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Laakmann, Elena ; Witzel, Isabell ; Fasching, Peter Andreas ; Rezai, Mahdi ; Schem, Christian ; Solbach, Christine ; Tesch, Hans ; Klare, Peter ; Schneeweiss, Andreas ; Salat, Christoph ; Zahm, Dirk-Michael ; Blohmer, Jens-Uwe ; Ingold Heppner, Barbara ; Huober, Jens ; Hanusch, Claus ; Jackisch, Christian ; Reinisch, Mattea ; Untch, Michael ; Minckwitz, Gunter von ; Nekljudova, Valentina ; Müller, Volkmar ; Loibl, Sibylle
Background: The incidence of central nervous system (CNS) metastases in breast cancer patients is rising and has become a major clinical challenge. Only few data are published concerning risk factors for the development of CNS metastases as a first site of metastatic disease in breast cancer patients. Moreover, the incidence of CNS metastases after modern neoadjuvant treatment is not clear.
Methods: We analyzed clinical factors associated with the occurrence of CNS metastases as the first site of metastatic disease in breast cancer patients after neoadjuvant treatment in the trials GeparQuinto and GeparSixto (n = 3160) where patients received targeted treatment in addition to taxane and anthracycline-based chemotherapy.
Results: After a median follow-up of 61 months, 108 (3%) of a total of 3160 patients developed CNS metastases as the first site of recurrence and 411 (13%) patients had metastatic disease outside the CNS. Thirty-six patients (1%) developed both CNS metastases and other distant metastases as the first site of metastatic disease. Regarding subtypes of the primary tumor, 1% of luminal A-like (11/954), 2% of luminal B-like (7/381), 4% of HER2-positive (34/809), and 6% of triple-negative patients (56/1008) developed CNS metastases as the first site of metastatic disease.
In multivariate analysis, risk factors for the development of CNS metastases were larger tumor size (cT3–4; HR 1.63, 95% CI 1.08–2.46, p = 0.021), node-positive disease (HR 2.57, 95% CI 1.64–4.04, p < 0.001), no pCR after neoadjuvant chemotherapy (HR 2.29, 95% CI 1.32–3.97, p = 0.003), and HER2-positive (HR 3.80, 95% CI 1.89–7.64, p < 0.001) or triple-negative subtype (HR 6.38, 95% CI 3.28–12.44, p < 0.001).
Conclusions: Especially patients with HER2-positive and triple-negative tumors are at risk of developing CNS metastases despite effective systemic treatment. A better understanding of the underlying mechanisms is required in order to develop potential preventive strategies.
Bohmann, Ferdinand ; Kurka, Natalia ; Du Mesnil de Rochemont, Richard Klaus Frieder ; Gruber, Katharina ; Guenther, Joachim ; Rostek, Peter ; Rai, Heike ; Zickler, Philipp ; Ertl, Michael ; Berlis, Ansgar ; Poli, Sven ; Mengel, Annerose ; Ringleb, Peter ; Nagel, Simon ; Pfaff, Johannes ; Wollenweber, Frank Arne ; Kellert, Lars ; Herzberg, Moriz ; Köhler, Luzie Katharina ; Häusler, Karl Georg ; Alegiani, Anna ; Schubert, Charlotte ; Brekenfeld, Caspar ; Doppler, Christopher Emanuel Julian ; Onur, Özgür Abdullah ; Kabbasch, Christoph ; Manser, Tanja ; Pfeilschifter, Waltraud
Introduction: Acute stroke care delivered by interdisciplinary teams is time-sensitive. Simulation-based team training is a promising tool to improve team performance in medical operations. It has the potential to improve process times, team communication, patient safety, and staff satisfaction. We aim to assess whether a multi-level approach consisting of a stringent workflow revision based on peer-to-peer review and 2–3 one-day in situ simulation trainings can improve acute stroke care processing times in high volume neurocenters within a 6 months period.
Methods and Analysis: The trial is being carried out in a pre-test-post-test design at 7 tertiary care university hospital neurocenters in Germany. The intervention is directed at the interdisciplinary multiprofessional stroke teams. Before and after the intervention, process times of all direct-to-center stroke patients receiving IV thrombolysis (IVT) and/or endovascular therapy (EVT) will be recorded. The primary outcome measure will be the “door-to-needle” time of all consecutive stroke patients directly admitted to the neurocenters who receive IVT. Secondary outcome measures will be intervention-related process times of the fraction of patients undergoing EVT and effects on team communication, perceived patient safety, and staff satisfaction via a staff questionnaire.
