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The mortality of acute mesenteric ischaemia has remained high for decades despite improvements in diagnostic, interventional, and surgical techniques. The time to diagnosis of acute mesenteric ischaemia is the most important modifiable predictor of the outcome of the patient. Hence, focus on the specific history and recognition of predisposing factors set the course for time-saving and efficient diagnosis. The initial clinical stage of acute mesenteric ischaemia is characterized by the sudden onset of severe abdominal pain followed by a painless interval. The symptoms of non-occlusive mesenteric ischaemia and intestinal venous thrombosis are different and less specific than those of acute arterial occlusive ischaemia. Biphasic contrast-enhanced computed tomography is the diagnostic tool of choice for diagnosis of arterial and venous occlusion. A central occlusion of the superior mesenteric artery or signs of peritonitis require immediate surgery. However, endovascular techniques for arterial occlusion have taken on a greater importance today. In case of a peripheral embolism in patients with no signs of peritonitis, interventional pharmacotherapy with local fibrinolytic agents should be conducted. The accompanying intensive care management includes volume replacement, systemic anticoagulation, and antibiotic therapy, as well as close patient monitoring to exclude secondary organ failure.

Introduction: Acute mesenteric ischemia (AMI), either arterial or venous, is still a devastating disease with poor prognosis. It is unknown, whether AMI is associated with impaired quality of life (QoL) in long-term survivors. Material and Methods: This retrospective analysis includes 64 patients with occlusive arterial or venous mesenteric ischemia treated operatively between 2008 and 2016 at the University Medical Center Rostock. Short-term outcome with focus on comorbidities was measured by the Charlson comorbidity index (CCI) an instrument that operationally measures comorbidity based on 17 clinical parameters including age. Operative outcome in view of enterostomy placement and long-term outcome measured as QoL by the EQ-5D in the long-term survivors were evaluated. The EQ-5D is a standardized, self-reported five-dimension QoL questionnaire built to provide a simple and generic measure of health. Results: Thirty-day mortality was 60.9%, and in-hospital mortality was 70.3% (n = 45). No patient was discharged with a stoma. Patients with a primary anastomosis after the initial operation for AMI had a high leak rate of 27% (4/15 patients) compared to no dehiscence in the group of patients who had secondary anastomosis during second or third laparotomy. The long-term survivors had significantly lower CCI compared to the 45 nonsurvivors (median 4 [3, 4, 5, 6] vs. 6 [4, 5, 6, 7]). All long-term survivors had QoL assessment. QoL score was significantly impaired compared to an age- and sex-matched reference population. This impairment was not due to disease-specific sequelae such as presence of stool deviation or intestinal failure but due to preexisting risk factors as shown by an inverse relation between the CCI and QoL score. Conclusion: Herein, we show for the first time that long-term QoL in patients with AMI is impaired but this impairment is not due to disease-specific aspects but rather general risk factors underlying the presence of a higher level of comorbidities at the time of AMI.

INTRODUCTION: Neointima formation is closely linked to vascular stenosis and occurs after endothelial damage. Hydrogen sulfide is an endogenous pleiotropic mediator with numerous positive effects on the cardio vascular system. OBJECTIVE: This study evaluates the effect of the slow releasing hydrogen sulfide donor GYY4137 (GYY) on neointimal formation in vivo. METHODS: The effect of GYY on neointimal formation in the carotid artery was studied in the FeCl3 injury model in GYY- or vehicle-treated mice. The carotid arteries were studied at days 7 and 21 after treatment by means of histology and immunohistochemistry for proliferating cell nuclear antigen (PCNA) and alpha smooth muscle actin (α-SMA). RESULTS: GYY treatment significantly reduced the maximal diameter and the area of the newly formed neointima on both days 7 and 21 when compared to vehicle treatment. GYY additionally reduced the number of PCNA- and α-SMA-positive cells within the neointima on day 21 after FeCl3 injury of the carotid artery. CONCLUSIONS: Summarizing, single treatment with the slow releasing hydrogen sulfide donor GYY reduced the extent of the newly formed neointima by affecting the cellular proliferation at the site of vascular injury.

The European Parliament and the European Council on May 26, 2017 decided to introduce the new regulatory framework for medical devices. The transitional period of the so called Medical Device Regulation (EU 2017/745, MDR) should end on May 26, 2020. Currently the European Commission is working on a proposal to postpone the application for one year to relieve pressure from all stakeholders allowing them to fully focus on priorities related to the coronavirus crisis. From this date or most likely from May 26, 2021, manufacturers must present a CE-certificate according to the new MDR requirements not only for novel medical devices, but also for approved medical devices which are already on the market. The MDR will significantly complicate the process of bringing medical devices into market due to the increased requirements for the CE-certification process, particularly concerning increased documentation effort. This involves a risk for the translation of innovative products due to an overload of the overall system (manufacturers, Notified Bodies, experts) and might lead to shrinkage of the product range of existing products. Thankfully, adaption of transitional periods, special regulations, extensions of deadlines and most probably postponement of the MDR application date will ensure that there will be no gaps in medical supply that endanger patients. Establishing and keeping the relevant regulatory expertise up to date and devoting the necessary financial, time and human resources that is the biggest immediate challenge the medium-sized medical technology sector is facing in the near future. The current article, written about one month before the initially expected end of the first transition period on May 26, 2020, summarized the main aspects of the current state of MDR implementation with respect to regulatory novelties, the current legal basis in Germany, transition periods and changes in the requirements of CE-certification relevant technical documentation. Furthermore, challenges for existing and innovative medical devices were shortly discussed using a new stent based therapy of the proximal Fallopian tubal stenosis and transcatheter aortic valve implantation as two examples.

Background Anastomotic leakage after rectal resection represents a severe complication for the patient and requires an early and appropriate management. Endoscopic vacuum therapy (EVT) has become the treatment of choice for anastomotic leakage after rectal resection in several institutions in Germany, and commercially available systems are currently distributed in approximately 30 countries worldwide. However, there is no evidence that EVT is superior to any other treatment for anastomotic leakage after rectal resection. Methods Twenty-one patients treated with EVT for anastomotic leakage after rectal resection were retrospectively compared to a historical cohort of 41 patients that received conventional treatment. Primary endpoints were death, treatment success and long-term preservation of intestinal continuity. Secondary endpoints were length of hospital stay and duration of treatment. Results There was no difference in mortality (p = 0.624). The intention-to-treat analysis showed a significantly higher success rate of EVT compared to conventional treatment (95.2% vs. 65.9%, p = 0.011). EVT was associated with preservation of intestinal continuity in a significant higher percentage of patients than patients undergoing conventional treatment (86.7% vs. 37.5%, p = 0.001). Conventional treatment tended to a shorter length of hospital stay (31.1 vs. 42.2 days, p = 0.066) but with no difference in overall duration of treatment. Time until closing of a diverting stoma did not differ between groups (10.2 months in the EVT group vs. 9.4 months in the conventional treatment group, p = 0.721). Conclusion According to this retrospective study, conventional therapy and EVT are both options for the treatment of anastomotic leakage after rectal resection. EVT might be more effective in terms of definite healing and preservation of intestinal continuity.

