Towards Realistic 3D Models of Tumor Vascular Networks.

For reliable in silico or in vitro investigations in, for example, biosensing and drug delivery applications, accurate models of tumor vascular networks down to the capillary size are essential. Compared to images acquired with conventional medical imaging techniques, digitalized histological tumor slices have a higher resolution, enabling the delineation of capillaries. Volume rendering procedures can then be used to generate a 3D model. However, the preparation of such slices leads to misalignments in relative slice orientation between consecutive slices. Thus, image registration algorithms are necessary to re-align the slices. Here, we present an algorithm for the registration and reconstruction of a vascular network from histologic slices applied to 169 tumor slices. The registration includes two steps. First, consecutive images are incrementally pre-aligned using feature- and area-based transformations. Second, using the previous transformations, parallel registration for all images is enabled. Combining intensity- and color-based thresholds along with heuristic analysis, vascular structures are segmented. A 3D interpolation technique is used for volume rendering. This results in a 3D vascular network with approximately 400-450 vessels with diameters down to 25-30 µm. A delineation of vessel structures with close distance was limited in areas of high structural density. Improvement can be achieved by using images with higher resolution and or machine learning techniques.

Identifying radiomics signatures in body composition imaging for the prediction of outcome following pancreatic cancer resection.

Background: Computerized radiological image analysis (radiomics) enables the investigation of image-derived phenotypes by extracting large numbers of quantitative features. We hypothesized that radiomics features may contain prognostic information that enhances conventional body composition analysis. We aimed to investigate whether body composition-associated radiomics features hold additional value over conventional body composition analysis and clinical patient characteristics used to predict survival of pancreatic ductal adenocarcinoma (PDAC) patients. Methods: Computed tomography images of 304 patients undergoing elective pancreatic cancer resection were analysed. 2D radiomics features were extracted from skeletal muscle and subcutaneous and visceral adipose tissue (SAT and VAT) compartments from a single slice at the third lumbar vertebra. The study population was randomly split (80:20) into training and holdout subsets. Feature ranking with Least Absolute Shrinkage Selection Operator (LASSO) followed by multivariable stepwise Cox regression in 1000 bootstrapped re-samples of the training data was performed and tested on the holdout data. The fitted regression predictors were used as "scores" for a clinical (C-Score), body composition (B-Score), and radiomics (R-Score) model. To stratify patients into the highest 25% and lowest 25% risk of mortality compared to the middle 50%, the Harrell Concordance Index was used. Results: Based on LASSO and stepwise cox regression for overall survival, ASA ≥3 and age were the most important clinical variables and constituted the C-score, and VAT-index (VATI) was the most important body composition variable and constituted the B-score. Three radiomics features (SATI_original_shape2D_Perimeter, VATI_original_glszm_SmallAreaEmphasis, and VATI_original_firstorder_Maximum) emerged as the most frequent set of features and yielded an R-Score. Of the mean concordance indices of C-, B-, and R-scores, R-score performed best (0.61, 95% CI 0.56-0.65, p<0.001), followed by the C-score (0.59, 95% CI 0.55-0.63, p<0.001) and B-score (0.55, 95% CI 0.50-0.60, p=0.03). Kaplan-Meier projection revealed that C-, B, and R-scores showed a clear split in the survival curves in the training set, although none remained significant in the holdout set. Conclusion: It is feasible to implement a data-driven radiomics approach to body composition imaging. Radiomics features provided improved predictive performance compared to conventional body composition variables for the prediction of overall survival of PDAC patients undergoing primary resection.

Vessel Delineation Using U-Net: A Sparse Labeled Deep Learning Approach for Semantic Segmentation of Histological Images.

