Introduction

The ongoing phase 3 ESSENCE trial (NCT04822181) reported positive results for histological and non-invasive test (NIT) endpoints in an interim analysis of the first 800 randomised participants with biopsy-defined metabolic dysfunction-associated steatohepatitis (MASH) and F2/F3 fibrosis receiving once-weekly subcutaneous semaglutide 2.4 mg vs placebo. Participants receiving semaglutide achieved a mean weight loss of 10.5% vs 2.0% with placebo. In this post hoc analysis, we assessed the weight dependency of the effects of semaglutide 2.4 mg on study endpoints (NITs and histology) after 72 weeks of treatment, using weight loss-independent and weight loss-dependent pathways as covariates.

Aims & Methods

NITs and biopsies were assessed at baseline and week 72. MASH-related NIT responder endpoints were change in alanine aminotransferase (ALT; ≥17-unit reduction) and FibroScan-aspartate aminotransferase (FAST) score (≥0.22 reduction). Fibrosis-related NIT responder endpoints were change in vibration-controlled transient elastography (VCTE) liver stiffness measurement (30% reduction) and Enhanced Liver Fibrosis (ELF) score (≥0.5-unit reduction). Histological endpoints included resolution of MASH and improvement in fibrosis. All endpoints were assessed using logistic regression at week 72 with treatment as exposure, percentage weight loss from baseline to week 72 as mediator, and baseline type 2 diabetes status, fibrosis stage and body weight as covariates. The total and weight loss-independent and weight loss-dependent effect sizes were calculated as odds ratios (ORs), and missing data were omitted. All data are based on the full analysis set from the on-treatment observation period.

Results

For MASH-related endpoints, the total effect (OR [95% confidence interval (CI)]) for ALT, FAST score and resolution of MASH without worsening of fibrosis was 4.7 (3.3, 6.6), 6.9 (4.3, 10.9) and 3.9 (2.8, 5.5), respectively. ORs (95% CI) for the weight loss-independent effect were 3.0 (2.0, 4.6), 2.8 (1.7, 4.7) and 2.0 (1.4, 3.0), respectively; for the weight loss-dependent effect, ORs (95% CI) were 1.5 (1.2, 2.0), 2.5 (1.8, 3.4) and 1.9 (1.6, 2.4), respectively. Overall, 71.9%, 53.3% and 51.9% of the total effect for ALT, FAST score and resolution of MASH, respectively, were not mediated by weight loss. For the fibrosis-related endpoints, the total effect (OR [95% CI]) for VCTE, ELF score and improvement in fibrosis without worsening of MASH were 3.0 (2.0, 4.4), 4.5 (3.1, 6.4) and 2.1 (1.5, 3.1), respectively. ORs (95% CI) for the weight loss-independent effect were 1.7 (1.1, 2.7), 2.4 (1.6, 3.7) and 1.5 (1.0, 2.4), respectively; for the weight loss-dependent effect, ORs (95% CI) were 1.7 (1.4, 2.2), 1.9 (1.5, 2.3) and 1.4 (1.1, 1.8), respectively. This shows that 48.9%, 58.5% and 55.5% of the total effect for VCTE, ELF score and fibrosis improvement, respectively, were not mediated by weight loss.

Conclusion

Semaglutide 2.4 mg improved MASH-related histological and NIT endpoints and fibrosis-related NIT endpoints through equal contributions of weight loss-independent and weight loss-dependent metabolic mechanisms, with effects beyond weight loss.

