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Ortmann, Christina Ann ; Dorsheimer, Lena ; Abou-El-Ardat, Khalil ; Hoffrichter, Jennifer ; Aßmus, Birgit ; Bönig, Halvard-Björn ; Scholz, Anica ; Pfeifer, Heike ; Martin, Hans ; Schmid, Tobias ; Brüne, Bernhard ; Scheich, Sebastian ; Steffen, Björn ; Riemann, Julia ; Hermann, Stella ; Dukat, Alexandra ; Bug, Gesine ; Brandts, Christian Hubertus ; Wagner, Sebastian Alexander ; Serve, Hubert ; Rieger, Michael A.
Clonal hematopoiesis of indeterminate potential (CHIP) is caused by recurrent somatic mutations leading to clonal blood cell expansion. However, direct evidence of the fitness of CHIP-mutated human hematopoietic stem cells (HSCs) in blood reconstitution is lacking. Because myeloablative treatment and transplantation enforce stress on HSCs, we followed 81 patients with solid tumors or lymphoid diseases undergoing autologous stem cell transplantation (ASCT) for the development of CHIP. We found a high incidence of CHIP (22%) after ASCT with a high mean variant allele frequency (VAF) of 10.7%. Most mutations were already present in the graft, albeit at lower VAFs, demonstrating a selective reconstitution advantage of mutated HSCs after ASCT. However, patients with CHIP mutations in DNA-damage response genes showed delayed neutrophil reconstitution. Thus, CHIP-mutated stem and progenitor cells largely gain on clone size upon ASCT-related blood reconstitution, leading to an increased future risk of CHIP-associated complications.
Scholz, Mathias ; Rupp, Holger ; Puhlmann, Guido ; Ilg, Christiane ; Gerisch, Michael ; Dziock, Frank ; Follner, Klaus ; Foeckler, Francis ; Glaeser, Judith ; Konjuchow, Franziska ; Krüger, Frank ; Regner, Andreas ; Schwarze, Eckard ; Tümpling, Wolf von ; Duquesne, Sabine ; Liess, Matthias ; Werban, Ulrike ; Zacharias, Steffen ; Henle, Klaus
Deichbau und andere flussbautechnische Maßnahmen haben dazu geführt, dass die Mittlere Elbe ihre ursprünglichen Überschwemmungsgebiete verloren hat. Um die Auswirkungen der alljährlich auftretenden Hochwasserereignisse einzudämmen, wurden große Bereiche der Talniederung durch Deiche vom Überflutungsgeschehen abgetrennt. Diese Eingriffe in den Naturhaushalt ermöglichten gleichfalls eine intensive ackerbauliche Nutzung oder eine hochwassersichere Bebauung der Auen. Die natürliche Auendynamik ist heute weitestgehend auf einen schmalen Bereich entlang der Elbe beschränkt. Hinter den Deichen sind die für die Elbeauen typischen Lebensräume von der lebenswichtigen Auendynamik abgeschnitten. Angepasste Auenarten und -lebensgemeinschaften treten zugunsten von Allerweltsarten zurück. Eine Wiederanbindung von Altauenbereichen an das Überflutungsgeschehen ist deshalb eine der vordringlichsten Maßnahmen zur Revitalisierung gefährdeter Auenlebensräume und stellt eine Chance dar, einen nachhaltigen und modernen Hochwasserschutz mit Naturschutzzielen zu verbinden. An der Elbe entspricht das aktuelle Hochwasserschutzsystem nicht den heutigen Anforderungen an den Hochwasserschutz. Um jedoch jederzeit auf mögliche große Hochwasserereignisse reagieren zu können, entstanden Anfang der 1990er Jahre in den Anliegerländern der Elbe zahlreiche Pläne für Deichrückverlegungen.
Zielsetzung: Die Daten für das Jahr 2018 des Registers „Abdominelles Aortenaneurysma“ (AAA) des Deutschen Instituts für Gefäßmedizinische Gesundheitsforschung (DIGG) der Deutschen Gesellschaft für Gefäßchirurgie und Gefäßmedizin werden vorgestellt.
Methodik: Im Jahr 2018 beteiligten sich an dem Register insgesamt 135 Kliniken. Für die offene Versorgung (OR) des intakten AAA (iAAA) gaben 118 (87,4 %) Kliniken, für die endovaskuläre Versorgung (EVAR) des iAAA 133 (98,5 %) Kliniken Daten ein. Für das rupturierte AAA (rAAA) wurden von 80 Kliniken (59,3 %) (EVAR) bzw. 65 (48,1 %) Kliniken (OR) Patienten gemeldet. Ausgewertet wurden die Daten von 4051 stationär behandelten Patienten.
