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Background: Granulin is a secreted, glycosylated peptide—originated by cleavage from a precursor protein—which is involved in cell growth, tumor invasion and angiogenesis. However, the specific prognostic impact of granulin in human colorectal cancer has only been studied to a limited extent. Thus, we wanted to assess the expression of granulin in colorectal cancer patients to evaluate its potential as a prognostic biomarker. Methods: Expressional differences of granulin in colorectal carcinoma tissue (n = 94) and corresponding healthy colon mucosa were assessed using qRT-PCR. Immunohistochemistry was performed in colorectal cancer specimens (n = 97), corresponding healthy mucosa (n = 47) and colorectal adenomas (n = 19). Subsequently, the results were correlated with histopathological and clinical patients’ data. HCT-116 cells were transfected with siRNA for invasion and migration assays. Results: Immunohistochemistry and qRT-PCR revealed tumoral over expression of granulin in colorectal cancer specimens compared to corresponding healthy colon mucosa and adenomas. Tumoral overexpression of granulin was associated with a significantly impaired overall survival. Moreover, downregulation of granulin by siRNA significantly diminished the invasive capacities of HCT-116 cells in vitro. Conclusion: Expression of granulin differs in colorectal cancer tissue, adenomas and healthy colon mucosa. Furthermore, granulin features invasive and migrative capabilities and overexpression of granulin correlates with a dismal prognosis. This reveals its potential as a prognostic biomarker and granulin could be a worthwhile molecular target for individualized anticancer therapy.

Purpose: To investigate the clinical relevance of macrophages in liver metastasis of colorectal cancer and their influence on angiogenesis and patient survival. Moreover to evaluate specific blood monocytes as markers of disease recurrence. Experimental design: In a mouse model with spontaneous liver metastasis, the angiogenic characteristics of tumor- and metastasis (MAM)-associated macrophages were evaluated. Macrophages and the vasculature from 130 primary tumor (pTU) and 123 patients with liver metastasis were assessed. In vivo and in human samples, the clinical relevance of macrophage VEGFR1 expression was analyzed. Blood samples from patients (n = 157, 80 pTU and 77 liver metastasis) were analyzed for assessing VEGFR1-positive (VEGFR1+) cells as suitable biomarkers of disease recurrence. Results: The number of macrophages positively correlated with vascularization in metastasis. Both in the murine model as well as in primary isolated human cells, a subpopulation of MAMs expressing VEGFR1 were found highly angiogenic. While VEGFR1 expression in pTU patients did not predict prognosis; high percentage of VEGFR1+ cells in liver metastasis was associated with worse patient outcome. Interestingly, VEGFR1+-circulating monocytes in blood samples from patients with liver metastasis not only predicted progression but also site of recurrence. Conclusions: Our findings identify a new subset of proangiogenic VEGFR1+ MAMs in colorectal cancer that support metastatic growth and may become a liquid biomarker to predict disease recurrence in the liver.

Context Adipose tissue inflammation and dysregulated energy homeostasis are key mechanisms linking obesity and cancer. Distinct adipose tissue depots strongly differ in their metabolic profiles; however, comprehensive studies of depot-specific perturbations among patients with cancer are lacking. Objective We compared transcriptome profiles of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) from patients with colorectal cancer and assessed the associations of different anthropometric measures with depot-specific gene expression. Design Whole transcriptomes of VAT and SAT were measured in 233 patients from the ColoCare Study, and visceral and subcutaneous fat area were quantified via CT. Results VAT compared with SAT showed elevated gene expression of cytokines, cell adhesion molecules, and key regulators of metabolic homeostasis. Increased fat area was associated with downregulated lipid and small molecule metabolism and upregulated inflammatory pathways in both compartments. Comparing these patterns between depots proved specific and more pronounced gene expression alterations in SAT and identified unique associations of integrins and lipid metabolism–related enzymes. VAT gene expression patterns that were associated with visceral fat area poorly overlapped with patterns associated with self-reported body mass index (BMI). However, subcutaneous fat area and BMI showed similar associations with SAT gene expression. Conclusions This large-scale human study demonstrates pronounced disparities between distinct adipose tissue depots and reveals that BMI poorly correlates with fat mass–associated changes in VAT. Taken together, these results provide crucial evidence for the necessity to differentiate between distinct adipose tissue depots for a correct characterization of gene expression profiles that may affect metabolic health of patients with colorectal cancer.

To assess the putative impact of peridural analgesia on oncological outcome in patients undergoing resection of stages I–IV colon cancer. In a single-center study, 876 patients undergoing resection for primary colon cancer (AJCC stages I–IV) between 2001 and 2014 were analyzed. Mean follow-up of the entire cohort was 4.2 ± 3.5 years. Patients who did and did not receive peridural analgesia were compared using Cox regression and propensity score analyses. Overall, 208 patients (23.7%) received peridural analgesia. Patients’ characteristics were biased with regard to the use of peridural analgesia (propensity score 0.296 ± 0.129 vs. 0.219 ± 0.108, p

Background Current guidelines recommend neoadjuvant therapy for patients with stage II or III rectal cancer. The addition of platinum derivatives to fluoropyrimidine-based chemoradiotherapy has been frequently investigated, but their role in this setting remains controversial. Methods PubMed, Cochrane Library, and Web of Science were systematically searched for randomized trials comparing chemoradiotherapy with or without platinum agents in stage II or III rectal cancer. Main outcome parameters were overall and disease-free survival, additional outcomes included pathological complete response, isolated local recurrence, distant recurrence, toxicity, and perioperative morbidity. Time-to-event data were pooled as hazard ratios (HRs) by the inverse variance method and binary outcomes as odds ratios (ORs) by the Peto method with their respective 95% confidence interval (CI). All statistical tests were two-sided. Results Ten randomized controlled trials with data on 5599 patients were included in the meta-analysis. Platinum derivatives did not statistically significantly improve overall survival (HR = 0.93, 95% CI = 0.82 to 1.05, P = .23), disease-free survival (HR = 0.91, 95% CI = 0.83 to 1.01, P = .07), or local recurrence (OR = 0.83, 95% CI = 0.66 to 1.05, P = .12). However, it led to a statistically significant increase of pathological complete response (OR = 1.31, 95% CI = 1.10 to 1.55, P = .002) and a statistically significant reduction of distant recurrence (OR = 0.78, 95% CI = 0.66 to 0.92, P = .004). Benefits were accompanied by higher rates of grade 3 or 4 toxicities. Conclusions Intensified neoadjuvant chemoradiotherapy with the addition of platinum derivatives cannot be recommended routinely because it did not improve overall or disease-free survival and was associated with increased toxicity. It needs to be elucidated whether the benefits in distant recurrence and pathological complete response may be advantageous for selected high-risk patients.

Background Hyperglycemia has been reported in some patients after curative insulinoma resection but no systematic investigation of glucose metabolism has been shown in a larger cohort of these patients. Therefore, it is still unknown, whether long lasting hyperinsulinism in insulinoma patients induces insulin resistance, which may jeopardize the postoperative health status of these patients. Methods Early postoperative fasting serum glucose levels were measured in all insulinoma patients after curative tumor resection during the first 48 h, being operated between 2011 and 2018, retrospectively. Results Of 77 (100%) patients with benign, spontaneous occuring insulinoma 51 (66.2%) patients were operated on by tumor enucleation. In 15 (19.5%) patients a left pancreatic resection was performed and in 11 (14.3%) patients the pancreatic head or the middle console of pancreatic corpus were excised. In 32 (41.6%) cases the highest fasting postoperative glucose levels were measured between 140–200 mg/dl. In 16 (20.8%) patients the glucose serum levels reached values above 200 mg/dl and in 4 (5.2%) patients short term substitution with insulin was indicated. Only one (1.3%) of these patients developed diabetes mellitus with the need of ongoing insulin treatment. Major postoperative complications were registered in 31 of all 77 patients (40.3%) and in 9 of 16 patients (56.3%) with postoperative glucose levels above 200 mg/dl. This difference was not statistically significant. Conclusions Early postoperative (first 48 h) fasting serum glucose levels in insulinoma patients showed significant hyperglycemia above 200 mg/dl in only few patients (20.8%) and chronic postoperative Diabetes mellitus developed in only one of 77 patients (

