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Hoogakker, Babette A. A. ; Smith, Robin S. ; Singarayer, Joy ; Marchant, Robert ; Prentice, I. Colin ; Allen, Judy R. M. ; Anderson, R. Scott ; Bhagwat, Shonil A. ; Behling, Hermann ; Borisova, Olga ; Bush, Mark B. ; Correa-Metrio, Alexander ; De Vernal, Anne ; Finch, Jemma M. ; Fréchette, Bianca ; Lozano-García, Socorro ; Gosling, William D. ; Granoszewski, Wojciech ; Grimm, Eric C. ; Grüger, Eberhard ; Hanselman, Jennifer ; Harrison, Sandy P. ; Hill, Trevor R. ; Huntley, Brian ; Jimenez-Moreno, Gonzalo ; Kershaw, Arnold Peter ; Ledru, Marie-Pierre ; Magri, Donatella ; McKenzie, Merna ; Müller, Ulrich ; Nakagawa, Takeshi ; Novenko, Elena ; Penny, Daniel ; Sadori, Laura ; Scott, Louis ; Stevenson, Janelle ; Valdes, Paul J. ; Vandergoes, Marcus ; Velichko, Andrey ; Whitlock, Cathy ; Tzedakis, Chronis
A new global synthesis and biomization of long (> 40 kyr) pollen-data records is presented, and used with simulations from the HadCM3 and FAMOUS climate models to analyse the dynamics of the global terrestrial biosphere and carbon storage over the last glacial–interglacial cycle. Global modelled (BIOME4) biome distributions over time generally agree well with those inferred from pollen data. The two climate models show good agreement in global net primary productivity (NPP). NPP is strongly influenced by atmospheric carbon dioxide (CO2) concentrations through CO2 fertilization. The combined effects of modelled changes in vegetation and (via a simple model) soil carbon result in a global terrestrial carbon storage at the Last Glacial Maximum that is 210–470 Pg C less than in pre-industrial time. Without the contribution from exposed glacial continental shelves the reduction would be larger, 330–960 Pg C. Other intervals of low terrestrial carbon storage include stadial intervals at 108 and 85 kaBP, and between 60 and 65 kaBP during Marine Isotope Stage 4. Terrestrial carbon storage, determined by the balance of global NPP and decomposition, influences the stable carbon isotope composition (δ 13C) of seawater because terrestrial organic carbon is depleted in 13C. Using a simple carbon-isotope mass balance equation we find agreement in trends between modelled ocean δ 13C based on modelled land carbon storage, and palaeo-archives of ocean δ 13C, confirming that terrestrial carbon storage variations may be important drivers of ocean δ 13 C changes.
Hoogakker, Babette A. A. ; Smith, Robin S. ; Singarayer, Joy ; Marchant, Robert ; Prentice, I. Colin ; Allen, Judy R. M. ; Anderson, R. Scott ; Bhagwat, Shonil A. ; Behling, Hermann ; Borisova, Olga ; Bush, Mark B. ; Correa-Metrio, Alexander ; De Vernal, Anne ; Finch, Jemma M. ; Fréchette, Bianca ; Lozano-García, Socorro ; Gosling, William D. ; Granoszewski, Wojciech ; Grimm, Eric C. ; Grüger, Eberhard ; Hanselman, Jennifer ; Harrison, Sandy P. ; Hill, Trevor R. ; Huntley, Brian ; Jimenez-Moreno, Gonzalo ; Kershaw, Arnold Peter ; Ledru, Marie-Pierre ; Magri, Donatella ; McKenzie, Merna ; Müller, Ulrich ; Nakagawa, Takeshi ; Novenko, Elena ; Penny, Daniel ; Sadori, Laura ; Scott, Louis ; Stevenson, Janelle ; Valdes, Paul J. ; Vandergoes, Marcus ; Velichko, Andrey ; Whitlock, Cathy ; Tzedakis, Chronis
A new global synthesis and biomization of long (> 40 kyr) pollen-data records is presented and used with simulations from the HadCM3 and FAMOUS climate models and the BIOME4 vegetation model to analyse the dynamics of the global terrestrial biosphere and carbon storage over the last glacial–interglacial cycle. Simulated biome distributions using BIOME4 driven by HadCM3 and FAMOUS at the global scale over time generally agree well with those inferred from pollen data. Global average areas of grassland and dry shrubland, desert, and tundra biomes show large-scale increases during the Last Glacial Maximum, between ca. 64 and 74 ka BP and cool substages of Marine Isotope Stage 5, at the expense of the tropical forest, warm-temperate forest, and temperate forest biomes. These changes are reflected in BIOME4 simulations of global net primary productivity, showing good agreement between the two models. Such changes are likely to affect terrestrial carbon storage, which in turn influences the stable carbon isotopic composition of seawater as terrestrial carbon is depleted in 13C.
Müller-von der Grün, Jens ; Martin, Daniel ; Stöver, Timo ; Ghanaati, Shahram Michael ; Rödel, Claus ; Balermpas, Panagiotis
Background: With the aging population and a rising incidence of squamous cell carcinoma of the head and neck (SCCHN), there is an emerging need for developing strategies to treat elderly patients.
Patients and Methods: We retrospectively analyzed 158 patients treated with definitive, concurrent chemoradiotherapy (CRT) for SCCHN. Clinicopathological characteristics, acute toxicities, and oncological outcomes were compared between patients younger and older than (or of age equal to) 65, 70, and 75 years.
Results: RT dose, chemotherapy regimen, and total chemotherapy dose were balanced between the groups. After a median follow-up of 29 months, overall survival (OS), progression-free survival (PFS), local control rate, and distant metastasis-free survival stratified by age of ≥65, ≥70, or ≥75 years revealed no differences. The rate of acute toxicities was also not higher for older patients. Worse ECOG performance score (ECOG 2-3) was associated with impaired OS () and PFS ().
