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  • 1
    In: Neuro-Oncology, 2018, Vol. 20(suppl6), pp.vi133-vi133
    Description: Abstract BACKGROUND IDH1-mutated gliomas are associated with less abundant and phenotypically skewed innate and adaptive immune cell infiltrates compared to IDH1 wild-type tumors. Despite this, the most frequent mutation, IDHR132H, represents a clonal shared neoantigen and mutations in IDH are associated with a more favorable prognosis. While the tumor cell-intrinsic consequences of the oncometabolite R-2-hydroxyglutarate (R-2-HG) accumulating in IDH1-mutated gliomas as a result of a neomorphic enzymatic function, are well-characterized, potential direct paracrine effects of R-2-HG influencing the glioma immune microenvironment remain incompletely understood. METHODS AND RESULTS By means of comprehensive analyses of expression datasets from human gliomas and syngeneic murine tumor models as well as transporter studies we demonstrate that R-2-HG is imported by both microglia and macrophages via SLC family transporters and suppresses their function in a paracrine manner. Functional analyses of microglia and macrophages indicate an R-2-HG-driven induction of tolerogenicity as evidenced by accumulation of IL10 and TGFβ and suppression of MHC-II expression, which results in impaired activation of antigen-specific T cells and activation of immune checkpoint molecules. Multi-level signature profiling of human tumor-infiltrating as well as primary immune cells was complemented by reporter gene assays and pathway analyses and revealed that R-2-HG activates the cytosolic transcription factor aryl hydrocarbon receptor (AHR), a key immunomodulatory target of immunosuppressive tryptophan metabolism. Functional relevance of R-2-HG-mediated, AHR-driven impairment of myeloid cell immunity was demonstrated in vivo by pharmacological AHR inhibition, increasing the efficacy of checkpoint blockade. CONCLUSION R-2-HG impairs antitumor immunity in IDH1-mutated gliomas by activating the AHR in innate immune cells, thus suppressing the innate immune microenvironment by compromising antigen presentation and activation of antigen-specific T cells. This, together with recent findings on inhibitory effects on T cell immunity, represents a novel mechanism of immune evasion of an immunogenic driver mutation and opens a novel therapeutic approach to IDH1-mutated gliomas.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    Language: English
    In: Nature medicine, August 2018, Vol.24(8), pp.1192-1203
    Description: The oncometabolite (R)-2-hydroxyglutarate (R-2-HG) produced by isocitrate dehydrogenase (IDH) mutations promotes gliomagenesis via DNA and histone methylation. Here, we identify an additional activity of R-2-HG: tumor cell-derived R-2-HG is taken up by T cells where it induces a perturbation of nuclear factor of activated T cells transcriptional activity and polyamine biosynthesis, resulting in suppression of T cell activity. IDH1-mutant gliomas display reduced T cell abundance and altered calcium signaling. Antitumor immunity to experimental syngeneic IDH1-mutant tumors induced by IDH1-specific vaccine or checkpoint inhibition is improved by inhibition of the neomorphic enzymatic function of mutant IDH1. These data attribute a novel, non-tumor cell-autonomous role to an oncometabolite in shaping the tumor immune microenvironment.
    Keywords: Immunity ; Glutarates -- Metabolism ; T-Lymphocytes -- Immunology
    ISSN: 10788956
    E-ISSN: 1546-170X
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  • 3
    In: Current Opinion in Oncology, 2018, Vol.30(6), pp.368-374
    Description: PURPOSE OF REVIEW: The present review introduces recent progress in eliciting the role of mutant isocitrate dehydrogenase (IDH) in gliomas, especially regarding its mode of action as a modulator of antitumor immune response, and provides rationales for targeting mutant IDH in glioma immunotherapy. Both the development of small molecule inhibitors repressing the enzymatic activity of mutant IDH and novel, mechanism-led combination immunotherapies are discussed. RECENT FINDINGS: Since the discovery of highly frequent IDH mutations in low-grade gliomas and nonsolid malignancies, its tumor cell-intrinsic effects have been intensively investigated. Tumor cells expressing mutant IDH display profound alterations of redox control capacity, phospholipid profile, and ATP supply. Recent findings suggest that IDH mutations – via intricate, yet druggable pathways – cause immunological alterations, highlighting the importance of oncogenic drivers as modulators of antitumor immunity and targets for immunotherapy. SUMMARY: Mutant IDH is not only a disease-defining biomarker and oncogenic driver in glioma, but is also a neoantigen and a regulator of glioma immune evasion. Effective and specific strategies targeting the immunomodulatory properties of mutant IDH may complement current (immuno-)therapeutic strategies and approved antiglioma treatments to improve outcome.