Purpose Smurf2 is a member of the homologous to E6-AP carboxyl terminus family of E3 ubiquitin ligases. Changes in their expression pattern are known to contribute to tumorigenesis. Smurf2 plays a decisive role in cell differentiation, proliferation, and migration and exhibits a dual role in cancer - functioning as both oncogene and tumor suppressor. Dysregulation of Smurf2 in different cancer types has been described, besides colorectal cancer (CRC). We therefore examined the expression and oncogenic potential of Smurf2 in human CRC patients. Materials and methods Expression levels of Smurf2 were analyzed via qRT-PCR in CRC specimens and healthy mucosa from 98 patients who had undergone surgery due to CRC. Spatial expression of Smurf2 was additionally studied by immunohistochemistry. siRNA-mediated knockdown of Smurf2 was applied for migration and invasion assays in DLD-1 and SW-480 cells. Results Smurf2 was significantly overexpressed in CRC tissue compared to corresponding healthy colon mucosa. Smurf2 expression levels differed significantly between microsatellite instable (MSI) and microsatellite stable (MSS) CRC. In patients suffering from MSS CRC, high tumoral expression of Smurf2 was significantly associated with impaired overall survival. Consistently, in vitro analysis revealed that knockdown of Smurf2 reduced the invasive and migratory potential of MSS CRC cells. Conclusion Smurf2 expression is upregulated in CRC specimens and affects survival dependent on patients' MSI status. Moreover, Smurf2 supports cancer cell migration and invasion, collectively suggesting an oncogenic function in CRC.

Purpose: Obesity is associated with increased incidence and mortality in rectal cancer (RC). However, an obesity paradox in the sense of a protective effect of obesity is discussed controversially. We evaluated whether adipose tissue distribution has an impact on medical (MC) and surgical complications (SC) after RC surgery. Methods: A total of 296 RC patients underwent oncological surgery and multidetector CT with quantification of total (TAT), visceral (VAT), and subcutaneous adipose tissue (SAT). Logistic regressions on SC (anastomotic leakage [n = 26], wound infection [n = 58], bleeding [n = 12], abscess [n = 32], bladder dysfunction [n = 24], burst abdomen [n = 10]), and MC (pulmonary [n = 22], cardiac [n = 18], urinary tract infection [n = 9], sepsis [n = 5]) were performed. Results: High pelvicVAT was associated with reduced risk for overall SC (OR = 0.915, p = 0.012) and anastomotic leakage (OR = 0.587, p = 0.024, CI: 0.369/0.934). In contrast, CT-quantified obesity was associated with increased risk for wound infection, bladder dysfunction, burst abdomen, overall MC, and cardiac complications (ORs up to 1.423). BMI was not associated with any SC or MC. Conclusion: An obesity paradox with a protective effect of CT-quantified adipose tissue was confirmed for anastomotic leakage and overall SC. In contrast, high adipose tissue was associated with higher risk for other SC and MC. These results show a more complex influence of body composition on MC and SC. CT-quantified obesity is able to provide deeper insights to explain the obesity paradox beyond BMI.

Liver fibrosis, eventually progressing to cirrhosis necessitating liver transplantation, poses a significant clinical problem. Oxygen shortage (hypoxia) and hypoxia-inducible transcription factors (HIFs) have been acknowledged as important drivers of liver fibrosis. The significance of oxygen-sensing HIF prolyl-hydroxylase (PHD) enzymes in this context has, however, remained elusive. In this study, we demonstrate that loss of PHD1 (PHD1-/-) attenuates the development of liver fibrosis in mice subjected to chronic bile duct injury, induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine. This effect was accompanied with reduced recruitment of inflammatory leukocytes and attenuated occurrence of profibrotic myofibroblasts in PHD1-/- livers. Further analyses focused on the significance of PHD1 in the activation of hepatic stellate cells (HSCs), which represent the driving force in liver fibrosis. Primary HSCs isolated from PHD1-/- mice displayed significantly attenuated myofibroblast differentiation and profibrogenic properties compared with HSCs isolated from wild-type mice. Consistently, the expression of various profibrogenic and promitogenic factors was reduced in PHD1-/- HSCs, without alterations in HIF-1α protein levels. Of importance, PHD1 protein was expressed in HSCs within human livers, and PHD1 transcript expression was significantly increased with disease severity in hepatic tissue from patients with liver fibrosis. Collectively, these findings indicate that PHD1 deficiency protects against liver fibrosis and that these effects are partly due to attenuated activation of HSCs. PHD1 may represent a therapeutic target to alleviate liver fibrosis.

The identification of patients at high-risk for colorectal cancer (CRC) recurrence remains an unmet clinical need. The aim of this study was to investigate associations of metabolites with risk of recurrence in stage II/III CRC patients. A targeted metabolomics assay (128 metabolites measured) was performed on pre-surgery collected EDTA plasma samples from n = 440 newly diagnosed stage II/III CRC patients. Patients have been recruited from four prospective cohort studies as part of an international consortium: Metabolomic profiles throughout the continuum of CRC (MetaboCCC). Cox proportional hazard models were computed to investigate associations of metabolites with recurrence, adjusted for age, sex, tumor stage, tumor site, body mass index, and cohort, false discovery rate (FDR) was used to account for multiple testing. Sixty-nine patients (15%) had a recurrence after a median follow-up time of 20 months. We identified 13 metabolites that were nominally associated with a reduced risk of recurrence. None of the associations were statistically significant after controlling for multiple testing. Pathway topology analyses did not reveal statistically significant associations between recurrence and alterations in metabolic pathways (e.g., sphingolipid metabolism p = 0.04, pFDR = 1.00). To conclude, we did not observe statistically significant associations between metabolites and CRC recurrence using a well-established metabolomics assay. The observed results require follow-up in larger studies.

Changes in the gut microbiome have already been associated with postoperative complications in major abdominal surgery. However, it is still unclear whether these changes are transient or a long-lasting effect. Therefore, the aim of this prospective clinical pilot study was to examine long-term changes in the gut microbiota and to correlate these changes with the clinical course of the patient. Methods: In total, stool samples of 62 newly diagnosed colorectal cancer patients undergoing primary tumor resection were analyzed by 16S-rDNA next-generation sequencing. Stool samples were collected preoperatively in order to determine the gut microbiome at baseline as well as at 6, 12, and 24 months thereafter to observe longitudinal changes. Postoperatively, the study patients were separated into two groups—patients who suffered from postoperative complications (n = 30) and those without complication (n = 32). Patients with postoperative complications showed a significantly stronger reduction in the alpha diversity starting 6 months after operation, which does not resolve, even after 24 months. The structure of the microbiome was also significantly altered from baseline at six-month follow-up in patients with complications (p = 0.006). This was associated with a long-lasting decrease of a large number of species in the gut microbiota indicating an impact in the commensal microbiota and a long-lasting increase of Fusobacterium ulcerans. The microbial composition of the gut microbiome shows significant changes in patients with postoperative complications up to 24 months after surgery.

Background Fusobacterium nucleatum (Fn), a bacterium associated with a wide spectrum of infections, has emerged as a key microbe in colorectal carcinogenesis. However, the underlying mechanisms and clinical relevance of Fn in colorectal cancer (CRC) remain incompletely understood. Patients and Methods We examined associations between Fn abundance and clinicopathologic characteristics among 105 treatment-naive CRC patients enrolled in the international, prospective ColoCare Study. Electronic medical charts, including pathological reports, were reviewed to document clinicopathologic features. Quantitative real-time polymerase chain reaction (PCR) was used to amplify/detect Fn DNA in preoperative fecal samples. Multinomial logistic regression was used to analyze associations between Fn abundance and patient sex, age, tumor stage, grade, site, microsatellite instability, body mass index (BMI), alcohol consumption, and smoking history. Cox proportional hazards models were used to investigate associations of Fn abundance with overall survival in adjusted models. Results Compared to patients with undetectable or low Fn abundance, patients with high Fn abundance (n = 22) were 3-fold more likely to be diagnosed with rectal versus colon cancer (odds ratio [OR] = 3.01; 95% confidence interval [CI], 1.06-8.57; P = .04) after adjustment for patient sex, age, BMI, and study site. Patients with high Fn abundance also had a 5-fold increased risk of being diagnosed with rectal cancer versus right-sided colon cancer (OR = 5.32; 95% CI, 1.23-22.98; P = .03). There was no statistically significant association between Fn abundance and overall survival. Conclusion Our findings suggest that Fn abundance in fecal samples collected prior to surgery varies by tumor site among treatment-naive CRC patients. Overall, fecal Fn abundance may have diagnostic and prognostic significance in the clinical management of CRC.

