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Purpose The treatment of anastomotic leakage after left colorectal surgery remains challenging. Since its introduction, endoscopic negative pressure therapy (ENPT) has proven to be advantageous, reducing the necessity of surgical revision. The aim of our study is to present our experience with endoscopic treatment of colorectal leakages and to identify potential factors influencing treatment outcome. Methods Patients who underwent endoscopic treatment of colorectal leakage were retrospectively analyzed. Primary endpoint was the healing rate and success of endoscopic therapy. Results We identified 59 patients treated with ENPT between January 2009 and December 2019. The overall closure rate was 83%, whereas only 60% of the patients were successfully treated with ENPT and 23% needed further surgery. The time between diagnosis of leakage and uptake of endoscopic treatment did not influence the closure rate, but patients with chronic fistula (> 4 weeks) showed a significantly higher reoperation rate than those with an acute fistula (94% vs 6%, p = 0.01). Conclusion ENPT is a successful treatment option for colorectal leakages, which appears to be more favorable when started early. Further studies are still needed to better describe its healing potential, but it deserves an integral role in the interdisciplinary treatment of anastomotic leakages.

Purpose: Pancreatic cancer is one of the most devastating diseases with a 5-year survival rate of 3% to 5%. Here, we investigated whether circulating tumor cells (CTC) may predict metastatic spread and survival in pancreatic cancer patients.Experimental Design: In a prospective study, we enrolled 69 pancreatic cancer patients. In peripheral blood, CTCs were identified by MACS enrichment (anti-cytokeratin/anti-EpCam) and subsequent automated analysis after combined anti-cytokeratin/anti-CD45/DAPI staining. CTC results were correlated to established clinicopathologic risk factors, detection of disseminated tumor cells (DTC) in bone marrow, and clinical outcome (follow-up time: 48 months).Results: Median patient survival was 11 months (0–48 months). Thirty-eight patients were male and 31 were female, and the majority received gemcitabine (58/69). CTCs were present in 23 of 69 patients (33.3%) ranging from 1 to 19 cells (17 with >1 CTC). Although clinicopathologic parameters and DTC status did not correlate with CTC incidence, progression-free survival (PFS) and overall survival (OS) were significantly reduced in CTC-positive patients in univariate (P = 0.009, PFS; P = 0.030, OS, both log rank) and multivariate analysis [HR = 4.543; confidence interval (CI), 1.549–13.329; P = 0.006, PFS; HR = 2.093; CI, 1.081–4.050; P = 0.028, OS, both Cox regression). Also within patients receiving chemotherapy, PFS was significantly reduced in CTC-positive patients in univariate (P = 0.013) and multivariate (HR = 4.203; CI, 1.416–12.471; P = 0.010) analysis.Conclusions: CTCs affect the outcome of patients with pancreatic cancer independent from other risk factors, including patients receiving (adjuvant) cytotoxic therapy. CTC stratification may allow a better upfront identification of patients with a longer lifespan who might profit from new adjuvant therapies. Clin Cancer Res; 24(12); 2844–50. ©2018 AACR.

Supplemental Figure S1: Relative Survival of PDAC patients with different blood groups. Kaplan Meier survival plot shows relative survival of PDAC patients in blood group O (blue), blood group A (green), blood group B (yellow) and blood group AB (purple). No significant statistical association was observed.

Purpose: The ABO gene locus is associated with the risk of developing pancreatic ductal adenocarcinoma (PDAC) resulting in an increased incidence in individuals with non-O blood groups. Up to 90% of PDAC specimens display alterations in mucin type O-GalNAc glycosylation. Because aberrant O-GalNAc glycans (Tn and T antigen) are structurally related to blood group A and B glycans, we investigated the role of IgM isoagglutinins in PDAC.Experimental Design: Binding studies of IgM isoagglutinins toward blood group A, B, Tn antigen, and T antigen glycoconjugates from patients with PDAC and healthy individuals were conducted. Isoagglutinin titers and total IgM were compared between patients with PDAC and control group. An anti-A antibody was used for immunoprecipitation of aberrant O-glycosylated tumor proteins and subsequent mass spectromic analysis.Results: We found that IgM isoagglutinins bind blood group antigens, Tn and T glycoconjugates as well as tumor-derived glycoproteins. Blood group A isoagglutinins exhibited a strong binding toward blood group B antigen and T antigen, whereas blood group B showed binding to blood group A antigen and Tn antigen. Furthermore, we confirmed a decreased frequency in individuals with blood group O and observed a significant decrease of IgM isoagglutinin titers in PDAC sera compared with control sera, whereas total IgM levels were unaltered. We identified new PDAC-derived O-GalNAc glycoproteins by mass spectrometry using a blood group A-specific antibody.Conclusion: Our data elucidated a novel interaction of blood group IgM isoagglutinins and PDAC O-GalNAc glycoproteins that may contribute to the pathogenesis and progression of pancreatic cancer. Clin Cancer Res; 20(23); 6117–26. ©2014 AACR.

Supplements Table 1. Multivariate analyses of progression-free survival and overall survival (n=57) of chemo-receiving patients.

