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PURPOSE: There are limited prospective data on predictors of patient-reported outcomes (PROs) after whole-breast irradiation (WBI) plus a boost. We sought to characterize longitudinal PROs and cosmesis in a randomized trial comparing conventionally fractionated (CF) versus hypofractionated (HF) WBI. METHODS AND MATERIALS: From 2011 to 2014, women aged ≥40 years with Tis-T2 N0-N1a M0 breast cancer who underwent a lumpectomy with negative margins were randomized to CF-WBI (50 Gray [Gy]/25 fractions plus boost) versus HF-WBI (42.56 Gy/16 fractions plus boost). At baseline (pre-radiation), at 6 months, and yearly thereafter through 5 years, PROs included the Breast Cancer Treatment Outcome Scale (BCTOS), Functional Assessment of Cancer Therapy−Breast (FACTB), and Body Image Scale; cosmesis was reported by the treating physician using Radiation Therapy Oncology Group cosmesis values. Multivariable mixed-effects growth curve models evaluated associations of the treatment arm and patient factors with outcomes and tested for relevant interactions with the treatment arm. RESULTS: A total of 287 patients were randomized, completing a total of 14,801 PRO assessments. The median age was 60 years, 37% of patients had a bra cup size ≥D, 44% were obese, and 30% received chemotherapy. Through 5 years, there were no significant differences in PROs or cosmesis by treatment arm. A bra cup size ≥D was associated with worse BCTOS cosmesis (P < .001), BCTOS pain (P = .001), FACT-B Trial Outcome Index (P = .03), FACT-B Emotional Well-being (P = .03), and Body Image Scale (P = .003) scores. Physician-rated cosmesis was worse in patients who were overweight (P = .02) or obese (P < .001). No patient subsets experienced better PROs or cosmesis with CF-WBI. CONCLUSIONS: Both CF-WBI and HF-WBI confer similar longitudinal PROs and physician-rated cosmesis through 5 years of follow-up, with no relevant subsets that fared better with CF-WBI. This evidence supports broad adoption of hypofractionation with boost, including in patients receiving chemotherapy and in a population with a high prevalence of obesity. The associations of large breast size and obesity with adverse outcomes across multiple domains highlight the opportunity to engage at-risk patients in lifestyle intervention strategies, as well as to consider alternative radiation treatment regimens.

BACKGROUND Secondary lymphedema after surgical interventions is a progressive, chronic disease that is still not completely curable. Over the past years, a multitude of surgical therapy options have been described. AIM To summarize the single-center complications in lymph vessel (LVTx) and free vascularized lymph node transfer (VLNT). METHODS In total, the patient collective consisted of 87 patients who were undergoing treatment for secondary leg lymphedema during the study period from March 2010 to April 2020. The data collection was performed preoperatively during consultations, as well as three weeks, six months and twelve months after surgical treatment. In the event of complications, more detailed follow-up checks were carried out. In total n = 18 robot-assisted omental lymph node transplantations, n = 33 supraclavicular lymph node transplantations and n = 36 Lymph vessel transplantations were analyzed. An exemplary drawing is shown in Figure 1. A graphical representation of patient selection is shown in Figure 2. Robotic harvest was performed with the Da Vinci Xi Robot Systems (Intuitive Surgical, CA, United States). RESULTS In total, 11 male and 76 female patients were operated on. The mean age of the patients at study entry was: omental VLNT: 57.45 ± 8.02 years; supraclavicular VLNT: 49.76 ± 4.16 years and LVTx: 49.75 ± 4.95 years. The average observation time postoperative was: omental VLNT: 18 ± 3.48 mo; supraclavicular VLNT: 14.15 ± 4.9 and LVTx: 14.84 ± 4.46 mo. In our omental VLNT, three patients showed a slight abdominal sensation of tension within the first 12 postoperative days. No other donor side morbidities occurred. No intraoperative conversion to open technique was needed. Our supraclavicular VLNT collective showed 10 lift defect morbidities with one necessary surgical intervention. In our LVTx collective, 12 cases of donor side morbidity were registered. In one case, surgical intervention was necessary. CONCLUSION Concerning donor side morbidity, robot-assisted omental VLNT is clearly superior to supraclavicular lymph node transplantation and LVTx.

Das deutsche Gesundheitswesen und insbesondere chirurgische Kliniken stehen aufgrund eines zunehmenden Fachkraftemangels vor erheblichen Herausforderungen. Dieser Mangel an qualifiziertem Personal fuhrt nicht nur zu Einschrankungen in der Patientenversorgung, sondern wirkt sich auch negativ auf die Mitarbeitergesundheit aus, da das vorhandene Personal den Ausfall entsprechend kompensieren muss. Verstarkt wird diese Situation durch die Anspruche und Erwartungen neuer Mitarbeitergenerationen, die vor allem Bereiche wie Fuhrung, Arbeitszeit sowie Vereinbarkeit von Familie und Beruf betreffen. Diese Veranderungen werden zwangslaufig zu einem Umdenken von Klinikleitung und Geschaftsfuhrung fuhren mussen, um zukunftig die Funktionsfahigkeit und Qualitat der medizinischen Versorgung durch Kliniken aufrechterhalten zu konnen. Das Ziel dieser Arbeit ist eine personliche Einschatzung der aktuellen und zukunftigen Situation chirurgischer Kliniken in Deutschland mit einem Fokus auf Personalmanagement und Leadership.