Importance: The incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer.Observations: Within the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts.Conclusions and Relevance: The clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes.

Background Folates, including folic acid, may play a dual role in colorectal cancer development. Folate is suggested to be protective in early carcinogenesis but could accelerate growth of premalignant lesions or micrometastases. Whether circulating concentrations of folate and folic acid, measured around time of diagnosis, are associated with recurrence and survival in colorectal cancer patients is largely unknown. Methods Circulating concentrations of folate, folic acid, and folate catabolites p-aminobenzoylglutamate and p-acetamidobenzoylglutamate were measured by liquid chromatography-tandem mass spectrometry at diagnosis in 2024 stage I-III colorectal cancer patients from European and US patient cohort studies. Multivariable-adjusted Cox proportional hazard models were used to assess associations between folate, folic acid, and folate catabolites concentrations with recurrence, overall survival, and disease-free survival. Results No statistically significant associations were observed between folate, p-aminobenzoylglutamate, and p-acetamidobenzoylglutamate concentrations and recurrence, overall survival, and disease-free survival, with hazard ratios ranging from 0.92 to 1.16. The detection of folic acid in the circulation (yes or no) was not associated with any outcome. However, among patients with detectable folic acid concentrations (n = 296), a higher risk of recurrence was observed for each twofold increase in folic acid (hazard ratio = 1.31, 95% confidence interval = 1.02 to 1.58). No statistically significant associations were found between folic acid concentrations and overall and disease-free survival. Conclusions Circulating folate and folate catabolite concentrations at colorectal cancer diagnosis were not associated with recurrence and survival. However, caution is warranted for high blood concentrations of folic acid because they may increase the risk of colorectal cancer recurrence.

To determine associations between physical activity (PA), sedentary behavior (SB), and oxidative stress in colorectal cancer patients, ColoCare Study participants in Germany wore an accelerometer 6 and/or 12 months after surgery. Spearman partial correlations were used to assess associations between PA and urinary concentrations of oxidized guanine, a validated marker of oxidative stress. There were no significant associations between PA or SB and oxidized guanine in n = 76 measurements (ng/mg creatinine; r = 0.03, p = 0.76 for PA, r = –0.05, p = 0.69 for SB). Novelty Objectively measured PA was not associated with a marker of oxidative stress in colorectal cancer patients.

Background: Obesity, defined by body mass index (BMI), measured at colorectal cancer (CRC) diagnosis has been associated with postoperative complications and survival outcomes. However, BMI does not allow for a differentiation between fat and muscle mass. Computed tomography (CT)-defined body composition more accurately reflects different types of tissue and their associations with health-related quality of life (HRQoL) during the first year of disease, but this has not been investigated yet. We studied the role of visceral and subcutaneous fat area (VFA and SFA) and skeletal muscle mass (SMM) on longitudinally assessed HRQoL in CRC patients. Methods: A total of 138 newly diagnosed CRC patients underwent CT scans at diagnosis and completed questionnaires prior to and six and twelve months post-surgery. We investigated the associations of VFA, SFA, and SMM with HRQoL at multiple time points. Results: A higher VFA was associated with increased pain six and twelve months post-surgery (&beta, = 0.06, p = 0.04 and &beta, = 0.07, p = 0.01) and with worse social functioning six months post-surgery (&beta, = &minus, 0.08, p = 0.01). Higher SMM was associated with increased pain twelve months post-surgery (&beta, = 1.03, p &lt, 0.01). Conclusions: CT-quantified body composition is associated with HRQoL scales post-surgery. Intervention strategies targeting a reduction in VFA and maintaining SMM might improve HRQoL in CRC patients during the first year post-surgery.

Esophagectomy for oncological reasons is associated with high morbidity, which was intended to be reduced by a minimally invasive approach. Main problem of the minimally invasive approach is the challenge of a safe intrathoracic anastomosis. To address this problem several methods such as a collar anastomosis instead of an intrathoracic anastomosis with poor functional outcome, hybrid techniques with an open approach to the demanding intrathoracic circular stapled anastomosis ore robotic assistance have been used. We demonstrate the minimally invasive linear stapler technique for the intrathoracic esophagogastrostomy, which can be applied quite easily even without robotic assistance.The abdominal part is performed with the patient in French position. After division of the greater omentum along the gastroepiploic arcade and the spleen as well as the perigastric incision of the lesser omentum 6cm from the pylorus a 4,5 cm gastric conduit is created in linear stapler technique. Next an intraabdominal and transhiatal systematic lymphadenectomy is performed. For the thoracic part the patient is repositioned in a left side position. The thoracic lymphadenectomy is completed, and the specimen removed via mini-thoracotomy. For the anastomosis the esophageal stump is incised, and the gastric conduit is opened 5 cm from the oral resection line. Once the stapler is fired and removed the remaining opening is hand-sewn in a modified double-layer technique.The side-to-side esophagogastrostomy in linear stapler technique seems to be a quite easily feasible and safe alternative for the reconstruction after minimally invasive esophagectomy. To confirm this, the method is currently investigated in a randomized controlled trial.

PURPOSE: Underlying mechanisms of the relationship between body fatness and colorectal cancer remain unclear. This study investigated associations of circulating metabolites with visceral (VFA), abdominal subcutaneous (SFA) and total fat area (TFA) in colorectal cancer patients. METHODS: Pre-surgery plasma samples from 212 patients (stage I-IV) from the ColoCare Study were used to perform targeted metabolomics. VFA, SFA and TFA were quantified by computed tomography scans. Partial correlation and linear regression analyses of VFA, SFA and TFA with metabolites were computed and corrected for multiple testing. Cox proportional hazards were used to assess two-year survival. RESULTS: In patients with metastatic tumors, SFA and TFA were statistically significantly inversely associated with 16 glycerophospholipids (SFA: p(FDR) range: 0.017-0.049; TFA: p(FDR) range: 0.029-0.048), while VFA was not. Doubling of ten of the aforementioned glycerophospholipids was associated with increased risk of death in patients with metastatic tumors, but not in patients with non-metastatic tumors (p(het) range: 0.00044 – 0.049). Doubling of PC ae C34:0 was associated with nine-fold increased risk of death in metastatic tumors (Hazard Ratio [HR], 9.05; 95% confidence interval [CI], 2.17-37.80); an inverse association was observed in non-metastatic tumors (HR, 0.17; 95% CI, 0.04-0.87; p(het)=0.00044). CONCLUSION: These data provide initial evidence that glycerophospholipids in metastatic colorectal cancer are uniquely associated with subcutaneous adiposity, and may impact overall survival.

BACKGROUND The liver is the most common site of colorectal liver metastases (CRLM) and surgical resection improves overall survival in selected patients. Here, we investigate outcomes and relevant prognostic factors after repeated hepatic resections for CRLM. METHODS From a prospective database, 578 patients who underwent 788 resections of colorectal liver metastases were included into this study. In total, 169 patients underwent a second and 41 patients had a third operation due to intrahepatic metastatic recurrence. Univariate and multivariate analyses were performed to determine prognostic risk factors. RESULTS 5-year overall survival was 36.7% (95% CI: 30.2%; 43.2%) and 10-year survival was 20.3% (95% CI: 7.6%; 33.0%) in patients undergoing single resection. In patients undergoing a second or third resection, 5- and 10-year survival rates were 56.6% (95% CI: 45.0%; 68.2%) and 21.9% (95% CI: 6.8%; 37.0%) or 53.2% (95% CI: 32.4%; 74.0%) and 25.4%, respectively. In patients undergoing single resection, established markers (number, size and pattern of CRLM [p = 0.030/0.015/

Solid tumors are rich ecosystems of numerous different cell types whose interactions lead to immune escape and resistance to immunotherapy in virtually all patients with metastatic cancer. Here, we have developed a 3D model of human solid tumor tissue that includes tumor cells, fibroblasts, and myeloid and lymphoid immune cells and can represent over a million cells over clinically relevant timeframes. This model accurately reproduced key features of the tissue architecture of human colorectal cancer and could be informed by individual patient data, yielding in silico tumor explants. Stratification of growth kinetics of these explants corresponded to significantly different overall survival in a cohort of patients with metastatic colorectal cancer. We used the model to simulate the effect of chemotherapy, immunotherapies, and cell migration inhibitors alone and in combination. We classified tumors according to tumor and host characteristics, showing that optimal treatment strategies markedly differed between these classes. This platform can complement other patient-specific ex vivo models and can be used for high-throughput screening of combinatorial immunotherapies. Significance: This patient-informed in silico tumor growth model allows testing of different cancer treatment strategies and immunotherapies on a cell/tissue level in a clinically relevant scenario. Cancer Res; 78(17); 5155–63. ©2018 AACR.