    Keywords: Immunotherapy – Usage ; Immunotherapy – Research ; Gliomas – Care and Treatment ; Gliomas – Research;
    ISSN: 1040-8746
    E-ISSN: 1531703X
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  • 4
    Language: English
    In: International Journal of Surgery Protocols, 2017, Vol.3, pp.7-13
    Description: Surgical proficiency is highly dependent on continuous and efficient training. However, efficacy of training hinges on questions such as accessibility and how intuitively the training can be translated into reality. Minimally invasive surgery (MIS) in particular relies on adequate training modalities in order to compensate for its additional psychomotor and visuospatial challenges. The increasing demand for MIS procedures longs for further enhancement of training and steep learning curves. We are investigating a nouveau training concept that continuously utilizes the first person view as addendum to laparoscopic view. We hypothesize this approach to be more intuitive thus faster and more naturally to apprehend than a laparoscopic view only and aim to establish a new standard to implement into training curricula. The present study is conducted as a monocentric, two-arm randomized trial. Participants undergo a training curriculum in laparoscopic suturing and knot tying, using e-learning video material with either the first-person perspective of the surgeon or the laparoscopic view only. Primary endpoint is the total training time needed to reach a predefined proficiency level. Participants are evaluated by blinded raters using validated checklists. Number of attempts, procedure and knot quality subscore difference as well as metric parameter analysis from the first and last knots analyzed as secondary endpoints. Furthermore, trainees are assessed with regard to surgical background, basic skills level and spatial awareness. A total sample size of 80 participants for the analysis of the primary endpoint was determined, which will be performed as a two-sided -test. Ethical approval was obtained from the Ethics Committee of the Medical Faculty at Heidelberg University (Code S-334/2011). This trial was registered with the German Clinical Trials Register (DRKS) in Freiburg, Germany, on May 6th (DRKS00009997). The results will be published and presented at appropriate conferences.
    Keywords: Minimally Invasive Surgery ; Education ; Training ; Laparoscopy ; Perspective ; First-Person View ; Education
    ISSN: 2468-3574
    E-ISSN: 2468-3574
    Source: ScienceDirect Journals (Elsevier)
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  • 5
    Language: English
    In: Trials, 06 February 2017, Vol.18(1), pp.56
    Description: Chest tube insertion is a standard intervention for management of various injuries of the thorax. Quick and accurate execution facilitates efficient therapy without further complications. Here, we propose a new training concept comprised of e-learning elements as well as continuous rating using an objective structured assessment of technical skills (OSATS) tool. The study protocol is presented for a randomized trial to evaluate e-learning with app-based serious gaming for chest drain insertion. The proposed randomized trial will be carried out at the Department of Orthopedics and Traumatology at Heidelberg University in the context of regular curricular teaching for medical students (n = 90, 3rd to 6th year). The intervention group will use e-learning with the serious gaming app Touch Surgery (TM) for chest drain insertion, whereas the control group uses serious gaming for an unrelated procedure. Primary endpoint is operative performance of chest drain insertion in a porcine cadaveric model according to OSATS. The randomized trial will help determine the value of e-learning with the serious gaming app Touch Surgery (TM) for chest drain insertion by using the OSATS score. The study will improve surgical training for trauma situations. Trial Registration Number, DRKS00009994 . Registered on 27 May 2016.