Interventions: We are applying a multi-level intervention in cooperation with three “STREAM multipliers” from each center. First step is a central meeting of the multipliers at the sponsor's institution with the purposes of algorithm review in a peer-to-peer process that is recorded in a protocol and an introduction to the principles of simulation training and debriefing as well as crew resource management and team communication. Thereafter, the multipliers cooperate with the stroke team trainers from the sponsor's institution to plan and execute 2–3 one-day simulation courses in situ in the emergency department and CT room of the trial centers whereupon they receive teaching materials to perpetuate the trainings.
Clinical Trial Registration: STREAM is a registered trial at https://clinicaltrials.gov/ct2/show/NCT03228251.
Ziegler, Georg Christoph ; Ehlis, Ann-Christine ; Weber, Heike ; Vitale, Maria Rosaria ; Zöller, Johanna E. M. ; Ku, Hsing-Ping ; Schiele, Miriam A. ; Kürbitz, Laura I. ; Romanos, Marcel ; Pauli, Paul ; Kalisch, Raffael ; Zwanzger, Peter M. ; Domschke, Katharina ; Fallgatter, Andreas J. ; Reif, Andreas ; Lesch, Klaus-Peter J.
The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
Stöver, Timo ; Dazert, Stefan ; Plontke, Stefan K.-R. ; Kramer, S. ; Ambrosch, Petra ; Ahrens, Christoph ; Betz, Christian Stefan ; Beutner, Dirk ; Bohr, Christopher ; Bruchhage, Karl-Ludwig ; Canis, Martin ; Dietz, Andreas ; Guntinas-Lichius, Orlando ; Hagen, Rudolf ; Hosemann, Werner ; Iro, Heinrich ; Klußmann, Jens Peter ; Knopf, Andreas ; Lang, Stephan ; Leinung, Martin ; Lenarz, Thomas ; Löwenheim, Hubert Martin ; Matthias, Christian ; Mlynski, Robert Arndt ; Olze, Heidi ; Park, Jonas Jae-Hyun ; Plinkert, Peter K. ; Radeloff, Andreas Daniel ; Rotter, Nicole ; Rudack, Claudia ; Bozzato, Alessandro ; Schipper, Jörg H. ; Schrader, Martin ; Schuler, Patrick ; Strieth, Sebastian ; Stuck, Boris ; Volkenstein, Stefan ; Westhofen, Martin ; Wolf, Gregor ; Wollenberg, Barbara ; Zahnert, Thomas ; Zenk, Johannes ; Hoffmann, Thomas K.
Hintergrund: Ab Frühjahr 2020 kam es zur weltweiten Verbreitung von SARS-CoV‑2 mit der heute als erste Welle der Pandemie bezeichneten Phase ab März 2020. Diese resultierte an vielen Kliniken in Umstrukturierungen und Ressourcenverschiebungen. Ziel unserer Arbeit war die Erfassung der Auswirkungen der Pandemie auf die universitäre Hals-Nasen-Ohren(HNO)-Heilkunde für die Forschung, Lehre und Weiterbildung. Material und Methoden: Die Direktorinnen und Direktoren der 39 Universitäts-HNO-Kliniken in Deutschland wurden mithilfe einer strukturierten Online-Befragung zu den Auswirkungen der Pandemie im Zeitraum von März bis April 2020 auf die Forschung, Lehre und die Weiterbildung befragt. Ergebnisse: Alle 39 Direktorinnen und Direktoren beteiligten sich an der Umfrage. Hiervon gaben 74,4 % (29/39) an, dass es zu einer Verschlechterung ihrer Forschungstätigkeit infolge der Pandemie gekommen sei. Von 61,5 % (24/39) wurde berichtet, dass pandemiebezogene Forschungsaspekte aufgegriffen wurden. Von allen Kliniken wurde eine Einschränkung der Präsenzlehre berichtet und 97,5 % (38/39) führten neue digitale Lehrformate ein. Im Beobachtungszeitraum sahen 74,4 % der Klinikdirektoren die Weiterbildung der Assistenten nicht gefährdet. Schlussfolgerung: Die Ergebnisse geben einen Einblick in die heterogenen Auswirkungen der Pandemie. Die kurzfristige Bearbeitung pandemiebezogener Forschungsthemen und die Einführung innovativer digitaler Konzepte für die studentische Lehre belegt eindrücklich das große innovative Potenzial und die schnelle Reaktionsfähigkeit der HNO-Universitätskliniken, um auch während der Pandemie ihre Aufgaben in der Forschung, Lehre und Weiterbildung bestmöglich zu erfüllen.
