Prevalence of metabolic dysfunction-associated fatty liver disease after pancreatic surgery in a historical Belgian cohort and review of the literature.

Background and objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD) has been reported as a complication after pancreatic surgery. The aim of this study is to assess this phenomenon in a Belgian population, specifically in a period in time when less perioperative chemotherapy was given. Methods: We performed a retrospective monocentric cohort study with 124 selected patients who underwent pancreatic surgery - pancreaticoduodenectomy (PD), distal pancreatectomy (DP) or total pancreatectomy - between 2005 and 2014. Steatosis was assessed radiologically, using Hounsfield units on liver and spleen. Data on imaging, liver function, weight and other relevant parameters were gathered preoperatively as well as 2 and 6 months, 1 and 2 years after surgery. Results: Thirty-eight (31%) out of 124 patients developed liver steatosis at least at one point in time in the two years following surgery, with a prevalence of 21.0% at 2 months, 28.6% at 6 months, 16.4% at 1 year and 20.8 % at 2 years. A statistically significant association with preoperative AST and ALT values, administration of pancreatic enzyme supplementation as a surrogate for pancreatic exocrine insufficiency (PEI) and weight loss at 2 years was detected. Conclusion: MAFLD is seen in 31% of patients with PD or DP pancreatic resection in this retrospective analysis of a monocentric Belgian cohort. Both early and late onset of MAFLD was observed, implying that long-term follow-up is necessary. Clinical impact as well as a direct correlation with patients' weight and oral enzyme supplements needs to be further investigated.

Phase I PIANO trial-PIPAC-oxaliplatin and systemic nivolumab combination for gastric cancer peritoneal metastases: clinical and translational outcomes.

INTRODUCTION: Pressurized intraperitoneal aerosol chemotherapy-oxaliplatin (PIPAC-OX) induces direct DNA damage and immunogenic cell death in patients with gastric cancer peritoneal metastases (GCPM). Combining PIPAC-OX with immune checkpoint inhibition remains untested. We conducted a phase I first-in-human trial evaluating the safety and efficacy of PIPAC-OX combined with systemic nivolumab (NCT03172416). METHODS: Patients with GCPM who experienced disease progression on at least first-line systemic therapy were recruited across three centers in Singapore and Belgium. Patients received PIPAC-OX at 90 mg/m2 every 6 weeks and i.v. nivolumab 240 mg every 2 weeks. Translational studies were carried out on GCPM samples acquired during PIPAC-OX procedures. RESULTS: In total, 18 patients with GCPM were prospectively recruited. The PIPAC-OX and nivolumab combination was well tolerated with manageable treatment-related adverse events, although one patient suffered from grade 4 vomiting. At second and third PIPAC-OX, respectively, the median decrease in peritoneal cancer index (PCI) was -5 (interquartile range: -12 to +1) and -7 (interquartile range: -6 to -20) and peritoneal regression grade 1 or 2 was observed in 66.7% (6/9) and 100% (3/3). Translational analyses of 43 GCPM samples revealed enrichment of immune/stromal infiltration and inflammatory signatures in peritoneal tumors after PIPAC-OX and nivolumab. M2 macrophages were reduced in treated peritoneal tumor samples while memory CD4+, CD8+ central memory and naive CD8+ T-cells were increased. CONCLUSIONS: The first-in-human trial combining PIPAC-OX and nivolumab demonstrated safety and tolerability, coupled with enhanced T-cell infiltration within peritoneal tumors. This trial sets the stage for future combinations of systemic immunotherapy with locoregional intraperitoneal treatments.