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2,039 results on '"Jäger AT"'

1. Incidence and clinical spectrum of rhabdomyolysis in general neurology: a retrospective cohort study

Author: Jakob Rath, Karl Bointner, Hakan Cetin, Rosa Weng, Lorina Gopp, Fiona Jäger, Thomas Berger, Fritz Zimprich, Chiara Paternostro, Martin Krenn, Gudrun Zulehner, and Matthias Tomschik
Subjects: Adult, Male, medicine.medical_specialty, Neurology, Rhabdomyolysis, Muscular Diseases, Internal medicine, medicine, Humans, Creatine Kinase, Stroke, Genetics (clinical), Aged, Retrospective Studies, biology, business.industry, Incidence, Incidence (epidemiology), Acute kidney injury, Retrospective cohort study, Acute Kidney Injury, Middle Aged, medicine.disease, Pediatrics, Perinatology and Child Health, Cohort, biology.protein, Female, Creatine kinase, Neurology (clinical), Nervous System Diseases, business
Abstract: The objective of this retrospective cohort study was to evaluate demographic, clinical and laboratory characteristics of patients with rhabdomyolysis as defined by a serum creatine kinase (sCK) activity > 950 U/L. A total of 248 patients were recruited from the Department of Neurology, Medical University of Vienna, between 01/2000 and 12/2017, with a median sCK activity of 2,160 U/l (IQR 1,342–4,786). Seizures (31.9%), illicit drugs/alcohol (9.7%) and exercise (8.5%) were the most common trigger factors. Rhabdomyolysis incidence rates in specific neurological diseases as estimated by the ratio between rhabdomyolysis cases and the total number of cases with the corresponding disease were highest in myopathies (49.8/1,000 person-years, 95% CI 32.3–67.4), followed by epilepsy (16.4/1,000 person-years, 95% CI 12.8–20.0) and stroke (11.9/1,000 person-years, 95% CI 8.4–15.4). The half-life of sCK activity was 1.5 days in the total cohort. In myopathies, sCK activity was significantly higher as compared to other disease entities 7 days after the peak measurement (p = 0.0023). Acute kidney injury (AKI) developed in 18 patients (7.3%) with no AKI-related deaths during the study period. In conclusion, rhabdomyolysis occurred in a broad range of neurological entities but was associated with a favorable prognosis in most cases rarely resulting in AKI and death.
Published: 2021
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2. INR and not bilirubin levels predict postoperative morbidity in patients with malignant obstructive jaundice

Author: Stephan Schorn, Güralp O. Ceyhan, Carsten Jäger, Ihsan Ekin Demir, Helmut Friess, Florian Scheufele, E. Demir, Mine Sargut, and L Aichinger
Subjects: Male, medicine.medical_specialty, Bilirubin, medicine.medical_treatment, Kaplan-Meier Estimate, Malignancy, behavioral disciplines and activities, Pancreaticoduodenectomy, chemistry.chemical_compound, Predictive Value of Tests, Pancreatic cancer, medicine, Humans, In patient, International Normalized Ratio, Aged, Retrospective Studies, business.industry, General Medicine, medicine.disease, Survival Analysis, Surgery, Pancreatic Neoplasms, Jaundice, Obstructive, chemistry, Pancreatic fistula, Drainage, Female, Obstructive jaundice, Bilirubin levels, business
Abstract: There are no established predictors for deciding between upfront surgery and PBD in pancreatic head malignancy. Once PBD is present, the ideal drainage-time remains elusive. The aim was, to identify predictors in jaundiced patients and ideal PBD-duration.Analysis of 304 patients with pancreatic head malignancy (56% with PBD, n = 170) undergoing pancreaticoduodenectomy was performed. Postoperative morbidity and survival were analyzed.Postoperative complications increased after PBD (98.2% vs. 88.8%; p 0.001). Patients with PBD received more postoperative antibiotics (42.4% vs. 21.6%; p 0.001) and wound infections were increased (21.4% vs. 9.4%; p = 0.006). INR predicted postoperative morbidity (p = 0.026), whereas serum-bilirubin (p = 0.708), leucocytes (p = 0.158) and MELD-score (p = 0.444) had no impact. Complications were not different between long (4 weeks) and short (4 weeks) PBD-duration (p = 0.608). No life-threatening complications (CDIV + V) occurred after long drainage (0.0% vs. 8.9%; p = 0.028) and long-term survival was not compromised.INR is a suitable predictor for postoperative outcome, while serum-bilirubin levels had no predictive value. The INR can help deciding between PBD and upfront surgery. If PBD is inevitable, drainage duration of4 weeks reduced major complications.Clinical study.
Published: 2021
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3. Severe Dysbiosis and Specific Haemophilus and Neisseria Signatures as Hallmarks of the Oropharyngeal Microbiome in Critically Ill Coronavirus Disease 2019 (COVID-19) Patients

Author: Roman Rohrbach, Silvana Hengler, Alwin Krämer, Rogier Gaiser, Michael W. Müller, Felix J.F. Herth, Jochen Schneider, Dina Khalid, Nyssa Cullin, Theresa Hippchen, Christoph K. Stein-Thoeringer, Peter Hau, Stamatia M Papagiannarou, Matthias P. Ebert, Dirk Jäger, Yascha Khodamoradi, Andreas Teufel, Maria J G T Vehreschild, Ralf Bartenschlager, Bernd Salzberger, Daniel Duerschmied, Juliana de Castilhos, Andreas Hiergeist, Paul Schnitzler, André Gessner, Eran Elinav, Melanie Neubauer, Sabine Schmidt, Hendrik Poeck, Roland M. Schmid, Hanna Schumacher, Uta Merle, Tonia Müller-Esch, Bettina Beuthien-Baumann, Sabrina Kunz, Eli Zamir, and Johann F Eberhardt
Subjects: Adult, Microbiology (medical), medicine.medical_specialty, medicine.drug_class, Critical Illness, medicine.medical_treatment, Antibiotics, Haemophilus, microbiome, medicine.disease_cause, Internal medicine, intensive medical care, Major Article, medicine, Humans, Microbiome, Coronavirus, Mechanical ventilation, biology, SARS-CoV-2, business.industry, Microbiota, COVID-19, dysbiosis, medicine.disease, biology.organism_classification, Cross-Sectional Studies, AcademicSubjects/MED00290, machine learning, Infectious Diseases, Respiratory virus, Neisseria, business, Dysbiosis
Abstract: Background At the entry site of respiratory virus infections, the oropharyngeal microbiome has been proposed as a major hub integrating viral and host immune signals. Early studies suggested that infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with changes of the upper and lower airway microbiome, and that specific microbial signatures may predict coronavirus disease 2019 (COVID-19) illness. However, the results are not conclusive, as critical illness can drastically alter a patient’s microbiome through multiple confounders. Methods To study oropharyngeal microbiome profiles in SARS-CoV-2 infection, clinical confounders, and prediction models in COVID-19, we performed a multicenter, cross-sectional clinical study analyzing oropharyngeal microbial metagenomes in healthy adults, patients with non-SARS-CoV-2 infections, or with mild, moderate, and severe COVID-19 (n = 322 participants). Results In contrast to mild infections, patients admitted to a hospital with moderate or severe COVID-19 showed dysbiotic microbial configurations, which were significantly pronounced in patients treated with broad-spectrum antibiotics, receiving invasive mechanical ventilation, or when sampling was performed during prolonged hospitalization. In contrast, specimens collected early after admission allowed us to segregate microbiome features predictive of hospital COVID-19 mortality utilizing machine learning models. Taxonomic signatures were found to perform better than models utilizing clinical variables with Neisseria and Haemophilus species abundances as most important features. Conclusions In addition to the infection per se, several factors shape the oropharyngeal microbiome of severely affected COVID-19 patients and deserve consideration in the interpretation of the role of the microbiome in severe COVID-19. Nevertheless, we were able to extract microbial features that can help to predict clinical outcomes.
Published: 2021
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4. Direct cardiovascular complications and indirect collateral damage during the COVID-19 pandemic

Author: Edita Pogran, Achim Leo Burger, Johann Wojta, Christoph C Kaufmann, Serdar Farhan, Bernhard Jäger, Amro Ahmed, and Kurt Huber
Subjects: medicine.medical_specialty, Acute coronary syndrome, Myocarditis, Interventional procedure, Heart disease, Myocardial Infarction, Review Article, Disease, Pandemic, medicine, Humans, Myocardial infarction, Risk factor, Intensive care medicine, Pandemics, SARS-CoV-2, business.industry, Cardiogenic shock, COVID-19, Arrhythmias, Cardiac, General Medicine, medicine.disease, Cardiovascular Diseases, business, Arrhythmia, Venous thromboembolism
Abstract: The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), puts a heavy strain on healthcare systems around the globe with high numbers of infected patients. Pre-existing cardiovascular disease is a major risk factor for a severe clinical course of COVID-19 and is associated with adverse outcome. COVID-19 may directly exacerbate underlying heart disease and is frequently aggravated by cardiovascular complications, including arterial and venous thromboembolic events, malignant arrhythmia and myocardial injury. In addition to these direct cardiac manifestations of COVID-19, patients with cardiovascular disease face further indirect consequences of the pandemic, as the respective resources in the healthcare systems need to be redirected to cope with the high numbers of infected patients. Consecutively, a substantial decrease in cardiac procedures was reported during the pandemic with lower numbers of coronary angiographies and device implantations worldwide. As a consequence an increased number of out-of-hospital cardiac arrests, late-comers with subacute myocardial infarction and of patients presenting in cardiogenic shock or preshock were observed. Maintenance of high-quality cardiac care by avoiding a reduction of cardiac services is of utmost importance, especially in times of a pandemic.
Published: 2021
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5. COVID-19-related severe MS exacerbation with life-threatening Takotsubo cardiomyopathy in a previously stable patient and interference of MS therapy with long-term immunity against SARS-CoV-2

Author: Christoph Gumbinger, Lorenz H. Lehmann, Laura Bettina Jäger, Brigitte Wildemann, Florian Andre, Andrea Viehöver, Paul Schnitzler, Norbert Frey, and Sven Jarius
Subjects: Neurology, Neuroradiology, Neurosciences, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Exacerbation, SARS-CoV-2, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Cardiomyopathy, COVID-19, Long term immunity, Interference (genetic), medicine.disease, Letter to the Editors, Takotsubo Cardiomyopathy, Immunology, Humans, Medicine, Neurology (clinical), business
Published: 2021
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6. Does high adherence to contact precautions lead to low in-hospital transmission of multi-drug-resistant micro-organisms in the endemic setting?

Author: Andreas F. Widmer, Adrian Egli, S. Jäger, Jan A Roth, Marc Dangel, Andrea C. Büchler, Reno Frei, and Helena M. B. Seth-Smith
Subjects: Methicillin-Resistant Staphylococcus aureus, Microbiology (medical), medicine.medical_specialty, medicine.disease_cause, Vancomycin-Resistant Enterococci, Internal medicine, Scabies, Humans, Medicine, Cross Infection, Infection Control, business.industry, Transmission (medicine), Incidence (epidemiology), General Medicine, Staphylococcal Infections, medicine.disease, Hospitals, Checklist, Infectious Diseases, Contact precautions, Pharmaceutical Preparations, Staphylococcus aureus, Norovirus, Multi drug resistant, business
Abstract: Summary Background Conflicting results have been published on the impact of contact precautions (CPs) on reduction of transmission of multi-drug-resistant micro-organisms (MDROs) in the endemic setting. Ambiguous definitions coupled with low adherence partly explain these differences. Aim We prospectively monitored the level of adherence to CPs and aimed to relate it to in-hospital transmission of MDROs. Methods Between January 2016 and March 2018, all patients under CPs underwent continuous monitoring of adherence to CPs by routine on-site visits on days 0, 3 and 7 after initiating CPs using a standardized checklist. The protocol included 10 interventions that were routinely checked such as CP sign at the door as well as wearing of gowns and gloves upon entry to the patient room. Patients requiring CPs were defined as colonized or infected with MDROs (meticillin-resistant Staphylococcus aureus (MRSA), non-Escherichia coli extended-spectrum beta lactamase (ESBL) Enterobacterales, vancomycin-resistant enterococci (VRE) and carbapenem-resistant Gram-negative micro-organisms (CRGN)) as well as patients infected with respiratory viruses, norovirus, scabies and hypervirulent strains of Clostridioides difficile. Findings Overall, data from 13,756 CP records from 1378 visits of 812 patients were analysed. Adherence varied between 93% and 100% for each intervention, except for “separate space for contaminated material” with an adherence of 5.3–6.1%. The incidence of in-hospital transmission during the study period was extremely low for MRSA, VRE, non-E.coli ESBL Enterobacterales and CRGN with 0.00–0.064 cases/1000 patient days. Conclusion High adherence coupled with continuous monitoring of CPs correlated with a very low in-hospital transmission rate. These results indicate that CPs are highly effective if routine monitoring of adherence is implemented.
Published: 2021
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7. Milk intake and incident stroke and CHD in populations of European descent: a Mendelian randomisation study

Author: Emily Sonestedt, Krassimira Aleksandrova, H. Boeing, Fumiaki Imamura, L E T Vissers, Stephen Burgess, Anne Tjønneland, Cecilie Kyrø, E. Riboli, Y. T. van der Schouw, Liher Imaz, Catalina Bonet, John Danesh, W M M Verschuren, J.M.A. Boer, Nita G. Forouhi, I. Sluijs, Ioanna Tzoulaki, Olle Melander, Elisabete Weiderpass, Adam S. Butterworth, M J Sánches, M-D Chirlaque, M I Conchi, Matthias B. Schulze, Heinz Freisling, Dagfinn Aune, S Jäger, Salvatore Panico, Tammy Y.N. Tong, Vittorio Krogh, C C Dahm, Giovanna Masala, Torbjörn K. Nilsson, Frida Renström, Nicholas J. Wareham, Kim Overvad, Aurora Perez-Cornago, Vissers, LET [0000-0001-9044-0744], Freisling, H [0000-0001-8648-4998], Dahm, CC [0000-0003-0481-2893], Tong, TYN [0000-0002-0284-8959], Kyrø, C [0000-0002-9083-8960], van der Schouw, YT [0000-0002-4605-435X], and Apollo - University of Cambridge Repository
Subjects: European People, 030309 nutrition & dietetics, Multifunction cardiogram, Medicine (miscellaneous), ISCHEMIC-HEART-DISEASE, 0302 clinical medicine, Mendelian Randomization, Risk Factors, Neoplasms, PARTICIPANTS, Prospective Studies, Mendelian randomisation, Stroke, 2. Zero hunger, RISK, 0303 health sciences, Nutrition and Dietetics, Confounding, Mendelian Randomization Analysis, stroke, 3. Good health, PROSTATE-CANCER, Milk, Cardiovascular Diseases, LACTASE PERSISTENCE GENOTYPE, LIFE-STYLE, HEALTH, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, 030209 endocrinology & metabolism, Dairy, 03 medical and health sciences, Internal medicine, Mendelian randomization, BLOOD-PRESSURE RESPONSE, 0702 Animal Production, medicine, Humans, Animals, COHORT, cardiovascular diseases, Science & Technology, Nutrition & Dietetics, Proportional hazards model, business.industry, CONSUMPTION, Odds ratio, medicine.disease, Lactase persistence, CHD, dairy, 1111 Nutrition and Dietetics, business, 0908 Food Sciences
Abstract: We thank all EPIC participants and staff for their contribution to the study. We also thank staff from the EPIC-CVD coordinating centres for sample preparation and data handling. This research has been conducted using the UK Biobank Resource (application number 29916). Data on coronary artery disease have been contributed by CARDIoGRAMplusC4D investigators and have been downloaded from www.CARDIOGRAMPLUSC4D.ORG.I Sluijswas supported by a personal Dr. Dekker postdoctoral grant (2015T019) from the Netherlands Heart Foundation. NGF and FI acknowledge core Medical Research Council Epidemiology Unit support (MC_UU_12015/5) and NGF acknowledges NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014). The InterAct project was funded by the EU FP6 programme (grant number LSHM_CT_2006_037197) and provided the biomarker data in the sub-cohort that was used in the current study. These analyses were supported by Cancer Research UK (C8221/A19170). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS) PI13/00061 (EPIC-Granada) and PI13/01162 (EPIC-Murcia), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, ISCIII Health Research Funds RD12/0036/0018 (cofounded by FEDER funds/European Regional Development Fund ERDF) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 for EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK). EPIC-CVD has been supported by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), the European Research Council (268834), the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG13/13/30194 and RG/18/13/33946) and the National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust). The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html. L.E.T.V.analysed the data and drafted the manuscript. L. E. T. V., I. S. and Y. T. vdS. had access to all data for this study. L. E. T. V., I. S., Y. T. vdS., S. B., N. G. F., H. F., F. I., T. K. N., F. R., E. W., K. A., C. D., A. P. C., M. B. S., T. Y. N. T. and A. S. B. contributed to study conception, design and interpretation of data. All authors contributed to critical revision of the manuscript and approval of version to be published., Higher milk intake has been associated with a lower stroke risk, but not with risk of CHD. Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29 328 participants (4611 stroke; 9828 CHD) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD (eight European countries) and European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) case-cohort studies. rs4988235, a lactase persistence (LP) SNP which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777 024 participants (50 804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483 966 participants (61 612 cases) from CARDIoGRAM, UK Biobank, EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD (beta = 13 center dot 7 g/d; 95 % CI 8 center dot 4, 19 center dot 1) and EPIC-NL (36 center dot 8 g/d; 95 % CI 20 center dot 0, 53 center dot 5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/d 1 center dot 05; 95 % CI 0 center dot 94, 1 center dot 16) or CHD (1 center dot 02; 95 % CI 0 center dot 96, 1 center dot 08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (OR 1 center dot 02; 95 % CI 0 center dot 99, 1 center dot 05) or CHD (OR 0 center dot 99; 95 % CI 0 center dot 95, 1 center dot 03). Current Mendelian randomisation analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk., Netherlands Heart Foundation 2015T019, UK Research & Innovation (UKRI) Medical Research Council UK (MRC), European Commission MC_UU_12015/5, NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme IS-BRC-1215-20014, European Commission LSHM_CT_2006_037197, Cancer Research UK C8221/A19170, European Commission European Commission Joint Research Centre, International Agency for Research on Cancer, Danish Cancer Society, Deutsche Krebshilfe German Cancer Research Center (DKFZ) (Germany), Federal Ministry of Education & Research (BMBF), Deutsche Krebshilfe Deutsches Krebsforschungszentrum (Germany), Fondazione AIRC per la ricerca sul cancro Consiglio Nazionale delle Ricerche (CNR), Netherlands Government Netherlands Government, World Cancer Research Fund International (WCRF), Netherlands Government, Instituto de Salud Carlos III PI13/00061 PI13/01162, Junta de Andalucia Regional Government of Asturias (Spain) Regional Government of Basque Country (Spain) Regional Government of Murcia (Spain) Regional Government of Navarra (Spain), ISCIII Health Research Funds (FEDER funds/European Regional Development Fund ERDF) (Spain) RD12/0036/0018, Swedish Cancer Society Swedish Research Council County Council of Skane (Sweden) County Council of Vasterbotten (Sweden), European Commission Framework Programme 7 HEALTH-F2-2012-279233 European Research Council (ERC) European Commission 268834, UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MR/L003120/1 British Heart Foundation RG13/13/30194 RG/18/13/33946 National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust) UK Research & Innovation (UKRI) Medical Research Council UK (MRC) 1000143 MR/M012190/1 Cancer Research UK C8221/A19170 14136 C570/A16491
Published: 2022
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8. Initial Invasive or Conservative Strategy for Stable Coronary Disease