Disclosure

Philip N. Newsome reports grants from Novo Nordisk, and has received consulting fees from Boehringer Ingelheim, Madrigal and Novo Nordisk. PNN also reports honoraria as a speaker from AiCME, Echosens and Novo Nordisk; support for attending meetings for Novo Nordisk; and participation on an advisory board for Boehringer Ingelheim, GSK, Madrigal, Novo Nordisk and Sagimet.
Elisabetta Bugianesi served as a consultant or advisory board member for Boehringer Ingelheim, Gilead, Intercept, Merck, Novo Nordisk, Pfizer and ProSciento, and as a speaker for Gilead, Intercept, Merck, Novo Nordisk and Pfizer. EB has also received a research grant from Gilead for fatty liver research.
Vlad Ratziu received consulting fees from Boehringer Ingelheim, GSK, Madrigal, Novo Nordisk, ProSciento and Sagimet, and research grants (to institution) from MSD.
Mary E. Rinella consults for 89bio, Akero, Boehringer Ingelheim, CytoDyn, GSK, HistoIndex, Intercept, Madrigal, NGM Bio, Novo Nordisk, Sagimet and Sonic Incytes. MER has received fees for consulting or participation in advisory boards for Boehringer Ingelheim, Echosens, Eli Lilly and Novo Nordisk. MER also reports honoraria as a speaker for CME events sponsored by Boehringer Ingelheim, Madrigal and Novo Nordisk.
Michael Roden received lecture fees or served on advisory boards for AstraZeneca, Echosens, Eli Lilly, Madrigal, Merck-MSD, Novo Nordisk and Target RWE, and performed investigator-initiated research with support from Boehringer Ingelheim, Novo Nordisk and Nutricia/Danone to the German Diabetes Center.
Arun J. Sanyal consults for and advises AstraZeneca and Avant Santé. AJS also consults for and has received grants from Akero, BMS, Eli Lilly, Intercept, Madrigal and Novo Nordisk. AJS consults for and owns stock in Rivus, and consults for 89bio, AGED Diagnostics, Albireo, Alnylam, Altimmune, Boehringer Ingelheim, Echosens, Genentech, Gilead, GSK, HistoIndex, Mallinckrodt, Merck, NGM Bio, Novartis, PathAI, Pfizer, Poxel, Regeneron Pharmaceuticals, Inc., Salix, Siemens, Surrozen, Takeda, Terns and Zydus. AJS owns stock in Durect, Exalenz, Genfit, Indalo, Inversago and Tiziana, and has received royalties from Elsevier and Wolters Kluwer.
Adel Belloum, Niels Krarup, Anna Cali, Mohamed Tawfik and Thea Vestergaard are employees and stockholders of Novo Nordisk A/S.
Jörn M. Schattenberg declares consultant honoraria from 89bio, Alentis, Alexion, Altimmune, AstraZeneca, Bionorica, Boehringer Ingelheim, Gilead Sciences, GSK, Inventiva Pharma, Ipsen, Eli Lilly, Madrigal Pharmaceuticals, MSD, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi and Siemens Healthineers; speaker honoraria from AbbVie, Academic Medical Education, Boehringer Ingelheim, Echosens, Forum für Medizinische Fortbildung, Gilead Sciences, Madrigal Pharmaceuticals, MedicalTribune, MedPublico GmbH, MedScape and Novo Nordisk; and stockholder options in AGED Diagnostics and Hepta Bio.
Matthew J. Armstrong reports investigator fees from Novo Nordisk.
Anja Geerts reports no conflicts of interest.
Jacob George is supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia Program Grant (APP1053206), Project, Ideas and Investigator grants (APP2001692, APP1107178, APP1108422, APP1196492) and a Cancer Institute, NSW grant (2021/ATRG2028). He serves on advisory boards for AbbVie, AstraZeneca, Boehringer Ingelheim, Novo Nordisk and Roche.
Chun-Jen Liu reports no conflicts of interest.
Ewa Janczewska was involved in clinical trials and lectures with Novo Nordisk, was involved in clinical trials with Inventiva Pharma, MSD, Galectin, Dr Falk and Sanofi and reports travel grants from Novo Nordisk and Eli Lilly.
Håvard Midgard is involved in lectures with Novo Nordisk, AbbVie and Gilead, and reports ad boards for Boeringer Ingelheim, AbbVie and Gilead.
Igor Bakulin reports involvement in clinical trials for Novo Nordisk and Eli Lilly and lectures for AbbVie and Johnson & Johnson.

Introduction

​​​​​Pancreatic cancer (PC) has one of the poorest prognoses among malignancies. Early detection, particularly of stage 0 or stage 1 disease, is crucial to improving survival outcomes. However, conventional screening strategies based solely on family history or symptoms—as commonly practiced in Western countries—have shown limited sensitivity for early-stage PC. In Japan, more comprehensive approaches are being developed.

Aims & Methods

Low-grade relevant (LGR) factor	High-grade relevant (HGR) factor
・sporadic family history ・diabetes mellitus ・diabetes mellitus worsening ・stomach/back symptoms ・weight loss ・elevated serum pancreatic enzyme ・heavy alcohol consumption ・smoking history ・obesity	・familial PC ・hereditary PC syndrome/pancreatitis ・new-onset diabetes mellitus ・jaundice ・elevated serum tumor biomarkers ・chronic pancreatitis ・pancreatic cyst ・main pancreatic duct dilation
Score positive; 3 points or more	Score positive; 1 point or more

This nationwide, multicenter prospective study aimed to evaluate the utility of a novel scoring system for early PC detection among hospital outpatients. From August 2019 to May 2024, all outpatients presenting with symptoms, risk factors, subtle imaging abnormalities of the pancreas, or requesting pancreatobiliary screening at the Department of Gastroenterology in hospitals participating in the Early Pancreatic Cancer Screening Study (EPSS) were considered for inclusion. Consecutive patients who had no pancreatic tumors suspected by any imaging modalities were examined, no prior history of endoscopic ultrasound (EUS) examination for pancreatic disease, and/or no referrals from other hospitals specifically for PC diagnosis were prospectively enrolled. The system comprised low- and high-grade relevant (LGR/HGR) factors referring to both risk factors and diagnostic indicators, including symptoms and subtle imaging abnormalities associated with PC. Patients were classified as score-positive if they had ≥3 LGR or ≥1 HGR factor(s). Diagnostic yield for stage 0/1 and all-stage PC was compared between score-positive and score-negative groups. Diagnostic performance was also evaluated against previous large-scale Japanese data and Western screening methods based on family/genetic risk or symptoms. The sample size was determined based on a previous large-scale PC screening study in Japan.