Background: Component separation (CS) for tension-free approximation of fascial edges is the established technique for the repair of large ventral hernias mostly regarding midline defects. Recent studies suggest lower complication rates following a modified version of this technique using a partially endoscopic-assisted approach, whereas little is known about the quality of life (QoL) in the long-term evaluation of these patients. Methods: A retrospective study and analysis of patients undergoing hernia repair using an open CS (OCS) and endoscopically assisted CS (ECS) technique, respectively, from 2011 to 2016 at the Rostock University Medical Center. Patients underwent a mesh-based sublay reinforcement following a distinct CS with closure of the linea alba. Patient characteristics, technical details, and short-term postoperative outcomes were determined by a physician chart review. A health-related QoL survey (EQ-5D) including a pain assessment was evaluated at a median of 19.5 months postoperatively. Results: Thirty-five patients had a CS: 25 OCS and 10 ECS. Perioperative variables were comparable except for the median defect size (169 cm2 OCS vs. 86 cm2 ECS; p < 0.05) and maximum width of hernia (25 vs. 13 cm). Hospitalization lasted 16.6 days in the OCS group and 7.9 days in the endoscopic group (p = 0.04). Wound complications occurred in 24% of OCS and 10% of ECS patients. Conclusions: Patients in the ECS group had a shorter hospital stay and less minor and major wound complications. These advantages led to a faster recovery directly affecting the QoL in the ECS group. This effect diminishes in the long-term follow-up with a positive trend towards the OCS technique.

Introduction The constant increase in life expectancy for over 170 years is one of the biggest achievements of modern society. In Germany the probability of an 80-year-old person becoming 100 years old has increased by a factor of 20 since the 1950s. This fact has various implications for the clinical routine and therapeutic guidelines. In addition to the quantitative factors (e.g. complications, recurrence rate), the quality of life (QoL) as a patient-centered subjective factor should be taken into consideration in the treatment options for hernia repair. To compare heterogeneous cohorts of patients regarding the QoL, a standardization based on representative reference values is absolutely essential. Material and methods The study was based on data from the follow-up of 310 patients who underwent inguinal hernia repair at the surgery department of the University Hospital Rostock. The preoperative clinical examination of the patients and a questionnaire were supplemented by a postal follow-up survey postoperatively at a median of 20 months (follow-up rate 66%). Patient pain level was assessed by a visual analogue scale (VAS) and health-unspecific QoL by the EQ-5D questionnaire. Standardization of the EQ-5D was based on a survey on a normative German reference population. Results Analysis of the patients in the various treatment arms showed significant differences in age composition and health states (American Society of Anesthesologists, ASA scores) of the patient cohorts. A comparison of the QoL between the two mesh-based procedures, the transabdominal preperitoneal (TAPP) procedure and the Lichtenstein procedure, showed that complete recovery is possible after 6 months. A slight decrease in the QoL of the Lichtenstein cohort patients was ascertainable, which can be explained by the method and the higher age of the group. Taking the differences in age of the two groups into account led to a change of the QoL outcome. Conclusion The concept of QoL is currently becoming increasingly more important in the assessment of treatment procedures. When comparing several therapeutic procedures, a standardization must be undertaken to take the heterogeneity of patient cohorts into consideration. Analogous to the relative survival in cancer epidemiology, the measured QoL scores should be put in the relationship to the age and sex-specific reference of the general population in order to demonstrate the actual effect of the disease in question and its treatment.

IntroductionThe management of a patient suffering from blunt abdominal trauma (BAT) remains a challenge for the emergency physician. Within the last few years, the standard therapy for hemodynamically stable patients with BAT has transitioned to a non-operative approach. The purpose of this study is to evaluate the outcome of patients with BAT and to determine the reasons for failure of non-operative management (NOM).Materials and methodsAnalysis of 176 consecutive patients treated for BAT was conducted in a German level 1 trauma center from 2004 to 2011. Abdominal injuries were classified according to the American Association for the Surgery of Trauma (AAST). Patients included were demonstrated to have objective abdominal trauma with either free fluid on focused assessment with sonography for trauma (FAST) or computed tomography (CT), or proven organ injury.ResultsPatients, 142 of 176 (80.7%), with BAT were initially managed non-operatively, with a success rate of 90%. The rates of NOM success were higher among those with less severe injuries; 100% with Abbreviated Injury Scale (AIS) of 1. In total, 125 patients (71.0%) were managed non-operatively, and 51 (29.0%) required surgical intervention. NOM failure occurred in 9.2% of the patients, the most common reason being initially undiagnosed intestinal perforation (46.2%). Positive correlation was identified (r = 0.512; p ConclusionNOM was successful for the vast majority of blunt abdominal trauma patients, especially those with less severe injuries. NOM failure and operative delay were most commonly due to occult hollow viscus injury (HVI), the detection of which was achieved by close clinical observation and abdominal ultrasound in conjunction with monitoring for rising markers of infection and by multidetector computed tomography (MDCT) if additionally indicated. Based on this concept, the delay in operation in patients with NOM failure was short. This study underscores the feasibility and benefit of NOM in BAT.

A defunctioning stoma can become necessary in a relevant number of patients undergoing gastrointestinal surgery. As a matter of course, patients seek an early closure of the stoma. However, preoperative management of these patients varies and the prediction of continence after stoma removal can become challenging. Patients might be fully continent despite low manometric pressures and vice versa. An easy and reliable way to predict continence after stoma reversal would improve patients’ management and outcome. Although frequently performed in various surgical centers in Germany, there is no published data on the water-holding test. Hence, this is the first study evaluating the role of the test in clinical practice. We performed a prospective pilot study to evaluate the role of anorectal manometry and the water-holding procedure as a predictor of postoperative continence prior to stoma reversal. Inclusion criteria were a successfully passed water-holding test, any type of fecal diversion and the possibility of restoring intestinal continuity. Preoperative low manometric pressure levels were not an exclusion criteria for stoma reversal. Fifty-two patients with ostomy were consecutively enrolled in this study between October 2013 and February 2016. Anorectal manometry was performed in all patients prior to stoma reversal. After stoma removal, patients were followed-up for 6 months. Postoperative incontinence was determined using the Wexner incontinence score. A total of 52 patients (38 males, 14 females) were included at an average age of 59 (range 33–83) years. Most frequent indications for intestinal diversion were rectal cancer surgery, IBD-related surgery, or surgery for diverticular disease. Low anterior rectal resection was performed in 17 patients (32.7%), followed by a proctocolectomy in 9 (17.3%), colectomy in 9 (17.3%), and recto-sigmoid resection in 7 patients (13.5%). Median time from stoma creation to reversal was 206 days (range 48–871 days). All patients had successfully passed the standardized water-holding test. At the same time, the majority of patients had low preoperative manometric pressure values and would normally not have been reversed at that point. The median postoperative Wexner incontinence score was at 1.5 (range 0–20), 0.5 (range 0–14), and 0 (range 0–11) at 14, 60, and 180 days after stoma reversal. Low preoperative manometric squeeze and/or resting pressure levels were not associated with a higher postoperative incontinence score at 14, 60, or 180 days after stoma reversal. A standardized water-holding test can function as an easy and reliable method before stoma reversal to predict sufficient postoperative fecal continence. In case of a sufficient water-holding test despite low manometric pressure levels, the risk for postoperative anal incontinence seems to be low. Preoperative manometric pressure levels do not appear to predict postoperative continence.

This study investigated the impact of immune-related pathway inhibition, among them indolamine 2,3-dioxygenase (IDO), alone and together with immune cells on growth and viability of colorectal cancer (CRC) cells. A panel of patient-derived CRC cell lines with different molecular characteristics (CpG island methylator phenotype, chromosomal, and microsatellite instability) was included. Initial phenotyping of CRC cell lines (n=17) revealed high abundance of immunosuppressive checkpoint-molecules in general, but an individual profile for IDO. Presence of immune-related molecules was independent of the molecular subtype. Selective treatment of CRC cell lines showing high or low IDO expression (n=2 cell lines each) was performed with single agents and combinations of Indoximod, Curcumin, and Gemcitabine with and without the addition of peripheral blood lymphocytes (PBL) in an allogeneic setting. All substances affected CRC cell growth in a cell line specific manner. The combination of Curcumin and Gemcitabine proved to be most effective in tumor cell elimination. Functional read-out analyses identified cellular senescence, after both single and combined treatment. Curcumin alone exerted strong cytotoxic effects by inducing early and late apoptosis. Necrosis was not detectable at all. Addition of lymphocytes generally boosted antitumoral effects of all IDO-inhibitors, with up to 80 % cytotoxicity for the Curcumin treatment. Here, no obvious differences became apparent between individual cell lines. Combined application of Curcumin and low-dose chemotherapy is a promising strategy to kill tumor target cells and to stimulate antitumoral immune responses.

