90 results on '"Ruhnke L"'
Search Results
2. Biallelic TET2 mutations confer sensitivity to 5 '-azacitidine in acute myeloid leukemia
- Author
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Stölzel, F. (Friedrich), Fordham, S.E. (Sarah E.), Nandana, D. (Devi), Lin, W.Y. (Wei-Yu), Blair, H. (Helen), Elstob, C. (Claire), Bell, H.L. (Hayden L.), Mohr, B. (Brigitte), Ruhnke, L. (Leo), Kunadt, D. (Desiree), Dill, C. (Claudia), Allsop, D. (Daniel), Piddock, R. (Rachel), Soura, E.N. (Emmanouela-Niki), Park, C. (Catherine), Fadly, M. (Mohd), Rahman, T. (Thahira), Alharbi, A. (Abrar), Wobus, M. (Manja), Altmann, H. (Heidi), Röllig, C. (Christoph), Wagenführ, L. (Lisa), Jones, G.L. (Gail L.), Menne, T. (Tobias), Jackson, G.H. (Graham H.), Marr, H.J. (Helen J.), Fitzgibbon, J. (Jude), Onel, K. (Kenan), Meggendorfer, M. (Manja), Robinson, A. (Amber), Bziuk, Z. (Zuzanna), Bowes, E. (Emily), Heidenreich, O. (Olaf), Haferlach, T. (Torsten), Villar-Fernández, S. (Sara), Ariceta, B. (Beñat), Ayala, R. (Rosa), Altschuler, S.J. (Steven J.), Wu, L.F. (Lani F.), Prosper, F. (Felipe), Montesinos, P. (Pau), Martínez-López, J. (Joaquín), Bornhauser, M. (Martin), and Allan, J.M. (James M.)
- Abstract
Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5 '-azacitidine (5 '-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5 '-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5 '-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.
- Published
- 2023
3. Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers
- Author
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Jahn, A., primary, Rump, A., additional, Widmann, T.J., additional, Heining, C., additional, Horak, P., additional, Hutter, B., additional, Paramasivam, N., additional, Uhrig, S., additional, Gieldon, L., additional, Drukewitz, S., additional, Kübler, A., additional, Bermudez, M., additional, Hackmann, K., additional, Porrmann, J., additional, Wagner, J., additional, Arlt, M., additional, Franke, M., additional, Fischer, J., additional, Kowalzyk, Z., additional, William, D., additional, Weth, V., additional, Oster, S., additional, Fröhlich, M., additional, Hüllein, J., additional, Valle González, C., additional, Kreutzfeldt, S., additional, Mock, A., additional, Heilig, C.E., additional, Lipka, D.B., additional, Möhrmann, L., additional, Hanf, D., additional, Oleś, M., additional, Teleanu, V., additional, Allgäuer, M., additional, Ruhnke, L., additional, Kutz, O., additional, Knurr, A., additional, Laßmann, A., additional, Endris, V., additional, Neumann, O., additional, Penzel, R., additional, Beck, K., additional, Richter, D., additional, Winter, U., additional, Wolf, S., additional, Pfütze, K., additional, Geörg, C., additional, Meißburger, B., additional, Buchhalter, I., additional, Augustin, M., additional, Aulitzky, W.E., additional, Hohenberger, P., additional, Kroiss, M., additional, Schirmacher, P., additional, Schlenk, R.F., additional, Keilholz, U., additional, Klauschen, F., additional, Folprecht, G., additional, Bauer, S., additional, Siveke, J.T., additional, Brandts, C.H., additional, Kindler, T., additional, Boerries, M., additional, Illert, A.L., additional, von Bubnoff, N., additional, Jost, P.J., additional, Metzeler, K.H., additional, Bitzer, M., additional, Schulze-Osthoff, K., additional, von Kalle, C., additional, Brors, B., additional, Stenzinger, A., additional, Weichert, W., additional, Hübschmann, D., additional, Fröhling, S., additional, Glimm, H., additional, Schröck, E., additional, and Klink, B., additional
- Published
- 2022
- Full Text
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4. 732MO The combination of ICT01, a γ9δ2 T cell-activating mAb, plus pembrolizumab induces a broad antitumor immune response and disease control in patients with CPI-failure melanoma, NSCLC and bladder cancer: EVICTION trial
- Author
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Champiat, S., primary, Wermke, M., additional, Vicier, C., additional, de Bono, J.S., additional, Jungels, C., additional, Vey, N., additional, Kotecki, N., additional, Wetzko, K., additional, Ruhnke, L., additional, Garralda, E., additional, Galvao de Aguiar, V., additional, Lorusso, P., additional, de Gassart, A., additional, Valentin, E., additional, Brune, P., additional, Iche, M., additional, Leparquier, C., additional, Olive, D., additional, Marabelle, A., additional, and Frohna, P.A., additional
- Published
- 2022
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5. P449: NOVEL, FIRST-IN-CLASS, SOMATIC IDH2 DELETION-INSERTION VARIANT C.516_518DELINSTGC CONFERS BORDERLINE PHENOTYPE AND DOES NOT SHOW SUSCEPTIBILITY TO ENASIDENIB IN-VITRO
- Author
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Ruhnke, L., primary, Poitz, D. M., additional, Herold, S., additional, Dressler, S., additional, Dill, C., additional, Peitzsch, M., additional, Oelschlägel, U., additional, Frimmel, J., additional, Kunadt, D., additional, Kretschmann, T., additional, Altmann, H., additional, Stölzel, F., additional, Röllig, C., additional, Chavakis, T., additional, Baretton, G., additional, Schäfer-Eckart, K., additional, and Bornhäuser, M., additional
- Published
- 2022
- Full Text
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6. Genome-wide association study identifies susceptibility loci for acute myeloid leukemia
- Author