Conclusion: Definitive treatment with CRT for SCCHN is feasible and effective; even in advanced age treatment decisions should be made according to general condition and comorbidity, rather than calendar age alone.
Störmann, Philipp ; Klug, Alexander ; Nau, Christoph ; Verboket, René ; Leiblein, Maximilian ; Müller, Daniel ; Schweigkofler, Uwe ; Hoffmann, Reinhard ; Marzi, Ingo ; Lustenberger, Thomas
Since the introduction of rental E-scooters in Germany in mid-June 2019, the safety of this new means of transport has been the subject of extensive public debate. However, valid data on injuries and usage habits are not yet available. This retrospective two-center study included a total of 76 patients who presented to the emergency department following E-scooter-related accidents. The mean age was 34.3 ± 12.4 years and 69.7% of the patients were male. About half of the patients were admitted by ambulance (42.1%). Fractures were found in 48.6% of patients, and 27.6% required surgical treatment due to a fracture. The upper extremities were the most commonly affected body region, followed by injuries to the lower extremity and to the head and face. Only one patient had worn a helmet. In-hospital treatment was necessary for 26.3% of the cases. Patients presented to the emergency department mainly during the weekend and on-call times. This is the first report on E-scooter-related injuries in Germany. Accidents with E-scooters can cause serious injuries and, therefore, represent a further burden to emergency departments. The use of E-scooters appears to be mostly recreational, and the rate of use of protective gear is low.
Liebers, Nora ; Düll, Johannes ; Fitzgerald, Donnacha ; Kerkhoff, Andrea ; Nörenberg, Daniel ; Käbisch, Eva ; Acker, Fabian ; Fuhrmann, Stephan ; Leng, Corinna ; Welslau, Manfred ; Chemnitz, Jens ; Middeke, Jan Moritz ; Weber, Thomas ; Holtick, Udo ; Trappe, Ralf Ulrich ; Pfannes, Roald ; Liersch, Rüdiger ; Spoer, Christian ; Fuxius, Stefan ; Gebauer, Niklas ; Caillé, Léandra ; Geer, Thomas ; Könecke, Christian ; Keller, Ulrich ; Claus, Rainer ; Mougiakakos, Dimitrios ; Mayer, Stephanie ; Hüttmann, Andreas ; Pott, Christiane ; Trummer, Arne ; Wulf, Gerald ; Brunnberg, Uta ; Bullinger, Lars ; Heß, Georg ; Müller-Tidow, Carsten ; Glaß, Bertram ; Lenz, Georg ; Dreger, Peter ; Dietrich, Sascha
The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1%. The 6-month progression-free survival and overall survival (OS) was 27.7% and 49.6%, respectively. In the bridging cohort, 51.2% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients.
Fleischmann, Maximilian ; Martin, Daniel ; Peña-Llopis, Samuel ; Oppermann, Julius ; Müller-von der Grün, Jens ; Diefenhardt, Markus ; Chatzikonstantinou, Georgios ; Fokas, Emmanouil ; Rödel, Claus ; Strebhardt, Klaus ; Becker, Sven ; Rödel, Franz ; Tselis, Nikolaos
Introduction: Definitive chemoradiation (CRT) followed by high-dose-rate (HDR) brachytherapy (BT) represents state-of-the-art treatment for locally-advanced cervical cancer. Despite use of this treatment paradigm, disease-related outcomes have stagnated in recent years, indicating the need for biomarker development and improved patient stratification. Here, we report the association of Polo-like kinase (PLK) 3 expression and Caspase 8 T273 phosphorylation levels with survival among patients with cervical squamous cell carcinoma (CSCC) treated with CRT plus BT.
Methods: We identified 74 patients with FIGO Stage Ib to IVb cervix squamous cell carcinoma. Baseline immunohistochemical scoring of PLK3 and pT273 Caspase 8 levels was performed on pre-treatment samples. Correlation was then assessed between marker expression and clinical endpoints, including cumulative incidences of local and distant failure, cancer-specific survival (CSS) and overall survival (OS). Data were then validated using The Cancer Genome Atlas (TCGA) dataset.
Results: PLK3 expression levels were associated with pT273 Caspase 8 levels (p = 0.009), as well as N stage (p = 0.046), M stage (p = 0.026), and FIGO stage (p = 0.001). By the same token, pT273 Caspase 8 levels were associated with T stage (p = 0.031). Increased PLK3 levels corresponded to a lower risk of distant relapse (p = 0.009), improved CSS (p = 0.001), and OS (p = 0.003). Phospho T273 Caspase 8 similarly corresponded to decreased risk of distant failure (p = 0.021), and increased CSS (p < 0.001) and OS (p < 0.001) and remained a significant predictor for OS on multivariate analysis. TCGA data confirmed the association of low PLK3 expression with resistance to radiotherapy and BT (p < 0.05), as well as increased propensity for metastasis (p = 0.019). Finally, a combined PLK3 and pT273 Caspase 8 score predicted for decreased distant relapse (p = 0.005), and both improved CSS (p < 0.001) and OS (p < 0.001); this combined score independently predicted distant failure (p = 0.041) and CSS (p = 0.003) on multivariate analyses.
Conclusion: Increased pre-treatment tumor levels of PLK3 and pT273 Caspase 8 correspond to improved disease-related outcomes among cervical cancer patients treated with CRT plus BT, representing a potential biomarker in this context.