Author: Maron D. J., Hochman J. S., Reynolds H. R., Bangalore S., O'Brien S. M., Boden W. E., Chaitman B. R., Senior R., Lopez-Sendon J., Alexander K. P., Lopes R. D., Shaw L. J., Berger J. S., Newman J. D., Sidhu M. S., Goodman S. G., Ruzyllo W., Gosselin G., Maggioni A. P., White H. D., Bhargava B., Min J. K., John Mancini G. B., Berman D. S., Picard M. H., Kwong R. Y., Ali Z. A., Mark D. B., Spertus J. A., Krishnan M. N., Elghamaz A., Moorthy N., Hueb W. A., Demkow M., Mavromatis K., Bockeria O., Peteiro J., Miller T. D., Szwed H., Doerr R., Keltai M., Selvanayagam J. B., Gabriel Steg P., Held C., Kohsaka S., Mavromichalis S., Kirby R., Jeffries N. O., Harrell F. E., Rockhold F. W., Broderick S., Bruce Ferguson T., Williams D. O., Harrington R. A., Stone G. W., Rosenberg Y, ISCHEMIA Research Group: Joseph Ricci, A Tello Montoliu, A I Robero Aniorte, Abbey Mulder, Abhay A Laddu, Abhinav Goyal, Abhishek Dubey, Abhishek Goyal, Abigail Knighton, Abraham Oomman, Adam J Jaskowiak, Adam Kolodziej, Adam Witkowski, Adnan Hameed, Adriana Anesini, Afshan Hussain, Agne Juceviciene, Agne Urboniene, Agnes Jakal, Agnieszka Szramowska, Ahmad Khairuddin, Ahmed Abdel-Latif, Ahmed Adel, Ahmed Aljzeeri, Ahmed Kamal, Ahmed Talaat, Aimee Mann, Aira Contreras, Ajit Kumar, V K Kumar, Akemi Furukawa, Akshay Bagai, Akvile Smigelskaite, Alain Furber, Alain Rheault, Alaine Melanie Loehr, Alan Rosen, Albert Varga, Albertina Qelaj, Alberto Barioli, Aldo Russo, Alec Moorman, Alejandro Gisbert, Aleksandra Fratczak, Aleksandras Laucevicius, Alena Kuleshova, Alessandro Sionis, Alexander A Sirker, Alexander M Chernyavskiy, Alexandra Craft, Alexandra Vazquez, Alexandre Ciappina Hueb, Alexandre S Colafranseschi, Alexandre Schaan de Quadros, Alexandre Tognon, Ali Alghamdi, Alice Manica Muller, Aline Nogueira Rabaça, Aline Peixoto Deiro, Alison Hallam, Allegra Stone, Allison Schley, Almudena Castro, Alvaro Rabelo Ales, Amanda Germann, Amanda O'Malley, Amar Uxa, Amarachi Ojajuni, Amarino C Oliveira Jr, Amber B Hull, Ambuj Roy, Amer Zarka, Amir Janmohamed, Ammani Brown, Ammy Malinay, Amparo Martinez Monzonis, Amy J Richards, Amy Iskandrian, Amy Ollinger, Ana D Djordjevic-Dikic, Ana Fernández Martínez, Ana Gomes Almeida, Ana Paula Batista, Ana Rita Francisco, Ana S Mladenovic, Ana Santana, Anam Siddiqui, Anastasia M Kuzmina-Krutetskaya, Andras Vertes, Andre S Sousa, Andre Gabriel, André Schmidt, Andrea M Lundeen, Andrea Bartykowszki, Andrea Lorimer, Andrea Mortara, Andrea Pascual, Andreia Coelho, Andreia Rocha, Andrés García-Rincón, Andrew G Howarth, Andrew J Moriarty, Andrew Docherty, Andrew Starovoytov, Andrew Zurick, Andrzej Łabyk, Andrzej Swiatkowski, Andy Lam, Anelise Kawakami, Angela Hoye, Angela Kim, Angelique Smit, Angelo Nobre, Anil V Shah, Anja Ljubez, Anjali Anand, Ankush Sachdeva, Ann Greenberg, Ann Luyten, Ann Ostrander, Anna Di Donato, Anna Cichocka-Radwan, Anna Fojt, Anna Plachcinska, Anna Proietti, Anna Teresinska, Anne Marie Webb, Anne Cartwright, Anne Heath, Anne Mackin, Anong Amaritakomol, Anong Chaiyasri, Anoop Chauhan, Anoop Mathew, Anthony Gemignani, Anto Luigi Andres, Antonia Vega, Antonietta Hansen, Antonino Ginel Iglesias, Antonio Carlos Carvalho, Antonio Di Chiara, Antonio Serra Peñaranda, Antonio Carvalho, Antonio Colombo, Antonio Fiarresga, Anupama Rao, Aquiles Valdespino-Estrada, Araceli Boan, Areef Ishani, Ariel Diaz, Arijit Ghosh, Arintaya Prommintikul, Arline Roberts, Arnold H Seto, Arnold P Good, Arshed Quyyumi, Arthur J Labovitz, Arthur Kerner, Arturo S Campos-Santaolalla, Arunima Misra, Ashok Mukherjee, Ashok Seth, Ashraf Seedhom, Asim N Cheema, Asker Ahmed, Atul Mathur, Atul Verma, Audrey W Leong, Axel Åkerblom, Axelle Fuentes, Aynun Naher, Badhma Valaiyapathi, Baljeet Kaur, Bandula Guruge, Barbara Brzezińska, Barbara Nardi, Bartosz Czarniak, Bebek Singh, Begoña Igual, Bela Merkely, Belen Cid Alvarez, Benjamin J Spooner, Benjamin J W Chow, Benjamin Cheong, Benoy N Shah, Bernard de Bruyne, Bernardas Valecka, Bernhard Jäger, Beth A Archer, Beth Abramson, Beth Jorgenson, Bethany Harvey, Betsy O'Neal, Bev Atkinson, Bev Bozek, Bevin Lang, Bijulal Sasidharan, Bin Yang, Bin Zhang, Binoy Mannekkattukudy Kurian, Bjoern Goebel, Bob Hu, Bogdan A Popescu, Bogdan Crnokrak, Bolin Zhu, Bonnie J Kirby, Brandi D Zimbelman, Brandy Starks, Branko D Beleslin, Brenda Hart, Brian P Shapiro, Brian McCandless, Brianna Wisniewski, Brigham R Smith, Brooks Mirrer, Bruce McManus, Bruce Rutkin, Bruna Edilena Paulino, Bruna Maria Ascoli, Bryn Smith, Byron J Allen, C Michael Gibson, C Noel Bairey Merz, Calin Pop, Cameron Hague, Camila Thais de Ormundo, Candace Gopaul, Candice P Edillo, Carísi A Polanczyk, Carita Krannila, Carla Vicente, Carl-Éric Gagné, Carlo Briguori, Carlos Peña Gil, Carlos Alvarez, Carly Ohmart, Carmen C Beladan, Carmen Ginghina, Carol M Kartje, Caroline Alsweiler, Caroline Brown, Caroline Callison, Caroline Pinheiro, Caroline Rodgers, Caroline Spindler, Carolyn Corbett, Carrie Drum, Casey Riedberger, Catherine Bone, Catherine Fleming, Catherine Gordon, Catherine Jahrsdorfer, Catherine Lemay, Catherine Weick, Cathrine Patten, Cecilia Goletto, Cezary Kepka, Chandini Suvarna, Chang Xu, Chantale Mercure, Charle A Viljoen, Charlene Wiyarand, Charles Jia-Yin Hou, Charles Y Lui, Charles Cannan, Charles Cornet, Charlotte Pirro, Chataroon Rimsukcharoenchai, Chen Wang, Cheng-Ting Tsai, Chen-Yen Chien, Cheryl A Allardyce, Chester M Hedgepeth, Chetan Patel, Chiara Attanasio, Chih-Hsuan Yen, Chi-Ming Chow, Ching Min Er, Ching-Ching Ong, Cholenahally Nanjappa Manjunath, Chris Beck, Chris Buller, Christel Vassaliere, Christian Hamm, Christiano Caldeira, Christie Ballantyne, Christina Björklund, Christine R Hinton, Christine Bergeron, Christine Masson, Christine Roraff, Christine Shelley, Christophe Laure, Christophe Thuaire, Christopher Kinsey, Christopher McFarren, Christopher Spizzieri, Christopher Travill, Chun-Chieh Liu, Chung-Lieh Hung, Chunguang Li, Chun-Ho Yun, Chunli Xia, Ciarra Heard, Cidney Schultz, Clare Venn-Edmonds, Claudia P Hochberg, Claudia Wegmayr, Claudia Cortés, Claudia Escobar, Cláudia Freixo, Claudio T Mesquita, Clemens T Kadalie, Colin Berry, Constance Philander, Corine Thobois, Costantino Costantini, Courtney Page, Craig Atkinson, Craig Barr, Craig Paterson, Cristina Bare, Cynthia Baumann, Cynthia Burman, Dalisa Espinosa, Damien Collison, Dan Deleanu, Dan Elian, Dan Gao, Dana Oliver, Daniel P Vezina, Daniel O'Rourke, Daniele Komar, Danielle Schade, Darrel P Francis, Dastan Malaev, David A Bull, David E Winchester, David P Faxon, David Booth, David Cohen, David DeMets, David Foo, David Schlichting, David Taggart, David Waters, David Wohns, Davis Vo, Dawid Teodorczyk, Dawn Shelstad, Dawn Turnbull, Dayuan Li, Dean Kereiakes, Deborah 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Mohamed, Mahmud Al-Bustami, Majo X Joseph, Malgorzata Frach, Małgorzta Celińska-Spodar, Malte Helm, Manas Chacko, Mandy Murphy, Manitha Vinod, Manjula Rani, Manu Dhawan, Manuela Mombelli, Marcel Weber, Marcello Galvani, Marcelo Jamus Rodrigues, Marcia F Dubin, Marcia F Werner Bayer, Marcin Szkopiak, Marco Antonio Monsalve, Marco Bizzaro Santos, Marco Magnoni, Marco Marini, Marco Sicuro, Marco Zenati, Marcos Valério Coimbra Resende, Marek Roik, Margalit Bentzvi, Margaret Gilsenan, Margaret Iraola, Margot C Quinn, Maria A Alfonso, Maria Antonieta Pereira Moraes, María Dolores Martínez-Ruíz, María Fernanda Canales, Maria Inês Caetano, Maria P Corral, Maria Pérez García, Maria Victoria Actis, Maria Aguirre, Maria Andreasson, Maria Aprile, Maria Colton, Maria Eugenia Martin, Maria Lasala, Maria Lorenzo, Maria Posada, Maria Shier, Maria Thottam, Mariana V Furtado, Mariana Yumi Okada, Marianna D A Dracoulakis, Marianne De Andrade, Mariano Rubio, Marie Essermark, Marielle Scherrer-Crosbie, Marija T Petrovic, Marija Zdravkovic, Marilyn Black, Marina Garcia, Mario J Garcia, Mariola Szulik, Marisa Orgera, Mark A de Belder, Mark Harbinson, Mark Hyun, Mark Peterson, Mark Xavier, Marlowe Mosley, Marta Capinha, Marta Marcinkiewicz-Siemion, Marta Swiderek, Martha Meyer, Martina Ceseri, Martina Tricoli, Marvin Kronenberg, Mary Williams, Mary Ann Champagne, Mary Colleen Rogge, Mary R Soltau, Mary Streif, Massimo Villella, Massoud Leesar, Matei Claudia, Mateusz Solecki, Matías Nicolás Mungo, Matthew Wall Jr, Matthew Budoff, Matthew Jezior, Matthew Luckie, Matthias Friedrich, Mauren P Haeffner, Maximilian Tscharre, Max-Paul Winter, Mayana Almeida, Mayil S Krishnam, Mayuri Patel, Meenakshi Mishra, Megan Manocchia, Meghana Kakade, Melanie J Munro, Melissa D Chaplin, Melissa LeFevre, Mervyn Andiapen, Michael A Gibson, Michael B Rubens, Michael C Turner, Michael D Shapiro, Michael W Lee, Michael Berlowitz, Michael Davidson, Michael Mack, Michael McDaniel, Michael Mumma, Michal Wlodarczyk, Michel G Khouri, Michel S Slama, Michele Rawlins, Michelle M Bonner, Michelle M Seib, Michelle Chang, Michelle Crowder, Michelle Dixon, Michelle Mayon, Michelle McEvoy, Michelle Yee, Miguel M Fernandes, Miguel Nobre Menezes, Miguel Souto Bayarri, Miguel Barrero, Mikhail T Torosoff, Milan R Dobric, Milan Dobric, Milica Nikola Dekleva, Milind Avdhoot Gadkari, Millie Gomez, Min Tun Kyaw, Miriam Brooks, Miroslav Stevo Martinovic, Mitchel B Lustre, Mohammad Tariq Vakani, Mohammad El-Hajjar, Mohammed Al-Amoodi, Mohammed Hussain, Mohammed Saleem, Moisés Blanco-Calvo, Moisés Jiménez-Santos, Mona Bhatia, Monica Rosca, Monika Laukyte, Montserrat Gracida Blanca, Montserrat Vila Perales, Mouaz H Al-Mallah, Moysés de Oliveira Filho, Mpiko Ntsekhe, Muhamed Saric, Mulei Chen, Myriam Brousseau, Myrthes Emy Takiuti, Nada Cemerlic-Adjic, Nadia Asif, Nadia Gakou, Nafisa Hussain, Nana O Katamadze, Nancy L Clapp, Nancy Aedy, Nandita Nataraj, Nanette K Wenger, Naomi Uchida, Nasrul Ismail, Natalia S Oliveira, Natalia de Carvalho Maffei, Natalie Spitzer, Natasha C Putnam, Naved Aslam, Neamat Mowafy, Neeraj Pandit, Neeraj Parakh, Nevena Garcevic, Ngaire Meadows, Nhi N Tran, Nicholas Danchin, Nicki Lakeman, Nicola Johnston, Nicolas W Shammas, Nicole Saint Vrestil, Nicole Deming, Nier Zhong, Niket Patel, Nikola N Boskovic, Nikolaos Karogiannis, Nikos Werner, Nina Johnston, Ning Zhang, Ning Zhou, Niree Hindoyan, Nirmal Kumar, Nitika Chadha, Nitish Naik, Nodira Aripova, Noloyiso Mtana, Nona A Eskelson, Noor Syamira Mokhtar, Noppon Taksaudom, Nor Asiah Basri, Nora Marchelletta, Norma Hogg, Nungshi Jungla, Nuno Ferreira, Oksana A Lubyanaya, Olga B Nikolaeva, Olga Cañavate, Olga Sobrino, Olga Walesiak, Olga Walter, Olga Zdończyk, Olivia J Lim, Olivia Anaya, Olivia Mancilla, Olivier Dubourg, Olugbenga Bello, Omar Almousalli, Omar Thompson, Oni Olurinde, Or Harel, Osama Raheem, Oscar Méndiz, Óscar Prada-Delgado, Oz Shapira, P Christian Schulze, Pachara Panpunuan, Pal Maurovich-Horvat, Pallav Garg, Paloma Moraga, Pam Singh, Pamela Julian, Pamela Ouyang, Pamela Sigel, Pamela Woodard, Panpan Zhou, Paola Emanuela Poggio, Paola Smanio, Paolo Calabro, Paramjit Jeetley, Pascal Goube, Patricia K Nguyen, Patricia Alarie, Patricia Arakelian, Patricia Arsenault, Patricia Blaise, Patricia Brito, Patricia Cowper, Patricia Endsley, Patricia Mieses, Patrick B Alexander, Patrick Donnelly, Patrick Wilmot, Patrycja Lebioda, Paul C Gordon, Paul Der Mesropian, Paul Galiwango, Paul Hauptman, Paul Kennedy, Paula Beardsley, Paula García-González, Paulo Cury Rezende, Paulo Ricardo Caramori, Pavel S Kozlov, Pedro Canas Silva, Pedro Gabriel Melo Barros E Silva, Pedro Píccaro de Oliveira, Pedro Carvalho, Pedro Modas, Pedro Rio, Peeyush Jain, Peiyu He, Peter A McCullough, Peter H Stone, Peter M Pollak, Peter Douglass, Peter Henriksen, Peter OKane, Peter Ong, Philip Jones, Philip Rogal, Philippe Généreux, Philippe Menasche, Philippe Rheault, Phoebe Goold, Pierre Gervais, Pierre Michaud, Pilar Calvillo, Ping Chai, Piotr Jakubowski, Piotr Pruszczyk, Piotr Slomka, Piyamitr Sritara, Poay-Huan Loh, Poonam Sonawane, Pouneh Samadi, Pragnesh P Parikh, Prakash Deedwania, Pranav M Patel, Praneeth Polamuri, Pratiksha Sharma, Precilia Vasquez, Preeti Kamath, Prince Thomas, Priyadarshani Arambam, Puja K Mehta, Purvez Grant, Pushpa Naik, Qi Zhong, Qian Zhao, Qiang Zhou, Qianqian Yuan, Qin Yu, Qingxian Li, Qiulan Xie, Qiutang Zeng, R J Vindhya, R James Gerlach, Rachel King, Rada Vučić, Radmila Lyubarova, Radoslaw Pracon, Raewyn Fisher, Rafael Beyar, Rafael Diaz, Rafael Selgas, Raffaele Bugiardini, Raffaele Fanelli, Raisa Kavalakkat, V S Rajalekshmi, Rajat S Barua, Rajeev Menon, Rajesh Gopalan Nair, Rajesh Francis, Rajiv Narang, Rakesh Yadav, Ralph Alan Huston, T Ramakrishnan, Ramesh de Silva, Rami El Mahmoud, Ramiro Carvalho, Ramon de Jesús-Pérez, Ramona Stevens, Ran Leng, Ranjan Kachru, Ranjit Kumar Nath, Raquel Sanchez, Raven R Dwyer, Raven Lee, Ray Wyman, Raymond C Wong, Raymond W Little, Raymundo Ocaranza Sanchez, Rebecca J Wimmer, Rebecca Bariciano, Rebecca Otis, Rebekah R Herrmann, Reem Yunis, Reinette Hampson, Renato Abdala Karam, Renee C Hessian, Renee Kaneshiro, Reshma Ravindran, Reto Andreas Gamma, Reyna Bhandari, Reza Arsanjani, Ricardo L Lopes, Ricardo Mendes Oliveira, Ricardo Costa, Richa Bhatt, Richard F Davies, Richard H J Trimlett, Richard Goldweit, Rik Hermanides, Rine Nakanishi, Rinu R Sidh, Risha Patel, Rita Coram, Rizwan A Siddiqui, Rob S Beanlands, Robert J Hamburger, Robert K Riezebos, Robert M Donnino, Robert Bojar, Robert Chilton, Robert Guyton, Robert Henderson, Robert Kornberg, Robert Leber, Robert Mao, Robert Stenberg, Roberta P Santos, Roberto René Favaloro, Roberto Amati, Rodolfo G S D Lima, Rodrigo J Cerci, Rogerio Tumelero, Rohit Tandon, Roma Tewari, Romalisa Miranda-Peats, Ron Wald, Ronald A Mastouri, Ronald G Morford, Ronald G Schwartz, Ronald P Pedalino, Rongrong Hu, Ronnell A Hansen, Ronny A Cohen, Rory Hachamovitch, Rosa Homem, Rosa Sandonato, Rosane Laimer, Rosann Gans, Roxanne Yost, Roy Mathew, Rubén Baleón-Espinosa, Ruben Ramos, Rubine Gevorgyan, Rui Ferreira, Rui Jing, Ruth Pérez-Fernández, S K Dwivedi, S Ramakrishnan, Saadat Khan, Sabahat Bokhari, Sabu Thomas, Sadath Lubna, Sajeeda Parveen Khan, Sajeev Chakanalil Govindan, Saket Girotra, Saleem Kassam, Sallie Canada, Salvador Cruz-Flores, Samaa Mohamed, Samantha Ly, Sameh El Kaffas, Samia Massalha, Sampoornima Setty, Samuel Nwosu, Sandeep Seth, Sandeep Singh, Sander R Niehe, Sandra M Rivest, Sandra S Zier, Sandra Ahoud, Sandy Carr, Sanjay Ganapathi, Sanjay Shetty, Sanjeev Sharma, Santa Jimenez, Santhosh Satheesh, Santiago A Garcia, Sara Fernandez, Sara Karlsson, Sara Salkind, Sara Temiyasathit, Sarah Medina Rodriguez, Sarah Beaudry, Sarah Hadjih, Sarah Williams, Sarah Zahrani, Sarju Ralhan, Sasa Hinic, Sasko Kedev, Satinder Singh, Satoshi Yasuda, Satvic Cholenahally Manjunath, Sau Lee, Scott M Kaczkowski, Scott Kinlay, Sean W Hayes, Sebastian Sobczak, Senait Asier, Sergey A Sayganov, Seth I Sokol, Shaheen Pandie, Shaiful Azmi Yahaya, Shamir Mehta, Shao-Ping Nie, Sharad Chandra, Sharder Islam, Sharon Tai, Sheetal Rupesh Karwa, Sheri Ussery, Sheromani Bajaj, Sherron C Crook, Shigeyuki Nishimura, Shintaro Nakano, Shirin Heydari, Shiv Kumar Choudhary, Shivali Patel, Shobana Ganesan, Shruti Pandey, Shuyang Zhang, Shweta Hande, Siddharth Gadage, Sik-Yin V Tan, Silvia Zottis Poletti, Silvia Riera, Silvia Valbuena, Simon Walsh, Simona Maspoli, Simone Savaris, Si-Ting Feng, So Yang Cho, Solomon Yakubov, Songlin Zhu, Songtao Wang, Sonia Guerrero, Sonika Gupta, Sonja Salinger Martinovic, Sonya Brons, Sorin Brener, Sothinathan Gurunathan, Souheil Saba, Soundarya Nayak, Sowjanya Reddy, Srinivasa Potluri, Sriram Sudarshan, Srun Kuanprasert, Stacie Van Oosterhout, Stamatios Lerakis, Stanley E Cobos, Stefan C Bertog, Stefan M Simović, Stefan Weikl, Stefano Di Marco, Stefano Provasoli, Stephanie A Tirado, Stephanie C Boer, Stephanie M Lane, Stephanie Ferket, Stephanie Kelly, Stephanie Wasmiller, Stephen H McKellar, Stephen P Hoole, Stephen Fremes, Stephen Preston, Steve Leung, Steven A Fein, Steven J Lindsay, Steven P Sedlis, Steven Giovannone, Steven Michael, Steven Weitz, Stijn van Vugt, Subhash Banerjee, Sudhir Naik, Suellen Hosino, Sukie Desire, Sukit Yamwong, Suku T Thambar, Sulagna Mookherjee, Suman Singh, Sundeep Mishra, Sunil Kumar Verma, Supap Kulthawong, Supatchara Khwakhong, Surendra Naik, Suresh Babu, Surin Woragidpoonpol, Suryaprakash Narayanappa, Susan Derbyshire, Susan Gent, Susan Mathus, Susan Milbrandt, Susan Moore, Susan Regan, Susan Stinson, Susan Webber, Susana Silva, Susanna Stevens, Susanne Gruensfelder, Suthara Aramcharoen, Suvarna Kolhe, Suzana Tavares, Suzanne Arnold, Suzanne Welsh, Svetlana Apostolovic, Swapna Kunhunny, Ta-Chuan Hung, Taissa Zappernick, Tali Sharir, Talita Silva, Tamara Colaiácovo Soares, Tapan Umesh Pillay, Tarun K Mittal, Tatiana Trifonova, Tauane Bello Duarte, Tauqir Huk, Téodora Dutoiu, Terrance Chua, Terry Weyand, Thabitha Charles, Theodoros Kofidis, Theresa McCreary, Thierry Lefevre, Thippeekaa Arumairajah, Thitipong Tepsuwan, Thomas J Mulhearn, Thomas M Meyer, Thomas P Rocco, Thomas R Downes, Thomas Crain, Thomas Haldis, Thomas Mathew, Thomas Redick, Thounaojam Indira Devi, Thuraia Nageh, Tia Cauthren, Tiago Silva, Tiffany Little, Tijana Andric, Tina Harding, Titus Lau, Tiziana Formisano, Tiziano Moccetti, Tomasz Ciurus, Tomasz Mazurek, Tomasz Tarchalski, Toshiyuki Nagai, Tri Tran, Tricia Youn, Trish Tucker, Trudie Milner, Tuhina Bose, Tushar Kotecha, Udo Sechtem, Uma S Valeti, Umberto Cucchini, Umesh Badami, Upendra Kaul, V K Bahl, V S Narain, Valentina Casali, Valeria Godoy, Valerie Robesyn, Vamshi P Priya, Vandana Yadav, Vera McKinney, Veronica De Lenges, Veronica Tinnirello, Vicente Miro, Victor Navarro, Victoria Gumerova, Victoria Hernandez, Vidya Seeratan, Vijay Kumar, Vikentiy Y Kozulin, Viktoria Bulkley, Vilmar Veiga Jr, Vincent Setang, C P Vineeth, Virginai Pubull Nuñez, Virginia Fernández-Figares, Vitor Gomes, Viviana Gabriel, Viviane Dos Santos, Viviane Almeida, Vlad A Iliescu, Vladan Mudrenovic, Vladimir Dzavik, Vojislav L Giga, Walter Enrique Mogrovejo, Wan Xian Chan, Wanda C Marfori, Wanda Parker, Warangkana Mekara, Wassim Nona, Wayne Old, Wayne Pennachi, Weerachai Nawarawong, Wei Chen, Wei Su, Weibing Xing, Wei-Ren Lan, Wenda Crawford, Wendy L Stewart, Wendy Drewes, Wenhua Lin, William B Abernethy, William D Salerno, William F Fearon, William Vergoni, William Weintraub, Winnie C Sia, Wlodzimierz J Musial, Xacobe Flores-Ríos, Xavier Garcia-Moll Marimon, Xi Su, Xiang Ma, Xiangqiong Gu, Xiao Wang, Xiaomei Li, Xiaowei Yao, Xin Fu, Xin Su, Xin Zeng, Xinchun Yang, Xiuhong Li, Xuehua Fang, Xutong Wang, Yaming Geng, Yan Yan, Yanek Pépin-Dubois, Yanfu Wang, Yang Wang, Yanmeng Tian, Yaping Huang, Yechen Han, Yesenia Zambrano, Yi-Hsuan Yang, Ying Tung Sia, Yining Yang, Yitong Ma, Yolayfi Peralta, Yongjian Wu, Yu Kunwu, Yu Zhao, Yudong Peng, Yueh-Hung Lin, Yulan Zhao, Yumei Dong, Yunhai Zhao, Yutthaphan Wannasopha, Yvonne Taul, Zakir Sahul, Zalina Kudzoeva, Zbigniew Kalarus, Zeljko Z Markovic, Zhen Huang, Zheng Ji, Zhenyu Liu, Zhou Yue, Zhulin Zhang, Zhuxi Li, Zile Singh Meharwal, Ziliang Bai, Zixiang Yu, Zohra Huda, Zoltan Davidovits
Subjects: Male, Cardiac Catheterization, Computed Tomography Angiography, medicine.medical_treatment, Myocardial Ischemia, Coronary Disease, Coronary Artery Disease, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Coronary Angiography, ISCHEMIA Research Group, law.invention, Angina, Coronary artery disease, 0302 clinical medicine, Randomized controlled trial, law, Cardiovascular Disease, Myocardial Revascularization, 030212 general & internal medicine, Coronary Artery Bypass, 11 Medical and Health Sciences, Cardiac catheterization, General Medicine, Middle Aged, humanities, Cardiovascular Diseases, Cardiology, Female, Human, medicine.medical_specialty, Ischemia, Article, 03 medical and health sciences, Geriatric cardiology, Percutaneous Coronary Intervention, General & Internal Medicine, Internal medicine, medicine, Humans, Angina, Unstable, Aged, business.industry, Coronary Artery Bypa, Percutaneous coronary intervention, Bayes Theorem, medicine.disease, Heart failure, Quality of Life, business
Abstract: BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).
Published: 2020
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9. Phase 2 Trial of Oncolytic H-1 Parvovirus Therapy Shows Safety and Signs of Immune System Activation in Patients With Metastatic Pancreatic Ductal Adenocarcinoma

