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Pancreatic ductal adenocarcinoma (PDAC) is a disease with a poor prognosis. PDAC shows characteristic mutations within codon 12/13. Circulating tumor cells (CTC) detected in blood samples of patients with cancer are hypothesized as the means of systemic tumor spread. But less is known about morphological/molecular characteristics or the pathophysiological meaning of PDAC CTC.The aim of the study was a cytomorphological and genetic analysis of CTC from patients with PDAC followed by the correlation of the results with those of the corresponding tumor in the pancreas.Blood samples of 58 patients with PDAC and 10 "normal" control donors were processed through a size-based CTC isolation. KRAS-mutation analyses were performed for CTC and the primary tumor and the results were compared. Furthermore, their potential as a prognostic marker was evaluated.In patients with different UICC stages CTC were detected, but not in normal control patients. There was a trend for a worse median overall survival (OS) for patients with3 CTC/ml. Patients with a KRASDetection and characterization of CTC (for example by KRAS mutation analysis) may be useful for prognosis. Furthermore, it expands our knowledge of tumor biology and may detect possible tumor heterogeneity regarding the mutation profile of some cancer types.

A combination of platin-based perioperative chemotherapy (PBPC) plus surgical resection has become the standard of care in Europe for locally advanced esophagogastric adenocarcinoma (EGAC). In contrast to preoperative chemotherapy, the postoperative administration of chemotherapy is omitted in a high percentage of patients. We conducted this database study to analyse the impact of postoperative completion of perioperative chemotherapy on patient outcome.Patients with EGAC (cT3-4 and/or cN+) were treated with preoperative PBPC plus curative surgical resection. Patient demographics, postoperative tumour stages, histopathological regression (HPR) and administration of postoperative chemotherapy were correlated with overall survival.Of one-hundred-thirty-four patients, 76 received preoperative docetaxel, folinic acid, fluorouracil, oxaliplatin (FLOT), 53 patients epirubicin, cisplatin, folinic acid (ECF) and 5 epirubicin, oxaliplatin, capecitabine (EOX) chemotherapy. The 5-year-survival for the whole collective was 58%. Designated postoperative chemotherapy was omitted in 36% of the patients. 5-year-survival was 75.8% in patients who received pre- and post-operative chemotherapy and 40.3% in patients with only preoperative chemotherapy (p0.001). Histopathological regression, postoperative nodal status and administration of postoperative chemotherapy were identified as independent prognostic factors. Analysis of subgroups revealed a pronounced survival benefit after administration of postoperative chemotherapy in patients with ypN+ stages (5-year-survival 64.5% vs 9.7%, p = 0.002) and poor HPR (5-year-survival 55.5% vs 19.3%, p = 0.015).Our study provides further evidence that administration of postoperative chemotherapy may contribute to the achieved survival benefit of PBPC in patients with EGAC and implies a beneficial effect especially in presence of lymphonodular tumour involvement and limited HPR.

Isolation of circulating tumor cells (CTCs) holds the promise of diagnosing and molecular profiling cancers from a blood sample. Here, we test a simple new low-cost filtration device for CTC isolation in patients with pancreatic ductal adenocarcinoma (PDAC).Peripheral blood samples drawn from healthy donors and PDAC patients were filtered using ScreenCell devices, designed to capture CTCs for cytologic and molecular analysis. Giemsa-stained specimens were evaluated by a pancreatic cytopathologist blinded to the histological diagnosis. Circulating tumor cell DNA was subjected to KRAS mutational analysis.Spiking experiments demonstrated a CTC capture efficiency as low as 2 cells/mL of blood. Circulating tumor cells were identified by either malignant cytology or presence of KRAS mutation in 73% of 11 patients (P = 0.001). Circulating tumor cells were identified in 3 of 4 patients with early (≤American Joint Committee on Cancer stage IIB) and in 5 of 7 patients with advanced (≥ American Joint Committee on Cancer stage III) PDAC. No CTCs were detected in blood from 9 health donors.Circulating tumor cells can be found in most patients with PDAC of any stage, whether localized, locally advanced, or metastatic. The ability to capture, cytologically identify, and genetically analyze CTCs suggests a possible tool for the diagnosis and characterization of genetic alterations of PDAC.