Background: Islet autoimmunity may contribute to beta-cell dysfunction in type 2 diabetes (T2D). Its prevalence and clinical significance have not been rigorously determined. We investigated the prevalence of cellular and humoral islet autoimmunity in T2D and their relation to beta-cell function. Methods: The study was nested in the Glycemia Reduction Approaches in Diabetes – A Comparative Effectiveness (GRADE) study. Participants included 419 T2D patients (age 57·4±10·3 y [mean±SD], body mass index 33·6±6·2 kg/m2, diabetes duration 4·0±3·0 y, HbA1c 7·5±0·5%). We measured humoral (autoantibodies against GAD65, IA2, ZnT8) and cellular (T-cell autoreactivity against islet antigens) autoimmunity, beta-cell function (ratio of incremental area under the curve of C-peptide to that of glucose from 0–120 min of an oral glucose tolerance test [iAUC-CG]), and ratio of C-peptide to glucose from 0–30 min (∆C-peptide(0–30)/∆glucose(0–30)), and glycemic parameters. Findings: Cellular islet autoimmunity was present in 41·3%, humoral islet autoimmunity in 13·5%, and both in 5·3%. iAUC-CG and ∆C-peptide(0–30)/∆glucose(0–30) were lower among T-cell-positives than -negatives using two different adjustments for insulin sensitivity (iAUC-CG: 13·2% [95% CI 0·3, 24·4%] or 11·4% [95% CI 0·4, 21·2%] lower; ∆C-peptide(0–30)/∆glucose(0–30)) 19% [95% CI 3·1, 32·3%] or 17·7% [95% CI 2·6, 30·5%] lower). T-cell-positives had 0·17% higher HbA1c (95% CI 0·07,0·28) and 7·7 mg/dL higher fasting plasma glucose levels (95% CI 0·2,15·3) than T-cell-negatives. Interpretation: Islet autoimmunity is highly prevalent in patients with T2D. T-cell-mediated autoimmunity is associated with diminished beta-cell function and worse glycemic control. Funding Information: This study was funded by the NIH. This ancillary study to the GRADE study was independently funded by grant R01DK104832 (to AB and JPP) from the National Institute of Diabetes and Digestive and Kidney Diseases. The GRADE study is supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health under Award Number U01DK098246. The planning of GRADE was supported by a U34 planning grant from the NIDDK (U34-DK-088043). The American Diabetes Association supported the initial planning meeting for the U34 proposal. The National Heart, Lung, and Blood Institute and the Centers for Disease Control and Prevention also provided funding support. The Department of Veterans Affairs provided resources and facilities. Additional support was provided by grant numbers P30 DK017047, P30 DK020541-44, P30 DK020572, P30 DK072476, P30 DK079626, P30 DK092926, U54 GM104940, UL1 TR000439, UL1 TR000445, UL1 TR001108, UL1 TR001409, UL1 TR001449, UL1 TR002243, UL1 TR002345, UL1 TR002378, UL1 TR002489, UL1 TR002489, UL1 TR002529, UL1 TR002535, UL1 TR002537, and UL1 TR002548. Educational materials have been provided by the National Diabetes Education Program. Material support in the form of donated medications and supplies has been provided by Becton, Dickinson an Company, Bristol-Myers Squibb, Merck, NovoNordisk, Roche Diagnostics, and Sanofi. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: Nineteen centers obtained local Institutional Review Board approval for the ancillary study and contributed participants.

(1) Background: Sepsis is a leading cause of death and a global public health problem. Accordingly, deciphering the underlying molecular mechanisms of this disease and the determinants of its morbidity and mortality is pivotal. This study examined the effect of the rs951818 SNP of the negative costimulatory lymphocyte-activation gene 3 (LAG-3) on sepsis mortality and disease severity. (2) Methods: 707 consecutive patients with sepsis were prospectively enrolled into the present study from three surgical ICUs at University Medical Center Goettingen. Both 28- and 90-day mortality were analyzed as the primary outcome, while parameters of disease severity served as secondary endpoints. (3) Results: In the Kaplan–Meier analysis LAG-3 rs951818 AA-homozygote patients showed a significantly lower 28-day mortality (17.3%) compared to carriers of the C-allele (23.7%, p = 0.0476). In addition, these patients more often received invasive mechanical ventilation (96%) during the course of disease than C-allele carriers (92%, p = 0.0466). (4) Conclusions: Genetic profiling of LAG-3 genetic variants alone or in combination with other genetic biomarkers may represent a promising approach for risk stratification of patients with sepsis. Patient-individual therapeutic targeting of immune checkpoints, such as LAG-3, may be a future component of sepsis therapy. Further detailed investigations in clinically relevant sepsis models are necessary.

Introduction Catheter ablation for the treatment of Atrial Fibrillation (AF) is a modality of treatment in growing expansion. However the sustained long term response in preventing AF recurrence is poor for most patients, namely in those with a dilated left atrium. Purpose Our aim was to assess the utility of an echocardiographic parameter for left atrium function, the left atrial appendage velocity (LAAV), in predicting recurrences after catheter ablation. Methods We performed a 9 year retrospective analysis of all patients who underwent a successful catheter ablation for the treatment of atrial fibrillation and had a valid pre-procedural transesophagic echocardiogram in a single expert centre. Medical records were analysed for demographic, procedural data and outcomes. Results Seventy-three (73) patients fulfilled all inclusion criteria and were analysed. The mean age was 62±11 with a male preponderance (58,7%). The majority of patients (82,7%) had preserved left ventricle ejection fraction. Only 46% of patient had a volumetric assessment of the left atrium dimensions prior to ablation, with slight, moderate and severe dilation of the left atrium in 20%; 8,6% and 28,6% of patients. Of the patients subjected to an AF ablation the average LAAV was 50,6±19 cm/s, with 78% of patients with normal atrial appendage velocities. Patients with low LAAV ( Conclusions Patients with low left atrial appendage velocities had a lower long term success rate of catheter ablation, with higher rates of recurrence at 3 and 6 months and a trend towards higher recurrences at 1 year, with linear correlation which hypothesises the use of the left atrial appendage velocity as novel predictive parameter for an integrative model. Funding Acknowledgement Type of funding sources: None.

Many publications have investigated the ingestion and toxicity of metallic lead from hunting and the shooting sports. However, there is limited literature on toxicity associated with the ingestion of lead fishing weights, despite our knowledge of damage caused to many species from entanglement in lines, nets, and fish-hooks. This paper surveys current knowledge of species poisoned by ingestion of lead fishing gear and the types of gear that have been implicated. We review the impacts of lead fishing tackle on wildlife species and human health and describe the efficacy of efforts to reduce the use of lead tackle through voluntary, educational, and regulatory approaches to encourage adoption of non-toxic fishing gear. The authors emphasize the need for further research and policy initiatives to deal with this serious problem. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13280-019-01179-w) contains supplementary material, which is available to authorized users.

Perceiving faces and understanding emotions are key components of human social cognition. Prior research with adults and infants suggests that these social cognitive functions are supported by superior temporal cortex (STC) and medial prefrontal cortex (MPFC). We used functional near-infrared spectroscopy (fNIRS) to characterize functional responses in these cortical regions to faces in early childhood. Three-year-old children (n = 88, M(SD) = 3.15(.16) years) passively viewed faces that varied in emotional content and valence (happy, angry, fearful, neutral) and, for fearful and angry faces, intensity (100%, 40%), while undergoing fNIRS. Bilateral STC and MPFC showed greater oxygenated hemoglobin concentration values to all faces relative to objects. MPFC additionally responded preferentially to happy faces relative to neutral faces. We did not detect preferential responses to angry or fearful faces, or overall differences in response magnitude by emotional valence (100% happy vs. fearful and angry) or intensity (100% vs. 40% fearful and angry). In exploratory analyses, preferential responses to faces in MPFC were not robustly correlated with performance on tasks of early social cognition. These results link and extend adult and infant research on functional responses to faces in STC and MPFC and contribute to the characterization of the neural correlates of early social cognition.

