ECP 2023 Abstracts

S128 Virchows Archiv (2023) 483 (Suppl 1):S1–S391 13 negative carcinoma and an atypical biliary epithelium showing absence of staining for all the mismatch repair proteins. Conclusion: Extrahepatic cholangiocarcinoma is an aggressive neo- plasm with a dismal prognosis, partly due to limited treatment options. The PD-L1 positivity in a significant proportion of the cancer cases raises the potential utility of the immunotherapy regimen in this par- ticular pathology. A targeted therapy aimed at immune checkpoint regulators, such as Programmed-death Ligand 1 and correlated with the assessment of the mismatch repair proteins expression, could predict the clinical outcome and improve survival for these patients. The study was supported by grants of the Ministry of Research, Inno- vation and Digitization, CCCDI-UEFISCDI, project number PN- III-P1-1.1-TE-2021-0801 . PS-23-004 Impact of resection margins on recurrence patterns and progno- sis in resectable pancreatic ductal adenocarcinoma – a long-term population-based cohort study H. Blomstrand*, H. Olsson, B. Björnsson, H. Green, N. Elander *Department of Pathology, Linköping University Hospital, Department of Biomedical and Clinical Sciences, Linköping University, Sweden Background & objectives: Survival outcomes remain poor following resection of pancreatic cancer. To better guide postoperative manage- ment, more accurate prognostic models are needed. Previous studies suggest improved prognostic value when dividing R1 resections with regards to whether mobilization or transection margins were involved. Methods: In a population-based retrospective study covering 275 pan- creatic resections over eleven years, all specimen slides were carefully reviewed. The prognostic impact of pathological, laboratory and sur- gical factors, including margin clearance with R1 cases divided into affected margin type (mobilization (R1-mob)/transection (R1-trans)) or distance (standard <1mm clearance(R1-1mm)/tumour on ink(R1-ink)), were analysed with Cox regression. Results: Resection margin status was found to be a significant prognos- tic factor in the univariable analyses regardless of whether the R1-group was subdivided by margin type (median OS R1-mob 24.1 months, R1-trans 18.7 months and hazard ratio (HR) R1-mob 1.39, R1-trans 1.93, p<0.001 (R0 resections as reference)) or clearance (median OS R1-1mm 22.6 months, R1-ink 14.5 months and HR R1-1mm 1.43, R1-ink 2.40, p<0.001). However, only the latter of the two was an independent prog- nostic factor in the multivariable analysis (p=0.006) together with year of resection (survival improving over time), lymphovascular invasion, tumour differentiation grade, TNM 8th edition stage and adjuvant treatment. Conclusion: In the present study resection margin status with subdivision of the R1 group by margin clearance proved to be superior to division by margin type. The study indicates that tumour on ink might convey additional prognostic information and should be highlighted in the pathology report when present. Funding: FORSS (grant number 941207) County of Östergötland (grant numbers 962449 and 935580) PS-23-005 Mettl14-mediated m6A modification prevents NASH by regulating endoplasmic reticulum stress and oxidative stress Y. Chen*, Y. Shi *Department of Pathology & Institute of clinical Pathology, West China Hospital, Sichuan University, Chengdu, China Background & objectives: N6-methyladenosine (m6A) mRNA modification plays critical roles in multiple diseases, including Non- alcoholic steatohepatitis (NASH). However, the role of m6A methyl- transferase like 14 (Mettl14) in NASH remains largely unknown. Here, we identify Mettl14 as a key negative regulator of NASH pathogenesis. Methods: The role of Mettl14 was verified in Mettl14 deficient hepato- cytes and hepatocyte-specific Mettl14 knockout mice, which were fed with methionine and choline deficient diet (MCD). Western Blot and RNA dot blot were used to determine the expression of Mettl14, as well as global m6A modification. Furthermore, the molecular mecha- nisms were validated with histopathology, electron microscopy, RNA- sequencing and m6A-sequencing. Results: An overwhelming proportion of m6A-modified genes with up-regulated m6A levels is identified in the MCD-induced NASH mouse, and Mettl14 is upregulated. Hepatocyte-specific deletion of Mettl14 drives NASH progression, which is histologically character- ized by diffuse macrovesicular steatosis of hepatocytes, infiltration of inflammatory cells, and obvious fibrosis in portal areas. And more lipid droplets are deposited in Mettl14 ablated hepatocytes after palmitic acid treatment. mRNA transcripts, such as Stt3a, P4hb, Lman1, GCLC, and SLC7A11, encoding proteins involved in polypeptide processing and the synthesis of GSH, are m6A-hypomethylated, and their mRNA and protein levels are decreased. The hepatocytes are under severe endoplasmic reticulum (ER) stress and oxidative stress. Conclusion: We demonstrate a mechanism of Mettl14 in inhibiting NASH by negatively modulating ER stress and oxidative stress in an m6A-depend- ent manner. Mettl14 deficiency directly induces excessive ER stress by inhibiting the expression of ER polypeptide processing proteins, which in turn indirectly induces oxidative stress. On the other hand, Mettl14 inhibits the antioxidant reaction mediated by GSH, resulting in severe oxidative stress, thereby promoting the occurrence and development of NASH. PS-23-006 Loss of F-Box and leucine rich repeat protein 5 (FBXL5) expres- sion is associated with poor survival in patients with hepatocellular carcinoma Y.A. Cho*, S. Kim, C.K. Park, S.Y. Ha *Samsung Medical Center, Republic of Korea Background & objectives: The deficiency of F-Box and leucine rich repeat protein 5 (FBXL5), an iron-sensing ubiquitin ligase, triggers car- cinogenesis of hepatocellular carcinoma (HCC) due to iron overload. However, the expression of FBXL5 and its clinical implication have not been elucidated in HCC. Methods: We investigated FBXL5 protein expression using immuno- histochemistry in HCC tissue samples of two institutes, Samsung Medi- cal Center and Hallym University Sacred Heart Hospital. After setting cut-off value using X-tile software, we evaluated the relation between FBXL5 expression and various clinicopathological parameters. For external validation, the Cancer Genome Atlas (TCGA) cohort was used. Results: Among 374 cases, 70 cases showed low FBXL5 expression, which is less than 5% of tumour (18.7%). Low FBXL5 expression group showed inferior disease-specific survival (DSS; P = 0.002) and recurrence free survival (RFS; P=0.001) compared to high FBXL5 expression group and associated with non-viral aetiology (P = 0.024). Similar to our cohort, cases with low FBLX5 mRNA level showed inferior DSS and RFS (P<0.001 and P=0.002, respec- tively) than cases with high FBLX5 mRNA level in TCGA cohort. Conclusion: Low expression of FBXL5 is associated with inferior DSS and RFS in HCC patients in two institute cohorts and related with non- viral aetiology. FBXL5 can be used as a potential prognostic markers and therapeutic target for HCC. PS-23-007 Molecular heterogeneity of Primary liver carcinomas: early study J. Espírito Santo*, A.F. Ladeirinha, A. Alarcão, E. Strelet, M. Reis, R. Santos, L. Carvalho *Adult Liver Transplantation Unit, Coimbra Hospital and University Centre, Portugal