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Abstract Background The use of routine data will be essential in future healthcare research. Therefore, harmonizing procedure codes is a first step to facilitate this approach as international research endeavour. An example for the use of routine data on a large scope is the investigation of surgical site infections (SSI). Ongoing surveillance programs evaluate the incidence of SSI on a national or regional basis in a limited number of procedures. For example, analyses by the European Centre for Disease Prevention (ECDC) nine procedures and provides a mapping table for two coding systems (ICD9, National Healthcare Safety Network [NHSN]). However, indicator procedures do not reliably depict overall SSI epidemiology. Thus, a broader analysis of all surgical procedures is desirable. The need for manual translation of country specific procedures codes, however, impedes the use of routine data for such an analysis on an international level. This project aimed to create an international surgical procedure coding systems allowing for automatic translation and categorization of procedures documented in country-specific codes. Methods We included the existing surgical procedure coding systems of five European countries (France, Germany, Italy, Spain, and the United Kingdom [UK]). In an iterative process, country specific codes were grouped in ever more categories until each group represented a coherent unit based on method of surgery, interventions performed, extent and site of the surgical procedure. Next two ID specialist (arbitrated by a third in case of disagreement) independently assigned country-specific codes to the resulting categories. Finally, specialist from each surgical discipline reviewed these assignments for their respective field. Results A total number of 153 SALT (Staphylococcus aureus Surgical Site Infection Multinational Epidemiology in Europe) codes from 10 specialties were assigned to 15,432 surgical procedures. Almost 4000 (26%) procedure codes from the SALT coding system were classified as orthopaedic and trauma surgeries, thus this medical field represents the most diverse group within the SALT coding system, followed by abdominal surgical procedures with 2390 (15%) procedure codes. Conclusion Mapping country-specific codes procedure codes onto to a limited number of coherent, internally and externally validated codes proofed feasible. The resultant SALT procedure code gives the opportunity to harmonize big data sets containing surgical procedures from international centres, and may simplify comparability of future international trial findings. Trial registration The study was registered at clinicaltrials.gov under NCT03353532 on November 27th, 2017.

Abstract Introduction Recombinant adenoviral vector vaccines against severe acute respiratory syndrome coronavirus 2 have been observed to be associated with vaccine-induced immune thrombotic thrombocytopenia. Though vaccine-induced immune thrombotic thrombocytopenia is a rare complication after vaccination with recombinant adenoviral vector vaccines, it can lead to severe complications. In vaccine-induced immune thrombotic thrombocytopenia, the vector vaccine induces heparin-independent production of platelet factor 4 autoantibodies, resulting in platelet activation and aggregation. Therefore, patients suffering from vaccine-induced immune thrombotic thrombocytopenia particularly present with signs of arterial or venous thrombosis, often at atypical sites, but also signs of bleeding due to disseminated intravascular coagulation and severe thrombocytopenia. We describe herein a rare case of fulminant portomesenteric thrombosis and atraumatic splenic rupture due to vaccine-induced immune thrombotic thrombocytopenia. Case summary (main symptoms and therapeutic interventions) This case report presents the diagnosis and treatment of a healthy 29-year-old male Caucasian patient suffering from an extended portomesenteric thrombosis associated with atraumatic splenic rupture due to vaccine-induced immune thrombotic thrombocytopenia after the first dose of an adenoviral vector vaccine against severe acute respiratory syndrome coronavirus 2 [ChAdOx1 nCoV-19 (AZD1222)]. Therapeutic management of vaccine-induced immune thrombotic thrombocytopenia initially focused on systemic anticoagulation avoiding heparin and the application of steroids and intravenous immune globulins as per the recommendations of international societies of hematology and hemostaseology. Owing to the atraumatic splenic rupture and extended portomesenteric thrombosis, successful management of this case required splenectomy with additional placement of a transjugular intrahepatic portosystemic shunt to perform local thrombaspiration, plus repeated local lysis to reconstitute hepatopetal blood flow. Conclusion The complexity and wide spectrum of the clinical picture in patients suffering from vaccine-induced immune thrombotic thrombocytopenia demand an early interdisciplinary diagnostic and therapeutic approach. Severe cases of portomesenteric thrombosis in vaccine-induced immune thrombotic thrombocytopenia, refractory to conservative management, may require additional placement of a transjugular intrahepatic portosystemic shunt, thrombaspiration, thrombolysis, and surgical intervention for effective management.

Abstract Distinct regions harboring cancer stem cells (CSCs) have been identified within the microenvironment of various tumors, and as in the case of their healthy counterparts, these anatomical regions are termed “niche.” Thus far, a large volume of studies have shown that CSC niches take part in the maintenance, regulation of renewal, differentiation and plasticity of CSCs. In this review, we summarize and discuss the latest findings regarding CSC niche morphology, physical terrain, main signaling pathways and interactions within them. The cellular and molecular components of CSCs also involve genetic and epigenetic modulations that mediate and support their maintenance, ultimately leading to cancer progression. It suggests that the crosstalk between CSCs and their niche plays an important role regarding therapy resistance and recurrence. In addition, we updated diverse therapeutic strategies in different cancers in basic research and clinical trials in this review. Understanding the complex heterogeneity of CSC niches is a necessary pre-requisite for designing superior therapeutic strategies to target CSC-specific factors and/or components of the CSC niche.

Abstract Background In acute pancreatitis (AP), microcirculatory dysfunction and leukocyte activation contribute to organ damage, inflammation, and mortality. Given the role of macrophage activation, monocyte recruitment, and microthrombus formation in the early pathogenesis of AP, we examined the macrophage activation marker soluble mannose receptor (sCD206) and the endothelial function marker von Willebrand factor (vWF) in patients admitted for AP. Methods In an exploratory analysis, serum sCD206 and plasma vWF were prospectively analyzed on day 1 and day 3 in 81 patients with AP admitted to the hospital. In addition, blood samples from 59 patients with early AP admitted to the intensive care unit and symptom onset 48 h and/or patients with local complications. Results In the prospective cohort, 17% developed severe/necrotizing pancreatitis compared with 56% in the ICU cohort. Serum concentrations of sCD206 on admission were higher in patients with severe/necrotizing AP than in patients with non-severe edematous AP (prospective: 1.57 vs. 0.66 mg/l, P = 0.005; ICU: 1.76 vs. 1.25 mg/l, P = 0.006), whereas other inflammatory markers (leukocytes, C-reactive protein, procalcitonin) and disease severity (SOFA, SAPS II, APACHE II) did not show significant differences. Patients with severe/necrotizing AP had a greater increase in sCD206 than patients with non-severe edematous AP at day 3 in the prospective cohort. In contrast to routine coagulation parameters, vWF antigen levels were elevated on admission (prospective cohort: 375 vs. 257%, P = 0.02; ICU cohort: 240 vs. 184%, P = 0.03). When used as continuous variables, sCD206 and VWF antigen remained predictors of severe/necrotizing AP after adjustment for etiology and age in both cohorts. Conclusions sCD206 identifies patients at risk of severe AP at earlier timepoints than routine markers of inflammation and coagulation. Prospective studies are needed to investigate whether incorporating early or repeated measurements into the existing scoring system will better identify patients at increased risk for complications of AP.

Abstract Background The usage of smartphones in the daily clinical routine is an essential aspect however it seems that they also present an important distractor that needs to be evaluated. The aim of this prospective study was the evaluation of the influence of phone calls as distractors on the performance levels of medical students during an objective structured clinical examination (OSCE), simulating the normal clinical practice. Methods As the goal of an OSCE presents the examination of clinical skills of medical students in a realistic setting, more than 100 students recruited from the university hospital of Cologne participated in either OSCE I or II. During the OSCE I intravenous cannulation was simulated while OSCE II simulated an acute abdominal pain station. Participants had to perform each of these stations under two circumstances: a normal simulated OSCE and an OSCE station with phone call distraction. Their performance during both simulations was then evaluated. Results In OSCE I students achieved significantly more points in the intravenous cannulation station if they were not distracted by phone calls (M=6.44 vs M=5.95). In OSCE II students achieved significantly more points in the acute abdominal pain station if they were not distracted by phone calls (M=7.59 vs M=6.84). While comparing only those students that completed both stations in OSCE I/II participating students achieved significantly more points in both OSCE I and II if they were not distracted by phone calls. Conclusion The presented data shows that phone call distraction decreases the performance level of medical students during an OSCE station. Therefore, it is an indicator that distraction especially for younger doctors should be held to a minimum. On a second note distraction should be integrated in the medical education system as it plays an important role in clinical routine.