Kurth, Florian Michael ; Develoux, Michel ; Mechain, Matthieu ; Malvy, Denis ; Clerinx, Jan ; Antinori, Spinello ; Gjørup, Ida E. ; Gascon, Joaquím ; Mørch, Kristine ; Nicastri, Emanuele ; Ramharter, Michael ; Bartoloni, Alessandro ; Visser, Leo ; Rolling, Thierry ; Zanger, Philipp ; Calleri, Guido ; Salas‑Coronas, Joaquín ; Nielsen, Henrik ; Just‑Nübling, Gudrun ; Neumayr, Andreas ; Hachfeld, Anna ; Schmid, Matthias L. ; Antonini, Pietro ; Lingscheid, Tilman ; Kern, Peter ; Kapaun, Annette ; Cunha, José Saraiva da ; Pongratz, Peter ; Soriano‑Arandes, Antoni ; Schunk, Mirjam ; Suttorp, Norbert ; Hatz, Christoph ; Zoller, Thomas
Background: Malaria remains one of the most serious infections for travellers to tropical countries. Due to the lack of harmonized guidelines a large variety of treatment regimens is used in Europe to treat severe malaria.
Methods: The European Network for Tropical Medicine and Travel Health (TropNet) conducted an 8-year, multicentre, observational study to analyse epidemiology, treatment practices and outcomes of severe malaria in its member sites across Europe. Physicians at participating TropNet centres were asked to report pseudonymized retrospective data from all patients treated at their centre for microscopically confirmed severe Plasmodium falciparum malaria according to the 2006 WHO criteria.
Results: From 2006 to 2014 a total of 185 patients with severe malaria treated in 12 European countries were included. Three patients died, resulting in a 28-day survival rate of 98.4%. The majority of infections were acquired in West Africa (109/185, 59%). The proportion of patients treated with intravenous artesunate increased from 27% in 2006 to 60% in 2013. Altogether, 56 different combinations of intravenous and oral drugs were used across 28 study centres. The risk of acute renal failure (36 vs 17% p = 0.04) or cerebral malaria (54 vs 20%, p = 0.001) was significantly higher in patients ≥60 years than in younger patients. Respiratory distress with the need for mechanical ventilation was significantly associated with the risk of death in the study population (13 vs 0%, p = 0.001). Post-artemisinin delayed haemolysis was reported in 19/70 (27%) patients treated with intravenous artesunate.
Conclusion: The majority of patients with severe malaria in this study were tourists or migrants acquiring the infection in West Africa. Intravenous artesunate is increasingly used for treatment of severe malaria in many European treatment centres and can be given safely to European patients with severe malaria. Patients treated with intravenous artesunate should be followed up to detect and manage late haemolytic events.