Author: Mieke Mertens, Barbara Leuchs, Nicolas Hohmann, Oliver Sedlaczek, Meinhard Kieser, Jean Rommelaere, Veronika Frehtman, Ottheinz Krebs, Maximilian Pilz, Volker Daniel, Matthias M. Gaida, Jacek Hajda, Christoph Springfeld, A Mavratzas, Christine E. Engeland, Assia L. Angelova, Guy Ungerechts, Niels Halama, Michael Dahm, Jutta Schreiber, Bernard Huber, and Dirk Jäger
Subjects: H-1 parvovirus, Cancer Research, medicine.medical_specialty, Adenocarcinoma, Gastroenterology, Metastasis, Immune system, Pharmacokinetics, Internal medicine, medicine, Humans, Viral shedding, Aged, Oncolytic Virotherapy, business.industry, Middle Aged, medicine.disease, Gemcitabine, Oncolytic virus, Pancreatic Neoplasms, Clinical trial, Oncology, Tolerability, Immune System, business, Carcinoma, Pancreatic Ductal, medicine.drug
Abstract: Purpose: To investigate the safety, clinical efficacy, virus pharmacokinetics, shedding, and immune response after administration of an oncolytic parvovirus (H-1PV, ParvOryx) to patients with metastatic pancreatic ductal adenocarcinoma (PDAC) refractory to first-line therapy. Patients and Methods: This is a noncontrolled, single-arm, open-label, dose-escalating, single-center clinical trial. Seven patients with PDAC and at least one liver metastasis were included. ParvOryx was administered intravenously on 4 consecutive days and as an intralesional injection, 6 to 13 days thereafter. Altogether, three escalating dose levels were investigated. In addition, gemcitabine treatment was initiated on day 28. Results: ParvOryx showed excellent tolerability with no dose-limiting toxicities. One patient had a confirmed partial response and one patient revealed an unconfirmed partial response according to RECIST criteria. Both patients showed remarkably long surivial of 326 and 555 days, respectively. Investigation of pharmacokinetics and virus shedding revealed dose dependency with no excretion of active virus particles in saliva or urine and very limited excretion in feces. H-1PV nucleic acids were detected in tumor samples of four patients. All patients showed T-cell responses to viral proteins. An interesting immunologic pattern developed in tumor tissues and in blood of both patients with partial response suggesting immune activation after administration of ParvOryx. Conclusions: The trial met all primary objectives, revealed no environmental risks, and indicated favorable immune modulation after administration of ParvOryx. It can be considered a good basis for further systematic clinical development alone or in combination with immunomodulatory compounds.
Published: 2021
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10. Senile plaque calcification of the lamina circumvoluta medullaris in Alzheimer's disease

Author: Isabel Hilbrich, Carsten Jäger, Max Holzer, and Ralf Schober
Subjects: Pathology, medicine.medical_specialty, Lamina, business.industry, Hippocampus, General Medicine, Disease, Fascia, medicine.disease, Pathology and Forensic Medicine, medicine.anatomical_structure, Basal ganglia, medicine, Dementia, Neurology (clinical), Senile plaques, business, Calcification
Abstract: Vascular calcification is a common phenomenon in the elderly, predominantly appearing in the basal ganglia and in the lamina circumvoluta medullaris of the hippocampus. Calcifications are not an inherent feature of Alzheimer's disease. On the other hand, a rare presenile type of dementia with symmetrical Fahr-type calcifications and numerous neurofibrillary tangles without senile plaques has been described by Kosaka in 1994 and was termed "diffuse neurofibrillary tangles with calcification" (DNTC). We here report a case of Alzheimer's disease with calcifications both in the basal ganglia and in the lamina circumvoluta medullaris of the hippocampus, differing from DNTC by the presence of senile plaques. The calcifications in the hippocampus were not only vascular in nature but also covered amyloid-β- and phosphorylated tau-positive plaque-like structures that were linearly arranged along the dentate fascia in the CA1 sector, an unusual finding of pathogenetic interest.
Published: 2021
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11. The effect of timing of orthodontic therapy on the outcomes of regenerative periodontal surgery in patients with stage <scp>IV</scp> periodontitis: A multicenter randomized trial

Author: Ignacio Sanz Sanchez, Andreas Jäger, Lorena Gaveglio, Peter Wüllenweber, Conchita Martin, Daniele Cardaropoli, Rolf Fimmers, Christina Tietmann, Søren Jepsen, Karin Jepsen, and Eric Kutschera
Subjects: Periodontitis, medicine.medical_specialty, Interdisciplinary treatment, Periodontal surgery, business.industry, Bleeding on probing, medicine.disease, law.invention, Surgery, Treatment Outcome, Primary outcome, Randomized controlled trial, law, Periodontal Attachment Loss, Guided Tissue Regeneration, Periodontal, medicine, Humans, Periodontal Pocket, Periodontics, In patient, medicine.symptom, Stage iv, business, Follow-Up Studies
Abstract: Aim To compare the outcomes after early (4 weeks post-surgically) or late (6 months post-surgically) orthodontic therapy (OT) following regenerative surgery of intrabony defects (IDs). Material and methods In a multi-center, parallel-group, randomized clinical trial 43 patients with stage IV periodontitis were randomized to receive either early (n = 23) or late OT (n = 20) following regenerative surgery of IDs. Primary outcome was change in clinical attachment level (CAL) in one target ID at 12 months after surgery. Secondary outcomes were changes of probing pocket depth (PPD), bleeding on probing (BOP), and frequency of pocket closure. Results No statistically significant differences between groups could be observed for CAL gain (5.4 mm (± 2.1 mm) for early and 4.5 mm (± 1.7 mm) for late OT). PPD was reduced by 4.2 mm (±1.9 mm) in the early group, and by 3.9 mm (±1.5 mm) in the late group (p> 0.05). Pocket closure (PPD ≤ 4 mm) was obtained in 91% of defects in early compared to 85% in late OT. Conclusion In the interdisciplinary treatment of periodontitis stage IV, OT can be initiated already 4 weeks after regenerative surgery of IDs with favorable results, thus reducing the overall treatment time. This article is protected by copyright. All rights reserved.
Published: 2021
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12. FAP imaging in rare cancer entities—first clinical experience in a broad spectrum of malignancies

Author: Dirk Jäger, Walter Mier, F. L. Giesel, Clemens Kratochwil, Jürgen Debus, Claudia Kesch, J. Ristau, Heike Gampp, Jens Cardinale, Hendrik Rathke, Thomas Lindner, Katharina Dendl, Manuel Röhrich, Stefan A. Koerber, Sebastian Adeberg, Rebecca Finck, and Uwe Haberkorn
Subjects: Male, medicine.medical_specialty, Urinary system, Medizin, Broad spectrum, Fibroblast activation protein, alpha, Positron Emission Tomography Computed Tomography, medicine, Humans, Radiology, Nuclear Medicine and imaging, Prospective Studies, Prospective cohort study, Retrospective Studies, business.industry, Head and neck cancer, FAP imaging, 68 Ga-FAPI-PET/CT scan, Cancer, Biological Transport, General Medicine, Middle Aged, medicine.disease, Rare cancer, Primary tumor, Pancreatic Neoplasms, Original Article, Female, Radiology, 68 Ga-FAPI, business
Abstract: Purpose 68 Ga-FAPI (fibroblast activation protein inhibitor) is a rapidly evolving and highly promising radiotracer for PET/CT imaging, presenting excellent results in a variety of tumor entities, particularly in epithelial carcinomas. This retrospective analysis sought to evaluate the potential and impact of FAPI-PET/CT in rare cancer diseases with respect to improvement in staging and therapy, based on tracer uptake in normal organs and tumors. Material and methods Fifty-five patients with rare tumor entities, defined by a prevalence of 1 person out of 2000 or less, received a 68 Ga-FAPI-PET/CT scan. Fourteen women and 41 men (median age 60) were included within the following subgroups: cancer of unknown primary (n = 10), head and neck cancer (n = 13), gastrointestinal and biliary-pancreatic cancer (n = 17), urinary tract cancer (n = 4), neuroendocrine cancer (n = 4), and others (n = 7). Tracer uptake was quantified by standardized uptake values SUVmax and SUVmean and the tumor-to-background ratio (TBR) was determined (SUVmax tumor/SUVmean organ). Results In 20 out of 55 patients, the primary tumor was identified and 31 patients presented metastases (n = 88), characterized by a high mean SUVmax in primary (10.1) and metastatic lesions (7.6). The highest uptake was observed in liver metastases (n = 6) with a mean SUVmax of 9.8 and a high TBR of 8.7, closely followed by peritoneal carcinomatosis (n = 16) presenting a mean SUVmax of 9.8 and an excellent TBR of 29.6. In terms of the included subgroups, the highest uptake regarding mean SUVmax was determined in gastrointestinal and biliary-pancreatic cancer with 9.8 followed closely by urinary tract cancer with 9.5 and head and neck cancer (9.1). Conclusion Due to excellent tumor visualization and, thereby, sharp contrasts in terms of high TBRs in primary and metastatic lesions in different rare malignancies, 68 Ga-FAPI-PET/CT crystallizes as a powerful and valuable imaging tool, particularly with respect to epithelial carcinomas, and therefore an enhancement to standard diagnostics imaging methodologies. The realization of further and prospective studies is of large importance to confirm the potential of FAP imaging in oncology.
Published: 2021
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13. CME: Achtung, Lamelle! Pilzvergiftungen in der Praxis CME-Fragen

Author: Stefan Weiler, Katharina Schenk-Jäger, and Mirjam Gessler
Subjects: medicine.medical_specialty, Fatal outcome, General medical practice, biology, business.industry, Silibinin, General Medicine, medicine.disease, biology.organism_classification, chemistry.chemical_compound, Diarrhea, Intolerances, chemistry, Vomiting, Medicine, Amanita phalloides, medicine.symptom, Mushroom poisoning, business, Intensive care medicine
Abstract: Zusammenfassung. In der ärztlichen Praxis die banalen Unverträglichkeiten nach Konsum von Speisepilzen von einer sich anbahnenden Vergiftung mit potenziell tödlichem Ausgang zu unterscheiden ist nicht trivial. Trotzdem gibt es einige Kriterien, an denen man sich orientieren kann: Für eine Vergiftung mit Amatoxinen, den Giftstoffen z.B. im Grünen Knollenblätterpilz (Amanita phalloides) spricht eine Latenz von sechs Stunden oder mehr zwischen dem Konsum von nicht durch Fachpersonen kontrollierten Lamellenpilzen und dem Beginn meist heftiger Brechdurchfälle. Auch wenn die Therapieoptionen kontrovers diskutiert werden, hat sich die zeitnahe antidotale Behandlung mit Silibinin als zielführend erwiesen.
Published: 2021
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14. A systematic review on diagnostics and surgical treatment of adult right-sided Bochdalek hernias and presentation of the current management pathway

Author: Klaus Emmanuel, M. Lechner, Jan Philipp Ramspott, S Regenbogen, Tarkan Jäger, Frank Mayer, Philipp Schredl, and Ana Gabersek
Subjects: medicine.medical_specialty, Abdominal pain, business.industry, General surgery, Congenital diaphragmatic hernia, Retrospective cohort study, Cochrane Library, medicine.disease, Surgery, Bochdalek hernia, 03 medical and health sciences, 0302 clinical medicine, Systematic review, 030220 oncology & carcinogenesis, medicine, 030211 gastroenterology & hepatology, Hernia, Surgical emergency, medicine.symptom, business
Abstract: Purpose Bochdalek hernia is a congenital diaphragmatic hernia. The incidence in adults is estimated around 0.17%. Right-sided hernias are much more seldom than left-sided ones because of faster closure of the right pleuroperitoneal canal and the protective effect of the liver. Due to its rarity, there have been no large prospective or retrospective studies following great need for evidence-based diagnostics and treatment strategies. In this systematic review, we evaluated the current evidence of diagnostics, treatment, and follow-up of adult right-sided Bochdalek hernias. Methods According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines a systematic literature review was conducted in PubMed and Cochrane library from 2004 to January 2021. The literature search included all studies with non-traumatic right-sided Bochdalek hernias. Literature on left- or both-sided, pregnancy-associated, pediatric, and other types of hernias were explicitly excluded. Quality assessment of the included studies was performed. Results Database search identified 401 records. After eligibility screening 41 studies describing 44 cases of right-sided non-traumatic Bochdalek hernias in adulthood were included for final analysis. Based upon the systematic literature review, the current diagnostic, therapeutic, and follow-up management pathway for this rare surgical emergency is presented. Conclusion This systematic review underlined that most studies investigating management of adult non-traumatic right-sided Bochdalek hernias are of moderate to low methodological quality. Hernias tend to occur more frequently in middle-aged and older women presenting with abdominal pain and dyspnea. A rapid and accurate diagnosis following surgical repair and regular follow-up is mandatory. High-quality studies focusing on the management of this rare entity are urgently needed.
Published: 2021
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15. Real-World Experience of Talimogene Laherparepvec (T-VEC) in Old and Oldest-Old Patients with Melanoma: A Retrospective Single Center Study

Author: Roland Kaufmann, Manuel Jäger, Stefan Kippenberger, Johannes Kleemann, Eva Maria Valesky, and Markus Meissner
Subjects: advanced melanoma, education.field_of_study, medicine.medical_specialty, business.industry, Population, elderly patients, medicine.disease, Single Center, Clinical trial, Oncology, Cancer Management and Research, Internal medicine, intralesional therapy, Cohort, medicine, immunotherapy, cutaneous oncology, Skin cancer, business, Adverse effect, education, Talimogene laherparepvec, Progressive disease, Original Research, oncolytic virus
Abstract: Johannes Kleemann, Manuel JÃ¤ger, Eva Valesky, Stefan Kippenberger, Roland Kaufmann, Markus Meissner Department of Dermatology, Venerology and Allergology, University Hospital, Goethe University, Frankfurt am Main, GermanyCorrespondence: Johannes KleemannDepartment of Dermatology, Venereology and Allergy, University Hospital Frankfurt, Theodor-Stern-Kai 7, Frankfurt am Main, 60590, GermanyTel +4969 6301 5179Fax +49 69 6301 5117Email johannes.kleemann@kgu.dePurpose: Rising melanoma incidences lead to an increasing need for individual therapy strategies in old patients. Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus, approved for the local treatment of unresectable metastatic melanoma. Since data on the efficacy and safety of geriatric patients are sparse, this study was conducted to gain further real-world experience in the treatment of old and oldest-old patients with T-VEC and to obtain data on therapy costs in this population in Germany.Patients and Methods: We performed a retrospective analysis, including all patients with a minimum age of 75 years who were treated with T-VEC from August 2016 to September 2020 in the Skin Cancer Center of the University Hospital Frankfurt, Germany. Patient clinicopathological data, treatment responses, toxicities, treatment-specific data and therapy costs were assessed.Results: Twelve patients with a median age of 83 years (75â 89 years) at the start of treatment were identified. By the end of the study, three (25%) patients experienced complete remission (CR), four (33%) experienced partial response (PR), two patients (17%) remained at stable disease (SD) and three (25%) patients suffered from progressive disease (PD). Overall response rate was 58.3%, and durable response rate was 41.7%. There were no treatment-related adverse events grade 3 or higher. The median duration of treatment was seventeen weeks (3â 57 weeks). Median medication costs in the patients who had completed treatment (n=10) were calculated to be 27,325 Euros in Germany.Conclusion: This study provides further evidence for an effective use of T-VEC in old and oldest-old patients. The low rate of adverse events seems to be favorable compared to other systemic melanoma therapies. Furthermore, duration of treatment was short and therapy costs were lower than would have been expected from clinical trial data. Altogether, these data encourage the use of T-VEC in this special patient cohort.Keywords: intralesional therapy, immunotherapy, oncolytic virus, advanced melanoma, cutaneous oncology, elderly patients
Published: 2021
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16. Hemodynamic Status During Endovascular Stroke Treatment: Association of Blood Pressure with Functional Outcome

Author: Laura Bettina Jäger, Dorothea Kronsteiner, Meinhard Kieser, Min Chen, Silvia Schönenberger, Johannes Pfaff, Simon Schieber, Markus A Möhlenbruch, Martin Bendszus, Peter A. Ringleb, and Julian Bösel
Subjects: medicine.medical_specialty, Mean arterial pressure, medicine.medical_treatment, Acute ischemic stroke, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, Brain Ischemia, 03 medical and health sciences, 0302 clinical medicine, Modified Rankin Scale, Internal medicine, Post-hoc analysis, medicine, Humans, Prospective Studies, Prospective cohort study, Thrombectomy, Aged, Retrospective Studies, business.industry, Cerebral infarction, Endovascular Procedures, Odds ratio, Thrombolysis, medicine.disease, Stroke, Treatment Outcome, Blood pressure, Cardiology, Neurology (clinical), business, Original Work, 030217 neurology & neurosurgery
Abstract: Background Optimal blood pressure (BP) management during endovascular stroke treatment in patients with large-vessel occlusion is not well established. We aimed to investigate associations of BP during different phases of endovascular therapy with reperfusion and functional outcome. Methods We performed a post hoc analysis of a single-center prospective study that evaluated a new simplified procedural sedation standard during endovascular therapy (Keep Evaluating Protocol Simplification in Managing Periinterventional Light Sedation for Endovascular Stroke Treatment). BP during endovascular therapy in patients was managed according to protocol. Data from four different phases (baseline, pre-recanalization, post recanalization, and post intervention) were obtained, and mean BP values, as well as changes in BP between different phases and reductions in systolic BP (SBP) and mean arterial pressure (MAP) from baseline to pre-recanalization, were used as exposure variables. The main outcome was a modified Rankin Scale score of 0–2 three months after admission. Secondary outcomes were successful reperfusion and change in the National Institutes of Health Stroke Scale score after 24 h. Multivariable linear and logistic regression models were used for statistical analysis. Results Functional outcomes were analyzed in 139 patients with successful reperfusion (defined as thrombolysis in cerebral infarction grade 2b–3). The mean (standard deviation) age was 76 (10.9) years, the mean (standard deviation) National Institutes of Health Stroke Scale score was 14.3 (7.5), and 70 (43.5%) patients had a left-sided vessel occlusion. Favorable functional outcome (modified Rankin Scale score 0–2) was less likely with every 10-mm Hg increase in baseline (odds ratio [OR] 0.76, P = 0.04) and pre-recanalization (OR 0.65, P = 0.011) SBP. This was also found for baseline (OR 0.76, P = 0.05) and pre-recanalization MAP (OR 0.66, P = 0.03). The maximum Youden index in a receiver operating characteristics analysis revealed an SBP of 163 mm Hg and MAP of 117 mm Hg as discriminatory thresholds during the pre-recanalization phase to predict functional outcome. Conclusions In our protocol-based setting, intraprocedural pre-recanalization BP reductions during endovascular therapy were not associated with functional outcome. However, higher intraprocedural pre-recanalization SBP and MAP were associated with worse functional outcome. Prospective randomized controlled studies are needed to determine whether BP is a feasible treatment target for the modification of outcomes.
Published: 2021
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17. MicroRNA-sensitive oncolytic measles virus for chemovirotherapy of pancreatic cancer