Background Prolyl hydroxylase 1 (PHD1) is a prognostic marker in several cancers. Aims and scopes This study was undertaken to elucidate the clinical relevance of PHD1 in colorectal cancer (CRC) prognosis. Materials and methods We compared PHD1 expression on a tissue microarray (TMA) containing samples from 1800 CRCs with corresponding clinicopathological tumor variables and patient survival. Results While PHD1 staining was always high in benign colorectal epithelium, high PHD1 staining was detectable in only 71.8% of CRCs. Low PHD1 staining was associated with advanced tumor stage (p = 0.0101) and shortened overall survival in CRC patients (p = 0.0011). In a multivariable analysis including tumor stage, histological type and PHD1 staining revealed tumor stage and histological type (p p = 0.0202) to be independent prognostic markers for CRC. Conclusions In our cohort, loss of PHD1 expression independently identified a subset of CRC patients with poor overall survival and might, thus, be a promising prognostic marker. PHD1 targeting may even allow for specific therapeutic approaches for these patients.

Purpose Retinoic acid inducible protein 3 (RAI3) has been suggested as prognostic biomarker in several cancer types. The present study aimed to examine the role of RAI3 expression in non-small cell lung cancers (NSCLCs). Methods RAI3 protein expression was evaluated by immunohistochemistry in tissue microarray (TMA) sections from a retrospective cohort of more than 600 surgically resected NSCLCs and results were compared with clinicopathological features and follow-up data. Results While membranous RAI3 immunostaining was always strong in benign lung, strong RAI3 staining was only detectable in 14.7% of 530 interpretable NSCLCs. Within NSCLC subtypes, immunostaining intensity for RAI3 was significantly decreased in large cell lung cancers (LCLCs) and squamous cell carcinomas (SQCCs) relative to lung adenocarcinomas (LUACs) (P P = 0.6915). Conclusion Our study shows that RAI3 expression was not associated with clinical outcomes of NSCLC patients and cannot be considered as prognostic marker in lung cancer patients.

Strong RNA-binding motif protein 3 (RBM3) has recently been described to be linked to overall survival in many different cancer types. To better understand the impact of RBM3 expression in preneoplastic and neoplastic gastric tissue, RBM3 protein expression was analyzed on a pre-existing tissue microarray containing normal gastric epithelium, gastric dysplasia, and primary gastric adenocarcinoma specimens. Nuclear RBM3 expression was detectable in various intensities in benign gastric epithelium. Increased nuclear RBM3 expression was found in preneoplastic and neoplastic as compared to normal gastric epithelium (P

Introduction Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has repeatedly been suggested to be associated with tumorigenesis. To evaluate the role of LPCAT1 in esophageal cancer, LPCAT1 immunostaining was analyzed on a tissue microarray containing samples from esophageal cancer patients. Results In benign esophageal tissue, LPCAT1 staining was detectable in low intensities. LPCAT1 staining was increased in malignant as compared to benign esophageal tissue and was found in high intensity in 26.4% of 288 interpretable esophageal adenocarcinomas (EACs) and in 23.2% of 211 squamous cell carcinomas (ESCCs). Increased LPCAT1 staining was linked to undifferentiated tumor grading in both subtypes of EACs and ESCCs (p = 0.0273 and p = 0.0085). Conclusion However, LPCAT1 was not associated with prognosis of EAC and ESCC patients (p = 0.6838 and p = 0.4695) and thus cannot be considered a prognostic biomarker in esophageal cancers.

Background Intrathoracic anastomotic leaks represent a major complication after Ivor Lewis esophagectomy. There are two promising endoscopic treatment strategies in the case of leaks: the placement of self-expanding metal stents (SEMS) or endoscopic vacuum therapy (EVT). Up to date, there is no prospective data concerning the optimal endoscopic treatment strategy. This is a protocol description for the ESOLEAK trial, which is a first small phase 2 randomized trial evaluating the quality of life after treatment of anastomotic leaks by either SEMS placement or EVT. Methods This phase 2 randomized trial will be conducted at two German tertiary medical centers and include a total of 40 patients within 2 years. Adult patients with histologically confirmed esophageal cancer, who have undergone Ivor Lewis esophagectomy and show an esophagogastric anastomotic leak on endoscopy or present with typical clinical signs linked to an anastomotic leak, will be included in our study taking into consideration the exclusion criteria. After endoscopic verification of the anastomotic leak, patients will be randomized in a 1:1 ratio into two treatment groups. The intervention group will receive EVT whereas the control group will be treated with SEMS. The primary endpoint of this study is the subjective quality of life assessed by the patient using a systematic and validated questionnaire (EORTC QLQ C30, EORTC QLQ-OES18 questionnaire). Important secondary endpoints are healing rate, period of hospitalization, treatment-related complications, and overall mortality. Discussion The latest meta-analysis comparing implantation of SEMS with EVT in the treatment of esophageal anastomotic leaks suggested a higher success rate for EVT. The ESOLEAK trial is the first study comparing both treatments in a prospective manner. The aim of the trial is to find suitable endpoints for the treatment of anastomotic leaks as well as to enable an adequate sample size calculation and evaluate the feasibility of future interventional trials. Due to the exploratory design of this pilot study, the sample size is too small to answer the question, whether EVT or SEMS implantation represents the superior treatment strategy. Trial registration ClinicalTrials.gov NCT03962244. Registered on May 23, 2019. DRKS-ID DRKS00007941