Abstract Background In gastric cancer, nodal stage plays an important role. Insufficient lymph node harvesting or incomplete examination may lead to misclassification and affect postoperative strategy and group survival. This study’s objective was to determine the minimum number of examined lymph nodes needed in gastric cancer and compare this to the minimum lymph node count according to the current Union for International Cancer Control (UICC) classification using real world data. Methods Based on anatomical data, expected mean lymph node counts and their 95% confidence intervals for complete D2 lymphadenectomy were calculated. Using stochastic analysis, a threshold for correct classification in 95% of cases was determined. Survival data of nodal negative gastric cancer patients was extracted from the Surveillance, Epidemiology, and End Results (SEER)-Database for 2010–2017. Patients reaching at least the calculated theoretical threshold were compared to the minimum threshold according to the current UICC classification. Results The expected lymph node count was 30 (95% CI: 28–32; range 17–52), corresponding to a 27 lymph nodes. In nodal negative patients with exactly 16 and at least 27 examined lymph nodes, relative 5 year survival was 79 and 89% in T1/T2 and 39 and 64% T3/T4 gastric cancer, respectively. Theoretically, when only 16 lymph nodes are analyzed, nodal negative staging may be incorrect in up to 47% of cases. Conclusions A minimum threshold of 16 examined lymph nodes cannot be justified. Retrospective analysis confirmed systematic misclassification of patients with insufficient lymphadenectomy in nodal negative gastric cancer patients. Correct lymphadenectomy and thorough examination of the surgical specimen is mandatory.

Abstract Background Anastomotic leakage is the most important surgical complication following esophagectomy. A major cause of leakage is ischemia of the gastric tube that is used for reconstruction of the gastrointestinal tract. Generalized cardiovascular disease, expressed by calcifications of the aorta and celiac axis stenosis on a pre-operative CT scan, is associated with an increased risk of anastomotic leakage. Laparoscopic ischemic conditioning (ISCON) aims to redistribute blood flow and increase perfusion at the anastomotic site by occluding the left gastric, left gastroepiploic and short gastric arteries prior to esophagectomy. This study aims to assess the safety and feasibility of laparoscopic ISCON in selected patients with esophageal cancer and concomitant arterial calcifications. Methods In this prospective single-arm safety and feasibility trial based upon the IDEAL recommendations for surgical innovation, a total of 20 patients will be included recruited in 2 European high-volume centers for esophageal cancer surgery. Patients with resectable esophageal carcinoma (cT1-4a, N0–3, M0) with “major calcifications” of the thoracic aorta accordingly to the Uniform Calcification Score (UCS) or a stenosis of the celiac axis accordingly to the modified North American Symptomatic Carotid Endarterectomy Trial (NASCET) score on preoperative CT scan, who are planned to undergo esophagectomy are eligible for inclusion. The primary outcome variables are complications grade 2 and higher (Clavien-Dindo classification) occurring during or after laparoscopic ISCON and before esophagectomy. Secondary outcomes include intra- and postoperative complications of esophagectomy and the induction of angiogenesis by biomarkers of microcirculation and redistribution of blood flow by measurement of indocyanine green (ICG) fluorescence angiography. Discussion We hypothesize that in selected patients with impaired vascularization of the gastric tube, laparoscopic ISCON is feasible and can be safely performed 12–18 days prior to esophagectomy. Depending on the results, a randomized controlled trial will be needed to investigate whether ISCON leads to a lower percentage and less severe course of anastomotic leakage in selected patients. Trial registration Clinicaltrials.gov, NCT03896399 . Registered 4 January 2019.

Abstract Background The delivery of evidence-supported treatments (EST) in children’s mental health could be a valuable measure for monitoring mental healthcare quality; however, efforts to monitor the use of EST in real world systems are hindered by the lack of pragmatic methods. This mixed methods study examined the implementation and agency response rate of a pragmatic, claims-based measure of EST designed to be applied as a universal quality measure for child psychotherapy encounters in a state Medicaid system. Methods Implementation potential of the EST measure was assessed with healthcare leader rankings of the reporting method’s acceptability, appropriateness and feasibility (n = 53), and post-implementation ratings of EST rate accuracy. Ability of the healthcare system to monitor EST through claims was measured by examining the agency responsivity in using the claims-based measure across 98 Medicaid-contracted community mental health (CMH) agencies in Washington State. Results The analysis found the reporting method had high implementation potential. The method was able to measure the use of an EST for 83% of children covered by Medicaid with 58% CMH agencies reporting > 0 ESTs in one quarter. Qualitative analyses revealed that the most significant barrier to reporting ESTs was the operability of electronic health record systems and agencies’ mixed views regarding the accuracy and benefits of reporting. Conclusions Measurement of child mental health ESTs through Medicaid claims reporting has acceptable implementation potential and promising real world responsiveness from CMH agencies in one state. Variation in reporting by agency site and low to moderate perceived value by agency leaders suggests the need for additional implementation supports for wider uptake.

Abstract Background According to current guidelines, treatment of patients with hepatic oligometastasis in pancreatic cancer is not reflected and systemic chemotherapy is recommended in those patients. Retrospective data suggest beneficial outcomes in patients with hepatic oligometastasis, though prospective data from clinical trials addressing this particular patient group is not available. Methods In this single arm, phase-2 trial, survival data from patients receiving neoadjuvant chemotherapy followed by R0/R1 resection will be compared to historic data from patients with oligometastatic adenocarcinoma of the pancreas. The clinical trial will focus on a well-defined patient collective with metastatic load limited to the liver as target organ with a maximum of five metastases. The combination of liposomal irinotecan (nal-IRI), oxaliplatin (OX) and 5-fluouracil (5-FU)/folinic acid (FA) (nal-IRI + OX+ 5-FU/FA, NAPOX) was chosen as neoadjuvant chemotherapy; the choice was based on an ongoing clinical study in which NAPOX appeared manageable, with promising anti-tumor activity in first-line treatment of patients with metastatic pancreatic adenocarcinoma. In total 150 patients will be enrolled for this trial with an aim of 55 patients receiving a complete macroscopic synchronous tumor and metastatic resection. Discussion This is the first clinical study to prospectively evaluate the value of multimodality therapy concepts in oligometastatic pancreatic cancer. Trial registration numbers EudraCT 2019–002734-37 ; NCT04617457 .

Abstract Background Understanding what animals do in time and space is important for a range of ecological questions, however accurate estimates of how animals use space is challenging. Within the use of animal-attached tags, radio telemetry (including the Global Positioning System, ‘GPS’) is typically used to verify an animal’s location periodically. Straight lines are typically drawn between these ‘Verified Positions’ (‘VPs’) so the interpolation of space-use is limited by the temporal and spatial resolution of the system’s measurement. As such, parameters such as route-taken and distance travelled can be poorly represented when using VP systems alone. Dead-reckoning has been suggested as a technique to improve the accuracy and resolution of reconstructed movement paths, whilst maximising battery life of VP systems. This typically involves deriving travel vectors from motion sensor systems and periodically correcting path dimensions for drift with simultaneously deployed VP systems. How often paths should be corrected for drift, however, has remained unclear. Methods and results Here, we review the utility of dead-reckoning across four contrasting model species using different forms of locomotion (the African lion Panthera leo, the red-tailed tropicbird Phaethon rubricauda, the Magellanic penguin Spheniscus magellanicus, and the imperial cormorant Leucocarbo atriceps). Simulations were performed to examine the extent of dead-reckoning error, relative to VPs, as a function of Verified Position correction (VP correction) rate and the effect of this on estimates of distance moved. Dead-reckoning error was greatest for animals travelling within air and water. We demonstrate how sources of measurement error can arise within VP-corrected dead-reckoned tracks and propose advancements to this procedure to maximise dead-reckoning accuracy. Conclusions We review the utility of VP-corrected dead-reckoning according to movement type and consider a range of ecological questions that would benefit from dead-reckoning, primarily concerning animal–barrier interactions and foraging strategies.

Abstract Background Fine-scale data on animal position are increasingly enabling us to understand the details of animal movement ecology and dead-reckoning, a technique integrating motion sensor-derived information on heading and speed, can be used to reconstruct fine-scale movement paths at sub-second resolution, irrespective of the environment. On its own however, the dead-reckoning process is prone to cumulative errors, so that position estimates quickly become uncoupled from true location. Periodic ground-truthing with aligned location data (e.g., from global positioning technology) can correct for this drift between Verified Positions (VPs). We present step-by-step instructions for implementing Verified Position Correction (VPC) dead-reckoning in R using the tilt-compensated compass method, accompanied by the mathematical protocols underlying the code and improvements and extensions of this technique to reduce the trade-off between VPC rate and dead-reckoning accuracy. These protocols are all built into a user-friendly, fully annotated VPC dead-reckoning R function; Gundog.Tracks, with multi-functionality to reconstruct animal movement paths across terrestrial, aquatic, and aerial systems, provided within the Additional file 4 as well as online (GitHub). Results The Gundog.Tracks function is demonstrated on three contrasting model species (the African lion Panthera leo, the Magellanic penguin Spheniscus magellanicus, and the Imperial cormorant Leucocarbo atriceps) moving on land, in water and in air. We show the effect of uncorrected errors in speed estimations, heading inaccuracies and infrequent VPC rate and demonstrate how these issues can be addressed. Conclusions The function provided will allow anyone familiar with R to dead-reckon animal tracks readily and accurately, as the key complex issues are dealt with by Gundog.Tracks. This will help the community to consider and implement a valuable, but often overlooked method of reconstructing high-resolution animal movement paths across diverse species and systems without requiring a bespoke application.