Author: Sascha Bossow, Dirk Jäger, Christine E. Engeland, Christian Grossardt, Hans Martin Singh, Christof von Kalle, John C. Bell, Jan Dessila, Mathias F. Leber, Guy Ungerechts, and Karim Zaoui
Subjects: 0301 basic medicine, Cancer Research, pancreatic cancer, Virus, fluorouracil, Measles virus, 03 medical and health sciences, 0302 clinical medicine, Therapeutic index, prodrugs, Pancreatic cancer, medicine, Pharmacology (medical), cytosine deaminase, Virotherapy, RC254-282, biology, business.industry, Cytosine deaminase, chemovirotherapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prodrug, biology.organism_classification, medicine.disease, Oncolytic virus, microRNAs, 030104 developmental biology, miR-148a, Oncology, oncolytic viruses, 030220 oncology & carcinogenesis, measles virus, Cancer research, Molecular Medicine, Original Article, virotherapy, business
Abstract: Advanced pancreatic cancer is characterized by few treatment options and poor outcomes. Oncolytic virotherapy and chemotherapy involve complementary pharmacodynamics and could synergize to improve therapeutic efficacy. Likewise, multimodality treatment may cause additional toxicity, and new agents have to be safe. Balancing both aims, we generated an oncolytic measles virus for 5-fluorouracil-based chemovirotherapy of pancreatic cancer with enhanced tumor specificity through microRNA-regulated vector tropism. The resulting vector encodes a bacterial prodrug convertase, cytosine deaminase-uracil phosphoribosyl transferase, and carries synthetic miR-148a target sites in the viral F gene. Combination of the armed and targeted virus with 5-fluorocytosine, a prodrug of 5-fluorouracil, resulted in cytotoxicity toward both infected and bystander pancreatic cancer cells. In pancreatic cancer xenografts, a single intratumoral injection of the virus induced robust in vivo expression of prodrug convertase. Based on intratumoral transgene expression kinetics, we devised a chemovirotherapy regimen to assess treatment efficacy. Concerted multimodality treatment with intratumoral virus and systemic prodrug administration delayed tumor growth and prolonged survival of xenograft-bearing mice. Our results demonstrate that 5-fluorouracil-based chemovirotherapy with microRNA-sensitive measles virus is an effective strategy against pancreatic cancer at a favorable therapeutic index that warrants future clinical translation., Graphical abstract, This study describes a novel, virus-based therapeutic approach for treatment of pancreatic cancer. Our results demonstrate that 5-fluorouracil-based chemovirotherapy with microRNA-sensitive and prodrug convertase-encoding measles virus is an effective strategy against pancreatic cancer at a favorable therapeutic index.
Published: 2021

18. 68Ga-FAPI-PET/CT in patients with various gynecological malignancies

Author: Frederik L. Giesel, Ulrike Heger, Dirk Jäger, Stefan A. Koerber, Kgomotso M.G. Mokoala, Fabian Staudinger, Rebecca Finck, Katharina Dendl, Lisa Schillings, Uwe Haberkorn, Jürgen Debus, Manuel Röhrich, Clemens Kratochwil, and Mike Sathekge
Subjects: 0301 basic medicine, Leiomyosarcoma, medicine.medical_specialty, Urology, Metastasis, FAPI, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, medicine, Radiology, Nuclear Medicine and imaging, PET-CT, Fibroblast activation protein, business.industry, Endometrial cancer, Gynecological malignancies, Cancer, General Medicine, medicine.disease, Primary tumor, SUV, 030104 developmental biology, PET, 030220 oncology & carcinogenesis, Original Article, Ovarian cancer, business
Abstract: Purpose 68Ga-FAPI (fibroblast activation protein inhibitor) is a novel and highly promising radiotracer for PET/CT imaging. The aim of this retrospective analysis is to explore the potential of FAPI-PET/CT in gynecological malignancies. We assessed biodistribution, tumor uptake, and the influence of pre- or postmenopausal status on tracer accumulation in hormone-sensitive organs. Furthermore, a comparison with the current standard oncological tracer 18F-FDG was performed in selected cases. Patients and methods A total of 31 patients (median age 59.5) from two centers with several gynecological tumors (breast cancer; ovarian cancer; cervical cancer; endometrial cancer; leiomyosarcoma of the uterus; tubal cancer) underwent 68Ga-FAPI-PET/CT. Out of 31 patients, 10 received an additional 18F-FDG scan within a median time interval of 12.5 days (range 1–76). Tracer uptake was quantified by standardized uptake values (SUV)max and (SUV)mean, and tumor-to-background ratio (TBR) was calculated (SUVmax tumor/ SUVmean organ). Moreover, a second cohort of 167 female patients with different malignancies was analyzed regarding their FAPI uptake in normal hormone-responsive organs: endometrium (n = 128), ovary (n = 64), and breast (n = 147). These patients were categorized by age as premenopausal (n = 12), postmenopausal (>65 years; n = 68), and unknown menstrual status (35–65 years; n = 87), followed by an analysis of FAPI uptake of the pre- and postmenopausal group. Results In 8 out of 31 patients, the primary tumor was present, and all 31 patients showed lesions suspicious for metastasis (n = 81) demonstrating a high mean SUVmax in both the primary (SUVmax 11.6) and metastatic lesions (SUVmax 9.7). TBR was significantly higher in 68Ga-FAPI compared to 18F-FDG for distant metastases (13.0 vs. 5.7; p = 0.047) and by trend for regional lymph node metastases (31.9 vs 27.3; p = 0.6). Biodistribution of 68Ga-FAPI-PET/CT presented significantly lower uptake or no significant differences in 15 out of 16 organs, compared to 18F-FDG-PET/CT. The highest uptake of all primary lesions was obtained in endometrial carcinomas (mean SUVmax 18.4), followed by cervical carcinomas (mean SUVmax 15.22). In the second cohort, uptake in premenopausal patients differed significantly from postmenopausal patients in endometrium (11.7 vs 3.9; p p = 0.004), whereas no significant difference concerning ovaries (2.8 vs 1.6; p = 0.141) was observed. Conclusion Due to high tracer uptake resulting in sharp contrasts in primary and metastatic lesions and higher TBRs than 18F-FDG-PET/CT, 68Ga-FAPI-PET/CT presents a promising imaging method for staging and follow-up of gynecological tumors. The presence or absence of the menstrual cycle seems to correlate with FAPI accumulation in the normal endometrium and breast. This first investigation of FAP ligands in gynecological tumor entities supports clinical application and further research in this field.
Published: 2021

19. Perioperative changes in the plasma metabolome of patients receiving general anesthesia for pancreatic cancer surgery

Author: Stefan Fröhling, Markus W. Büchler, Gernot Poschet, Dirk Jäger, Judith Schenz, Florian Uhle, Johanna Mock-Ohnesorge, Andreas Mock, Thilo Hackert, and Markus A. Weigand
Subjects: medicine.medical_specialty, tumor, longitudinal, business.industry, Context (language use), Perioperative, anesthesia, Malignancy, medicine.disease, metabolomics, Surgery, Metabolomics, Oncology, Pancreatic cancer, Anesthesia, Anesthetic, medicine, Metabolome, Carnitine, business, plasma, medicine.drug, Research Paper
Abstract: Background: Modern anesthesia strives to offer personalized concepts to meet the patient’s individual needs in sight of clinical outcome. Still, little is known about the impact of anesthesia on the plasma metabolome, although many metabolites have been shown to modulate the function of various immune cells, making it particularly interesting in the context of oncological surgery. In this study longitudinal dynamics in the plasma metabolome during general anesthesia in patients undergoing pancreatic surgery were analyzed. Materials and Methods: Prospective, observational study with 10 patients diagnosed with pancreatic (pre-) malignancy and subjected to elective resection surgery under general anesthesia. Plasma metabolites (n = 630) were quantified at eight consecutive perioperative timepoints using mass spectrometry-based targeted metabolomics. Results: 39 metabolites significantly changed during the perioperative period. Tryptophan concentrations decreased by 45% with the maximum decrease after anesthesia induction (p = 6.24E-07), while taurine synthesis increased (p = 1.46E-04). Triacylglycerides and lysophosphatidylcholines were significantly reduced with increased liberation of free monounsaturated fatty acids (p = 0.03). Carnitine levels decreased significantly (p = 9.30E-04). Conclusions: The major finding of this study was perioperative tryptophan depletion and increased taurine synthesis. Both are essential for immune cell function and are therefore of significant interest for perioperative management. Further studies are needed to identify influencing anesthetic factors.
Published: 2021

20. Outcome of Radical Surgery for Simultaneous Liver and Lung Metastases Synchronous with Primary Colorectal Cancer

Author: Adam Dinnewitzer, Martin Varga, Burkhard H. A. von Rahden, Oliver O. Koch, Klaus Emmanuel, Tarkan Jäger, Jörg Hutter, and Franz Xaver Singhartinger
Subjects: medicine.medical_specialty, Lung, Colorectal cancer, business.industry, Rectum, medicine.disease, Surgery, Cardiac surgery, medicine.anatomical_structure, Cardiothoracic surgery, Pediatric surgery, medicine, Neurosurgery, Radical surgery, business
Abstract: Background Colorectal cancer (CRC) leads to metastatic disease in approximately 30% of patients. In patients with newly diagnosed CRC with both liver and lung metastases, curative resection is rarely possible. The aim of this study is to evaluate the overall (OS) and relapse-free survival (RFS) rates of these patients after resection with curative intent. Methods This study is a retrospective analysis of colorectal cancer patients (n=8, median age 54.3 years) with simultaneous liver and lung metastasis undergoing resection with curative intent between May 1st, 2002, to December 31st, 2016, at our institution. Results Colon was the primary tumour site in 2 patients and rectum in 6 patients. The median number of liver and lung metastases was 3 and 2, respectively. Patients received various treatment sequences individualized on tumour disease burden. R0 resection was achieved after all but one procedure. Two severe Clavien-Dindo grade IIIb complications were present. Median hospital stay was 9 (3–24) days per procedure. Tumour relapse was observed in all patients with median RFS of 9 (3–28) months and median OS of 40 (17–52) months. In 4 cases, where repeated resection of recurrent metastases (3 liver and 1 lung) was possible, the median OS was 43 months. Conclusion Our data suggests that patients seem to benefit from resection with curative intent, with tendency to prolonged OS and with acceptable complication rate. Tumour recurrence occurred in all patients. Repeated resection was beneficial and led to further prolonged OS.
Published: 2021
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21. Employment status and desire for work in severe mental illness: results from an observational, cross-sectional study

Author: Klemens Ajayi, Markus Jäger, Peter Brieger, Albert Putzhammer, Uta Gühne, Steffi G. Riedel-Heller, Karel Frasch, Johanna Breilmann, Bertram Schneeweiß, Andreas Küthmann, Alexander Pabst, Andreas Allgöwer, Stephan Heres, Jessica Baumgärtner, Alkomiet Hasan, Margrit Löbner, Peter Falkai, Thomas Becker, Michael Schwarz, Reinhold Kilian, and Markus Kösters
Subjects: Adult, medicine.medical_specialty, Health (social science), Adolescent, Social Psychology, Epidemiology, Cross-sectional study, Work ability, Psychological intervention, 03 medical and health sciences, 0302 clinical medicine, Occupational rehabilitation, Employment status, Employment, Supported, Mentally Ill Persons, Humans, Medicine, ddc:610, Psychiatry, Aged, Supported employment, Original Paper, Predictors, business.industry, Mental Disorders, Middle Aged, Mental illness, medicine.disease, 030227 psychiatry, Desire to work, Clinical trial, Psychiatry and Mental health, Cross-Sectional Studies, Workforce, Observational study, business, 030217 neurology & neurosurgery
Abstract: Purpose People with a severe mental illness (SMI) are at particular risk of occupational exclusion. Among the approaches to occupational rehabilitation, supported employment (SE) has been proven to be the most effective. A requirement to enter SE-programs is that individuals must want to seek competitive employment. The aim of this work is to investigate the relationship between serious mental illness and the desire to work including potential predictors. Methods This is a cross-sectional observational study of patients with SMI aged 18–65 years (n = 397). Patients were interviewed by trained staff using standardised instruments. The relationship between potential predictors and a strong preference for employment were analysed using a hierarchic binary logistic regression model. Results Only about one-quarter (27.9%) of SMI patients is in competitive employment. Another quarter is unemployed (25.9%). Results show that the desire for competitive employment is strong among more than half of the SMI patients. Among the unemployed, two-thirds express a strong desire for work. These individuals are an ideal target group for SE interventions. Comorbid chronic physical illness, diagnosis, and the subjectively judged ability to work are associated with the desire for work. Conclusion Our data confirm a substantial exclusion of individuals with SMI from the workforce. In general, care needs for workplace interventions are not being met and leave much room for improvement. In addition to employment status, the desire for work should be routinely assessed. Study registration The study was registered in the German Clinical Trials Register (DRKS) (https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00015801) and under the WHO-Platform “International Clinical Trials Registry Platform” (ICTRP) (https://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00015801) under the registration number DRKS00015801 before the start of recruitment (Registration date: 21.02.2019).
Published: 2021
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22. Health-related quality of life and utility outcomes with selinexor in relapsed/refractory diffuse large B-cell lymphoma

Author: Agnes Nagy, Rene-Olivier Casasnovas, Sameer Bakhshi, Sharon Shacham, Juan-Manuel Sancho, Ronit Gurion, Josée M. Zijlstra, Jatin P. Shah, Miklos Egyed, Brian T. Hill, Krzysztof Warzocha, Gabriel Tremblay, Michael W. Schuster, Fritz Offner, Reda Bouabdallah, Dimitrios Tomaras, Paolo Caimi, Andre Goy, Priyanka Samal, Catherine Thieblemont, Joost S.P. Vermaat, Matthew Ku, Ulrich Jäger, John Kuruvilla, Nagesh Kalakonda, George A Follows, Eric Van Den Neste, Miguel Ángel Canales Albendea, Michael Kauffman, Nada Hamad, Fatima De la Cruz, Patrick Daniele, Marie Maerevoet, Theodoros Vasilakopoulos, Federica Cavallo, Sylvain Choquet, Karyopharm Therapeutics Inc., Newton, MA, U918, Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Amsterdam UMC, Addenbrooke's Hospital, Cambridge University NHS Trust, Leiden University Medical Center (LUMC), Institute of Translational Medicine, University of Liverpool, Hackensack University Medical Center [Hackensack], Service d'Hématologie clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Catholique de Louvain = Catholic University of Louvain (UCL), Cleveland Clinic, Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Turin, Hospital Universitario Virgen del Rocío [Sevilla], University Health Network, St Vincent's Hospital Melbourne [Australia], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Medizinische Universität Wien = Medical University of Vienna, University Hospitals Case Medical Center, Tel Aviv University [Tel Aviv], Institute of Hematology and Transfusion Medicine[Warsaw, Poland] (IHTM), Germans Trias i Pujol Hospital, Barcelona Autonomous University, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Ghent University Hospital, National and Kapodistrian University of Athens (NKUA), Semmelweis University [Budapest], Hospital Universitario La Paz, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, and UCL - (SLuc) Service d'hématologie
Subjects: Male, Oncology, Cancer Research, Health utility, FACT-Lym, patient reported outcomes, MESH: Patient Reported Outcome Measures, MESH: Aged, 80 and over, 0302 clinical medicine, Quality of life, Recurrence, Medicine and Health Sciences, Aged, 80 and over, MESH: Aged, MESH: Middle Aged, health, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, Middle Aged, MESH: Drug Resistance, Neoplasm, 3. Good health, health-related quality of life, Hydrazines, EQ-5D-5L, patient-reported outcomes, 030220 oncology & carcinogenesis, Female, health utility, Lymphoma, Large B-Cell, Diffuse, MESH: Hydrazines, Adult, disutility of adverse events, medicine.medical_specialty, diffuse large B-cell lymphoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Refractory, Internal medicine, medicine, Humans, health state utility, selinexor, Patient Reported Outcome Measures, Aged, Health related quality of life, MESH: Humans, business.industry, MESH: Quality of Life, MESH: Adult, Triazoles, medicine.disease, MESH: Male, MESH: Recurrence, Lymphoma, MESH: Triazoles, utility, Drug Resistance, Neoplasm, Relapsed refractory, Quality of Life, MESH: Lymphoma, Large B-Cell, Diffuse, business, MESH: Female, Diffuse large B-cell lymphoma, Progressive disease, 030215 immunology
Abstract: Aim: Evaluate health-related quality of life (HRQoL) and health utility impact of single-agent selinexor in heavily pretreated patients with relapsed/refractory diffuse large B-cell lymphoma. Patients & methods: Functional Assessment of Cancer Therapy (FACT) - Lymphoma and EuroQoL five-dimensions five-levels data collected in the single-arm Phase IIb trial SADAL (NCT02227251) were analyzed with mixed-effects models. Results: Treatment responders maintained higher FACT - Lymphoma (p = 3 adverse events and serious adverse events were not associated with clinically meaningful negative QoL impacts.
Published: 2021
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23. Current practice in nutrition after allogeneic hematopoietic stem cell transplantation – Results from a survey among hematopoietic stem cell transplant centers

Author: M Middeke, A Simon, Anita Lawitschka, A Baumgartner, P Jäger, Jörg Halter, Daniel Wolff, Jann Arends, Hildegard T. Greinix, Gesine Bug, Silvan Klein, R Toenges, Christoph Schmid, I Hilgendorf, and Eva-Maria Wagner-Drouet
Subjects: 0301 basic medicine, Parenteral Nutrition, medicine.medical_specialty, Consensus, Neutropenia, medicine.medical_treatment, 030209 endocrinology & metabolism, Hematopoietic stem cell transplantation, Critical Care and Intensive Care Medicine, Nutrition Policy, Eating, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Germany, Internal medicine, medicine, Vitamin D and neurology, Humans, Practice Patterns, Physicians', 030109 nutrition & dietetics, Nutrition and Dietetics, business.industry, Body Weight, Malnutrition, Hematopoietic Stem Cell Transplantation, medicine.disease, Micronutrient, Comorbidity, Diet, Parenteral nutrition, Graft-versus-host disease, Austria, Health Care Surveys, Dietary Supplements, business, Switzerland
Abstract: Summary Background Allogeneic hematopoietic stem cell transplantation (alloHSCT) is frequently associated with impaired oral intake and malnutrition, which potentially increases morbidity and mortality. Therefore, nutrition is one of the major challenges in the post-transplant period. Methods To document the current clinical approach in nutritional treatment, we designed a questionnaire concerning the current practice in nutrition after alloHSCT and distributed it to German speaking centers performing alloHSCT in Germany, Austria and Switzerland between November 2018 and March 2020. Twenty-eight (39%) of 72 contacted centers completed the survey, 23 from Germany, two from Austria and three from Switzerland, representing 50% of alloHSCT activity within the participating countries in 2018. Results All centers reported having nutritional guidelines for patients undergoing alloHSCT, whereby 86% (n = 24) provided a low-microbial diet during the neutropenic phase. The criteria to start parenteral nutrition (PN) directly after alloHSCT seemed to be consistent, 75% (n = 21) of the corresponding centers started PN if the oral nutritional intake or the bodyweight dropped below a certain limit. In the setting of intestinal graft-versus-host disease (GvHD) the current practice appeared to be more heterogenous. About 64% (n = 18) of the centers followed a special diet, added food stepwise modulated by GvHD symptoms, while only four centers regularly stopped oral intake completely (intestinal GvHD grade >1). Half of the centers (54%, n = 15) applied a lactose-free diet, followed by 43% (n = 12) which provided fat- and 18% (n = 5) gluten-free food in patients with intestinal GvHD. Supplementation of micronutrients in acute intestinal GvHD patients was performed by 54% (n = 15) of the centers, whereas vitamin D (89%, n = 25) and vitamin B12 (68%, n = 19) was added regularly independently of the presence of GvHD. Only 5 (18%) participating centers ever observed a food-associated infection during hospitalization, whereas food-associated infections were reported to occur more often in the outpatient setting (64%, n = 18). Conclusion The survey documented a general consensus about the need for nutritional guidelines for patients undergoing alloHSCT. However, the nutritional treatment in clinical practice (i.e. lactose-, gluten- or fat-free in intestinal GvHD) as well as the use of food supplements was very heterogeneous. In line with current general recommendations the centers seemed to focus on safe food handling practice rather than providing a strict neutropenic diet. More high-quality data are required to provide evidence-based nutrition to patients during and after alloHSCT.
Published: 2021
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24. Development of imaging-based risk scores for prediction of intracranial haemorrhage and ischaemic stroke in patients taking antithrombotic therapy after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies

Author: Henry Ma, Eleni Sakka, Hugues Chabriat, Duncan Wilson, Appu Suman, Peter J. Kelly, SL Ho, Charlotte Zerna, Eric Jouvent, Lawrence K.S. Wong, Anthea Parry, Frances Harrington, Jan Stam, Christopher Patterson, Rustam Al-Shahi Salman, Shigeru Inamura, Krishna A Dani, Henry Houlden, Sebastian Thilemann, Kotaro Iida, Chao Xu, Eunbin Ko, Daniel Guisado-Alonso, Urs Fischer, Caroline E. Lovelock, Man Yu Tse, Wing Chi Fong, Azlisham Mohd Nor, Clare Shakeshaft, Philippe Maeder, Henrik Gensicke, Stefan T. Engelter, James Okwera, Christopher Chen, Dulka Manawadu, John F. Corrigan, Efrat Kliper, Shelagh B. Coutts, Alexander P. Leff, Kam Tat Leung, Chathuri Yatawara, Leopold Hertzberger, M. Eline Kooi, Kazuhisa Yoshifuji, Hing Lung Ip, Keon-Joo Lee, Sanjeevikumar Meenakishundaram, Hiroyuki Irie, Marc Randall, Hatice Ozkan, Hideo Hara, Jill Abrigo, Raquel Delgado-Mederos, Shaloo Singhal, Enrico Flossmann, Beatriz Gómez-Ansón, Paul O'Mahony, Carmen Barbato, Ahamad Hassan, Francesca M Chappell, Harald Proschel, Vincent Mok, Masashi Nishihara, Lakshmanan Sekaran, Derya Selcuk Demirelli, Chu Peng Hoi, Hakan Ay, Joan Martí-Fàbregas, Rebeca Marín, Anne Cristine Guevarra, Martin Cooper, Einor Ben Assayag, Anne-Marie Mendyk, Christine Roffe, Myung Suk Jang, Maarten van Gemert, Hannah Cohen, Jae-Sung Lim, YK Wong, Bonnie Y.K. Lam, Janet Putterill, Wouter Schoonewille, Nick S. Ward, Nikola Sprigg, Kui Kai Lau, Bernard Esisi, Peter M. Rothwell, Henk Verbiest, Kirsty Harkness, Elisa Merino, Gareth Ambler, Arumug Nallasivam, Nigel Smyth, Paul A. Armitage, Heinrich Mattle, Pol Camps-Renom, Martin M. Brown, David Cohen, Min Lou, Pankaj Sharma, Sarah Gunkel, Elles Douven, Andreas Charidimou, Djamil Vahidassr, Cathy Soufan, Alexandros A Polymeris, Michael G. Hennerici, Chris Moran, Rachel Marsh, Mahmud Sajid, Kyohei Fujita, David J. Werring, Joanna M. Wardlaw, Derek Hayden, Joseph Kwan, Timothy J. England, Jaap van der Sande, Luis Prats-Sánchez, Paul Guyler, Ryan Hoi Kit Cheung, Koon-Ho Chan, Frank-Erik de Leeuw, Simone Browning, Jon Scott, Adrian Barry, Alejandro Martínez-Domeño, Luc Bracoub, Dinesh Chadha, Ijaz Anwar, Deborah Kelly, Moon-Ku Han, Anil M. Tuladhar, Thomas Gattringer, Fiona Carty, Abduelbaset Elmarim, Syed Mansoor, Enrico Flossman, Dilek Necioglu Orken, Jane Sword, Velandai Srikanth, Ping Wing Ng, Thomas W. Leung, Richard Shek-kwan Chang, Hans Rolf Jäger, Marwan El-Koussy, Jeroen Hendrikse, Khaled Darawil, Kazunori Toyoda, Mathuri Prabhakaran, Karim Mahawish, Ethem Murat Arsava, Jihoon Kang, Kwok Kui Wong, Michael Power, Felix Fluri, Enas Lawrence, Maam Mamun, Sissi Ispoglou, Mathew Burn, Siu Hung Li, Henry K.F. Mak, Kaori Miwa, Els De Schryver, Franz Fazekas, Jonathan G. Best, Louise Shaw, Hen Hallevi, Keith W. Muir, Ilse Burger, Adrian Wong, Nils Peters, Susana Muñoz-Maniega, Yusuke Yakushiji, David Calvet, Mark White, Michael McCormick, Vinodh Krishnamurthy, David Hargroves, Jan C. Purrucker, Tae Jin Song, Masayuki Shiozawa, Noortje A.M. Maaijwee, Prasanna Aghoram, Nicolas Christ, Lino Ramos, Yannie Soo, Thanh G. Phan, Parashkev Nachev, David J. Seiffge, Kim Wiegertjes, Leo H. Bonati, Chahin Pachai, Oi Ling Chan, Yvo B.W.E.M. Roos, Santiago Medrano-Martorell, Natan M. Bornstein, Elizabeth A. Warburton, Richard Li, Prabel Datta, Pascal P. Gratz, Edmund Ka Ming Wong, Hedley C. A. Emsley, Marie-Yvonne Douste-Blazy, Gunaratam Gunathilagan, Nagaendran Kandiah, Masatoshi Koga, Roland Veltkamp, Lee-Anne Slater, Suk Fung Tsang, Beom Joon Kim, Simon Jung, Zeynep Tanriverdi, Sarah Caine, Peter J. Koudstaal, Laurence Legrand, Kari Saastamoinen, Ale Algra, Jean-Louis Mas, Christine Delmaire, Fidel Nuñez, Robert J. van Oostenbrugge, Sebastian Eppinger, Lillian Choy, Robert Luder, Vincent I.H. Kwa, Aad van der Lugt, Marie Dominique Fratacci, Stephen Makin, Layan Akijian, Régis Bordet, Mi Hwa Yang, Ying Zhou, Elio Giallombardo, Adrian R Parry-Jones, John S. Thornton, Amos D. Korczyn, Narayanaswamy Venketasubramanian, David J. Williams, Aravindakshan Manoj, Julie Staals, Solveig Horstmann, Dianne H.K. van Dam-Nolen, Claire Cullen, Benjamin Wagner, Jun Tanaka, Martin Dennis, Stef Bakker, Gregory Y.H. Lip, L. Jaap Kappelle, Robin Lemmens, Achim Gass, David Mangion, Matthew Smith, Toshio Imaizumi, Wenyan Liu, Jeremy Molad, Christopher Price, Paul J. Nederkoorn, P. J. A. M. Brouwers, Vincent Thijs, Sze Ho Ma, Mark Schembri, Peter Wilkinson, Janice E. O’Connell, Karen Ma, John Ly, Leonidas Panos, Chung Yan Chan, Toshihiro Ide, Christopher Traenka, Joost Jöbsis, Gargi Banerjee, Paul Berntsen, Michael J. Thrippleton, Raymond T.F. Cheung, Christopher Karayiannis, Werner H. Mess, Robert Simister, Jayesh Modi Medanta, Syuhei Ikeda, John Mitchell, Linxin Li, Mauro S.B. Silva, Eric Vicaut, John Coyle, Shoichiro Sato, Michelle Davis, Jonathan Birns, Richard J. Perry, Sean M. Murphy, KC Teo, Maria del C. Valdés Hernández, Bibek Gyanwali, Tarek A. Yousry, Kath Pasco, Sebastian Köhler, Joachim Fladt, Edward S. Hui, Philippe Lyrer, Young Dae Kim, Anna K. Heye, Eric E. Smith, Saima Hilal, Ender Uysal, Ji Hoe Heo, Ysoline Beigneux, Cisca Linn, Hee-Joon Bae, Simon Leach, Winnie C.W. Chu, Ronil V. Chandra, Neurology, ACS - Atherosclerosis & ischemic syndromes, ANS - Neurovascular Disorders, MUMC+: HZC Med Staf Spec Klinische Neurofys (9), RS: Carim - B06 Imaging, MUMC+: HZC Klinische Neurofysiologie (5), Klinische Neurowetenschappen, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Neurologie (3), RS: Carim - B05 Cerebral small vessel disease, MUMC+: Hersen en Zenuw Centrum (3), MUMC+: MA Med Staf Spec Neurologie (9), RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, Beeldvorming, and MUMC+: DA BV Klinisch Fysicus (9)
Subjects: Adult, Male, Risk, EXTERNAL VALIDATION, medicine.medical_specialty, Neurology, MODELS, Clinical Neurology, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Fibrinolytic Agents, Recurrence, Internal medicine, Antithrombotic, Humans, Medicine, Prospective cohort study, 610 Medicine & health, Stroke, METAANALYSIS, Aged, Ischemic Stroke, Science & Technology, medicine.diagnostic_test, business.industry, Proportional hazards model, Magnetic resonance imaging, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], medicine.disease, Magnetic Resonance Imaging, Ischemic Attack, Transient, ATRIAL-FIBRILLATION, Cardiology, Female, Neurology (clinical), Neurosciences & Neurology, business, Intracranial Hemorrhages, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Fibrinolytic agent, Cohort study
Abstract: Contains fulltext : 235277.pdf (Publisher’s version ) (Closed access) BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. FUNDING: British Heart Foundation and Stroke Association.
Published: 2021
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25. Myelomonocytic skewing in chronic myelomonocytic leukemia: phenotypic, molecular and biologic features and impact on survival

Author: Leopold Öhler, Elmir Graf, Eva Jäger, Peter Valent, Agnes Barna, Temeida Graf, Gregor Hoermann, and Klaus Geissler
Subjects: Male, Myeloid, Chronic myelomonocytic leukemia, Kaplan-Meier Estimate, RASopathy, Leukocyte Count, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, White blood cell, Genotype, Biomarkers, Tumor, medicine, Humans, Myeloid Cells, Epigenetics, CMML, in vitro cultures, business.industry, Leukemia, Myelomonocytic, Chronic, Original Articles, Hematology, General Medicine, Prognosis, medicine.disease, Phenotype, Pathophysiology, medicine.anatomical_structure, skewing, NGS, 030220 oncology & carcinogenesis, Mutation, Immunology, Disease Progression, Leukocytes, Mononuclear, ras Proteins, Female, Original Article, business, Biomarkers, Signal Transduction, 030215 immunology
Abstract: Background Myelomonocytic skewing is considered as a key pathophysiologic phenomenon in chronic myelomonocytic leukemia (CMML), but its prevalence and potential correlation with phenotypic, genotypic, and clinical features are poorly defined. Methods Skewed differentiation toward the myelomonocytic over erythroid commitment as indicated by an inverse ratio of myelomonocytic/erythroid colonies was investigated in 146 patients with CMML by semisolid in vitro cultures. Results There was a high prevalence of myelomonocytic skewing in patients with CMML (120/146, 82%); whereas, this phenomenon was rare in normal individuals (1/98, 1%). Patients with CMML with myelomonocytic skewing had higher white blood cell and peripheral blast cell counts, and lower platelet values. The number of mutations in genes of the epigenetic and/or splicing category was higher in CMML patients with as compared with patients without skewing. Patients with myelomonocytic skewing had more frequently mutations in RASopathy genes and higher growth factor independent myeloid colony formation. Interestingly, the lack of myelomonocytic skewing discriminated patients with CMML with a particularly favorable prognosis (60 vs 19 months, P = .003) and a minimal risk of transformation. Conclusion Myelomonocytic skewing as determined by semisolid cultures can discriminate subgroups of patients with CMML with a different phenotype, a different genotype, and a different prognosis.
Published: 2021
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26. Presentation of a rare, highly aggressive peritoneal disease: desmoplastic small round cell tumor and its therapeutic options

Author: Philipp Schredl, Daniel Neureiter, Klaus Emmanuel, Tarkan Jäger, and Jan Philipp Ramspott
Subjects: medicine.medical_specialty, Abdominal pain, medicine.diagnostic_test, Desmoplastic small-round-cell tumor, business.industry, medicine.medical_treatment, Physical examination, medicine.disease, Radiation therapy, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Ascites, Medicine, 030211 gastroenterology & hepatology, Surgery, Hyperthermic intraperitoneal chemotherapy, Sarcoma, Radiology, medicine.symptom, business, Abdominal surgery
Abstract: Summary Background Desmoplastic small round cell tumor is a rare highly aggressive peritoneal disease (sarcoma) with mortality rates up to 70% in the first 3 years after diagnosis. It mainly affects young men. Patients clinically complain about diffuse abdominal pain. Methods This case report describes the clinical course of a 69-year-old man who presented with recurrent abdominal pain. Physical examination, laboratory testing, imaging, and gastroscopy were performed. Intra-abdominal peritoneal biopsies were taken during diagnostic laparoscopy. Results Physical examination was unremarkable. Laboratory results showed elevated white blood cells, C‑reactive protein, and negative tumor markers. Computed tomography and positron emission tomography scan revealed extensive peritoneal metastases with diffuse intra-abdominal signal intensities and ascites. Gastroscopy was unremarkable, whereas diagnostic laparoscopy confirmed imaging results with a peritoneal cancer index of 39. Extensive immunohistochemical and consecutive molecular investigations led to the diagnosis of an intraperitoneal desmoplastic small round cell tumor. Conclusion Our case report demonstrates a very rare cause of recurrent abdominal pain. Desmoplastic small round cell tumor is a rare and highly aggressive undifferentiated sarcoma, which mainly affects young men. Treatment options include chemotherapy, radiotherapy, cytoreductive surgery, and/or hyperthermic intraperitoneal chemotherapy. Standardized treatment protocols are still lacking because only a few cases have been described so far. Differential diagnoses include all malignancies with peritoneal masses.
Published: 2021
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27. Leukocyte Telomere Length in Patients with Multiple Sclerosis and Its Association with Clinical Phenotypes

Author: Margit Schwartz, Michael Walter, Jan Bühring, Michael Hecker, Brit Fitzner, Uwe K. Zettl, Alexander Hartmann, and Kathrin Jäger
Subjects: Adult, Male, 0301 basic medicine, Oncology, Aging, medicine.medical_specialty, Multiple Sclerosis, Neurology, Adolescent, Immunosenescence, Neuroscience (miscellaneous), Disease, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Internal medicine, Leukocytes, medicine, Humans, In patient, Aged, Telomere length, business.industry, Multiple sclerosis, Telomere Homeostasis, Middle Aged, Telomere, medicine.disease, Phenotype, 030104 developmental biology, Real-time polymerase chain reaction, Original Article, Female, business, 030217 neurology & neurosurgery
Abstract: Aging is a significant factor influencing the course of multiple sclerosis (MS). Accelerated telomere attrition is an indicator of premature biological aging and a potential contributor to various chronic diseases, including neurological disorders. However, there is currently a lack of studies focusing on telomere lengths in patients with MS. We measured the average leukocyte telomere length (LTL) in biobanked DNA samples of 40 relapsing-remitting MS patients (RRMS), 20 primary progressive MS patients (PPMS), and 60 healthy controls using a multiplex quantitative polymerase chain reaction method. Changes in LTL over a period of >10 years were evaluated in a subset of 10 patients. Association analyses of baseline LTL with the long-term clinical profiles of the patients were performed using inferential statistical tests and regression models adjusted for age and sex. The cross-sectional analysis revealed that the RRMS group was characterized by a significantly shorter relative LTL, on average, as compared to the PPMS group and controls. Shorter telomeres at baseline were also associated with a higher conversion rate from RRMS to secondary progressive MS (SPMS) in the 10-year follow-up. The LTL decrease over time was similar in RRMS patients and PPMS patients in the longitudinal analysis. Our data suggest a possible contributory role of accelerated telomere shortening in the pathobiology of MS. The interplay between disease-related immune system alterations, immunosenescence, and telomere dynamics deserves further investigation. New insights into the mechanisms of disease might be obtained, e.g., by exploring the distribution of telomere lengths in specific blood cell populations. Supplementary Information The online version contains supplementary material available at 10.1007/s12035-021-02315-y.
Published: 2021
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28. Diabetes mellitus in intraductal papillary mucinous neoplasms: A systematic review and meta-analysis

Author: Stephan Schorn, Rüdiger Göß, Alexander Novotny, Helmut Friess, Ilaria Pergolini, Güralp O. Ceyhan, Ihsan Ekin Demir, and Carsten Jäger
Subjects: medicine.medical_specialty, MEDLINE, 030230 surgery, Risk Assessment, Gastroenterology, Global Burden of Disease, Pancreaticoduodenectomy, 03 medical and health sciences, Pancreatectomy, 0302 clinical medicine, Risk Factors, Internal medicine, Diabetes mellitus, Diabetes Mellitus, Prevalence, Humans, Medicine, Pancreatic duct, Invasive carcinoma, Intraductal papillary mucinous neoplasm, business.industry, Pancreatic Ducts, medicine.disease, Adenocarcinoma, Mucinous, Pancreatic Neoplasms, medicine.anatomical_structure, Dysplasia, 030220 oncology & carcinogenesis, Relative risk, Meta-analysis, Preoperative Period, Disease Progression, Surgery, business, Carcinoma, Pancreatic Ductal
Abstract: Our current knowledge of diabetes mellitus in intraductal papillary mucinous neoplasm is very limited and its prevalence and predictive value for malignant transformation are not clear. This study sought to systematically review the literature to define the prevalence of diabetes mellitus in intraductal papillary mucinous neoplasm and to evaluate the association of diabetes mellitus with the progression to high-grade dysplasia or invasive cancer.A PubMed/Medline systematic search was performed to identify studies reporting data on preoperative diabetes mellitus in intraductal papillary mucinous neoplasm. Articles meeting the predefined inclusion criteria were analyzed and a meta-analysis was performed. The study was preregistered (PROSPERO ID: CRD42020153581).From the initially detected 827 studies, 27 studies including resected patients with histologically confirmed intraductal papillary mucinous neoplasm were included. The global prevalence of preoperative diabetes mellitus was 25% (1,112 of 4,412); whereas new-onset/worsening diabetes mellitus was reported in 6% of patients (68 of 1,202). The meta-analysis revealed that patients with pre-existing diabetes mellitus had an increased risk of harboring a main pancreatic duct involvement (risk ratio 1.43, 95% confidence interval: 1.21-1.69, P.001), high-grade dysplasia (risk ratio 1.27, 95% confidence interval: 1.01-1.59, P = .04), and invasive cancer (risk ratio 1.61, 95% confidence interval: 1.33-1.95, P.001).The prevalence of diabetes mellitus in intraductal papillary mucinous neoplasm is high, and diabetic patients demonstrate an increased risk of a more aggressive disease. Therefore, diabetes mellitus should be increasingly considered in the stratification of patients with intraductal papillary mucinous neoplasm. Further investigations to determine the mechanisms behind the association with progression should be carried out.
Published: 2021
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29. Germline genetic factors influence the outcome of interferon-α therapy in polycythemia vera

Author: Jakob Weinzierl, Martin Schalling, Michael Zörer, Kurt Krejcy, Heinz Gisslinger, Roland Jäger, Christoph Klade, Jelena D. Milosevic Feenstra, Elisabeth Fuchs, Fiorella Schischlik, Edith Bogner, Robert Kralovics, and Bettina Gisslinger
Subjects: Oncology, medicine.medical_specialty, Immunology, Polymorphism, Single Nucleotide, Biochemistry, Germline, Open Reading Frames, Polycythemia vera, Interferon, Internal medicine, Statistical significance, medicine, Humans, Genetic Predisposition to Disease, Polycythemia Vera, Genetic association, Myeloid Neoplasia, business.industry, Interleukins, Interferon-alpha, Cell Biology, Hematology, Odds ratio, medicine.disease, Confidence interval, Treatment Outcome, Germ Cells, Cohort, Immunotherapy, business, Follow-Up Studies, medicine.drug
Abstract: Interferon-α (IFN-α)–based treatments can induce hematologic and molecular responses (HRs and MRs, respectively) in polycythemia vera (PV); however, patients do not respond equally. Germline genetic factors have been implicated in differential drug responses. We addressed the effect of common germline polymorphisms on HR and MR after treatment of PV in the PROUD-PV and CONTINUATION-PV studies in a total of 122 patients who received ropeginterferon alfa-2b. Genome-wide association studies using longitudinal data on HR and MR over a 36-month follow-up did not reveal any associations at the level of genome-wide statistical significance. Furthermore, we performed targeted association analyses at the interferon lambda 4 (IFNL4) locus, well known for its role in hepatitis C viral clearance and recently reported to influence HR during treatment of myeloproliferative neoplasms. We did not observe any association of IFNL4 polymorphisms with HR in our study cohort; however, we demonstrated a statistically significant effect of the functionally causative IFNL4 diplotype (haplotype pair, including the protein-coding variants rs368234815/rs117648444) on MR (P = 3.91 × 10−4; odds ratio, 10.80; 95% confidence interval, 2.39-69.97) as reflected in differential JAK2V617F mutational burden changes according to IFNL4 diplotype status. Stratification of patients with PV based on IFNL4 functionality may allow for optimizing patient management during IFN-α–based therapy.
Published: 2021
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30. Poly(<scp>ADP</scp>‐ribose) polymerase inhibition in pancreatic cancer

Author: Jens T. Siveke, John P. Neoptolemos, Dirk Jäger, Peter Bailey, Daniel Hübschmann, Anne Katrin Berger, Hans Martin Singh, and Christoph Springfeld
Subjects: Cancer Research, endocrine system diseases, medicine.medical_treatment, Medizin, Poly(ADP-ribose) Polymerase Inhibitors, Biology, Olaparib, Targeted therapy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Germline mutation, Maintenance therapy, Pancreatic cancer, Genetics, medicine, Animals, Humans, Clinical Trials as Topic, Chemotherapy, Recombinational DNA Repair, Immunotherapy, medicine.disease, Pancreatic Neoplasms, chemistry, 030220 oncology & carcinogenesis, PARP inhibitor, Cancer research, Carcinoma, Pancreatic Ductal
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Recently, the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib has been approved for maintenance therapy after successful platinum-based chemotherapy in patients with germline mutations in BRCA1 and BRCA2. Approval was based on the POLO study that has shown a significant improvement in progression-free survival for patients with metastatic PDAC after at least 4 months of platinum-based chemotherapy. Hopefully, this first biomarker-directed targeted therapy for a relevant subgroup of pancreatic cancer patients is only the beginning of an era of personalized therapy for pancreatic cancer. The potential role for PARPi in improving survival in patients with pancreatic cancer containing somatic tumor mutations has yet to be established. Multiple studies investigating whether PARPi therapy might benefit a larger group of pancreatic cancer patients with homologous recombination repair deficiency and whether combinations with chemotherapy, immunotherapy, or small molecules can improve efficacy are currently underway. We here review the molecular basis for PARPi therapy in PDAC patients and recent developments in clinical studies.
Published: 2021
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31. Small Vessel Disease and Ischemic Stroke Risk During Anticoagulation for Atrial Fibrillation After Cerebral Ischemia

Author: Houwei Du, Duncan Wilson, Gareth Ambler, Gargi Banerjee, Clare Shakeshaft, Hannah Cohen, Tarek Yousry, Rustam Al-Shahi Salman, Gregory Y.H. Lip, Henry Houlden, Martin M. Brown, Keith W. Muir, Hans Rolf Jäger, David J. Werring, Adrian Parry-Jones, Chris Patterson, Christopher Price, Abduelbaset Elmarimi, Anthea Parry, Arumug Nallasivam, Azlisham Mohd Nor, Bernard Esisi, David Bruce, Biju Bhaskaran, Christine Roffe, Claire Cullen, Clare Holmes, David Cohen, David Hargroves, David Mangion, Dinesh Chadha, Djamil Vahidassr, Dulka Manawadu, Elio Giallombardo, Elizabeth Warburton, Enrico Flossman, Gunaratam Gunathilagan, Harald Proschel, Hedley Emsley, Ijaz Anwar, Ilse Burger, James Okwera, Janet Putterill, Janice O’Connell, John Bamford, John Corrigan, Jon Scott, Jonathan Birns, Karen Kee, Kari Saastamoinen, Kath Pasco, Krishna Dani, Lakshmanan Sekaran, Lillian Choy, Liz Iveson, Maam Mamun, Mahmud Sajid, Martin Cooper, Mathew Burn, Matthew Smith, Michael Power, Michelle Davis, Nigel Smyth, Roland Veltkamp, Pankaj Sharma, Paul Guyler, Paul O’Mahony, Peter Wilkinson, Prabel Datta, Prasanna Aghoram, Rachel Marsh, Robert Luder, Sanjeevikumar Meenakishundaram, Santhosh Subramonian, Simon Leach, Sissi Ispoglou, Sreeman Andole, Timothy England, Aravindakshan Manoj, Harrington Frances, Habib Rehman, Jane Sword, Julie Staals, Karim Mahawish, Kirsty Harkness, Louise Shaw, Michael McCormick, Nikola Sprigg, Syed Mansoor, and Vinodh Krishnamurthy
Subjects: Male, medicine.medical_specialty, brain, Small vessel occlusion, Ischemia, Disease, Brain Ischemia, White matter, Recurrence, Internal medicine, Atrial Fibrillation, medicine, Humans, ischemic attack, transient, atrial fibrillation, anticoagulation, Aged, Ischemic Stroke, Aged, 80 and over, Advanced and Specialized Nursing, business.industry, Atrial fibrillation, Middle Aged, medicine.disease, medicine.anatomical_structure, Cerebral Small Vessel Diseases, Ischemic stroke, Cardiology, Female, Neurology (clinical), Small vessel, Cardiology and Cardiovascular Medicine, business, white matter
Abstract: Background and Purpose: The causes of recurrent ischemic stroke despite anticoagulation for atrial fibrillation are uncertain but might include small vessel occlusion. We investigated whether magnetic resonance imaging markers of cerebral small vessel disease (SVD) are associated with ischemic stroke risk during follow-up in patients anticoagulated for atrial fibrillation after recent ischemic stroke or transient ischemic attack. Methods: We analyzed data from a prospective multicenter inception cohort study of ischemic stroke or transient ischemic attack anticoagulated for atrial fibrillation (CROMIS-2 [Clinical Relevance of Microbleeds in Stroke Study]). We rated markers of SVD on baseline brain magnetic resonance imaging: basal ganglia perivascular spaces (number ≥11); cerebral microbleeds (number ≥1); lacunes (number ≥1); and white matter hyperintensities (periventricular Fazekas grade 3 or deep white matter Fazekas grade ≥2). We investigated the associations of SVD presence (defined as presence of ≥1 SVD marker) and severity (composite SVD score) with the risk of ischemic stroke during follow-up using a Cox proportional hazards model adjusted for congestive heart failure, hypertension, age >75, diabetes, stroke, vascular disease, age 65–74, female score. Results: We included 1419 patients (mean age: 75.8 years [SD, 10.4]; 42.1% female). The ischemic stroke rate during follow-up in patients with any SVD was 2.20 per 100-patient years (95% CI, 1.60–3.02), compared with 0.98 per 100 patient-years (95% CI, 0.59–1.62) in those without SVD ( P =0.008). After adjusting for congestive heart failure, hypertension, age >75, diabetes, stroke, vascular disease, age 65–74, female score, SVD presence remained significantly associated with ischemic stroke during follow-up (hazard ratio, 1.89 [95% CI, 1.01–3.53]; P =0.046); the risk of recurrent ischemic stroke increased with SVD score (hazard ratio per point increase, 1.33 [95% CI, 1.04–1.70]; P =0.023). Conclusions: In patients anticoagulated for atrial fibrillation after ischemic stroke or transient ischemic attack, magnetic resonance imaging markers of SVD are associated with an increased risk of ischemic stroke during follow-up; improved stroke prevention treatments are required in this population. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02513316.
Published: 2021
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32. Praxisrelevante pharmakogenetische Diagnostik zur Verbesserung der Arzneimitteltherapie