Background Short bowel syndrome results from extensive small bowel resection and induces adaptation of the remaining intestine. Ileocecal resection (ICR) is the most frequent situation in humans. Villus hypertrophy is one hallmark of mucosal adaptation, but the functional mechanisms of mucosal adaptation are incompletely understood. Aims The aim of the study was to characterize a clinically relevant model of short bowel syndrome but not intestinal failure in mice and to identify outcome predictors and mechanisms of adaptation. Methods Male C57BL6/J mice underwent 40% ICR and were followed for 7 or 14 days. Small bowel transection served as control. All mice underwent autopsy. Survival, body weight, wellness score, stool water content, plasma aldosterone concentrations, and paracellular permeability were recorded. Results Unlike controls, resected mice developed significant diarrhea with increased stool water. This was accompanied by sustained weight loss throughout follow-up. Villus length increased but did not correlate positively with adaptation. Plasma aldosterone concentrations correlated inversely with body weight at day 14. After ICR, intestinal epithelial (i.e., tight junctional) sodium permeability was increased. Conclusions 40% ICR results in moderate to severe short bowel syndrome. Successful adaptation to the short bowel situation involves villus elongation but does not correlate with the degree of villus elongation alone. In addition, increased intestinal epithelial sodium permeability facilitates sodium-coupled solute transport. Hyperaldosteronism correlates with the severity of weight loss, indicates volume depletion, and counterregulates water loss. Electronic supplementary material The online version of this article (10.1007/s10620-018-5420-x) contains supplementary material, which is available to authorized users.

Importance Total neoadjuvant therapy has been increasingly adopted for multimodal rectal cancer treatment. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy needs to be established. Objective To report the long-term results of the secondary end points prespecified in the Randomized Phase 2 Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy (CAO/ARO/AIO-12 trial) for Locally Advanced Rectal Cancer. Design, Setting, and Participants This secondary analysis of a randomized clinical trial included 311 patients who were recruited from the accrued CAO/ARO/AIO-12 trial population from June 15, 2015, to January 31, 2018, from 18 centers in Germany. Patients with cT3-4 and/or node-positive rectal adenocarcinoma were included in the analysis. Data were analyzed from June 15, 2015, to January 31, 2018. The follow-up analysis was conducted between January 31, 2018, and November 30, 2020. Interventions Patients were randomly assigned to group A for 3 cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy), or to group B for CRT before chemotherapy. Total mesorectal excision was scheduled on day 123 after the start of total neoadjuvant therapy in both groups. Main Outcomes and Measures The end points assessed in this secondary analysis included long-term oncologic outcomes, chronic toxicity, patient-reported outcome measures for global health status (GHS) and quality of life (QoL), and the Wexner stool incontinence score. Results Of the 311 patients enrolled, 306 were evaluable, including 156 in group A (mean [SD] age, 60 [11] years; 106 men [68%]) and 150 in group B (mean [SD] age, 62 [10] years; 100 men [67%]). After a median follow-up of 43 months (range, 35-60 months), the 3-year disease-free survival was 73% in both groups (hazard ratio, 0.95; 95% CI, 0.63-1.45,P = .82); the 3-year cumulative incidence of locoregional recurrence (6% vs 5%,P = .67) and distant metastases (18% vs 16%,P = .52) were not significantly different. Chronic toxicity grade 3 to 4 occurred in 10 of 85 patients (11.8%) in group A and 8 of 66 patients (9.9%) in group B at 3 years. The GHS/QoL score decreased after total mesorectal excision but returned to pretreatment levels 1 year after randomization with no difference between the groups. Stool incontinence deteriorated 1 year after randomization in both groups and only improved slightly at 3 years, but never reached baseline levels. Conclusions and Relevance This secondary analysis of a randomized clinical trial showed that CRT followed by chemotherapy resulted in higher pathological complete response without compromising disease-free survival, toxicity, QoL, or stool incontinence and is thus proposed as the preferred total neoadjuvant therapy sequence if organ preservation is a priority. Trial Registration ClinicalTrials.gov identifier:NCT02363374

Background/purpose Improval of flap viability is one of the main purposes in reconstructive surgery. The endogenous volatile mediator hydrogen sulfide (H2S) exerts plenty beneficial effects on blood rheology and protects from ischemia reperfusion injury. Methods Therefore this study analyzed whether H2S affects tissue necrosis and skin microcirculation during impaired perfusion in the axial pattern ear flap model in hairless mice. Necrosis and microcirculatory parameters were assessed by means of stereo- and intravital fluorescence microscopy before and immediately after flap creation as well as on days 2 and 4 after surgery. Treatment with H2S donor GYY4137 or its vehicle was performed either one-time after flap preparation or two-times with an additional injection on day 2. After 4 days ear tissues were taken and further analyzed histologically to study tissue edema. Results Compared to vehicle treatment, both one- and two-time treatment with GYY4137 significantly reduced tissue necrosis and improved microcirculation in the ear flap, apparently through capillary dilatation and increased functional capillary density. Histological analysis revealed a significantly reduced tissue edema formation in GYY4137-treated animals. While microcirculatory parameters in parts significantly improved by two-time GYY4137 treatment, ear thickness and edema formation were independent from treatment regime. Conclusions In summary H2S treatment is a promising attempt to improve microcirculation in critically perfused skin flaps and consequently to preserve flap viability.

The main goal of the Medical Device Regulation (MDR) is the improvement of patient safety by laying down rules concerning the approval of medical devices for human use in the European Union. The MDR contains an extension of the conformity assessment procedure for products in the higher risk categories IIb and III. The clinical testing and assessment are regulated more strictly by e.g. the scrutiny process conducted by expert panels following the technical certification. The demand for documentation is vastly increasing due to more detailed registration (UDI) and an extension of post-market surveillance. The German Society of Surgery (DGCH) and the German Society for Biomedical Engineering have already defined a staged concept for innovation testing and clinical assessment during finalization of the MDR that contains the highest level of patient safety while simultaneously maintaining the potential for innovation. Essential elements are present in the MDR and can be implemented in a targeted way. The 3‑year phase of national MDR-implementation must be used for a proactive adaptation. The DGCH is represented in the advisory council of the Federal Ministry of Health (BMG) by the Association of the Scientific Medical Societies in Germany (AWMF). The aim is a responsible harmonization of national structures with the regulations of the MDR by the construction of specific registries which should be the responsibility of medical societies. The early integration of health technology assessment will be of importance during the planning phase of product development to facilitate a positive decision on reimbursement.