Semantic segmentation is an important imaging analysis method enabling the identification of tissue structures. Histological image segmentation is particularly challenging, having large structural information while providing only limited training data. Additionally, labeling these structures to generate training data is time consuming. Here, we demonstrate the feasibility of a semantic segmentation using U-Net with a novel sparse labeling technique. The basic U-Net architecture was extended by attention gates, residual and recurrent links, and dropout regularization. To overcome the high class imbalance, which is intrinsic to histological data, under- and oversampling and data augmentation were used. In an ablation study, various architectures were evaluated, and the best performing model was identified. This model contains attention gates, residual links, and a dropout regularization of 0.125. The segmented images show accurate delineations of the vascular structures (with a precision of 0.9088 and an AUC-ROC score of 0.9717), and the segmentation algorithm is robust to images containing staining variations and damaged tissue. These results demonstrate the feasibility of sparse labeling in combination with the modified U-Net architecture.

[Future of University Medicine: How Important are Research and Teaching? - An Inventory]. / Zukunft der Universitätsmedizin: Welchen Stellenwert haben Forschung und Lehre noch? ­ Eine Bestandsaufnahme.

The requirements and challenges for the university hospitals in Germany are changing. Especially in surgical subjects, it is more and more difficult to adequately serve these three pillars of university medicine - clinic, research and education. This survey was intended to determine the status quo of general and visceral surgery at universities, in order to provide a basis for proposed solutions.For this online survey, 1505 visceral surgeons at the 38 university clinics were contacted. The questionnaire contained 29 questions on the structure of the clinic, scientific motivation, opportunities for time-off and the appreciation of academic achievements. The type and scope of student courses and the preparation for them were also determined. With regard to patient care, the type and number of services and the course of surgical training were examined. Based on the data published on the websites of the individual clinics on the number, gender, position and academic title of the doctors, a demographic analysis of university visceral surgeons could also be created.Of 1505 surgeons successfully contacted, 352 took part in the survey, which corresponds to a response rate of 23.4%. Of the participants, 93.5% were scientifically active, the majority being in the field of clinical data collection. Many indicated that they were also active in translational and/or experimental research, while educational research was rarely named. 45% confirmed that they could perform scientific work during their normal working hours. The reward for this activity was mostly in the form of time-off for congresses and clinical appreciation. Most participants stated that they were involved in 3-4 student courses per week, with 24.4% reporting that they were not adequately prepared for them.The compatibility of the classic three pillars of clinic, research and teaching continues to be of great relevance. There is a high level of motivation among the participating visceral surgeons not to neglect research and teaching, despite increasing economic pressure in the field of patient care. However, arrangements must be created in order to reward and promote commitment in research and teaching in a structured way.

Tumor ratio of unsaturated to saturated sulfatide species is associated with disease-free survival in intrahepatic cholangiocarcinoma.

PURPOSE: Cholangiocarcinoma (CCA) is a malignancy arising from the bile duct epithelium and has a poor outcome. Sulfatides are lipid components of lipid rafts, and are implicated in several cancer types. In the liver, sulfatides are specifically present in the bile ducts. Here, sulfatide abundance and composition were analyzed using mass spectrometry imaging in intrahepatic CCA (iCCA) tumor tissue, and correlated with tumor biology and clinical outcomes. METHODS: Sulfatides were analyzed in iCCA (n = 17), hepatocellular carcinoma (HCC, n = 10) and colorectal liver metastasis (CRLM, n = 10) tumor samples, as well as tumor-distal samples (control, n = 16) using mass spectrometry imaging. Levels of sulfatides as well as the relative amount in structural classes were compared between groups, and were correlated with clinical outcomes for iCCA patients. RESULTS: Sulfatide localization was limited to the respective tumor areas and the bile ducts. Sulfatide abundance was similar in iCCA and control tissue, while intensities were notably higher in CRLM in comparison with control (18-fold, P < 0.05) and HCC tissue (47-fold, P < 0.001). Considerable variation in sulfatide abundance was observed in iCCA tumors. A high ratio of unsaturated to saturated sulfatides was associated with reduced disease-free survival (10 vs. 20 months) in iCCA. The sulfatide pattern in HCC deviated from the other groups, with a higher relative abundance of odd- versus even-chain sulfatides. CONCLUSION: Sulfatides were found in tumor tissue of patients with iCCA, with sulfatide abundance per pixel being similar to bile ducts. In this explorative study, sulfatide abundance was not related to overall survival of iCCA patients. A high ratio of unsaturated to saturated sulfatides was associated with earlier tumor recurrence in patients with iCCA.

