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Inter‐alpha‐trypsin inhibitor heavy chain 5 (ITIH5) has been identified as a metastasis suppressor gene in pancreatic cancer. Here, we analyzed ITIH5 promoter methylation and protein expression in The Cancer Genome Atlas (TCGA) dataset and three tissue microarray cohorts (n = 618), respectively. Cellular effects, including cell migration, focal adhesion formation and protein tyrosine kinase activity, induced by forced ITIH5 expression in pancreatic cancer cell lines were studied in stable transfectants. ITIH5 promoter hypermethylation was associated with unfavorable prognosis, while immunohistochemistry demonstrated loss of ITIH5 in the metastatic setting and worsened overall survival. Gain‐of‐function models showed a significant reduction in migration capacity, but no alteration in proliferation. Focal adhesions in cells re‐expressing ITIH5 exhibited a smaller and more rounded phenotype, typical for slow‐moving cells. An impressive increase of acetylated alpha‐tubulin was observed in ITIH5‐positive cells, indicating more stable microtubules. In addition, we found significantly decreased activities of kinases related to focal adhesion. Our results indicate that loss of ITIH5 in pancreatic cancer profoundly affects its molecular profile: ITIH5 potentially interferes with a variety of oncogenic signaling pathways, including the PI3K/AKT pathway. This may lead to altered cell migration and focal adhesion formation. These cellular alterations may contribute to the metastasis‐inhibiting properties of ITIH5 in pancreatic cancer.

Abstract Background Perihilar cholangiocarcinoma (pCCA) is a malignant tumor of the hepatobiliary system which is still associated with a challenging prognosis. Postoperative complications play a crucial role in determining the overall prognosis of patients with pCCA. Changes in body composition (BC) have been shown to impact the prognosis of various types of tumors. Therefore, our study aimed to investigate the correlation between BC, postoperative complications and oncological outcome in patients with pCCA. Methods All patients with pCCA who underwent curative‐intent surgery for pCCA between 2010 and 2022 were included in this analysis. BC was assessed using preoperative computed tomography and analyzed with the assistance of a 3D Slicer software. Univariate and multivariate binary logistic regression analyses were conducted to examine the relationship between BC and clinical characteristics including various measurements of postoperative complications and Cox regressions and Kaplan–Meier analysis to evaluate oncological risk factors in the study cohort. Results BC was frequently altered in patients undergoing curative‐intent liver resection for pCCA (n = 204) with 52.5% of the patients showing obesity, 55.9% sarcopenia, 21.6% sarcopenic obesity, 48.5% myosteatosis, and 69.1% visceral obesity. In multivariate analysis, severe postoperative complications (Clavien‐Dindo ≥3b) were associated with body mass index (BMI) (Odds ratio (OR) = 2.001, p = 0.024), sarcopenia (OR = 2.145, p = 0.034), and myosteatosis (OR = 2.097, p = 0.017) as independent predictors. Furthermore, sarcopenia was associated with reduced overall survival (OS) in pCCA patients (sarcopenia vs. no‐sarcopenia, 21 months vs. 32 months, p = 0.048 log rank). Conclusions BC is highly associated with severe postoperative complications in patients with pCCA and shows tendency to be associated impaired overall survival. Preoperative assessment of BC and interventions to improve BC might therefore be key to improve outcome in pCCA patients undergoing surgical therapy.

Abstract Background Myosteatosis is associated with perioperative outcomes in orthotopic liver transplantation (OLT). Here, we investigated the effects of body composition and myosteatosis on long‐term graft and patient survival following OLT. Methods Clinical data from 225 consecutive OLT recipients from a prospective database were retrospectively analysed (May 2010 to December 2017). Computed tomography‐based lumbar skeletal muscle index (SMI) (muscle mass) and mean skeletal muscle radiation attenuation (SM‐RA) (myosteatosis) were calculated using a segmentation tool (3D Slicer). Patients with low skeletal muscle mass (low SMI) and myosteatosis (low SM‐RA) were identified using predefined and validated cut‐off values. Results The mean donor and recipient age was 55 ± 16 and 54 ± 12 years, respectively. Some 67% of the recipients were male. The probability of graft and patient survival was significantly lower in patients with myosteatosis compared with patients with higher SM‐RA values (P = 0.011 and P = 0.001, respectively). Low skeletal muscle mass alone was not associated with graft and patient survival (P = 0.273 and P = 0.278, respectively). Dividing the cohort into quartiles, based on the values of SMI and SM‐RA, resulted in significant differences in patient but not in graft survival (P = 0.011). Even though multivariable analysis identified low SM‐RA as an important prognostic marker (hazard ratio: 2.260, 95% confidence interval: 1.177–4.340, P = 0.014), myosteatosis lost its significance when early mortality (90 days) was excluded from the final multivariable model. Patients with myosteatosis showed significantly higher all‐cause mortality and in particular higher rates of deaths due to respiratory and septic complication (P = 0.002, P = 0.022, and P = 0.049, respectively). Conclusions Preoperative myosteatosis may be an important prognostic marker in patients undergoing deceased donor liver transplantation. The prognostic value of myosteatosis seems to be particularly important in the early post‐operative phase. Validation in prospective clinical trials is warranted.