Zusammenfassung Hintergrund Patienten mit einer Querschnittlähmung entwickeln syndromspezifische, viszeralchirurgisch relevante Krankheitsbilder, die im Rahmen des akuten spinalen Schocks auftreten können oder Folge der zumeist progredienten neurogenen Darmfunktionsstörung (NBD) mit Ausbildung eines Colon elongatum und/oder Megakolons sind. Auch die akuten abdominalchirurgischen Notfälle, wie akute Appendizitis, Cholezystitis, Divertikultis oder Ileusbilder, stellen den Kliniker bei untypischer oder teils fehlender Klinik vor diagnostische und therapeutische Herausforderungen. Einen zunehmenden Stellenwert nimmt die Ausweitung adipositaschirurgischer Indikationen auf Patienten mit einer Querschnittlähmung ein Ziel der Arbeit Dieser Artikel soll einen Überblick über die speziellen Anforderungen und Aspekte in der Behandlung dieses speziellen Patientenkollektivs geben und die Evidenz querschnittspezifischer viszeralchirurgischer Behandlungen aufzeigen. Material und Methoden Es wurde eine selektive Literaturrecherche in den Datenbanken Medline und Cochrane Library in deutscher und englischer Sprache (1985–2020) durchgeführt. Ergebnisse und Diskussion Die klinische Behandlung querschnittgelähmter Patienten erfordert einen profunden Kenntnisstand über die pathophysiologischen Veränderungen bei unterschiedlicher Querschnitthöhe (oberes vs. unteres motorisches Neuron) und die Phasen der Erkrankung (spinaler Schock vs. Langzeitverlauf). Fehlende oder atypische klinische Symptome akuter Erkrankungen verzögern eine rasche Diagnosefindung und machen eine frühzeitige Durchführung gezielter Diagnostik unabdingbar. Die Evidenz der chirurgischen Behandlung der akuten und chronischen Folgen der NBD ist gering und basiert auf Fallserien und „case reports“ ebenso wie die für spezielle Indikationen wie adipositaschirurgische Eingriffe.

Background Esophageal anastomotic leakage still represents a challenging complication after esophageal surgery. Endoscopically placed self-expandable metal stents (SEMS) are the treatment of choice, but since the introduction of endoscopic vacuum therapy (EVT) for esophageal leakage 10 years ago, increasing evidence has demonstrated that EVT might be a superior alternative. Therefore, we performed a systematic review and meta-analysis to compare the effectiveness and related morbidity of SEMS and EVT in the treatment of esophageal leak. Methods We systematically searched for studies comparing SEMS and EVT to treat anastomotic leakage after esophageal surgery. Predefined end points including outcome, treatment success, endoscopy, treatment duration, hospitalization time, morbidity, and mortality were assessed and included in the meta-analysis. Results Five retrospective studies including 274 patients matched the inclusion criteria. Compared with stenting, EVT was significantly associated with a higher rate of leak closure (odds ratio [OR] 3.14, 95 % confidence interval [CI] 1.23 to 7.98), more endoscopic device changes (pooled median difference of 3.09; 95 %CI 1.54 to 4.64]), a shorter duration of treatment (pooled median difference –11.90 days; 95 %CI –18.59 to –5.21 days), and a lower mortality rate (OR 0.39, 95 %CI 0.18 to 0.83). There were no significant differences in short-term and major complications. Conclusions Owing to the retrospective quality of the studies with potential biases, the results of the meta-analysis must be interpreted with caution. However, the analysis indicates the potential benefit of EVT, which should be further investigated with standardized and prospectively collected data.

Background The aim of this study is to evaluate whether adenocarcinomas of the esophagogastric junction (AEG) are better staged as cancers of the esophagus (TNM-EC) or stomach (TNM-GC) according to the 8th edition of the UICC classification. Methods A single-center cohort of 246 patients operated on for AEG type II was staged according to the 8th edition of the UICC classification for esophageal and stomach cancer. Kaplan-Meier and univariate Cox regression analyses were performed to investigate the impact on survival. Results For AEG type II TNM-EC classified most of the patients (n = 126; 51.2%) to UICC stage IIIC and IVA while TNM-GC more evenly distributed the patients over the stages. Hazard ratios increased in between all stages in a stepwise manner except between stage IA and IIA for TNM-EC and between stage IIB and IIIA for TNM-GC. Survival curves for TNM-GC demonstrated significant differences between all four major UICC stages, while in TNM-EC no significant difference between stage I and II was found. When comparing the area under the curves of both staging systems a marginal superiority for TNM-EC was found. Conclusion Neither the esophageal nor the stomach staging system is flawless in predicting survival in AEG type II. A marginal superiority of the TNM-EC was found in discriminating survival rates after three and five years. However, the advantage of the TNM-GC lies in the division of the N3 category into N3a and N3b. We therefor suggest a similar division in future TNM-EC classifications to improve its prognostic value.

