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Grottenthaler, Julia M. ; Werner, Christoph R. ; Steurer, Martina ; Spengler, Ulrich ; Berg, Thomas ; Engelmann, Cornelius ; Wedemeyer, Heiner ; Hahn, Thomas von ; Stremmel, Wolfgang ; Pathil-Warth, Anita ; Seybold, Ulrich ; Schott, Eckart ; Blessin, Usha ; Sarrazin, Christoph ; Welker, Martin-Walter ; Harrer, Ellen ; Scholten, Stefan ; Hinterleitner, Clemens ; Lauer, Ulrich Manfred ; Malek, Nisar Peter ; Berg, Christoph Peter
Objectives: The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively.
Methods: When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7–21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)).
Results: Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up.
Conclusion: DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.
Brill, Stefan ; Müller, Joachim ; Hagen, Rudolf ; Möltner, Alexander ; Brockmeier, Steffi-Johanna ; Stark, Thomas ; Helbig, Silke ; Maurer, Jan ; Zahnert, Thomas ; Zierhofer, Clemens ; Nopp, Peter ; Anderson, Ilona ; Strahl, Stefan
Background: The standard electrode array for the MED-EL MAESTRO cochlear implant system is 31 mm in length which allows an insertion angle of approximately 720°. When fully inserted, this long electrode array is capable of stimulating the most apical region of the cochlea. No investigation has explored Electrically Evoked Compound Action Potential (ECAP) recordings in this region with a large number of subjects using a commercially available cochlear implant system. The aim of this study is to determine if certain properties of ECAP recordings vary, depending on the stimulation site in the cochlea. Methods: Recordings of auditory nerve responses were conducted in 67 subjects to demonstrate the feasibility of ECAP recordings using the Auditory Nerve Response Telemetry (ART™) feature of the MED-EL MAESTRO system software. These recordings were then analyzed based on the site of cochlear stimulation defined as basal, middle and apical to determine if the amplitude, threshold and slope of the amplitude growth function and the refractory time differs depending on the region of stimulation. Results: Findings show significant differences in the ECAP recordings depending on the stimulation site. Comparing the apical with the basal region, on average higher amplitudes, lower thresholds and steeper slopes of the amplitude growth function have been observed. The refractory time shows an overall dependence on cochlear region; however post-hoc tests showed no significant effect between individual regions. Conclusions :Obtaining ECAP recordings is also possible in the most apical region of the cochlea. However, differences can be observed depending on the region of the cochlea stimulated. Specifically, significant higher ECAP amplitude, lower thresholds and steeper amplitude growth function slopes have been observed in the apical region. These differences could be explained by the location of the stimulating electrode with respect to the neural tissue in the cochlea, a higher density, or an increased neural survival rate of neural tissue in the apex. Trial registration: The Clinical Investigation has the Competent Authority registration number DE/CA126/AP4/3332/18/05.
In this study, we report the results of a long-term investigation on changes in population size and fledging success of Northern Lapwing on Wangerooge, a German Wadden Sea island. This population is increasing over a period of 34 years in contrast to numerous populations in North-western Europe. The reproductive success however declines over time and also with population density. Both effects cannot be considered separately due to autocorrelation. However, it is noted that the population on Wangerooge is not sustained by local recruitment only. This outcome is even more alarming as coastal areas and islands are considered as rare high quality meadow bird habitats. According to the present results Wangerooge cannot be considered as a source habitat for Northern Lapwings in North-western Germany.