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

Abstract Background HIV-positive mothers who face the dual burden of HIV-positive status and motherhood, may benefit from holistic services that include early childhood development (ECD). We evaluated the acceptability and impact of integrated ECD-PMTCT interventions for mothers and their children. Methods We implemented an integrated ECD-PMTCT intervention in 4 health facilities in Malawi for HIV-positive mothers and their infants. WHO/UNICEF Care for Child Development (CCD) education and counseling sessions were offered during routine PMTCT visits between infant age 1.5–24 months. From June–July 2019, we conducted in-depth interviews with 29 mothers enrolled in the intervention for ≥6 months across 4 health facilities. The interview guide focused on perceived impact of the intervention on mothers’ ECD and PMTCT practices, including barriers and facilitators, and unmet needs related to the program. Data were coded and analyzed using constant comparison methods in Atlas ti.8. Results The vast majority of mothers believed the ECD-PMTCT intervention improved their overall experience with the PMTCT services, strengthened their relationship with providers, and excited and motivated them to attend PMTCT services during the postpartum period. Unlike prior experience, mothers felt more welcome at the health facility, and looked forward to the next visit in order to interact with other mothers and learn new ECD skills. Mothers formed new social support networks with other mothers engaged in ECD sessions, and they provided emotional and financial support to one another, including encouragement regarding ART adherence. Mothers believed their infants reached developmental milestones faster compared to non-intervention children they observed at the same age, and they experienced improved engagement in caregiving activities among male caregivers. Nearly half of women requested additional support with depression or anxiety, coping mechanisms to deal with the stresses of life, or support in building positive dynamics with their male partner. Conclusion The integrated ECD-PMTCT intervention improved mother’s experiences with PMTCT programs and health care providers, increased ECD practices such as responsive and stimulating parenting, and created social support networks for women with other PMTCT clients.

Abstract Background Given that psychopharmacological approaches routinely used to treat mood-related problems may result in adverse outcomes in mood dysregulated adolescents at familial risk for bipolar disorder (BD), Mindfulness-Based Cognitive Therapy for Children (MBCT-C) provides an alternative effective and safe option. However, little is known about the brain mechanisms of beneficial outcomes from this intervention. Herein, we aimed to investigate the network-level neurofunctional effects of MBCT-C in mood dysregulated adolescents. Methods Ten mood dysregulated adolescents at familial risk for BD underwent a 12-week MBCT-C intervention. Resting-state functional magnetic resonance imaging (fMRI) was performed prior to and following MBCT-C. Topological metrics of three intrinsic functional networks (default mode network (DMN), fronto-parietal network (FPN) and cingulo-opercular network (CON)) were investigated respectively using graph theory analysis. Results Following MBCT-C, mood dysregulated adolescents showed increased global efficiency and decreased characteristic path length within both CON and FPN. Enhanced functional connectivity strength of frontal and limbic areas were identified within the DMN and CON. Moreover, change in characteristic path length within the CON was suggested to be significantly related to change in the Emotion Regulation Checklist score. Conclusions 12-week MBCT-C treatment in mood dysregulated adolescents at familial risk for BD yield network-level neurofunctional effects within the FPN and CON, suggesting enhanced functional integration of the dual-network. Decreased characteristic path length of the CON may be associated with the improvement of emotion regulation following mindfulness training. However, current findings derived from small sample size should be interpreted with caution. Future randomized controlled trials including larger samples are critical to validate our findings.

Abstract Background The consent management is an essential component for supporting the implementation of consents and withdrawals and thus, the realisation of patient’s rights. In MIRACUM, one of the four consortia of the Medical Informatics Initiative (MII), ten university hospitals intend to integrate the generic Informed Consent Service® (gICS) in their Data Integration Center (DIC). To provide a tool that supports the local workflows of the MIRACUM sites, the gICS should be improved. Methods We used three standardised questionnaires with 46 questions to elicit requirements from the ten sites. Each site answered the questions from the current and the desired future perspective. This made it possible to understand the individual processes at each site and it was possible to identify features and improvements that were generally necessary. Results The results of the survey were classified according to their impact on the gICS. Feature requests of new functionalities, improvements of already implemented functionalities and conceptual support for implementing processes were identified. This is the basis for an improved gICS release to support the ten sites’ individual consent management processes. Conclusions A release plan for the feature requests and improvements was coordinated with all sites. All sites have confirmed that the implementation of these features and enhancements will support their software-based consent management processes.

Abstract Background Biochar is a relatively new soil amendment method in agricultural practices that can improve the ecosystem services of soils. Biochar has commonly been applied to less fertile or contaminated soils, specifically sandy-textured and contaminated sandy soils, to improve their properties. However, the available literature indicates that not all sandy-textured and contaminated sandy soils show the same response to biochar applications, as the sign and size of the effect vary across studies. More specifically, primary studies show heterogeneous and potentially conflicting impacts of biochar application on a set of ecosystem services provided by these types of soils; namely, biomass production, water cycle, nutrient cycle, and climate regulation. Therefore, the objective of the present study is to systematically review the available evidence base to synthesise the impact and drivers of biochar amendments on four specific ecosystem services provided by sandy-textured and contaminated sandy soils. Methods This review follows the guideline of the Collaboration for Environmental Evidence and corresponds to the ROSES (RepOrting standards for Systematic Evidence Synthesis) reporting standard. A comprehensive search strategy will be employed to cover peer-reviewed and gray literature through bibliographic databases, organizational and institutional websites, and web searches. Search terms and strategies have been developed to identify the impact of biochar on the ecosystem services of sandy-textured soils. The search results will be screened first by their title and abstract, and then by their full text. Two literature reviewers will do this based on eligibility criteria. A validity assessment will be conducted to critically appraise and assess the validity of studies using a common validity framework for environmental studies. Data will be extracted from the studies that are found to be valid for the review. Narrative synthesis and meta-analysis will be employed to synthesise the review results.

Abstract Background Serum transferrin levels represent an independent predictor of mortality in patients with liver failure. Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of hepatocyte functions. The aim of this study was to explore whether serum transferrin reflects HNF4α activity. Methods Factors regulating transferrin expression in alcoholic hepatitis (AH) were assessed via transcriptomic/methylomic analysis as well as chromatin immunoprecipitation coupled to DNA sequencing. The findings were corroborated in primary hepatocytes. Serum and liver samples from 40 patients with advanced liver disease of multiple etiologies were also studied. Results In patients with advanced liver disease, serum transferrin levels correlated with hepatic transferrin expression (r = 0.51, p = 0.01). Immunohistochemical and biochemical tests confirmed reduced HNF4α and transferrin protein levels in individuals with cirrhosis. In AH, hepatic gene-gene correlation analysis in liver transcriptome revealed an enrichment of HNF4α signature in transferrin-correlated transcriptome while transforming growth factor beta 1 (TGFβ1), tumor necrosis factor α (TNFα), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) negatively associated with transferrin signature. A key regulatory region in transferrin promoter was hypermethylated in patients with AH. In primary hepatocytes, treatment with TGFβ1 or the HNF4α inhibitor BI6015 suppressed transferrin production, while exposure to TNFα, IL-1β, and IL-6 had no effect. The correlation between hepatic HNF4A and transferrin mRNA levels was also seen in advanced liver disease. Conclusions Serum transferrin levels constitute a prognostic and mechanistic biomarker. Consequently, they may serve as a surrogate of impaired hepatic HNF4α signaling and liver failure.

Abstract Background Expression of CXCR4, a chemokine (C-X-C motif) receptor that plays a central role in tumor growth and metastasis of circulating tumor cells, has been described in a variety of solid tumors. A high expression of CXCR4 has a prognostic significance with regard to overall and progression-free survival and offers a starting point for targeted therapies. In this context, [68]Ga-Pentixafor-Positron Emission Tomography/Computer Tomography (PET/CT) offers promising possibility of imaging the CXCR4 expression profile. We set out to compare a [18F] fluorodeoxyglucose (FDG)-PET/CT and a [68Ga]Pentixafor-PET/CT in (re-)staging and radiation planning of patients with localized esophageal cancer. Materials and methods In this retrospective analysis, ten patients, with adeno- or squamous cell carcinoma of the esophagus (n = 3 and n = 7, respectively), which were scheduled for radio (chemo) therapy, were imaged using both Pentixafor and FDG PET/CT examinations. All lesions were visually rated as Pentixafor and FDG positive or negative. For both tracers, SUVmax was measured all lesions and compared to background. Additionally, immunohistochemistry of CXCR4 was obtained in patients undergoing surgery. Results FDG-positive tumor-suspicious lesions were detected in all patients and a total of 26 lesions were counted. The lesion-based analysis brought equal status in 14 lesions which were positive for both tracers while five lesions were FDG positive and Pentixafor negative and seven lesions were FDG negative, but Pentixafor positive. Histopathologic correlation was available in seven patients. The CXCR4 expression of four non-pretreated tumour lesion samples was confirmed immunohistochemically. Conclusion Our data shows that additional PET/CT imaging with Pentixafor for imaging the CXCR4 chemokine receptor is feasible but heterogeneous in both newly diagnosed and pretreated recurrent esophageal cancer. In addition, the Pentixafor PET/CT may serve as complementary tool for radiation field expansion in radiooncology.

