IP-10/CXCL10 induction in human pancreatic cancer stroma influences lymphocytes recruitment and correlates with poor survival IP-10/CXCL10 induction in human pancreatic cancer stroma influences lymphocytes recruitment and correlates with poor survival

Precision cut liver slices (PCLSs) retain the structure and cellular composition of the native liver and represent an improved system to study liver fibrosis compared to two‐dimensional mono‐ or co‐cultures. The aim of this study was to develop a bioreactor system to increase the healthy life span of PCLSs and model fibrogenesis. PCLSs were generated from normal rat or human liver, or fibrotic rat liver, and cultured in our bioreactor. PCLS function was quantified by albumin enzyme‐linked immunosorbent assay (ELISA). Fibrosis was induced in PCLSs by transforming growth factor beta 1 (TGFβ1) and platelet‐derived growth factor (PDGFββ) stimulation ± therapy. Fibrosis was assessed by gene expression, picrosirius red, and α‐smooth muscle actin staining, hydroxyproline assay, and soluble ELISAs. Bioreactor‐cultured PCLSs are viable, maintaining tissue structure, metabolic activity, and stable albumin secretion for up to 6 days under normoxic culture conditions. Conversely, standard static transwell‐cultured PCLSs rapidly deteriorate, and albumin secretion is significantly impaired by 48 hours. TGFβ1/PDGFββ stimulation of rat or human PCLSs induced fibrogenic gene expression, release of extracellular matrix proteins, activation of hepatic myofibroblasts, and histological fibrosis. Fibrogenesis slowly progresses over 6 days in cultured fibrotic rat PCLSs without exogenous challenge. Activin receptor‐like kinase 5 (Alk5) inhibitor (Alk5i), nintedanib, and obeticholic acid therapy limited fibrogenesis in TGFβ1/PDGFββ‐stimulated PCLSs, and Alk5i blunted progression of fibrosis in fibrotic PCLS. Conclusion: We describe a bioreactor technology that maintains functional PCLS cultures for 6 days. Bioreactor‐cultured PCLSs can be successfully used to model fibrogenesis and demonstrate efficacy of antifibrotic therapies.

Early allograft failure (EAF) is a major determinant of outcome after liver transplant (LT).^1-6 Concerns have been raised on the acceptance of increased-risk donors (eg, elderly, highly comorbid, steatotic, donors after circulatory death [DCD]). The acceptance of individuals with such conditions might offset otherwise achieved survival improvements.^7-10 In addition, the introduction of machine perfusion (MP) has led to the acceptance of grafts at higher risk of failure.^11-15

Background Factors influencing long‐term outcome after surgical resection for duodenal adenocarcinoma are unclear. Methods A prospectively created database was reviewed for patients undergoing surgery for duodenal adenocarcinoma in six UK hepatopancreaticobiliary centres from 2000 to 2013. Factors influencing overall survival and disease‐free survival (DFS) were identified by regression analysis. Results Resection with curative intent was performed in 150 (84·3 per cent) of 178 patients. The postoperative morbidity rate for these patients was 40·0 per cent and the in‐hospital mortality rate was 3·3 per cent. Patients who underwent resection had a better median survival than those who had a palliative surgical procedure (84 versus 8 months; P < 0·001). The 1‐, 3‐ and 5‐year overall survival rates for patients who underwent resection were 83·9, 66·7 and 51·2 per cent respectively. Median DFS was 53 months, and 1‐ and 3‐year DFS rates were 80·8 and 56·5 per cent respectively. Multivariable analysis revealed that node status (hazard ratio 1·73, 95 per cent c.i. 1·07 to 2·79; P = 0·006) and lymphovascular invasion (hazard ratio 3·49, 1·83 to 6·64; P = 0·003) were associated with overall survival. Conclusion Resection of duodenal adenocarcinoma in specialist centres is associated with good long‐term survival. Lymphovascular invasion and nodal metastases are independent prognostic indicators.