Golgi Protein 73 (GP73) Serum Levels Predict Outcome after Resection of Biliary Tract Cancer.

BACKGROUND: Tumor resection represents the only potentially curative therapy for patients with biliary tract cancer. Nevertheless, disease recurrence is observed in about 50% of patients, leading to a 5-years survival rate of less than 50%. The Golgi protein 73 (GP73), a type II Golgi transmembrane protein, exerts important functions of intracellular protein processing and transportation. Circulating GP73 has recently been suggested as a prognostic marker following resection of hepatocellular carcinoma (HCC) but its role in the context of BTC has remained unknown. In this study, we evaluate a potential role of circulating GP73 as a novel biomarker in patients with resectable BTC. METHODS: GP73 serum levels were measured by immunoassay in n = 97 BTC and n = 40 HCC patients as well as n = 31 healthy controls. Results were correlated with clinical data. RESULTS: Serum GP73 levels were significantly elevated in BTC patients compared to healthy controls but lower compared to HCC patients. The combination of GP73/CA19-9 showed a sensitivity and specificity of 83.5% and 90.3% regarding the differentiation of BTC patients and healthy controls. BTC patients with baseline GP73 levels above the ideal cut-off value (42.47 ng/mL) showed a significantly reduced median overall survival (193 days) compared to patients with preoperative GP73 levels below this cut-off (882 days). These results were confirmed in uni- and multivariate Cox-regression analysis including several clinicopathological parameters such as age, ECOG performance status, tumor stage as well as established tumor markers and parameters of liver and kidney function. CONCLUSIONS: GP73 represents a previously unrecognized biomarker in the patients with resectable BTC that identifies patients with an impaired postoperative outcome. If larger clinical trials confirmed these findings, measurement of GP73 serum levels might become a novel tool in the challenging preoperative stratification process of patients with resectable BTC.

Using the Global Trigger Tool in surgical and neurosurgical patients: A feasibility study.

BACKGROUND: The Global Trigger Tool (GTT) has become a worldwide used method for estimating adverse events through a retrospective patient record review. However, little is known about the facilitators and the challenges in the GTT-implementation process. Thus, this study followed two aims: First, to apply a comprehensive set of feasibility criteria to qualitatively and systematically assess the GTT-implementation process in three departments of German university hospitals. Second, to identify the facilitators and the obstacles met in the GTT-implementation process and to derive recommendations for supporting other hospitals in implementing the GTT in clinical practice. METHODS: The study used a qualitative documentary method based on process documentation, with written and verbal feedback from the reviewer, as well as evaluating the study sites during the implementation process. The study was conducted in three departments, each in a different German university hospital. The authors applied a comprehensive set of 22 feasibility criteria assessing the level of challenge in GTT implementation. The results were synthesized and they focused on the facilitators and the challenges. RESULTS: Of these 22 feasibility criteria, nine were assessed as a low-level challenge, eleven regarded as a moderate-level challenge, and two with a problematic level of challenge. In particular, the lack of time and staff resources, the quality of the information in the patient records, organizational procedures, and local issues, posed major challenges in the implementation process. By contrast, the use of local coordinators and an external expert made important contributions to the GTT implementation. CONCLUSIONS: Considering the facilitators and the obstacles beforehand may help with the implementation of the GTT in routine practice. In particular, early and effective planning can reduce or prevent critical challenges in terms of time, staff resources, and organizational aspects.

Comparative Analysis of Circulating Biomarkers for Patients Undergoing Resection of Colorectal Liver Metastases.