Rosenbaum, Clemens Mathias ; Vetterlein, Malte Wolfram ; Fisch, Margit ; Reiß, Philipp ; Worst, Thomas ; Kranz, Jennifer ; Steffens, Joachim ; Kluth, Luis ; Pfalzgraf, Daniel Philipp
Objectives: Bladder neck contracture (BNC) is a bothersome complication following endoscopic treatment for benign prostatic hyperplasia (BPH). The objective of our study was to give a more realistic insight into contemporary endoscopic BNC treatment and to evaluate and identify risk factors associated with inferior outcome. Material and Methods: We identified patients who underwent transurethral treatment for BNC secondary to previous endoscopic therapy for BPH between March 2009 and October 2016. Patients with vesico-urethral anastomotic stenosis after radical prostatectomy were excluded. Digital charts were reviewed for re-admissions and re-visits at our institutions and patients were contacted personally for follow-up. Our non-validated questionnaire assessed previous urologic therapies (including radiotherapy, endoscopic, and open surgery), time to eventual further therapy in case of BNC recurrence, and the modality of recurrence management. Results: Of 60 patients, 49 (82%) and 11 (18%) underwent transurethral bladder neck resection and incision, respectively. Initial BPH therapy was transurethral resection of the prostate (TURP) in 54 (90%) and holmium laser enucleation of the prostate (HoLEP) in six (10%) patients. Median time from prior therapy was 8.5 (IQR 5.3–14) months and differed significantly in those with (6.5 months; IQR 4–10) and those without BNC recurrence (10 months; IQR 6–20; p = 0.046). Thirty-three patients (55%) underwent initial endoscopic treatment, and 27 (45%) repeated endoscopic treatment for BNC. In initially-treated patients, time since BPH surgery differed significantly between those with a recurrence (median 7.5 months; IQR 6–9) compared to those treated successfully (median 12 months; IQR 9–25; p = 0.01). In patients with repeated treatment, median time from prior BNC therapy did not differ between those with (4.5 months; IQR 2–12) and those without a recurrence (6 months; IQR 6–10; p = 0.6). Overall, BNC treatment was successful in 32 patients (53%). The observed success rate of BNC treatment was significantly higher after HoLEP compared to TURP (100% vs. 48%; p = 0.026). Type of BNC treatment, number of BNC treatment, and age at surgery did not influence the outcome. Conclusions: A longer time interval between previous BPH therapy and subsequent BNC incidence seems to favorably affect treatment success of endoscopic BNC treatment, and transurethral resection and incision appear equally effective. Granted the relatively small sample size, BNC treatment success seems to be higher after HoLEP compared to TURP, which warrants validation in larger cohorts.
Deuchler, Svenja ; Ackermann, Hanns ; Singh, Pankaj ; Kohnen, Thomas ; Wagner, Clemens ; Koch, Frank H.
Introduction: For management of complicated retinal detachments, a pars plana vitrectomy with temporary silicone oil (SO) fill is the method of choice. According to literature, the retinal redetachment rate varies between <10% and >70% with around 36% in our own group (retrospective data analysis, n = 119 eyes).
Methods: The main goal was to reduce the retinal redetachment rate. Standard operating procedures (SOPs) and evaluation protocols (EVALPs) were developed to prospectively analyse risk factors. Lab analysis of SO was performed, and the role of surgical experience was evaluated and investigated with Eyesi®.
Results: We achieved a significant reduction of the retinal redetachment rate (to 6.80%, n = 101, p = 0.002). After surgery with SO injection, neither further membrane peeling (in 16.5%) nor retinal laser coagulation (in 100%) during revision surgery had a significant effect on the reattachment rate (p = 0.167, p = 0.23), while extensive additional laser coagulation reduced visual acuity (p = 0.01). A 3-port approach had to be set up to complete SO removal. A difference in success rate depending on surgical experience was confirmed, and the performance in Eyesi correlated with that in the patients' eye.
Conclusions: A SOP- and EVALP-based management and new strategies to secure the surgical performance seem to be essential for successful surgery.
Graf, Christiana ; Welzel, Tania Mara ; Bogdanou, Dimitra ; Vermehren, Johannes ; Beckel, Anita ; Bojunga, Jörg ; Friedrich-Rust, Mireen ; Dietz, Julia ; Kubesch, Alica ; Mondorf, Antonia Maria ; Fischer, Sarah ; Lutz, Thomas ; Stoffers, Philipp Clemens ; Herrmann, Eva ; Poynard, Thierry ; Zeuzem, Stefan ; Dultz, Georg ; Mihm, Ulrike
Background: Chronic hepatitis C virus (HCV) infections are causally linked with metabolic comorbidities such as insulin resistance, hepatic steatosis, and dyslipidemia. However, the clinical impact of HCV eradication achieved by direct-acting antivirals (DAAs) on glucose and lipid homeostasis is still controversial. The study aimed to prospectively investigate whether antiviral therapy of HCV with DAAs alters glucose and lipid parameters. Methods: 50 patients with chronic HCV who were treated with DAAs were screened, and 49 were enrolled in the study. Biochemical and virological data, as well as noninvasive liver fibrosis parameters, were prospectively collected at baseline, at the end of treatment (EOT) and 12 and 24 weeks post-treatment. Results: 45 of 46 patients achieved sustained virologic response (SVR). The prevalence of insulin resistance (HOMA-IR) after HCV clearance was significantly lower, compared to baseline (5.3 ± 6.1 to 2.5 ± 1.9, p < 0.001), which is primarily attributable to a significant decrease of fasting insulin levels (18.9 ± 17.3 to 11.7 ± 8.7; p = 0.002). In contrast to that, HCV eradication resulted in a significant increase in cholesterol levels (total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein (HDL-C) levels) and Controlled Attenuated Score (CAP), although BMI did not significantly change over time (p = 0.95). Moreover, HOMA-IR correlated significantly with noninvasive liver fibrosis measurements at baseline und during follow-up (TE: r = 0.45; p = 0.003, pSWE: r = 0.35; p = 0.02, APRI: r = 0.44; p = 0.003, FIB-4: r = 0.41; p < 0.001). Conclusion: Viral eradication following DAA therapy may have beneficial effects on glucose homeostasis, whereas lipid profile seems to be worsened.