Results

Of 3,287 patients, 2,531 were score-positive and 756 were score-negative. PC was diagnosed in 283 patients (8.6%), including 67 with stage 0/1 disease. The detection rate of stage 0/1 PC was significantly higher in score-positive than in score-negative patients (2.6% vs. 0.7%, P=.001). Compared to a previous Japanese study (0.78%), this study showed a significantly higher detection rate (P<.001). The sensitivity of the scoring system for stage 0/1 PC was 93.1%, significantly outperforming Western-style approaches (12.5% for family/genetic risk and 50.0% for symptom-based screening; both P<.001), while maintaining comparable accuracy. Even combining family/genetic risk and symptoms, sensitivity remained lower than that of the scoring system (56.9%, P<.001). For all-stage PC, both the accuracy and sensitivity of the diagnosis based on the scoring system were significantly higher than those based on family/genetic risk, symptom, or the combination of symptom and family/genetic risk (P = .030, .004, .002 for accuracy; and all P <.001 for sensitivity, respectively). Among the 283 PC cases, 23.7% were stage 0/1, 15.9% were ≤10 mm, and 45.6% underwent surgical resection. Multivariate logistic analysis identified older age, worsening diabetes, and MPD dilation as significant independent predictors of stage 0/1 PC.

Conclusion

The scoring system demonstrated superior sensitivity and comparable accuracy to traditional screening strategies for detecting early-stage PC. Its use in outpatient settings may facilitate earlier diagnosis and intervention, thereby improving resectability and prognosis.

References

Klein AP. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol 2021;18:493-502.
Hanada K, Okazaki A, Hirano N, et al. Diagnostic strategies for early pancreatic cancer. J Gastroenterol 2015;50:147-54.
Sagami R, Hayasaka K, Ujihara T, et al. Role of EUS combined with a newly modified scoring system to detect pancreatic high-grade precancerous lesions. Endosc Ultrasound 2022.

Introduction

Early detection of neoplasia in Barrett’s Esophagus (BE) remains challenging. Although computer-aided detection (CADe) systems are increasingly available to support endoscopists, successful CADe implementation largely depends on the quality of endoscopic images, which can vary significantly in clinical practice. This study introduces an innovative computer-aided quality (CAQ) system designed for BE endoscopy, capable of assessing various image quality parameters, providing real-time feedback to the endoscopist, and operating in conjunction with an established CADe system.

Aims & Methods

The CAQ system was trained on 4,926 images from 243 BE patients to assess both objective (e.g., blurriness, illumination, and specular reflections) and subjective (i.e., mucosal cleanliness and esophageal expansion) image quality factors. The system is able to provide real-time feedback on these quality parameters to the endoscopist. Additionally, it is configured to function as a preprocessing filter for a previously developed CADe system, automatically excluding lower-quality images. To validate the CAQ system’s performance as a standalone tool, we constructed an endoscopic image quality test set, which included 647 images from 51 non-dysplastic BE patients across eight hospitals. These images were annotated for objective (e.g. motion blur, lighting) and subjective (i.e. esophageal expansion, mucosal cleanliness) image quality parameters by two experts. Additionally, to evaluate the CAQ system’s role as a preprocessing step for an established CADe system, we created the Barrett CADe test set, containing 956 frames from 62 neoplastic BE patients and 557 frames from 35 non-dysplastic BE patients from 12 Barrett referral centers. Outcome measures included agreement scores with experts for standalone image quality assessment and sensitivity, specificity, and Area-under-the-Curve (AUC) for BE neoplasia detection.

Results

As a stand-alone system, the CAQ system achieved Cohen’s Kappa scores for agreement with expert annotators of 0.73, 0.91, and 0.89 for objective image quality parameters, mucosal cleanliness, and esophageal expansion, respectively—comparable to inter-annotator scores of 0.73, 0.93, and 0.83. When used as a preprocessing filter for the CADe system, the CAQ system improved the CADe's sensitivity from 82% to 90% and the AUC from 87% to 91%, while specificity remained stable at 75% (Table 1).

Table 1. Performance of the CADe system for Barrett’s neoplasia detection with and without the CAQ system.

Evaluated by	Sensitivity, %, (95% CI)	Specificity, %, (95% CI)	AUC, %, (95% CI)
CADe	82.2 (79.7 - 84.5)	74.7 (70.9 - 78.1)	87.2 (79.9 - 94.5)
CAQ + CADe	89.9 (87.2 - 92.1)	74.7 (70.0 - 78.9)	91.4 (82.0 - 100)

Conclusion

This study introduces the first CAQ system specifically aimed at automated quality control in BE endoscopy. As a standalone tool, the system effectively distinguishes poorly from well-visualized mucosa. When combined with an established CADe system, it enhances detection rates for neoplasia, highlighting its potential to improve diagnostic accuracy in BE surveillance.