Surgical tumor resection has evolved as a potentially curative therapy for patients with resectable colorectal liver metastases (CRLM). However, disease recurrence is common and the available preoperative stratification strategies are often imprecise to identify the ideal candidates for surgical treatment, resulting in a postoperative 5-year survival rate below 50%. Data on the prognostic value of CEA, CA19-9 and other common laboratory parameters after CRLM resection are scarce and partly inconclusive. Here, we analyzed the prognostic potential of circulating CEA and CA19-9 in comparison to other standard laboratory markers in resectable CRLM patients. Serum levels of tumor markers and other laboratory parameters were analyzed in 125 patients with CRLM undergoing tumor resection at a tertiary referral center. Results were correlated with clinical data and outcome. Both tumor markers were significantly elevated in CRLM patients compared to healthy controls. Interestingly, elevated levels of CEA, CA19-9 and C-reactive protein (CRP) were associated with an unfavorable prognosis after CRLM resection in Kaplan-Meier curve analysis. However, only CEA and not CA19-9 or CRP serum levels were an independent prognostic marker in multivariate Cox regression analysis. Our data demonstrate that circulating levels of CEA rather than CA19-9 might be a valuable addition to the existing preoperative stratification algorithms to identify patients with a poor prognosis after CRLM resection.

Iron Oxide Nanoparticle-Based Hyperthermia as a Treatment Option in Various Gastrointestinal Malignancies.

Iron oxide nanoparticle-based hyperthermia is an emerging field in cancer treatment. The hyperthermia is primarily achieved by two differing methods: magnetic fluid hyperthermia and photothermal therapy. In magnetic fluid hyperthermia, the iron oxide nanoparticles are heated by an alternating magnetic field through Brownian and Néel relaxation. In photothermal therapy, the hyperthermia is mainly generated by absorption of light, thereby converting electromagnetic waves into thermal energy. By use of iron oxide nanoparticles, this effect can be enhanced. Both methods are promising tools in cancer treatment and are, therefore, also explored for gastrointestinal malignancies. Here, we provide an extensive literature research on both therapy options for the most common gastrointestinal malignancies (esophageal, gastric and colorectal cancer, colorectal liver metastases, hepatocellular carcinoma, cholangiocellular carcinoma and pancreatic cancer). As many of these rank in the top ten of cancer-related deaths, novel treatment strategies are urgently needed. This review describes the efforts undertaken in vitro and in vivo.

3D-Printed Replica and Porcine Explants for Pre-Clinical Optimization of Endoscopic Tumor Treatment by Magnetic Targeting.

BACKGROUND: Animal models have limitations in cancer research, especially regarding anatomy-specific questions. An example is the exact endoscopic placement of magnetic field traps for the targeting of therapeutic nanoparticles. Three-dimensional-printed human replicas may be used to overcome these pitfalls. METHODS: We developed a transparent method to fabricate a patient-specific replica, allowing for a broad scope of application. As an example, we then additively manufactured the relevant organs of a patient with locally advanced pancreatic ductal adenocarcinoma. We performed experimental design investigations for a magnetic field trap and explored the best fixation methods on an explanted porcine stomach wall. RESULTS: We describe in detail the eight-step development of a 3D replica from CT data. To guide further users in their decisions, a morphologic box was created. Endoscopies were performed on the replica and the resulting magnetic field was investigated. The best fixation method to hold the magnetic field traps stably in place was the fixation of loops at the stomach wall with endoscopic single-use clips. CONCLUSIONS: Using only open access software, the developed method may be used for a variety of cancer-related research questions. A detailed description of the workflow allows one to produce a 3D replica for research or training purposes at low costs.

Levels of Circulating PD-L1 Are Decreased in Patients with Resectable Cholangiocarcinoma.

