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To identify a prognostic significant gene signature for predicting colorectal cancer (CRC) recurrence.Traditional prognostic risk assessment in stage II/III CRC patients remains controversial. Epithelial-mesenchymal transition is thought to be closely related to the malignant progression of tumors. Thus, it is promising to establish a prognostic model based on epithelial-mesenchymal transition-related gene (ERG) signature.We retrospectively analyzed transcriptome profiles and clinical information of 1780 stage II/III CRC patients from 15 public datasets. Coefficient variant analysis was used to select reference genes for normalizing gene expression levels. Univariate, LASSO, and multivariate Cox regression analyses were combined to develop the ERG signature predicting disease-free survival (DFS). The patients were divided into high-risk and low-risk based on the ERG signature recurrence risk score. The survival analysis was performed in different CRC cohorts.The proposed ERG signature contained 7 cancer-related ERGs and 3 reference genes. The ERG signature recurrence risk score was prognostically relevant in all cohorts ( P0.05) and proved as an independent prognostic factor in the training cohort. In the pooled cohort, high-risk CRC patients exhibited worse DFS ( P0.0001) and overall survival ( P =0.0058) than low-risk patients. The predictive performance of the ERG signature was superior to Oncotype DX colon cancer. An integrated decision tree and nomogram were developed to improve prognosis evaluation.The identified ERG signature is a promising and powerful biomarker predicting recurrence in CRC patients. Moreover, the presented ERG signature might help to stratify patients according to their tumor biology and contribute to personalized treatment.

Background The effect of bacterobilia on morbidity after pancreatoduodenectomy remains unclear. The aim of this study was to examine the influence of positive intraoperative bile cultures and perioperative antibiotic prophylaxis on morbidity measured using the Comprehensive Complication Index, a weighted composite of postoperative complications. Methods Intraoperative bile cultures of 182 patients who underwent pancreatoduodenectomy were obtained. We examined the effect of intraoperative bile cultures and perioperative antibiotic prophylaxis on the Comprehensive Complication Index and the occurrence of postoperative complications. To this aim, we performed general linear models controlling for relevant demographic and perioperative factors. Results Positive (versus negative) intraoperative bile cultures were associated with a higher mean Comprehensive Complication Index (25.34 vs 16.81, P = .025). The mean Comprehensive Complication Index differed significantly between individuals with positive intraoperative bile cultures and bacterial strains not covered by perioperative antibiotic prophylaxis (26.2) versus positive intraoperative bile cultures and bacterial strains sensitive to perioperative antibiotic prophylaxis (22.7) (P = .045). Positive (versus negative) intraoperative bile cultures were associated with 4.75 times (95% confidence interval: 1.74–13.00, P = .002) greater odds of wound infections. The odds of wound infection were 1.93 times (95% confidence interval: .47–8.04) greater in those with positive intraoperative bile cultures and adequate perioperative antibiotic prophylaxis and 6.14 times (95% confidence interval: 2.17–17.35) greater in those with positive intraoperative bile cultures and inadequate perioperative antibiotic prophylaxis (versus negative intraoperative bile cultures) (P = .001). Conclusion Bacterobilia is associated with a significant increase in Comprehensive Complication Index and wound infections after pancreatoduodenectomy, which may be reduced by administration of a specific perioperative antibiotic prophylaxis. Acquisition of bile cultures sampled through the external conduit of patients with preoperative biliary drainage could help in selecting a specific perioperative antibiotic prophylaxis and patients with bile duct stents might benefit from broad spectrum perioperative antibiotic prophylaxis.

Introduction: There is no standard treatment after resection of colorectal liver metastases and the role of systemic therapy remains controversial. To avoid over- or undertreatment, proper risk stratification with regard to postoperative treatment strategy is highly needed. We recently demonstrated the prognostic relevance of EMT-related (epithelial-mesenchymal transition) genes in stage II/III CRC. As EMT is a major step in CRC progression, we now aimed to analyse the prognostic relevance of EMT-related genes in stage IV CRC using the study cohort of the FIRE-3 trial, an open-label multi-centre randomised controlled phase III trial of patients with metastatic CRC. Methods: Overall and progression free survival were considered as endpoints (n = 350). To investigate the prognostic relevance of EMT-related genes on either endpoint, we compared predictive performance of different models using clinical data only to models using gene data in addition to clinical data, expecting better predictive performance if EMT-related genes have prognostic value. In addition to baseline models (Kaplan Meier (KM), (regularised) Cox), Random Survival Forest (RSF), and gradient boosted trees (GBT) were fit to the data. Repeated, nested five-fold cross-validation was used for hyperparameter optimisation and performance evaluation. Predictive performance was measured by the integrated Brier score (IBS). Results: The baseline KM model showed the best performance (OS: 0.250, PFS: 0.251). None of the other models were able to outperform the KM when using clinical data only according to the IBS scores (OS: 0.253 (Cox), 0.256 (RSF), 0.284 (GBT); PFS: 0.254 (Cox), 0.256 (RSF), 0.276 (GBT)). When adding gene data, performance of GBT improved slightly (OS: 0.262 vs. 0.284; PFS: 0.268 vs. 0.276), however, none of the models performed better than the KM baseline. Conclusion: Overall, the results suggest that the prognostic relevance of EMT-related genes may be stage-dependent and that EMT-related genes have no prognostic relevance in stage IV CRC.