Adamczewski-Musch, Jörn ; Arnold, Oliver ; Behnke, Claudia ; Belounnas, Amel ; Belyaev, Alexander ; Berger-Chen, Jia-Chii ; Blanco, Alberto ; Blume, Christoph ; Böhmer, Michael ; Bordalo, Paula ; Chernenko, Sergey ; Chlad, Lukáš ; Ciepał, Izabela ; Deveaux, Christina Anna ; Dreyer, Jörn ; Epple, Eliane ; Fabbietti, Laura ; Fateev, Oleg ; Filip, Peter ; Fonte, Paulo ; Franco, Celso ; Friese, Jürgen ; Fröhlich, Ingo ; Galatyuk, Tetyana ; Garzón, Juan A. ; Gernhäuser, Roman ; Golubeva, Marina ; Greifenhagen, Robert ; Guber, Fedor ; Gumberidze, Malgorzata ; Harabasz, Szymon ; Heinz, Torsten ; Hennino, Thierry ; Hlaváč, Stanislav ; Höhne, Claudia ; Holzmann, Romain ; Ierusalimov, Alexander P. ; Ivashkin, Alexander ; Kämpfer, Burkhard ; Karavicheva, Tatiana L. ; Kardan, Behruz ; Koenig, Ilse ; Koenig, Wolfgang ; Kohls, Marvin ; Kolb, Burkhard W. ; Korcyl, Grzegorz ; Kornakov, Georgy ; Kornas, Frédéric Julian ; Kotte, Roland ; Kugler, Andrej ; Kunz, Tobias ; Kurepin, Alexei ; Kurilkin, Aleksey K. ; Kurilkin, Pavel ; Ladygin, Vladimir P. ; Lalik, Rafał Tomasz ; Lapidus, Kirill ; Lebedev, Alexander ; Lopes, Luis Alberto Vieira ; Lorenz, Manuel ; Mahmoud, Tariq ; Maier, Ludwig W. ; Malige, Akshay ; Mangiarotti, Alessio ; Markert, Jochen ; Matulewicz, Tomasz ; Maurus, Steffen ; Metag, Volker ; Michel, Jan ; Mihaylov, Dimitar ; Morozov, Sergey ; Müntz, Christian ; Münzer, Robert Helmut ; Naumann, Lothar ; Nowakowski, Krzysztof ; Parpottas, Yannis ; Pechenov, Vladimir ; Pechenova, Olga ; Petukhov, Oleg ; Piasecki, Krzysztof ; Pietraszko, Jerzy ; Przygoda, Witold ; Pysz, Krzysztof ; Ramos, Sérgio ; Ramstein, Béatrice ; Rathod, Narendra ; Reshetin, Andrey ; Rodríguez Ramos, Pablo ; Rosier, Philippe ; Rost, Adrian ; Sadovsky, Alexander ; Salabura, Piotr ; Scheib, Timo ; Schuldes, Heidi ; Schwab, Erwin ; Scozzi, Federico ; Seck, Florian ; Sellheim, Patrick ; Selyuzhenkov, Ilya ; Siebenson, Johannes Stephan ; Silva, Luis ; Singh, U. ; Smyrski, Jerzy ; Sobolev, Yuri G. ; Spataro, Stefano ; Spies, Simon ; Ströbele, Herbert ; Stroth, Joachim ; Sturm, Christian ; Svoboda, Ondřej ; Szala, Melanie ; Tlustý, Pavel ; Traxler, Michael ; Tsertos, Haralabos ; Usenko, Evgeny A. ; Wagner, Vladimir ; Wendisch, Christian ; Wiebusch, Michael ; Wirth, Joana ; Wójcik, Daniel Krzysztof ; Zanevsky, Yuri V. ; Zumbruch, Peter W.
In this letter we report the first multi-differential measurement of correlated pion-proton pairs from 2 billion Au+Au collisions at sNN=2.42 GeV collected with HADES. In this energy regime the population of Δ(1232) resonances plays an important role in the way energy is distributed between intrinsic excitation energy and kinetic energy of the hadrons in the fireball. The triple differential d3N/dMπ±pdpTdy distributions of correlated π±p pairs have been determined by subtracting the πp combinatorial background using an iterative method. The invariant-mass distributions in the Δ(1232) mass region show strong deviations from a Breit-Wigner function with vacuum width and mass. The yield of correlated pion-proton pairs exhibits a complex isospin, rapidity and transverse-momentum dependence. In the invariant mass range 1.1<Minv(GeV/c2)<1.4, the yield is found to be similar for π+p and π−p pairs, and to follow a power law 〈Apart〉α, where 〈Apart〉 is the mean number of participating nucleons. The exponent α depends strongly on the pair transverse momentum (pT) while its pT-integrated and charge-averaged value is α=1.5±0.08st±0.2sy.