Müller, Beate ; Klaaßen-Mielke, Renate ; González-González, Ana I. ; Grandt, Daniel ; Hammerschmidt, Reinhard ; Köberlein-Neu, Juliane ; Kellermann-Mühlhoff, Petra ; Trampisch, Hans Joachim ; Beckmann, Till ; Düvel, Lara ; Surmann, Bastian ; Flaig, Benno ; Ihle, Peter ; Söling, Sara ; Grandt, Simone ; Dinh, Truc Sophia ; Piotrowski, Alexandra ; Meyer, Ingo ; Karbach, Ute ; Harder, Sebastian ; Perera, Rafael ; Glasziou, Paul ; Pfaff, Holger ; Greiner, Wolfgang ; Gerlach, Ferdinand M. ; Timmesfeld, Nina ; Muth, Christiane
Introduction: Clinically complex patients often require multiple medications. Polypharmacy is associated with inappropriate prescriptions, which may lead to negative outcomes. Few effective tools are available to help physicians optimise patient medication. This study assesses whether an electronic medication management support system (eMMa) reduces hospitalisation and mortality and improves prescription quality/safety in patients with polypharmacy. Methods and analysis: Planned design: pragmatic, parallel cluster-randomised controlled trial; general practices as randomisation unit; patients as analysis unit. As practice recruitment was poor, we included additional data to our primary endpoint analysis for practices and quarters from October 2017 to March 2021. Since randomisation was performed in waves, final study design corresponds to a stepped-wedge design with open cohort and step-length of one quarter. Scope: general practices, Westphalia-Lippe (Germany), caring for BARMER health fund-covered patients. Population: patients (≥18 years) with polypharmacy (≥5 prescriptions). Sample size: initially, 32 patients from each of 539 practices were required for each study arm (17 200 patients/arm), but only 688 practices were randomised after 2 years of recruitment. Design change ensures that 80% power is nonetheless achieved. Intervention: complex intervention eMMa. Follow-up: at least five quarters/cluster (practice). recruitment: practices recruited/randomised at different times; after follow-up, control group practices may access eMMa. Outcomes: primary endpoint is all-cause mortality and hospitalisation; secondary endpoints are number of potentially inappropriate medications, cause-specific hospitalisation preceded by high-risk prescribing and medication underuse. Statistical analysis: primary and secondary outcomes are measured quarterly at patient level. A generalised linear mixed-effect model and repeated patient measurements are used to consider patient clusters within practices. Time and intervention group are considered fixed factors; variation between practices and patients is fitted as random effects. Intention-to-treat principle is used to analyse primary and key secondary endpoints.
Sievers, Philipp ; Henneken, Sophie C. ; Blume, Christina ; Sill, Martin ; Schrimpf, Daniel ; Stichel, Damian ; Okonechnikov, Konstantin ; Reuss, David ; Benzel, Julia ; Maaß, Kendra K. ; Kool, Marcel ; Sturm, Dominik ; Zheng, Tuyu ; Ghasemi, David R. ; Kohlhof-Meinecke, Patricia ; Cruz, Ofelia ; Suñol, Mariona ; Lavarino, Cinzia ; Ruf, Viktoria ; Boldt, Henning B. ; Pagès, Mélanie ; Pouget, Celso ; Schweizer, Leonille ; Kranendonk, Mariëtte E. G. ; Akhtar, Noreen ; Bunkowski, Stephanie ; Stadelmann, Christine ; Schüller, Ulrich ; Müller, Wolf C. ; Dohmen, Hildegard ; Acker, Till ; Harter, Patrick Nikolaus ; Mawrin, Christian ; Beschorner, Rudi ; Brandner, Sebastian ; Snuderl, Matija ; Abdullaev, Zied ; Aldape, Kenneth ; Gilbert, Mark R. ; Armstrong, Terri S. ; Ellison, David W. ; Capper, David ; Ichimura, Koichi ; Reifenberger, Guido ; Grundy, Richard G. ; Jabado, Nada ; Krskova, Lenka ; Zapotocky, Michal ; Vicha, Ales ; Varlet, Pascale ; Wesseling, Pieter ; Rutkowski, Stefan ; Korshunov, Andrey ; Wick, Wolfgang ; Pfister, Stefan ; Jones, David T. W. ; Deimling, Andreas von ; Pajtler, Kristian Wilfried ; Sahm, Felix
Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