// Karl-Frederick Karstens 1 , Eugen Bellon 1 , Adam Polonski 1 , Gerrit Wolters-Eisfeld 1 , Nathaniel Melling 1 , Matthias Reeh 1 , Jakob R. Izbicki 1 and Michael Tachezy 1 1 Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg Eppendor, Hamburg, Germany Correspondence to: Karl-Frederick Karstens, email: k.karstens@uke.de Keywords: neural cell adhesion molecule L1-like protein (CHL1); gastrointestinal stroma tumor (GIST); survival; prognosis; serum Received: December 31, 2019 Accepted: March 03, 2020 Published: March 31, 2020 ABSTRACT Introduction: Diagnosis of gastrointestinal stroma tumors (GIST) is based on the histological evaluation of tissue specimens. Reliable systemic biomarkers are lacking. We investigated the local expression of the neural cell adhesion molecule L1-like protein (CHL1) in GIST and determined whether soluble CHL1 proteoforms could serve as systemic biomarkers. Material and Methods: Expression of CHL1 was analyzed in primary tumor specimens and metastases. 58 GIST specimens were immunohistochemically stained for CHL1 on a tissue microarray (TMA). Systemic CHL1 levels were measured in sera derived from 102 GIST patients and 91 healthy controls by ELISA. Results were statistically correlated with clinicopathological parameters. Results: CHL1 expression was detected in GIST specimens. Reduced tissue expression was significantly associated with advanced UICC stages ( p = 0.036) and unfavorable tumor localization ( p = 0.001). CHL1 serum levels are significantly elevated in GIST patients ( p < 0.010). Elevated CHL1 levels were significantly associated with larger tumors ( p = 0.023), advanced UICC stage ( p = 0.021), and an increased Fletcher score ( p = 0.041). Moreover, patients with a higher CHL1 serum levels displayed a significantly shortened recurrence free survival independent of other clinicopathological variables. Conclusion: Local CHL1 expression and serum CHL1 levels show a reverse prognostic behavior, highlighting the relevance of proteolytic shedding of the molecule. The results of the study indicate a potential role of serum CHL1 as a diagnostic and prognostic marker in GIST.

The p16 tumor suppressor is coded by CDKN2A (9p21) and plays an important role during carcinogenesis and tumor progression in numerous tumor entities. The aim of our study was to evaluate the prognostic role of p16 expression and CDKN2A deletion in esophageal cancer (EC). Therefore, we analyzed p16 and KI67 expression by immunohistochemistry and 9p21 deletion by fluorescence in-situ hybridization on a tissue microarray including 398 adenocarcinomas (AC) and 293 squamous cell carcinomas (SCC) with clinical follow up-data. p16 positivity was found in 30.2% of AC and 13.9% of SCC and CDKN2A deletion in 32.1% of AC and 33.5% of SCC. In SCC p16 immunostaining correlated with low tumor stage (P = 0.014). In AC Ki67 positivity was associated with high tumor stage (P = 0.001), presence of lymph node metastasis (P = 0.009), high UICC stage (P = 0.001) and poor grading (P = 0.005). Overall survival (OS) was shorter for patients with high Ki67 labeling index (Ki67LI; P = 0.009) and negative p16 immunostaining (P = 0.026). In both histological tumor types, CDKN2A deletion showed no association with phenotype or outcome. Proportional cox-regression modeling revealed patients’ age, tumor stage, lymph node metastasis and Ki67 labeling index as independent prognostic markers in AC. In SCC, only patients’ age and tumor stage proved to be independent prognosticators. In summary, our study shows that loss of p16 expression and high Ki67LI is linked to shortened OS in AC. CDKN2A deletion shows no relevant association with tumor phenotype and patient outcome.

Anastomotic or stump leakage is a common and serious complication of colorectal surgery. The objective of this study was to retrospectively investigate the clinical use and potential benefit of transanal rinsing treatment (TRT) using an innovative rinsing catheter (RC) after treatment with endoscopic vacuum therapy (EVT). Patients with leakage after low colorectal surgery who had been treated with EVT were retrospectively analyzed. A subset of patients was trained to perform TRT with a specially developed RC. We investigated the rate of complete healing of the leakage, septic complications, failure of the therapy, surgical revisions, ostomy closure rate, and complications related to endoscopic therapy. Between February 2007 and January 2014, 98 patients with local complications after low colorectal surgery, treated with EVT, were identified. Eighty-nine patients were analyzed (the treatment of nine patients was stopped due to medical or technical problems): 31 patients were treated with EVT only (EVT group) and 58 patients with EVT followed by TRT (EVT/TRT group). Complete healing of the leakage was significantly better in the EVT/TRT group [84% vs. 58% (p < 0.009)], and significantly fewer septic complications needing surgical revision were detected [3% vs. 11% (p = 0.001)]. No significant differences regarding endoscopy-related complications and ostomy closure were found between EVT and EVT/TRT patients. The use of patient-administered TRT with an innovative, customized RC after EVT is technically feasible and reliable and significantly improves therapeutic results. Further prospective trials with larger patient groups are needed to validate the results of our study.