Ergebnisse: 2800 iAAA (75,8 %) wurden endovaskulär und 895 (24,2 %) offen versorgt. Bei den endovaskulär versorgten Patienten mit iAAA verlief der Eingriff in 86,4 % der Fälle komplikationslos. Es verstarben insgesamt 32 Patienten (1,1 %) bis zur Entlassung. Bei den offen versorgten Patienten wiesen 73,4 % der Patienten keine Komplikationen auf. Verstorben sind insgesamt 42 Patienten (4,7 %). Von den 356 Patienten mit rAAA wurden 192 (53,9 %) endovaskulär und 164 (46,1 %) offen versorgt. Nur 11,0 % der mit OR versorgten Patienten, aber 23,4 % bei EVAR wiesen freies Blut in der Bauchhöhle auf. Bei EVAR sind 30,7 % der Patienten während des stationären Aufenthalts verstorben, bei OR 20,1 %.
Schlussfolgerung: Die Ergebnisse des Jahres 2018 zu Klinikletalität und Morbidität bei endovaskulärer und offener Versorgung des iAAA bestätigen weitestgehend die publizierten Ergebnisse für die Jahre 2013 bis 2017. Beim rAAA wurde 2018 erstmals über mehr endovaskuläre als offene Versorgungen berichtet – mit Ergebnissen, die denen der Vorjahre diametral entgegengesetzt waren. Patienten mit EVAR wiesen die höhere Komorbidität als Patienten mit OR auf und die Klinikletalität war höher. Es bleiben die Ergebnisse der Folgejahre abzuwarten, um diesen Trend genauer bewerten zu können.
Klein, Leah Maria ; Chang, Johannes ; Gu, Wenyi ; Manekeller, Steffen ; Jansen, Christian ; Lingohr, Philipp ; Praktiknjo, Michael ; Kalf, Jörg C. ; Schulz, Martin ; Spengler, Ulrich ; Straßburg, Christian P. ; Cárdenas, Andrés ; Arroyo, Vicente ; Trebicka, Jonel
Acute‐on‐chronic liver failure (ACLF) is a syndrome with high short‐term mortality. Precipitating events, including hemorrhage and infections, contribute to ACLF development, but the role of surgery remains unknown. We investigated the development of ACLF in patients with cirrhosis undergoing surgery. In total, 369 patients with cirrhosis were included in the study. The clinical and laboratory data were collected prior to and on days 1‐2, 3‐8, and 9‐28, and at 3 and 12 months after surgery. Surgery type was classified as limited or extensive, as well as liver and nonliver surgery. A total of 39 patients had baseline ACLF. Surgery was performed during acute decompensation in 35% of the rest of the 330 patients, and 81 (24.5%) developed ACLF within 28 days after surgery. Surrogate markers of systemic inflammation were similar in patients who developed ACLF or not. Age, sex, serum sodium, baseline bacterial infection, and abdominal nonliver surgery were independent predictors for the development of ACLF after surgery. Patients who developed ACLF within 28 days after surgery had a higher mortality at 3, 6, and 12 months. Survival did not differ between patients with ACLF at surgery and those developing ACLF after surgery. Development of ACLF within 28 days after surgery and elevated alkaline phosphatase and international normalized ratio were independent predictors of 90‐day mortality. Independent predictors of 1‐year all‐cause mortality were alkaline phosphatase, Model for End‐Stage Liver Disease score, and preoperative hepatic encephalopathy, whereas nonliver surgery was associated with improved survival. ACLF frequently develops in patients with cirrhosis undergoing surgery, especially in those with active bacterial infection, lower serum sodium, and kidney or coagulation dysfunction. Prognoses of ACLF both at and after surgery are similarly poor. Patients with cirrhosis should be carefully managed perioperatively.