Background Many carcinomas have recurrent chromosomal aneuploidies specific to the tissue of tumor origin. The reason for this specificity is not completely understood. Methods In this study, we looked at the frequency of chromosomal arm gains and losses in different cancer types from the The Cancer Genome Atlas (TCGA) and compared them to the mean gene expression of each chromosome arm in corresponding normal tissues of origin from the Genotype-Tissue Expression (GTEx) database, in addition to the distribution of tissue-specific oncogenes and tumor suppressors on different chromosome arms. Results This analysis revealed a complex picture of factors driving tumor karyotype evolution in which some recurrent chromosomal copy number reflect the chromosome arm-wide gene expression levels of the their normal tissue of tumor origin. Conclusions We conclude that the cancer type-specific distribution of chromosomal arm gains and losses is potentially “hardwiring” gene expression levels characteristic of the normal tissue of tumor origin, in addition to broadly modulating the expression of tissue-specific tumor driver genes.

Background/objective Burnout is common among resident physicians, which has the potential to translate into diagnostic and management errors. Our study investigates the relationship between sleepiness, depression, anxiety, burnout, and lack of professional fulfillment with clinical performance during a critically ill patient simulation. Methods/Approach: Emergency medicine residents were recruited to participate in a high-fidelity simulation case of a critically ill patient. A survey with validated wellbeing measures (National Institutes of Health Patient-Reported Outcomes Measurement Information System (NIH PROMIS), Linzer burnout measure, and professional fulfillment index) was administered prior to the simulation. Each encounter was video-recorded and analyzed by two blinded raters based on a binary critical-actions checklist. Time-to-intubation, management errors, and misdiagnosis rates were assessed. Results Twenty residents participated, with most subjects endorsing sleepiness (70%) and less than half reporting depression (40%) and anxiety (45%). Burnout was identified to be in 50% of participants by the Linzer measure and 85% by the professional fulfillment index. No significant difference was found between mean performance scores in sleepy, depressed, and anxious cohorts in comparison to groups without those symptoms. Similarly, burnout and professional fulfillment did not yield any significant difference, nor did comparisons with time to intubation, management errors, and frequency of misdiagnosis. Conclusion Resident burnout, depression, anxiety, sleepiness, and lack of professional fulfillment did not appear to have a measurable impact on clinical performance in managing a critically ill patient. There is no evidence from this study that the lack of resident physician well-being adversely impacts patient care by increasing errors in management or misdiagnoses during this high-fidelity simulation.

Background Postnatal maternal anxiety is common (estimates as high as 40% prevalence) and is associated with altered mother-infant interactions (e.g., reduced maternal emotional expression and engagement). Neural circuitry supporting infants' face and emotion processing develops in their first year. Thus, early exposure to maternal anxiety may impact infants' developing understanding of emotional displays. We examine whether maternal anxiety is associated with individual differences in typically developing infants' neural responses to emotional faces. Methods One hundred and forty two mother-infant dyads were assessed when infants were 5, 7, or 12 months old. Infants' electroencephalographic (EEG) data were recorded while passively viewing female happy, fearful, and angry faces. Three event-related potential (ERP) components, each linked to face and emotion processing, were evaluated: NC, N290, and P400. Infant ERP amplitude was related to concurrent maternal-report anxiety assessed with the Spielberger State-Trait Anxiety Inventory (Trait form). Results Greater maternal anxiety predicted more negative NC amplitude for happy and fearful faces in left and mid-central scalp regions, beyond covarying influences of maternal depression symptoms, infant negative emotionality, and infant age. Conclusions Postnatal maternal anxiety is related to infants' neural processing of emotional expressions. Infants of mothers endorsing high trait anxiety may need additional attentional resources to process happy and fearful faces (expressions less likely experienced in mother-infant interactions). Future research should investigate mechanisms underlying this association, given possibilities include experiential, genetic, and prenatal factors.

Simple Summary Resistance to chemoradiotherapy represents a fundamental problem in modern oncology because it exposes patients to the potential negative side-effects of both radiation and chemotherapy without any clinical benefit. This study uncovers that the inflammatory signaling hub STAT3 conspires with the cell fate regulator NOTCH in rendering tumor cells refractory to chemoradiotherapy. The dichotomic signal alliance is based on a so-far unknown STAT3 target gene, RBPJ, providing the transcriptionally active partner of NOTCH intracellular domain. Unexpectedly, the latter is permanently produced by tonic proteolysis. Tumor mouse models and cancer patient cohorts demonstrate the usefulness of the STAT3/NOTCH axis as biomarker for patient stratification, and importantly, that STAT3 inhibition is a promising treatment option for re-sensitization of CRT-refractory tumors. Abstract Resistance of tumor cells to chemoradiotherapy represents a fundamental problem in clinical oncology. The underlying mechanisms are actively debated. Here we show that blocking inflammatory cytokine receptor signaling via STAT3 re-sensitized treatment-refractory cancer cells and abolished tumor growth in a xenograft mouse model when applied together with chemoradiotherapy. STAT3 executed treatment resistance by triggering the expression of RBPJ, the key transcriptional regulator of the NOTCH pathway. The mandatory RBPJ interaction partner, NOTCH intracellular domain, was provided by tumor cell-intrinsic expression of NOTCH ligands that caused tonic NOTCH proteolysis. In fact, NOTCH inhibition phenocopied the effect of blocking STAT3 signaling. Moreover, genetic profiling of rectal cancer patients revealed the importance of the STAT3/NOTCH axis as NOTCH expression correlated with clinical outcome. Our data uncovered an unprecedented signal alliance between inflammation and cellular development that orchestrated resistance to chemoradiotherapy. Clinically, our findings allow for biomarker-driven patient stratification and offer novel treatment options.

Introduction Hypertrophic cardiomyopathy (HCM) is the main cause of sudden cardiac death in the young and a cause of heart failure and death at any age. Nevertheless, adverse long-term outcomes are not easy to predict. Objectives To assess the prevalence, predictors and prognostic value of right ventricular (RV) dysfunction in patients (pts) with HCM. Methods Retrospective single-center study of consecutive pts with HCM evaluated in a specialized medical appointment. Selected those submitted to cardiac magnetic resonance imaging (MRI) as the gold-standard for RV function assessment. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, ventricular arrhythmias with hemodynamic instability and unplanned heart failure admission. Results Were included 112 pts (mean age at first appointment 57±15 years, 63% male). Septal asymmetric phenotype was the most frequent (75%), with a mean septal wall thickness of 18±4 mm. Late gadolinium enhancement was observed in 82%, mostly intramyocardial (67%) and in joint points (47%). RV dysfunction was detected in 6 pts (5.4%) and RV free wall hypertrophy in 3 pts (2.7%); no patient presented RV dilation. Factors associated with RV dysfunction were left atria area (HR 1.07/unit, 95% CI 1.01–1.12, p=0.02), left ventricular ejection fraction (HR 0.91/unit, 95% CI 0.86–0.97, p=0.02) and the presence of left ventricle wall motion abnormalities (HR 7, 95% CI 1.3–38, p=0.03) in cardiac MRI. During a mean follow-up of 60±31 months, the combined primary endpoint occurred in 15 pts (13%), significantly more in pts with RV dysfunction (HR 5.1, 95% CI 1.1–24, p=0.038) (graphic 1). Patients with RV dysfunction also presented more atrial fibrillation / flutter episodes during follow-up (HR 6.4, 95% CI 2.1–20, p=0.001). Conclusions Although not common, right ventricular dysfunction was associated with a higher rate of cardiovascular events. These results support a potential role of right ventricular function in the risk stratification of patients with hypertrophic cardiomyopathy. Figure 1 Funding Acknowledgement Type of funding source: None

