohort 2 enrolled only Dx-positive patients. Patients were randomized to receive intravenous (IV) tulisokibart 1000 mg on day 1 and 500 mg at weeks 2, 6, and 10 or placebo; after the 12-week induction period, all participants had the option to continue in the OLE period. Participants were classified as induction responders (defined as reduction of ≥2 points and ≥30% in modified Mayo score from baseline, accompanied by a reduction ≥1 in rectal bleeding subscore or absolute rectal bleeding subscore ≤1 at week 12) or induction nonresponders. Cohort 1 induction responders in the tulisokibart group were randomized (stratified by Dx status) to receive open-label IV tulisokibart 100 mg or 250 mg every 4 weeks at week 14 until week 170. We report data from cohort 1 through week 50 of the OLE period: clinical and endoscopic efficacy outcomes and biomarkers through week 50 are reported for cohort 1 induction responders from the tulisokibart group whereas safety through week 50 are reported for cohort 1 induction responders from both the tulisokibart group and the placebo group. Descriptive statistics were used to summarize observed data.

Results

47 of 68 tulisokibart-treated patients in cohort 1 were induction responders and were randomized to receive tulisokibart 250 mg (n = 25) or 100 mg (n = 22). Improvements in clinical, endoscopic, and biomarker outcomes observed with tulisokibart were generally maintained through week 50 in both dose groups (Table). However, at week 50, a greater proportion of patients achieved clinical and endoscopic outcomes with tulisokibart 250 mg vs 100 mg. In the safety population, (tulisokibart 250 mg, n = 35; 100 mg, n = 30), through week 50, AEs occurred in 63% and 77% of patients receiving tulisokibart 250 mg and 100 mg, respectively; most were mild to moderate in severity. Serious AEs occurred in 1 patient (3%) and two patients (7%) in the tulisokibart 250 mg and 100 mg groups, respectively.

Conclusion

At week 50, maintenance of treatment effect was generally observed in cohort 1 induction responders in the tulisokibart group. A trend for higher efficacy with tulisokibart 250 mg vs 100 mg maintenance treatment was observed at week 50. Tulisokibart was well tolerated with no identified safety signals. Larger trials are needed to confirm these findings.

References

1. Sands B, et al. J Crohns Colitis. 2023;17(Supplement_1):i56-i59.

Disclosure

CM has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, BioJAMP, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, and Takeda; speaker’s fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Pendopharm, Pfizer, and Takeda; royalties from Springer Publishing; and research support from Ferring and Pfizer.
SH has received advisory fees from Eli Lilly and Tilotts.
MPS has received educational grants or research support from Gilead and Celltrion, speakers fees from Janssen, AbbVie, Ferring, Takeda, Pfizer, Shire, Celltrion, Eli-Lilly and Dr. Falk Pharma, and has served on advisory boards for Janssen, Takeda, Pfizer, Celgene, AbbVie, MSD, Emerge Health, Gilead, BMS, Celltrion, and Eli-Lilly.
JKA, MY, and BD are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA
BGF is a consultant for AbbVie, AbolerIS, AgomAB Therapeutics, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport Inc., Arena Pharma, Atomwise, Avoro Capital Advisors, BioJamp, Biora Therapeutics, Boehringer Ingelheim, Boxer, Bristol Myers Squibb/Celgene, Celsius Therapeutics, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1 Capital, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, GlaxoSmithKline, Gossamer Pharma, Hinge Bio, Hot Spot Therapeutics, Imhotex, Immunic Therapeutics, InDex Pharmaceuticals, JAKAcademy, Janssen, Japan Tobacco Inc., Kaleido Biosciences, Landos Biopharma, Leadiant, L.E.K. Consulting, Lenczner Slaght, LifeSci Capital, Lilly, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic Therapeutics, Mylan, OM Pharma, Origo BioPharma, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer, Play to Know AG, Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen Inc., Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx Biosciences, VHSquared Ltd., Viatris, Ysios, Ysopia, and Zealand Pharma; on the Speakers’ Bureau for AbbVie, Janssen, and Takeda; and on advisory boards for AbbVie, Amgen, AMT, AnaptysBio, Axio Research, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, EcoR1 Capital, Genentech/Roche, GlaxoSmithKline, InDex Pharmaceuticals, Janssen, Lilly, MiroBio, Morphic, Origo BioPharma, Pfizer, Progenity, Prometheus, REDX Pharma, Sanofi, Takeda, Teva, and Tillotts Pharma.
BES reports consulting fees from AbbVie, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Envied Biosciences, Evommune, Ferring, Fresenius Kabi, Fiat, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Microba, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Spyre Therapeutics, Sun Pharma, Surrozen, Target RWE,Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Lilly; research grants, consulting and speaking fees and other support from Bristol Myers Squibb, Janssen, Pfizer, Takeda; research grants and consulting fees from Theravance Biopharma; and stock/stock options from Ventyx Biopharma.

Introduction

Acute pancreatitis (AP) is a common clinical emergency, with 20%–30% of cases progressing to severe acute pancreatitis (SAP), which has a mortality rate of up to 40%. Gut microbiota dysbiosis is closely associated with AP severity, yet its underlying mechanisms remain unclear.