Weber, Sarah ; Magh, Aaron ; Hogardt, Michael ; Kempf, Volkhard A. J. ; Vehreschild, Maria J. G. T. ; Serve, Hubert ; Scheich, Sebastian ; Steffen, Björn
Bloodstream infections (BSI) are a frequent complication in patients with hematological and oncological diseases. However, the impact of different bacterial species causing BSI and of multiple BSI remains incompletely understood. We performed a retrospective study profiling 637 bacterial BSI episodes in hematological and oncological patients. Based on the 30-day (30d) overall survival (OS), we analyzed different types of multiple BSI and grouped BSI-associated bacteria into clusters followed by further assessment of clinical and infection-related characteristics. We discovered that polymicrobial BSI (different organisms on the first day of a BSI episode) and sequential BSI (another BSI before the respective BSI episode) were associated with a worse 30d OS. Different bacterial groups could be classified into three BSI outcome clusters based on 30d OS: favorable (FAV) including mainly common skin contaminants, Escherichia spp. and Streptococcus spp.; intermediate (INT) including mainly Enterococcus spp., vancomycin-resistant Enterococcus spp., and multidrug-resistant gram-negative bacteria (MDRGN); and adverse (ADV) including MDRGN with an additional carbapenem-resistance (MDRGN+CR). A polymicrobial or sequential BSI especially influenced the outcome in the combination of two INT cluster BSI. The presence of a polymicrobial BSI and the assignment into the BSI outcome clusters were identified as independent risk factors for 30d mortality in a Cox multivariate regression analysis. The assignment to a BSI outcome cluster and the differentiated perspective of multiple BSI open new insights into the prognosis of patients with BSI and should be further validated in other patient cohorts.
Scheich, Sebastian ; König, Rosalie ; Wilke, Anne ; Lindner, Sarah ; Reinheimer, Claudia ; Wichelhaus, Thomas Alexander ; Hogardt, Michael ; Kempf, Volkhard A. J. ; Kessel, Johanna ; Weber, Sarah ; Martin, Hans ; Bug, Gesine ; Serve, Hubert ; Steffen, Björn
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers potential cure to acute myeloid leukemia (AML) patients. However, infections with commensal bacteria are an important cause for non-relapse mortality (NRM). We have previously described the impact of multidrug-resistant organism (MDRO) colonization on the survival of allo-HSCT patients. In the aforementioned publication, according to consensus, we there did not consider the opportunistic gram-negative bacterium Stenotrophomonas maltophilia (S. maltophilia) to be an MDRO. Since rate of S. maltophilia colonization is increasing, and it is not known whether this poses a risk for allo-HSCT patients, we here analyzed here its effect on the previously described and now extended patient cohort. We report on 291 AML patients undergoing allo-HSCT. Twenty of 291 patients (6.9%) were colonized with S. maltophilia. Colonized patients did not differ from non-colonized patients with respect to their age, remission status before allo-HSCT, donor type and HSCT-comorbidity index. S. maltophilia colonized patients had a worse overall survival (OS) from 6 months up to 60 months (85% vs. 88.1% and 24.7% vs. 59.7%; p = 0.007) due to a higher NRM after allo-HSCT (6 months: 15% vs. 4.8% and 60 months: 40.1% vs. 16.2% p = 0.003). The main cause of mortality in colonized patients was infection (46.2% of all deaths) and in non-colonized patients relapse (58.8% of all deaths). 5/20 colonized patients developed an invasive infection with S. maltophilia. The worse OS after allo-HSCT due to higher infection related mortality might implicate the screening of allo-HSCT patients for S. maltophilia and a closer observation of colonized patients as outpatients.
Kutter, Steffen ; Weiss, Manfred S. ; Wille, Georg ; Golbik, Ralph ; Spinka, Michael ; König, Stephan
The mechanism by which the enzyme pyruvate decarboxylase from yeast is activated allosterically has been elucidated. A total of seven three-dimensional structures of the enzyme, of enzyme variants or of enzyme complexes from two yeast species (three of them reported here for the first time) provide detailed atomic resolution snapshots along the activation coordinate. The prime event is the covalent binding of the substrate pyruvate to the side chain of cysteine 221, thus forming a thiohemiketal. This reaction causes the shift of a neighbouring amino acid, which eventually leads to the rigidification of two otherwise flexible loops, where one of the loops provides two histidine residues necessary to complete the enzymatically competent active site architecture. The structural data are complemented and supported by kinetic investigations and binding studies and provide a consistent picture of the structural changes, which occur upon enzyme activation.