Abstract Background Iatrogenic severe hyperglycemia (ISH) caused by glucose-containing i.v. solution is a potentially fatal treatment error. The objective of this study was to investigate the causes, circumstances, course of disease, and complications of ISH > 300 mg/dl (16.7 mmol/l) in neonates and children. Methods We emailed a survey to 105 neonatal and pediatric intensive care units in Germany, Austria, and Switzerland, asking to retrospectively report cases of ISH. Results We received 11 reports about premature infants to children. Four patients (36%) had poor outcome: 2 died and 2 suffered persistent sequelae. The highest observed blood glucose was at median 983 mg/dl (54.6 mmol/l) (range 594–2240 mg/dl; 33.0–124.3 mmol/l) and median time to normoglycemia was 7 h (range 2–23). Blood glucose was higher and time to normoglycemia longer in patients with poor outcome. Invasive therapy was required in 73% (mechanical ventilation) and 50% (vasopressor therapy) of patients, respectively. Administration of insulin did not differ between outcome groups. Patients with poor outcome showed coma (100% vs. 40%) and seizures (75% vs. 29%) more frequently than those with good outcome. Conclusions ISH is a severe condition with high morbidity and mortality. Further research to amplify the understanding of this condition is needed, but focus should largely be held on its prevention.

Abstract Background Keratins (Ks) represent tissue-specific proteins. K18 is produced in hepatocytes while K19, the most widely used ductular reaction (DR) marker, is found in cholangiocytes and hepatic progenitor cells. K18-based serum fragments are commonly used liver disease predictors, while K19-based serum fragments detected through CYFRA21-1 are established tumor but not liver disease markers yet. Since DR reflects the severity of the underlying liver disease, we systematically evaluated the usefulness of CYFRA21-1 in different liver disease severities and etiologies. Methods Hepatic expression of ductular keratins (K7/K19/K23) was analyzed in 57 patients with chronic liver disease (cohort i). Serum CYFRA21-1 levels were measured in 333 Austrians with advanced chronic liver disease (ACLD) of various etiologies undergoing hepatic venous pressure gradient (HVPG) measurement (cohort ii), 231 French patients with alcoholic cirrhosis (cohort iii), and 280 hospitalized Germans with decompensated cirrhosis of various etiologies (cohort iv). Results (i) Hepatic K19 levels were comparable among F0–F3 fibrosis stages, but increased in cirrhosis. Hepatic K19 mRNA strongly correlated with the levels of other DR-specific keratins. (ii) In ACLD, increased serum CYFRA21-1 associated with the presence of clinically significant portal hypertension (CSPH; HVPG ≥ 10 mmHg) (OR = 5.87 [2.95–11.68]) and mortality (HR = 3.02 [1.78–5.13]; median follow-up 22 months). (iii) In alcoholic cirrhosis, elevated serum CYFRA21-1 indicated increased risk of death/liver transplantation (HR = 2.59 [1.64–4.09]) and of HCC (HR = 1.74 [1.02–2.96]) over the long term (median follow-up 73 months). (iv) In decompensated cirrhosis, higher serum CYFRA21-1 predicted 90-day mortality (HR = 2.97 [1.92–4.60]) with a moderate accuracy (AUROC 0.64), independently from established prognostic scores. Conclusions Hepatic K19 mRNA and serum CYFRA21-1 levels rise in cirrhosis. Increased CYFRA21-1 levels associate with the presence of CSPH and reliably indicate mortality in the short and long term independently of conventional liver biochemistry markers or scoring systems. Hence, the widely available serum CYFRA21-1 constitutes a novel, DR-related marker with prognostic implications in patients with different settings of advanced liver disease.

Abstract Background Three-dimensional (3D) stereoscopic vision is crucial to perform any kind of manual task. The reduction from real life 3D to virtual two-dimensional (2D) sight is a major challenge in minimally invasive surgery (MIS). A 3D display technique has been shown to reduce operation time and mistakes and to improve the learning curve. Therefore, the use of a3D display technique seems to optimize surgical performance for novice and experienced surgeons. Inspired by consumer electronics, a 4K display technique was recently introduced to MIS. Due to its high resolution and zoom effect, surgeons should benefit from it. The aim of this study is to evaluate if “state-of-the-art” 3D- vs. 4K-display techniques could influence surgical performance. Methods A randomized, cross-over, single-institution, single-blinded trial is designed. It compares the primary outcome parameter “surgical performance”, represented by “performance time ”and “number of mistakes”, using a passive polarizing 3D and a 4K display system (two arms) to perform different tasks in a minimally invasive/laparoscopic training parkour. Secondary outcome parameters are the mental stress load (National Aeronautics and Space Administration (NASA) Task Load Index) and the learning curve. Unexperienced novices (medical students), non-board-certified, and board-certified abdominal surgeons participate in the trial (i.e., level of experience, 3 strata). The parkour consists of seven tasks (for novices, five tasks), which will be repeated three times. The 1st run of the parkour will be performed with the randomized display system, the 2nd run with the other one. After each run, the mental stress load is measured. After completion of the parkour, all participants are evaluated by an ophthalmologist for visual acuity and stereoscopic vision with five tests. Assuming a correlation of 0.5 between measurements per subject, a sample size of 36 per stratum is required to detect a standardized effect of 0.5 (including an additional 5% for a non-parametric approach) with a power of 80% at a two-sided type I error of 5%. Thus, altogether 108 subjects need to be enrolled. Discussion Complex surgical procedures are performed in a minimally invasive/laparoscopic technique. This study should provide some evidence to decide which display technique a surgeon could choose to optimize his performance. Trial registration ClinicalTrials.gov, NCT03445429 . Registered on 7 February 2018.

Abstract Background Adenocarcinoma of the gastroesophageal junction (GEJ) Siewert type II can be resected by transthoracic esophagectomy or transhiatal extended gastrectomy. Both allow for a complete tumor resection, yet there is an ongoing controversy about which surgical approach is superior with regards to quality of life, oncological outcomes and survival. While some studies suggest a better oncological outcome after transthoracic esophagectomy, others favor transhiatal extended gastrectomy for a better postoperative quality of life. To date, only retrospective studies are available, showing ambiguous results. Methods This study is a multinational, multicenter, randomized, clinical superiority trial. Patients (n = 262) with a GEJ type II tumor resectable by both transthoracic esophagectomy and transhiatal extended gastrectomy will be enrolled in the trial. Type II tumors are defined as tumors with their midpoint between ≤1 cm proximal and ≤ 2 cm distal of the top of gastric folds on preoperative endoscopy. Patients will be included in one of the participating European sites and are randomized to either transthoracic esophagectomy or transhiatal extended gastrectomy. The trial is powered to show superiority for esophagectomy with regards to the primary efficacy endpoint overall survival. Key secondary endpoints are complete resection (R0), number and localization of tumor infiltrated lymph nodes at dissection, post-operative complications, disease-free survival, quality of life and cost-effectiveness. Postoperative survival and quality of life will be followed-up for 24 months after discharge. Further survival follow-up will be conducted as quarterly phone calls up to 60 months. Discussion To date, as level 1 evidence is lacking, there is no consensus on which surgery is superior and both surgeries are used to treat GEJ type II carcinoma worldwide. The CARDIA trial is the first randomized trial to compare transthoracic esophagectomy versus transhiatal extended gastrectomy in patients with GEJ type II tumors. Several quality control measures were implemented in the protocol to ensure data reliability and increase the trial’s significance. It is hypothesized that esophagectomy allows for a higher rate of radical resections and a more complete mediastinal lymph node dissection, resulting in a longer overall survival, while still providing an acceptable quality of life and cost-effectiveness. Trial registration The trial was registered on August 2nd 2019 at the German Clinical Trials Register under the trial-ID DRKS00016923 .

Abstract Background Gastric cancer is one of the deadliest cancer entities worldwide. While surgery is the only curative treatment option in early tumors, for locally advanced and metastatic patients further therapeutic targets are needed. Several studies not only reported mutations but also amplifications of the KRAS locus in different cancer entities. More recently, KRAS amplification was discussed as a new therapeutic target. Little is known about the (prognostic) relevance and (heterogenic) distribution of KRAS amplification in gastric adenocarcinomas, especially in Non-Asian patients. Methods Amplification of the KRAS locus and corresponding protein expression was analyzed in 582 gastric adenocarcinomas employing fluorescence in-situ hybridization (FISH) and immunohistochemistry. Amplification status was correlated with clinico-pathological features, clinical outcome and molecular tumor data including a correlation to the TCGA subtypes of gastric carcinoma. Results KRAS amplification was detected in 27 out of 470 analysable tumors (5.7%) and correlated with protein expression of KRAS in all amplified tumors. Within the KRAS amplified gastric tumors 14/27 (51.9%) showed a heterogeneous distribution with also KRAS non-amplified tumor parts. According to TCGA 24 tumors (88.8%) were related to chromosomal instable tumors (CIN). The survival analysis of the entire patient cohort did not show any difference in overall survival in dependence on the KRAS status. However, a significant survival difference with a worse outcome for patients with KRAS amplified tumors was identified when analysing patients without neoadjuvant pre-treatment. Conclusions We confirm the unfavorable prognosis of KRAS amplified tumors reported by other studies in (Asian) patient groups, at least in patients without neoadjuvant pre-treatment. Within KRAS amplified tumors we revealed intratumoral heterogeneity that may define a (more aggressive) tumor cell population which is more frequently observed in patients with lymph node metastases. Despite the heterogeneous distribution of KRAS amplified tumor clones, KRAS amplified locally advanced or metastasized gastric adenocarcinomas represent a therapeutically highly relevant tumor subgroup.