Author: Roman Tremmel, Elke Schaeffeler, Severin Schricker, Simon Jäger, and Matthias Schwab
Subjects: medicine.medical_specialty, medicine.diagnostic_test, business.industry, MEDLINE, General Medicine, medicine.disease, 030226 pharmacology & pharmacy, Clinical Practice, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Pharmacogenomics, medicine, Personalized medicine, Drug reaction, business, Intensive care medicine, Adverse drug reaction, Genetic testing
Abstract: Pharmacogenomics (PGx) is a key component of personalized medicine to improve clinical outcome of drug therapy and/or to avoid adverse drug reactions. Major efforts are currently spent internationally to implement PGx diagnostics into clinical practice. Evidence-based recommendations for dose-adjusted treatment which are established by international expert groups covering clinical and pharmacological expertise are publicly available. Clinical relevant examples for PGx diagnostics such as genetic testing for dihydropyrimidin-dehydrogenase and thiopurin-S-methyltransferase, as well as for various cytochrome P450 enzymes are summarized to promote the clinical implementation process of PGx in Germany.
Published: 2021
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33. International Impact of COVID-19 on the Diagnosis of Heart Disease

Author: Einstein, A. J., Shaw, L. J., Hirschfeld, C., Williams, M. C., Villines, T. C., Better, N., Vitola, J. V., Cerci, R., Dorbala, S., Raggi, P., Choi, A. D., Lu, B., Sinitsyn, V., Sergienko, V., Kudo, T., Norgaard, B. L., Maurovich-Horvat, P., Campisi, R., Milan, E., Louw, L., Allam, A. H., Bhatia, M., Malkovskiy, E., Goebel, B., Cohen, Y., Randazzo, M., Narula, J., Pascual, T. N. B., Pynda, Y., Dondi, M., Gerd Hinterleitner, Paez D., Yao, Lu, Olga, Morozova, Zhuoran, Xu, Juan, Lopez-Mattei, Purvi, Parwani, Mohammad Nawaz Nasery, Artan, Goda, Ervina, Shirka, Rabie, Benlabgaa, Salah, Bouyoucef, Abdelkader, Medjahedi, Qais, Nailli, Mariela, Agolti, Roberto Nicolas Aguero, Maria Del Carmen Alak, Lucia Graciela Alberguina, Guillermo, Arroñada, Andrea, Astesiano, Alfredo, Astesiano, Carolina Bas Norton, Pablo, Benteo, Juan, Blanco, Juan Manuel Bonelli, Jose Javier Bustos, Raul, Cabrejas, Jorge, Cachero, Alejandro, Canderoli, Silvia, Carames, Patrícia, Carrascosa, Ricardo, Castro, Oscar, Cendoya, Luciano Martin Cognigni, Carlos, Collaud, Claudia, Cortes, Javier, Courtis, Daniel, Cragnolino, Mariana, Daicz, Alejandro De La Vega, Silvia Teresa De Maria, Horacio Del Riego, Fernando, Dettori, Alejandro, Deviggiano, Laura, Dragonetti, Mario, Embon, Ruben Emilio Enriquez, Jorge, Ensinas, Fernando, Faccio, Adolfo, Facello, Diego, Garofalo, Ricardo, Geronazzo, Natalia, Gonza, Lucas, Gutierrez, Miguel Angel Guzzo, Victor, Hasbani, Melina, Huerin, Victor, Jäger, Julio Manuel Lewkowicz, Maria Nieves, A López De Munaín, Jose Maria Lotti, Alejandra, Marquez, Osvaldo, Masoli, Edgardo, Mastrovito, Matias, Mayoraz, Graciela Eva Melado, Anibal, Mele, Maria Fernanda Merani, Alejandro Horacio Meretta, Susana, Molteni, Marcos, Montecinos, Eduardo, Noguera, Carlos, Novoa, Claudio Pereyra Sueldo, Sebastian Perez Ascani, Pablo, Pollono, Maria Paula Pujol, Alejandro, Radzinschi, Gustavo, Raimondi, Marcela, Redruello, Marina, Rodríguez, Matías, Rodríguez, Romina Lorena Romero, Arturo Romero Acuña, Federico, Rovaletti, Lucas San Miguel, Lucrecia, Solari, Bruno, Strada, Sonia, Traverso, Sonia Simona Traverzo, Maria Del Huerto Velazquez Espeche, Juan Sebastian Weihmuller, Juan, Wolcan, Susana, Zeffiro, Mari, Sakanyan, Scott, Beuzeville, Raef, Boktor, Patrick, Butler, Jennifer, Calcott, Loretta, Carr, Virgil, Chan, Charles, Chao, Woon, Chong, Mark, Dobson, D'Arne, Downie, Girish, Dwivedi, Barry, Elison, Jean, Engela, Roslyn, Francis, Anand, Gaikwad, Ashok Gangasandra Basavaraj, Bruce, Goodwin, Robert, Greenough, Christian, Hamilton-Craig, Victar, Hsieh, Subodh, Joshi, Karin, Lederer, Kenneth, Lee, Joseph, Lee, John, Magnussen, Nghi, Mai, Gordon, Mander, Fiona, Murton, Dee, Nandurkar, Johanne, Neill, Edward, O'Rourke, Patricia, O'Sullivan, George, Pandos, Kunthi, Pathmaraj, Alexander, Pitman, Rohan, Poulter, Manuja, Premaratne, David, Prior, Lloyd, Ridley, Natalie, Rutherford, Hamid, Salehi, Connor, Saunders, Luke, Scarlett, Sujith, Seneviratne, Deepa, Shetty, Ganesh, Shrestha, Jonathan, Shulman, Vijay, Solanki, Tony, Stanton, Murch, Stuart, Michael, Stubbs, Ian, Swainson, Kim, Taubman, Andrew, Taylor, Paul, Thomas, Steven, Unger, Anthony, Upton, Shankar, Vamadevan, William Van Gaal, Johan, Verjans, Demetrius, Voutnis, Victor, Wayne, Peter, Wilson, David, Wong, Kirby, Wong, John, Younger, Gudrun, Feuchtner, Siroos, Mirzaei, Konrad, Weiss, Natallia, Maroz-Vadalazhskaya, Olivier, Gheysens, Filip, Homans, Rodrigo, Moreno-Reyes, Agnès, Pasquet, Veronique, Roelants, Caroline, M Van De Heyning, Raúl Araujo Ríos, Valentina, Soldat-Stankovic, Sinisa, Stankovic, Maria Helena Albernaz Siqueira, Augusto, Almeida, Paulo Henrique Alves Togni, Jose Henrique Andrade, Luciana, Andrade, Carlos, Anselmi, Roberta, Araújo, Guilherme, Azevedo, Sabbrina, Bezerra, Rodrigo, Biancardi, Gabriel Blacher Grossman, Simone, Brandão, Diego Bromfman Pianta, Lara, Carreira, Bruno, Castro, Tien, Chang, Fernando Cunali Jr, Roberto, Cury, Roberto, Dantas, Fernando de Amorim Fernandes, Andrea De Lorenzo, Robson De Macedo Filho, Fernanda, Erthal, Fabio, Fernandes, Juliano, Fernandes, Thiago Ferreira De Souza, Wilson Furlan Alves, Bruno, Ghini, Luiz, Goncalves, Ilan, Gottlieb, Marcelo, Hadlich, Vinícius, Kameoka, Ronaldo, Lima, Adna, Lima, Rafael Willain Lopes, Ricardo Machado, E Silva, Tiago, Magalhães, Fábio Martins Silva, Luiz Eduardo Mastrocola, Fábio, Medeiros, José Claudio Meneghetti, Vania, Naue, Danilo, Naves, Roberto, Nolasco, Cesar, Nomura, Joao Bruno Oliveira, Eduardo, Paixao, Filipe Penna De Carvalho, Ibraim, Pinto, Priscila, Possetti, Mayra, Quinta, Rodrigo Rizzo Nogueira Ramos, Ricardo, Rocha, Alfredo, Rodrigues, Carlos, Rodrigues, Leila, Romantini, Adelina, Sanches, Sara, Santana, Leonardo Sara da Silva, Paulo, Schvartzman, Cristina Sebastião Matushita, Tiago, Senra, Afonso, Shiozaki, Maria Eduarda Menezes de Siqueira, Cristiano, Siqueira, Paola, Smanio, Carlos Eduardo Soares, José Soares Junior, Marcio Sommer Bittencourt, Bernardo, Spiro, Cláudio Tinoco Mesquita, Jorge, Torreao, Rafael, Torres, Marly, Uellendahl, Guilherme Urpia Monte, Otávia, Veríssimo, Estevan Vieira Cabeda, Felipe Villela Pedras, Roberto, Waltrick, Marcello, Zapparoli, Hamid, Naseer, Marina, Garcheva-Tsacheva, Irena, Kostadinova, Youdaline, Theng, Gad, Abikhzer, Rene, Barette, Benjamin, Chow, Dominique, Dabreo, Matthias, Friedrich, Ria, Garg, Mohammed Nassoh Hafez, Chris, Johnson, Marla, Kiess, Jonathon, Leipsic, Eugene, Leung, Robert, Miller, Anastasia, Oikonomou, Stephan, Probst, Idan, Roifman, Gary, Small, Vikas, Tandon, Adwait, Trivedi, James, White, Katherine, Zukotynski, Jose, Canessa, Gabriel Castro Muñoz, Carmen, Concha, Pablo, Hidalgo, Cesar, Lovera, Teresa, Massardo, Luis Salazar Vargas, Pedro, Abad, Harold, Arturo, Sandra, Ayala, Luis, Benitez, Alberto, Cadena, Carlos, Caicedo, Antonio Calderón Moncayo, Sharon, Gomez, Claudia, T Gutierrez Villamil, Claudia, Jaimes, Juan Luis Londoño Blair, Luz, Pabon, Mauricio, Pineda, Juan Carlos Rojas, Diego, Ruiz, Manuel Valencia Escobar, Andres, Vasquez, Damiana, Vergel, Alejandro, Zuluaga, Isabel Berrocal Gamboa, Gabriel, Castro, Ulises, González, Ana, Baric, Tonci, Batinic, Maja, Franceschi, Maja Hrabak Paar, Mladen, Jukic, Petar, Medakovic, Viktor, Persic, Marina, Prpic, Ante, Punda, Juan Felipe Batista, Juan Manuel Gómez Lauchy, Yamile Marcos Gutierrez, Rayner, Menéndez, Amalia, Peix, Luis, Rochela, Christoforos, Panagidis, Ioannis, Petrou, Vaclav, Engelmann, Milan, Kaminek, Vladimír, Kincl, Otto, Lang, Milan, Simanek, Jawdat, Abdulla, Morten, Bøttcher, Mette, Christensen, Lars Christian Gormsen, Philip, Hasbak, Søren, Hess, Paw, Holdgaard, Allan, Johansen, Kasper, Kyhl, Kristian Altern Øvrehus, Niels Peter Rønnow Sand, Rolf, Steffensen, Anders, Thomassen, Zerahn, Bo, Alfredo, Perez, Giovanni Alejandro Escorza Velez, Mayra Sanchez Velez, Islam Shawky Abdel Aziz, Mahasen, Abougabal, Taghreed, Ahmed, Ahmed, Asfour, Mona, Hassan, Alia, Hassan, Ahmed, Ibrahim, Sameh, Kaffas, Ahmed, Kandeel, Mohamed Mandour Ali, Ahmad, Mansy, Hany, Maurice, Sherif, Nabil, Mahmoud, Shaaban, Ana Camila Flores, Anne, Poksi, Juhani, Knuuti, Velipekka, Kokkonen, Martti, Larikka, Valtteri, Uusitalo, Matthieu, Bailly, Samuel, Burg, Jean-François, Deux, Vincent, Habouzit, Fabien, Hyafil, Olivier, Lairez, Franck, Proffit, Hamza, Regaieg, Laure, Sarda-Mantel, Vania, Tacher, Roman, P Schneider, Harold, Ayetey, George, Angelidis, Aikaterini, Archontaki, Sofia, Chatziioannou, Ioannis, Datseris, Christina, Fragkaki, Panagiotis, Georgoulias, Sophia, Koukouraki, Maria, Koutelou, Eleni, Kyrozi, Evangelos, Repasos, Petros, Stavrou, Pipitsa, Valsamaki, Carla, Gonzalez, Goleat, Gutierrez, Alejandro, Maldonado, Klara, Buga, Ildiko, Garai, Erzsébet, Schmidt, Balint, Szilveszter, Edit, Várady, Nilesh, Banthia, Jinendra Kumar Bhagat, Rishi, Bhargava, Vivek, Bhat, Partha, Choudhury, Vijay Sai Chowdekar, Aparna, Irodi, Shashank, Jain, Elizabeth, Joseph, Sukriti, Kumar, Girijanandan, Mahapatra, Deepanjan, Mitra, Bhagwant Rai Mittal, Ahmad, Ozair, Chetan, Patel, Tapan, Patel, Ravi, Patel, Shivani, Patel, Sudhir, Saxena, Shantanu, Sengupta, Santosh, Singh, Bhanupriya, Singh, Ashwani, Sood, Atul, Verma, Erwin, Affandi, Padma Savenadia Alam, Edison, Edison, Gani, Gunawan, Habusari, Hapkido, Basuki, Hidayat, Aulia, Huda, Anggoro Praja Mukti, Djoko, Prawiro, Erwin Affandi Soeriadi, Hilman, 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Faletti, Evelina, Faragasso, Mohsen, Farsad, Paola, Ferro, Luigia, Florimonte, Viviana, Frantellizzi, Fabio Massimo Fringuelli, Marco, Gatti, Angela, Gaudiano, Alessia, Gimelli, Raffaele, Giubbini, Francesca, Giuffrida, Salvatore, Ialuna, Riccardo, Laudicella, Lucia, Leccisotti, Lucia, Leva, Liga, Riccardo, Carlo, Liguori, Giampiero, Longo, Margherita, Maffione, Maria Elisabetta Mancini, Claudio, Marcassa, Barbara, Nardi, Sara, Pacella, Giovanna, Pepe, Gianluca, Pontone, Sabina, Pulizzi, Natale, Quartuccio, Lucia, Rampin, Fabrizio, Ricci, Pierluigi, Rossini, Giuseppe, Rubini, Vincenzo, Russo, Gian Mauro Sacchetti, Gianmario, Sambuceti, Massimo, Scarano, Roberto, Sciagrà, Massimiliano, Sperandio, Antonella, Stefanelli, Guido, Ventroni, Stefania, Zoboli, Dainia, Baugh, Duane, Chambers, Ernest, Madu, Felix, Nunura, Hiroshi, Asano, Chimura Misato Chimura, Shinichiro, Fujimoto, Koichiro, Fujisue, Tomohisa, Fukunaga, Yoshimitsu, Fukushima, Kae, Fukuyama, Jun, Hashimoto, Yasutaka, Ichikawa, 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Matis, Michael, Mckenna, Tony, Mcrae, Fernando, Mendoza, Michael, Merhige, David, Min, Chanan, Moffitt, Karen, Moncher, Warren, Moore, Shamil, Morayati, Michael, Morris, Mahmud, Mossa-Basha, Zorana, Mrsic, Venkatesh, Murthy, Prashant, Nagpal, Kyle, Napier, Katarina, Nelson, Prabhjot, Nijjar, Medhat, Osman, Edward, Passen, Amit, Patel, Pravin, Patil, Ryan, Paul, Lawrence, Phillips, Venkateshwar, Polsani, Rajaram, Poludasu, Brian, Pomerantz, Thomas, Porter, Ryan, Prentice, Amit, Pursnani, Mark, Rabbat, Suresh, Ramamurti, Florence, Rich, Hiram Rivera Luna, Austin, Robinson, Kim, Robles, Cesar, Rodríguez, Mark, Rorie, John, Rumberger, Raymond, Russell, Philip, Sabra, Diego, Sadler, Mary, Schemmer, U Joseph Schoepf, Samir, Shah, Nishant, Shah, Sujata, Shanbhag, Gaurav, Sharma, Steven, Shayani, Jamshid, Shirani, Pushpa, Shivaram, Steven, Sigman, Mitch, Simon, Ahmad, Slim, David, Smith, Alexandra, Smith, Prem, Soman, Aditya, Sood, Monvadi Barbara Srichai-Parsia, James, Streeter, Albert, T Ahmed Tawakol, Dustin, Thomas, Randall, Thompson, Tara, Torbet, Desiree, Trinidad, Shawn, Ullery, Samuel, Unzek, Seth, Uretsky, Srikanth, Vallurupalli, Vikas, Verma, Alfonso, Waller, Ellen, Wang, Parker, Ward, Gaby, Weissman, George, Wesbey, Kelly, White, David, Winchester, David, Wolinsky, Sandra, Yost, Michael, Zgaljardic, Omar, Alonso, Mario, Beretta, Rodolfo, Ferrando, Miguel, Kapitan, Fernando, Mut, Omoa, Djuraev, Gulnora, Rozikhodjaeva, Ha Le Ngoc, Son Hong Mai, Xuan Canh Nguyen, Einstein, A. J., Shaw, L. J., Hirschfeld, C., Williams, M. C., Villines, T. C., Better, N., Vitola, J. V., Cerci, R., Dorbala, S., Raggi, P., Choi, A. D., Lu, B., Sinitsyn, V., Sergienko, V., Kudo, T., Norgaard, B. L., Maurovich-Horvat, P., Campisi, R., Milan, E., Louw, L., Allam, A. H., Bhatia, M., Malkovskiy, E., Goebel, B., Cohen, Y., Randazzo, M., Narula, J., Pascual, T. N. B., Pynda, Y., Dondi, M., Paez, D., Cuocolo, A., Einstein, A, Shaw, L, Hirschfeld, C, Williams, M, Villines, T, Better, N, Vitola, J, Cerci, R, Dorbala, S, Raggi, P, Choi, A, Lu, B, Sinitsyn, V, Sergienko, V, Kudo, T, Norgaard, B, Maurovich-Horvat, P, Campisi, R, Milan, E, Louw, L, Allam, A, Bhatia, M, Malkovskiy, E, Goebel, B, Cohen, Y, Randazzo, M, Narula, J, Pascual, T, Pynda, Y, Dondi, M, Paez, D, Pacella, S, and Erba, P
Subjects: INCAPS COVID Investigators Group, Heart disease, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Diagnostic Techniques, Cardiovascular, coronavirus, global health, IAEA, Disease, Telehealth, Cardiorespiratory Medicine and Haematology, 030204 cardiovascular system & hematology, Cardiovascular, 0302 clinical medicine, cardiovascular disease, cardiac testing, COVID-19, diagnostic techniques, cardiovascular, health care surveys, heart diseases, humans, international agencies, Pandemic, Global health, 030212 general & internal medicine, COVID-19 Heart Disease, Cause of death, STATEMENT, Heart Disease, International Agencie, Public Health and Health Services, Biomedical Imaging, Cardiology and Cardiovascular Medicine, Human, medicine.medical_specialty, Heart Diseases, 03 medical and health sciences, Clinical Research, medicine, Humans, Personal protective equipment, Heart Disease - Coronary Heart Disease, business.industry, International Agencies, medicine.disease, the, coronaviru, Diagnostic Techniques, Good Health and Well Being, Clinical research, Cardiovascular System & Hematology, Health Care Survey, Health Care Surveys, Emergency medicine, Global Health, business
Abstract: BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic has adversely affected diagnosis and treatment of noncommunicable diseases. Its effects on delivery of diagnostic care for cardiovascular disease, which remains the leading cause of death worldwide, have not been quantified. OBJECTIVES The study sought to assess COVID-19`s impact on global cardiovascular diagnostic procedural volumes and safety practices. METHODS The International Atomic Energy Agency conducted a worldwide survey assessing alterations in cardiovascular procedure volumes and safety practices resulting from COVID-19. Noninvasive and invasive cardiac testing volumes were obtained from participating sites for March and April 2020 and compared with those from March 2019. Availability of personal protective equipment and pandemic-related testing practice changes were ascertained. RESULTS Surveys were submitted from 909 inpatient and outpatient centers performing cardiac diagnostic procedures, in 108 countries. Procedure volumes decreased 42% from March 2019 to March 2020, and 64% from March 2019 to April 2020. Transthoradc echocardiography decreased by 59%, transesophageat echocardiography 76%, and stress tests 78%, which varied between stress modalities. Coronary angiography (invasive or computed tomography) decreased 55% (p < 0.001 for each procedure). hi multivariable regression, significantly greater reduction in procedures occurred for centers in countries with lower gross domestic product. Location in a low-income and lower-middle-income country was associated with an additional 22% reduction in cardiac procedures and less availability of personal protective equipment and teteheatth. CONCLUSIONS COVID-19 was associated with a significant and abrupt reduction in cardiovascular diagnostic testing across the globe, especially affecting the world's economically challenged. Further study of cardiovascular outcomes and COVID-19-related changes in care delivery is warranted. (C) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.
Published: 2021
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34. Outcomes in patients treated with chimeric antigen receptor T-cell therapy who were admitted to intensive care (CARTTAS): an international, multicentre, observational cohort study