Gaiser, Maria ; Lorenzen, Sylvie ; Merx, Kirsten ; Trojan, Jörg ; Ocvirk, Janja ; Ettrich, Thomas Jens ; Batran, Salah-Eddin al- ; Schulz, Holger ; Homann, Nils ; Feustel, Hans‐Peter ; Schatz, Michael ; Kripp, Melanie ; Schulte, Nadine ; Heeger, Steffen ; Vlassak, Soetkin ; Koch, Winfried ; Hofheinz, Ralf-Dieter
Acne‐like skin reactions frequently occur in patients undergoing treatment with drugs inhibiting the epidermal growth factor receptor. Recently, the effects of vitamin K1 containing cream (Reconval K1) as prophylactic skin treatment in addition to doxycycline were explored in a double‐blind randomized phase II trial (EVITA) in patients with metastatic colorectal cancer receiving cetuximab. EVITA demonstrated a trend towards less severe skin rash in Reconval K1‐treated patients using the tripartite WoMo skin reaction grading score as a thorough tool for quantification of drug related skin reactions. This gender‐specific analysis of the EVITA trial evaluated the application of the WoMo score for assessment of epidermal growth factor receptor (EGFR)‐related skin toxicities according to treatment arm and gender. To show the robustness of results parametric and non‐parametric statistical analyses were conducted. All three parts of the WoMo score independently demonstrated the superiority of the treatment arm (Reconval K1) regarding a significant reduction in acneiform skin reactions in women. Men did not benefit from Reconval K1 cream at any time point in none of the WoMo score analyses. The treatment effect in women was confirmed by the use of skin rash categories based on the final WoMo overall score and mixed effect longitudinal multiple linear regression analysis. The WoMo score represents a sensitive tool for studies exploiting treatments against EGFR mediated acne‐like skin rash. Part C of the WoMo score seems to be sufficient for quantification of drug related skin toxicities in further studies. Standard WoMo skin reaction score values for future studies are provided.
Gaiser, Maria ; Lorenzen, Sylvie ; Merx, Kirsten ; Trojan, Jörg ; Ocvirk, Janja ; Ettrich, Thomas Jens ; Batran, Salah-Eddin al- ; Schulz, Holger ; Homann, Nils ; Feustel, Hans-Peter ; Schatz, Michael ; Kripp, Melanie ; Schulte, Nadine ; Heeger, Steffen ; Vlassak, Soetkin ; Koch, Winfried ; Hofheinz, Ralf-Dieter
Zielsetzung: Die Daten für das Jahr 2019 des Registers „Abdominelles Aortenaneurysma“ (AAA) des Deutschen Instituts für Gefäßmedizinische Gesundheitsforschung (DIGG) der Deutschen Gesellschaft für Gefäßchirurgie und Gefäßmedizin werden vorgestellt.
Methodik: Im Jahr 2019 beteiligten sich an dem Register insgesamt 109 Kliniken. Für die offene Versorgung (OR) des intakten AAA (iAAA) gaben 78 (71,6 %) Kliniken, für die endovaskuläre Versorgung (EVAR) des iAAA 102 (93,6 %) Kliniken Daten ein. Für das rupturierte AAA (rAAA) wurden von 36 Kliniken (33,0 %) (EVAR) bzw. 50 (45,9 %) Kliniken (OR) Patienten gemeldet. Ausgewertet wurden die Daten von 1967 stationär behandelten Patienten. Von den insgesamt 1793 iAAA waren 1501 infrarenal (83,7 %) und 292 (16,3 %) juxtarenal gelegen.
Ergebnisse: 1429 iAAA (79,7 %) wurden endovaskulär und 364 (20,3 %) offen versorgt. Bei den endovaskulär versorgten Patienten mit iAAA verlief der Eingriff in 86,3 % der Fälle komplikationslos. Es verstarben insgesamt 15 Patienten (1,0 %) bis zur Entlassung. Bei den offen versorgten Patienten wiesen 67,0 % der Patienten keine Komplikationen auf. Verstorben sind insgesamt 20 Patienten (5,5 %). Bei EVAR war die Klinikletalität bei Versorgung juxtarenaler AAA mit 3,7 % signifikant höher als bei Versorgung infrarenaler AAA mit 0,6 % (p = 0,002), bei OR konnten hingegen keine signifikanten Unterschiede hinsichtlich der Klinikletalität aufgezeigt werden (juxtarenal 4,8 %, infrarenal 5,8 %; p = 0,470). Von den 174 Patienten mit rAAA wurden 80 (46,0 %) endovaskulär und 94 (54,0 %) offen versorgt. Bei EVAR sind 20,0 % der Patienten während des stationären Aufenthalts verstorben, bei OR 36,2 %.
Schlussfolgerung: Die Ergebnisse des Jahres 2019 zu Klinikletalität und Morbidität bei endovaskulärer und offener Versorgung des iAAA bestätigen weitgehend die publizierten Ergebnisse für die Jahre 2013 bis 2018. Beim rAAA sind die Ergebnisse der einzelnen Jahresberichte hingegen widersprüchlich, die kleinen berichteten jährlichen Fallzahlen erlauben nur Aussagen über größere Zeiträume.