Abstract Introduction Current guidelines advocate empirical antibiotic treatment (EAT) in haematological patients with febrile neutropenia. However, the optimal duration of EAT is unknown. In 2011, we have introduced a protocol, promoting discontinuation of carbapenems as EAT after 3 days in most patients and discouraging the standard use of vancomycin. This study assesses the effect of introducing this protocol on carbapenem and vancomycin use in high-risk haematological patients and its safety. Methods A retrospective before-after study was performed comparing a cohort from 2007 to 2011 (period I, before restrictive EAT use) with a cohort from 2011 to 2014 (period II, restrictive EAT use). Neutropenic episodes related to chemotherapy or stem cell transplantation (SCT) in patients with acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS) were analysed. The primary outcome was the use of carbapenems and vancomycin as EAT during neutropenia, expressed as days of therapy (DOT)/100 neutropenic days and analysed with interrupted time series (ITS). Also the use of other antibiotics was analysed. Safety measurements included 30-day mortality, ICU admittance within 30 days after start of EAT and positive blood cultures with carbapenem-susceptible microorganisms. Results Three hundred sixty-two neutropenic episodes with a median duration of 18 days were analysed, involving 201 patients. ITS analysis showed decreased carbapenem use with a step change of − 16.1 DOT/100 neutropenic days (95% CI − 26.77 to − 1.39) and an overall reduction of 21.6% (8.7 DOT/100 neutropenic days). Vancomycin use decreased with a step change of − 13.7 DOT/100 neutropenic days (95% CI − 23.75 to − 3.0) and an overall reduction of 54.7% (14.6 DOT/100 neutropenic days). The use of all antibiotics combined decreased from 155.6 to 138 DOT/100 neutropenic days, a reduction of 11.3%. No deaths directly related to early discontinuation of EAT were identified, also no notable difference in ICU-admission (9/116 in period I, 9/152 in period II) and positive blood cultures (4/116 in period I, 2/152 in period II) was detected. Conclusion The introduction of a protocol promoting restrictive use of EAT resulted in reduction of carbapenem and vancomycin use and appears to be safe in AML or high-risk MDS patients with febrile neutropenia during chemotherapy or SCT.

Abstract Background Total knee replacement (TKR) or total hip replacement (THR) are common and effective procedures in patients with osteoarthritis (OA) to restore physical function and reduce joint related pain. Patient education plays an important role in the treatment process aiming to develop necessary self-management skills to facilitate recovery and ensure long-term success. We have developed a mobile app (RECOVER-E) for iOS and Android smartphones which provides important information on the preoperative phase, surgery and recovery. The concomitant study will determine the efficacy of RECOVER-E on patients’ surgical outcomes. Methods/design This study is a non-randomized, multi-centre (4 sites), double-arm, controlled trial with 1:1 assignment. 160 patients undergoing primary TKR or THR will be recruited from January until October 2019 in 4 German hospitals. Both groups will receive standard care. Additionally, the intervention group will use the app RECOVER-E. Measurements will be taken 4–6 weeks before surgery, on the day of admission to the hospital, on the first and 7th postoperative day and 3 months post-surgery. Primary outcome will be self-reported physical function measured on the activities of daily living (ADL) subscale of the Knee injury and Osteoarthritis Outcome Score (KOOS) and the Hip disability and Osteoarthritis Outcome Score (HOOS) for patients with knee and hip osteoarthritis, respectively. Secondary outcomes include the subscales for pain, symptoms, function in sport and recreation and knee/hip-related quality of life of the HOOS and KOOS, preoperative anxiety, measured by the Hospital Anxiety and Depression Scale (HADS), as well as, pain at rest and pain during activity measured by a numerical rating scale (NRS). Primary endpoint is 3 months post-surgery. Discussion Mobile Health (mHealth) has become increasingly important in patient-centred health care aiming to enhance patient involvement and self-management capabilities. To our knowledge this is the first study to investigate the effect of an evidence-based mobile app on patient reported outcomes after joint replacement. This study should provide evidence supporting the use of mHealth to facilitate recovery and open up new possibilities for patient care in joint replacement. Trial registration DRKS Data Management retrospectively registered. DRKS-ID: DRKS00012744.

Abstract Background The SWI/SNF complex is an important chromatin remodeler, commonly dysregulated in cancer, with an estimated mutation frequency of 20%. ARID1A is the most frequently mutated subunit gene. Almost nothing is known about the other familiar members of the SWI/SNF complexes, SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1), in oesophageal adenocarcinoma (EAC). Methods We analysed a large cohort of 685 patients with EAC. We used four different antibodies to detect a loss-of-protein of ARID1A BRM, BRG1 and INI1 by immunohistochemistry and correlated these findings with molecular and clinical data. Results Loss of ARID1A, BRG1, BRM and INI1 was observed in 10.4, 3.4, 9.9 and 2% of EAC. We found a co-existing protein loss of ARID1A and BRM in 9.9% and of ARID1A and BRG1 in 2.2%. Patients with loss of ARID1A and TP53 wildtype EACs showed a shortened overall survival compared with AIRDA1A-positive tumours [median overall survival was 60.1 months (95%CI 1.2–139.9 months)] in patients with ARIDA-1A expression and 26.2 months (95%CI 3.7–19.1 months) in cases of ARIDA-1A loss (p = 0.044). Tumours with loss or expression of ARID1A and TP53 loss were not associated with a difference in survival. Only one tumour revealed high microsatellite instability (MSI-H) with concomitant ARID1A loss. All other ARID1A loss-EACs were microsatellite-stable (MSS). No predictive relevance was seen for SWI/SNF-complex alterations and simultaneous amplification of different genes (PIK3CA, KRAS, c-MYC, MET, GATA6, ERBB2). Conclusion Our work describes, for the first time, loss of one of the SWI/SNF ATPase subunit proteins in a large number of adenocarcinomas of the oesophagus. Several papers discuss possible therapeutic interventions for tumours showing a loss of function of the SWI/SNF complex, such as PARP inhibitors or PI3K and AKT inhibitors. Future studies will be needed to show whether SWI/SNF complex-deficient EACs may benefit from personalized therapy.

Abstract Background To date, patients with metastasized pancreatic ductal adenocarcinoma (PDAC M1) are regarded as a uniform collective. We hypothesize the existence of oligometastatic disease (OMD): a state of PDAC M1 disease with better tumor biology, limited metastasis, and increased survival. Methods Data of 128 PDAC M1 patients treated at the University of Cologne between 2008 and 2018 was reviewed. Interdependence between clinical parameter was calculated using the Mann-Whitney U-Test. Survival curves were generated using the Kaplan-Meier method and analyzed using the log-rank test. Results Eighty-one (63%) patients had metastases confined to one organ (single organ metastasis, SOG) whereas the remaining 47 (37%) showed multiple metastatic sites (multi-organ metastasis, MOG). Survival analysis revealed a median overall survival (OS) of 12.2 months for SOG vs 4.5 months for MOG (95% CI 5.7–9.8; p

Abstract Background Despite consistent recognition of their influence, empirical study of how outer setting factors (e.g., policies, financing, stakeholder relationships) influence public systems’ investment in and adoption of evidence-based treatment (EBT) is limited. This study examined associations among unmodifiable (e.g., demographic, economic, political, structural factors) and modifiable (e.g., allocation of resources, social processes, policies, and regulations) outer setting factors and adoption of behavioral health EBT by US states. Methods Multilevel models examined relationships between state characteristics, an array of funding and policy variables, and state adoption of behavioral health EBTs for adults and children across years 2002–2012, using data from the National Association for State Mental Health Program Directors Research Institute and other sources. Results Several unmodifiable state factors, including per capita income, controlling political party, and Medicaid expansion, predicted level of state fiscal investments in EBT. By contrast, modifiable factors, such as interagency collaboration and investment in research centers, were more predictive of state policies supportive of EBT. Interestingly, level of adult EBT adoption was associated with state fiscal supports for EBT, while child EBT adoption was predicted more by supportive policies. State per capita debt and direct state operation of services (versus contracting for services) predicted both child and adult EBT adoption. Conclusions State-level EBT adoption and associated implementation support is associated with an interpretable array of policy, financing, and oversight factors. Such information expands our knowledge base of the role of the outer setting in implementation and may provide insight into how best to focus efforts to promote EBT for behavioral health disorders.