Emons, Georg ; Auslander, Noam ; Jo, Peter ; Kitz, Julia ; Azizian, Azadeh ; Hu, Yue ; Hess, Clemens F. ; Rödel, Claus ; Sax, Ulrich ; Salinas-Riester, Gabriela ; Ströbel, Philipp ; Kramer, Frank ; Beissbarth, Tim ; Ghadimi, Michael ; Ruppin, Eytan ; Ried, Thomas ; Gaedcke, Jochen Werner Christian ; Grade, Marian
Purpose: Preoperative (neoadjuvant) chemoradiotherapy (CRT) and total mesorectal excision is the standard treatment for rectal cancer patients (UICC stage II/III). Up to one-third of patients treated with CRT achieve a pathological complete response (pCR). These patients could be spared from surgery and its associated morbidity and mortality, and assigned to a “watch and wait” strategy. However, reliably identifying pCR based on clinical or imaging parameters remains challenging.
Experimental design: We generated gene-expression profiles of 175 patients with locally advanced rectal cancer enrolled in the CAO/ARO/AIO-94 and -04 trials. One hundred and sixty-one samples were used for building, training and validating a predictor of pCR using a machine learning algorithm. The performance of the classifier was validated in three independent cohorts, comprising 76 patients from (i) the CAO/ARO/AIO-94 and -04 trials (n = 14), (ii) a publicly available dataset (n = 38) and (iii) in 24 prospectively collected samples from the TransValid A trial.
Results: A 21-transcript signature yielded the best classification of pCR in 161 patients (Sensitivity: 0.31; AUC: 0.81), when not allowing misclassification of non-complete-responders (False-positive rate = 0). The classifier remained robust when applied to three independent datasets (n = 76).
Conclusion: The classifier can identify >1/3 of rectal cancer patients with a pCR while never classifying patients with an incomplete response as having pCR. Importantly, we could validate this finding in three independent datasets, including a prospectively collected cohort. Therefore, this classifier could help select rectal cancer patients for a “watch and wait” strategy.
Translational relevance: Forgoing surgery with its associated side effects could be an option for rectal cancer patients if the prediction of a pathological complete response (pCR) after preoperative chemoradiotherapy would be possible. Based on gene-expression profiles of 161 patients a classifier was developed and validated in three independent datasets (n = 76), identifying over 1/3 of patients with pCR, while never misclassifying a non-complete-responder. Therefore, the classifier can identify patients suited for “watch and wait”.
Deuchler, Svenja ; Wagner, Clemens ; Singh, Pankaj ; Müller, Michael ; Al-Dwairi, Rami ; Benjilali, Rachid ; Schill, Markus ; Ackermann, Hanns ; Bon, Dimitra ; Kohnen, Thomas ; Schoene, Benjamin ; Koss, Michael Janusz ; Koch, Frank H.
Purpose: To evaluate the efficacy of the virtual reality training simulator Eyesi to prepare surgeons for performing pars plana vitrectomies and its potential to predict the surgeons’ performance.
Methods: In a preparation phase, four participating vitreoretinal surgeons performed repeated simulator training with predefined tasks. If a surgeon was assigned to perform a vitrectomy for the management of complex retinal detachment after a surgical break of at least 60 hours it was randomly decided whether a warmup training on the simulator was required (n = 9) or not (n = 12). Performance at the simulator was measured using the built-in scoring metrics. The surgical performance was determined by two blinded observers who analyzed the video-recorded interventions. One of them repeated the analysis to check for intra-observer consistency. The surgical performance of the interventions with and without simulator training was compared. In addition, for the surgeries with simulator training, the simulator performance was compared to the performance in the operating room.
Results: Comparing each surgeon’s performance with and without warmup trainingshowed a significant effect of warmup training onto the final outcome in the operating room. For the surgeries that were preceeded by the warmup procedure, the performance at the simulator was compared with the operating room performance. We found that there is a significant relation. The governing factor of low scores in the simulator were iatrogenic retinal holes, bleedings and lens damage. Surgeons who caused minor damage in the simulation also performed well in the operating room.