IntroductionThe role of CD147 as an important indicator of tumor prognosis remains controversially discussed in literature. We focused on the prognostic significance of CD147 expression in esophageal cancer patients. While some studies report that CD147 is an unfavorable prognostic factor in esophageal squamous cell carcinoma, others showed no significant correlation. However, only one study draws attention to the significance of CD147 in esophageal adenocarcinoma, which is one of the most rapidly increasing neoplasms in the western world.MethodsTo finally clarify the impact of CD147 as a prognostic factor, especially for esophageal adenocarcinomas, we analyzed CD147 expression in a tissue microarray of 359 esophageal adenocarcinomas and 254 esophageal squamous cell cancer specimens. For the immuno-histochemical analysis, we used a primary antibody specific for CD147. Staining intensity and proportion of positive tumor cells were scored (negative, weak, moderate, strong staining). These findings were compared to normal esophageal tissue and correlated to the histopathological tumor phenotype and survival data.ResultsCD147 expression was detectable in weak intensities in benign esophageal tissue (85.78%) and expressed in predominately moderate to strong intensities in esophageal cancer (88.34%). Strong CD147 immunostaining was linked to increased infiltration depth (p = 0.015) and differentiation (p = 0.016) in esophageal squamous cell cancer but revealed no significant correlation with histopathology of adenocarcinoma. Moreover, CD147 intensity was unrelated to overall survival in this collective for both subtypes of esophageal cancer.ConclusionThus, our data show that CD147 has no prognostic value, neither in esophageal adenocarcinoma nor squamous cell carcinoma.

Patients with paraplegia develop syndrome-specific complications relevant to visceral surgery, which occur in the context of the acute spinal shock or as a consequence of the progressive neurogenic bowel dysfunction (NBD) with the formation of an elongated colon and/or megacolon. Moreover, acute abdominal emergencies, such as acute appendicitis, cholecystitis, diverticulitis and ileus images, pose particular challenges for the clinician when the clinical signs are atypical or even absent. The expansion of indications for obesity surgery to include patients with a paraplegic syndrome, whose independence and quality of life can be impaired due to the restricted mobility, especially by obesity, is becoming increasingly more important.This article provides an overview of the special requirements and aspects in the treatment of this special patient collective and to show the evidence of paraplegia-specific visceral surgery treatment.Targeted literature search in Medline and Cochrane library (German and English, 1985-2020).The clinical treatment of paraplegic patients requires in-depth knowledge of the pathophysiological changes at the different height of the paraplegia (upper versus lower motor neuron) and the phase of the disease (spinal shock versus long-term course). Missing or atypical clinical symptoms of acute diseases delay a quick diagnosis and make early diagnosis essential. The evidence for surgical treatment of the acute and chronic consequences of NBD is based on small retrospective series and case reports, as is that for special indications such as obesity surgery.HINTERGRUND: Patienten mit einer Querschnittlähmung entwickeln syndromspezifische, viszeralchirurgisch relevante Krankheitsbilder, die im Rahmen des akuten spinalen Schocks auftreten können oder Folge der zumeist progredienten neurogenen Darmfunktionsstörung (NBD) mit Ausbildung eines Colon elongatum und/oder Megakolons sind. Auch die akuten abdominalchirurgischen Notfälle, wie akute Appendizitis, Cholezystitis, Divertikultis oder Ileusbilder, stellen den Kliniker bei untypischer oder teils fehlender Klinik vor diagnostische und therapeutische Herausforderungen. Einen zunehmenden Stellenwert nimmt die Ausweitung adipositaschirurgischer Indikationen auf Patienten mit einer Querschnittlähmung ein ZIEL DER ARBEIT: Dieser Artikel soll einen Überblick über die speziellen Anforderungen und Aspekte in der Behandlung dieses speziellen Patientenkollektivs geben und die Evidenz querschnittspezifischer viszeralchirurgischer Behandlungen aufzeigen.Es wurde eine selektive Literaturrecherche in den Datenbanken Medline und Cochrane Library in deutscher und englischer Sprache (1985–2020) durchgeführt.Die klinische Behandlung querschnittgelähmter Patienten erfordert einen profunden Kenntnisstand über die pathophysiologischen Veränderungen bei unterschiedlicher Querschnitthöhe (oberes vs. unteres motorisches Neuron) und die Phasen der Erkrankung (spinaler Schock vs. Langzeitverlauf). Fehlende oder atypische klinische Symptome akuter Erkrankungen verzögern eine rasche Diagnosefindung und machen eine frühzeitige Durchführung gezielter Diagnostik unabdingbar. Die Evidenz der chirurgischen Behandlung der akuten und chronischen Folgen der NBD ist gering und basiert auf Fallserien und „case reports“ ebenso wie die für spezielle Indikationen wie adipositaschirurgische Eingriffe.

Ein Erratum zu dieser Publikation wurde veröffentlicht: 10.1007/s00104-021-01364-2

Pancreatic cancer presents with a dismal mortality rate and is in urgent need of methods for early detection with potential for timely intervention. All living cells, including cancer cells, generate exosomes. We previously discovered double stranded genomic DNA in exosomes derived from the circulation of pancreatic cancer patients, which enabled the detection of prevalent mutations associated with the disease. Here, we report a proof-of-concept study that demonstrates the potential clinical utility of circulating exosomal DNA for identification of KRASG12D and TP53R273H mutations in patients with pancreas-associated pathologies, including pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP) and intraductal papillary mucinous neoplasm (IPMN), and in healthy human subjects. In 48 clinically annotated serum samples from PDAC patients, digital PCR analyses of exosomal DNA identified KRASG12D mutation in 39.6% of cases, and TP53R273H mutation in 4.2% of cases. KRASG12D and TP53R273H mutations were also detected in exosomal DNA from IPMN patients (2 out of 7 with KRASG12D, one of which also co-presented with TP53R273H mutation). Circulating exosomal DNA in 5 out of 9 CP patients enabled the detection of KRASG12D mutation. In 114 healthy subject-derived circulating exosomal DNA, 2.6% presented with KRASG12D mutation and none with TP53R273H mutation. This study highlights the value of circulating exosomal DNA for a rapid, low-cost identification of cancer driving mutations. The identification of mutations in IPMN patients and healthy subjects suggests that liquid biopsies may allow potential assessment of cancer risk but with a cautionary note that detection of clinical cancer cannot be assumed.