Zusammenfassung Hintergrund In den vergangenen Jahrzehnten wurden verschiedene Varianten der Ösophagusresektion und Rekonstruktion für die kurative Therapie des Ösophaguskarzinoms beschrieben und technisch weiterentwickelt. Insbesondere die minimal-invasiven Verfahren kommen in den letzten Jahren zunehmend zum Einsatz. Die Arbeit stellt die Technik der laparoskopisch-thorakotomischen En-bloc-Ösophagusresektion mit intrathorakaler Ösophagogastrostomie als Hybridverfahren vor (HMIÖ). Patienten und Methoden Am Universitätsklinikum Freiburg wurde von Mai 2013 bis April 2014 bei 23 Patienten mit Ösophaguskarzinom eine Ösophagusresektion durchgeführt. Hiervon erfolgte der Eingriff bei 13 Patienten als offene Ösophagusresektion (OÖ) und bei 10 Patienten in HMIÖ-Technik. Ergebnisse Die Operationstechnik der HMIÖ wird detailliert in den einzelnen Operationsschritten beschrieben. Es konnte bei der HMIÖ eine R0-Resektionsrate von 100 % erreicht werden sowie eine mit der OÖ vergleichbare Lymphknotenzahl bei der Lymphadenektomie (Median 29 vs. 27). Operationsdauer (Median 347 vs. 412 min), Intensivaufenthalt (Median 6 vs. 9 Tage) und Krankenhausaufenthaltsdauer (Median 13 vs. 17 Tage) stellten sich bei der HMIÖ kürzer dar als bei der OÖ. Die postoperative Gesamtmorbidität (40 % vs. 69 %) und insbesondere die postoperative pulmonale Morbidität (10 % vs. 46 %) waren bei der HMIÖ verringert. Anastomoseninsuffizienzen und postoperative Mortalität traten bei der HMIÖ im eigenen Kollektiv nicht auf. Schlussfolgerung Die Technik der HMIÖ vereint Vorteile minimal-invasiver Zugänge auf die postoperative pulmonale Morbidität mit der Sicherheit einer konventionellen Rekonstruktion und Anastomose. Weitere Vorteile ergeben sich durch eine verringerte Operationsdauer und Krankenhausverweildauer.

Postpancreatectomy hemorrhage is a rare but often severe complication after pancreatic resection. The aim of this retrospective study was to define incidence and risk factors of postpancreatectomy hemorrhage and to evaluate treatment options and outcome. Clinical data was extracted from a prospectively maintained database. Descriptive statistics, univariate and multivariate risk factor analysis by binary logistic regression were performed with SPSS software at a significance level of p = 0.05. N = 1,082 patients with pancreatic resections between 1994 and 2012 were included. Interventional angiography was successful in about half of extraluminal bleeding. A total of 78 patients (7.2 %) had postpancreatectomy hemorrhage (PPH), and 29 (2.7 %) were grade C PPH. Multivariate modeling disclosed a learning effect, age, BMI, male sex, intraoperative transfusion, portal venous and multivisceral resection, pancreatic fistula and preoperative biliary drainage as independent predictors of severe postpancreatectomy hemorrhage. High-risk histopathology, age, transfusion, pancreatic fistula, postpancreatectomy hemorrhage and pancreatojejunostomy in pancreatoduodenectomies were independent predictors of mortality. Our study identifies clinically relevant risk factors for postpancreatectomy hemorrhage and mortality. Interventional treatment of extraluminal hemorrhage is successful in about half of the cases and if unsuccessful constitutes a valuable adjunct to operative hemostasis. Based on our observations, we propose a treatment scheme for PPH. Risk factor analysis suggests appropriate patient selection especially for extended resections and pancreatogastrostomy for reconstruction in pancreatoduodenectomy.