Tumor resection represents the only curative treatment option for patients with biliary tract cancers (BTCs), including intrahepatic cholangiocarcinoma (CCA), perihilar and extrahepatic CCA and gallbladder cancer. However, many patients develop early tumor recurrence and are unlikely to benefit from surgery. Therefore, markers to identify ideal surgical candidates are urgently needed. Circulating programmed cell death 1 ligand 1 (PD-L1) has recently been associated with different malignancies, including pancreatic cancer which closely resembles BTC in terms of patients' prognosis and tumor biology. Here, we aim at evaluating a potential role of circulating PD-L1 as a novel biomarker for resectable BTC. METHODS: Serum levels of PD-L1 were analyzed by ELISA in 73 BTC patients and 42 healthy controls. RESULTS: Circulating levels of preoperative PD-L1 were significantly lower in patients with BTC compared to controls. Patients with low PD-L1 levels displayed a strong trend towards an impaired prognosis, and circulating PD-L1 was negatively correlated with experimental markers of promalignant tumor characteristics such as CCL1, CCL21, CCL25 and CCL26. For 37 out of 73 patients, postoperative PD-L1 levels were available. Interestingly, after tumor resection, circulating PD-L1 raised to almost normal levels. Notably, patients with further decreasing PD-L1 concentrations after surgery showed a trend towards an impaired postoperative outcome. CONCLUSION: Circulating PD-L1 levels were decreased in patients with resectable BTC. Lack of normalization of PD-L1 levels after surgery might identify patients at high risk for tumor recurrence or adverse outcome.

Magnetic Fluid Hyperthermia as Treatment Option for Pancreatic Cancer Cells and Pancreatic Cancer Organoids.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a meager prognosis due to its chemotherapy resistance. A new treatment method may be magnetic fluid hyperthermia (MFH). Magnetoliposomes (ML), consisting of superparamagnetic iron oxide nanoparticles (SPION) stabilized with a phospholipid-bilayer, are exposed to an alternating magnetic field (AMF) to generate heat. To optimize this therapy, we investigated the effects of MFH on human PDAC cell lines and 3D organoid cultures. MATERIAL AND METHODS: ML cytotoxicity was tested on Mia PaCa-2 and PANC-1 cells and on PDAC 3D organoid cultures, generated from resected tissue of patients. The MFH was achieved by AMF application with an amplitude of 40-47 kA/m and a frequency of 270 kHz. The MFH effect on the cell viability of the cell lines and the organoid cultures was investigated at two different time points. Clonogenic assays evaluated the impairment of colony formation. Altering ML set-ups addressed differences arising from intra- vs extracellular ML locations. RESULTS: Mia PaCa-2 and PANC-1 cells showed no cytotoxic effects at ML concentrations up to 300 µg(Fe)/mL and 225 µg(Fe)/mL, respectively. ML at a concentration of 225 µg(Fe)/mL were also non-toxic for PDAC organoid cultures. MFH treatment using exclusively extracellular ML presented the highest impact on cell viability. Clonogenic assays demonstrated remarkable impairment as long-term outcome in MFH-treated PDAC cell lines. Additionally, we successfully treated PDAC organoids with extracellular ML-derived MFH, resulting in notably reduced cell viabilities 2h and 24 h post treatment. Still, PDAC organoids seem to partly recover from MFH after 24 h as opposed to conventional 2D-cultures. CONCLUSION: Treatment with MFH strongly diminished pancreatic cancer cell viability in vitro, making it a promising treatment strategy. As organoids resemble the more advanced in vivo conditions better than conventional 2D cell lines, our organoid model holds great potential for further investigations.

Nanomagnetic Actuation of Hybrid Stents for Hyperthermia Treatment of Hollow Organ Tumors.

This paper describes a magnetic nanotechnology that locally enables hyperthermia treatment of hollow organ tumors by using polymer hybrid stents with incorporated magnetic nanoparticles (MNP). The hybrid stents are implanted and activated in an alternating magnetic field to generate therapeutically effective heat, thereby destroying the tumor. Here, we demonstrate the feasibility of nanomagnetic actuation of three prototype hybrid stents for hyperthermia treatment of hollow organ tumors. The results show that the heating efficiency of stent filaments increases with frequency from approximately 60 W/gFe (95 kHz) to approximately 250 W/gFe (270 kHz). The same trend is observed for the variation of magnetic field amplitude; however, heating efficiency saturates at approximately 30 kA/m. MNP immobilization strongly influences heating efficiency showing a relative difference in heating output of up to 60% compared to that of freely dispersed MNP. The stents showed uniformly distributed heat on their surface reaching therapeutically effective temperatures of 43 °C and were tested in an explanted pig bile duct for their biological safety. Nanomagnetic actuation of hybrid stents opens new possibilities in cancer treatment of hollow organ tumors.