Adamczewski-Musch, Jörn ; Arnold, Oliver Werner ; Behnke, Claudia ; Belounnas, Amel ; Belyaev, Alexei V. ; Berger-Chen, Jia-Chii ; Biernat, Jacek ; Blanco, Alberto ; Blume, Christoph ; Böhmer, Michael ; Bordalo, Paula ; Chernenko, Sergey P. ; Chlad, Lukáš ; Deveaux, Christina Anna ; Dreyer, Jörg ; Dybczak, Adrian ; Epple, Eliane ; Fabbietti, Laura ; Fateev, Oleg ; Filip, Peter ; Fonte, Paulo ; Franco, Celso ; Friese, Jürgen ; Fröhlich, Ingo ; Galatyuk, Tetyana ; Garzón, Juan A. ; Gernhäuser, Roman ; Golubeva, Marina ; Greifenhagen, Robert ; Guber, Fedor ; Gumberidze, Malgorzata ; Harabasz, Szymon ; Heinz, Tobias ; Hennino, Thierry ; Hlaváč, Stanislav ; Höhne, Claudia ; Holzmann, Romain ; Ierusalimov, Alexander P. ; Ivashkin, Alexander ; Kämpfer, Burkhard ; Karavicheva, Tatiana L. ; Kardan, Behruz ; Koenig, Ilse ; Koenig, Wolfgang ; Kolb, Burkhard W. ; Korcyl, Grzegorz ; Kornakov, Georgy ; Kotte, Roland ; Kugler, Andrej ; Kunz, Tobias ; Kurepin, Alexander ; Kurilkin, Aleksey K. ; Kurilkin, Pavel ; Ladygin, Vladimir P. ; Lalik, Rafał Tomasz ; Lapidus, Kirill ; Lebedev, Alexei ; Lopes, Luis Alberto Vieira ; Lorenz, Manuel ; Mahmoud, Tariq ; Maier, Ludwig W. ; Mangiarotti, Alessio ; Markert, Jochen ; Maurus, Steffen ; Metag, Volker ; Michel, Jan ; Mihaylov, Dimitar ; Morozov, Sergey ; Müntz, Christian ; Münzer, Robert Helmut ; Naumann, Lothar ; Nowakowski, Krzysztof ; Palka, Marek ; Parpottas, Yannis ; Pechenov, Vladimir ; Pechenova, Olga ; Petukhov, Oleg ; Pietraszko, Jerzy ; Przygoda, Witold ; Ramos, Sérgio ; Ramstein, Béatrice ; Reshetin, Andrey ; Rodriguez Ramos, Pablo ; Rosier, Philippe ; Rost, Adrian ; Sadovsky, Alexander ; Salabura, Piotr ; Scheib, Timo ; Schuldes, Heidi ; Schwab, Erwin ; Scozzi, Federico ; Seck, Florian ; Sellheim, Patrick ; Selyuzhenkov, Ilya ; Siebenson, Johannes Stephan ; Silva, Luis ; Sobolev, Yuri G. ; Spataro, Stefano ; Spies, Simon ; Ströbele, Herbert ; Stroth, Joachim ; Strzempek, Paweł ; Sturm, Christian Thomas ; Svoboda, Ondřej ; Szala, Melanie ; Tlustý, Pavel ; Traxler, Michael ; Tsertos, Haralabos ; Usenko, Evgeny A. ; Wagner, Vladimir ; Wendisch, Christian ; Wiebusch, Michael ; Wirth, Joana ; Zanevsky, Yuri V. ; Zumbruch, Peter W. ; Leifels, Yvonne
We present first data on sub-threshold production of Ks0 mesons and Λ hyperons in Au+Au collisions at sNN=2.4 GeV. We observe an universal 〈Apart〉 scaling of hadrons containing strangeness, independent of their corresponding production thresholds. Comparing the yields, their 〈Apart〉 scaling, and the shapes of the rapidity and the pt spectra to state-of-the-art transport model (UrQMD, HSD, IQMD) predictions, we find that none of them can simultaneously describe these observables with reasonable χ2 values.