ZusammenfassungAls schwierige chirurgische Situation wird jedes Problem, das zu einem erhöhten Risiko für intra- oder postoperative Komplikationen führen kann, bezeichnet. Bezogen auf diese Definition wurde von Korenkov et al. eine präoperative Klassifikation erweiterter intraoperativer Schwierigkeiten entwickelt. Diese Klassifikation bezieht sich auf das Ausmaß der chirurgisch-technischen Schwierigkeiten von Schweregrad 1 – technisch einfach zu operieren, bis Schweregrad 4 – jede operationstechnische Handlung ist sehr schwierig. Für die Evaluierung des Schweregrads der intraoperativen Komplikationen schlug die Arbeitsgruppe um Kaafarani die Klassifikation der intraoperativen negativen Ereignisse vor. In Abhängigkeit vom Schweregrad wurden die intraoperativen Komplikationen auf 6 Klassen von der 1. (unproblematisch beseitigte Komplikationen) bis zur 6. Klasse (intraoperativer Exitus letalis) aufgeteilt. Für eine Systematisierung des Schweregrads der postoperativen Komplikationen hat sich weltweit die Klassifikation von Clavien-Dindo etabliert. In dieser Klassifikation sind die postoperativen Komplikationen von Schweregrad 1 (jede Abweichung vom normalen postoperativen Verlauf mit „minimaler“ Behandlung) bis zum Schweregrad 5 (Tod des Patienten) aufgeteilt. Gestützt auf die vorgeschlagenen Klassifikationen und auf die Problematik der individuellen Entscheidungen in der Chirurgie entstand die Grundidee, ein Register (SCS-Register) zu etablieren. Das Hauptprinzip solcher Studien ist die Ansammlung der individuellen Erfahrungen von operierenden Chirurgen. Die wissenschaftliche Analyse fokussiert sich auf die Sondersituationen, bei denen das Behandlungskonzept an die individuelle Patientensituation adaptiert war und manchmal von den gängigen Standards abwich. Die Registrierung und Bearbeitung der angemeldeten Fälle wird auf der Basis der entsprechenden IT-Plattform anonym geführt. Das Ziel dieses Registers ist, die schwierigen chirurgischen Fälle bundesweit zu sammeln, zu registrieren und zu analysieren, um für die operierenden Chirurgen eine zugängliche Datenbank zu gestalten. Dabei wird für jeden Chirurgen die Möglichkeit bestehen, nachzulesen, wie der eine oder andere Kollege in ähnlich schwierigen Situationen gehandelt hat.

Objectives:The aim of this study was to investigate the effect of pylorus resection on postoperative delayed gastric emptying (DGE) after partial pancreatoduodenectomy (PD).Background:PD is the standard treatment for tumors of the pancreatic head. Preservation of the pylorus has been widely accepted

Only a few studies have analyzed multimodal treatment concepts in the subgroup of signet-ring-cell containing upper gastrointestinal (GI) cancer. Recent retrospective, multicentric data favor primary resection without neoadjuvant chemotherapy for gastric signet-ring-cell containing carcinomas (SRCs). We compared the outcomes of primarily resected carcinomas with neoadjuvantly treated, locally advanced esophagogastric SRCs.A total of 310 patients with esophagogastric SRC-staged cT3/4/Nany/Many from a prospective unicentric database were included in this study; 192 (61.9%) received neoadjuvant therapy (NEO group) and 118 (38.1%) were primarily resected (RES group).Overall, 128 (41.3%) patients presented with adenocarcinoma of the esophagogastric junction (AEG) and 182 (58.7%) presented with gastric cancer. Neoadjuvant therapy was significantly associated with resection in curative intent (NEO: 91.1%; RES: 75.4%; P = 0.001), improved (y)pT category (P = 0.035), improved (y)pN category (P 0.001), and R0 resections (curative intent cohort: 76.0% in NEO vs. 60.7% in RES; P = 0.010), among others, but not with postoperative complications. Overall survival was significantly improved by neoadjuvant treatment {median survival 28.5 months (95% confidence interval [CI] 14.4-39.6) vs. RES: 14.9 months (10.6-17.5); P 0.001}, as well as in subgroups (AEG and gastric tumors, R0-resected patients, and patients with and without relevant comorbidities). Independent prognostic factors were neoadjuvant therapy (hazard ratio [HR] 0.66; P = 0.023), pT4 category (HR 1.71; P = 0.041), pN2 category (HR 1.86; P = 0.013), pN3 category (HR 2.40; P 0.001), pM1 category (HR 1.95; P = 0.003), age 70 years (HR 1.79; P = 0.006), gastric localization (HR 0.69; P = 0.032), American Society of Anesthesiologists classification 3/4 (HR 1.71; P = 0.004), and incomplete resection R1/2 (HR 1.6; P = 0.014).Our results demonstrate a survival advantage for advanced-stage esophagogastric SRC patients by neoadjuvant treatment.

Anastomotic leakage is the most dreaded complication after rectal resection and total mesorectal excision, leading to increased morbidity and mortality. Formation of a diverting ileostomy is generally performed to protect anastomotic healing. Identification of variables predicting anastomotic leakage might help to select patients who are under increased risk for the development of anastomotic leakage prior to surgery. The objective of this study was to assess the applicability of a nomogram as prognostic model for the occurrence of anastomotic leakage after rectal resection in a cohort of rectal cancer patients. Nine hundred seventy-two consecutive patients who underwent surgery for rectal cancer were retrospectively analyzed. Univariate and multivariable Cox regression analyses were used to determine independent risk factors associated with anastomotic leakage. Receiver operating characteristics (ROC) curve analysis was performed to calculate the sensitivity, specificity, and overall model correctness of a recently published nomogram and an adopted risk score based on the variables identified in this study as a predictive model. Male sex (p = 0.042), obesity (p = 0.017), smoking (p = 0.012), postoperative bleeding (p = 0.024), and total protein level ≤ 5.6 g/dl (p = 0.007) were identified as independent risk factors for anastomotic leakage. The investigated nomogram and the adopted risk score failed to reach relevant areas under the ROC curve greater than 0.700 for the prediction of anastomotic leakage. The proposed nomogram and the adopted risk score failed to reliably predict the occurrence of anastomotic leakage after rectal resection. Risk scores as prognostic models for the prediction of anastomotic leakage, independently of the study population, still need to be identified.

Folate‐mediated one‐carbon metabolism (FOCM) is a key pathway essential for nucleotide synthesis, DNA methylation, and repair. This pathway is a critical target for 5‐fluorouracil (5‐FU), which is predominantly used for colorectal cancer (CRC) treatment. A comprehensive assessment of polymorphisms in FOCM‐related genes and their association with prognosis has not yet been performed. Within 1,739 CRC cases aged ≥30 years diagnosed from 2003 to 2007 (DACHS study), we investigated 397 single nucleotide polymorphisms (SNPs) and 50 candidates in 48 FOCM‐related genes for associations with overall‐ (OS) and disease‐free survival (DFS) using multiple Cox regression (adjusted for age, sex, stage, grade, BMI, and alcohol). We investigated effect modification by 5‐FU‐based chemotherapy and assessed pathway‐specific effects. Correction for multiple testing was performed using false discovery rates (FDR). After a median follow‐up time of 5.0 years, 585 patients were deceased. For one candidate SNP in MTHFR and two in TYMS, we observed significant inverse associations with OS (MTHFR: rs1801133, C677T: HR het = 0.81, 95% CI: 0.67–0.97; TYMS: rs1001761: HR het = 0.82, 95% CI: 0.68–0.99 and rs2847149: HR het = 0.82, 95% CI: 0.68–0.99). After FDR correction, one polymorphism in paraoxonase 1 (PON1; rs3917538) was significantly associated with OS (HR het = 1.28, 95% CI: 1.07–1.53; HR hzv = 2.02, 95% CI:1.46–2.80; HR logAdd = 1.31, pFDR = 0.01). Adjusted pathway analyses showed significant associations for pyrimidine biosynthesis (P = 0.04) and fluorouracil drug metabolism (P