Introduction The approach to Acute Coronary Syndromes is based on robust high quality evidence, currently systematized in European endorsed guidelines. However most trials that support such guidelines excluded or included a small percentage of the very elderly, namely nonagenarian patients, and the clinical decision in this age range is subjected to high interpersonal and inter-hospital variability. Purpose Our aim was to assess the approach to nonagenarian patients with Acute Coronary Syndromes (ACS), in what regards the choice of percutaneous coronary intervention or conservative management and determine in-hospital and at 1 year outcomes. Methods We performed a 9 year retrospective analysis of all patients with age equal or greater than ninety (90) admitted with ACS in Portugal. Medical records were analysed for demographic, procedural data and outcomes. Results Seven hundred and fourteen (714) nonagenarian patients were admitted with ACS, which corresponded to 2.4% of the total cohort. The mean age was 92±2 with a female preponderance (58.7%). There was a high rate of cardiovascular risk factor with hypertension in 81.3%; Dyslipidemia in 46.1% Diabetes Mellitus in 23.4%; and other comorbidities with 21% of prior ACS, 14.4% with Heart Failure, 11% with cerebrovascular events and 15.4% with chronic kidney failure. The ACS was categorized as ST elevation Myocardial Infarction (STEMI) in 43.9%, non- STEMI (NSTEMI) in 45.8%, and unstable angina (UA) in 2%. Two hundred and sixty-eight (268), 37.8% of the cohort, were submitted to percutaneous coronary intervention (PCI), mainly due to STEMI (68.3%). This cohort were composed of patients with less comorbidities (statistically significant less valvular heart disease, heart failure, peripherical artery disease and dementia although more oncological diseases). There was no difference in the severity of ACS, as categorized by the Kilip Kimbal (KK) classification, mechanical complication or depressed ejection fraction between the 2 groups. (p>0.05 for all) There was a statistically significant increase of advanced atrioventricular block (10.6 vs 4.4%; p 0.002; Logistic regression OR 3.12; IC95 [1.37–7.15], p 0.007) and major bleeding (1.8 vs 5.5%; p 0.008; Logistic regression OR 3.36; IC95 [1.36–8.32] p 0.009) in the PCI group. There was no difference in in-hospital re-infarction, cardiac arrest, stroke or death. (p>0.05 for all) The follow up at 1 year was performed in two hundred and fifty-six (256) patients, 30.9% submitted to PCI. Although the survival analysis demonstrated a trend towards improvement in 1-year survival and cardiovascular readmissions in the intervention group, it did not reach statistical significance. (p>0.05 for all) Conclusions PCI was performed in about a third of nonagenarians presenting with ACS. Our cohort demonstrated a greater rate of in-hospital complications without a significant in-hospital or at 1 year clinical benefit. Funding Acknowledgement Type of funding source: None

The unprecedented COVID-19 pandemic has resulted in rapidly evolving best practices for transmission reduction, diagnosis, and treatment. A regular influx of new information has upended traditionally static hospital protocols, adding additional stress and potential for error to an already overextended system. To help equip frontline emergency clinicians with up-to-date protocols throughout the evolving COVID-19 crisis, our team set out to create a dynamic digital tool that centralized and standardized resources from a broad range of platforms across our hospital. Using a design thinking approach, we rapidly built, tested, and deployed a solution using simple, out-of-the-box web technology that enables clinicians to access the specific information they seek within moments. This platform has been rapidly adopted throughout the emergency department, with up to 70% of clinicians using the digital tool on any given shift and 78.6% of users reporting that they "agree" or "strongly agree" that the platform has affected their management of COVID-19 patients. The tool has also proven easily adaptable, with multiple protocols being updated nearly 20 times over two months without issue. This paper describes our development process, challenges, and results to enable other institutions to replicate this process to ensure consistent, high-quality care for patients as the COVID-19 pandemic continues its unpredictable course.

In den letzten vier Jahrzehnten hat sich die Therapie des Rektumkarzinoms grundlegend verandert und so zu einer deutlichen Prognoseverbesserung gefuhrt. Masgebliche Meilensteine waren hier die Einfuhrung der totalen mesorektalen Exzision und die Implementierung multimodaler Therapiestrategien. Komplementiert wurden diese Fortschritte durch die konsequente Umsetzung einer standardisierten histopathologischen Aufarbeitung des chirurgischen Resektates sowie die Einfuhrung einer hochauflosenden MRT-Diagnostik. Zudem wurden neue Operationsverfahren eingefuhrt wie die laparoskopische und kurzlich auch die robotische Rektumresektion. Weitere technische Neuerungen umfassen beispielsweise das pelvine Neuromonitoring oder die Fluoreszenzbildgebung. Ziel dieser Ubersichtsarbeit ist es, die Evidenz fur ausgewahlte, zum Teil kontrovers diskutierte Prinzipien der chirurgischen Therapie des Rektumkarzinoms zu evaluieren.

Purpose The adoption of hypofractionated whole-breast irradiation (HF-WBI) remains low, in part because of concerns regarding its safety when used with a tumor bed boost or in patients who have received chemotherapy or have large breast size. To address this, we conducted a randomized, multicenter trial to compare conventionally fractionated whole-breast irradiation (CF-WBI; 50 Gy/25 fx + 10 to 14 Gy/5 to 7 fx) with HF-WBI (42.56 Gy/16 fx + 10 to 12.5 Gy/4 to 5 fx). Patients and Methods From 2011 to 2014, 287 women with stage 0 to II breast cancer were randomly assigned to CF-WBI or HF-WBI, stratified by chemotherapy, margin status, cosmesis, and breast size. The trial was designed to test the hypothesis that HF-WBI is not inferior to CF-WBI with regard to the proportion of patients with adverse cosmetic outcome 3 years after radiation, assessed using the Breast Cancer Treatment Outcomes Scale. Secondary outcomes included photographically assessed cosmesis scored by a three-physician panel and local recurrence-free survival. Analyses were intention to treat. Results A total of 286 patients received the protocol-specified radiation dose, 30% received chemotherapy, and 36.9% had large breast size. Baseline characteristics were well balanced. Median follow-up was 4.1 years. Three-year adverse cosmetic outcome was 5.4% lower with HF-WBI ( Pnoninferiority = .002; absolute risks were 8.2% [n = 8] with HF-WBI v 13.6% [n = 15] with CF-WBI). For those treated with chemotherapy, adverse cosmetic outcome was higher by 4.1% (90% upper confidence limit, 15.0%) with HF-WBI than with CF-WBI; for large breast size, adverse cosmetic outcome was 18.6% lower (90% upper confidence limit, −8.0%) with HF-WBI. Poor or fair photographically assessed cosmesis was noted in 28.8% of CF-WBI patients and 35.4% of HF-WBI patients ( P = .31). Three-year local recurrence-free survival was 99% with both HF-WBI and CF-WBI ( P = .37). Conclusion Three years after WBI followed by a tumor bed boost, outcomes with hypofractionation and conventional fractionation are similar. Tumor bed boost, chemotherapy, and larger breast size do not seem to be strong contraindications to HF-WBI.