Adamczewski-Musch, Jörn ; Arnold, Oliver Werner ; Behnke, Claudia ; Belounnas, Amel ; Belyaev, Alexei V. ; Berger-Chen, Jia-Chii ; Biernat, Jacek ; Blanco, Alberto ; Blume, Christoph ; Böhmer, Michael ; Bordalo, Paula ; Chernenko, Sergey P. ; Chlad, Lukáš ; Deveaux, Christina Anna ; Dreyer, Jörn ; Dybczak, Adrian ; Epple, Eliane ; Fabbietti, Laura ; Fateev, Oleg ; Filip, Peter ; Fonte, Paulo ; Franco, Celso ; Friese, Jürgen ; Fröhlich, Ingo ; Galatyuk, Tetyana ; Garzón, Juan A. ; Gernhäuser, Roman ; Golubeva, Marina ; Greifenhagen, Robert ; Guber, Fedor ; Gumberidze, Malgorzata ; Harabasz, Szymon ; Heinz, Tobias ; Hennino, Thierry ; Hlaváč, Stanislav ; Höhne, Claudia ; Holzmann, Romain ; Ierusalimov, Alexander P. ; Ivashkin, Alexander ; Kämpfer, Burkhard ; Karavicheva, Tatiana L. ; Kardan, Behruz ; Koenig, Ilse ; Koenig, Wolfgang ; Kolb, Burkhard W. ; Korcyl, Grzegorz ; Kornakov, Georgy ; Kotte, Roland ; Kugler, Andrej ; Kunz, Tobias ; Kurepin, Alexander ; Kurilkin, Aleksey K. ; Kurilkin, Pavel ; Ladygin, Vladimir P. ; Lalik, Rafał Tomasz ; Lapidus, Kirill ; Lebedev, Alexei ; Lopes, Luis Alberto Vieira ; Lorenz, Manuel ; Mahmoud, Tariq ; Maier, Ludwig W. ; Mangiarotti, Alessio ; Markert, Jochen ; Matulewicz, Tomasz ; Maurus, Steffen ; Metag, Volker ; Michel, Jan ; Mihaylov, Dimitar ; Morozov, Sergey ; Müntz, Christian ; Münzer, Robert Helmut ; Naumann, Lothar ; Nowakowski, K. ; Palka, Marek ; Parpottas, Yannis ; Pechenov, Vladimir ; Pechenova, Olga ; Petukhov, Oleg ; Piasecki, Krzysztof ; Pietraszko, Jerzy ; Przygoda, Witold ; Ramos, Sérgio ; Ramstein, Béatrice ; Reshetin, Andrey ; Rodriguez Ramos, Pablo ; Rosier, Philippe ; Rost, Adrian ; Sadovsky, Alexander ; Salabura, Piotr ; Scheib, Timo ; Schuldes, Heidi ; Schwab, Erwin ; Scozzi, Federico ; Seck, Florian ; Sellheim, Patrick ; Selyuzhenkov, Ilya ; Siebenson, Johannes Stephan ; Silva, Luis ; Sobolev, Yuri G. ; Spataro, Stefano ; Spies, Simon ; Ströbele, Herbert ; Stroth, Joachim ; Strzempek, Paweł ; Sturm, Christian Thomas ; Svoboda, Ondřej ; Szala, Melanie ; Tlustý, Pavel ; Traxler, Michael ; Tsertos, Haralabos ; Usenko, Evgeny A. ; Wagner, Vladimir ; Wendisch, Christian ; Wiebusch, Michael ; Wirth, Joana ; Wójcik, Daniel Krzysztof ; Zanevsky, Yuri V. ; Zumbruch, Peter W.
We investigate identical pion HBT intensity interferometry in central Au+Au collisions at 1.23A GeV. High-statistics π−π− and π+π+ data are measured with HADES at SIS18/GSI. The radius parameters, derived from the correlation function depending on relative momenta in the longitudinally comoving system and parametrized as three-dimensional Gaussian distribution, are studied as function of transverse momentum. A substantial charge-sign difference of the source radii is found, particularly pronounced at low transverse momentum. The extracted source parameters agree well with a smooth extrapolation of the center-of-mass energy dependence established at higher energies, extending the corresponding excitation functions down towards a very low energy.