DNA methylation is recognized as one of several epigenetic regulators of gene expression and as potential driver of carcinogenesis through gene-silencing of tumor suppressors and activation of oncogenes. However, abnormal methylation, even of promoter regions, does not necessarily alter gene expression levels, especially if the gene is already silenced, leaving the exact mechanisms of methylation unanswered. Using a large cohort of matching DNA methylation and gene expression samples of colorectal cancer (CRC; n = 77) and normal adjacent mucosa tissues (n = 108), we investigated the regulatory role of methylation on gene expression. We show that on a subset of genes enriched in common cancer pathways, methylation is significantly associated with gene regulation through gene-specific mechanisms. We built two classification models to infer gene regulation in CRC from methylation differences of tumor and normal tissues, taking into account both gene-silencing and gene-activation effects through hyper- and hypo-methylation of CpGs. The classification models result in high prediction performances in both training and independent CRC testing cohorts (0.92

Background Prevention of surgical-site infection (SSI) has received increasing attention. Clinical trials have focused on the role of skin antisepsis in preventing SSI. The benefit of combining antiseptic chlorhexidine with alcohol has not been compared with alcohol-based skin preparation alone in a prospective controlled clinical trial. Methods Between August and October 2014, patients undergoing abdominal surgery received preoperative skin antisepsis with 70 per cent isopropanol (PA). Those treated between November 2014 and January 2015 received 2 per cent chlorhexidine with 70 per cent isopropanol (CA). The primary endpoint was SSI on postoperative day (POD) 10, which was evaluated using univariable analysis, and a multivariable logistic regression model correcting for known independent risk factors for SSI. The study protocol was published in the German Registry of Clinical Studies (DRKS00011174). Results In total, 500 patients undergoing elective midline laparotomy were included (CA 221, PA 279). The incidence of superficial and deep SSIs was significantly different on POD 10: 14 of 212 (6·6 per cent) among those treated with CA and 32 of 260 (12·3 per cent) in those who received PA (P = 0·038). In the multivariable analysis, skin antisepsis with CA was an independent factor for reduced incidence of SSI on POD 10 (P = 0·034). Conclusion This study showed a benefit of adding chlorhexidine to alcohol for skin antisepsis in reducing early SSI compared with alcohol alone.

While several trials have compared laparoscopic to open surgery for colon cancer showing similar oncological results, oncological quality of laparoscopic versus open rectal resection is not well investigated. A systematic literature search for randomized controlled trials was conducted in MEDLINE, the Cochrane Library, and Embase. Qualitative and quantitative meta-analyses of short-term (rate of complete resections, number of harvested lymph nodes, circumferential resection margin positivity) and long-term (recurrence, disease-free and overall survival) oncologic results were conducted. Fourteen randomized controlled trials were identified including 3528 patients. Patients in the open resection group had significantly more complete resections (OR 0.70; 95% CI 0.51–0.97; p = 0.03) and a higher number of resected lymph nodes (mean difference − 0.92; 95% CI − 1.08 to 0.75; p

The present study compared the prognostic value of the lymph node ratio (LNR) and the 6th and the 7th TNM edition as three different lymph node classifications for rectal cancer patients.A total of 630 patients who underwent total mesorectal excision for primary rectal cancer between October 2001 and December 2007 were included. Prognostic factors of overall survival were analyzed using Cox proportional hazards models.The median follow-up was 36.1 months and the 5-year overall survival rate was 70.3 ± 4.7%. The median number of lymph nodes was 15.0 (12.0-19.0). All three lymph node evaluations correlated with survival (p 0.0001). The assessment of nodal status in the 7th TNM edition enabled further prognostic stratification. The prognostic value of the three classifications were independent of neoadjuvant therapy and lymph node count. On multivariate analyses, the N2 stage of the 6th TNM edition (Hazard ratio 2.08; 95% confidence interval 1.21-3.58) and the N2b stage of the 7th TNM edition (2.18; 1.17-4.07) correlated with poor survival. A LNR of 0.42-0.69 was also associated with unfavorable prognosis (2.97; 1.46-6.03), as was an LNR 0.69 (2.51; 1.04-6.05). The LNR did not provide prognostic information in addition to the N stage of the TNM classifications.The evaluated lymph node classifications were of comparable prognostic utility in patients with rectal cancer. The LNR did not provide prognostic information in addition to the N stage of the TNM classifications.

Salinomycin, a polyether antibiotic, is a well-known inhibitor of human cancer stem cells. Chemical modification of the allylic C20 hydroxyl of salinomycin has enabled access to synthetic analogs that display increased cytotoxic activity compared to the native structure. The aim of this study was to investigate the activity of a cohort of C20-O-acyl analogs of salinomycin on human colorectal cancer cell lines in vitro. Two human colorectal cancer cell lines (SW480 and SW620) were exposed to three C20-O-acylated analogs and salinomycin. The impact of salinomycin and its analogs on tumor cell number, migration, cell death, and cancer stem cell specifity was analyzed. Exposure of human colorectal cancer cells to the C20-O-acylated analogs of salinomycin resulted in reduced tumor cell number and impaired tumor cell migration at lower concentrations than salinomycin. When used at higher (micromolar) concentrations, these effects were accompanied by induction of apoptotic cell death. Salinomycin analogs further expose improved activity against cancer stem cells compared to salinomycin.

Despite the fact that the local immunological microenvironment shapes the prognosis of colorectal cancer, immunotherapy has shown no benefit for the vast majority of colorectal cancer patients. A better understanding of the complex immunological interplay within the microenvironment is required. In this study, we utilized wet lab migration experiments and quantitative histological data of human colorectal cancer tissue samples (n = 20) including tumor cells, lymphocytes, stroma, and necrosis to generate a multiagent spatial model. The resulting data accurately reflected a wide range of situations of successful and failed immune surveillance. Validation of simulated tissue outcomes on an independent set of human colorectal cancer specimens (n = 37) revealed the model recapitulated the spatial layout typically found in human tumors. Stroma slowed down tumor growth in a lymphocyte-deprived environment but promoted immune escape in a lymphocyte-enriched environment. A subgroup of tumors with less stroma and high numbers of immune cells showed high rates of tumor control. These findings were validated using data from colorectal cancer patients (n = 261). Low-density stroma and high lymphocyte levels showed increased overall survival (hazard ratio 0.322, P = 0.0219) as compared with high stroma and high lymphocyte levels. To guide immunotherapy in colorectal cancer, simulation of immunotherapy in preestablished tumors showed that a complex landscape with optimal stroma permeabilization and immune cell activation is able to markedly increase therapy response in silico. These results can help guide the rational design of complex therapeutic interventions, which target the colorectal cancer microenvironment. Cancer Res; 77(22); 6442–52. ©2017 AACR.