Zusammenfassung Hintergrund Trotz der Weiterentwicklung der medikamentösen Therapie und eines mittlerweile signifikant späteren OP-Zeitpunkts wird bei einem Großteil der Patienten mit Morbus Crohn im Laufe der weiterhin kausal unheilbaren Erkrankung eine oder mehrere chirurgische Interventionen notwendig. Methodik Retrospektive Analyse 120 konsekutiver Patienten, die aufgrund eines Morbus Crohn an der Universitätsmedizin Rostock (UMR) operiert wurden. Die statistische Auswertung erfolgte mittels SPSS. Ergebnisse Insgesamt wurden 284 Operationen an 120 Patienten erfasst, wovon 207 Eingriffe an der UMR durchgeführt wurden. Das mittlere Alter bei Erstoperation lag bei 38 Jahren (Range: 17 – 66), die Erstdiagnose des Morbus Crohn erfolgte im Alter von 30 Jahren (Range: 9 – 62). Jeder Patient wurde während seiner Erkrankung 2 – 3 × operiert (Range: 1 – 9). Je älter Patienten bei Erstdiagnose waren, desto kürzer war das Intervall bis zur Erstoperation. Die Anzahl der Operationen pro Patient wurde von Lokalisation und Verhalten der Erkrankung signifikant beeinflusst, wobei ein penetrierendes Verhalten mit einer höheren und ein Befall des terminalen Ileums (L1) mit einer niedrigeren OP-Frequenz assoziiert waren. Risikofaktoren für Komplikationen > Grad III nach Clavien-Dindo waren unter anderem ein höheres Alter bei Operation sowie bei Erstdiagnose, ein verminderter Albuminspiegel und ein erhöhtes CRP. Anastomoseninsuffizienzen waren ebenfalls mit den genannten Risikofaktoren sowie der präoperativen Einnahme von > 20 mg Prednisolonäquivalent pro Tag bzw. einer Gesamtdosis von > 280 mg über die letzten 14 Tage vor OP assoziiert. Anastomosenkonfiguration sowie ein mikroskopischer Befall der Resektionsränder hatten keinen statistisch signifikanten Einfluss auf die Entstehung einer Anastomoseninsuffizienz. Schlussfolgerung Eine Diagnosestellung nach dem 30. Lebensjahr war in dieser Analyse mit einem signifikant früheren OP-Zeitpunkt assoziiert. Patienten mit Befall des terminalen Ileums (L1) hatten eine signifikant geringere OP-Frequenz als Patienten mit Kolon- oder kombiniertem Morbus-Crohn-Befall. Alter, Albumin, CRP und eine Steroidmedikation > 20 mg pro Tag zeigten sich als Prädiktoren für perioperative Komplikationen.

Background Adjuvant chemotherapy (adCx) is an integral part of multimodal treatment in resected pancreatic ductal adenocarcinoma (PDAC) and is recommended by the German S3 guideline since 2007 in all patients. We aimed to investigate the impact of this guideline at our institution. Methods In 151 of 403 pancreatic resections performed histopathology revealed PDAC. Follow-up data were available from 143 patients (95%) representing our study group. The rate of recommended, initiated and fully completed adCx was analyzed for period 1 (09/2003–07/2007) and period 2 (08/2007–08/2014). Results Our study group comprised 49 patients in period 1 and 94 patients in period 2. AdCx was recommended, initiated and completed in 42/49 (86%), 34/49 (69%) and 22/49 (45%) patients in period 1 and in 93/94 (99%), 78/94 (83%) and 49/94 (52%) patients in period 2, respectively. Only the increase in recommendations for adCx was statistically significant (p = 0.0024). Overall, only 50% (71/143) of patients fully completed the Cx protocol. Completed adCx resulted in a significantly longer (p = 0.0225) overall survival compared to patients with incomplete or without adCx. Multiple logistic regression revealed adCx (p = 0.0046) as independent factor of survival. The hazard ratio for fully completed adCx was 0.406 and for incomplete adCx 0.567. Conclusion Our results indicate a high acceptance of the S3-guidline recommendation for adCx in resected PDAC in a routine setting, which, however, is completed in only 50% of all patients. Fully completed adCx had the most powerful effect on improving overall survival., Highlights • After S3 guideline implementation only the increase in recommendations for adCx was statistically significant. • Overall, only 50% (71/143) of patients fully completed their Cx protocol. • Completed adCx resulted in a significantly longer overall survival compared to patients with incomplete or without adCx. • Multiple logistic regression revealed adCx as an independent factor of survival. • Our results indicate a high acceptance of the S3-guidline recommendation for adCx in resected PDAC in the routine setting.

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.

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.

Postoperative, iatrogenic or spontaneous upper gastrointestinal defects result in significant morbidity and mortality of the patients. In the last few years, endoscopic vacuum therapy (EVT) has been recognized as a new promising method for repairing upper gastrointestinal defects of different etiology. However, probably due to insufficient data and no commercially available system for EVT of the upper gastrointestinal tract, until the end of 2014, covering of esophageal defects with self-expanding metal stents (SEMS) were still the mainstay of endoscopic therapy. The aim of this article is to review the data available about EVT for various upper gastrointestinal defects. A selective literature search was conducted in Medline and PubMed (2007–2016), taking into account all the published case series and case reports reporting on the use of EVT in the management of upper gastrointestinal defects. EVT works through intracorporal application of negative pressure at the defect zone with an electronic controlled vacuum device along a polyurethane sponge drainage. This results in closure of the esophageal defect and internal drainage of the septic focus, simultaneously. Compared to stenting, EVT enables regular viewing of wound conditions with control of the septic focus and adjustment of therapy. Moreover, endoscopical negative pressure is applicable in all esophageal regions (cricopharygeal, tubular, gastroesophageal junction) and in anastomotic anatomic variants. EVT can be used solely as a definite treatment or as a complimentary therapy combined with operative revision. In total, there are published data of more than 200 patients with upper gastrointestinal defects treated with EVT, showing succes rates from 70–100%. The available data indicate that EVT is feasible, safe and effective with good short-term and long-term clinical outcomes in the damage control of upper GI-tract leaks. Still, a prospective multi-center study has to be conducted to proof the definite benefit of EVT for patients with esophageal defects.

Background Objective, reliable and easy screening for peripheral artery disease (PAD) is essential to confirm the diagnosis and initiate the respective treatment. Therefore, a new non-invasive hyperspectral camera (TIVITA® Tissue) was tested in patients with and without PAD. Objective It was hypothesized that the oxygenation parameters of the TIVITA® Tissue correlate to established modalities for detection of PAD and allow differentiation between individuals with and without PAD. Methods Evaluation of tissue oxygenation was performed in the angiosome of the medial plantar artery in 25 healthy young people and in 24 patients with and 25 patients without PAD in comparable age. Thereby, superficial oxygenation (StO2) and near-infrared (NIR) perfusion index were measured with the TIVITA® Tissue. Additionally, the ankle-brachial-index (ABI), the complaint free walking distance and the vascular quality of life were assessed and demographic data were obtained from all participants. Results TIVITA® Tissue analysis revealed significantly reduced StO2 and NIR perfusion index in PAD compared to healthy young participants and patients without PAD. StO2 and NIR perfusion index positively correlated with ABI, the complaint free walking distance and the vascular quality of life score. Conclusions In summary, this new hyperspectral imaging camera bears great potential for PAD screening as well as for follow up.

Background: Neoadjuvant radiochemotherapy (nRCT) is an important component in the treatment of advanced rectal cancer. Endoscopic vacuum therapy (EVT) has become the treatment of choice for anastomotic leakage after rectal resection in many institutions in Germany. Published case series report on average success and stoma reversal rates of more than 80%. However, so far, there is no distinct report on the potential influence of nRCT on EVT. Methods: A total of 11 patients treated with EVT for anastomotic leakage after nRCT and rectal resection were retrospectively compared with a cohort of eight patients with rectal anastomotic leakage without neoadjuvant treatment. Primary endpoints were death, treatment success, and long-term preservation of intestinal continuity. Secondary endpoint was the duration of treatment. Statistical analysis was performed using Statistical Package for Social Science (SPSS) version 23.0. Results: There was no difference in mortality (0%), success rate (90.9% versus 100%, p = 0.381), or long-term preservation of continuity (63.6% versus 62.5%, p = 0.960). After nRCT, patients showed a significant longer duration of EVT (31.1 days versus 15.9 days, p = 0.040) which was associated with a significantly higher number of sponge applications (9.6 versus 5.0, p = 0.042). Conclusions: In our analysis, EVT showed success in over 90% of patients with anastomotic leakage after rectal resection for colorectal cancer, regardless of neoadjuvant treatment. However, in case of anastomotic leakage, nRCT seems to be associated with the need for a significant longer duration of EVT.