Conclusions: Despite the large variation of conditions, the effect of a warmup training as well as a relation between the performance at the simulator and in the operating room was found with statistical significance. Simulator training is able to serve as a warmup to increase the average performance.
Voskens, Caroline J. ; Goldinger, Simone M. ; Loquai, Carmen ; Robert, Caroline ; Kähler, Katharina C. ; Berking, Carola ; Bergmann, Tanja Regina ; Bockmeyer, Clemens Luitpold ; Eigentler, Thomas Kurt ; Fluck, Michael ; Garbe, Claus ; Gutzmer, Ralf ; Grabbe, Stephan ; Hauschild, Axel ; Hein, Rüdiger ; Hundorfean, Gheorghe ; Justich, Armin ; Keller, Ullrich ; Klein, Christina ; Mateus, Christine ; Mohr, Peter ; Pätzold, Sylvie ; Satzger, Imke ; Schadendorf, Dirk ; Schlaeppi, Marc ; Schuler, Gerold ; Schuler-Thurner, Beatrice ; Trefzer, Uwe ; Ulrich, Jens ; Vaubel, Julia ; Moos, Roger von ; Weder, Patrik ; Wilhelm, Tabea ; Göppner, Daniela ; Dummer, Reinhard ; Heinzerling, Lucie
Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.
Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.
Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.
Cremer, Sebastian ; Pilgram, Lisa ; Berkowitsch, Alexander ; Stecher, Melanie ; Rieg, Siegbert ; Shumliakivska, Mariana ; Bojkova, Denisa ; Wagner, Julian Uwe Gabriel ; Aslan, Galip Servet ; Spinner, Christoph Daniel ; Luxán, Guillermo ; Hanses, Frank ; Dolff, Sebastian Conrad Johannes ; Piepel, Christiane ; Ruppert, Clemens ; Günther, Andreas ; Rüthrich, Maria Madeleine ; Vehreschild, Jörg Janne ; Wille, Kai ; Haselberger, Martina Maria ; Heuzeroth, Hanno ; Hansen, Arne ; Eschenhagen, Thomas ; Cinatl, Jindrich ; Ciesek, Sandra ; Dimmeler, Stefanie ; Borgmann, Stefan ; Zeiher, Andreas M.
Aims: Patients with cardiovascular comorbidities have a significantly increased risk for a critical course of COVID-19. As the SARS-CoV2 virus enters cells via the angiotensin-converting enzyme receptor II (ACE2), drugs which interact with the renin angiotensin aldosterone system (RAAS) were suspected to influence disease severity.
Methods and results: We analyzed 1946 consecutive patients with cardiovascular comorbidities or hypertension enrolled in one of the largest European COVID-19 registries, the Lean European Open Survey on SARS-CoV-2 (LEOSS) registry. Here, we show that angiotensin II receptor blocker intake is associated with decreased mortality in patients with COVID-19 [OR 0.75 (95% CI 0,59–0.96; p = 0.013)]. This effect was mainly driven by patients, who presented in an early phase of COVID-19 at baseline [OR 0,64 (95% CI 0,43–0,96; p = 0.029)]. Kaplan-Meier analysis revealed a significantly lower incidence of death in patients on an angiotensin receptor blocker (ARB) (n = 33/318;10,4%) compared to patients using an angiotensin-converting enzyme inhibitor (ACEi) (n = 60/348;17,2%) or patients who received neither an ACE-inhibitor nor an ARB at baseline in the uncomplicated phase (n = 90/466; 19,3%; p<0.034). Patients taking an ARB were significantly less frequently reaching the mortality predicting threshold for leukocytes (p<0.001), neutrophils (p = 0.002) and the inflammatory markers CRP (p = 0.021), procalcitonin (p = 0.001) and IL-6 (p = 0.049). ACE2 expression levels in human lung samples were not altered in patients taking RAAS modulators.
Conclusion: These data suggest a beneficial effect of ARBs on disease severity in patients with cardiovascular comorbidities and COVID-19, which is linked to dampened systemic inflammatory activity.