Author: Marie-Therese Rubio, Roberta Di Blasi, Gilles Salles, Miguel A Perales, Kada Klouche, Muriel Picard, Pierre Sesques, Eric Mariotte, Michael Darmon, Boris Böll, Philippe R. Bauer, Sanjay Chawla, Kevin Rakszawski, Nahema Issa, Anne Huynh, Guillaume Cartron, Florence Rabian, Peter Borchmann, Michael Joannidis, Sabine Furst, Sophie de Guibert, Lara Zafrani, Patrice Ceballos, Nicolas Boissel, David Beauvais, Catherine Thieblemont, François-Xavier Gros, Alberto Mussetti, Gabriel Moreno-González, Adel Maamar, Florent Wallet, Faezeh Legrand, Julien Leroy, Quentin Quelven, Djamel Mokart, Valentin Ortiz, Christian Recher, Jakob Rudzki, Laura Platon, Pleun Hemelaar, Benoit Tessoulin, Reuben Benjamin, Sandrine Valade, Pedro Castro, Gennadii Galstian, Amélie Seguin, Peter Schellongowski, Anna Sureda, Alice Gallo De Moraes, Philipp Wohlfarth, Bruno Levy, Andry Van de Louw, Jorge Garcia Borrega, Julio Delgado, Ibrahim Yakoub-Agha, Nathalie Fégueux, Laveena Munshi, Yi Lin, Emmanuel Bachy, Stéphanie Harel, Sara Fernández, Bertrand Arnulf, Thomas Gastinne, Elie Azoulay, Didier Blaise, Amandine Le Bourgeois, Louis Voigt, Cécile Borel, Anne-Sophie Moreau, Christian Chabannon, Ulrich Jäger, Virginie Lemiale, Olga Gavrilina, Victoria Metaxa, Thomas Staudingert, Edouard Forcade, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Barcelona, CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), King's College Hospital (KCH), Mayo Clinic [Rochester], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Roger Salengro [Lille], Penn State Health Milton S. Hershey Medical Center, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Penn State System, Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Universitätsklinikum Köln (Uniklinik Köln), Hôpital Saint-André, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Radboud University Medical Center [Nijmegen], Universitat de Barcelona (UB), University of Toronto, Medizinische Universität Wien = Medical University of Vienna, Leopold Franzens Universität Innsbruck - University of Innsbruck, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Soins Intensifs [CHRU Nancy], Radboud University Medical Centre [Nijmegen, The Netherlands], University of Innsbruck, and National Research Center for Hematology [Moscow, Russia]
Subjects: Male, MESH: Neurotoxicity Syndromes, MESH: Registries, [SDV]Life Sciences [q-bio], MESH: Multiple Myeloma, Immunotherapy, Adoptive, Severity of Illness Index, law.invention, MESH: Proportional Hazards Models, Medicina intensiva, Clinical trials, 0302 clinical medicine, law, Clinical endpoint, Medicine, Infection control, Registries, MESH: Treatment Outcome, MESH: Middle Aged, Medical record, Hazard ratio, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, MESH: Follow-Up Studies, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Intensive care unit, 3. Good health, Survival Rate, Cytokine release syndrome, Intensive Care Units, Treatment Outcome, 030220 oncology & carcinogenesis, MESH: Immunotherapy, Adoptive, Female, Neurotoxicity Syndromes, Lymphoma, Large B-Cell, Diffuse, Cytokine Release Syndrome, Multiple Myeloma, Care of the sick, Cohort study, Adult, medicine.medical_specialty, Critical Care, MESH: Survival Rate, Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0], MESH: Cytokine Realease Syndrome, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, MESH: Critical Care, Internal medicine, Intensive care, MESH: Severity of Illness Index, Humans, Cura dels malalts, Critical care medicine, Proportional Hazards Models, MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Humans, business.industry, MESH: Lymphomz, Large B-Cell, Diffuse, MESH: Adult, MESH: Intensive care Units, medicine.disease, MESH: Male, business, MESH: Female, Assaigs clínics, 030215 immunology, Follow-Up Studies
Abstract: Summary Background Chimeric antigen receptor (CAR) T-cell therapy can induce side-effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), which often require intensive care unit admission. The aim of this study was to describe management of critically ill CAR T-cell recipients in intensive care. Methods This international, multicentre, observational cohort study was done in 21 intensive care units in France, Spain, the USA, the UK, Russia, Canada, Germany, and Austria. Eligible patients were aged 18 years or older; had received CAR T-cell therapy in the past 30 days; and had been admitted to intensive care for any reason. Investigators retrospectively included patients admitted between Feb 1, 2018, and Feb 1, 2019, and prospectively included patients admitted between March 1, 2019, and Feb 1, 2020. Demographic, clinical, laboratory, treatment, and outcome data were extracted from medical records. The primary endpoint was 90-day mortality. Factors associated with mortality were identified using a Cox proportional hazard model. Findings 942 patients received CAR T-cell therapy, of whom 258 (27%) required admission to intensive care and 241 (26%) were included in the analysis. Admission to intensive care was needed within median 4·5 days (IQR 2·0–7·0) of CAR T-cell infusion. 90-day mortality was 22·4% (95% CI 17·1–27·7; 54 deaths). At initial evaluation on admission, isolated cytokine release syndrome was identified in 101 patients (42%), cytokine release syndrome and ICANS in 93 (39%), and isolated ICANS in seven (3%) patients. Grade 3–4 cytokine release syndrome within 1 day of admission to intensive care was found in 50 (25%) of 200 patients and grade 3–4 ICANS in 38 (35%) of 108 patients. Bacterial infection developed in 30 (12%) patients. Life-saving treatments were used in 75 (31%) patients within 24 h of admission to intensive care, primarily vasoactive drugs in 65 (27%) patients. Factors independently associated with 90-day mortality by multivariable analysis were frailty (hazard ratio 2·51 [95% CI 1·37–4·57]), bacterial infection (2·12 [1·11–4·08]), and lifesaving therapy within 24 h of admission (1·80 [1·05–3·10]). Interpretation Critical care management is an integral part of CAR T-cell therapy and should be standardised. Studies to improve infection prevention and treatment in these high-risk patients are warranted. Funding Groupe de Recherche Respiratoire en Reanimation Onco-Hematologique.
Published: 2021
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35. Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability–High/Mismatch Repair–Deficient Metastatic Colorectal Cancer: KEYNOTE-164

Author: Chloe E. Atreya, Tae Won Kim, Elena Elez, Ravit Geva, Hiroki Hara, Tong Dai, Hiroya Taniguchi, Luis A. Diaz, Dung T. Le, Patrick McKay Boland, Rosine Guimbaud, Salah-Eddin Al-Batran, Todd S. Crocenzi, Matthew Burge, Thierry André, Petr Kavan, Dirk Jäger, Eric Van Cutsem, Yi Cui, Takayuki Yoshino, Patricia Marinello, Bert H. O'Neil, Institut Català de la Salut, [Le DT] Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD. [Kim TW] Asan Medical Center, Seoul, Republic of Korea. [Van Cutsem E] University Hospitals Gasthuisberg Leuven, KU Leuven, Leuven, Belgium. [Geva R] Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. [Jäger D] Nationales Centrum Tumorerkrankungen, Heidelberg, Germany. [Hara H] Saitama Cancer Center, Saitama, Japan. [Elez E] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Male, 0301 basic medicine, Cancer Research, Colorectal cancer, Medicaments antineoplàstics - Ús terapèutic, Pembrolizumab, Other subheadings::Other subheadings::/drug therapy [Other subheadings], DNA Mismatch Repair, Cohort Studies, 0302 clinical medicine, Open label study, Còlon - Càncer, Neoplasms, Monoclonal, Gastrointestinal Cancer, 80 and over, Humanized, Antitumor activity, Treatment refractory, Neoplasms::Neoplastic Processes::Neoplasm Metastasis [DISEASES], Middle Aged, neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES], Treatment Outcome, Immunological, Oncology, 030220 oncology & carcinogenesis, Recte - Càncer, Female, DNA mismatch repair, Microsatellite Instability, Colorectal Neoplasms, Intravenous, Adult, Infusions, Clinical Sciences, Oncology and Carcinogenesis, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Antineoplastic Agents, and over, Antibodies, Monoclonal, Humanized, Drug Administration Schedule, Antibodies, Young Adult, 03 medical and health sciences, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES], RAPID COMMUNICATIONS, medicine, Humans, Oncology & Carcinogenesis, Aged, business.industry, Microsatellite instability, medicine.disease, 030104 developmental biology, neoplasias::procesos neoplásicos::metástasis neoplásica [ENFERMEDADES], Cancer research, business, Biomarkers
Abstract: PURPOSE KEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) colorectal cancer (CRC). METHODS This phase II open-label study involved 128 centers worldwide. Eligible patients were age ≥ 18 years and had metastatic MSI-H/dMMR CRC treated with ≥ 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti–vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or ≥ 1 prior line of therapy (cohort B). MSI-H/dMMR status was assessed locally. Patients received pembrolizumab 200 mg every 3 weeks for up to 2 years until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate by RECIST version 1.1 by independent central review. Secondary end points were duration of response, progression-free survival (PFS), overall survival, safety, and tolerability. RESULTS A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached). Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in ≥ 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A. CONCLUSION Pembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR CRC.
Published: 2019

36. Paclitaxel-loaded biodegradable ROS-sensitive nanoparticles for cancer therapy

Author: Eliézer Jäger, Petr Štěpánek, Alessandro Jäger, Bo Nyström, Tore Skotland, Gunhild Mari Mælandsmo, Abhilash D. Pandya, Martin Hrubý, Shahla Bagheri Fam, Vladimir Sincari, Anita Höcherl, and Kirsten Sandvig
Subjects: inorganic chemicals, Biodistribution, Biophysics, Pharmaceutical Science, Bioengineering, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Flow cytometry, Biomaterials, HeLa, chemistry.chemical_compound, In vivo, Drug Discovery, medicine, chemistry.chemical_classification, Reactive oxygen species, medicine.diagnostic_test, biology, Chemistry, Organic Chemistry, technology, industry, and agriculture, General Medicine, 021001 nanoscience & nanotechnology, medicine.disease, biology.organism_classification, In vitro, 0104 chemical sciences, Paclitaxel, Cancer research, 0210 nano-technology, Infiltration (medical)
Abstract: Background Reactive oxygen species (ROS), such as hydrogen peroxide and superoxide, trigger biodegradation of polymer-based nanoparticles (NPs) bearing pinacol-type boronic ester groups. These NPs may selectively release their cargo, in this case paclitaxel (PTX), at the high levels of ROS present in the intracellular environment of inflamed tissues and most tumors. Purpose The main objective was to determine anti-tumor efficacy of PTX-loaded ROS-sensitive NPs and to examine whether macrophage infiltration had any impact on treatment efficacy. Methods NPs were synthesized and their characteristics in the presence of H2O2 were demonstrated. Both confocal microscopy as well as flow cytometry approaches were used to determine degradation of ROS-sensitive NPs. HeLa cells were cultured in vitro and used to establish tumor xenografts in nude mice. In vivo experiments were performed to understand toxicity, biodistribution and anti-tumor efficacy of the NPs. Moreover, we performed immunohistochemistry on tumor sections to study infiltration of M1 and M2 subsets of macrophages. Results We demonstrated that PTX delivered in NPs containing a ROS-sensitive polymer exhibits a better anti-tumor efficacy than PTX in NPs containing ROS-non-sensitive polymer, free PTX or Abraxane® (nab-PTX). The biodistribution revealed that ROS-sensitive NPs exhibit retention in liver, spleen and lungs, suggesting a potential to target cancer metastasizing to these organs. Finally, we demonstrated a correlation between infiltrated macrophage subsets and treatment efficacy, possibly contributing to the efficient anti-tumor effects. Conclusion Treatment with ROS-sensitive NPs containing PTX gave an improved therapeutic effect in HeLa xenografts than their counterpart, free PTX or nab-PTX. Our data revealed a correlation between macrophage infiltration and efficiency of the different antitumor treatments, as the most effective NPs resulted in the highest infiltration of the anti-tumorigenic M1 macrophages.
Published: 2019
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37. The Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML)

Author: Paul Knöbl, Elmir Graf, Gerald Webersinke, Ulrich Germing, Heinz Sill, Andreas L. Petzer, Renate Marschon, Sigrid Machherndl-Spandl, Klaus Geissler, Peter Valent, Thomas Nösslinger, Peter Bettelheim, Ilse Schwarzinger, Leopold Öhler, Heinz Tüchler, Bruno Schneeweiss, Gregor Hoermann, Ulrich Jäger, Sonja Heibl, Jörg Berger, Agnes Barna, Bernhard Doleschal, Thamer Sliwa, Felix Keil, Harald Esterbauer, Josef Thaler, Ansgar Weltermann, Reinhard Stauder, Bojana Borjan, Temeida Graf, Regina Reisner, Michael Gurbisz, Otto Zach, Eva Jäger, Ruth Jilch, Rajko Kusec, Ernst Ulsperger, Armin Zebisch, Michael Pfeilstöcker, Christoph Geissler, and Wolfgang R. Sperr
Subjects: Adult, Male, Oncology, medicine.medical_specialty, Biomedical Research, Information Storage and Retrieval, Chronic myelomonocytic leukemia, Patient characteristics, 030204 cardiovascular system & hematology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, Functional methods, Genotype, Humans, Medicine, 030212 general & internal medicine, Aged, Aged, 80 and over, Data source, CMML, business.industry, CFU-GM, Cytogenetics, Leukemia, Myelomonocytic, Chronic, In vitro culture, General Medicine, Middle Aged, Prognosis, medicine.disease, Real life data, Austria, NGS, Cohort, Female, Original Article, business, RAS
Abstract: Summary In the Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML) clinicolaboratory real-life data have been captured from 606 CMML patients from 14 different hospitals over the last 30 years. It is the only large biodatabase worldwide in which functional methods such as semisolid in vitro cultures complement modern molecular methods such as next generation sequencing. This provides the possibility to comprehensively study the biology of CMML. The aim of this study was to compare patient characteristics with published CMML cohorts and to validate established prognostic parameters in order to examine if this real-life database can serve as a representative and useful data source for further research. After exclusion of patients in transformation characteristics of 531 patients were compared with published CMML cohorts. Median values for age, leukocytes, hemoglobin, platelets, lactate dehydrogenase (LDH) and circulating blasts were within the ranges of reported CMML series. Established prognostic parameters including leukocytes, hemoglobin, blasts and adverse cytogenetics were able to discriminate patients with different outcome. Myeloproliferative (MP) as compared to myelodysplastic (MD)-CMML patients had higher values for circulating blasts, LDH, RAS-pathway mutations and for spontaneous myelomonocytic colony growth in vitro as well as more often splenomegaly. This study demonstrates that the patient cohort of the ABCMML shares clinicolaboratory characteristics with reported CMML cohorts from other countries and confirms phenotypic and genotypic differences between MP-CMML and MD-CMML. Therefore, results obtained from molecular and biological analyses using material from the national cohort will also be applicable to other CMML series and thus may have a more general significance.
Published: 2019
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38. Kidney transplantation after rescue allocation—meticulous selection yields the chance for excellent outcome

Author: Svea Misselwitz, Quirin Bachmann, Maike Büttner-Herold, Carsten Jäger, Lutz Renders, Kerstin Amann, Carlos Torrez, Ming Wen, Alexander Novotny, Stephan Kemmner, Volker Assfalg, Christoph Schmaderer, Uwe Heemann, Flora Haberfellner, and Norbert Hüser
Subjects: Adult, Male, medicine.medical_specialty, Tissue and Organ Procurement, Adolescent, Waiting Lists, 030232 urology & nephrology, Human leukocyte antigen, 030230 surgery, Expanded Criteria Donor, Donor Selection, Resource Allocation, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Biopsy, Humans, Medicine, Child, Kidney transplantation, Aged, Retrospective Studies, Aged, 80 and over, Transplantation, medicine.diagnostic_test, business.industry, Patient Selection, Graft Survival, Confounding, Middle Aged, medicine.disease, Kidney Transplantation, Comorbidity, Tissue Donors, Survival Rate, Treatment Outcome, Nephrology, Child, Preschool, Female, Kidney Diseases, business
Abstract: BackgroundThe small number of organ donors forces transplant centres to consider potentially suboptimal kidneys for transplantation. Eurotransplant established an algorithm for rescue allocation (RA) of kidneys repeatedly declined or not allocated within 5 h after procurement. Data on the outcomes and benefits of RA are scarce to date.MethodsWe conducted a retrospective 8-year analysis of transplant outcomes of RA offers based on our in-house criteria catalogue for acceptance and decline of organs and potential recipients.ResultsRA donors and recipients were both older compared with standard allocation (SA). RA donors more frequently had a history of hypertension, diabetes or fulfilled expanded criteria donor key parameters. RA recipients had poorer human leucocyte antigen (HLA) matches and longer cold ischaemia times (CITs). However, waiting time was shorter and delayed graft function, primary non-function and biopsy-proven rejections were comparable to SA. Five-year graft and patient survival after RA were similar to SA. In multivariate models accounting for confounding factors, graft survival and mortality after RA and SA were comparable as well.ConclusionsFacing relevant comorbidities and rapid deterioration with the risk of being removed from the waiting list, kidney transplantation after RA was identified to allow for earlier transplantation with excellent outcome. Data from this survey propose not to reject categorically organs from multimorbid donors with older age and a history of hypertension or diabetes to aim for the best possible HLA matching and to carefully calculate overall expected CIT.
Published: 2020
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39. Rapidly progressive skin changes in a kidney transplant patient

Author: Hans Bösmüller, Stephan Forchhammer, Sebastian Volc, and Daniela Jäger
Subjects: medicine.medical_specialty, business.industry, medicine, MEDLINE, Dermatology, medicine.disease, business, Kidney transplantation, Surgery
Published: 2020
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40. In cis TP53 and RAD51C pathogenic variants may predispose to sebaceous gland carcinomas

Author: Matthias Stiller, Konrad Platzer, Hendrik Bläker, Carolin Meier, Astrid Monecke, Elisabeth Jäger, Rami Abou Jamra, Diana Le Duc, Johannes R. Lemke, Julia Hentschel, Sonja Neuser, Aleksander Markovic, and Mirjana Ziemer
Subjects: Adult, Male, Sebaceous gland, Biology, Article, Germline, Cancer syndrome, 03 medical and health sciences, 0302 clinical medicine, Genetics research, Genetics, medicine, Humans, Genetic Predisposition to Disease, Sebaceous Gland Neoplasms, Cancer genetics, Genetics (clinical), 030304 developmental biology, Genetic testing, 0303 health sciences, medicine.diagnostic_test, Carcinoma, medicine.disease, Penetrance, DNA-Binding Proteins, Chromosome 17 (human), Phenotype, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Mutation, Cancer research, RAD51C, Sebaceous gland carcinoma, Tumor Suppressor Protein p53
Abstract: Pathogenic variants inTP53have been classically thought to cause Li-Fraumeni syndrome (LFS), a cancer predisposition with high risks for various childhood- and adult-onset malignancies. However, increased genetic testing has lately revealed, that pathogenic variant carriers exhibit a broader range of phenotypes and that penetrance may be dependent both on variant type and modifiers. Using next generation sequencing and short tandem repeat analysis, we identified germline pathogenic variants inTP53andRAD51Clocated incison chromosome 17 in a 43-year-old male, who has developed a rare sebaceous gland carcinoma (SGC) but so far no tumors of the LFS spectrum. This course mirrors aTrp53-Rad51c-double-mutantcismouse-model, which similarly develops SGC, while the characteristicTrp53-associated tumor spectrum occurs with significantly lower frequency. Therefore, we propose that co-occurent pathogenic variants inRAD51CandTP53may predispose to SGC, reminiscent of Muir-Torre syndrome. Further, this report supports the diversity of clinical presentations associated with germlineTP53alterations, and thus, the proposed expansion of LFS to heritableTP53-related cancer syndrome.
Published: 2020
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41. Arterial Spin Labeling MRI in Carotid Stenosis: Arterial Transit Artifacts May Predict Symptoms

Author: Alberto Di Napoli, John Gregson, S. F. Cheng, Julia Emily Markus, David Atkinson, Martin M. Brown, Toby Richards, Hans Rolf Jäger, and Magdalena Sokolska
Subjects: medicine.medical_specialty, genetic structures, business.industry, digestive, oral, and skin physiology, Aged, Artifacts, Carotid Stenosis, Contrast Media, Female, Hemodynamics, Humans, Image Interpretation, Computer-Assisted, Magnetic Resonance Angiography, Male, Middle Aged, Plaque, Atherosclerotic, Spin Labels, medicine.disease, Stenosis, Arterial Spin Labeling MRI, Text mining, Internal medicine, medicine, Cardiology, Radiology, Nuclear Medicine and imaging, Transit (astronomy), business
Abstract: Arterial transit artifacts at arterial spin-labeling MRI were the only factor associated with recent ischemic symptoms in participants with carotid stenosis.
Published: 2020
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42. An extracellular vesicle-related gene expression signature identifies high-risk patients in medulloblastoma

Author: Tobias Lautwein, Kornelius Kerl, Viktoria Melcher, Markus Missler, Monika Graf, Christian Krebs, Annalen Bleckmann, Dörthe Holdhof, Stefan M. Pfister, Martin Sill, Kerstin Menck, Marta Interlandi, Sonja Korbanka, Thomas K Albert, Astrid Rohlmann, Ulrich Schüller, Natalia Moreno, Melanie Schoof, Gerd Meyer zu Hörste, Michael C. Frühwald, Martin Dugas, and Natalie Jäger
Subjects: Male, Medulloblastoma, Cancer Research, Tumor microenvironment, biology, Editorials, Extracellular vesicle, medicine.disease, Transcriptome, Extracellular Vesicles, Prostate cancer, Oncology, Cell culture, Gene expression, medicine, biology.protein, Cancer research, Humans, Hedgehog Proteins, Neurology (clinical), Sonic hedgehog, Cerebellar Neoplasms
Abstract: BackgroundMedulloblastoma (MB) is a malignant brain tumor in childhood. It comprises 4 subgroups with different clinical behaviors. The aim of this study was to characterize the transcriptomic landscape of MB, both at the level of individual tumors as well as in large patient cohorts.MethodsWe used a combination of single-cell transcriptomics, cell culture models and biophysical methods such as nanoparticle tracking analysis and electron microscopy to investigate intercellular communication in the MB tumor niche.ResultsTumor cells of the sonic hedgehog (SHH)–MB subgroup show a differentiation blockade. These cells undergo extensive metabolic reprogramming. The gene expression profiles of individual tumor cells show a partial convergence with those of tumor-associated glial and immune cells. One possible cause is the transfer of extracellular vesicles (EVs) between cells in the tumor niche. We were able to detect EVs in co-culture models of MB tumor cells and oligodendrocytes. We also identified a gene expression signature, EVS, which shows overlap with the proteome profile of large oncosomes from prostate cancer cells. This signature is also present in MB patient samples. A high EVS expression is one common characteristic of tumors that occur in high-risk patients from different MB subgroups or subtypes.ConclusionsWith EVS, our study uncovered a novel gene expression signature that has a high prognostic significance across MB subgroups.
Published: 2020
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43. Low Self-Perception of Malnutrition in Older Hospitalized Patients