The volatile transmitter hydrogen sulfide (H2S) is known for its various functions in vascular biology. This study evaluates the effect of the H2S-donor GYY4137 (GYY) on thrombus stability and microvascular thrombolysis. Human whole blood served for all in vitro studies and was analyzed in a resting state, after stimulation with thrombin-receptor activating peptide (TRAP) and after incubation with 10 or 30 mM GYY or its vehicle DMSO following TRAP-activation, respectively. As a marker for thrombus stability, platelet-leukocyte aggregation was assessed using flow cytometry after staining of human whole blood against CD62P and CD45, respectively. Furthermore, morphology and quantity of platelet-leukocyte aggregation were studied by means of scanning electron microscopy (scanning EM). Therefore, platelets were stained for CD62P followed by immuno gold labeling. In vivo, the dorsal skinfold chamber preparation was performed for light/dye induction of thrombi in arterioles and venules using intravital fluorescence microscopy. Thrombolysis was assessed 10 and 22 h after thrombus induction and treatment with the vehicle, GYY, or recombinant tissue plasminogen activator (rtPA). Flow cytometry revealed an increase of CD62P/CD45 positive aggregates after TRAP stimulation of human whole blood, which was significantly reduced by preincubation with 30 mM GYY. Scanning EM additionally showed a reduced platelet-leukocyte aggregation and a decreased leukocyte count within the aggregates after preincubation with GYY compared to TRAP stimulation alone. Further on, morphological signs of platelet activation were found markedly reduced upon treatment with GYY. In mice, both GYY and rtPA significantly accelerated arteriolar and venular thrombolysis compared to the vehicle control. In conclusion, GYY impairs thrombus stability by reducing platelet-leukocyte aggregation and thereby facilitates endogenous thrombolysis.

// Claudia Maletzki 1, * , Franziska Beyrich 1, * , Maja Huhns 2 , Ernst Klar 3 , Michael Linnebacher 1 1 Molecular Oncology and Immunotherapy, Department of General Surgery, University of Rostock, 18057 Rostock, Germany 2 Institute of Pathology, University of Rostock, 18057 Rostock, Germany 3 Department of General Surgery, University of Rostock, 18057 Rostock, Germany * These authors have contributed equally to this work Correspondence to: Claudia Maletzki, email: claudia.maletzki@med.uni-rostock.de Keywords: murine tumor models, MMR deficiency, cell line establishment, tumor microenvironment, MSI target genes Received: February 29, 2016 Accepted: June 06, 2016 Published: July 18, 2016 ABSTRACT Mice lines homozygous negative for one of the four DNA mismatch repair (MMR) genes ( MLH1, MSH2, PMS2, MSH6 ) were generated as models for MMR deficient (MMR-D) diseases. Clinically, hereditary forms of MMR-D include Lynch syndrome (characterized by a germline MMR gene defect) and constitutional MMR-D, the biallelic form. MMR-D knockout mice may be representative for both diseases. Here, we aimed at characterizing the MLH1 -/- model focusing on tumor-immune microenvironment and identification of coding microsatellite mutations in lymphomas and gastrointestinal tumors (GIT). All tumors showed microsatellite instability (MSI) in non-coding mononucleotide markers. Mutational profiling of 26 coding loci in MSI + GIT and lymphomas revealed instability in half of the microsatellites, two of them ( Rfc3 and Rasal2 ) shared between both entities. MLH1 -/- tumors of both entities displayed a similar phenotype (high CD71, FasL, PD-L1 and CTLA-4 expression). Additional immunofluorescence verified the tumors’ natural immunosuppressive character (marked CD11b/CD200R infiltration). Vice versa , CD3 + T cells as well as immune checkpoints molecules were detectable, indicative for an active immune microenvironment. For functional analysis, a permanent cell line from an MLH1 -/- GIT was established. The newly developed MLH1 -/- A7450 cells exhibit stable in vitro growth, strong invasive potential and heterogeneous drug response. Moreover, four additional MSI target genes ( Nktr1 , C8a , Taf1b , and Lig4 ) not recognized in the primary were identified in this cell line. Summing up, molecular and immunological mechanisms of MLH1 -/- driven carcinogenesis correlate well with clinical features of MMR-D. MLH1 -/- knockout mice combine characteristics of Lynch syndrome and constitutional MMR-D, making them suitable models for preclinical research aiming at MMR-D related diseases.

This study analysed the impact of anandamide, cannabidiol (CBD), and WIN55,212-2 on platelet activity and thrombogenesis for the first time. The effects of the cannabinoids on venular thrombosis were studied in the ear of hairless mice. Cannabinoid treatment was performed either once or repetitive by a once-daily administration for three days. To assess the role of cyclooxygenase metabolites in the putative action of anandamide, in vivo studies likewise included a combined administration of anandamide with indomethacin. In vitro, the effect of the cannabinoids on human platelet activation was studied by means of P-selectin expression using flow cytometry. Platelets were analysed under resting or thrombin receptor activating peptide (TRAP)-stimulated conditions, both after cannabinoid treatment alone and after TRAP stimulation and subsequent cannabinoid exposure. Finally, platelet count was assessed after treatment with high concentrations of anandamide. Anandamide, but not CBD and WIN55,212-2, significantly accelerated thrombus growth after one-time treatment as compared to vehicle control. Co-administration with indomethacin neutralized this effect. However, thrombogenesis was not altered by repeated treatment with the cannabinoids. In vitro, anandamide was shown to elicit a concentration-dependent activation of resting human platelets. However, at higher concentrations anandamide reduced the response to TRAP activation associated with a decrease of platelet count. CBD and WIN55,212-2 neither increased nor reduced activation of platelets. Acute exposure to anandamide elicits a cyclooxygenase-dependent prothrombotic effect in vivo. Anandamide seems to affect human platelet activation by a concentration-dependent toxic effect. By contrast, CBD and WIN55,212-2 were not associated with induction of thrombosis or activation of platelets. © 2016 BioFactors, 42(6):581-590, 2016.

Background. For development of individualized treatment on a routine basis, transfer of patients’ tumor tissue in a xenograft model (i.e., generation of patient-derived xenografts (PDX)) is desirable for molecular, biochemical, or functional analyses. Drawbacks are dissatisfactory tumor take rates, the necessity of fast tumor tissue processing, and extensive logistics demanding teamwork of surgeons, pathologists, and laboratory researchers. Methods. The take rates of ten colorectal cancer (CRC) tissue samples in immunodeficient mice were compared after direct cryopreservation and after a 24 h cooling period at 4°C prior to cryopreservation. Additionally, the effect of simultaneous Matrigel application on the take rates was investigated. Beside take rates, tumor growth characteristics and cell culture success were analyzed. Results. Tumor takes of CRC tissue samples were significantly improved after Matrigel application (8 versus 15 takes, p=0.04). As expected, they diminished furthermore after 24 h cooling. Application of Matrigel could counteract this decrease significantly (2 versus 7 takes, p=0.03). Cumulative take rate after cryopreservation was satisfactory (70%). Conclusion. Matrigel application after 24 h delay in tissue processing facilitates CRC PDX model development. These data help developing strategies for individualized tumor therapies in the context of multicenter clinical studies and for basic research on primary patient tumors.