Möhler, Markus ; Gepfner-Tuma, Irina ; Maderer, Annett ; Thuss-Patience, Peter ; Rüssel, Jörn ; Hegewisch-Becker, Susanna ; Wilke, Hansjochen ; Batran, Salah-Eddin al- ; Rafiyan, Mohammad-Reza ; Weißinger, Florian ; Schmoll, Hans-Joachim ; Kullmann, Frank ; Fischer von Weikersthal, Ludwig ; Siveke, Jens ; Weusmann, Jens ; Kanzler, Stephan ; Schimanski, Carl Christoph ; Otte, Melanie ; Schollenberger, Lukas ; König, Jochem ; Galle, Peter Robert
Background: As a multi-targeted anti-angiogenic receptor tyrosine kinase (RTK) inhibitor sunitinib (SUN) has been established for renal cancer and gastrointestinal stromal tumors. In advanced refractory esophagogastric cancer patients, monotherapy with SUN was associated with good tolerability but limited tumor response.
Methods: This double-blind, placebo-controlled, multicenter, phase II clinical trial was conducted to evaluate the efficacy, safety and tolerability of SUN as an adjunct to second and third-line FOLFIRI (NCT01020630). Patients were randomized to receive 6-week cycles including FOLFIRI plus sodium folinate (Na-FOLFIRI) once every two weeks and SUN or placebo (PL) continuously for four weeks followed by a 2-week rest period. The primary study endpoint was progression-free survival (PFS). Preplanned serum analyses of VEGF-A, VEGF-D, VEGFR2 and SDF-1α were performed retrospectively.
Results: Overall, 91 patients were randomized, 45 in each group (one patient withdrew). The main grade ≥3 AEs were neutropenia and leucopenia, observed in 56 %/20 % and 27 %/16 % for FOLFIRI + SUN/FOLFIRI + PL, respectively. Median PFS was similar, 3.5 vs. 3.3 months (hazard ratio (HR) 1.11, 95 % CI 0.70–1.74, P = 0.66) for FOLFIRI + SUN vs. FOLFIRI + PL, respectively. For FOLFIRI + SUN, a trend towards longer median overall survival (OS) compared with placebo was observed (10.4 vs. 8.9 months, HR 0.82, 95 % CI 0.50–1.34, one-sided P = 0.21). In subgroup serum analyses, significant changes in VEGF-A (P = 0.017), VEGFR2 (P = 0.012) and VEGF-D (P < 0.001) serum levels were observed.
Conclusions: Although sunitinib combined with FOLFIRI did not improve PFS and response in chemotherapy-resistant gastric cancer, a trend towards better OS was observed. Further biomarker-driven studies with other anti-angiogenic RTK inhibitors are warranted.
Trial registration: This study was registered prospectively in the NCT Clinical Trials Registry (ClinicalTrials.gov) under NCT01020630 on November 23, 2009 after approval by the leading ethics committee of the Medical Association of Rhineland-Palatinate, Mainz, in coordination with the participating ethics committees (see Additional file 2) on September 16, 2009.
Hobe, Marc von ; Bekki, Slimane ; Borrmann, Stephan ; Cairo, Francesco ; D'Amato, Francesco ; Di Donfrancesco, Guido ; Dörnbrack, Andreas ; Ebersoldt, Andreas ; Ebert, Martin ; Emde, Claudia ; Engel, Ines ; Ern, Manfred ; Frey, Wiebke ; Grießbach, Sabine ; Grooß, Jens-Uwe ; Gulde, Thomas ; Günther, Gebhard ; Hösen, Maria Elisabeth ; Hoffmann, Lars ; Homonnai, Viktoria ; Hoyle, Christopher Robert ; Isaksen, I. S. A. ; Jackson, David R. ; Jánosi, Imre M. ; Kandler, Konrad ; Kalicinsky, Christoph ; Keil, Andrea ; Khaykin, Sergey M. ; Khosrawi, Farahnaz ; Kivi, Rigel ; Kuttippurath, Jayan ; Laube, Johannes Christian ; Lefèvre, Franck ; Lehmann, Ralph ; Ludmann, Sabrina ; Luo, Beiping P. ; Marchand, Marion ; Meyer, Jessica ; Mitev, Valentin ; Molleker, Sergej ; Müller, Rolf ; Oelhaf, Hermann ; Olschewski, Friedhelm ; Orsolini, Yvan ; Peter, Thomas ; Pfeilsticker, Klaus ; Piesch, Christof ; Pitts, Michael C. ; Poole, Lamont R. ; Pope, Francis D. ; Ravegnani, Fabrizio ; Rex, Markus ; Riese, Martin ; Röckmann, Thomas ; Rognerud, Bjørg ; Roiger, Anke ; Rolf, Christian ; Santee, Michelle L. ; Scheibe, Monika ; Schiller, Cornelius ; Schlager, Hans ; Siciliani de Cumis, Matteo ; Sitnikov, Nikolay ; Søvde, Ole Amund ; Spang, Reinhold ; Spelten, Nicole ; Stordal, Frode ; Sumińska-Ebersoldt, Olga ; Viciani, Silvia ; Volk, C.-Michael ; vom Scheidt, Marcel ; Ulanovski, Alexey ; Gathen, Peter von der ; Walker, Kaley A. ; Wegner, Tobias ; Weigel, Ralf ; Weinbruch, Stephan ; Wetzel, Gerald ; Wienhold, Franck G. ; Wintel, Johannes ; Wohltmann, Ingo ; Woiwode, Wolfgang ; Young, Isla A. K. ; Yushkov, Vladimir ; Zobrist, Bernhard ; Stroh, Fred