Abstract Objective Calcitonin is considered to be a biomarker of medullary thyroid carcinoma and C-cell hyperplasia, but calcitonin can also be elevated in about 30% of the patients with end-stage kidney disease. We reported preoperative calcitonin serum levels in 31 patients on hemodialysis before parathyroid surgery, evaluate influencing factors on calcitonin levels and determine postoperative calcitonin levels after parathyroid surgery. Results Median preoperative serum calcitonin was 8 pg/ml (range 2 to 165 pg/ml), serum calcitonin concentration declined postoperatively to 3 pg/ml (range 1 to 192 pg/ml). There was a strong positive correlation between pre- and postoperative serum calcitonin levels (r = 0.92; p > 0.01). Elevated preoperative serum calcitonin concentrations (more than 10 pg/ml) were found in 14 out of 32 dialysis-dependent patients (44%). Preoperative calcitonin levels of male patients were significantly higher than female patients. Hypercalcitoninemia showed a positive correlation to body mass index (p

Abstract Background Molecular markers predicting survival in esophageal adenocarcinoma (EAC) are rare. Specifically, in favorable oncologic situations, e.g. nodal negativity or major neoadjuvant therapy response, there is a lack of additional risk factors that serve to predict patients’ outcome more precisely. This study evaluated X-linked inhibitor of apoptosis protein (XIAP) as a potential marker improving outcome prediction. Methods Tissue microarrays from 362 patients that were diagnosed with resectable EAC were included in the study. XIAP was stained by immunohistochemistry and correlated to clinical outcome, molecular markers and markers of the cellular tumor microenvironment. Results XIAP did not impact on overall survival (OS) in the whole study collective. Subgroup analyses stratifying for common genetic markers (TP53, ERBB2, ARID1A/SWI/SNF) did not disclose any impact of XIAP expression on survival. Detailed subgroup analyses of [1] nodal negative patients, [2] highly T-cell infiltrated tumors and [3] therapy responders to neoadjuvant treatment revealed a significant inverse role of high XIAP expression in these specific oncologic situations; elevated XIAP expression detrimentally affected patients’ outcome in these subgroups. [1]: OS XIAP low: 202 months (m) vs. XIAP high: 38 m; [2]: OS 116 m vs. 28.2 m; [3]: OS 31 m vs. 4 m). Conclusions Our data suggest XIAP expression in EAC as a worthy tool to improve outcome prediction in specific oncologic settings that might directly impact on clinical diagnosis and treatment of EAC in the future.

Abstract Background Arm-lymphedema is a major complication after breast cancer. Recent studies demonstrate the validity of predicting Breast Cancer Related Lymphedema (BCRL) by self-reports. We aimed to investigate the rate of BCRL and its risk factors in the long-term using self-reported symptoms. Methods Data was collected from 385 patients who underwent multimodal therapy for nodal positive breast cancer, including breast conserving surgery, axillary dissection, and local or locoregional radiotherapy. Two validated questionnaires were used for the survey of BCRL (i.e. LBCQ-D and SDBC-D). These were analysed collectively with retrospective data of our medical records. Results 23.5% (n = 43) suffered a permanent BCRL (stage II-III) after a median follow-up time of 10.1 years (4.9–15.9 years); further 11.5% (n = 23) reported at least one episode of reversible BCRL (Stage 0-I) during the follow-up time. 87.1% of the patients with lymphedema developed this condition in the first two years. Adjuvant chemotherapy was a significant risk factor for the appearance of BCRL (p = 0.001; 95%-CI 7.7–10.2). Conclusions Breast cancer survivors face a high risk of BCRL, particularly if axillary dissection was carried out. Almost 90% of BCRL occurred during the first two years after radiotherapy. Self-report of symptoms seems to be a suitable instrument of early detection of BCRL.

Abstract Background Exosomes are small membrane-bound vesicles that contribute to tumor progression and metastasis by mediating cell-to-cell communication and modifying the tumor microenvironment at both local and distant sites. However, little is known about the predominant factors in exosomes that contribute to breast cancer (BC) progression. MTA1 is a transcriptional co-regulator that can act as both a co-activator and co-repressor to regulate pathways that contribute to cancer development. MTA1 is also one of the most up-regulated proteins in cancer, whose expression correlates with cancer progression, poor prognosis and increased metastatic potential. Methods We identified MTA1 in BC exosomes by antibody array and confirmed expression of exosome-MTA1 across five breast cancer cells lines. Ectopic expression of tdTomato-tagged MTA1 and exosome transfer were examined by fluorescent microscopy. CRISPR/Cas9 genetic engineering was implemented to knockout MTA1 in MCF7 and MDA-MB-231 breast cancer cells. Reporter assays were used to monitor hypoxia and estrogen receptor signaling regulation by exosome-MTA1 transfer. Results Ectopic overexpression of tdTomato-MTA1 in BC cell lines demonstrated exosome transfer of MTA1 to BC and vascular endothelial cells. MTA1 knockout in BC cells reduced cell proliferation and attenuated the hypoxic response in these cells, presumably through its co-repressor function, which could be rescued by the addition of exosomes containing MTA1. On the other hand, consistent with its co-activator function, estrogen receptor signaling was enhanced in MTA1 knockout cells and could be reversed by addition of MTA1-exosomes. Importantly, MTA1 knockout sensitized hormone receptor negative cells to 4-hydroxy tamoxifen treatment, which could be reversed by the addition of MTA1-exosomes. Conclusions This is the first report showing that BC exosomes contain MTA1 and can transfer it to other cells resulting in changes to hypoxia and estrogen receptor signaling in the tumor microenvironment. These results, collectively, provide evidence suggesting that exosome-mediated transfer of MTA1 contributes to BC progression by modifying cellular responses to important signaling pathways and that exosome-MTA1 may be developed as a biomarker and therapeutic target for BC.

Abstract Background Carcinomas of the small bowel are rare tumors usually with dismal prognosis. Most recently, some potentially treatable molecular alterations were described. We emphasize the growing evidence of individualized treatment options in small bowel carcinoma. Methods We performed a DNA- based multi-gene panel using ultra-deep sequencing analysis (including 14 genes with up to 452 amplicons in total; KRAS, NRAS, HRAS, BRAF, DDR2, ERBB2, KEAP1, NFE2L2, PIK3CA, PTEN, RHOA, BRCA1, BRCA2 and TP53) as well as an RNA-based gene fusion panel including ALK, BRAF, FGFR1, FGFR2, FGFR3, MET, NRG1, NTRK1, NTRK2, NTRK3, RET and ROS1 on eleven formalin fixed and paraffin embedded small bowel carcinomas. Additionally, mismatch-repair-deficiency was analyzed by checking the microsatellite status using the five different mononucleotide markers BAT25, BAT26, NR-21, NR-22 and NR-27 and loss of mismatch repair proteins using four different markers (MLH1, MSH6, MSH2, PMS2). Results In five out of eleven small bowel carcinomas we found potentially treatable genetic alterations. Three patients demonstrated pathogenic (class 5) BRCA1 or BRCA2 mutations – one germline-related in a mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN). Two additional patients revealed an activating ERBB2 mutation or PIK3CA mutation. Furthermore two tumors were highly microsatellite-instable (MSI-high), in one case associated to Lynch-syndrome. We did not find any gene fusions. Conclusion Our results underscore, in particular, the relevance of potentially treatable molecular alterations (like ERBB2, BRCA and MSI) in small bowel carcinomas. Further studies are needed to proof the efficacy of these targeted therapies in small bowel carcinomas.

Abstract Background HER2 (ERBB2 or HER2/neu) is a tyrosine-kinase increasing cell proliferation. Overexpression/amplification of HER2 is correlated with worse prognosis in solid malignancies. Consequently, HER2 targeting is established in breast and upper gastrointestinal tract cancer. There are conflicting data concerning the impact of HER2 overexpression on esophageal adenocarcinoma (EAC), as most studies do not differ between cancers of the esophagus/gastroesophageal junction and the stomach. The aim of this study was to analyze the expression/amplification of HER2 in EAC in correlation to clinicopathological data to verify its prognostic impact. Methods We analyzed 428 EAC patients that underwent transthoracic thoraco-abdominal esophagectomy between 1997 and 2014. We performed HER2 immunohistochemistry (IHC) according to the guidelines and fluorescence-in-situ-hybridization (FISH) for IHC score2+, using tissue micro arrays (TMA) with up to eight biopsies from the surface and infiltration area of a single tumor for evaluating HER2-heterogeneity and single-spot TMA. The HER2-status was correlated with clinicopathological data. Results HER2-positivity was found in up to 14.9% in our cohort (IHC score 3+ or IHC score 2+ with gene amplification) and demonstrated a significantly better overall survival (OS) in correlation to HER2-negative tumors (median OS 70.1 vs. 24.6 months, p = 0.006). HER2-overexpression was more frequently seen in lower tumor stages (pT1/pT2, p = 0.038), in the absence of lymphatic metastases (pN0/pN+, p = 0.020), and was significantly associated with better histological grading (G1/G2) (p = 0.041). Conclusion We demonstrated a positive prognostic impact of HER2 overexpression in a large cohort of EAC, contrary to other solid malignancies including gastric cancer and breast cancer, but consistent to the results of a large study on EAC from 2012.