Chang, Johannes ; Höfer, Pauline ; Böhling, Nina ; Lingohr, Philipp ; Manekeller, Steffen ; Kalff, Jörg C. ; Dohmen, Jonas ; Kaczmarek, Dominik J. ; Jansen, Christian ; Meyer, Carsten ; Straßburg, Christian P. ; Trebicka, Jonel ; Praktiknjo, Michael
Background & Aims: Acute-on-chronic liver failure (ACLF) is a syndrome associated with organ failure and high short-term mortality. Recently, the role of surgery as a precipitating event for ACLF has been characterised. However, the impact of preoperative transjugular intrahepatic portosystemic shunt (TIPS) placement on ACLF development in patients with cirrhosis undergoing surgery has not been investigated yet.
Methods: A total of 926 patients (363 with cirrhosis undergoing surgery and 563 patients with TIPS) were screened. Forty-five patients with preoperative TIPS (TIPS group) were 1:1 propensity matched to patients without preoperative TIPS (no-TIPS group). The primary endpoint was the development of ACLF within 28 and 90 days after surgery. The secondary endpoint was 1-year mortality. Results were confirmed by a differently 1:2 matched cohort (n = 176).
Results: Patients in the no-TIPS group had significantly higher rates of ACLF within 28 days (29 vs. 9%; p = 0.016) and 90 days (33 vs. 13%; p = 0.020) after surgery as well as significantly higher 1-year mortality (38 vs. 18%; p = 0.023) compared with those in the TIPS group. Surgery without preoperative TIPS and Chronic Liver Failure Consortium–Acute Decompensation (CLIF-C AD) score were independent predictors for 28- and 90-day ACLF development and 1-year mortality after surgery, especially in patients undergoing visceral surgery. In the no-TIPS group, a CLIF-C AD score of >45 could be identified as cut-off for patients at risk for postoperative ACLF development benefiting from TIPS.
Conclusions: This study suggests that preoperative TIPS may result in lower rates of postoperative ACLF development especially in patients undergoing visceral surgery and with a CLIF-C AD score above 45.
Lay summary: Acute-on-chronic liver failure (ACLF) is a syndrome that is associated with high short-term mortality. Surgical procedures are a known precipitating event for ACLF. This study investigates the role of preoperative insertion of a transjugular intrahepatic portosystemic shunt (TIPS) on postoperative mortality and ACLF development. Patients with TIPS insertion before a surgical procedure exhibit improved postoperative survival and lower rates of postoperative ACLF, especially in patients undergoing visceral surgery and with a high CLIF-C AD prognostic score. Thus, this study suggests preoperative TIPS insertion in those high-risk patients.
Eckardt, Jan-Niklas ; Stasik, Sebastian ; Kramer, Michael ; Röllig, Christoph ; Krämer, Alwin ; Scholl, Sebastian ; Hochhaus, Andreas ; Crysandt, Martina ; Brümmendorf, Tim Henrik ; Naumann, Ralph ; Steffen, Björn ; Kunzmann, Volker ; Einsele, Hermann ; Schaich, Markus ; Burchert, Andreas ; Neubauer, Andreas ; Schäfer-Eckart, Kerstin ; Schliemann, Christoph ; Krause, Stefan W. ; Herbst, Regina ; Hänel, Mathias ; Frickhofen, Norbert ; Noppeney, Richard ; Kaiser, Ulrich ; Baldus, Claudia ; Kaufmann, Martin ; Rácil, Zdenek ; Platzbecker, Uwe ; Berdel, Wolfgang E. ; Mayer, Jiří ; Serve, Hubert ; Müller-Tidow, Carsten ; Ehninger, Gerhard ; Stölzel, Friedrich ; Kroschinsky, Frank ; Schetelig, Johannes ; Bornhäuser, Martin ; Thiede, Christian ; Middeke, Jan Moritz
Simple Summary: Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Clinical phenotypes of frequent mutations and their impact on patient outcome are well established. However, the role of rare mutations often remains elusive. We retrospectively analyzed 1529 newly diagnosed and intensively treated AML patients for mutations of BCOR and BCORL1. We report a distinct co-mutational pattern that suggests a role in disease progression rather than initiation, especially affecting mechanisms of DNA-methylation. Further, we found loss-of-function mutations of BCOR to be independent markers of poor outcomes in multivariable analysis. Therefore, loss-of-function mutations of BCOR need to be considered for AML management, as they may influence risk stratification and subsequent treatment allocation.
Abstract: Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.