Objective Renal abnormalities are commonly considered in the work up of pediatric patients with external ear malformations. However, there is little consensus regarding an appropriate renal screening protocol for patients with microtia. We sought to characterize renal abnormalities detected on ultrasonography in pediatric patients with microtia. Methods We conducted a retrospective cohort study of pediatric patients diagnosed with microtia who underwent renal ultrasound from 1991 to 2014 at a single tertiary academic institution. Renal ultrasound reports and medical records were reviewed to assess for renal abnormalities and to determine whether patients required specialist follow-up or interventions. Audiograms and otolaryngology notes were used to determine patterns of hearing loss. The following additional information was recorded from the electronic medical records: patient sex, microtia grade (I-IV), microtia laterality, and known associated syndromes. Characteristics were compared between those who did and did not have renal ultrasound findings using Fisher's exact test. Univariate logistic regression analysis was performed to determine factors associated with renal ultrasound findings. Results The majority of patients in this cohort were syndromic (n = 51, 64%) with grade III microtia (n = 46, 58%) and conductive hearing loss (n = 58, 72%). Syndromic children with microtia demonstrated a higher crude rate of renal ultrasound abnormalities (22%) than children with isolated microtia (7%). Of these patients, 69% required specialist follow-up. Univariate logistic regression analysis did not identify predictors that were significantly associated with renal ultrasound findings. Conclusion Fairly high rates of abnormalities in syndromic and non-syndromic patients may warrant screening renal ultrasound in all patients with microtia, especially given the high percentage of findings requiring renal follow-up. A prospective study to formally evaluate screening efficacy is needed.

Purpose: Shorter fractionation radiation regimens for palliation of bone metastases result in lower financial and social costs for patients and their caregivers and have similar efficacy as longer fractionation schedules, although practice patterns in the United States show poor adoption. We investigated whether prospective peer review can increase use of shorter fractionation schedules. Methods: In June 2016, our practice mandated peer review of total dose and fractionation for all patients receiving palliative treatment during our weekly chart rounds. We used descriptive statistics and Fisher’s exact test to compare lengths of treatment of uncomplicated bone metastases before and after implementation of the peer review process. Results: Between July 2015 and December 2016, a total of 242 palliative treatment courses were delivered, including 105 courses before the peer review intervention and 137 after the intervention. We observed greater adoption of shorter fractionation regimens after the intervention. The use of 8 Gy in one fraction increased from 2.8% to 13.9% of cases postadoption. Likewise, the use of 20 Gy in five fractions increased from 25.7% to 32.8%. The use of 30 Gy in 10 fractions decreased from 55.2% to 47.4% ( P = .002), and the use of ≥ 11 fractions decreased from 16.2% before the intervention to 5.8% after ( P = .006). Conclusion: Prospective peer review of palliative regimens for bone metastases can lead to greater adoption of shorter palliative fractionation schedules in daily practice, in accordance with national guidelines. This simple intervention may therefore benefit patients and their caregivers as well as provide value to the health care system.

Background: Adoption of HF-WBI remains low due in part to concerns regarding its safety when used with a tumor bed boost or in patients who have received chemotherapy or have large breast size. To address this, we conducted a randomized, multicenter trial to compare CF-WBI (50Gy/25fx+10-14Gy/5-7fx) to HF-WBI (42.56Gy/16fx+10-12.5Gy/4-5fx). Methods: From 2011 and 2014, 287 women with stage 0-II breast cancer, age ≥40 years, were randomized to CF-WBI or HF-WBI, stratified by chemotherapy and breast size. The primary outcome was the proportion of patients with adverse Breast Cancer Treatment Outcomes Scale (BCTOS) cosmetic score three years post-WBI, defined as a score of ≥2.5 (a score of 1 indicates no difference between the treated breast and contralateral breast, 2-slight difference, 3-moderate difference, 4-large difference). Secondary patient-reported outcomes included BCTOS functional status, BCTOS breast pain, Body Image Scale (BIS), and the FACT-B Trial Outcome Index (TOI). Additional secondary outcomes included photographically-assessed cosmesis scored by a 3-physician panel blinded to randomization arm using the RTOG scale, physician-assessed CTCAEv4.0, overall survival (OS), local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS). Chi-square, Fisher's exact, Wilcoxon's rank sum, logistic regression, and log-rank tests evaluated differences by treatment arm; survival was measured using the Kaplan-Meier method. All analyses were intention-to-treat. Results: Of 287 patients enrolled, 286 received the protocol-specified radiation dose. Thirty percent received chemotherapy (73% anthracycline, 92% taxane, 22% trastuzumab), 37% had large breast size (D cup or larger), and 44% were obese (BMI≥30). All baseline characteristics were well-balanced by treatment arm (P>0.05). Median follow-up is 4.1 years. For the primary outcome, adverse BCTOS cosmetic score at 3 years was noted in 13.6% (n=15/110) of CF-WBI and 8.2% (n=8/97) of HF-WBI patients (P=0.22). There were trends for lower risk of adverse BCTOS cosmetic score with HF-WBI, compared to CF-WBI, among patients who did not receive chemotherapy (OR=0.25, 95%CI 0.06-1.03; Pinteraction=0.07) or with large breast size (OR=0.26, 95%CI 0.07-0.98; Pinteraction=0.08). There were no patient subgroups where risk of adverse BCTOS cosmetic outcome was significantly higher with HF-WBI compared to CF-WBI. For secondary outcomes, there was no difference by treatment arm for BCTOS functional status (P=0.83), BCTOS breast pain (P=0.69), BIS (P=0.45), or FACT-B TOI (P=0.79). Poor-fair cosmetic outcome at 3 years assessed by the 3-physician panel was noted in 28.8% of CF-WBI patients and 35.4% of HF-WBI patients (P=0.31). In total, 19% CF-WBI patients and 20% of HF-WBI patients had a grade 2-3 toxicity at the three-year evaluation, with no difference by treatment arm (P=0.84). Five-year OS, LRFS, and DMFS were 99%, 98%, and 99%, respectively, with no difference by treatment arm (P=0.68, 0.37, 0.62). Conclusions: Three years after WBI followed by a tumor bed boost, outcomes with HF and CF are similar. Tumor bed boost, modern chemotherapy, and large breast size do not appear to be clinically meaningful contraindications to HF-WBI. Citation Format: Shaitelman SF, Lei X, Thompson A, Schlembach P, Arzu I, Bloom ES, Buchholz DJ, Chronowski GM, Dvorak T, Grade EJ, Hoffman KE, Kelly P, Perkins GH, Reed V, Shah S, Stauder MC, Strom EA, Tereffe W, Woodward WA, Baumann D, Amaya D, Guerra W, Morrison M, Hortobagyi G, Hunt KK, Buchholz TA, Smith BD. Three-year outcomes with hypofractionated (HF) versus conventionally fractionated (CF) whole breast irradiation (WBI) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-02.

Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer. The Wnt-transcription factor, TCF7L2, is overexpressed in primary rectal cancers that are resistant to chemoradiotherapy and TCF7L2 mediates resistance to chemoradiotherapy. However, it is unclear whether the resistance is mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. Here, inhibition of β-catenin by siRNAs or a small-molecule inhibitor (XAV-939) resulted in sensitization of colorectal cancer cells to chemoradiotherapy. To investigate the potential role of Wnt/β-catenin signaling in controlling therapeutic responsiveness, nontumorigenic RPE-1 cells were stimulated with Wnt-3a, a physiologic ligand of Frizzled receptors, which increased resistance to chemoradiotherapy. This effect could be recapitulated by overexpression of a degradation-resistant mutant of β-catenin (S33Y), also boosting resistance of RPE-1 cells to chemoradiotherapy, which was, conversely, abrogated by siRNA-mediated silencing of β-catenin. Consistent with these findings, higher expression levels of active β-catenin were observed as well as increased TCF/LEF reporter activity in SW1463 cells that evolved radiation resistance due to repeated radiation treatment. Global gene expression profiling identified several altered pathways, including PPAR signaling and other metabolic pathways, associated with cellular response to radiation. In summary, aberrant activation of Wnt/β-catenin signaling not only regulates the development and progression of colorectal cancer, but also mediates resistance of rectal cancers to chemoradiotherapy. Implications: Targeting Wnt/β-catenin signaling or one of the downstream pathways represents a promising strategy to increase response to chemoradiotherapy. Mol Cancer Res; 15(11); 1481–90. ©2017 AACR.

We report the case of a 70-year-old man who presented with hematochezia, anaemia, and severe abdominal pain 6 days after polypectomy. Contrast-enhanced ultrasound and computed tomography revealed no signs of free intra-abdominal air but showed intra-abdominal and intra-luminal bleeding. The patient was referred to colonoscopy in the operation room, which showed a coagula and venous bleeding at the polypectomy site. Emergency laparotomy was performed and revealed a large intra-abdominal mesocolic hematoma, which was surgically removed. The patient’s post-operative recovery was uneventful. While few reports of splenic vessel rupture after colonoscopy due to traction on the splenocolic ligament have been published, delayed mesocolic hematoma without evidence of organ damage has not been reported so far. Clinicians need to be aware of these rare but life-threatening complications following colonoscopy.

A patent umbilical vein is a rare condition in healthy volunteers, but can be detected in up to 11% of patients with liver cirrhosis as a consequence of portal hypertension.We report the case of a 52-year-old woman who was admitted to our department with acute abdominal pain after blunt trauma to her forehead and abdomen. She had a history of alcohol abuse with liver cirrhosis that had been classified as Child–Pugh stage C 5 years earlier. Signs of portosystemic shunting had been present at an earlier endoscopy, and esophageal varices were found.Clinical examination revealed typical signs of liver cirrhosis, and ultrasound examination showed an aneurysm of 6 cm of the umbilical vein, which had not been present at earlier examinations. After lowering portal hypertension by inserting a transjugular intrahepatic portosystemic shunt, an open surgical resection of the aneurysmal umbilical vein was performed without complications. The patient recovered well and was discharged from the hospital 10 days later.We hypothesize that the abdominal trauma prompted or aggravated umbilical vein aneurysm in this patient with liver cirrhosis and portal hypertension. Due to the risk of rupture, a surgery-based resection is a valuable treatment option.

A 68-year-old man was admitted to our hospital with a dyspnea. On physical examination the patient was not distressed. Chest X-ray demonstrated an extensive left pleural effusion (A). Pleural aspiration showed an exsudate with elevated LDH of 464 U/L (0-100 U/l). The diagnostic thoracoscopy revealed disseminated black nodules on the visceral and parietal pleura (B) and a pleurodesis was performed after obtaining multiple biopsies. The melanoma cells showed a strong cytoplasmatic HMB-45 reaction (C). Immunohistochemical staining revealed a malignant melanoma with expression of PD-L1 in 3% of the tumor cells, the moleculargenetic examination proofed a BRAF V600 mutation. The patient was treated with the kinase inhibitor Trametinib and the tyrosinkinase inhibitor Tafiniar. He had initially a good response but died 10 months later after presenting to our clinic. 3 years prior the patient had a removal of a malign melanoma on the right upper thorax wall and the surgical exploration showed micrometastases in the sentinel lymphnode of the right axilla. (SSM Clark Level IV). At that time a immunotherapy with interferon alpha 2a was initiated.

There is growing interest in the use of telomere length as a biomarker of health and a predictor of later morbidity and mortality. However, little is known about developmentally expected telomere erosion over the first years of life. This gap hinders our ability to interpret the meaning of relative telomere length and rate of attrition in relation to risk factors and health outcomes. The overall goal of this study was to examine the rate of relative telomere length attrition in a large, normative sample of healthy children (N = 630) followed from infancy to three years of age. A secondary goal was to explore associations between sociodemographic characteristics and telomere erosion over this time period. Relative telomere length was assessed from DNA in saliva samples collected in infancy (M = 8.6 months), age 2 years (M = 25.2 months), and age 3 years (M = 38.3 months). In the sample as a whole, relative telomere length decreased from infancy to 2 years but remained stable from 2 years to 3 years. Notably, increases in relative telomere length were observed in 29 % of children between infancy and 2 years of age and in 46 % of children between 2 and 3 years of age; 62 % of children showed both increases and decreases in relative telomere length across the study period. Females showed longer relative telomere length than males, regardless of timepoint. There was some evidence that parental age and family finances were associated with changes in child relative telomere length across time. Overall, the findings suggest that telomere length attrition is not uniform across the early years of life, with the most rapid attrition occurring during the first two years, and that increases as well as decreases in telomere length during this period are commonly observed.