The main goal of the Medical Device Regulation (MDR) is the improvement of patient safety by laying down rules concerning the approval of medical devices for human use in the European Union. The MDR contains an extension of the conformity assessment procedure for products in the higher risk categories IIb and III. The clinical testing and assessment are regulated more strictly by e.g. the scrutiny process conducted by expert panels following the technical certification. The demand for documentation is vastly increasing due to more detailed registration (UDI) and an extension of post-market surveillance. The German Society of Surgery (DGCH) and the German Society for Biomedical Engineering have already defined a staged concept for innovation testing and clinical assessment during finalization of the MDR that contains the highest level of patient safety while simultaneously maintaining the potential for innovation. Essential elements are present in the MDR and can be implemented in a targeted way. The 3‑year phase of national MDR-implementation must be used for a proactive adaptation. The DGCH is represented in the advisory council of the Federal Ministry of Health (BMG) by the Association of the Scientific Medical Societies in Germany (AWMF). The aim is a responsible harmonization of national structures with the regulations of the MDR by the construction of specific registries which should be the responsibility of medical societies. The early integration of health technology assessment will be of importance during the planning phase of product development to facilitate a positive decision on reimbursement.

In recent decades, developments in drug therapy have significantly postponed the need for surgery. Nevertheless, the majority of patients with Crohn's disease still require one or more surgical interventions during the course of their disease. An analysis of epidemiological data as well as the surgical results of our own patients should help to identify risk factors for early surgery, re-operations and perioperative complications.A retrospective analysis including 120 consecutive patients with Crohn's disease and needing surgical intervention was carried out at the University Hospital of Rostock (UMR), Germany. Statistical analysis was performed using SPSS.A total of 284 operations were recorded in 120 patients, of which 207 were performed on the UMR. The mean age at first surgery was 38 years (range: 17 - 66); initial diagnosis of Crohn's was on average at the age of 30 (range: 9 - 62). Each patient was operated 2 - 3 times during the course of their disease (range 1 - 9). Patients older than 30 years had significantly shorter time interval to the first operation. The number of operations per patient was significantly influenced by the localisation and behaviour of the disease. Penetrative behavior was associated with more frequent operations and terminal ileum involvement (L1) with significantly less frequent operations. Risk factors for complication of at least grade III according to Clavien-Dindo included greater age at surgery and at first diagnosis, decreased albumin levels and increased CRP. Anastomotic leakages were also associated with these risk factors as well as preoperative intake of 20 mg prednisolone equivalent per day or cumulative dosage of 280 mg over the last 14 days prior to surgery. Anastomosis configuration and microscopic involvement of the resection margins had no statistically significant influence on the development of anastomotic leakage.Diagnosis after the age of 30 was associated with a significantly earlier need for surgery in this analysis. Patients with terminal ileum involvement (L1) had a significantly lower surgical frequency than patients with colon or combined Crohn's disease. Age, albumin, CRP and a steroid medication 20 mg per day were predictors for perioperative complications.Trotz der Weiterentwicklung der medikamentösen Therapie und eines mittlerweile signifikant späteren OP-Zeitpunkts wird bei einem Großteil der Patienten mit Morbus Crohn im Laufe der weiterhin kausal unheilbaren Erkrankung eine oder mehrere chirurgische Interventionen notwendig.Retrospektive Analyse 120 konsekutiver Patienten, die aufgrund eines Morbus Crohn an der Universitätsmedizin Rostock (UMR) operiert wurden. Die statistische Auswertung erfolgte mittels SPSS.Insgesamt wurden 284 Operationen an 120 Patienten erfasst, wovon 207 Eingriffe an der UMR durchgeführt wurden. Das mittlere Alter bei Erstoperation lag bei 38 Jahren (Range: 17 – 66), die Erstdiagnose des Morbus Crohn erfolgte im Alter von 30 Jahren (Range: 9 – 62). Jeder Patient wurde während seiner Erkrankung 2 – 3 × operiert (Range: 1 – 9). Je älter Patienten bei Erstdiagnose waren, desto kürzer war das Intervall bis zur Erstoperation. Die Anzahl der Operationen pro Patient wurde von Lokalisation und Verhalten der Erkrankung signifikant beeinflusst, wobei ein penetrierendes Verhalten mit einer höheren und ein Befall des terminalen Ileums (L1) mit einer niedrigeren OP-Frequenz assoziiert waren. Risikofaktoren für Komplikationen Grad III nach Clavien-Dindo waren unter anderem ein höheres Alter bei Operation sowie bei Erstdiagnose, ein verminderter Albuminspiegel und ein erhöhtes CRP. Anastomoseninsuffizienzen waren ebenfalls mit den genannten Risikofaktoren sowie der präoperativen Einnahme von 20 mg Prednisolonäquivalent pro Tag bzw. einer Gesamtdosis von 280 mg über die letzten 14 Tage vor OP assoziiert. Anastomosenkonfiguration sowie ein mikroskopischer Befall der Resektionsränder hatten keinen statistisch signifikanten Einfluss auf die Entstehung einer Anastomoseninsuffizienz.Eine Diagnosestellung nach dem 30. Lebensjahr war in dieser Analyse mit einem signifikant früheren OP-Zeitpunkt assoziiert. Patienten mit Befall des terminalen Ileums (L1) hatten eine signifikant geringere OP-Frequenz als Patienten mit Kolon- oder kombiniertem Morbus-Crohn-Befall. Alter, Albumin, CRP und eine Steroidmedikation 20 mg pro Tag zeigten sich als Prädiktoren für perioperative Komplikationen.

AIM To establish patient-individual tumor models of rectal cancer for analyses of novel biomarkers, individual response prediction and individual therapy regimens. METHODS Establishment of cell lines was conducted by direct in vitro culturing and in vivo xenografting with subsequent in vitro culturing. Cell lines were in-depth characterized concerning morphological features, invasive and migratory behavior, phenotype, molecular profile including mutational analysis, protein expression, and confirmation of origin by DNA fingerprint. Assessment of chemosensitivity towards an extensive range of current chemotherapeutic drugs and of radiosensitivity was performed including analysis of a combined radio- and chemotherapeutic treatment. In addition, glucose metabolism was assessed with 18F-fluorodeoxyglucose (FDG) and proliferation with 18F-fluorothymidine. RESULTS We describe the establishment of ultra-low passage rectal cancer cell lines of three patients suffering from rectal cancer. Two cell lines (HROC126, HROC284Met) were established directly from tumor specimens while HROC239 T0 M1 was established subsequent to xenografting of the tumor. Molecular analysis classified all three cell lines as CIMP-0/ non-MSI-H (sporadic standard) type. Mutational analysis revealed following mutational profiles: HROC126: APCwt, TP53wt, KRASwt, BRAFwt, PTENwt; HROC239 T0 M1: APCmut, P53wt, KRASmut, BRAFwt, PTENmut and HROC284Met: APCwt, P53mut, KRASmut, BRAFwt, PTENmut. All cell lines could be characterized as epithelial (EpCAM+) tumor cells with equivalent morphologic features and comparable growth kinetics. The cell lines displayed a heterogeneous response toward chemotherapy, radiotherapy and their combined application. HROC126 showed a highly radio-resistant phenotype and HROC284Met was more susceptible to a combined radiochemotherapy than HROC126 and HROC239 T0 M1. Analysis of 18F-FDG uptake displayed a markedly reduced FDG uptake of all three cell lines after combined radiochemotherapy. CONCLUSION These newly established and in-depth characterized ultra-low passage rectal cancer cell lines provide a useful instrument for analysis of biological characteristics of rectal cancer.