Minimally Invasive Thoracoabdominal Esophagectomy Is Superior to Minimally Invasive Gastrectomy in Terms of Health-Related Quality of Life.

Background and Objectives: There are two operative approaches for adenocarcinomas of the esophagogastric junction: thoracoabdominal esophagectomy or transhiatal extended gastrectomy. Both procedures can be performed minimally invasively. Dependent on the exact localization of the tumor, both approaches are feasible. Aim of this study was to compare the health-related quality of life (HRQOL) of patients after minimally invasive esophagectomy (MIE) with patients who underwent minimally invasive gastrectomy (MIG). Methods: All patients who underwent MIE or gastrectomy for malignoma since 2014 were identified from our clinical database. The identified patients were contacted and asked to fill out a quality of life questionnaire (QLQ) for general and gastrointestinal QOL (European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-OG25). Results: Global HRQOL scores were higher in patients after MIE than after MIG. After MIE, global HRQOL scores were close to the control population. In cancer-specific syndromes, patients after MIE reported lower symptom scores for financial problems, eating, reflux, and eating with others than patients after MIG. Conclusion: In terms of HRQOL, MIE proved superior to MIG in long-term follow-up in this study. Patients after MIE reported a HRQOL close to that of a healthy reference population.

[The Maastricht Education System in Aachen - a Few Miles Away or Worlds Apart?] / Das niederländische Weiterbildungssystem in Aachen ­ nur wenige Kilometer oder Welten entfernt? Ergebnisse einer Machbarkeitsstudie.

INTRODUCTION: Education for residents in surgery varies not only throughout the world, but also throughout Europe. Our clinic is well connected to Maastricht University Medical in Centre in the Netherlands (European Surgical Centre Aachen Maastricht). On the other hand, there are clear differences in resident programs. In the Netherlands, a structured feedback according to the OSATS concept (Objective Structured Assessment of Technical Skills) is mandatory after every operation performed by residents. The aim of the present study was to transfer the OSATS concept from Maastricht to Aachen and to evaluate the feasibility and benefits of this concept for surgical education. MATERIAL AND METHODS: The OSATS concept was implemented for 3 months in our clinic within a prospective clinical trial. Seven out of 10 residents that were working in our clinic at that time participated in the study (70%). Half of these were assigned to structured written feedback after every autonomously performed operation. Additionally, all participants performed structured written proper feedback according to the OSATS concept. The primary endpoint was the feasibility of the OSATS concept in our clinic; secondary endpoints were the benefits for the residents and the differences between external and self-evaluation. RESULTS: The OSATS-concept was easily implemented in our clinic and met wide acceptance. Evaluation was performed after a mean of 70% of operations. External evaluation was regarded as more beneficial for residents than self-evaluation. Structured written evaluation according to the OSATS concept was not time-consuming (< 3 minutes) and most residents (86%) supported permanent implementation of the OSATS concept in our clinic. CONCLUSION: The OSATS concept is a suitable approach to provide structured feedback to residents in continuous education. It can easily be implemented in resident education in Germany. Structured, written feedback by senior physicians is perceived as beneficial by residents.

Applying the Global Trigger Tool in German Hospitals: A Pilot in Surgery and Neurosurgery.