The cell adhesion molecule close homologue of L1 (CHL1) is a potential tumour suppressor and was recently detected in non-small cell lung cancer (NSCLC) specimens. The expression pattern, prognostic, and functional role of CHL1 in NSCLCs is unknown. We evaluated the protein expression of CHL1 by immunohistochemistry in 2161 NSCLC patients based on a tissue microarray. The results were correlated with clinical, histopathological, and patient survival data (Chi square test, t test, and log-rank test, respectively). A multivariate analysis (Cox regression) was performed to validate its impact on patients’ survival. CHL1 was expressed in NSCLC patients and was significantly overexpressed in lung adenocarcinomas and squamous cell carcinomas compared to neuroendocrine and large cell carcinomas of the lung (p

Purpose: Esophageal perforations are associated with high morbidity and mortality. Different nonoperative and operative treatment options have been proposed. This study focuses on the impact of different surgical treatments in nonmalignant esophageal perforations and tries to identify predictors of mortality in a single tertiary center over a 15-year period. Methods: From 2002 to 2017, patients with surgically managed esophageal perforation were identified from our database. Patients with esophageal malignancies were excluded. Etiology, clinical data, treatment, and outcome were analyzed. A multivariate logistic regression analysis was performed to investigate the impact on mortality. Results: A total of 72 patients were identified. The majority of perforations were iatrogenic (54.2%) followed by Boerhaave’s syndrome (23.6%). Most ruptures were found in the distal third of the esophagus (59.7%) measuring p < 0.0001) and mortality (p = 0.032). A correlation between an increasing perforation length with sepsis (p = 0.012) was observed. A higher Perforation Severity Score (PSS; OR 4.430; 95% CI 1.143–17.174; p = 0.031) and a higher American Society of Anesthesiologists (ASA) score (OR 2.923; 95% CI 1.011–8.448; p = 0.048) were associated with mortality in multivariate analysis. Conclusion: Esophageal perforations are associated with high mortality, and larger ruptures are associated with worse outcome. Rapid diagnosis and treatment are crucial for patient survival. Hence, PSS and ASA score help to identify high-risk patients. The advantage of surgical management lies in the rapid control of the septic focus in an already critically ill patient. Though, the kind of surgical technique needs to be adjusted to the individual situation.

Background Systemic inflammation is a key factor in tumor growth. C-reactive protein and albumin are parameters of systemic inflammation from the Glasgow Prognostic Score (GPS). The purpose was to evaluate the prognostic role of GPS in a homogeneous population of gastric cancer patients undergoing surgical treatment only. Methods Patients underwent operations between 2009 and 2014. Those who had received perioperative treatment or had other malignancies or inflammatory diseases were excluded. Eighty-eight patients met all inclusion criteria (age >18 years, documented preoperative serum levels of albumin and C-reactive protein, histologically proven gastric cancer, curative operation, including lymphadenectomy). C-reactive protein and albumin levels were retrieved from our prospective database. GPS was correlated with clinicopathologic characteristics and outcome. Results Increasing GPS was linked to aggressive tumor biology in terms of tumor size (GPS 0: 51.2% T1 and T2, 48.8% T3 and T4; GPS 1: 23.8% T1 and T2, 76.2% T3 and T4; GPS 2: 23.1% T1 and T2, 76.9% T3 and T4; P = .026), synchronous distant metastases (GPS 0: 47.1% M0, 0.0% M1; GPS 1: 25.9% M0, 0.0% M1; GPS 2: 27.1% M0, 100.0% M1; P = .030), venous vessel invasion (GPS 0: 91.2% V0, 8.8% V1; GPS 1: 66.7% V0, 33.3% V1; GPS 2: 55.0% V0, 45.0% V1; P = .008), resection margin status (GPS 0: 97.4% R0, 2.6% R1; GPS 1: 90.0% R0, 10.0% R1; GPS 2: 77.3% R0, 22.7% R1; P = .044), reduced overall survival (GPS 0: median 25.2 months [range 0.4–106.0]; GPS 1: 15.3 [0.2–59.5]; GPS 2: 5.8 [0.1–55.3]; P = .016) with median overall survival in the whole cohort being 16.2 months (range 0.1–106.0) and perioperative mortality (GPS 0: 0.0% of perioperative deaths, GPS 1: 20.0%, GPS 2: 80.0%; P = .036). Furthermore, GPS was identified as an independent prognosticator of overall survival (P = .033). A gradual decrease in survival between GPS subgroups was evident. Conclusion GPS represents an independent prognostic factor for long-term outcome in resected gastric cancer patients without perioperative treatment and is strongly associated with perioperative mortality.