Randall, Joshua C. ; Winkler, Thomas W. ; Kutalik, Zoltán ; I. Berndt, Sonja ; Jackson, Anne U. ; Monda, Keri L. ; Kilpeläinen, Tuomas O. ; Esko, Tõnu ; Mägi, Reedik ; Li, Shengxu ; Workalemahu, Tsegaselassie ; Feitosa, Mary F. ; Croteau-Chonka, Damien C. ; Day, Felix R. ; Fall, Tove ; Ferreira, Teresa ; Gustafsson, Stefan ; Locke, Adam E. ; Mathieson, Iain ; Scherag, André ; Vedantam, Sailaja ; Wood, Andrew R. ; Liang, Liming ; Steinthorsdottir, Valgerdur ; Thorleifsson, Gudmar ; Dermitzakis, Emmanouil T. ; Dimas, Antigone S. ; Karpe, Fredrik ; Min, Josine L. ; Nicholson, George ; Clegg, Deborah J. ; Person, Thomas ; Krohn, Jon P. ; Bauer, Sabrina ; Buechler, Christa ; Eisinger, Kristina ; Bonnefond, Amélie ; Froguel, Philippe ; Hottenga, Jouke-Jan ; Prokopenko, Inga ; Waite, Lindsay L. ; Harris, Tamara B. ; Smith, Albert Vernon ; Shuldiner, Alan R. ; McArdle, Wendy L. ; Caulfield, Mark J. ; Munroe, Patricia B. ; Grönberg, Henrik ; Chen, Yii-Der Ida ; Li, Guo ; Beckmann, Jacques S. ; Johnson, Toby ; Thorsteinsdottir, Unnur ; Teder-Laving, Maris ; Khaw, Kay-Tee ; Wareham, Nicholas J. ; Zhao, Jing Hua ; Amin, Najaf ; Oostra, Ben A. ; Kraja, Aldi T. ; Province, Michael A. ; Cupples, L. Adrienne ; Heard-Costa, Nancy L. ; Kaprio, Jaakko ; Ripatti, Samuli ; Surakka, Ida ; Collins, Francis S. ; Saramies, Jouko ; Tuomilehto, Jaakko ; Jula, Antti ; Salomaa, Veikko ; Erdmann, Jeanette ; Hengstenberg, Christian ; Loley, Christina ; Schunkert, Heribert ; Lamina, Claudia ; Wichmann, Heinz Erich ; Albrecht, Eva ; Gieger, Christian ; Hicks, Andrew A. ; Johansson, Åsa ; Pramstaller, Peter P. ; Kathiresan, Sekar ; Speliotes, Elizabeth K. ; Penninx, Brenda W. J. H. ; Hartikainen, Anna-Liisa ; Jarvelin, Marjo-Riitta ; Gyllensten, Ulf ; Boomsma, Dorret I. ; Campbell, Harry ; Wilson, James F. ; Chanock, Stephen J. ; Farrall, Martin ; Goel, Anuj ; Medina-Gomez, Carolina ; Rivadeneira, Fernando ; Estrada, Karol ; Uitterlinden, André G. ; Hofman, Albert ; Zillikens, M. Carola ; Heijer, Martin den ; Kiemeney, Lambertus Adrianus ; Maschio, Andrea ; Hall, Per ; Tyrer, Jonathan ; Teumer, Alexander ; Völzke, Henry ; Kovacs, Peter ; Tönjes, Anke ; Mangino, Massimo ; Spector, Tim D. ; Hayward, Caroline ; Rudan, Igor ; Hall, Alistair S. ; Samani, Nilesh J. ; Attwood, Antony Paul ; Sambrook, Jennifer G. ; Hung, Joseph ; Palmer, Lyle J. ; Lokki, Marja-Liisa ; Sinisalo, Juha ; Boucher, Gabrielle ; Huikuri, Heikki ; Lorentzon, Mattias ; Ohlsson, Claes ; Eklund, Niina ; Eriksson, Johan G. ; Barlassina, Cristina ; Rivolta, Carlo ; Nolte, Ilja M. ; Snieder, Harold ; Klauw, Melanie M. van der ; Vliet-Ostaptchouk, Jana V. van ; Gejman, Pablo V. ; Shi, Jianxin ; Jacobs, Kevin B. ; Wang, Zhaoming ; Bakker, Stephan J. L. ; Mateo Leach, Irene ; Navis, Gerjan ; Harst, Pim van der ; Martin, Nicholas Gordon ; Medland, Sarah E. ; Montgomery, Grant W. ; Yang, Jian ; Chasman, Daniel I. ; Ridker, Paul M. ; Rose, Lynda M. ; Lehtimäki, Terho ; Raitakari, Olli ; Absher, Devin ; Iribarren, Carlos ; Basart, Hanneke ; Hovingh, Kees G. ; Hyppönen, Elina ; Power, Chris ; Power, Chris ; Anderson, Denise ; Beilby, John P. ; Hui, Jennie ; Jolley, Jennifer ; Sager, Hendrik ; Bornstein, Stefan R. ; Schwarz, Peter E. H. ; Kristiansson, Kati ; Perola, Markus ; Lindström, Jaana ; Swift, Amy J. ; Uusitupa, Matti ; Atalay, Mustafa ; Lakka, Timo A. ; Rauramaa, Rainer ; Bolton, Jennifer L. ; Fowkes, Gerry ; Fraser, Ross M. ; Price, Jackie F. ; Fischer, Krista ; KrjutÅ¡kov, Kaarel ; Metspalu, Andres ; Mihailov, Evelin ; Langenberg, Claudia ; Luan, Jian'an ; Ong, Ken K. ; Chines, Peter S. ; Keinanen-Kiukaanniemi, Sirkka M. ; Saaristo, Timo E. ; Edkins, Sarah ; Franks, Paul W. ; Hallmans, Göran ; Shungin, Dmitry ; Morris, Andrew David ; Palmer, Colin N. A. ; Erbel, Raimund ; Moebus, Susanne ; Nöthen, Markus Maria ; Pechlivanis, Sonali ; Hveem, Kristian ; Narisu, Narisu ; Hamsten, Anders ; Humphries, Steve E. ; Strawbridge, Rona J. ; Tremoli, Elena ; Grallert, Harald ; Thorand, Barbara ; Illig, Thomas ; Koenig, Wolfgang ; Müller-Nurasyid, Martina ; Peters, Annette ; Böhm, Bernhard O. ; Kleber, Marcus E. ; März, Winfried ; Winkelmann, Bernhard R. ; Kuusisto, Johanna ; Laakso, Markku ; Arveiler, Dominique ; Cesana, Giancarlo ; Kuulasmaa, Kari ; Virtamo, Jarmo ; Yarnell, John W. G. ; Kuh, Diana ; Wong, Andrew ; Lind, Lars ; Faire, Ulf de ; Gigante, Bruna ; Magnusson, Patrik K. E. ; Pedersen, Nancy L. ; Dedoussis, George ; Dimitriou, Maria ; Kolovou, Genovefa ; Kanoni, Stavroula ; Stirrups, Kathleen ; Bonnycastle, Lori L. ; Njølstad, Inger ; Wilsgaard, Tom ; Ganna, Andrea ; Rehnberg, Emil ; Hingorani, Aroon ; Kivimaki, Mika ; Kumari, Meena ; Assimes, Themistocles L. ; Barroso, Inês ; Boehnke, Michael ; Borecki, Ingrid B. ; Deloukas, Panos ; Fox, Caroline S. ; Frayling, Timothy ; Groop, Leif C. ; Haritunians, Talin ; Hunter, David ; Ingelsson, Erik ; Kaplan, Robert ; Mohlke, Karen L. ; North, Kari E. ; Lindgren, Cecilia M. ; Qi, Lu ; Loos, Ruth J. F. ; Heid, Iris M. ; Hirschhorn, Joel N. ; McCarthy, Mark I. ; Abecasis, Gonçalo R. ; Stefansson, Kari ; Strachan, David P. ; Schlessinger, David ; O'Connell, Jeffrey R. ; Duijn, Cornelia M. van
Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
Coutandin, Daniel ; Osterburg, Christian ; Srivastav, Ratnesh Kumar ; Sumyk, Manuela ; Kehrlößer, Sebastian ; Gebel, Jakob ; Tuppi, Marcel ; Hannewald, Jens ; Schäfer, Birgit ; Salah, Eidarus ; Mathea, Sebastian ; Müller-Kuller, Uta ; Doutch, James ; Grez, Manuel ; Knapp, Stefan ; Dötsch, Volker
Mammalian oocytes are arrested in the dictyate stage of meiotic prophase I for long periods of time, during which the high concentration of the p53 family member TAp63α sensitizes them to DNA damage-induced apoptosis. TAp63α is kept in an inactive and exclusively dimeric state but undergoes rapid phosphorylation-induced tetramerization and concomitant activation upon detection of DNA damage. Here we show that the TAp63α dimer is a kinetically trapped state. Activation follows a spring-loaded mechanism not requiring further translation of other cellular factors in oocytes and is associated with unfolding of the inhibitory structure that blocks the tetramerization interface. Using a combination of biophysical methods as well as cell and ovary culture experiments we explain how TAp63α is kept inactive in the absence of DNA damage but causes rapid oocyte elimination in response to a few DNA double strand breaks thereby acting as the key quality control factor in maternal reproduction.
The Kinase Chemogenomic Set (KCGS): an open science resource for kinase vulnerability identification
(2021)
Wells, Carrow I. ; Al-Ali, Hassan ; Andrews, David M. ; Asquith, Christopher R. M. ; Axtman, Alison D. ; Đikić, Ivan ; Ebner, Daniel ; Ettmayer, Peter ; Fischer, Christian ; Frederiksen, Mathias ; Futrell, Robert E. ; Gray, Nathanael S. ; Hatch, Stephanie B. ; Knapp, Stefan ; Lücking, Ulrich ; Michaelides, Michael ; Mills, Caitlin E. ; Müller, Susanne ; Owen, Dafydd R. ; Picado, Alfredo ; Saikatendu, Kumar S. ; Schröder, Martin ; Stolz, Alexandra ; Tellechea, Mariana ; Turunen, Brandon J. ; Vilar, Santiago ; Wang, Jinhua ; Zuercher, William J. ; Willson, Timothy M. ; Drewry, David H.
We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS), current Version 1.0, is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.
The ICON single-column mode
(2021)
Bašták Ďurán, Ivan ; Köhler, Martin ; Eichhorn-Müller, Astrid ; Maurer, Vera ; Schmidli, Jürg ; Schomburg, Annika ; Klocke, Daniel ; Göcke, Tobias ; Schäfer, Sophia ; Schlemmer, Linda ; Dewani, Noviana
The single-column mode (SCM) of the ICON (ICOsahedral Nonhydrostatic) modeling framework is presented. The primary purpose of the ICON SCM is to use it as a tool for research, model evaluation and development. Thanks to the simplified geometry of the ICON SCM, various aspects of the ICON model, in particular the model physics, can be studied in a well-controlled environment. Additionally, the ICON SCM has a reduced computational cost and a low data storage demand. The ICON SCM can be utilized for idealized cases—several well-established cases are already included—or for semi-realistic cases based on analyses or model forecasts. As the case setup is defined by a single NetCDF file, new cases can be prepared easily by the modification of this file. We demonstrate the usage of the ICON SCM for different idealized cases such as shallow convection, stratocumulus clouds, and radiative transfer. Additionally, the ICON SCM is tested for a semi-realistic case together with an equivalent three-dimensional setup and the large eddy simulation mode of ICON. Such consistent comparisons across the hierarchy of ICON configurations are very helpful for model development. The ICON SCM will be implemented into the operational ICON model and will serve as an additional tool for advancing the development of the ICON model.
Müller-von der Grün, Jens ; Winkelmann, Anne Ria ; Burck, Iris ; Martin, Daniel ; Rödel, Franz ; Wild, Peter Johannes ; Bankov, Katrin ; Weigert, Andreas ; Kur, Ivan ; Brandts, Christian Hubertus ; Filmann, Sonja Natalie ; Issing, Christian ; Thönissen, Philipp Nikolaus ; Tanneberger, Anna Maria ; Rödel, Claus ; Ghanaati, Shahram Michael ; Balermpas, Panagiotis
Background: To study neoadjuvant chemoradiotherapy (nCRT) and potential predictive factors for response in locally advanced oral cavity cancer (LA-OCC).
