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

In Nonalcoholic steatohepatitis (NASH), several pathogenetic mechanisms occur as explained by the “multiple hit pathogenesis”. However, the characteristic inflammation of NASH is orchestrated by the innate immunity, since Kupffer cells are triggered by PAMPs and DAMPs, and recruit monocytes (Mo), which repopulate the liver with new macrophages, perpetuating inflammation.
The recent promising field of immunometabolism showed that myeloid cells undergo a metabolic reprogramming to sustain the pro-inflammatory activity, suggesting novel immunosuppressive approaches by targeting cellular metabolism. However, immune cell bioenergetic alterations in chronic diseases such as NASH, are substantially unexplored.

Aims & Methods

Here, we questioned whether circulating Mo in NASH presented immunometabolic alterations. 20 NASH patients (histologically determined) and 10 healthy controls were enrolled for isolation of circulating CD14+ Mo from peripheral blood. Mo were used for analysis of bioenergetics and mitochondrial function, and RNA/protein isolation. To do this, glycolysis and mitochondrial respiration (MR) were quantified with extracellular acidification rate and oxygen consumption rate, respectively, by using a Seahorse HS Mini analyser (Agilent). Respiratory chain (RC) complexes enzymatic activities and H₂O₂ production rate were analysed. In a second step, the effect of succinate dehydrogenase (SDH) inhibition was investigated in vitro by exposing patient Mo to dimethyl malonate (DMM), and in vivo by using a preclinical model of NASH. In particular, wild-type (C57BL/6) mice were fed with high-fat and high-cholesterol (HF-HC) diet for 8 weeks. From week 6 to week 8 mice were i.p. injected with DMM (160 mg/kg), or vehicle (PBS) every second day.

Results

NASH Mo presented a peculiar bioenergetic profile characterized by a significant increase of both glycolysis and MR compared to controls, with a preponderant change of glycolysis. Basal and maximal respirations were higher in NASH Mo, although this resulted not only in more ATP production, but also in a very high proton leak. In accordance with this, we found that NASH Mo showed a higher enzymatic activity of RC complex I and complex II. However, using pyruvate/malate and succinate as substrates we observed that complex I and II activities produced high levels of H₂O₂ with consequent mitochondrial oxidative stress. Taken together these results highlighted that Mo in NASH have a bioenergetic reprogramming with increase of glycolysis and mitochondrial dysfunction. The mRNA expression of 78 targets, included in the PrimePCR^TM array “mitochondria energy metabolism plus”, showed the significant down-regulation of 7 genes, while 32 genes resulted up-regulated. Most of these genes encoded for RC complex subunits, and in particular, 3 out of 4 SDH subunits resulted more expressed. SDH is an enzyme complex also known as RC complex II, and its role in driving the metabolic rewiring of macrophages has been recently demonstrated. Therefore, considering the higher activity and expression of RC complexes, and in particular the SDH, we tried to expose NASH Mo to DMM, a SDH inhibitor with demonstrated immunomodulatory properties. Interestingly, DMM normalized glycolysis and MR levels, abrogating Il-1β and TNF-α expression. Moreover, HF-HC fed mice were treated with DMM, improving steatohepatitis in terms of liver injury, steatosis and inflammation. The macrophage amount in the liver was reduced and the expression of M2 markers such as arginase1 and CD163 was partially restored by DMM.

Conclusion

Mo immunometabolism might be targeted in NASH.