Introduction

MAESTRO-NASH (NCT03900429) is an ongoing 54-month, randomized, double-blind, placebocontrolled Phase 3 trial evaluating the efficacy of resmetirom in patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) and fibrosis. 966 patients with biopsy-confirmed NASH were randomized 1:1:1 to resmetirom 80 mg, resmetirom 100 mg, or placebo administered once daily. Histologic endpoints were assessed after 52 weeks. Dual primary endpoints at Week 52 were achieved with both resmetirom 80 mg and 100 mg: NASH resolution with no worsening of fibrosis (NR) or ≥1-stage reduction in fibrosis with no worsening of NAS (FR).

Aims & Methods

Adults with ≥3 metabolic risk factors, liver stiffness ≥8.5 kPa, hepatic fat ≥8%, biopsy-confirmed NASH with F1B-F3 fibrosis, and NAS ≥4 were eligible to participate in MAESTRO-NASH. In this analysis, the relationship of changes in (1) FibroScan CAP, (2) Fibroscan VCTE, and (3) alanine aminotransferase (ALT) to histological response (NR and/or FR) in the resmetirom 80 mg, resmetirom 100 mg, and placebo groups was assessed.

Results

Patients with biopsy-confirmed NASH with fibrosis had high metabolic risk including obesity (mean BMI=36), type 2 diabetes (70%), hypertension (78%), and 10-year ASCVD risk score>14. Baseline mean (SD) FibroScan VCTE was 13.3 (6.8), 13.6 (7.1), and 12.9 (5.6) kPa for the resmetirom 80 mg, resmetirom 100 mg, and placebo groups. Baseline ELF across all fibrosis groups was 9.8 (0.87). FIB-4 across all dose groups was 1.3. CAP improved with resmetirom treatment. CAP improvement in individual resmetirom patients predicted both NR and FI responses; however, even no change in CAP predicted biopsy responses higher than the mean for placebo. A CAP improvement in placebo patients did not predict an FI on biopsy. VCTE was improved over time (1-3 years) years relative to placebo in resmetirom treated patients. Resmetirom treated patients, even those with no VCTE improvement, had higher NASH resolution and fibrosis improvement responses than the mean placebo response rates. VCTE improvement was poorly predictive of a placebo FI or NR response; worsening of VCTE in placebo patients predicted a lower-than-average NASH resolution and fibrosis improvement. Both doses of resmetirom significantly reduced ALT approximately 30% relative to placebo. In resmetirom treated patients, higher % reductions in ALT were associated with higher NR and FI on biopsy. For resmetirom treated patients without a reduction in ALT, the NASH resolution and fibrosis improvement responses were predicted to be higher than the mean placebo biopsy responses.

Conclusion

ALT was reduced and CAP and VCTE improved was by resmetirom relative to placebo. However, biopsy responses were not always associated with changes in these markers. Additional analyses, including artificial intelligence (AI)-based assessments of histological response, are ongoing.

Disclosure

Authors are investigators in the MAESTRO-NASH trial or employees of Madrigal Pharmaceuticals.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) surveillance programs are recommended for individuals with a PDAC lifetime-risk ≥5% to improve outcomes.¹ While familial adenomatous polyposis (FAP) is linked to increased PDAC risk, robust data to guide surveillance recommendations is lacking.^2,3 This study evaluates PDAC risk in a large FAP-cohort and cost-effectiveness of PDAC-surveillance in this group.

Aims & Methods

Data were collected from FAP cohorts in the United States (US) and the Netherlands (NL), including individuals (≥18 years) with a confirmed (likely) pathogenic APC variant. To minimize ascertainment bias, individuals whose initial visit or registration was prompted by a PDAC diagnosis were excluded from the analysis. Cumulative PDAC incidence, adjusted for death as competing risk, was calculated for the FAP cohorts and compared with control data from the Netherlands Cancer Registry and Statistics Netherlands. The cost-effectiveness of surveillance was evaluated using our previously developed Markov model.⁴ In comparison to the previous study, the model was modified by setting the inflation rate at 3%, discontinuing surveillance at age 75 and incorporating the relative risk derived from our FAP cohort.

Results

The US-cohort (n=357) and the NL-cohort (n=1000) had a median age at the end of follow-up of 46 years (IQR, 32.0-60.0) and 60 years (IQR, 47.5-72.5), respectively. Female participants comprised 52.9% of the US-cohort and 47.2% of the NL-cohort. Within the US-cohort, three PDAC cases were identified, however, two individuals had been referred to the Mayo Clinic at the time of PDAC diagnosis and were subsequently excluded from the analysis to reduce the risk of ascertainment bias. When combining both FAP-cohorts, the cumulative risk of PDAC by age 70 was 0.7% (95% CI, 0.3-1.8). Detailed cumulative risk estimates, stratified by cohort and age, are presented in Table 1. For comparison, the cumulative incidence of PDAC in the general population at age 70 was 0.32% (95% CI, 0.31-0.33), corresponding to a relative risk of 2.2 (95% CI, 0.9-5.7) for individuals with FAP. The cost-effectiveness analysis estimated that annual magnetic resonance imaging-based PDAC surveillance, starting at age 40, would be considered cost-effective if the relative risk reached at least 4.0, based on a willingness-to-pay threshold of $100 000.