Introduction Reflux promotes esophageal adenocarcinomas (EAC) creating a chronic inflammatory environment. EAC show an increasing incidence in the Western World and median survival rates are still low. The main reasons for poor prognosis despite new multimodal therapies are diagnosis of EACs at an already advanced stage and distant metastases. Hence, we wanted to investigate the presence of systemic inflammatory interleukins (IL) and their impact on patient prognosis. Material and methods Systemic expression levels of pro- and anti-inflammatory markers (IL-2, IL-4, IL-6, IL-10, IL-17A and IL-22) in the sera of 43 EAC patients without neoadjuvant radiochemotherapy were measured by flow cytometric analysis. A correlation to clinicopathological data was performed. Log-rank and Cox regression analysis were used to investigate the impact on patient survival. 43 sera of age and gender matched healthy volunteers were used as controls. Results Increased systemic IL-6 (p = 0.044) and lower IL-17A (p = 0.002) levels were found in EAC patients as opposed to controls. A correlation of IL-10 levels with an increased T stage was found (p = 0.020). Also, systemic IL-10 levels were highly elevated in patients with distant metastasis (p

Immunohistochemistry studies on p53 inactivation in esophageal cancer are available with inconclusive results. Data on the combined effect of p53 protein accumulation and TP53 genomic deactivation in large scale studies for esophageal cancer are currently lacking. A tissue microarray with 691 esophageal cancer samples was analyzed by p53 immunohistochemistry and fluorescence in situ hybridization (FISH). Nuclear p53 accumulation was observed in 45.9% of patients with adenocarcinoma (AC) and in 40.0% in squamous cell carcinoma (SCC). Heterozygous TP53 deletions occurred in 40.9% in AC and in 19.4% in SCC. Homozygous deletions did not occur at all. High-level p53 immunostaining was associated with shortened overall survival in AC and SCC while TP53 deletions alone showed no correlation with survival. High-level p53 immunostaining in patients with AC was associated with advanced tumor (P=0.019) and Union for International Cancer Control stages (P=0.004), grading (P=0.027) and the resection margin status (P=0.006). Associations between p53 immunostaining and SCC were not found. TP53 deletions were found to be associated with advanced tumor stages (P=0.028) and the presence of lymph node metastasis (P=0.009) in SCC. In conclusion, strong p53 immunostaining, but not TP53 deletion alone, is associated with unfavorable outcomes and may therefore represent a clinically useful molecular marker in esophageal cancer.

Purpose: Pancreatic cancer is one of the most devastating diseases with a 5-year survival rate of 3% to 5%. Here, we investigated whether circulating tumor cells (CTC) may predict metastatic spread and survival in pancreatic cancer patients. Experimental Design: In a prospective study, we enrolled 69 pancreatic cancer patients. In peripheral blood, CTCs were identified by MACS enrichment (anti-cytokeratin/anti-EpCam) and subsequent automated analysis after combined anti-cytokeratin/anti-CD45/DAPI staining. CTC results were correlated to established clinicopathologic risk factors, detection of disseminated tumor cells (DTC) in bone marrow, and clinical outcome (follow-up time: 48 months). Results: Median patient survival was 11 months (0–48 months). Thirty-eight patients were male and 31 were female, and the majority received gemcitabine (58/69). CTCs were present in 23 of 69 patients (33.3%) ranging from 1 to 19 cells (17 with >1 CTC). Although clinicopathologic parameters and DTC status did not correlate with CTC incidence, progression-free survival (PFS) and overall survival (OS) were significantly reduced in CTC-positive patients in univariate (P = 0.009, PFS; P = 0.030, OS, both log rank) and multivariate analysis [HR = 4.543; confidence interval (CI), 1.549–13.329; P = 0.006, PFS; HR = 2.093; CI, 1.081–4.050; P = 0.028, OS, both Cox regression). Also within patients receiving chemotherapy, PFS was significantly reduced in CTC-positive patients in univariate (P = 0.013) and multivariate (HR = 4.203; CI, 1.416–12.471; P = 0.010) analysis. Conclusions: CTCs affect the outcome of patients with pancreatic cancer independent from other risk factors, including patients receiving (adjuvant) cytotoxic therapy. CTC stratification may allow a better upfront identification of patients with a longer lifespan who might profit from new adjuvant therapies. Clin Cancer Res; 24(12); 2844–50. ©2018 AACR.

Hintergrund Die Appendektomie ist die haufigste, nicht elektive Operation in der Allgemeinchirurgie. Trotz des fraglichen Nutzens werden die laborchemischen Entzundungsparameter vor, aber auch nach der Appendektomie haufig bestimmt. So stellt sich regelhaft die Frage, ob Patienten trotz Zunahme der Leukozyten oder des C-reaktiven Proteins im Serum (CRP) entlassen werden konnen.

Purpose: The ABO gene locus is associated with the risk of developing pancreatic ductal adenocarcinoma (PDAC) resulting in an increased incidence in individuals with non-O blood groups. Up to 90% of PDAC specimens display alterations in mucin type O-GalNAc glycosylation. Because aberrant O-GalNAc glycans (Tn and T antigen) are structurally related to blood group A and B glycans, we investigated the role of IgM isoagglutinins in PDAC. Experimental Design: Binding studies of IgM isoagglutinins toward blood group A, B, Tn antigen, and T antigen glycoconjugates from patients with PDAC and healthy individuals were conducted. Isoagglutinin titers and total IgM were compared between patients with PDAC and control group. An anti-A antibody was used for immunoprecipitation of aberrant O-glycosylated tumor proteins and subsequent mass spectromic analysis. Results: We found that IgM isoagglutinins bind blood group antigens, Tn and T glycoconjugates as well as tumor-derived glycoproteins. Blood group A isoagglutinins exhibited a strong binding toward blood group B antigen and T antigen, whereas blood group B showed binding to blood group A antigen and Tn antigen. Furthermore, we confirmed a decreased frequency in individuals with blood group O and observed a significant decrease of IgM isoagglutinin titers in PDAC sera compared with control sera, whereas total IgM levels were unaltered. We identified new PDAC-derived O-GalNAc glycoproteins by mass spectrometry using a blood group A-specific antibody. Conclusion: Our data elucidated a novel interaction of blood group IgM isoagglutinins and PDAC O-GalNAc glycoproteins that may contribute to the pathogenesis and progression of pancreatic cancer. Clin Cancer Res; 20(23); 6117–26. ©2014 AACR .