Background: The lethality of acute mesenteric ischemia (AMI) remains quite high with 50-70%. The main reasons for that are the fact that AMI is rarely taken into consideration by the differential diagnosis of acute abdomen, the time-consuming diagnostic process, and the lack of a standardized therapeutic concept. The present interdisciplinary review aims to increase awareness among physicians and to help improve clinical outcomes. Methods: This clinical therapeutic review is based on author expertise as well as a selective literature survey in PubMed based on the term ‘mesenteric ischemia', combined with the terms ‘arterial', ‘clinical presentation', ‘diagnosis', ‘therapy', ‘surgery', and ‘interventional radiology'. Based on these search results as well as on the guidelines of the German Society of Vascular Surgery, the American College of Cardiology, and the American Heart Association, we present an interdisciplinary treatment concept. Results: AMI is a vascular emergency that can be successfully treated only within the first hours after the onset of symptoms. Computed tomography angiography is the diagnostic method of choice. Intensive care unit treatment can prevent the occurrence of multiple organ failure. Treatment primarily consists of the revascularization of the mesenteric arteries. Endovascular techniques should be given priority, whereas signs of peritonitis or a central arterial occlusion with high thrombus load primarily require a surgical approach in order to save time and increase patient safety. Additional bowel resections can play a significant role in the treatment of intestinal sepsis. Conclusion: Prompt and goal-oriented diagnosis and consistent treatment of AMI within 4-6 h from the onset of symptoms can be decisive for the reduction of AMI-associated lethality. In order for this to happen, a standardized concept of emergency treatment needs to be implemented.

Background: Anorectal surgery covers a wide spectrum of surgery. Diagnostic workup of anorectal disease is based on clinical examination with basic functional tests followed by more elaborate diagnostic tests. Since the incidence of anorectal disorders increases with age, more patients will present in outpatient clinics, thus underlining the relevance of this topic. Methods: A PubMed literature search was performed using the terms ‘anal incontinence', ‘anal and rectal surgery', ‘functional diagnostics', and combinations of these terms. No restriction regarding publication year or publication type was applied but randomized trials, ‘metanalyses', or guidelines were ranked higher. Only articles in English or German were included. Results: The diagnostic value of digital rectal examination, anal manometry and endosonography, the water holding procedure, contrast enema, and incontinence scores is summarized. Conclusion: The article focusses on basic clinical and functional diagnostic tests which can be easily applied in the pre- and postoperative setting to evaluate the postoperative outcome.

Background Postoperative pancreatic fistula (POPF) is a major factor for morbidity and mortality after pancreatic resection. Risk stratification for POPF is important for adjustment of treatment, selection of target groups in trials and quality assessment in pancreatic surgery. In this study, we built a risk-prediction model for POPF based on a large number of predictor variables from the German pancreatic surgery registry StuDoQ|Pancreas. Methods StuDoQ|Pancreas was searched for patients, who underwent pancreatoduodenectomy from 2014 to 2016. A multivariable logistic regression model with elastic net regularization was built including 66 preoperative und intraoperative parameters. Cross-validation was used to select the optimal model. The model was assessed via area under the ROC curve (AUC) and calibration slope and intercept. Results A total of N = 2488 patients were included. In the optimal model the predictors selected were texture of the pancreatic parenchyma (soft versus hard), body mass index, histological diagnosis pancreatic ductal adenocarcinoma and operation time. The AUC was 0.70 (95% CI 0.69–0.70), the calibration slope 1.67 and intercept 1.12. In the validation set the AUC was 0.65 (95% CI 0.64–0.66), calibration slope and intercept were 1.22 and 0.42, respectively. Conclusion The model we present is a valid measurement instrument for POPF risk based on four predictor variables. It can be applied in clinical practice as well as for risk-adjustment in research studies and quality assurance in surgery.

International audience; Endogenous retroviruses are remnants of retroviral infections. In contrast to their human counterparts, murine endogenous retroviruses (mERV) still can synthesize infectious particles and retrotranspose. Xenotransplanted human cells have occasionally been described to be mERV infected. With genetic engineered mice and patient-derived xenografts (PDXs) on the rise as eminent research tools, we here systematically investigated, if different tumor models harbor mERV infections. Relevant mERV candidates were first preselected by next generation sequencing (NGS) analysis of spontaneous lymphomas triggered by colorectal cancer (CRC) PDX tissue. Two primer systems were designed for each of these candidates (AblMLV, EcoMLV, EndoPP, MLV, and preXMRV) and implemented in an quantitative real-time (RT-qPCR) screen using murine tissues (n = 11), PDX-tissues (n = 22), PDX-derived cell lines (n = 13), and patientderived tumor cell lines (n = 14). The expression levels of mERV varied largely both in the PDX samples and in the mouse tissues. No mERV signal was, however, obtained from cDNA or genomic DNA of CRC cell lines. Expression of EcoMLV was higher in PDX than in murine tissues; for EndoPP it was the opposite. These two were thus further investigated in 40 additional PDX. In addition, four patient-derived cell lines free of any mERV expression were subcutaneously injected into immunodeficient mice. Outgrowing cell-derived xenografts barely expressed EndoPP. In contrast, the expression of EcoMLV was even higher than in surrounding mouse tissues. This expression gradually vanished within few passages of re-cultivated cells. In summary, these results strongly imply that: (i) PDX and murine tissues in general are likely to be contaminated by mERV, (ii) mERV are expressed transiently and at low level in fresh PDX-derived cell cultures, and (iii) mERV integration into the genome of human cells is unlikely or at least a very rare event. Thus, mERVs are stowaways present in murine cells, in PDX tissues and early thereof-derived cell cultures. We conclude that further analysis is needed concerning their impact on results obtained from studies performed with PDX but also with murine tumor models.

AIM To establish cell line and patient-derived xenograft (PDX) models for neuroendocrine carcinomas (NEC) which is highly desirable for gaining insight into tumor development as well as preclinical research including biomarker testing and drug response prediction. METHODS Cell line establishment was conducted from direct in vitro culturing of colonic NEC tissue (HROC57). A PDX could also successfully be established from vitally frozen tumor samples. Morphological features, invasive and migratory behavior of the HROC57 cells as well as expression of neuroendocrine markers were vastly analyzed. Phenotypic analysis was done by microscopy and multicolor flow cytometry. The extensive molecular-pathological profiling included mutation analysis, assessment of chromosomal and microsatellite instability; and in addition, fingerprinting (i.e., STR analysis) was performed from the cell line in direct comparison to primary patient-derived tissues and the PDX model established. Drug responsiveness was examined for a panel of chemotherapeutics in clinical use for the treatment of solid cancers. RESULTS The established cell line HROC57 showed distinct morphological and molecular features of a poorly differentiated large-cell NEC with KI-67 > 50%. Molecular-pathological analysis revealed a CpG island promoter methylation positive cell line with microsatellite instability being absent. The following mutation profile was observed: KRAS (wt), BRAF (mut). A high sensitivity to etoposide, cisplatin and 5-FU could be demonstrated while it was more resistant towards rapamycin. CONCLUSION We successfully established and characterized a novel patient-derived NEC cell line in parallel to a PDX model as a useful tool for further analysis of the biological characteristics and for development of novel diagnostic and therapeutic options for NEC.