Einleitung: Das Pankreaskarzinom (PDAC) ist eine der todlichsten Krebserkrankungen uberhaupt. Sowohl fruh-diagnostische als auch therapeutische Verfahren fehlen. Beim Mammakarzinom werden zirkulierende Tumorzellen (CTCs) bereits erfolgreich zur erweiterten Diagnostik und als prognostische Marker eingesetzt. Beim PDAC ist die Bedeutung von CTCs bisher unklar. Ziel: Die Isolation und genetische Charakterisierung von CTCs bei Patienten mit PDAC sowie deren Evaluation als prognostischer Marker. Methodik: Blutproben von Patienten mit PDAC wurden vor Therapie auf das Vorhandensein von CTCs untersucht. Hierfur wurde die „isolation by size of epithelial cells“ (ISET) Methode eingesetzt. Parallel wurden Filter fur die zytologische und genetische Untersuchung verwendet. Das Zell-Lysat wurde mittels wild-typ KRAS PNA-Clamping PCR auf KRAS Mutationen untersucht und sequenziert. Die Ergebnisse wurden mit demografischen und klinischen Daten sowie dem Uberleben korreliert. Ergebnis: Bei 56 Patienten mit PDAC wurden Blutproben auf CTCs untersucht.10 Proben (17.9%) hatten weder eine KRAS Mutation noch ein positives zytologisches Ergebnis und waren CTC negativ, 46 Proben (82,1%) waren CTC positiv. Diese Proben hatten entweder maligne Zellen in der Zytologie (n = 9), oder eine KRAS Mutation (n = 21) in den CTCs oder beides (n = 16). CTCs wurden bei Patienten der UICC Stadien IIA-IV gefunden, nicht jedoch bei IA oder IB Tumoren. Sie waren nachweisbar sowohl bei lokalisiertem Tumor als auch bei Vorliegen von Metastasen. Das pure Vorhandensein von CTCs war dabei nicht signifikant mit dem medianen Uberleben korreliert (CTC negativ 9 vs. CTC positiv 10,5 Monate; p = 0,92). In den CTCs fanden sich verschiedene Typen von KRAS Mutationen. Patienten mit der Variante KRAS G12V (n = 14) zeigten ein besseres medianes Uberleben (24,5 Monate), als Patienten mit KRAS wild typ oder ohne detektierte CTC (n = 19; 8 Monate) oder andere KRAS Mutationen (n = 23; 10 Monate). Dies war jedoch nicht signifikant (p = 0,43). Fazit: CTCs konnen zuverlassig bei vielen Stadien des PDAC gefunden werden. Ihre klinische Bedeutung bleibt jedoch unklar – potenziell sind Subtypen der CTC oder bestimmte genetische Mutationen mit besserem Uberleben assoziiert. Weitere Studien – auch von Oberflachenmarkern – sind notwendig.

Die total-laparoskopische Gastrektomie beim Magenkarzinom ist eine anspruchsvolle Operation, die auch in Europa in spezialisierten Zentren zunehmend durchgefuhrt wird. Die laparoskopische Gastrektomie und die laparoskopische D2-Lymphadenektomie, aber vor allem die total-laparoskopische Rekonstruktion sind technisch anspruchsvolle operative Schritte, deren Technik international in verschiedenen Variationen, aber bisher nur wenig standardisiert durchgefuhrt wird. In dem vorgestellten Video zeigen wir die laparoskopische Technik der totalen Gastrektomie mit D2-Lymphadenektomie und Rekonstruktion mittels intrakorporaler Osophagojejunostomie als End-zu-Seit-Anastomose in zirkularer Staplertechnik. Die laparoskopische Operationstechnik der Gastrektomie, der D2-Lymphadenektomie und der total-laparoskopischen Rekonstruktion der Speisepassage werden detailliert beschrieben und in dem zugehorigen Video demonstriert.

Background: Fundamental experimental research into intestinal anastomotic healing in rodent models will gain increasing interest in the future. Methods: The aim of this study was to describe our 5-year experience with a standardized experimental setup of small and large bowel anastomoses in a rodent model and present a basic set of assessment tools investigating anastomotic healing. Anastomotic technique, perioperative complications such as anastomotic insufficiency (AI) and obstructive ileus were in the focus. Results: During different studies with varying study patterns, 167 rat small bowel anastomoses and 120 colonic anastomoses were performed. Overall mortality was 3.6% in small bowel and 2.5% in colonic anastomoses, AI occurred in 2.9 and 4%, respectively. A postoperative obstructive ileus was seen in 3/167 small bowel anastomoses and none in the colonic group. Conclusion: When performing experimental intestinal anastomoses in a standardized operative setting and critically considering special perioperative issues, the incidence of relevant complications can be maintained at an adequately low level.

In the past decades various techniques of esophagectomy for the curative treatment of esophageal cancer have been described. Especially minimally invasive techniques of esophagectomy have been used increasingly in the last decade. Technical issues and results of hybrid laparoscopic-thoracotomic en bloc esophagectomy with intrathoracic esophagogastric anastomosis (HMIE) are presented and discussed in the article.Between May 2013 and April 2014 a total of 23 patients underwent esophagectomy for esophageal cancer at the University of Freiburg Medical Center. Of these patients 10 were treated by HMIE and the other 13 patients had open esophagectomy (OE).A detailed description of the operative technique of HMIE is given in a step-by-step fashion. Margin negative resection was achieved in all patients after HMIE and OE and the median lymph node yield of lymphadenectomy in HMIE and OE (29 vs. 27) was nearly the same. The medium duration of the operation (347 min vs. 412 min) and median length of stay on the intensive care unit (6 days vs. 9 days) and hospital (13 days vs. 17 days) were decreased in HMIE patients compared to OE, respectively. Overall postoperative morbidity (40 % vs. 69 %) and especially pulmonary morbidity (10 % vs. 46 %) were also favorable in HMIE. No anastomotic leakage and postoperative in-hospital mortality occurred after HMIE.The HMIE procedure combines the advantages of minimally invasive operative approaches on especially postoperative pulmonary morbidity after esophagectomy with the high safety of anastomosis and reconstruction achieved in OE. Further advantages are shorter duration of operation and shorter length of hospital stay in HMIE.