Recently, the activated leukocyte cell adhesion molecule (CD166) was identified as an “inert” cancer stem cell (CSC) marker for non-small cell lung cancer (NSCLC). Few data exist regarding the clinical relevance of CD166 expression in NSCLC. We evaluated the expression of CD166 using immunohistochemistry in a large cohort of NSCLC patients (n = 1,910) on a tissue microarray basis. Expression was inversely associated with tumor size and lymph node status. Grading slightly failed to be significantly inversely associated, and survival analysis revealed no significant survival benefit of CD166-positive patients. Due to the results of this study, the theory of CD166 as a CSC marker for NSCLC must be questioned. The association of CD166 with smaller tumors and no nodal metastases does not make it a typical CSC marker. Further studies are required to investigate the functional role of CD166 in NSCLC. Stem Cells 2014;32:1429–1436

Pancreatic cancer is still one of the most aggressive oncological diseases with a 5-year mortality rate below 10%. Surgery remains the only curative treatment; however, most patients present with late-stage disease deemed unresectable, either due to extensive local vascular involvement or the presence of distant metastasis. In the detection of hepatic metastases, the current standard is palliative chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) or nab-paclitaxel with gemcitabine. Once hepatic metastases are diagnosed, the guidelines do not recommend resection of the primary tumor. Recent findings suggest that some patients with non-resectable diseases initially have survival rates as good as those with initially resectable disease when they are able to undergo surgical resection. Synchronous resection of both the primary tumour as well as the liver metastases may be beneficial and improves the outcome.

Non-small lung cancer is the leading cause of cancer-related mortality worldwide. For a deeper understanding of tumor biology, we established a pair of cell lines derived from a primary tumor and a corresponding lymph node metastasis.The cell line BC4323 from the primary tumor (PT) and a mediastinal lymph node metastasis (LN) were derived from an adenocarcinoma (pT2, pN2, G3, UICC stage IIIa) in a 47-year-old female patient. Comparative characterization was performed by in vitro analysis. A murine xenograft was established for analysis of in vivo behavior.Chromosomal aberrations were detected in multiple chromosomal sections throughout the entire genome, with only a few differences between PT and LN cells. High-level Kirsten ras oncogene homolog (KRAS) mutation and amplification were seen based on a chromosomal translocation and novel assembled chromosome. In contrast to the genomic level, at the mRNA and protein levels, multiple differences were detectable, in particular in markers for cell adhesion [e.g. epithelial cell adhesion molecule (EpCAM), CD44, P-selectin binding, epidermal growth factor receptor (EGFR) and integrin alphaV] and the epithelial-mesenchymal transition. Due to accelerated tumor growth in vivo by the PT cells, a shortened overall survival was seen (60 vs. 101 days, p=0.005).We provide detailed analysis of a cell line derived from a primary tumor and a corresponding LN metastasis. This unique feature allows further investigative analysis of the differences and regulatory processes underlying the metastatic process during tumor progression in non-small cell lung cancer.

Background The activated leukocyte cell adhesion molecule (ALCAM, CD166) has been reported to be involved in tumorigenesis of colorectal cancer (CRC) and to function as a cancer stem cell marker. Controversial data exist regarding the prognostic power of ALCAM expression in CRC. Here, we evaluate the expression of ALCAM in a cohort of CRC patients and its usage as a prognostic marker for survival. Materials and methods Tissue specimens from 299 patients with CRC treated between 1993 and 2006 were analyzed via ALCAM immunohistochemistry (clone MOG/07) using a tissue microarray. Results were correlated with clinical, histopathological, and patient survival data (Chi-square test, Kaplan–Meier analysis, and log-rank test, respectively). Multivariate analysis also was performed (Cox regression). Results ALCAM is expressed in most primary (76%) and secondary (62%) CRC lesions ( P = 0.014). Immunohistochemistry revealed an inverse association with tumor grading ( P = 0.002) but not with any other clinical or histopathological data. Kaplan–Meier survival analysis revealed a significant overall survival benefit in the group of ALCAM-positive patients ( P = 0.019). Multivariate analysis showed that ALCAM is an independent positive prognostic marker for overall survival ( P = 0.023). Conclusions ALCAM expression is a positive prognostic marker for overall survival of CRC patients, and its detection might help to optimize the existing prognostic staging system. Elevated expression in higher differentiated tumors might indicate a potential role in the early steps of tumorigenesis, and its loss might be associated with reduced cellular adhesion, resulting in a higher metastatic potential of the tumor. Further studies must be conducted investigating these hypotheses.