Methods: The INVERT trial is an ongoing single-center, prospective phase 2, proof-of-principle trial. Operable patients with stage III-IVA squamous cell carcinomas of the oral cavity were eligible and received nCRT consisting of 60 Gy with concomitant cisplatin and 5-fluorouracil. Surgery was scheduled 6-8 weeks after completion of nCRT. Explorative, multiplex immunohistochemistry (IHC) was performed on pretreatment tumor specimen, and diffusion-weighted magnetic resonance imaging (DW-MRI) was conducted prior to, during nCRT (day 15), and before surgery to identify potential predictive biomarkers and imaging features. Primary endpoint was the pathological complete response (pCR) rate.
Results: Seventeen patients with stage IVA OCC were included in this interim analysis. All patients completed nCRT. One patient died from pneumonia 10 weeks after nCRT before surgery. Complete tumor resection (R0) was achieved in 16/17 patients, of whom 7 (41%, 95% CI: 18-67%) showed pCR. According to the Clavien-Dindo classification, grade 3a and 3b complications were found in 4 (25%) and 5 (31%) patients, respectively; grade 4-5 complications did not occur. Increased changes in the apparent diffusion coefficient signal intensities between MRI at day 15 of nCRT and before surgery were associated with better response (p=0.022). Higher abundances of programmed cell death protein 1 (PD1) positive cytotoxic T-cells (p=0.012), PD1+ macrophages (p=0.046), and cancer-associated fibroblasts (CAFs, p=0.036) were associated with incomplete response to nCRT.
Conclusion: nCRT for LA-OCC followed by radical surgery is feasible and shows high response rates. Larger patient cohorts from randomized trials are needed to further investigate nCRT and predictive biomarkers such as changes in DW-MRI signal intensities, tumor infiltrating immune cells, and CAFs.
Heitel, Pascal ; Faudone, Giuseppe ; Helmstädter, Moritz ; Schmidt, Jurema ; Kaiser, Astrid ; Tjaden, Amelie ; Schröder, Martin ; Müller, Susanne ; Schierle, Simone ; Pollinger, Julius Carl ; Merk, Daniel
Non-alcoholic steatohepatitis (NASH) - a hepatic manifestation of the metabolic syndrome - is a multifactorial disease with alarming global prevalence. It involves steatosis, inflammation and fibrosis in the liver, thus demanding multiple modes of action for robust therapeutic efficacy. Aiming to fuse complementary validated anti-NASH strategies in a single molecule, we have designed and systematically optimized a scaffold for triple activation of farnesoid X receptor (FXR), peroxisome proliferator-activated receptor (PPAR) α and PPARδ. Pilot profiling of the resulting triple modulator demonstrated target engagement in native cellular settings and in mice, rendering it a suitable tool to probe the triple modulator concept in vivo. In DIO NASH in mice, the triple agonist counteracted hepatic inflammation and reversed hepatic fibrosis highlighting the potential of designed polypharmacology in NASH.
Willems, Laurent Maximilian ; Rosenow, Felix ; Schubert-Bast, Susanne ; Kurlemann, Gerhard ; Zöllner, Johann Philipp ; Bast, Thomas ; Bertsche, Astrid ; Bettendorf, Ulrich ; Ebrahimi-Fakhari, Daniel ; Grau, Janina ; Hahn, Andreas ; Hartmann, Hans ; Hertzberg, Christoph ; Hornemann, Frauke ; Immisch, Ilka ; Jacobs-LeVan, Julia ; Klein, Karl Martin ; Klotz, Kerstin Alexandra ; Kluger, Gerhard ; Knake, Susanne ; Knuf, Markus ; Marquard, Klaus ; Mayer, Thomas ; Meyer, Sascha ; Muhle, Hiltrud ; Müller-Schlüter, Karen ; Podewils, Felix von ; Ruf, Susanne ; Sauter, Matthias ; Schäfer, Hannah ; Schlump, Jan-Ulrich ; Syrbe, Steffen ; Thiels, Charlotte ; Trollmann, Regina ; Wiemer-Kruel, Adelheid ; Wilken, Bernd ; Zukunft, Bianca ; Strzelczyk, Adam
Background: The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder. Objective: The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient’s perspective. Methods: A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC. Results: Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m2 (median: 5.6 mg/m2, range 2.0–15.1 mg/m2) in children and adolescents and 4 ± 2.1 mg/m2 (median: 3.7 mg/m2, range 0.8–10.1 mg/m2) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items ‘tiredness’, ‘skin problems’ and ‘mouth/gum problems’, which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE. Conclusions: From the patients’ perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis.
Bruns, Nora ; Willemsen, Lea Y. ; Holtkamp, Katharina ; Kamp, Oliver ; Dudda, Marcel ; Kowall, Bernd ; Stang, Andreas ; Hey, Florian ; Blankenburg, Judith ; Sabir, Hemmen ; Eifinger, Frank ; Fuchs, Hans ; Haase, Roland ; Andrée, Clemens ; Heldmann, Michael ; Potratz, Jenny Charlotte ; Kurz, Daniel ; Schumann, Anja ; Müller-Knapp, Merle ; Mand, Nadine ; Doerfel, Claus ; Dahlem, Peter ; Rothoeft, Tobias ; Ohlert, Manuel ; Silkenbäumer, Katrin ; Dohle, Frank ; Indraswari, Fithri ; Niemann, Frank ; Jahn, Peter ; Merker, Michael ; Braun, Nicole ; Nunez, Francisco Brevis ; Engler, Matthias ; Heimann, Konrad ; Wolf, Gerhard K ; Wulf, Dominik ; Hankel, Saskia ; Freymann, Holger ; Allgaier, Nicolas ; Knirsch, Felix ; Dercks, Martin ; Reinhard, Julia ; Hoppenz, Marc ; Felderhoff-Müser, Ursula ; Dohna-Schwake, Christian
Children’s and adolescents’ lives drastically changed during COVID lockdowns worldwide. To compare accident- and injury-related admissions to pediatric intensive care units (PICU) during the first German COVID lockdown with previous years, we conducted a retrospective multicenter study among 37 PICUs (21.5% of German PICU capacities). A total of 1444 admissions after accidents or injuries during the first lockdown period and matched periods of 2017–2019 were reported and standardized morbidity ratios (SMR) were calculated. Total PICU admissions due to accidents/injuries declined from an average of 366 to 346 (SMR 0.95 (CI 0.85–1.05)). Admissions with trauma increased from 196 to 212 (1.07 (0.93–1.23). Traffic accidents and school/kindergarten accidents decreased (0.77 (0.57–1.02 and 0.26 (0.05–0.75)), whereas household and leisure accidents increased (1.33 (1.06–1.66) and 1.34 (1.06–1.67)). Less neurosurgeries and more visceral surgeries were performed (0.69 (0.38–1.16) and 2.09 (1.19–3.39)). Non-accidental non-suicidal injuries declined (0.73 (0.42–1.17)). Suicide attempts increased in adolescent boys (1.38 (0.51–3.02)), but decreased in adolescent girls (0.56 (0.32–0.79)). In summary, changed trauma mechanisms entailed different surgeries compared to previous years. We found no evidence for an increase in child abuse cases requiring intensive care. The increase in suicide attempts among boys demands investigation.