Objective: High-throughput metabolomics assays can generate thousands of biomarker measurements and provide novel opportunities for prognostic modeling in colorectal cancer (CRC) research. The high dimensionality of metabolic data brings unforeseen statistical challenges and traditional variable selection methods may not perform well due to simultaneous challenges of computational expediency, statistical accuracy, and algorithmic stability. The Iterative Sure Independence Screening (ISIS) has demonstrated superior theoretical properties in handling such situations, and may be a viable alternative. Methods: In a prospective study of 77 newly diagnosed CRC patients (stage I-IV), pre-surgical urinary samples were analyzed on a gas chromatography-mass spectrometry platform. After exclusion of metabolites with >30% coefficient of variation, 168 metabolites remained for statistical analysis. Raw measures were processed following a standard normalization pipeline. The primary outcome was overall survival (OS) as measured from date of cancer diagnosis. In addition to metabolomics data, the predictor set included baseline clinical characteristics, such as age, sex, body mass index, tumor site, tumor stage, and receipt of neo-adjuvant and/or adjuvant treatment. We applied the ISIS method with Lasso penalty on a Cox regression model (ISIS-Lasso) to identify features associated with OS. Cox models with either Lasso regularization or backward selection were also considered as competing methods. The performance of the models was assessed through two standard performance matrices: Uno's time-dependent Area Under the Curve (tAUC) and Brier's score, both with resample-based validation. Results: Based on bootstrapped tAUC curves, we demonstrated that the screening step in ISIS can significantly improve model performance, since its predicted mean (and median) AUC are larger across clinically relevant follow-up time points (2 and 5 years after diagnosis) relative to the corresponding measures from the other two models. The prediction error based on Brier's score with 0.632+ bootstrap from ISIS-Lasso was also noticeably lower compared to the model from backward selections. Based on the ISIS-Lasso model, we identified two features, that were predictive of OS in CRC patients: tumor stage and cystine. When fixing all other clinical measures, patients with early stage (I-III) had 52% lower risk of death, compared to late stage (IV); 1 standard deviation of increase of cystine level was associated with 62% increased risk of death. Conclusion: We have demonstrated the feasibility and effectiveness of an ISIS-based method to improve selection of prognostic models derived from metabolomics data. This may be especially useful for studies with moderate sample sizes. We have identified cystine as a potentially important prognostic biomarker. Citation Format: Tengda Lin, Biljana Gigic, Kenneth Boucher, Ben Haaland, David Liesenfeld, Robert Owen, Petra Schrotz-King, Jourgen Boehm, Anita Peoples, Augustin Scalbert, Martin Schneider, Jane Figueiredo, William Grady, Christopher Li, David Shibata, Erin Siegel, Adetunji Toriola, Alexis Ulrich, Neli Ulrich, Jincheng Shen, Jennifer Ose. Application of iterative sureindependence screening to improve urinary metabolomics-based prediction of survival in colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 892.

Anastomotic leakage is the most frequent cause of postoperative mortality following esophageal surgery. However, no gold standard for diagnosing and managing leakage has been established. Continuous clinical judgment is extremely important; therefore, to optimize the management of leakage, we established a special group for decision-making in cases of suspected leakage in the early postoperative period. Between January 2010 and December 2016, 234 consecutive patients underwent elective esophageal resection with a thoracoabdominal incision. In 2014, we established a group consisting of a surgeon, surgical endoscopist, and anesthesiologist for decision-making in cases of suspected leakage. They discussed emerging problems and decided on further diagnostics or therapy. The data were documented prospectively and compared to the years prior to 2014. Two hundred and thirty-four consecutive patients were enrolled in the study, 110 in the years 2010–2013 (group A), and 124 in the years 2014–2016 (group B). Neither patients’ characteristics nor the rate of anastomotic leakage differed significantly between the two study groups. The hospital mortality rate was 10% (11 patients) in group A and 4.8% (six patients) in group B. Most interestingly, mortality due to anastomotic leakage was 35% in group A (9/26), whereas it decreased significantly to 6.5% (2/31 patients) (P

Smoking tobacco is a known risk factor for the development of colorectal cancer, and for mortality associated with the disease. Smoking has been reported to be associated with changes in DNA methylation in blood and in lung tumour tissues, although there has been scant investigation of how epigenetic factors may be implicated in the increased risk of developing colorectal cancer. To identify epigenetic changes associated with smoking behaviours, we performed epigenome-wide analysis of DNA methylation in colorectal tumours from 36 never smokers, 47 former smokers and 13 active smokers, and adjacent mucosa from 49 never smokers, 64 former smokers and 18 active smokers. Our analyses identified 15 CpG sites within the APC 1A promoter that were significantly hypermethylated and 14 CpG loci within the NFATC1 gene body that were significantly hypomethylated (pLIS

To investigate the association of serum 25-hydroxyvitamin D (25(OH)D3) with survival in a large prospective cohort study of colorectal cancer (CRC) patients. The study population consisted of 2,910 patients diagnosed with CRC between 2003 and 2010 who participated in the DACHS study, a multicenter study from Germany with comprehensive long-term follow-up. 25(OH)D3 was determined in serum samples collected shortly after cancer diagnosis by High Performance Liquid Chromatography-Electro Spray Ionization-Mass Spectrometry. Analyses of survival outcomes were performed using Cox regression with comprehensive adjustment for relevant confounders. The majority (59%) of CRC patients were vitamin D deficient (serum 25(OH)D3 levels 45.20 nmol/L), those in the lowest 25(OH)D3 quintile (

The optimal surgical approach for adenocarcinoma directly at the esophagogastric junction (AEG II) is still under debate. This study aims to evaluate the differences between right thoracoabdominal esophagectomy (TAE) (Ivor–Lewis operation) and transhiatal extended gastrectomy (THG) for AEG II. From a prospective database, 242 patients with AEG II (TAE, n = 56; THG, n = 186) were included and analyzed according to characteristics and perioperative morbidity and mortality and overall survival (chi-square, Mann–Whitney U, log-rank, Cox regression). Groups were comparable at baseline with exception of age. Patients older than 70 years were more frequently resected by THG (p = 0.003). No differences in perioperative morbidity (p = 0.197) and mortality (p = 0.711) were observed, including anastomotic leakages (p = 0.625) and pulmonary complications (p = 0.494). There was no significant difference in R0 resection (p = 0.719) and number of resected lymph nodes (p = 0.202). Overall median survival was 38.4 months. Survival after TAE was significantly longer than after THG (median OS not reached versus 33.6 months, p = 0.02). Multivariate analysis revealed pN-category (p

Background Recurrence of colorectal liver metastases after a first hepatectomy is common (4–48% of patients). This review investigates the utility of repeated hepatic resection of colorectal liver metastases. Methods A systematic search of the literature was performed in the Cochrane Library, MEDLINE, EMBASE, and trial registers. All studies comparing repeated hepatic resection for colorectal liver metastases with patients who underwent only one hepatectomy were eligible. Outcome criteria were safety parameters and survival rates. Data were analyzed using the random-effects model. Results In eight observational clinical studies, 450 patients with repeated hepatic resection were compared with 2669 single hepatic resections. Morbidity such as hepatic insufficiency (OR [95% CI] 1.46 [0.69; 3.08], p = 0.32) and biliary leakage and fistula (OR [95% CI] 1.22 [0.80; 1.85], p = 0.35) was comparable between the two groups. Mortality (OR [95% CI] 1.13 [0.46; 2.74], p = 0.79) and overall survival (HR [95% CI] 1.00 [0.63; 1.60], p = 0.99) were not significantly different between the two groups. Discussion Repeated hepatic resection for colorectal liver metastases is safe in selected patients. A prospective, multicenter high-quality trial or register study of repeated hepatic resection will be required to clarify patient-oriented outcomes such as overall survival and quality of life.

The aim was to investigate available evidence regarding effectiveness and safety of surgical versus conservative treatment of acute appendicitis.There is ongoing debate on the merits of surgical and conservative treatment for acute appendicitis.A systematic literature search (Cochrane Library, Medline, Embase) and hand search of retrieved reference lists up to January 2016 was conducted to identify randomized and nonrandomized studies. After critical appraisal, data were analyzed using a random-effects model in a Mantel-Haenszel test or inverse variance to calculate risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CIs).Four trials and four cohort studies (2551 patients) were included. We found that 26.5% of patients in the conservative group needed appendectomy within 1 year, resulting in treatment effectiveness of 72.6%, significantly lower than the 99.4% in the surgical group, (RR 0.75; 95% CI 0.7-0.79; P = 0.00001; I = 62%). Overall postoperative complications were comparable (RR 0.95; 95% CI 0.35-2.58; P = 0.91; I = 0%), whereas the rate of adverse events (RR 3.18; 95% CI 1.63-6.21; P = 0.0007; I = 1%) and the incidence of complicated appendicitis (RR 2.52; 95% CI 1.17-5.43; P = 0.02; I = 0%) were significantly higher in the antibiotic treatment group. Randomized trials showed significantly longer hospital stay in the antibiotic treatment group (RR 0.3 days; 95% CI 0.07-0.53; P = 0.009; I = 49%).Although antibiotics may prevent some patients from appendectomies, surgery represents the definitive, one-time only treatment with a well-known risk profile, whereas the long-term impact of antibiotic treatment on patient quality of life and health care costs is unknown. This systematic review and meta-analysis helps physicians and patients in choosing between treatment options depending on whether they are risk averse or risk takers.