Table 1. Adjusted cumulative incidence of pancreatic ductal adenocarcinoma in individuals with familial adenomatous polyposis

Conclusion

This is the largest cohort study to date to assess PDAC risk in individuals with FAP. Our findings indicate that PDAC risk in FAP patients is not significantly higher than in the general population. Moreover, their surveillance is shown not to be cost-effective.

References

1. Goggins M, Overbeek KA, Brand R, Syngal S, Del Chiaro M, Bartsch DK, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut. 2020;69(1):7-17.
2. Giardiello FM, Offerhaus GJ, Lee DH, Krush AJ, Tersmette AC, Booker SV, et al. Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut. 1993;34(10):1394-6.
3. Karstensen JG, Bülow S, Højen H, Jelsig AM, Jespersen N, Andersen KK, et al. Cancer in Patients With Familial Adenomatous Polyposis: A Nationwide Danish Cohort Study With Matched Controls. Gastroenterology. 2023;165(3):573-81.e3.
4. Corral JE, Das A, Bruno MJ, Wallace MB. Cost-effectiveness of Pancreatic Cancer Surveillance in High-Risk Individuals: An Economic Analysis. Pancreas. 2019;48(4):526-36.

Disclosure

None

Introduction

Endoscopic stenting proved to be a valid surgery-sparing approach for upper gastrointestinal benign pathological conditions, mainly refractory benign strictures and post-surgical transmural defects. Niti-S™ Beta-2™ EKxxxxFNT2 esophageal covered stents were specifically designed to treat these conditions preventing stent migration and embedment.

Aims & Methods

We conducted a monocentric retrospective analysis on prospectively collected data regarding patients undergoing EKxxxxFNT2 placement for benign indication between January 2019 and December 2024, considering demographic, anthropometric, clinical and technical variables, and evaluating safety and efficacy profiles.

Results

A total of 32 patients were included (M 53.1%, median age 63 years), 25 (78.1%) post-surgical. Indication for stent placement was leakage in 16/32 cases (50%), and stricture/compression and fistula both in 8/32 (25%). Most frequently applied stent (16/32, 50%) was Niti-S™ Beta-2™ EKxxxxFNT2 esophageal covered stent 24 mm x 200 mm. Technical success was achieved in 100% of the cases. No periprocedural AEs were registered, 4 stents (12.5%) migrated. Median time to oral refeeding was 4 days [IQR 2-10]. Stents were removed after a median time of 34 days [IQR 17.3-41.5]. Three patients (9.4%) died before stent removal. Overall clinical success rate was 26/32 cases (81.3%); anastomotic leakage as indication proved to be significantly more frequent among the unsuccessful group [5/6 (83.3%) VS 7/26 (26.9%), p=0.0012]. Two cases (8%) of stenosis relapse were reported, all successfully endoscopically treated.

Conclusion

Double-bump antimigratory Niti-S™ Beta-2™ EKxxxxFNT2 esophageal covered stents proved to be a safe, effective, and rapid therapeutic option for patients with complex benign upper gastrointestinal conditions.

References

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Medas R, Ferreira-Silva J, Girotra M, Barakat M, Tabibian JH, Rodrigues-Pinto E (2023) Best Practices in Esophageal, Gastroduodenal, and Colonic Stenting. GE Port J Gastroenterol 30:19–34. https://doi.org/10.1159/000527202
Fuccio L, Hassan C, Frazzoni L, Miglio R, Repici A (2016) Clinical outcomes following stent placement in refractory benign esophageal stricture: a systematic review and meta-analysis. Endoscopy 48:141–148. https://doi.org/10.1055/s-0034-1393331
Spaander MCW, van der Bogt RD, Baron TH, Albers D, Blero D, de Ceglie A, Conio M, Czakó L, Everett S, Garcia-Pagán J-C, Ginès A, Jovani M, Repici A, Rodrigues-Pinto E, Siersema PD, Fuccio L, van Hooft JE (2021) Esophageal stenting for benign and malignant disease: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2021. Endoscopy 53:751–762. https://doi.org/10.1055/a-1475-0063
Boerlage TCC, Houben GPM, Groenen MJM, van der Linde K, van de Laar AWJM, Emous M, Fockens P, Voermans RP (2018) A novel fully covered double-bump stent for staple line leaks after bariatric surgery: a retrospective analysis. Surg Endosc 32:3174–3180. https://doi.org/10.1007/s00464-018-6034-2