Aims & Methods

This study aimed to elucidate how microbiota dysbiosis exacerbates AP.AP was induced in Specific Pathogen-Free (SPF) and Germ-Free (GF) C57BL/6 male mice to investigate the effects of microbiota dysbiosis on neutrophil recruitment, neutrophil extracellular trap (NET) formation, pancreatic injury, and systemic inflammation. Single-cell sequencing of neutrophils from SPF and GF AP mice was conducted to assess microbiota-driven changes in neutrophil distribution, gene expression, and signaling pathways. Serum cfDNA levels were measured in 50 AP patients and 30 healthy controls. Key findings were validated in vivo and in vitro.

Results

Serum cfDNA (NETs) levels were significantly elevated in AP patients compared to healthy controls and decreased during recovery. GF-treated mice exhibited reduced pancreatic edema, inflammatory infiltration, and acinar cell necrosis, with lower pathology scores. Immunohistochemistry confirmed decreased MPO and F4/80-positive cells in pancreatic tissues, while ELISA showed reduced levels of amylase, lipase, IL-6, and TNF-α in GF-treated mice. Single-cell sequencing revealed a lower proportion of pancreatic neutrophils and an increase in acinar cells in GF-treated mice, whereas the NET formation pathway was activated in SPF-treated mice. The TLR2/MYD88/NLRP3/Caspase-1 signaling cascade, which promotes NET formation, was also activated in SPF mice. Consistent with pathway analysis, CXCL1, CCL9, and CXCR2 expression was upregulated, while Reg3β expression was downregulated in SPF_AP mice. Dual immunofluorescence demonstrated reduced MPO/CitH3 (NETs) formation in GF-treated mice. Neutrophils from GF-treated mice released significantly less cfDNA upon PMA stimulation. Serum cfDNA levels were elevated in both AP-induced mice and AP patients.

Conclusion

Gut microbiota dysbiosis exacerbates AP severity by promoting neutrophil recruitment, activating the TLR2/NLRP3/MYD88/Caspase-1 signaling cascade, and enhancing NET formation, leading to aggravated pancreatic injury and systemic inflammation. These findings highlight microbiota modulation as a potential therapeutic strategy to prevent AP progression.

Disclosure

The authors declare that they have no conflict of interests.

Introduction

Blood-based liquid biopsy for comprehensive genomic profiling is available for cancer patients; however, given the limited amount of circulating tumor-derived DNA in plasma, it remained challenging to detect pancreatic ductal adenocarcinoma (PDA) at earlier stages. We sought to determine the usefulness of pancreatic juice-containing DNA collected from a site more proximal to the tumor in the early diagnosis of pancreatic cancer.

Aims & Methods

We evaluated the mutation detection in DNA from the duodenal fluid as an alternative biospecimen obtained by a less-invasive approach relative to endoscopic biopsy. In 296 patients diagnosed with PDA (n=175), IPMN (n=61), or other pancreatic diseases (n=60) were recruited in seven institutions. Duodenal fluid was collected from the duodenal lumen through the endoscopic channel and pancreatic juice was obtained directly from the pancreatic duct through a catheter during the ERP examination. Together with plasma cfDNA, both digestive fluid-included DNA was extracted, and molecular barcode sequencing (Ion Amplseq HD) targeting five pancreatic cancer-associated genes, namely, KRAS, GNAS, TP53, CDKN2A, and SMAD4, were performed. Detected mutations were evaluated for concordance with surgically resected tissue or needle biopsy.

Results

DNA extracted from the duodenal fluids (DFDNA) and pancreatic juice (PjDNA) had a much higher yield (avg. 25.4 ng/mL, and 7.7 ng/mL, respectively) than plasma cell-free DNA (avg. 1.3 ng/ml). While most plasma cfDNA had a typical fragmentation pattern with the highest peak at 160 bp, DFDNA and PjDNA showed various fragmentation patterns. Using molecular barcode sequencing, hotspot mutations detected in the DFDNA (n=148) showed 50.7% concordance of the mutations in resected PDA lesions, whereas only 24.1% concordance in the plasma cfDNA (n=114). In contrast to plasma cfDNA, where liquid-tissue matches were limited to advanced stages of cancer, DFDNA assay enabled the higher concordance through a wide range of PDA stages, even Stage 0 (83.3%) or I (45.5%) UICC 8th, or IPMN cases. Furthermore, PjDNA showed a much higher concordance rate (88%, n=25) than DFDNA. In DFDNA and PjDNA, mutations that originated from the primary lesions and from multicentric/concomitant lesions such as IPMN were detected effectively.

Conclusion

Digestive fluid-derived DNA can be a potent biospecimen to detect mutations with higher yield and sensitivity than plasma cfDNA. For practical diagnostics testing, optimized collection and storage of the duodenal fluid and methods for purification of the nucleic acids are needed. Besides as a diagnostic tool, genomic profiling of DFDNA can offer better surveillance for individuals at high-risk or annual checkups for healthy people. PjDNA can predict the presence of neoplastic lesions with extremely high probability and has a powerful potential for further testing before a more definitive diagnosis, even without histological evidence of cancer.

Disclosure

Yusuke Ono, Kenji Takahashi, Yusuke Mizukami: Research grants from Hitachi High-Tech Corporation.