Periodontal furcation lesions: a survey of diagnosis and management by general dental practitioners
(2021)
Nibali, Luigi ; Shemie, Melissa ; Li, Guanhong ; Ting, Rachel ; Asimakopoulou, Koula ; Barbagallo, Giovanni ; Lee, Ryan ; Eickholz, Peter ; Kocher, Thomas ; Walter, Clemens ; Aimetti, Mario ; Rüdiger, Stefan
Aim: The aim of this study was to explore general dental practitioners' (GDPs) attitude to periodontal furcation involvement (FI). Materials and methods: An online survey focused on diagnosis and management of periodontal FI was circulated to GDPs in seven different countries. Results: A total of 400 responses were collected. Nearly a fifth of participants reported rarely or never taking 6-point pocket charts; 65.8% of participants had access to a Nabers probe in their practice. When shown clinical pictures and radiographs of FI-involved molars, the majority of participants correctly diagnosed it. Although 47.1% of participants were very/extremely confident in detecting FI, only 8.9% felt very/extremely confident at treating it. Differences in responses were detected according to country and year of qualification, with a trend towards less interest in periodontal diagnosis and treatment in younger generations. Lack of knowledge of management/referral pathways (reported by 22.8%) and lack of correct equipment were considered the biggest barriers to FI management. Most participants (80.9%) were interested in learning more about FI, ideally face to face followed by online tutorials. Conclusions: Plans should be put in place to improve general dentists' knowledge and ability to manage FI, as this can have a significant impact on public health.
Lederer-Woods, Claudia ; Battino, Umberto ; Ferreira, Pedro G. ; Gawlik, Aleksandra ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Heinitz, Stephan ; Lerendegui-Marco, Jorge ; Mengoni, Alberto ; Reifarth, René ; Tattersall, Ashley ; Valenta, Stanislav ; Weiß, Christina ; Aberle, Oliver ; Andrzejewski, Józef ; Audouin, Laurent ; Bécares, Vicente ; Bacak, Michael ; Balibrea Correa, Javier ; Barbagallo, Massimo ; Barros, Susana C.C. ; Bečvář, František ; Beinrucker, Clemens ; Belloni, Fabio ; Berthoumieux, Eric ; Billowes, Jonathan ; Bosnar, Damir ; Brugger, Markus ; Caamaño, Manuel ; Calviño Tavares, Francisco ; Calviani, Marco ; Cano-Ott, Daniel ; Cerutti, Francesco ; Chiaveri, Enrico ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Cosentino, Luigi ; Damone, Lucia Anna ; Deo, Kapil ; Diakaki, Maria ; Dietz, Mirco ; Domingo-Pardo, César ; Dressler, Rugard ; Dupont, Emmeric ; Durán, Ignacio ; Fernández Domínguez, Beatriz ; Ferrari, Alfredo ; Finocchiaro, Paolo ; Frost, Robert J. W. ; Furman, Valter ; Göbel, Kathrin ; García Ríos, Aczel Regino ; Gheorghe, Ioana ; Glodariu, Tudor ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Goverdovski, Andrey ; Griesmayer, Erich ; Harada, Hideo ; Heftrich, Tanja ; Hernández Prieto, Álvaro ; Heyse, Jan ; Jenkins, David ; Jericha, Erwin ; Käppeler, Franz ; Kadi, Yacine ; Katabuchi, Tatsuya ; Kavrigin, Pavel ; Ketlerov, Vladimir ; Khryachkov, Vitaly ; Kimura, Akinori ; Kivel, Nikolay ; Knapová, Ingrid ; Kokkoris, Michael ; Krtička, Milan ; Leal Cidoncha, Esther ; Leeb, Helmut ; Licata, Mauro ; Lo Meo, Sergio ; Losito, Roberto ; Macina, Daniela ; Marganiec, Justyna ; Martínez, Trinitario ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Matteucci, Francesca ; Mendoza Cembranos, Emilio ; Milazzo, Paolo Maria ; Mingrone, Federica ; Mirea, Mihail ; Montesano, Simone ; Musumarra, Agatino ; Nolte, Ralf ; Palomo Pinto, Francisco Rogelio ; Paradela Dobarro, Carlos ; Patronis, Nikolas ; Pavlik, Andreas ; Perkowski, Jarosław ; Porras Sánchez, José Ignacio ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Riego Pérez, Albert ; Robles Manzano, Maria Soledad ; Rubbia, Carlo ; Ryan, James A. ; Sabaté-Gilarte, Marta ; Saxena, Alok ; Schillebeeckx, Peter ; Schmidt, Stefan ; Schumann, Dorothea ; Sedyshev, Pavel V. ; Smith, Alastair Gavin ; Stamatopoulos, Athanasios ; Suryanarayana, Saraswatula Venkata ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarifeño-Saldivia, Ariel ; Tassan-Got, Laurent ; Tsinganis, Andrea ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Warren, Stephen J. ; Weigand, Mario ; Wright, Tobias ; Žugec, Petar
73Ge(n, γ ) cross sections were measured at the neutron time-of-flight facility n_TOF at CERN up to neutron energies of 300 keV, providing for the first time experimental data above 8 keV. Results indicate that the stellar cross section at kT = 30 keV is 1.5 to 1.7 times higher than most theoretical predictions. The new cross sections result in a substantial decrease of 73Ge produced in stars, which would explain the low isotopic abundance of 73Ge in the solar system.