OBJECTIVE: The aim of the study was to assess the feasibility and potential of the Global Trigger Tool (GTT) for identifying adverse events (AEs) in different specialties in German hospitals. METHODS: A total of 120 patient records were randomly selected from two surgical and one neurosurgery departments of three university hospitals in Germany for a period of 2 months per department between January and July 2017. The records were reviewed using an adaptation of the German version of the Institute for Healthcare Improvement GTT. RESULTS: Thirty-nine records (32.5%) contained at least one AE. A total of 53 AEs were found in these 39 records. The incidences of AEs were 18.9% and 35.9% in the two surgical departments and 45.3% in neurosurgery. This corresponded to AE rates of 25.5 to 72.1 per 1000 patient-days and from 25.0 to 60.0 per 100 admissions across the three departments. A total of 71.7% of all identified AEs resulted in temporary harm (category E), 26.4% in temporary harm, requiring prolonged hospitalization (category F), and 1.9% in permanent patient harm. We also identified practical challenges, such as the necessary adaptation of the GTT relative to the respective department. CONCLUSIONS: The application of the GTT is feasible and represents an effective instrument for quality measurement when adapted to the departmental specifics. The trigger detection with the GTT is a valuable addition for proactive analyses of high-risk processes.

Circulating levels of microRNA193a-5p predict outcome in early stage hepatocellular carcinoma.

While tumor resection and liver transplantation (LT) represent potentially curative therapeutic options for patients with early-stage hepatocellular carcinoma (HCC), the identification of the ideal surgical candidates has remained challenging. Just recently, miRNA-193a-5p was described as a tumor suppressor in murine and human HCC but only little is known about circulating miRNA-193a-5p in HCC patients. Here, we evaluated serum levels of miR-193a-5p by qPCR in 41 HCC patients undergoing tumor resection (n = 33) or LT (n = 8) and 20 controls. Circulating relative miR-193a-5p levels were significantly elevated in HCC patients compared to healthy controls. While relative miR-193a-5p levels were comparable between patients of different underlying disease etiology and tumor size, high relative miR-193a-5p levels were predictive for the patients' postoperative outcome, which was confirmed in uni- and multivariate Cox-regression analysis. As such, HCC patients with a preoperative relative miR-193a-5p level above the ideal cut-off value (3.57) had a median overall survival (OS) of only 451 days compared to 1158 days in patients with a relative miR-193a-5p level below this cut-off value. Our data support a novel function of miR-193a-5p as a biomarker in early-stage HCC patients that might help to identify the best surgical candidates in terms of postoperative outcome.

Circulating levels of soluble urokinase plasminogen activator receptor predict outcome after resection of biliary tract cancer.

BACKGROUND & AIMS: Surgical resection is the only potentially curative therapy for patients with biliary tract cancer (BTC), but 5-year survival rates after tumor resection have remained below 30%, corroborating the need for better stratification tools to identify the ideal surgical candidates. The soluble urokinase plasminogen activator receptor (suPAR) represents a mediator of inflammation and has been associated with distinct types of cancer. In this study, we evaluated a potential role of suPAR as a novel biomarker in patients undergoing BTC resection. METHODS: Tumor expression of uPAR was analyzed by immunohistochemistry in 108 BTC samples. Serum levels of suPAR were analyzed by ELISA in a training and validation cohort comprising a total of 117 patients with BTC and 76 healthy controls. RESULTS: High tumoral uPAR expression was associated with an adverse outcome after BTC resection. Accordingly, circulating levels of suPAR were significantly elevated in patients with BTC compared to healthy controls, as well as in patients with primary sclerosing cholangitis. Using a small training set, we established an optimal prognostic suPAR cut-off value of 3.72 ng/ml for patients with BTC. Importantly, preoperative suPAR serum levels above this cut-off value were associated with significantly impaired overall survival in both the training and validation cohort. Multivariate Cox-regression analysis including various clinicopathological parameters such as tumor stage, markers of inflammation and organ dysfunction, as well as tumor markers, revealed circulating suPAR levels as an independent prognostic marker following BTC resection. Finally, high preoperative suPAR levels were indicative of acute kidney injury after tumor resection. CONCLUSION: Circulating suPAR represents a previously unrecognized biomarker in patients with resectable BTC, which might help to preoperatively identify the ideal candidates for liver surgery. LAY SUMMARY: Surgical resection represents the only curative treatment option for patients with biliary tract cancer, but not all patients benefit to the same extent in terms of overall survival. Here, we provide evidence that serum levels of an inflammatory mediator (suPAR) are indicative of a patient's postoperative outcome and might thus help to identify the ideal surgical candidates.