Nußer, Ronja ; Bianco, Giovanni ; Kraus, Daniel ; Larrieu, Laurent ; Feldhaar, Heike ; Schleuning, Matthias ; Müller, Jörg
Tree-related microhabitats (TreMs) describe the microhabitats that a tree can provide for a multitude of other taxonomic groups and have been proposed as an important indicator for forest biodiversity (Asbeck et al., 2021). So far, the focus of TreM studies has been on temperate forests, although many trees in the tropics harbour exceptionally high numbers of TreMs. In this study, TreMs in the lowland tropical forests of the Choco (Ecuador) and in the mountain tropical forests of Mount Kilimanjaro (Tanzania) were surveyed. Our results extend the existing typology of TreMs of Larrieu et al. (2018) to include tropical forests and enabled a comparison of the relative recordings and diversity of TreMs between tropical and temperate forests. A new TreM form, Root formations, and three new TreM groups, concavities build by fruits or leaves, dendrotelms, and root formations, were established. In total, 15 new TreM types in five different TreM groups were specified. The relative recordings of most TreMs were similar between tropical and temperate forests. However, ivy and lianas, and ferns were more common in the lowland rainforest than in temperate forests, and bark microsoil, limb breakage, and foliose and fruticose lichens in tropical montane forest than in lowland rainforest. Mountain tropical forests hosted the highest diversity for common and dominant TreM types, and lowland tropical forest the highest diversity for rare TreMs. Our extended typology of tree-related microhabitats can support studies of forest-dwelling biodiversity in tropical forests. Specifically, given the ongoing threat to tropical forests, TreMs can serve as an additional tool allowing rapid assessments of biodiversity in these hyperdiverse ecosystems.
Maurer, Gabriele D. ; Brucker, Daniel P. ; Bähr, Roy Oliver ; Harter, Patrick Nikolaus ; Hattingen, Elke ; Walenta, Stefan ; Müller-Klieser, Wolfgang ; Steinbach, Joachim Peter ; Rieger, Johannes
Background: Even in the presence of oxygen, malignant cells often highly depend on glycolysis for energy generation, a phenomenon known as the Warburg effect. One strategy targeting this metabolic phenotype is glucose restriction by administration of a high-fat, low-carbohydrate (ketogenic) diet. Under these conditions, ketone bodies are generated serving as an important energy source at least for non-transformed cells. Methods: To investigate whether a ketogenic diet might selectively impair energy metabolism in tumor cells, we characterized in vitro effects of the principle ketone body 3-hydroxybutyrate in rat hippocampal neurons and five glioma cell lines. In vivo, a non-calorie-restricted ketogenic diet was examined in an orthotopic xenograft glioma mouse model. Results: The ketone body metabolizing enzymes 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and 2), 3-oxoacid-CoA transferase 1 (OXCT1) and acetyl-CoA acetyltransferase 1 (ACAT1) were expressed at the mRNA and protein level in all glioma cell lines. However, no activation of the hypoxia-inducible factor-1alpha (HIF-1alpha) pathway was observed in glioma cells, consistent with the absence of substantial 3-hydroxybutyrate metabolism and subsequent accumulation of succinate. Further, 3-hydroxybutyrate rescued hippocampal neurons from glucose withdrawal-induced cell death but did not protect glioma cell lines. In hypoxia, mRNA expression of OXCT1, ACAT1, BDH1 and 2 was downregulated. In vivo, the ketogenic diet led to a robust increase of blood 3-hydroxybutyrate, but did not alter blood glucose levels or improve survival. Conclusion: In summary, glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodies in vitro, suggesting a potential disadvantage of tumor cells compared to normal cells under a carbohydrate-restricted ketogenic diet. Further investigations are necessary to identify co-treatment modalities, e.g. glycolysis inhibitors or antiangiogenic agents that efficiently target non-oxidative pathways.