Laparoscopic total gastrectomy for early and advanced gastric cancer is an exacting procedure which is increasingly performed in specialised institutions. Not only gastric resection and extended lymphadenectomy but especially the reconstruction by oesophagojejunostomy is a technically demanding and vulnerable operative step. In this article we present our laparoscopic technique of total gastrectomy with extended lymphadenectomy and complete intracorporal reconstruction by end-to-side circular stapled oesophagojejunostomy. The operative technique of the gastric resection, the extended lymphadenectomy and the reconstruction are described in detail in a step-by-step approach and demonstrated in a supplemental video.

Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by an aggressive biology and poor prognosis. Experimental evidence has suggested a role for the transcriptional repressor Zinc finger E-box binding homeobox 1 (ZEB1) in epithelial-mesenchymal transition, invasion, and metastasis in PDAC. ZEB1 expression has been observed in cancer cells as well as stromal fibroblasts. Our study aimed to evaluate the prognostic value of ZEB1 expression in PDAC tissue. Methods Patient baseline and follow-up data were extracted from a prospectively maintained database. After clinicopathologic re-review, serial sliced tissue slides were immunostained for ZEB1, E-cadherin, vimentin, and pan-cytokeratin. ZEB1 expression in cancer cells and adjacent stromal fibroblasts was graded separately and correlated to routine histopathologic parameters and survival after resection. Results A total of 117 cases of PDAC were included in the study. High ZEB1 expression in cancer cells and in stromal cancer-associated fibroblasts was associated with poor prognosis. There was also a trend for poor prognosis with a lymph node ratio of greater than 0.10. In line with its role as an inducer of epithelial-mesenchymal transition, ZEB1 expression in cancer cells was positively correlated with Vimentin expression and negatively with E-Cadherin expression. In multivariate analysis, stromal ZEB1 expression grade was the only independent factor of survival after resection. Conclusion Our data suggest that ZEB1 expression in cancer cells as well as in stromal fibroblasts are strong prognostic factors in PDAC. Stromal ZEB1 expression is identified for the first time as an independent predictor of survival after resection of PDAC. This observation suggests that therapies targeting ZEB1 and its downstream pathways could hit both cancer cells and supporting cancer-associated fibroblasts.

Supplemental Digital Content is available in the text, Pancreatic ductal adenocarcinoma (PDAC) is characterized by a strong fibrotic stromal reaction and diffuse growth pattern. Peritumoral fibrosis is often evident during surgery but only distinguishable from tumor by microscopic examination. The aim of this study was to investigate the role of clearance of fibrotic stromal reaction at the mesopancreatic resection margin as a criterion for radical resection and preoperative assessment of resectability. Mesopancreatic stromal clearance status (S-status) was defined as the presence or absence (S+/S0) of fibrotic stromal reaction at the mesopancreatic resection margin. Detailed retrospective clinicopathologic re-evaluation of margin status and preoperative cross-sectional imaging was performed in a cohort of 91 patients operated for pancreatic head PDAC from 2001 to 2011. Conventional margin positive resection (R+, tumor cells directly at the margin) was found in 36%. However, S-status further divided the margin negative (R0) group into patients with median survival of 14 months versus 31 months (S+ versus S0, P = 0.005). Overall rate of S+ was 53%. S-status and lymph node ratio constituted the only independent predictors of survival. Stranding of the superior mesenteric artery fat sheath was the only independent radiologic predictor of S+ resection, and achieved a 71% correct prediction of S-status. Mesopancreatic stromal clearance is a major determinant of curative resection in PDAC, and preoperative prediction by cross-sectional imaging is possible, setting the basis for a new definition of borderline resectability.