    Keywords: Chest Tube Insertion ; Education ; Hematothorax ; Pneumothorax ; Serious Gaming ; Training ; Chest Tubes ; Mobile Applications ; Students, Medical ; Video Games ; Computer-Assisted Instruction -- Methods ; Drainage -- Instrumentation ; Education, Medical, Undergraduate -- Methods ; Intubation, Intratracheal -- Instrumentation
    E-ISSN: 1745-6215
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  • 6
    Language: English
    In: BMC Medical Education, 01 December 2018, Vol.18(1), pp.1-9
    Description: Abstract Background There is an increasing need for objective and validated educational concepts. This holds especially true for surgical procedures like chest tube insertion (CTI). Thus, we developed an instrument for objectification of learning successes: the assessment scale based on Objective Structured Assessment of Technical Skill (OSATS) for chest tube insertion, which is evaluated in this study. Primary endpoint was the evaluation of intermethod reliability (IM). Secondary endpoints are ‘indirect’ interrater reliability (IR) and construct validity of the scale (CV). Methods Every participant (N = 59) performed a CTI on a porcine thorax. Participants received three ratings (one ‘direct’ on site, two ‘indirect’ via video rating). IM compares ‘direct’ with ‘indirect’ ratings. IR was assessed between ‘indirect’ ratings. CV was investigated by subgroup analysis based on prior experience in CTI for ‘direct’ and ‘indirect’ rating. Results We included 59 medical students to our study. IM showed moderate conformity (‘direct’ vs. ‘indirect 1’ ICC = 0.735, 95% CI: 0.554–0.843; ‘direct’ vs. ‘indirect 2’ ICC = 0.722, 95% CI 0.533–0.835) and good conformity between ‘direct’ vs. ‘average indirect’ rating (ICC = 0.764, 95% CI: 0.6–0.86). IR showed good conformity (ICC = 0.84, 95% CI: 0.707–0.91). CV was proven between subgroups in ‘direct’ (p = 0.037) and ‘indirect’ rating (p = 0.013). Conclusion Results for IM suggest equivalence for ‘direct’ and ‘indirect’ ratings, while both IR and CV was demonstrated in both rating methods. Thus, the assessment scale seems a reliable method for rating trainees’ performances ‘directly’ as well as ‘indirectly’. It may help to objectify and facilitate the assessment of training of chest tube insertion.
    Keywords: Osats ; Chest Tube Insertion ; Education ; Training ; Video Rating ; Intermethod Reliability ; Medicine ; Education
    E-ISSN: 1472-6920
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  • 7
    Language: English
    In: Innovative surgical sciences, December 2017, Vol.2(4), pp.255-260
    Description: Evidence should define and guide modern clinical care, yet many relevant questions in surgical practice remain unconfirmed by substantial data. Evidence-based medicine requires both the implementation of its principles in day-to-day work and the acquisition of new evidence preferably by randomized controlled trials and systematic reviews. Meaningful clinical research, however, is challenging to conduct, and its overall infrastructure in Germany was, until recently, considered poor compared to other leading countries. Although this has been significantly improved after the establishment of the Study Center of the German Surgical Society (SDGC) and the surgical clinical trial network CHIR-, limited focus has been put on the training, teaching, and recruitment of medical students to become competent clinical researchers and clinician scientists. To ensure continuing comprehensive clinical research in surgery, CHIR- aims to establish a student-driven multicenter research network in Germany, which is embedded in both the national CHIR- and the pan-European and international frameworks. Student-Initiated German Medical Audits (SIGMA) is a product of the strong collaboration between clinical scientists and medical trainees, enabling students to contribute to high-quality clinical trials. Additionally, participants are offered extensive training to support the next generation of research-active clinicians. Starting on 2018, SIGMA will perform its first multicenter observational study in Germany.
    Keywords: Chir-Net ; Patronus ; SIGMA ; Clinical Trial ; Evidence-Based Medicine ; Medical Education ; Research Personnel
    E-ISSN: 2364-7485
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  • 8
    Language: German
    In: GMS Journal for Medical Education, 01 November 2018, Vol.35(4), p.Doc48
    Description: Background: Chest tube insertion is a standard intervention for management of various injuries of the thorax. Efficient clinical training of this and similar bed-side procedures is equally demanded and improvable. Here, we propose a nouveau...