Significant reductions in stratospheric ozone occur inside the polar vortices each spring when chlorine radicals produced by heterogeneous reactions on cold particle surfaces in winter destroy ozone mainly in two catalytic cycles, the ClO dimer cycle and the ClO/BrO cycle. Chlorofluorocarbons (CFCs), which are responsible for most of the chlorine currently present in the stratosphere, have been banned by the Montreal Protocol and its amendments, and the ozone layer is predicted to recover to 1980 levels within the next few decades. During the same period, however, climate change is expected to alter the temperature, circulation patterns and chemical composition in the stratosphere, and possible geo-engineering ventures to mitigate climate change may lead to additional changes. To realistically predict the response of the ozone layer to such influences requires the correct representation of all relevant processes. The European project RECONCILE has comprehensively addressed remaining questions in the context of polar ozone depletion, with the objective to quantify the rates of some of the most relevant, yet still uncertain physical and chemical processes. To this end RECONCILE used a broad approach of laboratory experiments, two field missions in the Arctic winter 2009/10 employing the high altitude research aircraft M55-Geophysica and an extensive match ozone sonde campaign, as well as microphysical and chemical transport modelling and data assimilation. Some of the main outcomes of RECONCILE are as follows: (1) vortex meteorology: the 2009/10 Arctic winter was unusually cold at stratospheric levels during the six-week period from mid-December 2009 until the end of January 2010, with reduced transport and mixing across the polar vortex edge; polar vortex stability and how it is influenced by dynamic processes in the troposphere has led to unprecedented, synoptic-scale stratospheric regions with temperatures below the frost point; in these regions stratospheric ice clouds have been observed, extending over >106km2 during more than 3 weeks. (2) Particle microphysics: heterogeneous nucleation of nitric acid trihydrate (NAT) particles in the absence of ice has been unambiguously demonstrated; conversely, the synoptic scale ice clouds also appear to nucleate heterogeneously; a variety of possible heterogeneous nuclei has been characterised by chemical analysis of the non-volatile fraction of the background aerosol; substantial formation of solid particles and denitrification via their sedimentation has been observed and model parameterizations have been improved. (3) Chemistry: strong evidence has been found for significant chlorine activation not only on polar stratospheric clouds (PSCs) but also on cold binary aerosol; laboratory experiments and field data on the ClOOCl photolysis rate and other kinetic parameters have been shown to be consistent with an adequate degree of certainty; no evidence has been found that would support the existence of yet unknown chemical mechanisms making a significant contribution to polar ozone loss. (4) Global modelling: results from process studies have been implemented in a prognostic chemistry climate model (CCM); simulations with improved parameterisations of processes relevant for polar ozone depletion are evaluated against satellite data and other long term records using data assimilation and detrended fluctuation analysis. Finally, measurements and process studies within RECONCILE were also applied to the winter 2010/11, when special meteorological conditions led to the highest chemical ozone loss ever observed in the Arctic. In addition to quantifying the 2010/11 ozone loss and to understand its causes including possible connections to climate change, its impacts were addressed, such as changes in surface ultraviolet (UV) radiation in the densely populated northern mid-latitudes.