Ballo, Olivier Karl Friedrich ; Kreisel, Eva-Maria ; Eladly, Fagr ; Brunnberg, Uta ; Stratmann, Jan Alexander ; Hunyady, Peter Marton ; Hogardt, Michael ; Wichelhaus, Thomas A. ; Kempf, Volkhard A. J. ; Steffen, Björn ; Vehreschild, Jörg Janne ; Vehreschild, Maria J. G. T. ; Finkelmeier, Fabian ; Serve, Hubert ; Brandts, Christian Hubertus
Patients with acute myeloid leukemia (AML) are often exposed to broad-spectrum antibiotics and thus at high risk of Clostridioides difficile infections (CDI). As bacterial infections are a common cause for treatment-related mortality in these patients, we conducted a retrospective study to analyze the incidence of CDI and to evaluate risk factors for CDI in a large uniformly treated AML cohort. A total of 415 AML patients undergoing intensive induction chemotherapy between 2007 and 2019 were included in this retrospective analysis. Patients presenting with diarrhea and positive stool testing for toxin-producing Clostridioides difficile were defined to have CDI. CDI was diagnosed in 37 (8.9%) of 415 AML patients with decreasing CDI rates between 2013 and 2019 versus 2007 to 2012. Days with fever, exposition to carbapenems, and glycopeptides were significantly associated with CDI in AML patients. Clinical endpoints such as length of hospital stay, admission to ICU, response rates, and survival were not adversely affected. We identified febrile episodes and exposition to carbapenems and glycopeptides as risk factors for CDI in AML patients undergoing induction chemotherapy, thereby highlighting the importance of interdisciplinary antibiotic stewardship programs guiding treatment strategies in AML patients with infectious complications to carefully balance risks and benefits of anti-infective agents.
Recktenwald, Steffen Michael ; Simionato, Greta ; Lopes, Marcelle Guedes de Medeiros ; Gamboni, Fabia ; Dzieciatkowska, Monika ; Meybohm, Patrick ; Zacharowski, Kai ; Knethen, Andreas von ; Wagner, Christian ; Kästner, Lars ; D’Alessandro, Angelo ; Quint, Stephan
Coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and can affect multiple organs, among which is the circulatory system. Inflammation and mortality risk markers were previously detected in COVID-19 plasma and red blood cells (RBCs) metabolic and proteomic profiles. Additionally, biophysical properties, such as deformability, were found to be changed during the infection. Based on such data, we aim to better characterize RBC functions in COVID-19. We evaluate the flow properties of RBCs in severe COVID-19 patients admitted to the intensive care unit by using microfluidic techniques and automated methods, including artificial neural networks, for an unbiased RBC analysis. We find strong flow and RBC shape impairment in COVID-19 samples and demonstrate that such changes are reversible upon suspension of COVID-19 RBCs in healthy plasma. Vice versa, healthy RBCs resemble COVID-19 RBCs when suspended in COVID-19 plasma. Proteomics and metabolomics analyses allow us to detect the effect of plasma exchanges on both plasma and RBCs and demonstrate a new role of RBCs in maintaining plasma equilibria at the expense of their flow properties. Our findings provide a framework for further investigations of clinical relevance for therapies against COVID-19 and possibly other infectious diseases.
Editor's evaluation
This report illustrates a comprehensive account detailing the marked alteration of red blood cell (RBC) morphology that occurs with COVID-19 infection. A particularly important result is the observation that RBC morphology is dramatically affected by plasma from COVID-19 patients and reversible with plasma from healthy donors. The claims of the manuscript are well supported by the data, and the approaches used are thoughtful and rigorous. The results are important for consideration of the broader pathophysiology of COVID-19, particularly with regard to the impact on vascular biology and will be of interest to the readership of eLife.
Eckert, Anne ; Eckert, Gunter P. ; Kastl, Andrea ; Leutner, Silke ; Leutz, Steffen ; Schindowski, Katharina ; Steiner, Barbara ; Sych, Michael ; Müller, Walter E.
