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Muscle-wasting and disease-related malnutrition are highly prevalent in patients with chronic liver diseases (CLD) as well as in liver transplant (LT) candidates. Alterations of body composition (BC) such as sarcopenia, myosteatosis and sarcopenic obesity and associated clinical frailty were tied to inferior clinical outcomes including hospital admissions, length of stay, complications, mortality and healthcare costs in various patient cohorts and clinical scenarios. In contrast to other inherent detrimental individual characteristics often observed in these complex patients, such as comorbidities or genetic risk, alterations of the skeletal muscle and malnutrition are considered as potentially modifiable risk factors with a major clinical impact. Even so, there is only limited high-level evidence to show how these pathologies should be addressed in the clinical setting. This review discusses the current state-of-the-art on the role of BC assessment in clinical outcomes in the setting of CLD and LT focusing mainly on sarcopenia and myosteatosis. We focus on the disease-related pathophysiology of BC alterations. Based on these, we address potential therapeutic interventions including nutritional regimens, physical activity, hormone and targeted therapies. In addition to summarizing existing knowledge, this review highlights novel trends, and future perspectives and identifies persisting challenges in addressing BC pathologies in a holistic way, aiming to improve outcomes and quality of life of patients with CLD awaiting or undergoing LT. [ABSTRACT FROM AUTHOR]

Drug combination therapies for cancer treatment show high efficacy but often induce severe side effects, resulting in dose or cycle number reduction. We investigated the impact of neoadjuvant chemotherapy (neoCTx) adaptions on treatment outcome in 59 patients with pancreatic ductal adenocarcinoma (PDAC). Resections with tumor‐free margins were significantly more frequent when full‐dose neoCTx was applied. We determined if patient‐derived organoids (PDOs) can be used to personalize poly‐chemotherapy regimens by pharmacotyping of treatment‐naïve and post‐neoCTx PDAC PDOs. Five out of ten CTx‐naïve PDO lines exhibited a differential response to either the FOLFIRINOX or the Gem/Pac regimen. NeoCTx PDOs showed a poor response to the neoadjuvant regimen that had been administered to the respective patient in 30% of cases. No significant difference in PDO response was noted when comparing modified treatments in which the least effective single drug was removed from the complete regimen. Drug testing of CTx‐naïve PDAC PDOs and neoCTx PDOs may be useful to guide neoadjuvant and adjuvant regimen selection, respectively. Personalizing poly‐chemotherapy regimens by omitting substances with low efficacy could potentially result in less severe side effects, thereby increasing the fraction of patients receiving a full course of neoadjuvant treatment. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background: Biliary cancer, comprising cholangio‐ and gallbladder carcinomas, is associated with high mortality due to asymptomatic disease onset and resulting late diagnosis. Currently, no robust diagnostic biomarker is clinically available. Therefore, we explored the feasibility of extracellular vesicles (EVs) as a liquid biopsy tool for biliary cancer screening and hepatobiliary cancer differentiation. Methods: Serum EVs of biliary cancer, hepatocellular carcinoma, colorectal cancer and non‐small cell lung cancer patients, as well as from healthy individuals, were isolated by sequential two‐step centrifugation and presence of indicated EVs was evaluated by fluorescence activated cell sorting (FACS) analysis. Results: Two directly tumour‐related antigen combinations (AnnV+CD44v6+ and AnnV+CD44v6+CD133+) and two combinations related to progenitor cells from the tumour microenvironment (AnnV+CD133+gp38+ and AnnV+EpCAM+ CD133+gp38+) were associated with good diagnostic performances that could potentially be used for clinical assessment of biliary cancer and differentiation from other cancer entities. With 91% sensitivity and 69% specificity AnnV+CD44v6+ EVs showed the most promising results for differentiating biliary cancers from HCC. Moreover using a combined approach of EV levels of the four populations with serum AFP values, we obtained a perfect separation of biliary cancer and HCC with sensitivity, specificity, positive and negative predictive value all reaching 100% respectively. Conclusions: EV phenotyping, especially if combined with serum AFP, represents a minimally invasive, accurate liquid biopsy tool that could improve cancer screening and differential diagnosis of hepatobiliary malignancies. [ABSTRACT FROM AUTHOR]