Stamatopoulos, Athanasios ; Tsinganis, Andrea ; Colonna, Nicola ; Vlastou, Rosa ; Kokkoris, Michael ; Schillebeeckx, Peter ; Plompen, Arjan J. M. ; Heyse, Jan ; Žugec, Petar ; Barbagallo, Massimo ; Calviani, Marco ; Berthoumieux, Eric ; Chiaveri, Enrico ; Aberle, Oliver ; Andrzejewski, Józef ; Audouin, Laurent ; Bécares, Vicente ; Bacak, Michael ; Balibrea Correa, Javier ; Barros, Susana C.C. ; Bečvář, František ; Beinrucker, Clemens ; Belloni, Fabio ; Billowes, Jonathan ; Boccone, Vittorio ; Bosnar, Damir ; Brugger, Markus ; Caamaño, Manuel ; Calviño Tavares, Francisco ; Cano-Ott, Daniel ; Cerutti, Francesco ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Cosentino, Luigi ; Damone, Lucia Anna ; Deo, Kapil ; Diakaki, Maria ; Domingo-Pardo, César ; Dressler, Rugard ; Dupont, Emmeric ; Durán, Ignacio ; Fernández Domínguez, Beatriz ; Ferrari, Alfredo ; Ferreira, Pedro G. ; Finocchiaro, Paolo ; Frost, Robert J. W. ; Furman, Valter ; Göbel, Kathrin ; Gómez Hornillos, María Belén ; García Ríos, Aczel Regino ; Gheorghe, Ioana ; Glodariu, Tudor ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Goverdovski, Andrey ; Griesmayer, Erich ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Harada, Hideo ; Heftrich, Tanja ; Heinitz, Stephan ; Hernández Prieto, Álvaro ; Jenkins, David ; Jericha, Erwin ; Käppeler, Franz ; Kadi, Yacine ; Katabuchi, Tatsuya ; Kavrigin, Pavel ; Ketlerov, Vladimir ; Khryachkov, Vitaly ; Kimura, Atsushi ; Kivel, Nikolay ; Krtička, Milan ; Leal Cidoncha, Esther ; Lederer, Claudia ; Leeb, Helmut ; Lerendegui-Marco, Jorge ; Licata, Mauro ; Lo Meo, Sergio ; Losito, Roberto ; Macina, Daniela ; Marganiec, Justyna ; Martı́nez, Trinitario ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Matteucci, Francesca ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Milazzo, Paolo Maria ; Mingrone, Federica ; Mirea, Mihail ; Montesano, Simone ; Musumarra, Agatino ; Nolte, Ralf ; Palomo Pinto, Francisco Rogelio ; Paradela Dobarro, Carlos ; Patronis, Nikolas ; Pavlik, Andreas ; Perkowski, Jarosław ; Porras Sánchez, José Ignacio ; Praena, Javier ; Quesada Molina, José Manuel ; Rauscher, Thomas ; Reifarth, René ; Riego Pérez, Albert ; Robles Manzano, Maria Soledad ; Rubbia, Carlo ; Ryan, James ; Sabaté-Gilarte, Marta ; Saxena, Alok ; Schmidt, Stefan ; Schumann, Dorothea ; Sedyshev, Pavel V. ; Smith, Alastair Gavin ; Suryanarayana, Saraswatula Venkata ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarifeño-Saldivia, Ariel ; Tassan-Got, Laurent ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vlachoudis, Vasilis ; Wallner, Anton ; Warren, Stephen J. ; Weigand, Mario ; Weiß, Christina ; Wright, Tobias
The accurate knowledge of the neutron-induced fission cross-sections of actinides and other isotopes involved in the nuclear fuel cycle is essential for the design of advanced nuclear systems, such as Generation-IV nuclear reactors. Such experimental data can also provide the necessary feedback for the adjustment of nuclear model parameters used in the evaluation process, resulting in the further development of nuclear fission models. In the present work, the 240Pu(n,f) cross-section was measured at CERN's n_TOF facility relative to the well-known 235U(n,f) cross section, over a wide range of neutron energies, from meV to almost MeV, using the time-of-flight technique and a set-up based on Micromegas detectors. This measurement was the first experiment to be performed at n_TOF's new experimental area (EAR-2), which offers a significantly higher neutron flux compared to the already existing experimental area (EAR-1). Preliminary results as well as the experimental procedure, including a description of the facility and the data handling and analysis, are presented.