Abstract Background Collision tumors are rare cases with two different tumor entities growing synchronously. While adenocarcinoma of the pancreas is the most common pancreatic tumor with an incidence of 10 per 100.000, retroperitoneal liposarcoma remains very rare. This is the first report of a collision tumor between these two tumor entities. Case presentation Demographic details: The tumor was diagnosed in a 64 male Caucasian patient. Besides atrial fibrillation, arterial hypertension and a hypothyroidism there is no relevant medical history especially no history of cancer. Clinical details: During a routine check-up an unclassified tumor of the pancreatic tail was diagnosed. The lab showed no pathologies. Tumor markers were negative for carbohydrate antigen 19–9 and 72–4 (CA 19–9, CA 72–4) and carcinoembryonic antigen (CEA). Alpha-fetoprotein (AFP) and neuron specific enolase (NSE) were both elevated (AFP 97kU/l, (

Abstract Background The relevance of estrogen receptor (ER) expression in pancreatic ductal adenocarcinoma (PDAC) is largely unknown. Clinical trials targeting ER with selective estrogen receptor modulators in pancreatic cancer did not show any benefit. Here, we analyze the impact of recently characterized ER isoform beta on survival in a cohort of patients with resected PDAC. Methods Eighty-four patients having undergone pancreatic resection for PDAC at a single institution were identified. Tissue microarrays were constructed of archival tumor specimens. The expression of ER beta was determined by immunohistochemistry and quantified by a system established for estrogen receptor expression in breast cancer. ER beta expression was then correlated with clinicopathological parameters, and univariate and multivariate survival analyses were performed. Results Nuclear expression of ER beta was found in 31% of tumors. No significant correlation was found between ER beta expression and TNM status, tumor grade, age or sex. Univariate analysis revealed nodal metastasis and the expression of ER beta as factors correlating with a shorter overall survival and disease free survival. When comparing ER beta expression in patients surviving more than 24 months with those who died from the tumor within 12 or 24 months, respectively, a significantly lower ER beta expression was found in the long term survivors. In multivariate analysis, ER beta expression was demonstrated to be an independent predictor of shorter overall survival. Conclusions In resected PDAC, expression of ER beta seems to correlate with poor prognosis. These data may help to identify patients who may benefit from additional systemic therapy including selective estrogen receptor modulators.

Abstract Background The role of the kidney in glucose homeostasis has gained global interest. Kidneys are innervated by renal nerves, and renal denervation animal models have shown improved glucose regulation. We hypothesized that stimulation of renal nerves at kilohertz frequencies, which can block propagation of action potentials, would increase urine glucose excretion. Conversely, we hypothesized that low frequency stimulation, which has been shown to increase renal nerve activity, would decrease urine glucose excretion. Methods We performed non-survival experiments on male rats under thiobutabarbital anesthesia. A cuff electrode was placed around the left renal artery, encircling the renal nerves. Ureters were cannulated bilaterally to obtain urine samples from each kidney independently for comparison. Renal nerves were stimulated at kilohertz frequencies (1–50 kHz) or low frequencies (2–5 Hz), with intravenous administration of a glucose bolus shortly into the 25–40-min stimulation period. Urine samples were collected at 5–10-min intervals, and colorimetric assays were used to quantify glucose excretion and concentration between stimulated and non-stimulated kidneys. A Kruskal-Wallis test was performed across all stimulation frequencies (α = 0.05), followed by a post-hoc Wilcoxon rank sum test with Bonferroni correction (α = 0.005). Results For kilohertz frequency trials, the stimulated kidney yielded a higher average total urine glucose excretion at 33 kHz (+ 24.5%; n = 9) than 1 kHz (− 5.9%; n = 6) and 50 kHz (+ 2.3%; n = 14). In low frequency stimulation trials, 5 Hz stimulation led to a lower average total urine glucose excretion (− 40.4%; n = 6) than 2 Hz (− 27.2%; n = 5). The average total urine glucose excretion between 33 kHz and 5 Hz was statistically significant (p

Abstract Background Adenocarcinomas or combined adeno-neuroendocrine carcinomas (MANEC) of small bowel usually have a dismal prognosis with limited systemic therapy options. This is the first description of a patient showing a germline-related BRCA1 mutated MANEC of his ileum. The tumor presented a susceptibility to a combined chemotherapy and the PARP1-inhibitor olaparib. Case presentation A 74-year old male patient presented with a metastasized MANEC of his ileum. Due to clinical symptoms his ileum-tumor and the single brain metastasis were removed. We verified the same pathogenic (class 5) BRCA1 mutation in different tumor locations. There was no known personal history of a previous malignant tumor. Nevertheless we identified his BRCA1 mutation as germline-related. A systemic treatment was started including Gemcitabine followed by selective internal radiotherapy (SIRT) to treat liver metastases and in the further course Capecitabine but this treatment finally failed after 9 months and all liver metastases showed progression. The treatment failure was the reason to induce an individualized therapeutic approach using combined chemotherapy of carboplatin, paclitaxel and the Poly (ADP-ribose) polymerase- (PARP)-inhibitor olaparib analogous to the treatment protocol of Oza et al. All liver metastases demonstrated with significant tumor regression after 3 months and could be removed. In his most current follow up from December 2017 (25 months after his primary diagnosis) the patient is in a very good general condition without evidence for further metastases. Conclusion We present first evidence of a therapy susceptible germline-related BRCA1 mutation in small bowel adeno-neuroendocrine carcinoma (MANEC). Our findings offer a personalized treatment option. The germline background was unexpected in a 74-year old man with no previously known tumor burden. We should be aware of the familiar background in tumors of older patients as well.

Abstract Background Colorectal cancer (CRC) is the fourth leading cause of cancer related deaths worldwide and prognosis in advanced tumor stage still remains poor. Since CK1 isoforms have been reported to be deregulated in several tumor entities CK1 has emerged as a novel drug target in cancer therapy. In this study we set out to investigate whether CK1α might have the potential to serve as prognostic marker. Methods CK1α RNA and protein expression levels in healthy and tumor tissue of CRC patients were analyzed using quantitative real-time PCR and Western Blot analysis, respectively. Prognostic relevance was investigated by correlating obtained CK1α expression levels with patients’ survival rate generating Kaplan-Meier survival plots. Results It could be shown that CK1α is overexpressed in colorectal tumor tissue compared to normal tissue and CK1α overexpression in tumor tissue correlates with poor survival in CRC patients. Results become more significant when only considering patients with high-grade tumors, as well as patients assigned to UICC II and UICC III stage. Furthermore, Cox regression analysis revealed that CK1α is an independent prognostic factor. In addition, tumors expressing decreased levels of the kinase reveal positive effects on overall survival when localized in the right colon compared to those in the left side. Conclusion In summary, this study provides evidence for the first time that CK1α RNA levels might serve as prognostic marker for CRC.

Abstract Background Standard survival analysis fails to give insight into what happens to a patient after a first outcome event (like first relapse of a disease). Multi-state models are a useful tool for analyzing survival data when different treatments and results (intermediate events) can occur. Aim of this study was to implement a multi-state model on data of patients with rectal cancer to illustrate the advantages of multi-state analysis in comparison to standard survival analysis. Methods We re-analyzed data from the RCT FOGT-2 study by using a multi-state model. Based on the results we defined a high and low risk reference patient. Using dynamic prediction, we estimated how the survival probability changes as more information about the clinical history of the patient becomes available. Results A patient with stage UICC IIIc (vs UICC II) has a higher risk to develop distant metastasis (DM) or both DM and local recurrence (LR) if he/she discontinues chemotherapy within 6 months or between 6 and 12 months, as well as after the completion of 12 months CTx with HR 3.55 (p = 0.026), 5.33 (p = 0.001) and 3.37 (p

Abstract Background Thyroid hemorrhage is considered to be an uncommon complication following blunt trauma to the neck. This condition is potentially life-threatening due to airway compression and may therefore require emergency airway management and surgical intervention in some cases. Case presentation We present the case of a 52-year-old woman who experienced a traumatic thyroid gland rupture (right lobe) with subsequent active arterial bleeding from branches of the inferior thyroid artery. On the same day, the patient presented to our emergency department with a painful swelling of the neck with an inspiratory stridor and hoarseness a few hours after a cycling accident. A right hemithyroidectomy was performed. The postoperative course was uneventful. We identified 33 additional cases published in English literature within the last 30 years, reporting blunt trauma to the neck with hemorrhagic complication of the thyroid gland. We provide a systematic review and particularly consider the aspects of endocrine surgery. Conclusion The treatment approach for patients with blunt thyroid trauma should be dependent on the extent of the thyroid injury. Patients with tracheal compression, active bleeding and increasing hoarseness/shortness of breath require emergency airway control and often surgical exploration for hemorrhage control followed by resection of the ruptured thyroid. Importantly, in contrast to routine thyroid surgery, no electromyographic endotracheal tube is used during emergency intubation. Exchange of an endotracheal tube should be carefully evaluated due to difficult airway management in this setting. For protection against double-sided recurrent nerve palsy and postoperative hypoparathyroidism, a unilateral approach is preferable whenever possible.

After publication of our article [1] the authors have notified us that one of the names has been incorrectly spelled.