Endoscopic vacuum therapy (EVT) has been established in Germany for the treatment of anastomotic leakage after rectal resection. Continuous or intermittent suction and drainage decrease bacterial contamination, secretion, and local edema promoting perfusion and granulation at the same time. However, data for use and long-term results of EVT in colorectal surgery are still scarce and are often limited by short-term follow-up. Here, we aimed at analyzing the treatment spectrum and long-term outcome of EVT for defects of the lower gastrointestinal tract. This is a retrospective single-center analysis of EVT for defects of the lower gastrointestinal tract of different etiology in 41 patients over a time period of 8 years (2007–2015) with a mean follow-up of 36 (2–89) months. In total, 426 polyurethane sponges were placed in lower GI defects of 41 patients (31 male, 10 female) with a median age of 70 years (range, 29–91). Most frequent indications for EVT were anastomotic leakage after rectal resection (n = 20), Hartmann’s stump insufficiency (n = 12), and rectal perforation (n = 3). The median number of sponge insertions was six (range, 1–37) with a mean changing interval of 3 days (range, 1–5). Median time of therapy was 20 days. A successful vacuum therapy with local control of the septic focus was achieved in 18 of 20 patients (90 %) with anastomotic leakage after rectal resection and in nine of 12 patients with a Hartmann’s stump insufficiency. In 15 of 19 (79 %) patients with a diverting stoma, take-down after successful treatment was possible. Median time to closure was 244 days (range, 152–488 days). To our knowledge, this retrospective observation of EVT application for rectal lesions represents the largest patient series in literature. EVT has earned its indication in complication management after colorectal surgery and can achieve a successful control of a local septic focus in the majority of patients.

Background Volume–outcome relationships related to major surgery may be of limited value if observation ends at the point of discharge without taking transfers and later events into consideration. Methods The volume–outcome relationship in patients who underwent pancreatic surgery between 2008 and 2010 was assessed using claims data for all inpatient episodes from Germany's largest provider of statutory health insurance covering about 30 per cent of the population. Multiple logistic regression models with random effects were used to analyse the effect of hospital volume (using volume quintiles) on 1-year mortality, adjusting for age, sex, primary disease, type of surgery and co-morbidities. Additional outcomes were in-hospital (including transfer to other hospitals until final discharge) and 90-day mortality. Results Of 9566 patients identified, risk-adjusted 1-year mortality was significantly higher in the three lowest-volume quintiles compared with the highest-volume quintile (odds ratio 1·73, 1·53 and 1·37 respectively). A similar, but less pronounced, effect was demonstrated for in-hospital and 90-day mortality. The effect of hospital volume on 1-year mortality was comparable to the effect of co-morbid conditions such as renal failure. Conclusion Although mortality related to pancreatic surgery is influenced by many factors, this study demonstrated lower mortality at 1 year in high-volume centres in Germany.

Background: The primary treatment of ulcerative colitis (UC) is conservative; surgical intervention is carried out in the case of therapy-refractory situation, imminent or malignant transformation, or complications. Surgery for UC should be indicated by interdisciplinary means. Despite the development of drug therapy - in particular the introduction of biologics -, a surgical intervention becomes necessary in a relevant proportion of patients with UC throughout lifetime. Methods: A selective literature search was conducted, taking into account the current studies, reviews, meta-analyses, and guidelines. PubMed served as a database. The present work gives an overview of the surgical options, outcome as well as peri- and postoperative management for patients with UC. Results: Approximately 20% of patients with UC will require surgery during the course of their disease. The rate of colectomy after a disease duration of 10 years is at approximately 16%. Unlike Crohn's disease, UC is principally surgically curable since it is naturally limited to the colon and rectum. Restorative proctocolectomy with an ileal pouch-anal anastomosis represents the surgical treatment of choice. Large studies show a postoperative complication rate of around 30% and a low mortality of 0.1% for this procedure. Chronic pouchitis is one of the main factors limiting the surgical success of curing UC. Despite a high postoperative complication rate, there is a long-term pouch success rate of >90% after 10 and 20 years of follow-up. Conclusion: A close cooperation between the various disciplines in the pre- and postoperative setting is essential for an optimal outcome of patients with UC. Despite a 30% rate of early postoperative complications, normal quality of life can ultimately be reached in more than 90% of patients in experienced centers.

Graft rinse prior reperfusion in liver transplantation (LT) is believed to reduce the incidence of postreperfusion syndrome and improve clinical outcome. A MEDLINE search was performed to obtain a comprehensive review of the published literature dealing with graft rinse in LT. Moreover, all thirty-four LT centers in the Eurotransplant (ET) region were invited to participate in an online survey to whether or not graft rinse is performed and whether further research in the field is needed. Seventeen reports have been found to investigate graft rinse protocols in 1894 LT recipients. Eighteen of the thirty centers that participated in the online survey performed graft rinse prior reperfusion in LT. The most commonly used rinse solution was albumin. Nineteen centers stated interest in participating in a multicenter RCT in the field. The published literature does not provide concluding appraisal of the benefit of graft rinse in LT. Graft rinse protocols are not standardized and are based on personal experience. Appropriately designed clinical trials addressing the topic are demanded. The online survey appears to be a helpful tool for the evaluation of clinical practice and future research topics in the transplant community.

As it has been demonstrated that bioactive substances can be delivered locally using coated surgical suture materials, the authors developed a vascular endothelial growth factor (VEGF)-releasing suture material that should promote vascularization and potentially wound healing. In this context, the study focused on the characterization of the developed suture material and the verification of its biological activity, as well as establishing a coating process that allows reproducible and stable coating of a commercially available polydioxanone suture material with poly(l-lactide) (PLLA) and 0.1μg and 1.0μg VEGF. The in vitro VEGF release kinetics was studied using a Sandwich ELISA. The biological activity of the released VEGF was investigated in vitro using human umbilical vein endothelial cells. The potential of the VEGF-releasing suture material was also studied in vivo 5days after implantation in the hind limb of Wistar rats, when the histological findings were analyzed. The essential results, enhanced cell viability in vitro as well as significantly increased vascularization in vivo, were achieved using PLLA/1.0μg VEGF-coated suture material. Furthermore, ELISA measurements revealed a high reproducibility of the VEGF release behavior. Based on the results achieved regarding the dose-effect relationship of VEGF, the stability during its processing and the release behavior, it can be predicted that a bioactive suture material would be successful in later in vivo studies. Therefore, this knowledge could be the basis for future studies, where bioactive substances with different modes of action are combined for targeted, overall enhancement of wound healing.

Background Duplex ultrasound is the first choice in diagnostics and surveillance of stenoses of the internal carotid arteries before and even after surgery. Therefore, the quality of duplex ultrasound is crucial to investigate these vascular pathologies. Objective Aim of this study was the evaluation whether different surgical techniques affect the postoperative quality of duplex ultrasound. Methods In a time period from January to May 2015 duplex ultrasound of the cervical vessels was performed in 75 patients after unilateral endarterectomy of the internal carotid artery at our department between 2006 and 2012. Thereby, the non-operated contralateral side served as a control. Study groups were defined by the surgical techniques of eversion- or thrombendarterectomy with patch plasty using different patch materials and/or a haemostatic sealant. Duplex ultrasound analysis included acoustic impedance, extinction of ultrasound, thickness of skin and individual anatomic aspects of the patients. Results Carotid endarterectomy itself reduced intravascular grey levels, skin thickness and increased extinction of duplex ultrasound when compared to the non-operated side of the neck. In contrast, neither the kind of chosen operative technique nor the use of different patch materials or the application of a haemostatic sealant showed an effect in this regards. Conclusions Whereas carotid endarterectomy per se worsens the quality of postoperative duplex ultrasound, the different analysed surgical techniques as well as used patches and the application of a haemostatic sealant can be assumed to be equal regarding the quality of postoperative ultrasound.