Background Textbook outcome (TO) is a multidimensional measure reflecting the ideal outcome after surgery. As a benchmarking tool, it provides an objective overview of quality of care. Uniform definitions of TO in hepato-pancreato-biliary (HPB) surgery are missing. This study aimed to provide a definition of TO in HPB surgery and identify obstacles and predictors for achieving it. Methods A systematic literature search was conducted using PubMed, Embase, and Cochrane Database according to PRISMA guidelines. Studies published between 1993 and 2021 were retrieved. After selection, two independent reviewers extracted descriptive statistics and derived summary estimates of the occurrence of TO criteria and obstacles for achieving TO using co-occurrence maps. Results Overall, 30 studies were included. TO rates ranged between 16–69 per cent. Commonly chosen co-occurring criteria to define TO included ‘no prolonged length of stay (LOS)’, ‘no complications’, ‘no readmission’, and ‘no deaths’. Major obstacles for achieving TO in HPB surgery were prolonged LOS, complications, and readmission. On multivariable analysis, TO predicted better overall and disease-free survival in patients with cancer. Achievement of TO was more likely in dedicated centres and associated with procedural and structural indicators, including high case-mix index and surgical volume. Conclusion TO is a useful quality measure to benchmark surgical outcome. Future definitions of TO in HPB surgery should include ‘no prolonged LOS’, ‘no complications’, ‘no readmission’, and ‘no deaths’.

Hepatic ischemia-reperfusion injury (IRI) represents a major challenge during liver surgery, liver preservation for transplantation, and can cause hemorrhagic shock with severe hypoxemia and trauma. The reduction of blood supply with a concomitant deficit in oxygen delivery initiates various molecular mechanisms involving the innate and adaptive immune response, alterations in gene transcription, induction of cell death programs, and changes in metabolic state and vascular function. Hepatic IRI is a major cause of morbidity and mortality, and is associated with an increased risk for tumor growth and recurrence after oncologic surgery for primary and secondary hepatobiliary malignancies. Therapeutic strategies to prevent or treat hepatic IRI have been investigated in animal models but, for the most part, have failed to provide a protective effect in a clinical setting. This review focuses on the molecular mechanisms underlying hepatic IRI and regeneration, as well as its clinical implications. A better understanding of this complex and highly dynamic process may allow for the development of innovative therapeutic approaches and optimize patient outcomes.

In cancer patients, surgical removal of the primary tumor is one of the major steps within a multimodal therapy concept toward eliminating the disease and limiting further progression. In this respect, surgical trauma can have potent effects on the patient's immune system. Intraoperative blood loss associated with major surgical trauma leads to reduced blood flow, regional hypoxia, metabolic, and microenvironmental alterations stimulating an inflammatory response characterized by the release of pro-inflammatory cytokines (i.e., TNF-α, IL-6) and acute-phase proteins. The inflammatory state is accompanied by and intertwined with a counter-regulatory anti-inflammatory response reflected in the rise of anti-inflammatory cytokines (i.e., transforming growth factor-β) and prostaglandins (i.e., prostaglandin E2) which can lead to a depression of cell-mediated immunity and systemic immunosuppression. This results in a highly vulnerable state with concurrent expression of pro- and anti-inflammatory cytokines alternately predominating. The immunosuppressive state is characterized by a reduced antigen-presentation capacity of macrophages, alterations in lymphocyte proliferation, and activation as well as a shift of the Th1/Th2 (T helper cells 1 and 2) balance toward Th2 and a decrease in natural killer cell activity. The severity of the immunosuppression thereby correlates with the extent and the duration of the surgical procedure. Growing evidence suggests that the immunosuppressive state following hemorrhage and surgical trauma might not only be a risk factor for postoperative complications but also facilitate tumor proliferation, metastatic growth, and recurrence. This article provides an overview of the cascade of events and underlying mechanisms resulting in immunosuppression and describes the impact of hemorrhage and major surgical trauma on tumor growth and recurrence. Attempts to control for perioperative inflammation thereby reducing the adverse effects of postoperative immunosuppression could have positive effects on tumor growth, metastasis formation, and recurrence.