ZusammenfassungAls schwierige chirurgische Situation wird jedes Problem, das zu einem erhöhten Risiko für intra- oder postoperative Komplikationen führen kann, bezeichnet. Bezogen auf diese Definition wurde von Korenkov et al. eine präoperative Klassifikation erweiterter intraoperativer Schwierigkeiten entwickelt. Diese Klassifikation bezieht sich auf das Ausmaß der chirurgisch-technischen Schwierigkeiten von Schweregrad 1 – technisch einfach zu operieren, bis Schweregrad 4 – jede operationstechnische Handlung ist sehr schwierig. Für die Evaluierung des Schweregrads der intraoperativen Komplikationen schlug die Arbeitsgruppe um Kaafarani die Klassifikation der intraoperativen negativen Ereignisse vor. In Abhängigkeit vom Schweregrad wurden die intraoperativen Komplikationen auf 6 Klassen von der 1. (unproblematisch beseitigte Komplikationen) bis zur 6. Klasse (intraoperativer Exitus letalis) aufgeteilt. Für eine Systematisierung des Schweregrads der postoperativen Komplikationen hat sich weltweit die Klassifikation von Clavien-Dindo etabliert. In dieser Klassifikation sind die postoperativen Komplikationen von Schweregrad 1 (jede Abweichung vom normalen postoperativen Verlauf mit „minimaler“ Behandlung) bis zum Schweregrad 5 (Tod des Patienten) aufgeteilt. Gestützt auf die vorgeschlagenen Klassifikationen und auf die Problematik der individuellen Entscheidungen in der Chirurgie entstand die Grundidee, ein Register (SCS-Register) zu etablieren. Das Hauptprinzip solcher Studien ist die Ansammlung der individuellen Erfahrungen von operierenden Chirurgen. Die wissenschaftliche Analyse fokussiert sich auf die Sondersituationen, bei denen das Behandlungskonzept an die individuelle Patientensituation adaptiert war und manchmal von den gängigen Standards abwich. Die Registrierung und Bearbeitung der angemeldeten Fälle wird auf der Basis der entsprechenden IT-Plattform anonym geführt. Das Ziel dieses Registers ist, die schwierigen chirurgischen Fälle bundesweit zu sammeln, zu registrieren und zu analysieren, um für die operierenden Chirurgen eine zugängliche Datenbank zu gestalten. Dabei wird für jeden Chirurgen die Möglichkeit bestehen, nachzulesen, wie der eine oder andere Kollege in ähnlich schwierigen Situationen gehandelt hat.

Objective We sought to assess whether pharmacological inhibition of hypoxia-inducible transcription factor (HIF)-prolyl hydroxylase enzymes (PHD1, PHD2, and PHD3) is a suitable strategy to stimulate liver regeneration after partial hepatectomy for colorectal liver metastases (CRLM). Background Liver regeneration occurs in a hypoxic environment. PHD1 to PHD3 are molecular oxygen sensors and increasingly considered as putative therapeutic targets. However, little is known about the effect of pharmacological PHD inhibition on tumor expansion, and on liver regeneration after surgical resection. Methods Various mouse models of liver regeneration after extended partial hepatectomy and portal vein ligation for multiple bilobar CRLM were applied to assess the effect of the small molecule pan-PHD inhibitor ethyl-3,4-dihydroxybenzoate (EDHB) on liver regeneration and metastatic tumor growth. Metabolism and biodistribution of EDHB were analyzed using liquid chromatography coupled to tandem mass spectrometry. Results EDHB selectively augmented liver regeneration after partial hepatectomy and portal vein ligation, and increased the expression of cell cycle-promoting cyclin proteins, without enhancing metastatic tumor growth. Systemically administered EDHB and its active metabolite 3,4-dihydroxybenzoic acid accumulated in the liver to selectively induce hepatoprotective effects in the liver, but not in tumor tissue, without humoral adverse effects. Conclusions Pharmacological inhibition of PHDs using EDHB might represent a novel and safe strategy in the treatment of multiple bilobar CRLM.

Background Preoperative nutritional status has an impact on patients' clinical outcome. For pancreatic surgery, however, it is unclear which nutritional assessment scores adequately assess malnutrition associated with postoperative outcome. Methods Patients scheduled for elective pancreatic surgery at the University of Heidelberg were screened for eligibility. Twelve nutritional assessment scores were calculated before operation, and patients were categorized as either at risk or not at risk for malnutrition by each score. The postoperative course was monitored prospectively by assessors blinded to the nutritional status. The primary endpoint was major complications evaluated for each score in a multivariable analysis corrected for known risk factors in pancreatic surgery. Results Overall, 279 patients were analysed. A major complication occurred in 61 patients (21·9 per cent). The proportion of malnourished patients differed greatly among the scores, from 1·1 per cent (Nutritional Risk Index) to 79·6 per cent (Nutritional Risk Classification). In the multivariable analysis, only raised amylase level in drainage fluid on postoperative day 1 (odds ratio (OR) 4·91, 95 per cent c.i. 1·10 to 21·84; P = 0·037) and age (OR 1·05, 1·02 to 1·09; P = 0·005) were significantly associated with major complications; none of the scores was associated with, or predicted, postoperative complications. Conclusion None of the nutritional assessment scores defined malnutrition relevant to complications after pancreatic surgery and these scores may thus be abandoned.

Ventral incisional hernia is the most common long-term complication after an abdominal operation. Among newly diagnosed colorectal cancer patients, we screened the preoperative plasma proteome to explore predictive markers for the development of an incisional hernia.We utilized preoperative plasma samples of 72 newly diagnosed colorectal cancer patients who underwent midline incision for tumor resection between 2010 and 2013. A total of 21 patients with incisional hernia occurrence were matched with 51 patients with at least 18 months follow-up without an incisional hernia by sex, age, and body mass index. To assess predictive markers of incisional hernia risk, we screened the plasma proteome for2,000 distinct proteins using a well-validated antibody microarray test. Paired t tests were used to compare protein levels between cases and controls. A gene-set-enrichment analysis (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) was applied to test for differences in signaling pathways between the 2 groups.The proteome screen identified 25 proteins that showed elevated or reduced plasma levels in the hernia group compared to the control group (nominal P values .05). Several proteins were in pathways associated with wound healing (CCL21, SHBG, BRF2) or cell adhesion (PCDH15, CDH3, EPCAM).Our study shows that there are multiple individual and groups of plasma proteins that could feasibly predict the personal hernia risk prior to undergoing an operation. Further investigations in larger, independent sample sets are warranted to replicate findings and validate clinical utility of potential biomarkers. After validation, such a biomarker could be incorporated into a multifactorial risk model to guide clinical decision-making.

Background The International Study Group on Pancreatic Surgery has stated that at least 12 lymph nodes should be evaluated for staging of pancreatic cancer. The aim of this population-based study was to evaluate whether the number of positive lymph nodes refines staging. Methods Patients who underwent pancreatectomy for stage I–II pancreatic cancer between 2004 and 2012 were identified from the Surveillance, Epidemiology, and End Results database. The predictive value of the number of positive lymph nodes for survival was assessed by generalized receiver operating characteristic (ROC) curve analysis and propensity score-adjusted Cox regression analysis. Results Some 5036 patients were included, with a median of 18 (i.q.r. 15–24) lymph nodes examined. Positive lymph nodes were found in 3555 patients (70·6 per cent). The median duration of follow-up was 15 (i.q.r. 8–28) months. ROC curve analysis revealed that two positive lymph nodes best discriminated overall survival. Patients with one or two positive lymph nodes (pN1a) and those with three or more positive lymph nodes (pN1b) had an increased risk of overall mortality compared with patients who were node-negative (pN0): hazard ratio (HR) 1·47 (95 per cent c.i. 1·33 to 1·64) and HR 2·01 (1·82 to 2·22) respectively. These findings were confirmed by propensity score-adjusted Cox regression analysis. The 5-year overall survival rates were 39·8 (95 per cent c.i. 36·5 to 43·3) per cent for patients with pN0, 21·0 (18·6 to 23·6) per cent for those with pN1a and 11·4 (9·9 to 13·3) per cent for patients with pN1b disease. Conclusion The number of positive lymph nodes in the resection specimen is a prognostic factor in patients with pancreatic cancer.