Introduction: Oncogenic mutation within the KRAS gene represents a negative predictor for treatment response to anti-epidermal growth factor receptor (EGFR) in patients with colorectal cancer. Recently, we have shown no relevant heterogeneity for KRAS mutation status within and between pre- and posttherapeutic samples from the primary tumor in patients with locally advanced rectal cancer. The aim of this study was to evaluate the intertumoral heterogeneity of KRAS mutation status between the primary tumor and the corresponding metastasis or local recurrence in the similar cohort and to evaluate the ideal representative tissue for KRAS mutation testing. Materials and methods: KRAS mutation status was analyzed from 47 patients with locally advanced rectal cancer, which were enrolled in the CAO/ARO/AIO-94 or CAO/ARO/AIO-04 trial. Mutations in KRAS codons 12, 13, and 61 were analyzed by using the KRAS RGQ PCR Kit (therascreen® KRAS test). Six patients needed to be excluded due to incomplete follow up data. 11 patients showed a relapse of the disease during the follow up presented by distant metastases or local recurrence. DNA from representative areas of metastatic tissue was obtained from formalin-fixed paraffin-embedded specimens. Results: The mean patient age was 64.13 ± 10.64 years. In total, 19 patients showed a KRAS mutation (46.34%) in the primary tumor. Of the eleven patients with a metastatic disease or local recurrence, five patients showed a KRAS mutation whereas six patients had a KRAS wildtype status. Metastatic localizations included the liver (n = 2), lung (n = 4), local recurrence (n = 1), liver + lung (n = 3), lung + local recurrence (n = 1). For these eleven patients with paired data available for the primary tumor and metastatic tissue, a significant KRAS mutation status concordance was detected in 81.18% (9/11) of the patients (p = 0.03271). Only two patients showed intertumoral heterogeneity, which harbored in one patient a KRAS G12C mutation status in the primary tumor, but a G12V KRAS mutation status in the corresponding lung lesion, and in the other patient a G12A mutation in the primary lesion and a WT in the lung metastasis. Conclusions: We show a significant concordance of the KRAS mutation status between tumor samples obtained from the primary tumor and the corresponding metastasis and/ or local recurrence in patients with rectal cancer indicating no relevant intertumoral heterogeneity. Our data suggest that sampling either the primary (pre- or posttherapeutical tumor tissue) or metastatic lesion may be valid for the initial evaluation of KRAS mutation status predicting the response to anti-EGFR treatment and guiding clinical decisions. Open-Access-Publikationsfonds 2020 peerReviewed

A 32 year old female patient, with a medical history of an ill-characterized Pulmonary Arterial Hypertension associated with congenital heart disease, lost in the follow up with no medical therapy, attended an emergency department for a gynecological hemorrhage at 16 weeks of pregnancy. Due to high maternity mortality risk, informed consent was obtained, and termination of pregnancy was performed. She was then referred to our pulmonary hypertension center. At our center she had complains of fatigue with moderate intensity exertion, classified in a class II of the World Health Organization (WHO) classification, but was otherwise asymptomatic, with no history of dyspnea, angina or syncope. There was allusion to a self-limited episode of hemoptysis in the past. On physical examination she had an increased pulmonary component of the second heart sound, continuous heart murmur in left sternal border and no cyanosis (O2 peripheral saturation in the upper and lower limbs of 99% at room air). The performed echocardiograms (both transthoracic and transesophageal) showed an estimated systolic pulmonary artery pressure of 120 mmHg with severe right ventricular hypertrophy and systolic dysfunction. There was dilatation of the trunk and right pulmonary artery. The left pulmonary artery was not seen. Biochemical evaluation and viral serologies were unremarkable. The pulmonary function tests and the arterial blood gases were normal. Cardiac MRI demonstrated the presence of a right aortic arch and a right patent arterial duct. An anomalous origin of the left pulmonary artery from the ascending thoracic aorta could be noted. Associated congenital cardiac defects were excluded. A right heart catheterization confirmed the presence of severe pulmonary hypertension with mean pulmonary artery pressure of 86 mmHg and Pulmonary vascular resistance of 11 Wood Units. A large persistent arterial duct to the right pulmonary artery was confirmed with persistent left to right shunt. The left pulmonary artery was visualized when injection was performed in the aortic root. Coronary arteries were normally implanted. The patient was started on Sildenafil and Bosentan (later replaced by Macitentan due to hepatic toxicity). After 3 years of follow up, there was an improvement in symptoms and in the 6 minutes walking test, remaining in a low risk category and on a WHO class I. This case reports a very rare congenital abnormality identified in an adult patient. Despite the complex anatomy and severe pulmonary hypertension, the patient is reasonably well under medical therapy and close follow up. Abstract P1728 Figure. Cardiac MRI Cine Sequences

Background ARID1A (AT-rich interactive domain-containing protein 1A) is a subunit of the BAF chromatin remodeling complex and plays roles in transcriptional regulation and DNA damage response. Mutations in ARID1A that lead to inactivation or loss of expression are frequent and widespread across many cancer types including colorectal cancer (CRC). A tumor suppressor role of ARID1A has been established in a number of tumor types including CRC where the genetic inactivation of Arid1a alone led to the formation of invasive colorectal adenocarcinomas in mice. Mechanistically, ARID1A has been described to largely function through the regulation of enhancer activity. Methods To mimic ARID1A-deficient colorectal cancer, we used CRISPR/Cas9-mediated gene editing to inactivate the ARID1A gene in established colorectal cancer cell lines. We integrated gene expression analyses with genome-wide ARID1A occupancy and epigenomic mapping data to decipher ARID1A-dependent transcriptional regulatory mechanisms. Results Interestingly, we found that CRC cell lines harboring KRAS mutations are critically dependent on ARID1A function. In the absence of ARID1A, proliferation of these cell lines is severely impaired, suggesting an essential role for ARID1A in this context. Mechanistically, we showed that ARID1A acts as a co-factor at enhancers occupied by AP1 transcription factors acting downstream of the MEK/ERK pathway. Consistently, loss of ARID1A led to a disruption of KRAS/AP1-dependent enhancer activity, accompanied by a downregulation of expression of the associated target genes. Conclusions We identify a previously unknown context-dependent tumor-supporting function of ARID1A in CRC downstream of KRAS signaling. Upon the loss of ARID1A in KRAS-mutated cells, enhancers that are co-occupied by ARID1A and the AP1 transcription factors become inactive, thereby leading to decreased target gene expression. Thus, targeting of the BAF complex in KRAS-mutated CRC may offer a unique, previously unknown, context-dependent therapeutic option in CRC. Electronic supplementary material The online version of this article (10.1186/s13148-019-0690-5) contains supplementary material, which is available to authorized users.