Abstract Background Microorganisms influence the chemical milieu of their environment, and chemical metabolites can affect ecological processes. In built environments, where people spend the majority of their time, very little is known about how surface-borne microorganisms influence the chemistry of the indoor spaces. Here, we applied multidisciplinary approaches to investigate aspects of chemical microbiology in a house. Methods We characterized the microbial and chemical composition of two common and frequently wet surfaces in a residential setting: kitchen sink and bathroom shower. Microbial communities were studied using culture-dependent and independent techniques, including targeting RNA for amplicon sequencing. Volatile and soluble chemicals from paired samples were analyzed using state-of-the-art techniques to explore the links between the observed microbiota and chemical exudates. Results Microbial analysis revealed a rich biological presence on the surfaces exposed in kitchen sinks and bathroom shower stalls. Microbial composition, matched for DNA and RNA targets, varied by surface type and sampling period. Bacteria were found to have an average of 25× more gene copies than fungi. Biomass estimates based on qPCR were well correlated with measured total volatile organic compound (VOC) emissions. Abundant VOCs included products associated with fatty acid production. Molecular networking revealed a diversity of surface-borne compounds that likely originate from microbes and from household products. Conclusions Microbes played a role in structuring the chemical profiles on and emitted from kitchen sinks and shower stalls. Microbial VOCs (mVOCs) were predominately associated with the processing of fatty acids. The mVOC composition may be more stable than that of microbial communities, which can show temporal and spatial variation in their responses to changing environmental conditions. The mVOC output from microbial metabolism on kitchen sinks and bathroom showers should be apparent through careful measurement, even against a broader background of VOCs in homes, some of which may originate from microbes in other locations within the home. A deeper understanding of the chemical interactions between microbes on household surfaces will require experimentation under relevant environmental conditions, with a finer temporal resolution, to build on the observational study results presented here.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies today with an urgent need for novel therapeutic strategies. Biomarker analysis helps to better understand tumor biology and might emerge as a tool to develop personalized therapies. The aim of the study is to investigate four promising biomarkers to predict the clinical course and particularly the pattern of tumor recurrence after surgical resection. Design Patients undergoing surgery for PDAC can be enrolled into the PANCALYZE trial. Biomarker expression of CXCR4, SMAD4, SOX9 and IFIT3 will be prospectively assessed by immunohistochemistry and verified by rt.-PCR from tumor and adjacent healthy pancreatic tissue of surgical specimen. Immunohistochemistry expression pattern of all four biomarkers will be combined into a single score. Beginning with the hospital stay clinical data from enrolled patients will be collected and followed. Different adjuvant chemotherapy protocols will be used to create subgroups. The combined biomarker expression score will be correlated with the further clinical course of the patients to test the hypothesis if CXCR4 positive, SMAD4 negative, SOX9 positive, IFIT3 positive tumors will predominantly develop metastatic spread. Discussion Pancreatic cancer is associated with different patterns of progression requiring personalized therapeutic strategies. Biomarker expression analysis might be a tool to predict the pattern of tumor recurrence and discriminate patients that develop systemic metastatic disease from those with tumors that rather develop local recurrence over time. This data might lead to personalized adjuvant treatment decisions as patients with tumors that stay localized might benefit from adjuvant local therapies like radiochemotherapy as compared to those with systemic recurrence who would benefit exclusively from chemotherapy. Moreover, the pattern of propagation might be a predefined characteristic of pancreatic cancer determined by the genetic signature of the tumor. In the future, biomarker expression analysis could be performed on tumor biopsies to develop personalized therapeutic pathways right after diagnosis of cancer. Trial registration German Clinical Trials Register, DRKS00006179 .

Abstract Background Obesity has been associated with increased incidence of colorectal cancer. Adipose tissue dysfunction accompanied with alterations in the release of adipocytokines has been proposed to contribute to cancer pathogenesis and progression. The aim of this study was to analyze plasma concentrations of several adipose tissue expressed hormones in colorectal cancer patients (CRC) and morbidly obese (MO) patients and to compare these concentrations to clinicopathological parameters. Methods Plasma concentrations of adiponectin, resistin, leptin, active plasminogen activator inhibitor (PAI)-1, monocyte chemotactic protein (MCP)-1, interleukin (IL)-1 alpha, and tumor necrosis factor (TNF)-alpha were determined in 67 patients operated on for CRC (31 rectal cancers, 36 colon cancers), 37 patients operated on for morbid obesity and 60 healthy blood donors (BD). Results Compared to BD, leptin concentrations were lowered in CRC patients whereas those of MO patients were elevated. Adiponectin concentrations were only lowered in MO patients. Concentrations of MCP-1, PAI-1, and IL-1 alpha were elevated in both CRC and MO patients, while resistin and TNF-alpha were similarly expressed in MO and CRC patients compared to BD. Resistin concentrations positively correlated with tumor staging (p Conclusions The results suggest that both MO and CRC have low-grade inflammation as part of their etiology.

Abstract Background A variety of multimodal treatment options are available for colorectal cancer and many patients want to be involved in decisions about their therapies. However, their desire for autonomy is limited by lack of disease-specific knowledge. Visual aids may be helpful tools to present complex data in an easy-to-understand, graphic form to lay persons. The aim of the present study was to evaluate the treatment preferences of healthy persons and patients using visual aids depicting multimodal treatment options for colorectal cancer. Methods We designed visual aids for treatment scenarios based on four key studies concerning multimodal treatment of colorectal cancer. The visual aids were composed of diagrams depicting outcome parameters and side effects of two treatment options. They were presented to healthy persons (n = 265) and to patients with colorectal cancer (n = 102). Results Most patients and healthy persons could make immediate decisions after seeing the diagrams (range: 88% – 100%). Patients (79%) chose the intensive-treatment option in the scenario with a clear survival benefit. In scenarios without survival benefit, all groups clearly preferred the milder treatment option (range: 78% - 90%). No preference was seen in the scenario depicting equally intense treatment options with different timing (neoadjuvant vs. adjuvant) but without survival benefit. Conclusions Healthy persons’ and patients’ decisions using visual aids seem to be influenced by quality-of-life aspects rather than recurrence rates especially in situations without survival benefit. In the future visual aids may help to improve the management of patients with colorectal cancer.

Abstract Background Adaptation of pathogens to their hosts depends critically on factors affecting pathogen reproductive rate. While pathogen reproduction is the end result of an intricate interaction between host and pathogen, the relative contributions of host and pathogen genotype to variation in pathogen life history within the host are not well understood. Untangling these contributions allows us to identify traits with sufficient genetic variation for selection to act and to identify mechanisms of coevolution between pathogens and their hosts. We investigated the effects of pathogen and host genotype on three life-history components of pathogen fitness; infection efficiency, latent period, and sporulation capacity, in the oat crown rust fungus, Puccinia coronata f.sp. avenae, as it infects oats (Avena sativa). Results We show that both pathogen and host genotype significantly affect total spore production but do so through their effects on different life-history stages. Pathogen genotype has the strongest effect on the early stage of infection efficiency, while host genotype most strongly affects the later life-history stages of latent period and sporulation capacity. In addition, host genotype affected the relationship between pathogen density and the later life-history traits of latent period and sporulation capacity. We did not find evidence of pathogen-by-host genotypic (GxG) interactions. Conclusion Our results illustrate mechanisms by which variation in host populations will affect the evolution of pathogen life history. Results show that different pathogen life-history stages have the potential to respond differently to selection by host or pathogen genotype and suggest mechanisms of antagonistic coevolution. Pathogen populations may adapt to host genotypes through increased infection efficiency while their plant hosts may adapt by limiting the later stages of pathogen growth and spore production within the host.

Abstract Acute lung injury and acute respiratory distress syndrome are clinical entities of multi-factorial origin frequently seen in traumatically injured patients requiring intensive care. We performed an unsystematic search using PubMed and the Cochrane Database of Systematic Reviews up to January 2012. The purpose of this article is to review recent evidence for the pathophysiology and the management of acute lung injury/acute respiratory distress syndrome in the critically injured patient. Lung protective ventilation remains the most beneficial therapy. Future trials should compare intervention groups to controls receiving lung protective ventilation, and focus on relevant outcome measures such as duration of mechanical ventilation, length of intensive care unit stay, and mortality.

Abstract Background To evaluate the value of KRAS codon 13 mutations in patients with advanced colorectal cancer (advanced CRC) treated with oxaliplatin and fluoropyrimidines. Methods Tumor specimens from 201 patients with advanced CRC from a randomized, phase III trial comparing oxaliplatin/5-FU vs. oxaliplatin/capecitabine were retrospectively analyzed for KRAS mutations. Mutation data were correlated to response data (Overall response rate, ORR), progression-free survival (PFS) and overall survival (OS). Results 201 patients were analysed for KRAS mutation (61.2% males; mean age 64.2 ± 8.6 years). KRAS mutations were identified in 36.3% of tumors (28.8% in codon 12, 7.4% in codon 13). The ORR in codon 13 patients compared to codon 12 and wild type patients was significantly lower (p = 0.008). There was a tendency for a better overall survival in KRAS wild type patients compared to mutants (p = 0.085). PFS in all patients was not different in the three KRAS genetic groups (p = 0.72). However, we found a marked difference in PFS between patients with codon 12 and 13 mutant tumors treated with infusional 5-FU versus capecitabine based regimens. Conclusions Our data suggest that the type of KRAS mutation may be of clinical relevance under oxaliplatin combination chemotherapies without the addition of monoclonal antibodies in particular when overall response rates are important. Trial registration number 2002-04-017