What can we learn from other countries-lessons from the CAJC Happiness Report.

Most countries have their own programs and requirements for surgical residency. To investigate the differences as well as the advantages and disadvantages of the programs and to explore the happiness of the residents in the different countries, the Surgical Working Group of "Young Surgeons" of the German Society for General and Visceral Surgery has designed a questionnaire. It focuses on three parts: structural and legal requirements, operating room (OR)- and non-OR-related content of the program, and contentment of the residents. In this opinion paper, first the results are shared by the description of the programs in nine different countries. It is shown that the requirements to become a surgeon differ highly between the different countries. Nonetheless, a structured curriculum, the possibility of feedback or a surgical mentoring program, and transparency regarding the OR schedule seem to be important to all residents to reach job satisfaction.

CXCR6 Inhibits Hepatocarcinogenesis by Promoting Natural Killer T- and CD4+ T-Cell-Dependent Control of Senescence.

BACKGROUND & AIMS: Inflammation in the liver provokes fibrosis, but inflammation is also important for tumor surveillance. Inhibitors of chemokine pathways, such as CXCL16 and CXCR6 regulation of lymphocyte trafficking, are being tested as antifibrotic agents, but their effects on the development of hepatocellular carcinoma (HCC) are unclear. We assessed the roles of CXCR6-dependent immune mechanisms in hepatocarcinogenesis. METHODS: C57BL/6J wild-type (WT) mice and CXCR6-deficient mice (Cxcr6eGfp/eGfp) were given injections of diethylnitrosamine (DEN) to induce liver cancer and α-galactosylceramide to activate natural killer T (NKT) cells. We also performed studies in mice with conditional, hepatocyte-specific deletion of NEMO, which develop inflammation-associated liver tumors (NemoLPC-KO and NemoLPC-KOCxcr6eGfp/eGfp mice). We collected liver tissues from patients with cirrhosis (n = 43), HCC (n = 35), and neither of these diseases (control individuals, n = 25). Human and mouse liver tissues were analyzed by histology, immunohistochemistry, flow cytometry, RNA expression arrays (from sorted hepatic lymphocytes), and matrix-assisted laser desorption/ionization imaging. Bone marrow was transferred from Cxcr6eGfp/eGfp or WT mice to irradiated C57BL/6J mice, and spleen and liver cells were analyzed by flow cytometry. CD4+ T cells or NKT cells were isolated from the spleen and liver of CD45.1+ WT mice and transferred into CXCR6-deficient mice after DEN injection. RESULTS: After DEN injection, CXCR6-deficient mice had a significantly higher tumor burden than WT mice and increased tumor progression, characterized by reduced intrahepatic numbers of invariant NKT and CD4+ T cells that express tumor necrosis factor and interferon gamma. Livers of NemoLPC-KOCxcr6eGfp/eGfp mice had significantly more senescent hepatocytes than livers of NemoLPC-KO mice. In studies of bone-marrow chimeras, adoptive cell transfer experiments, and analyses of NemoLPC-KO mice, we found that NKT and CD4 T cells promote the removal of senescent hepatocytes to prevent hepatocarcinogenesis, and that this process required CXCR6. Injection of WT with α-galactosylceramide increased removal of senescent hepatocytes by NKT cells. We observed peritumoral accumulation of CXCR6-associated lymphocytes in human HCC, which appeared reduced compared with cirrhosis tissues. CONCLUSIONS: In studies of mice with liver tumors, we found that CXCR6 mediated NKT-cell and CD4+ T-cell removal of senescent hepatocytes. Antifibrotic strategies to reduce CXCR6 activity in liver, or to reduce inflammation or modulate the immune response, should be tested for their effects on hepatocarcinogenesis.