Kaiser, Steffen ; Byrne, Shane R. ; Ammann, Gregor ; Asadi-Atoi, Paria ; Borland, Kayla ; Brecheisen, Roland ; DeMott, Michael S. ; Gehrke, Tim Herbert ; Hagelskamp, Felix ; Heiß, Matthias ; Yoluç, Yasemin ; Liu, Lili ; Zhang, Qinghua ; Dedon, Peter C. ; Cao, Bo ; Kellner, Stefanie
In this report, we perform structure validation of recently reported RNA phosphorothioate (PT) modifications, a new set of epitranscriptome marks found in bacteria and eukaryotes including humans. By comparing synthetic PT-containing diribonucleotides with native species in RNA hydrolysates by high-resolution mass spectrometry (MS), metabolic stable isotope labeling, and PT-specific iodine-desulfurization, we disprove the existence of PTs in RNA from E. coli, S. cerevisiae, human cell lines, and mouse brain. Furthermore, we discuss how an MS artifact led to the initial misidentification of 2′-O-methylated diribonucleotides as RNA phosphorothioates. To aid structure validation of new nucleic acid modifications, we present a detailed guideline for MS analysis of RNA hydrolysates, emphasizing how the chosen RNA hydrolysis protocol can be a decisive factor in discovering and quantifying RNA modifications in biological samples.
Hundley, William Gregory ; Bluemke, David A. ; Bogaert, Jan ; Flamm, Scott D. ; Fontana, Marianna ; Friedrich, Matthias ; Große-Wortmann, Lars ; Karamitsos, Theodoros D. ; Kramer, Christopher M. ; Kwong, Raymond Y. ; McConnell, Michael ; Nagel, Eike ; Neubauer, Stefan ; Nijveldt, Robin ; Pennell, Dudley J. ; Petersen, Steffen Erhard ; Raman, Subha V. ; Rossum, Albert C. van
Comprehensive analysis of tumour sub-volumes for radiomic risk modelling in locally advanced HNSCC
(2020)
Leger, Stefan ; Zwanenburg, Alex ; Leger, Karoline ; Lohaus, Fabian ; Linge, Annett ; Schreiber, Andreas ; Kalinauskaite, Goda ; Tinhofer, Inge ; Guberina, Nika ; Guberina, Maja ; Balermpas, Panagiotis ; Müller-von der Grün, Jens ; Ganswindt, Ute ; Belka, Claus ; Peeken, Jan Caspar ; Combs, Stephanie E. ; Boeke, Simon ; Zips, Daniel ; Richter, Christian ; Krause, Mechthild ; Baumann, Michael ; Troost, Esther Gera Cornelia ; Löck, Steffen
Simple Summary: Radiomic risk models are usually based on imaging features, which are extracted from the entire gross tumour volume (GTV entire ). This approach does not explicitly consider the complex biological structure of the tumours. Therefore, in this retrospective study, we investigated the prognostic value of radiomic analyses based on different tumour sub-volumes using computed tomography imaging of patients with locally advanced head and neck squamous cell carcinoma who were treated with primary radio-chemotherapy. The GTV entire was cropped by different margins to define the rim and corresponding core sub-volumes of the tumour. Furthermore, the best performing tumour rim sub-volume was extended into surrounding tissue with different margins. As a result, the models based on the 5 mm tumour rim and on the 3 mm extended rim sub-volume showed an improved performance compared to models based on the corresponding tumour core. This indicates that the consideration of tumour sub-volumes may help to improve radiomic risk models.
Abstract: Imaging features for radiomic analyses are commonly calculated from the entire gross tumour volume (GTVentire). However, tumours are biologically complex and the consideration of different tumour regions in radiomic models may lead to an improved outcome prediction. Therefore, we investigated the prognostic value of radiomic analyses based on different tumour sub-volumes using computed tomography imaging of patients with locally advanced head and neck squamous cell carcinoma. The GTVentire was cropped by different margins to define the rim and the corresponding core sub-volumes of the tumour. Subsequently, the best performing tumour rim sub-volume was extended into surrounding tissue with different margins. Radiomic risk models were developed and validated using a retrospective cohort consisting of 291 patients in one of the six Partner Sites of the German Cancer Consortium Radiation Oncology Group treated between 2005 and 2013. The validation concordance index (C-index) averaged over all applied learning algorithms and feature selection methods using the GTVentire achieved a moderate prognostic performance for loco-regional tumour control (C-index: 0.61 ± 0.04 (mean ± std)). The models based on the 5 mm tumour rim and on the 3 mm extended rim sub-volume showed higher median performances (C-index: 0.65 ± 0.02 and 0.64 ± 0.05, respectively), while models based on the corresponding tumour core volumes performed less (C-index: 0.59 ± 0.01). The difference in C-index between the 5 mm tumour rim and the corresponding core volume showed a statistical trend (p = 0.10). After additional prospective validation, the consideration of tumour sub-volumes may be a promising way to improve prognostic radiomic risk models.