The standard treatment of locally advanced esophageal cancer comprises multimodal treatment concepts including preoperative chemoradiotherapy (CRT) followed by radical surgical resection. However, despite intensified treatment approaches, 5-year survival rates are still low. Therefore, new strategies are required to overcome treatment resistance, and to improve patients’ outcome. In this study, we investigated the impact of Wnt/β-catenin signaling on CRT resistance in esophageal cancer cells. Experiments were conducted in adenocarcinoma and squamous cell carcinoma cell lines with varying expression levels of Wnt proteins and Wnt/β-catenin signaling activities. To investigate the effect of Wnt/β-catenin signaling on CRT responsiveness, we genetically or pharmacologically inhibited Wnt/β-catenin signaling. Our experiments revealed that inhibition of Wnt/β-catenin signaling sensitizes cell lines with robust pathway activity to CRT. In conclusion, Wnt/β-catenin activity may guide precision therapies in esophageal carcinoma patients.

In der Allgemein- und Viszeralchirurgie finden zunehmend moderne Technologien zur intraoperativen Visualisierung spezifischer anatomischer Strukturen Anwendung. Die Kombination der unterschiedlichen Verfahren ermoglicht eine mehrdimensionale intraoperative Darstellung. So ist es beispielsweise moglich, zwischen Normal- und Tumorgewebe zu unterscheiden und somit Tumorgrenzen exakter zu definieren. Ziel einer solchen intraoperativen Visualisierung von zu resezierendem und zu schonendem Gewebe ist es, eine rationale Balance zwischen onkologischer Radikalitat und funktionellem Ergebnis zu erzielen. Zudem konnen derartige Techniken auch uber die Physiologie bzw. Integritat bestimmter Strukturen Auskunft geben. So kann z. B. die Perfusion oder der Sauerstoffgehalt des Gewebes intraoperativ analysiert werden. Allerdings ist der Stellenwert der einzelnen Techniken fur den klinischen Alltag noch nicht abschliesend geklart. Die vorliegende Ubersichtsarbeit stellt die wesentlichen modernen Visualisierungsverfahren mit Fokus auf die intraoperative Computertomographie und Magnetresonanztomographie sowie die „erweiterte Realitat“, die Fluoreszenzbildgebung und die Optoakustik vor.

NG2-glia in the adult brain are known to proliferate and differentiate into mature and myelinating oligodendrocytes throughout lifetime. However, the role of these newly generated oligodendrocytes in the adult brain still remains little understood. Here we took advantage of the Sox10-iCreERT2 x CAG-eGFP x Esco2fl/fl mouse line in which we can specifically ablate proliferating NG2-glia in adult animals. Surprisingly, we observed that the generation of new oligodendrocytes in the adult brain was severely affected, although the number of NG2-glia remained stable due to the enhanced proliferation of non-recombined cells. This lack of oligodendrogenesis led to the elongation of the nodes of Ranvier as well as the associated paranodes, which could be locally rescued by myelinating oligodendrocytes differentiated from transplanted NG2-glia deriving from wildtype mice. Repetitive measurements of conduction velocity in the corpus callosum of awake animals revealed a progressive deceleration specifically in the mice lacking adult oligodendrogenesis that resulted in progressive motor deficits. In summary, here we demonstrated for the first time that axon function is not only controlled by the reliable organization of myelin, but also requires a dynamic and continuous generation of new oligodendrocytes in the adult brain. GLIA 2016;64:2201–2218

Background The oncological outcome of patients with rectal cancer has improved considerably over the past few decades. This is mainly due to the introduction of the surgical concept of total mesorectal excision (TME) and the implementation of multimodal treatment strategies. Additionally, it has recently been demonstrated that the oncological results of open and laparoscopic TME are comparable. For some time there has been an ongoing debate on the potential relevance of robotic assistance systems in visceral surgery. The aim of this study was to evaluate the operative and perioperative outcomes of patients with rectal or rectosigmoid cancer, who were operated on using the Da Vinci Surgical System. Patients and results We retrospectively analysed the outcomes of 202 consecutive patients, who were operated between September 2010 and November 2015 in three Surgical Centers. The cohort consisted of 136 men and 66 women with a mean BMI of 28. We performed the following procedures: 49 anterior rectal resections, 119 low anterior rectal resections, and 34 abdominoperineal excisions. Conversion to an open procedure was required in 13 patients. Non-surgical complications (n = 27) occurred in 24 patients (12%) and surgical complications (n = 67) in 62 patients (31%). Most complications were due to abdominal or sacral wound infections (n = 25) and anastomotic leaks (n = 18). The mortality rate within 30 days was 2%. The rate of R0 resections was 95%, with circumferential resection margins being negative in 98% of the patients. The quality of the mesorectal resection was scored as good in 91% of the patients. Conclusions The Da Vinci Surgical System can be used safely and with a low complication rate for surgical treatment of rectal cancer. While primary evidence suggests that the outcome of robotic-assisted surgery is comparable with open and laparoscopic surgery, its definitive value has to be determined upon publication of the prospective randomized ROLARR trial. The main advantages of the Da Vinci system are its endowristed instruments with multiple degrees of freedom and its optimised visualisation (3D, stable camera platform controlled by the surgeon). Another positive feature is the significant ergonomic advantage for the surgeon.

SUMMARYMost carcinomas have characteristic chromosomal aneuploidies specific to the tissue of tumor origin. The reason for this specificity is unknown. As aneuploidies directly affect gene expression, we hypothesized that cancer-type specific aneuploidies, which emerge at early stages of tumor evolution, confer adaptive advantages to the physiological requirements of the tissue of origin. To test this hypothesis, we compared chromosomal aneuploidies reported in the TCGA database to chromosome arm-wide gene expression levels of normal tissues from the GTEx database. We find that cancer-type specific chromosomal aneuploidies mirror differential gene expression levels specific to the respective normal tissues which cannot be explained by copy number alterations of resident cancer driver genes. We propose that cancer-type specific aneuploidies “hard-wire” chromosome arm-wide gene expression levels present in normal tissues, favoring clonal expansion and tumorigenesis.One sentence summaryThe clonal evolution of cancer is initiated by tissue-specific transcriptional requirements

Die roboterassistierte Chirurgie reprasentiert einen deutlichen Fortschritt in der minimal-invasiven Chirurgie, da sie viele technische Limitationen der konventionellen Laparoskopie uberwindet. Aktuell kommt in der chirurgischen Onkologie uberwiegend das Da-Vinci-Op.-System zum Einsatz, welches als „Master-Slave-System“ im Prinzip einem computerassistierten Telemanipulator entspricht. Trotz hoher Kosten und weitgehend fehlender klinischer Evidenz hat die Da-Vinci-assistierte Chirurgie in den letzten Jahren stetig an Bedeutung gewonnen und wird mit steigender Frequenz eingesetzt. Ziel dieser Ubersichtsarbeit ist es, aktuelle Moglichkeiten in der roboterassistierten Chirurgie aufzuzeigen und die Evidenz fur ausgewahlte Eingriffe in der chirurgischen Onkologie zu diskutieren. Es handelt sich nicht um eine systematische Ubersichtsarbeit oder Metaanalyse. Exemplarisch werden folgende Disziplinen betrachtet: Viszeralchirurgie, Thoraxchirurgie, Gynakologie und Urologie.