Gastric cancer (GC) is a very heterogenous disease necessitating further stratification for prognostic and therapeutic aspects. Based on the recommendation of The Asisan Cancer Research Group (ACRG) recently established four molecular subtypes (MSI, MSS/EMT, MSS/TP53+, MSS/TP53-) which require molecular expression analysis. The technology required for comprehensive molecular analysis is expensive and not applicable for routine diagnostics. Thus, in this study we established a classification system utilizing immunohistochemistry and morphology-based analyses as surrogate markers in order to reproduce the ACRG molecular subtypes of gastric cancer. To clarify the clinical relevance of the novel classification system, we performed a correlation with established clinical parameters.The study cohort consisted of 189 patients with GC (UICC III and IV). Using immunohistochemistry, the following markers were analysed: MLH1, MSH2, MSH6, PMS2 (as a surrogate for microsatellite status), p53, SOX9. We assessed tumor budding as a surrogate for EMT to distinguish between MSS/EMT and MSS/non-EMT groups.Immunohistochemical and morphologic subtyping classified cases as follows: 10% MSI, 35% MSS/EMT, 16% MSS/TP53 + and 39% MSS/TP53-. Subtypes significantly correlated with the Lauren classification, tumor stage, venous invasion and SOX9 expression (p .05). There was no significant correlation between molecular subtype and lymph node growth pattern.We propose a simple algorithm for molecular subtyping of GC using universally available immunohistochemistry, which correlates with clinical parameters and is cost-effective and applicable in diagnostic routine. This classification might prospectively help to determine patient prognosis, optimize patient care and homogenize patient cohorts for clinical trials.

Background In gastric cancer (GC), extracapsular growth (ECG) pattern of lymph node metastases is associated with decreased overall survival rates compared to intracapsular lymph node metastases (ICG). Epithelial-to-mesenchymal transition (EMT) plays a pivotal role in hematogenous metastatic spread. Aim of the present study was to analyze if EMT related genes are involved in the growth pattern of lymph node metastases in GC. Methods Out of our prospective database with 529 patients who underwent surgical resection for GC between 2002 and 2014 forty lymph node positive patients were identified (20 ECG, 20 ICG). The expression of 84 EMT-associated genes were analyzed by RT2 Profiler PCR Array (n=20). Results were validated by Real-Time PCR (n=20). Results GC with ECG showed differently expressed EMT related genes. GC leading to ECG showed an upregulation of three and downregulation of eleven genes. Those differences, however, could not be confirmed in PCR analysis. Conclusions This study demonstrates that EMT related genes are not responsible for the different growth patterns of lymph node metastases in GC. Further studies are required to evaluate the underlying mechanisms of ECG in GC as it might provide a potential therapeutic target for this subgroup of more aggressive tumors in the future.

Background Tumor stem cells play a role in metastatic spread in colorectal cancer (CRC). The oncogene LIN28A/B, a prognostic marker in CRC, is involved in tumorigenesis and maintains stem cell function. Therefore, it was the aim of the present study to clarify whether LIN28A/B is involved in metastatic spread in CRC. Methods Expression of LIN28A/B was analyzed in patients with colon adenocarcinoma in a matched case-control study comparing patients with corresponding liver metastases (n = 42) and patients without hepatic spread within five years (n = 42) by applying immunohistochemistry. Further, LIN28A/B expression was correlated with stem cell associated markers (SOX2, CD133). Results LIN28A and B expression significantly correlated with SOX2 expression (p = .02, and p = .04 respectively) but not with CD133 expression. This correlation between LIN28 A/B and SOX2 was not reflected in differences in hepatic spread. In this respect, there was no significant association between LIN28A/B expression and liver metastases. Conclusion LIN28A/B might be involved in tumor initiation and progression in CRC but is not associated with hepatic spread.

Metastasis is the major cause of death in patients with colorectal carcinoma (CRC). The most common sites of metastasis are the liver and the peritoneum. Peritoneal carcinomatosis is often considered the end stage of the disease after the tumor has spread to the liver. However, almost half of CRC patients with peritoneal carcinomatosis do not present with liver metastasis. This brings up the question of whether peritoneal spread can still be considered as the end stage of a metastasized CRC or whether it should just be interpreted as a site of metastasis alternative to the liver. This review tries to discuss this question and summarize the current status of literature on potential characteristics in tumor biology in the primary tumor, i.e., factors (transcription factors and direct and indirect E-cadherin repressors) and pathways (WNT, TGF-β, and RAS) modulating EMT, regulation of EMT on a posttranscriptional and posttranslational level (miRNAs), and angiogenesis. In addition to tumor-specific characteristics, factors in the tumor microenvironment, immunological markers, ways of transport of tumor cells, and adhesion molecules appear to differ between hematogenous and peritoneal spread. Factors such as integrins and exosomal integrins, cancer stem cell phenotype, and miRNA expression appear to contribute in determining the metastatic route. We went through each step of the metastasis process comparing hematogenous to peritoneal spread. We identified differences with respect to organotropism, epithelial-mesenchymal transition, angiogenesis and inflammation, and tumor microenvironment which will be further elucidated in this review. A better understanding of the underlying mechanisms and contributing factors of metastasis development in CRC has huge relevance as it is the foundation to help find specific targets for treatment of CRC.