    Keywords: Chest Tube Insertion ; Education ; Training ; Assesssment ; Hematothorax ; Pneumothorax ; Medicine ; Education
    ISSN: 2366-5017
    E-ISSN: 2366-5017
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  • 9
    Language: English
    In: Journal of Surgical Education, March 2018, Vol.75(2), pp.510-515
    Description: This study aimed to compare the effectiveness of Halsted’s method “see one, do one, and teach one” with Peyton’s Four-Step Approach for teaching intracorporal suturing and knot tying (ICKT). Laparoscopically naïve medical students ( = 60) were randomized to teaching of ICKT with either Halsted’s ( = 30) or Peyton’s method ( = 30) for 60 minutes. Each student’s first 3 and final sutures were evaluated using Objective Structured Assessment of Technical Skills (OSATS), procedural implementation, knot quality, total time, and suture placement accuracy. Performance score and OSATS-PSC always differed significantly in favor of Peyton’s group (p = 0.001). OSATS-GRS (p = 0.01) and task time (p = 0.03) differed only in the summary of the first 3 sutures in favor of Peyton’s group. There were no significant intergroup differences in knot quality and accuracy. Peyton’s Four-Step Approach is the preferable method for learning complex laparoscopic skills like ICKT.
    Keywords: Laparoscopy ; Education ; Peyton ; Halsted ; Minimally Invasive Surgery ; Knot Tying ; Practice-Based Learning and Improvement ; Interpersonal and Communication Skills ; Education
    ISSN: 1931-7204
    E-ISSN: 1878-7452
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  • 10
    In: Zentralblatt für Chirurgie, 2017, Vol.142(06)
    In: Zentralblatt für Chirurgie, 2017, Vol.142(06), pp.560-565
    Description: Der Ärztemangel ist besonders in den chirurgischen Fächern spürbar. Dachverbände bemühen sich um die Rekrutierung neuen Nachwuchses. Vielversprechend für frühe Interessenbildung scheinen Studierendenforen im Kontext fachspezifischer Kongresse. Beim Dreiländertreffen für Minimal Invasive Chirurgie (MIC) 2016 in Heidelberg wurde ein beispielhaftes Studierendenforum durchgeführt. Ziel war die Evaluation des Studierendenforums aus Studierendensicht für Empfehlungen zukünftiger Veranstaltungen. Von insgesamt 60 teilnehmenden Studierenden nahmen 50% (30/60) an der Evaluation teil. Auf einer 5-Punkte-Likert-Skala wurden einzelne Programmpunkte, die Zunahme spezieller Interessen, der persönliche Benefit und die Wahrscheinlichkeit einer erneuten Teilnahme beurteilt. Beim Studierendenforum zeigte sich der Interessenzuwachs für die MIC mit einer positiven Bewertung von 60% (18/30) der Studierenden am stärksten. Der Interessenzuwachs für die Chirurgie im Allgemeinen und für die robotische Chirurgie im Spezifischen war mit 57% (17/30) positiven Bewertungen minimal geringer. Unter den einzelnen Programmpunkten wurde der laparoskopische Hands-on-Workshop mit 90% (27/30) positiven Bewertungen am besten bewertet. Die Studierenden wünschten sich noch mehr Möglichkeiten zum direkten Austausch mit erfahrenem Personal. Von den Studierenden gaben 67% (40/60) an, definitiv oder sehr wahrscheinlich erneut teilzunehmen. Der Erfolg des Studierendenforums bestätigte sich am deutlichen Interessenzuwachs für die MIC und die Chirurgie im Allgemeinen. Hands-on-Workshops erfahren eine sehr gute Resonanz. Der Kontaktaufbau zwischen Studierenden und erfahrenem Personal sollte gezielt gefördert werden. Für die Debatte über eine ausgeglichene Work-Life-Balance ist das zur Reduzierung von Vorurteilen von besonderer Bedeutung. Hinsichtlich des Nachwuchsproblems chirurgischer Fachgebiete stellt das Konzept des Studierendenforums eine wertvolle Maßnahme dar und sollte etabliert und konsequent weiterentwickelt werden.
    Keywords: Studierendenforum ; Dreiländertreff ; Minimalinvasive chirurgie ; Nachwuchs ; Ärztemangel ; Studentsʼ symposium ; Minimally invasive surgery ; Young surgeons ; Promotion ; Physician shortage
    ISSN: 0044-409X
    E-ISSN: 1438-9592
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