Purpose Soft tissue sarcomas (STS) of the retroperitoneum and the lower limb with invasion of major blood vessels are very rare malignancies. This study analyses the outcome of patients with vascular replacement during resection of STS of the retroperitoneum and the lower extremity with either arterial or concomitant arterial and venous infiltration. Methods Patients with vascular replacement during resection of sarcoma of the retroperitoneum and the lower extremity between 1990 and 2014 were included in this retrospective single center study. Patients with a sole infiltration of a major vein were excluded. The follow up was obtained from medical records, the general practitioner and a clinical examination whenever possible. The main endpoints were survival, graft patency and the rate of major amputations. Results Fourty seven patients were included in this study. Twenty patients have received an operation for a retroperitoneal STS, twenty seven for a STS of the lower extremity. The median follow-up was 24.5 months. The median survival was 113 months with a median tumor-free survival of 25 months. The two-year patency for arterial bypasses in the retroperitoneum and the lower extremity was 88% and 66%, respectively. Limb salvage rate was 89%. Conclusions Invasion of major blood vessels is no contraindication for a resection of a STS in the retroperitoneum and the lower extremity, but it is accompanied by a high postoperative morbidity. Since surgical resection is the only curative therapy in these patients, it should also be offered to patients with infiltration of major blood vessels.

Background In metastatic disease (M1), chemotherapy (expected survival: 6–10 months) is considered the only treatment option. The aim of this study was to evaluate the outcome of curative M1 PDAC resections. Methods Prospective data of all patients undergoing primary tumour and metastasis resection for stage IV PDAC during a 12-year period was analysed regarding localisation (liver or distant interaortocaval lymph nodes; ILN), morbidity and survival. Patients were stratified with regard to syn- or metachronous metastases resection. Results Patients (n = 128) undergoing PDAC and metastases resection (intention-to-treat, oligometastatic stage; liver n = 85; ILN n = 43) were included. Surgical morbidity and 30-day mortality after synchronous resection of M1 tumours were 45% and 2.9%, respectively. Overall median survival after M1 resection was 12.3 months in both groups. Long-term outcome showed a 5-year survival of 8.1% after surgery for both liver metastases and 10.1% following ILN resection. Conclusions The present collective is the largest series of resected metastatic PDAC and shows that resection of liver or ILN metastases can be done safely and should be considered as it may be superior to palliative treatment, and it is associated with long-term survival of 10% in selected patients. Further studies to stratify patients for these procedures are warranted.

Patient-derived cancer xenografts (PDX) are widely used to identify and evaluate novel therapeutic targets, and to test therapeutic approaches in preclinical mouse avatar trials. Despite their widespread use, potential caveats of PDX models remain considerably underappreciated. Here, we demonstrate that EBV-associated B-lymphoproliferations frequently develop following xenotransplantation of human colorectal and pancreatic carcinomas in highly immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl /SzJ (NSG) mice (18/47 and 4/37 mice, respectively), and in derived cell cultures in vitro. Strikingly, even PDX with carcinoma histology can host scarce EBV-infected B-lymphocytes that can fully overgrow carcinoma cells during serial passaging in vitro and in vivo. As serial xenografting is crucial to expand primary tumor tissue for biobanks and cohorts for preclinical mouse avatar trials, the emerging dominance of B-lymphoproliferations in serial PDX represents a serious confounding factor in these models. Consequently, repeated phenotypic assessments of serial PDX are mandatory at each expansion step to verify "bona fide" carcinoma xenografts.

Zusammenfassung Hintergrund Die onkologische Ösophagektomie ist mit hoher Morbidität verbunden. Mit minimal invasiven Operationsverfahren ist verschiedentlich versucht worden, diese zu reduzieren. Hauptproblem ist dabei die intrathorakale Anastomose. Es existieren verschiedene Techniken, mit dem Problem umzugehen, wie die Anlage einer funktionell problematischen zervikalen Anastomose, die offene Anlage der thorakalen Anastomose (Hybrid-Technik) oder die robotergestützte Anlage der technisch sehr anspruchsvollen Zirkularstapleranastomose. Als minimal invasiv auch ohne Roboterassistenz relativ einfach machbare Alternative zeigen wir die intrathorakale Seit-zu-Seit Ösophagogastrostomie in Linearstapler-Technik. Operationstechnik Der abdominelle Teil erfolgt in French-Lagerung. Nach Dissektion des Omentum majus entlang der gastroepiploischen Arkade und des Milzhilus sowie Trennung des Omentum minus 6 cm präpylorisch wird ein 4,5 cm breiter Magenschlauch in Linearstaplertechnik gebildet. Dann erfolgt die systematische abdominale und transmediastinale Lymphadenekotmie. Nach Umlagerung des Patienten in Links-Seitenlage wird die Lymphadenektomie thorakal komplettiert und das Präparat entfernt. Die Seit-zu-Seit Ösophagogastrostomie beginnt mit der Inzision des Ösophagusstumpfes. Dann wird der Magenschlauch mesonah 5 cm vom oralen Absetzungsrand inzidiert und ein Linearstapler über 3 cm in die beiden Inzisionen eingebracht und abgefeuert. Die verbleibende Öffnung wird mit einer fortlaufenden Naht modifiziert zweireihig quer verschlossen. Diskussion Die Seit-zu-Seit Ösophagogastrostomie in Linearstapler-Technik scheint eine einfache und sichere Alternative für die Rekonstruktion nach minimal invasiver Ösophagektomie zu sein. Die Methode wird aktuell in einer randomisiert kontrollierten Studie untersucht.

Cachexia is a multifactorial syndrome that is characterized by loss of skeletal muscle mass in cancer patients. The biological pathways involved remain poorly characterized. Here, we compare urinary metabolic profiles in newly diagnosed colorectal cancer patients (stage I&ndash, IV) from the ColoCare Study in Heidelberg, Germany. Patients were classified as cachectic (n = 16), pre-cachectic (n = 13), or non-cachectic (n = 23) based on standard criteria on weight loss over time at two time points. Urine samples were collected pre-surgery, and 6 and 12 months thereafter. Fat and muscle mass area were assessed utilizing computed tomography scans at the time of surgery. N = 152 compounds were detected using untargeted metabolomics with gas chromatography&ndash, mass spectrometry and n = 154 features with proton nuclear magnetic resonance spectroscopy. Thirty-four metabolites were overlapping across platforms. We calculated differences across groups and performed discriminant and overrepresentation enrichment analysis. We observed a trend for 32 compounds that were nominally significantly different across groups, although not statistically significant after adjustment for multiple testing. Nineteen compounds could be identified, including acetone, hydroquinone, and glycine. Comparing cachectic to non-cachectic patients, higher levels of metabolites such as acetone (Fold change (FC) = 3.17, p = 0.02) and arginine (FC = 0.33, p = 0.04) were observed. The two top pathways identified were glycerol phosphate shuttle metabolism and glycine and serine metabolism pathways. Larger subsequent studies are needed to replicate and validate these results.

Background Results of previous studies on the association of the CpG island methylator phenotype (CIMP) with colorectal cancer (CRC) prognosis were inconsistent and mostly based on different CIMP definitions. The current study aimed to comprehensively investigate the associations between DNA methylation on genes previously used to define CIMP status with CRC survival. Results Patients with CRC followed up for a median of 5.2 years were divided into a study cohort (n = 568) and a validation cohort (n = 308). DNA methylation was measured in tumor tissue using the Illumina Infinium HumanMethylation450 BeadChip and restricted to 43 genes used to define CIMP status in previous studies. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) of survival after CRC, including adjustment for tumor stage, microsatellite instability, and BRAF mutation status. In the study cohort, ten CpG sites were identified to be associated with CRC survival. Seven of these ten CpG sites were also associated with CRC survival in the validation cohort and were used to construct a prognostic score. CRC patients with a prognostic score of the lowest methylation level showed poorer disease-specific survival compared with patients with the highest methylation level in both the study cohort and the validation cohort (HR = 3.11 and 95% CI = 1.97–4.91, and HR = 3.06 and 95% CI = 1.71–5.45, respectively). Conclusions A CpG panel consisting of seven CpG sites was found to be strongly associated with CRC survival, independent from important clinical factors and mutations associated with CIMP. Further studies are required to confirm these findings. Electronic supplementary material The online version of this article (10.1186/s13148-019-0703-4) contains supplementary material, which is available to authorized users.