Glatzel, Daniel Karl ; Koeberle, Andreas ; Pein, Helmut ; Löser, Konstantin ; Stark, Anna ; Keksel, Nelli ; Werz, Oliver ; Müller, Rolf ; Bischoff, Iris ; Fürst, Robert
The enzyme acetyl-CoA carboxylase (ACC) plays a crucial role in fatty acid metabolism. In recent years, ACC has been recognized as a promising drug target for treating different diseases. However, the role of ACC in vascular endothelial cells (ECs) has been neglected so far. To characterize the role of ACC, we used the ACC inhibitor, soraphen A, as a chemical tool, and also a gene silencing approach. We found that ACC1 was the predominant isoform in human umbilical vein ECs as well as in human microvascular ECs and that soraphen A reduced the levels of malonyl-CoA. We revealed that ACC inhibition shifted the lipid composition of EC membranes. Accordingly, membrane fluidity, filopodia formation, and migratory capacity were reduced. The antimigratory action of soraphen A depended on an increase in the cellular proportion of PUFAs and, most importantly, on a decreased level of phosphatidylglycerol. Our study provides a causal link between ACC, membrane lipid composition, and cell migration in ECs. Soraphen A represents a useful chemical tool to investigate the role of fatty acid metabolism in ECs and ACC inhibition offers a new and valuable therapeutic perspective for the treatment of EC migration-related diseases.
Stabilization exercise (SE) is evident for the management of chronic non-specific low back pain (LBP). The optimal dose-response-relationship for the utmost treatment success is, thus, still unknown. The purpose is to systematically review the dose-response-relationship of stabilisation exercises on pain and disability in patients with chronic non-specific LBP. A systematic review with meta-regression was conducted (Pubmed, Web of Knowledge, Cochrane). Eligibility criteria were RCTs on patients with chronic non-specific LBP, written in English/German and adopting a longitudinal core-specific/stabilising/motor control exercise intervention with at least one outcome for pain intensity and/or disability. Meta-regressions (dependent variable = effect sizes (Cohens d) of the interventions (for pain and for disability), independent variable = training characteristics (duration, frequency, time per session)), and controlled for (low) study quality (PEDro) and (low) sample sizes (n) were conducted to reveal the optimal dose required for therapy success. From the 3,415 studies initially selected, 50 studies (n = 2,786 LBP patients) were included. N = 1,239 patients received SE. Training duration was 7.0 ± 3.3 weeks, training frequency was 3.1 ± 1.8 sessions per week with a mean training time of 44.6 ± 18.0 min per session. The meta-regressions’ mean effect size was d = 1.80 (pain) and d = 1.70 (disability). Total R2 was 0.445 and 0.17. Moderate quality evidence (R2 = 0.231) revealed that a training duration of 20 to 30 min elicited the largest effect (both in pain and disability, logarithmic association). Low quality evidence (R2 = 0.125) revealed that training 3 to 5 times per week led to the largest effect of SE in patients with chronic non-specific LBP (inverted U-shaped association). In patients with non-specific chronic LBP, stabilization exercise with a training frequency of 3 to 5 times per week (Grade C) and a training time of 20 to 30 min per session (Grade A) elicited the largest effect on pain and disability.
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.
Müller, Lukas ; Mähringer-Kunz, Aline ; Auer, Timo Alexander ; Fehrenbach, Uli ; Gebauer, Bernhard ; Haubold, Johannes ; Schaarschmidt, Benedikt Michael Sebastian ; Kim, Moon-Sung ; Hosch, René ; Nensa, Felix ; Kleesiek, Jens Philipp ; Diallo, Thierno Diawo ; Eisenblätter, Michel ; Kuzior, Hanna ; Röhlen, Natascha ; Bettinger, Dominik ; Steinle, Verena Maria ; Mayer, Philipp ; Zopfs, David ; Pinto dos Santos, Daniel ; Klöckner, Roman Trutz
Highlights:
• Assessment of body composition parameters in a large cohort of patients with HCC undergoing TACE.
• Fully automated artificial intelligence-based quantitative 3D volumetry of abdominal cavity tissue composition.
• Skeletal muscle volume and related parameters were independent prognostic factors in patients with HCC undergoing TACE.
Background & Aims: Body composition assessment (BCA) parameters have recently been identified as relevant prognostic factors for patients with hepatocellular carcinoma (HCC). Herein, we aimed to investigate the role of BCA parameters for prognosis prediction in patients with HCC undergoing transarterial chemoembolization (TACE).
Methods: This retrospective multicenter study included a total of 754 treatment-naïve patients with HCC who underwent TACE at six tertiary care centers between 2010–2020. Fully automated artificial intelligence-based quantitative 3D volumetry of abdominal cavity tissue composition was performed to assess skeletal muscle volume (SM), total adipose tissue (TAT), intra- and intermuscular adipose tissue, visceral adipose tissue, and subcutaneous adipose tissue (SAT) on pre-intervention computed tomography scans. BCA parameters were normalized to the slice number of the abdominal cavity. We assessed the influence of BCA parameters on median overall survival and performed multivariate analysis including established estimates of survival.
Results: Univariate survival analysis revealed that impaired median overall survival was predicted by low SM (p <0.001), high TAT volume (p = 0.013), and high SAT volume (p = 0.006). In multivariate survival analysis, SM remained an independent prognostic factor (p = 0.039), while TAT and SAT volumes no longer showed predictive ability. This predictive role of SM was confirmed in a subgroup analysis of patients with BCLC stage B.
Conclusions: SM is an independent prognostic factor for survival prediction. Thus, the integration of SM into novel scoring systems could potentially improve survival prediction and clinical decision-making. Fully automated approaches are needed to foster the implementation of this imaging biomarker into daily routine.
Impact and implications: Body composition assessment parameters, especially skeletal muscle volume, have been identified as relevant prognostic factors for many diseases and treatments. In this study, skeletal muscle volume has been identified as an independent prognostic factor for patients with hepatocellular carcinoma undergoing transarterial chemoembolization. Therefore, skeletal muscle volume as a metaparameter could play a role as an opportunistic biomarker in holistic patient assessment and be integrated into decision support systems. Workflow integration with artificial intelligence is essential for automated, quantitative body composition assessment, enabling broad availability in multidisciplinary case discussions.