Author: Rainer Wirth, I. Gehrke, Maryam Pourhassan, Gero Lueg, A. Rösler, Dorothee Volkert, Julia Kwiatkowski, and Martin Jäger
Subjects: Geriatrics, medicine.medical_specialty, Pediatrics, Hospitalized patients, business.industry, General Medicine, medicine.disease, Self perception, 03 medical and health sciences, Malnutrition, 0302 clinical medicine, Telephone interview, Weight loss, Acute care, Medicine, Observational study, 030212 general & internal medicine, Geriatrics and Gerontology, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Background Studies focusing on self-perception of nutritional status in older hospitalized patients are lacking. We aimed to examine the self-perception of body weight and nutritional status among older hospitalized patients compared to their actual body weight and nutritional status based on medical assessment. Materials and methods This observational cross-sectional study investigated 197 older participants (mean age 82.2±6.8 years, 61% women) who were consecutively admitted to the geriatric acute care ward. Body weight status and nutritional status were assessed using WHO-BMI classification and Mini Nutritional Assessment-Short Form (MNA-SF), respectively. Self-perceived body weight status and nutritional status were assessed with a standardized questionnaire. A follow-up was performed with a short telephone interview after three months. Results According to MNA-SF, 49% and 35% were at risk of malnutrition and malnourished, respectively. There was no agreement between self-perceived nutritional status and objective nutritional status according to MNA-SF (Kappa: 0.06). A slight agreement was found between subjective body weight status and objective body weight status according to WHO-BMI classification (Kappa: 0.19). A total of 184 patients completed the 3 months follow-up and additional 9 patients died during this time, of which 7 and 2 were malnourished and at risk of malnutrition according to MNA-SF, respectively. Of those who were malnourished and at risk of malnutrition based on MNA-SF and died during follow-up, 67.7% did not realize their malnutrition. Compared to the patients with normal nutritional status during hospitalization, malnourished patients based on MNA-SF had higher rates of unplanned hospital readmission and further weight loss and more often reported health deterioration and experienced death within three months after discharge. Conclusion No agreement between self-perceived nutritional status and objective nutritional status among older hospitalized patients was found. Our study highlights the need to raise knowledge about the issue of malnutrition and increase awareness of health risks associated with malnutrition among older hospitalized patients.
Published: 2020
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44. Impact of 68Ga-FAPI PET/CT Imaging on the Therapeutic Management of Primary and Recurrent Pancreatic Ductal Adenocarcinomas

Author: Frederik L. Giesel, Klaus Herfarth, Uwe Haberkorn, Dirk Jäger, Clemens Kratochwil, Stefan A. Koerber, Dawn P Liew, Annika K. Wefers, Jürgen Debus, Matthias Lang, Manuel Röhrich, Fabian Staudinger, Patrick Naumann, Hendrik Rathke, Jakob Liermann, and Peter L. Choyke
Subjects: medicine.medical_specialty, PET-CT, medicine.diagnostic_test, business.industry, Cancer, Retrospective cohort study, medicine.disease, digestive system diseases, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Stroma, Positron emission tomography, 030220 oncology & carcinogenesis, medicine, Pancreatitis, Radiology, Nuclear Medicine and imaging, Radiology, Pancreatic carcinoma, business, Progressive disease
Abstract: Pancreatic ductal carcinoma (PDAC) is a highly lethal cancer, and early detection and accurate staging are critical to prolonging survival. PDAC typically has a prominent stroma including cancer-associated fibroblasts that express fibroblast activation protein (FAP). FAP is a new target molecule for PET imaging of various tumors. In this retrospective study, we describe the clinical impact of PET/CT imaging using 68Ga-labeled FAP-inhibitors (68Ga-FAPI PET/CT) in 19 patients with PDAC (7 primary, 12 progressive/recurrent). Methods: All patients underwent contrast-enhanced CT (ceCT) for TNM staging before 68Ga-FAPI PET/CT imaging. PET scans were acquired 60 min after administration of 150–250 MBq of 68Ga-labeled FAP-specific tracers. To characterize 68Ga-FAPI uptake over time, additional scans after 10 or 180 min were acquired in 6 patients. SUVmax and SUVmean values of PDAC manifestations and healthy organs were analyzed. The tumor burden according to 68Ga-FAPI PET/CT was compared with TNM staging based on ceCT and changes in oncologic management were recorded. Results: Compared with ceCT, 68Ga-FAPI PET/CT results led to changes in TNM staging in 10 of 19 patients. Eight of 12 patients with recurrent/progressive disease were upstaged, 1 was downstaged, and 3 had no change. In newly diagnosed PDAC, 1 of 7 patients was upstaged, and the staging of 6 patients did not change. Changes in oncologic management occurred in 7 patients. Markedly elevated uptake of 68Ga-FAPI in PDAC manifestations after 1 h was seen in most cases. Differentiation from pancreatitis based on static imaging 1 h after injection was challenging. With respect to imaging after multiple time points, PDAC and pancreatitis showed a trend for differential uptake kinetics. Conclusion:68Ga-FAPI PET/CT led to restaging in half of the patients with PDAC and most patients with recurrent disease compared with standard of care imaging. The clinical value of 68Ga-FAPI PET/CT should be further investigated.
Published: 2020
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45. MRI-visible perivascular spaces as an imaging biomarker in Fabry disease

Author: Derralynn Hughes, Hans Rolf Jäger, Claudia A. M. Wheeler-Kingshott, Aine Merwick, Duncan Wilson, Elaine Murphy, Fay Bolsover, David J. Werring, Indran Davagnanam, Fatima Jichi, Lisa Cipolotti, D Lyndon, and Robin Lachmann
Subjects: Adult, Male, medicine.medical_specialty, Neurology, Imaging biomarker, Perivascular spaces, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Perivascular space, Neuroradiology, Fabry disease, Original Communication, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, Odds ratio, medicine.disease, Magnetic Resonance Imaging, White Matter, Hyperintensity, Stroke, medicine.anatomical_structure, Neurovascular disease, Cerebral Small Vessel Diseases, Cardiology, cardiovascular system, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Biomarkers
Abstract: Introduction Fabry disease (FD) is an X-linked lysosomal storage disorder resulting in vascular glycosphingolipid accumulation and increased stroke risk. MRI findings associated with FD include white matter hyperintensities (WMH) and cerebral microbleeds (CMBs), suggesting the presence of cerebral small vessel disease. MRI-visible perivascular spaces (PVS) are another promising marker of small vessel disease associated with impaired interstitial fluid drainage. We investigated the association of PVS severity and anatomical distribution with FD. Patients and methods We compared patients with genetically proven FD to healthy controls. PVS, WMH, lacunes and CMBs were rated on standardised sequences using validated criteria and scales, blinded to diagnosis. A trained observer (using a validated rating scale), quantified the total severity of PVS. We used logistic regression to investigate the association of severe PVS with FD. Results We included 33 FD patients (median age 44, 44.1% male) and 20 healthy controls (median age 33.5, 50% male). Adjusting for age and sex, FD was associated with more severe basal ganglia PVS (odds ratio (OR) 5.80, 95% CI 1.03–32.7) and higher total PVS score (OR 4.03, 95% CI 1.36–11.89). Compared with controls, participants with FD had: higher WMH volume (median 495.03 mm3 vs 0, p = 0.0008), more CMBs (21.21% vs none, p = 0.04), and a higher prevalence of lacunes (21.21% vs. 5%, p = 0.23). Conclusions PVS scores are more severe in FD than control subjects. Our findings have potential relevance for FD diagnosis and suggest that impaired interstitial fluid drainage might be a mechanism of white matter injury in FD.
Published: 2020

46. A Frameshift Peptide Neoantigen-Based Vaccine for Mismatch Repair-Deficient Cancers: A Phase I/IIa Clinical Trial

Author: Miriam Reuschenbach, Salah-Eddin Al-Batran, Mirjam Tariverdian, Julia Karbach, Elke Jäger, Claudia Pauligk, Magnus von Knebel Doeberitz, Mohammad-Reza Rafiyan, and Matthias Kloor
Subjects: Adult, Male, 0301 basic medicine, Cancer Research, Colorectal cancer, Injections, Subcutaneous, Cancer Vaccines, DNA Mismatch Repair, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigens, Neoplasm, medicine, Humans, Frameshift Mutation, Aged, Aged, 80 and over, business.industry, Immunogenicity, Proteins, Cancer, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, DNA-Binding Proteins, Vaccination, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Vaccines, Subunit, Cancer research, Female, Microsatellite Instability, DNA mismatch repair, Colorectal Neoplasms, business, Pol1 Transcription Initiation Complex Proteins
Abstract: Purpose: DNA mismatch repair (MMR) deficiency is a hallmark of Lynch syndrome, the most common inherited cancer syndrome. MMR-deficient cancer cells accumulate numerous insertion/deletion mutations at microsatellites. Mutations of coding microsatellites (cMS) lead to the generation of immunogenic frameshift peptide (FSP) neoantigens. As the evolution of MMR-deficient cancers is triggered by mutations inactivating defined cMS-containing tumor suppressor genes, distinct FSP neoantigens are shared by most MMR-deficient cancers. To evaluate safety and immunogenicity of an FSP-based vaccine, we performed a clinical phase I/IIa trial (Micoryx). Patients and Methods: The trial comprised three cycles of four subcutaneous vaccinations (FSP neoantigens derived from mutant AIM2, HT001, TAF1B genes) mixed with Montanide ISA-51 VG over 6 months. Inclusion criteria were history of MMR-deficient colorectal cancer (UICC stage III or IV) and completion of chemotherapy. Phase I evaluated safety and toxicity as primary endpoint (six patients), phase IIa addressed cellular and humoral immune responses (16 patients). Results: Vaccine-induced humoral and cellular immune responses were observed in all patients vaccinated per protocol. Three patients developed grade 2 local injection site reactions. No vaccination-induced severe adverse events occurred. One heavily pretreated patient with bulky metastases showed stable disease and stable CEA levels over 7 months. Conclusions: FSP neoantigen vaccination is systemically well tolerated and consistently induces humoral and cellular immune responses, thus representing a promising novel approach for treatment and even prevention of MMR-deficient cancer.
Published: 2020
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47. Sphincter-saving therapy for fistula-in-ano: long-term follow-up after FiLaC®

Author: A Wolicki, Pia Jäger, M. Senkal, and T Deska
Subjects: Anal fistula, medicine.medical_specialty, business.industry, Fistula, Gastroenterology, Fistulectomy, medicine.disease, Colorectal surgery, Surgery, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Medicine, Sphincter, 030211 gastroenterology & hepatology, Radical surgery, business, Abscess, Abdominal surgery
Abstract: The treatment of anal fistula remains a challenge between maintaining continence and radical surgery to prevent recurrence. Fistula-tract Laser Closure (FiLaC®) is a sphincter-saving technique using a radial emitting laser fibre to close the fistula tract. The aim of this study was to report long-term outcomes in patients who received FiLaC® therapy for transsphincteric and intersphincteric anal fistula between January 2011 and December 2017. A retrospective study was performed on patients who were treated with FiLaC®- for a transsphincteric and intersphincteric anal fistula at our institution between January 2011 and December 2017. In all patients, the FiLaC® procedure was combined with a closure of the internal orifice using a simple 3-0 Z stitch. Patient characteristics, previous proctological history, healing rates, failures and postoperative continence were investigated. The study included 83 patients [mean age 50.01 ± 14.59 years. 64 (77.1%) males] with a mean follow-up period of 41.99 (± 21.59) months (range 4–87 months). Thirteen patients (15.7%) had a recurrent fistula. 65 patients (78.3%) had undergone prior abscess drainage with insertion of a seton. The primary healing rate was 74.7% (62 of 83 patients) overall. Eleven (13.3%) of the 21 patients (25.3%) who failed FiLaC®-therapy underwent a second operation. In eight cases, Re-FiLaC® and in three cases, fistulectomy with closure of the internal orifice was performed. Afterwards 6 (54.5%) of these 11 patients could be considered cured: 3 who had fistulectomy and three who had Re-FiLaC® treatment. The overall healing rate after second FiLaC® was 78.3% (65 of 83 patients) while the overall healing rate for FiLaC® therapy combined with any second procedure was 81.9% (68 of 83 patients). The follow-up period in this group of 11 patients who received re-operation was 38 months (range 13–84 months). Changes in continence occurred in eight patients (9.6%). No patient reported major incontinence postoperatively. The FiLaC® procedure is associated with good healing rates in long-term follow-up and should be considered as a treatment option for transsphincteric and intersphincteric anal fistulae, especially due to the low complication rate and low risk of sphincter injury.
Published: 2020
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48. The relevance of CT-based geometric and radiomics analysis of whole liver tumor burden to predict survival of patients with metastatic colorectal cancer

Author: Dominik Nörenberg, Nils Jäger, Stefan Maurus, Volker Heinemann, Alexander Katzmann, Julian Walter Holch, Matthias F Froelich, Eva Gresser, Thomas Huber, Michael Sühling, Lian Liu, Oliver Taubmann, Alexander Mühlberg, and Jan Hendrik Moltz
Subjects: medicine.medical_specialty, Imaging biomarker, Colorectal cancer, business.industry, Whole liver, Tumor burden, Retrospective cohort study, General Medicine, medicine.disease, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Radiomics, 030220 oncology & carcinogenesis, medicine, Radiology, Nuclear Medicine and imaging, Radiology, business, Prognostic models, Neuroradiology
Abstract: To investigate the prediction of 1-year survival (1-YS) in patients with metastatic colorectal cancer with use of a systematic comparative analysis of quantitative imaging biomarkers (QIBs) based on the geometric and radiomics analysis of whole liver tumor burden (WLTB) in comparison to predictions based on the tumor burden score (TBS), WLTB volume alone, and a clinical model. A total of 103 patients (mean age: 61.0 ± 11.2 years) with colorectal liver metastases were analyzed in this retrospective study. Automatic segmentations of WLTB from baseline contrast-enhanced CT images were used. Established biomarkers as well as a standard radiomics model building were used to derive 3 prognostic models. The benefits of a geometric metastatic spread (GMS) model, the Aerts radiomics prior model of the WLTB, and the performance of TBS and WLTB volume alone were assessed. All models were analyzed in both statistical and predictive machine learning settings in terms of AUC. TBS showed the best discriminative performance in a statistical setting to discriminate 1-YS (AUC = 0.70, CI: [0.56, 0.90]). For the machine learning–based prediction for unseen patients, both a model of the GMS of WLTB (0.73, CI: [0.60, 0.84]) and the Aerts radiomics prior model (0.76, CI: [0.65, 0.86]) applied on the WLTB showed a numerically higher predictive performance than TBS (0.68, CI: [0.54, 0.79]), radiomics (0.65, CI: [0.55, 0.78]), WLTB volume alone (0.53, CI: [0.40. 0.66]), or the clinical model (0.56, CI: [0.43, 0.67]). The imaging-based GMS model may be a first step towards a more fine-grained machine learning extension of the TBS concept for risk stratification in mCRC patients without the vulnerability to technical variance of radiomics. • CT-based geometric distribution and radiomics analysis of whole liver tumor burden in metastatic colorectal cancer patients yield prognostic information. • Differences in survival are possibly attributable to the spatial distribution of metastatic lesions and the geometric metastatic spread analysis of all liver metastases may serve as robust imaging biomarker invariant to technical variation. • Imaging-based prediction models outperform clinical models for 1-year survival prediction in metastatic colorectal cancer patients with liver metastases.
Published: 2020
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49. <scp> GBA </scp> Variants in Parkinson's Disease: Clinical, Metabolomic, and Multimodal Neuroimaging Phenotypes

Author: Marina C. Ruppert, Alexander Drzezga, Enrico Glaab, Christian Jäger, Nico J. Diederich, Marc Tittgemeyer, Jean-Pierre Trezzi, David Eidelberg, Franziska Maier, Lars Timmermann, Carsten Eggers, Zdenka Hodak, Karsten Hiller, Katja Lohmann, Andrea Greuel, Yilong Ma, Fonds National de la Recherche - FnR [sponsor], and Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) [research center]
Subjects: 0301 basic medicine, Oncology, Parkinson's disease, Movement disorders, Biotechnologie [F06] [Sciences du vivant], Neurology [D14] [Human health sciences], Disease, genetics [Glucosylceramidase], Multidisciplinaire, généralités & autres [F99] [Sciences du vivant], 0302 clinical medicine, genetics [Parkinson Disease], diagnostic imaging [Parkinson Disease], Biotechnology [F06] [Life sciences], genetics, medicine.diagnostic_test, Parkinson Disease, Parkinson's disease genetics, Phenotype, Neurology, statistics, Positron emission tomography, Glucosylceramidase, GBA, multimodal functional neuroimaging, medicine.symptom, medicine.medical_specialty, genetics [Mutation], Neuroimaging, Multidisciplinary, general & others [F99] [Life sciences], 03 medical and health sciences, Internal medicine, medicine, Humans, Metabolomics, Dementia, ddc:610, Neurologie [D14] [Sciences de la santé humaine], Lewy body, business.industry, multimodal, medicine.disease, functional, 030104 developmental biology, Mutation, Neurology (clinical), business, Glucocerebrosidase, 030217 neurology & neurosurgery
Abstract: Background Alterations in the GBA gene (NM_000157.3) are the most important genetic risk factor for Parkinson's disease (PD). Biallelic GBA mutations cause the lysosomal storage disorder Gaucher's disease. The GBA variants p.E365K and p.T408M are associated with PD but not with Gaucher's disease. The pathophysiological role of these variants needs to be further explored. Objective This study analyzed clinical, neuropsychological, metabolic, and neuroimaging phenotypes of patients with PD carrying the GBA variants p.E365K and p.T408M. Methods GBA was sequenced in 56 patients with mid-stage PD. Carriers of GBA variants were compared with noncarriers regarding clinical history and symptoms, neuropsychological features, metabolomics, and multimodal neuroimaging. Blood plasma gas chromatography coupled to mass spectrometry, 6-[18 F]fluoro-L-Dopa positron emission tomography (PET), [18 F]fluorodeoxyglucose PET, and resting-state functional magnetic resonance imaging were performed. Results Sequence analysis detected 13 heterozygous GBA variant carriers (7 with p.E365K, 6 with p.T408M). One patient carried a GBA mutation (p.N409S) and was excluded. Clinical history and symptoms were not significantly different between groups. Global cognitive performance was lower in variant carriers. Metabolomic group differences were suggestive of more severe PD-related alterations in carriers versus noncarriers. Both PET scans showed signs of a more advanced disease; [18 F]fluorodeoxyglucose PET and functional magnetic resonance imaging showed similarities with Lewy body dementia and PD dementia in carriers. Conclusions This is the first study to comprehensively assess (neuro-)biological phenotypes of GBA variants in PD. Metabolomics and neuroimaging detected more significant group differences than clinical and behavioral evaluation. These alterations could be promising to monitor effects of disease-modifying treatments targeting glucocerebrosidase metabolism. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Published: 2020
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50. Prognostic factors and follow-up parameters in patients with paroxysmal nocturnal hemoglobinuria (PNH): experience of the Austrian PNH network

Author: Peter Bettelheim, Peter Valent, Eva Jäger, Gregor Hoermann, Sonja Heibl, Ilse Schwarzinger, Felix Keil, Wolfgang Füreder, Gabriele Stefanzl, W. R. Sperr, Georg Greiner, Armin Zebisch, Michael Pfeilstöcker, and Michael Kundi
Subjects: Male, Hemoglobinuria, Paroxysmal, Kaplan-Meier Estimate, Gastroenterology, 0302 clinical medicine, Bone Marrow, Pregnancy, Cause of Death, hemic and lymphatic diseases, Clinical endpoint, Medicine, Hematology, Hematopoietic Stem Cell Transplantation, Anemia, Aplastic, General Medicine, Acute Kidney Injury, Middle Aged, Eculizumab, Prognosis, Combined Modality Therapy, Hematologic disease, Austria, Creatinine, 030220 oncology & carcinogenesis, Disease Progression, Female, medicine.drug, Adult, medicine.medical_specialty, Anemia, Antibodies, Monoclonal, Humanized, Colony-Forming Units Assay, 03 medical and health sciences, Thromboembolism, Internal medicine, Humans, Aplastic anemia, business.industry, Myelodysplastic syndromes, Pregnancy Complications, Hematologic, medicine.disease, Clone Cells, Hematopoiesis, Complement Inactivating Agents, Myelodysplastic Syndromes, Paroxysmal nocturnal hemoglobinuria, business, Follow-Up Studies, 030215 immunology
Abstract: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease characterized by a deregulated complement system, chronic Coombs-negative, intravascular hemolysis, and a variable clinical course with substantial risk to develop thromboembolic events. We analyzed diagnostic and prognostic parameters as well as clinical endpoints in 59 adult patients suffering from PNH in 5 hematology centers in Austria (observation period: 1978-2015). Median follow-up time was 5.6 years. The median clone size at diagnosis amounted to 55% and was higher in patients with classical PNH (81%) compared to patients with PNH associated with aplastic anemia (AA) or myelodysplastic syndromes (MDS) (50%). The clone size also correlated with lactate dehydrogenase (LDH) levels. In one patient, anemia improved spontaneously and disappeared with complete normalization of LDH after 16 years. Seventeen patients received therapy with eculizumab. The rate of thromboembolic events was higher in the pre-eculizumab era compared with eculizumab-treated patients but did not correlate with the presence of age-related clonal hematopoiesis or any other clinical or laboratory parameters. Peripheral blood colony-forming progenitor cell counts were lower in PNH patients compared with healthy controls. Only two patients with classical PNH developed MDS. Overall, 7/59 patients died after 0.5-32 years. Causes of death were acute pulmonary hypertension, Budd-Chiari syndrome, and septicemia. Overall survival (OS) was mainly influenced by age and was similar to OS measured in an age-matched healthy Austrian control cohort. Together, compared with previous times, the clinical course and OS in PNH are favorable, which may be due to better diagnosis, early recognition, and eculizumab therapy.
Published: 2020
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