Weller, Johannes ; Schäfer, Niklas ; Schaub, Christina ; Potthoff, Anna-Laura ; Steinbach, Joachim Peter ; Schlegel, Uwe ; Sabel, Michael ; Hau, Peter ; Seidel, Clemens ; Krex, Dietmar ; Goldbrunner, Roland ; Pietsch, Torsten ; Tzaridis, Theophilos-Dimitrios ; Zeyen, Thomas ; Borger, Valeri ; Güresir, Erdem Özer ; Vatter, Hartmut ; Herrlinger, Ulrich ; Schneider, Matthias
Purpose: The role of obesity in glioblastoma remains unclear, as previous analyses have reported contradicting results. Here, we evaluate the prognostic impact of obesity in two trial populations; CeTeG/NOA-09 (n = 129) for MGMT methylated glioblastoma patients comparing temozolomide (TMZ) to lomustine/TMZ, and GLARIUS (n = 170) for MGMT unmethylated glioblastoma patients comparing TMZ to bevacizumab/irinotecan, both in addition to surgery and radiotherapy.
Methods: The impact of obesity (BMI ≥ 30 kg/m2) on overall survival (OS) and progression-free survival (PFS) was investigated with Kaplan–Meier analysis and log-rank tests. A multivariable Cox regression analysis was performed including known prognostic factors as covariables.
Results: Overall, 22.6% of patients (67 of 297) were obese. Obesity was associated with shorter survival in patients with MGMT methylated glioblastoma (median OS 22.9 (95% CI 17.7–30.8) vs. 43.2 (32.5–54.4) months for obese and non-obese patients respectively, p = 0.001), but not in MGMT unmethylated glioblastoma (median OS 17.1 (15.8–18.9) vs 17.6 (14.7–20.8) months, p = 0.26). The prognostic impact of obesity in MGMT methylated glioblastoma was confirmed in a multivariable Cox regression (adjusted odds ratio: 2.57 (95% CI 1.53–4.31), p < 0.001) adjusted for age, sex, extent of resection, baseline steroids, Karnofsky performance score, and treatment arm.
Conclusion: Obesity was associated with shorter survival in MGMT methylated, but not in MGMT unmethylated glioblastoma patients.
Dai, Danhua ; Wang, Xianwei ; Liu, Yiwei ; Yang, Xiao-Liang ; Glaubitz, Clemens ; Denysenkov, Vasyl ; He, Xiao ; Prisner, Thomas ; Mao, Jiafei
Nuclear magnetic resonance (NMR) spectroscopy is a powerful and popular technique for probing the molecular structures, dynamics and chemical properties. However the conventional NMR spectroscopy is bottlenecked by its low sensitivity. Dynamic nuclear polarization (DNP) boosts NMR sensitivity by orders of magnitude and resolves this limitation. In liquid-state this revolutionizing technique has been restricted to a few specific non-biological model molecules in organic solvents. Here we show that the carbon polarization in small biological molecules, including carbohydrates and amino acids, can be enhanced sizably by in situ Overhauser DNP (ODNP) in water at room temperature and at high magnetic field. An observed connection between ODNP 13C enhancement factor and paramagnetic 13C NMR shift has led to the exploration of biologically relevant heterocyclic compound indole. The QM/MM MD simulation underscores the dynamics of intermolecular hydrogen bonds as the driving force for the scalar ODNP in a long-living radical-substrate complex. Our work reconciles results obtained by DNP spectroscopy, paramagnetic NMR and computational chemistry and provides new mechanistic insights into the high-field scalar ODNP.
Breitung, Sven Thomas ; Lopez, Jakob J. ; Dürner, Gerd ; Glaubitz, Clemens ; Göbel, Michael ; Suhartono, Marcel
A mild synthetic method for N-formyl-Met-Leu-Phe-OH (1) is described. After Fmoc solid phase peptide synthesis, on-bead formylation and HPLC purification, more than 30 mg of the fully 13C/15N-labelled tripeptide 1 could be isolated in a typical batch. This peptide can be easily crystallised and is therefore well suited as a standard sample for setting up solid-state NMR experiments.