Rabasco Meneghetti, Asier ; Zwanenburg, Alex ; Leger, Stefan ; Leger, Karoline ; Troost, Esther Gera Cornelia ; Linge, Annett ; Lohaus, Fabian ; Schreiber, Andreas ; Kalinauskaite, Goda ; Tinhofer, Inge ; Guberina, Nika ; Guberina, Maja ; Balermpas, Panagiotis ; Müller-von der Grün, Jens ; Ganswindt, Ute ; Belka, Claus ; Peeken, Jan Caspar ; Combs, Stephanie E. ; Böke, Simon ; Zips, Daniel ; Krause, Mechthild ; Baumann, Michael ; Löck, Steffen
Purpose: To develop and validate a CT-based radiomics signature for the prognosis of loco-regional tumour control (LRC) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated by primary radiochemotherapy (RCTx) based on retrospective data from 6 partner sites of the German Cancer Consortium - Radiation Oncology Group (DKTK-ROG).
Material and methods: Pre-treatment CT images of 318 patients with locally advanced HNSCC were collected. Four-hundred forty-six features were extracted from each primary tumour volume and then filtered through stability analysis and clustering. First, a baseline signature was developed from demographic and tumour-associated clinical parameters. This signature was then supplemented by CT imaging features. A final signature was derived using repeated 3-fold cross-validation on the discovery cohort. Performance in external validation was assessed by the concordance index (C-Index). Furthermore, calibration and patient stratification in groups with low and high risk for loco-regional recurrence were analysed.
Results: For the clinical baseline signature, only the primary tumour volume was selected. The final signature combined the tumour volume with two independent radiomics features. It achieved moderately good discriminatory performance (C-Index [95% confidence interval]: 0.66 [0.55–0.75]) on the validation cohort along with significant patient stratification (p = 0.005) and good calibration.
Conclusion: We identified and validated a clinical-radiomics signature for LRC of locally advanced HNSCC using a multi-centric retrospective dataset. Prospective validation will be performed on the primary cohort of the HNprädBio trial of the DKTK-ROG once follow-up is completed.
Wiegand, Steffen B. ; Heidrich, Benjamin ; Susser, Simone ; Rogalska-Taranta, Magdalena ; Petersen, Jörg ; Böker, Klaus H. W. ; Grigorian, Natalia ; Link, Ralph ; Naumann, Uwe ; John, Christine ; Lüth, Stefan ; Malfertheiner, Peter ; Manns, Michael P. ; Wedemeyer, Heiner ; Sarrazin, Christoph ; Cornberg, Markus
Background: SNPs near the interferon lambda (IFNL) 3 gene are predictors for sustained virological response (SVR) in patients with chronic hepatitis C genotype (GT) 1. In addition, a dinucleotide frame shift in ss469415590 was described, which generates IFNL4. In this study, we compared the role of IFNL4 variants with IFNL3-(rs12979860) and IFNL3-(rs8099917) on response to pegylated (PEG)-IFN and Ribavirin (RBV) in patients with chronic hepatitis C GT2/3.
Methods: We recruited 1006 patients with chronic hepatitis C and GT2/3 in a large German registry. A treatment with PEG-IFN and Ribavirin was started by 959 patients. We performed genotyping of IFNL3 (rs12979860, n = 726; rs8099917, n = 687) and of IFNL4 (ss469415590; n = 631).
Results: Both preferable IFNL3 genotypes were associated with RVR (both p<0.0001) rather than with SVR (rs12979860: p = 0.251; rs8099917: p = 0.447). Only RVR was linked to SVR in univariate and multivariate analyzes (both p<0.001). Concordance of genotyping in patients with available serum samples and EDTA blood samples (n = 259) was more than 96% for both IFNL3 SNPs. IFNL3-(rs12979860) correlated with IFNL4: 99.2% of patients with IFNL3-(rs12979860)-CC were IFNL4-(ss469415590)-TT/TT. IFNL3-(rs12979860)-CT was linked with IFNL4-(ss469415590)-TT/ΔG (98.0%) and IFNL3-(rs12979860)-TT was associated with IFNL4-(ss469415590)-ΔG/ΔG (97.6%).
Conclusion: IFNL3 genotyping from serum was highly efficient and can be used as an alternative if EDTA whole blood is not available. In Caucasian GT2/3 patients genotyping for INFL4-(ss469415590) does not lead to additional information for the decision-making process. Importantly, IFNL3 SNPs were not associated with SVR but with RVR. Even in the era of new direct acting antiviral (DAA) therapies, IFNL3 testing may therefore still be considered for naïve GT2/3 patients to decide if dual Peg-IFN/RBV therapy is an option in resource limited regions.