Background: Intraoperative bile analysis during pancreatoduodenectomy (PD) is performed routinely at specialized centers worldwide. However, it remains controversial if and how intraoperative bacterobilia during PD affects morbidity and its management. The aim of the study was a systematic review and meta-analysis of intraoperative bacterobilia and its impact on patient outcome after PD.Methods: Five relevant outcomes of interest were defined, and a systematic review of the literature with meta-analysis was performed according to the PRISMA guidelines.Results: A total of 28 studies (8523 patients) were included. The median incidence of bacterobilia was 58% (interquartile range 51-67%). The most frequently isolated bacteria were Enterococcus species (51%), Klebsiella species (28%), and Escherichia coli (27%). Preoperative biliary drainage was significantly associated with bacterobilia (86 vs. 25%; RR 3.27; 95% confidence interval (CI) 2.42-4.42; p < 0.001). The incidence of surgical site infections (SSI) was significantly increased in cases with bacterobilia (RR 2.84; 95% CI 2.17-3.73; p < 0.001). Postoperative pancreatic fistula, overall postoperative morbidity, and mortality were not significantly influenced. Identical bacteria in bile and the infectious sources were found in 48% (interquartile range 34-59%) of the cases.Conclusions: Bacterobilia is detected during almost every second PD and is associated with an increased rate of SSI. The microbiome from intraoperative bile and postoperative infectious sources match in ~50% of patients, providing the option of early administration of calculated antibiotics and the determination of resistance patterns. [ABSTRACT FROM AUTHOR]

Epithelial-to-mesenchymal transition (EMT) contributes significantly to tumor progression and metastasis. The assessment of EMT-associated transcription factors could be a promising approach to identify biomarkers and potential therapeutic targets in colorectal cancer. In our study, we focused on the transcription factor 'Sine oculis homeobox' (SIX) 1, which is a member of the superfamily of the homeobox genes and has been described to promote EMT in different types of tumors. Immunohistochemistry against SIX1 was performed on colorectal mucosa, adenomas, carcinomas- in situ and primary adenocarcinomas. An expression score was developed and subsequently assessed for its prognostic value in two independent cohorts. Cohort 1 consisted of 128 patients with stage I-III colorectal cancer; cohort 2 included 817 patients with stage I-III colorectal cancer who had participated in the DACHS study. HCT-116 cells were transfected with SIX1 plasmids and subjected to migration and colony formation assays. The expression of SIX1 increases gradually from mucosa to colorectal adenocarcinomas ( p > 0.0001). Univariate and multivariate analyses reveal that high expression of SIX1 is associated with decreased overall survival (cohort 1: HR: 4.01, CI: 1.20-14.07, p = 0.025; cohort 2: HR: 1.43, CI: 1.014-2.02, p = 0.047). Overexpression of SIX1 induces a more mesenchymal-like phenotype in HCT-116 cells and enhances tumor migration. High expression of SIX1 is an independent prognostic marker in colorectal cancer. It might be a promising biomarker to stratify patients into different risk groups. Moreover, targeting SIX1 might be a novel therapeutic approach in patients with colorectal cancer. [ABSTRACT FROM AUTHOR]

The tumor edge of colorectal cancer and its adjacent peritumoral tissue is characterized by an invasion front-specific expression of genes that contribute to angiogenesis or epithelial-to-mesenchymal transition. Dysregulation of these genes has a strong impact on the invasion behavior of tumor cells. However, the invasion front-specific expression of microRNA (miRNA) still remains unclear. Therefore, the aim of the present study was to investigate miRNA expression patterns at the invasion front of colorectal liver metastases. Laser microdissection of colorectal liver metastases was performed to obtain separate tissue compartments from the tumor center, tumor invasion front, liver invasion front and pure liver parenchyma. Microarray expression analysis revealed 23 miRNA downregulated in samples from the tumor invasion front with respect to the same miRNA in the liver, the liver invasion front or the tumor center. By comparing samples from the liver invasion front with samples from pure liver parenchyma, the tumor invasion front and the tumor center, 13 miRNA were downregulated. By quantitative RT-PCR, we validated the liver invasion front-specific downregulation of miR-19b, miR-194, let-7b and miR-1275 and the tumor invasion front-specific downregulation of miR-143, miR- 145, let-7b and miR-638. Univariate analysis demonstrated that enhanced expression of miR-19b and miR-194 at the liver invasion front, and decreased expression of let-7 at the tumor invasion front, is an adverse prognostic marker of tumor recurrence and overall survival. In conclusion, the present study suggests that invasion front-specific downregulation of miRNA in colorectal liver metastases plays a pivotal role in tumor progression. [ABSTRACT FROM AUTHOR]