Developmental genes are known to regulate cell proliferation, migration, and differentiation; thus, it comes as no surprise that the misregulation of developmental genes plays an important role in the biology of human cancers. One such pathway that has received an increasing amount of attention for its function in carcinogenesis is the Hedgehog (Hh) pathway. Initially the domain of developmental biologists, the Hh pathway and one of its ligands, Sonic Hedgehog (Shh), have been shown to play an important role in body planning and organ development, particularly in the foregut endoderm. Their importance in human disease became known to cancer biologists when germline mutations that resulted in the unregulated activity of the Hh pathway were found to cause basal cell carcinoma and medulloblastoma. Since then, misexpression of the Hh pathway has been shown to play an important role in many other cancers, including those of the pancreas. In many institutions, investigators are targeting misexpression of the Hh pathway in clinical trials, but there is still much fundamental knowledge to be gained about this pathway that can shape its clinical utility. This review will outline the evolution of our understanding of this pathway as it relates to the pancreas, as well as how the Hh pathway came to be a high-priority target for treatment.

Cancer epithelial cells often migrate away from the primary tumor to invade into the surrounding tissues. Their migration is commonly assumed to be directed by pre-existent spatial gradients of chemokines and growth factors in the target tissues. Unexpectedly however, we found that the guided migration of epithelial cells is possible in vitro in the absence of pre-existent chemical gradients. We observed that both normal and cancer epithelial cells can migrate persistently and reach the exit along the shortest path from microscopic mazes filled with uniform concentrations of media. Using microscale engineering techniques and biophysical models, we uncovered a self-guidance strategy during which epithelial cells generate their own guiding cues under conditions of biochemical confinement. The self-guidance strategy depends on the balance between three interdependent processes: epidermal growth factor (EGF) uptake by the cells (U), the restricted transport of EGF through the structured microenvironment (T), and cell chemotaxis toward the resultant EGF gradients (C). The UTC self-guidance strategy can be perturbed by inhibition of signalling through EGF-receptors and appears to be independent from chemokine signalling. Better understanding of the UTC self-guidance strategy could eventually help devise new ways for modulating epithelial cell migration and delaying cancer cell invasion or accelerating wound healing.

A new therapeutic field is developing from bariatric surgery. Gastrointestinal surgery does not only seem to be a very efficacious method for weight reduction but may also have the potential to reduce obesity-related metabolic disorders. Even if there is still a lack of prospective randomized trials evaluating the correct indications for metabolic surgery in patients with type 2 diabetes mellitus, there is the legitimate expectation that the surgical approach can be successful. This article provides an overview of the current state of bariatric surgery and gives a surgical perspective on the treatment of type 2 diabetes mellitus.

A 23-year-old woman who 2 weeks before visiting our institution swallowed a plastic fork while attempting to induce vomiting during a party presented with progressive abdominal pain. Various techniques for removing foreign bodies from the intestinal tract have been described. We present the laparoscopic retrieval of a 15-cm fork from the duodenal bulb.The patient presented with leukocytosis and epigastric tenderness. An upper endoscopy revealed a plastic fork, tines up, perforating the duodenal bulb. The handle was irremovably lodged in the opposite part of the duodenum. Perforating objects and objects larger than 7 cm ought to be removed surgically to prevent esophageal perforation. The patient was placed in supine position with the surgeon standing between her legs. Four trocars, two 10-mm and two 5-mm, were used. We saw a slight swelling of the duodenum with few fibrin stripes and roughly 250 ml of white exudate. The fork tines were visible; there were no injuries to the liver. The tines were held with a clamp while the perforated intestinal wall was carefully dissected with a monopolar hug and later with an ACE harmonic scalpel due to bleeding. The fork was extracted in the proximal direction through the perforation injury. There was no severe necrosis and debridement was not necessary. The bowel was irrigated and continuously sutured with 3-0 PDS. Finally, the fork was retrieved through the 10-mm trocar incision.Operating time was 60 min and blood loss was roughly 100 ml. The patient's postoperative course was uneventful. One year after intervention, the patient is doing well.A fork may be swallowed, but usually does not spontaneously pass through the gastrointestinal tract. Early removal should be advised to avoid perforation and to minimize morbidity. Laparoscopic removal is a safe and feasible method of managing foreign bodies that are not removable endoscopically.

Introduction: When tumors are found to be adherent to the superior mesenteric or portal vein during pancreatoduodenectomy, en bloc portal venous resection (PVR) is an option to achieve complete tumor resection. It has also been reported that PVR without confirmed histopathologic portal venous infiltration (PVI) is associated with significantly better survival. The aim of this study was to evaluate oncologic outcome and prognostic factors in patients receiving PVR for pancreatic cancer. Methods: A unicenter retrospective study was performed on the basis of a prospectively maintained database. IBM SPSS Version 21 was used for all calculations with the significance level set to p=0.05. Results: From 2001 to 2013, 103 patients received pancreatoduodenectomy with PVR for pancreatic head cancer. Median survival in patients with PVR without PVI was 25 months, whereas confirmed PVI was associated with poor median survival of 14 months (p