Götze, Thorsten ; Batran, Salah-Eddin al- ; Pabst, Urs ; Reymond, Marc ; Tempfer, Clemens ; Bechstein, Wolf Otto ; Bankstahl, Ulli ; Gockel, Ines ; Königsrainer, Alfred ; Kraus, Thomas ; Mönig, Stefan Paul ; Rau, Beate ; Schwarzbach, Matthias ; Piso, Pompiliu
Background: Peritoneal metastasis is a common and dismal evolution of several gastrointestinal (GI) tumors, including gastric, colorectal, hepatobiliary, pancreatic, and other cancers. The therapy of peritoneal metastasis is largely palliative; with the aim of prolonging life and preserving its quality. In the meantime, a significant pharmacological advantage of intraperitoneal chemotherapy was documented in the preclinical model, and numerous clinical studies have delivered promising clinical results.
Methods: This is a prospective, open, randomized multicenter phase III clinical study with two arms that aims to evaluate the effects of pressurized intraperitoneal aerosol chemotherapy (PIPAC) combined with systemic chemotherapy vs. intravenous systemic chemotherapy alone on patients with metastatic upper GI tumors with a peritoneal seeding. Upper GI-adenocarcinomas originated from biliary tract, pancreas and stomach, or esophago- gastric junction are eligible. Patients in the study are treated with standard of care systemic palliative chemotherapy (mFOLFOX6) vs. PIPAC with intravenous (i.v.) chemotherapy (mFOLFOX6). Patients in first line with first diagnosed peritoneal seeding are eligible. Primary outcome is progression free survival (PFS).
Conclusions: PIPAC-procedure is explicit a palliative method but it delivers cytotoxic therapy like in hyperthermic intraperitoneal chemotherapy (HIPEC)-procedure directly to the tumor in a minimally invasive technique, without the need for consideration of the peritoneal-plasma barrier. The technique of PIPAC is minimally invasive and very gentle and the complete procedure takes only round about 45 min and, therefore, optimal in a clearly palliative situation where cure is not the goal. It is also ideal for using this approach in a first line situation, where deepest response should be achieved. The symbiosis of systemic therapy and potentially effective surgery has to be well-planned without deterioration of the patient due to aggressive way of surgery like in cytoreductive surgery (CRS)+HIPEC.
Trial registration: EudraCT: 2018-001035-40.
Liveblog München, 2. Februar
(2013)
Ewald, Jörg ; Hennekens, Stephan ; Conrad, Sven ; Wohlgemuth, Thomas ; Jansen, Florian ; Jenssen, Martin ; Cornelis, Johnny ; Michiels, Hans-Gerd ; Kayser, Jürgen ; Chytrý, Milan ; Gégout, Jean-Claude ; Breuer, Michael ; Abs, Clemens ; Walentowski, Helge ; Starlinger, Franz ; Godefroid, Sandrine
Within the last 30 years the role of nitrogen in Central European forests has changed fundamentally from limiting resource to environmental problem. As the retrospective tracking of nutrient availability by soil chemical and biogeochemical measurements faces serious problems, bioindication based on understorey species composition is indispensable for monitoring broad-scale eutrophication. Based on a broad survey of more than 100,000 forest vegetation plots accessible in electronic data-bases from Germany and adjacent countries, we calculated unweighted average Ellenberg nutrient values (mN) as a proxy of plant-available macronutrients. Based on the quantiles of the frequency distribution of mN in a regionally stratified sample, we define five trophic classes, which can be used to compare dimensionless mN values. We studied spatial patterns of average nutrient values within 17 regions and compared the periods from 1899 to 1975 and 1976 to 2006. After 1975 eutrophic (mN > 5.67) and hypertrophic (mN > 6.28) conditions were common everywhere except in the Alps and Saxony-Anhalt, but very oligotrophic conditions (mN < 3.44) were still widespread in regions with nutrient-poor bedrock. Before 1975 mN of plots had been lower than after 1975 in all but the southeastern regions. Between the pre- and post-1975 data the proportion of hypertrophic plots increased from 5.7 to 11.8%, and that of very oligo-trophic plots decreased from 14.6 to 8.3%. To remove bias resulting from uneven distribution, the dataset was stratified by five tree layer dominance types, period and region and resampled. In pre-1975 plots medians of mN increased in the order Pinus sylvestris, Quercus spp., Picea abies, Fagus sylvatica and Alnus spp, whereas the increase of mN was highest in forest types with historically low nutrient values. Therefore, the widespread change in mN must be attributed to the pronounced vegetation changes in Quercus and Pinus stands, indicating the importance of land-use change, i.e. recovery of nutrient cycles after hundreds of years of exploitation through coppicing, grazing and litter use. The analysis confirms eutrophication as a megatrend of modern vegetation change and demonstrates the high research potential of linking vegetation plot databases across large regions.