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Lin WY, Fordham SE, Hungate E, Sunter NJ, Elstob C, Xu Y, Park C, Quante A, Strauch K, Gieger C, Skol A, Rahman T, Sucheston-Campbell L, Wang J, Hahn T, Clay-Gilmour AI, Jones GL, Marr HJ, Jackson GH, Menne T, Collin M, Ivey A, Hills RK, Burnett AK, Russell NH, Fitzgibbon J, Larson RA, Le Beau MM, Stock W, Heidenreich O, Alharbi A, Allsup DJ, Houlston RS, Norden J, Dickinson AM, Douglas E, Lendrem C, Daly AK, Palm L, Piechocki K, Jeffries S, Bornhäuser M, Röllig C, Altmann H, Ruhnke L, Kunadt D, Wagenführ L, Cordell HJ, Darlay R, Andersen MK, Fontana MC, Martinelli G, Marconi G, Sanz MA, Cervera J, Gómez-Seguí I, Cluzeau T, Moreilhon C, Raynaud S, Sill H, Voso MT, Lo-Coco F, Dombret H, Cheok M, Preudhomme C, Gale RE, Linch D, Gaal-Wesinger J, Masszi A, Nowak D, Hofmann WK, Gilkes A, Porkka K, Milosevic Feenstra JD, Kralovics R, Grimwade D, Meggendorfer M, Haferlach T, Krizsán S, Bödör C, Stölzel F, Onel K, and Allan JM
- Subjects
RISK ,HLA ,OLDER PATIENTS ,AML ,hemic and lymphatic diseases ,HUMAN-LEUKOCYTE ANTIGEN ,HIF-1-ALPHA ,IMMUNE ESCAPE ,CLONAL EVOLUTION ,CANCER ,GENE-MUTATIONS - Abstract
Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10 -8 ; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10 -10 ; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).
- Published
- 2021
7. General Discussion
- Author
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Ruhnke, L. H., Dolezalek, Hans, editor, Reiter, Reinhold, editor, and Landsberg, Helmut E., editor
- Published
- 1976
- Full Text
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8. The Atlas/Centaur lightning strike incident
- Author
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Christian, H. J, Mazur, V, Fisher, B. D, Ruhnke, L. H, and Crouch, K
- Subjects
Space Transportation - Abstract
Consideration is given to an incident on March 26, 1987, in which an Atlas/Centaur 67 vehicle carrying a naval communication satellite was struck by a triggered, cloud-to-ground lightning flash about 48 s into the flight. The lightning current coupled a transient signal into the wiring of the Centaur digital computer unit, ultimately causing the breakup of the vehicle. The meteorological conditions at the time of the launch and the lightning flash triggered by the Atlas/Centaur 67 vehicle are analyzed on the basis of studies of the incident by the NASA Investigation Board.
- Published
- 1989
9. A rocket borne instrument to measure electric fields inside electrified clouds
- Author
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Ruhnke, L. H
- Subjects
Geophysics - Abstract
The development of a rocket borne instrument to measure electric fields in thunderstorms is described. Corona currents from a sharp needle atop a small rocket are used to sense the electric field. A high ohm resistor in series with the corona needle linearizes the relationship between corona current and electric field. The corona current feeds a relaxation oscillator, whose pulses trigger a transmitter which operates in the 395 to 410 MHz meteorological band. The instrument senses fields between 5 kV/m and 100 kV/m.
- Published
- 1971
10. Rocket borne instrument to measure electric fields inside electrified clouds
- Author
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Ruhnke, L. H
- Subjects
Instrumentation And Photography - Abstract
An apparatus for measuring the electric field in the atmosphere which includes a pair of sensors carried on a rocket for sensing the voltages in the atmosphere being measured is described. One of the sensors is an elongated probe with a fine point which causes a corona current to be produced as it passes through the electric field. An electric circuit is coupled between the probe and the other sensor and includes a high ohm resistor which linearizes the relationship between the corona current and the electric field being measured. A relaxation oscillator and transmitter are provided for generating and transmitting an electric signal having a frequency corresponding to the magnitude of the electric field.
- Published
- 1973
11. Determining distance to lightning strokes from a single station
- Author
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Ruhnke, L. H
- Subjects
Electronic Systems - Abstract
Electronic system can rapidly determine location of lightning strikes occurring within 30 km range. Longer distances are also determined, but with reduced accuracy. Studies have shown that lightning bolt emits electromagnetic wavefront; distance to lightning is determined from ratio of magnetic to electric field.
- Published
- 1973
12. A three-station lightning detection system
- Author
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Ruhnke, L. H
- Subjects
Instrumentation And Photography - Abstract
A three-station network is described which senses magnetic and electric fields of lightning. Directional and distance information derived from the data are used to redundantly determine lightning position. This redundancy is used to correct consistent propagation errors. A comparison is made of the relative accuracy of VLF direction finders with a newer method to determine distance to and location of lightning by the ratio of magnetic-to-electric field as observed at 400 Hz. It was found that VLF direction finders can determine lightning positions with only one-half the accuracy of the method that uses the ratio of magnetic-to-electric field.
- Published
- 1972
13. Computer simulation of a downward negative stepped leader and its interaction with a ground structure
- Author
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Mazur, V., primary, Ruhnke, L. H., additional, Bondiou-Clergerie, A., additional, and Lalande, P., additional
- Published
- 2000
- Full Text
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14. ELECTROHYDRODYNAMIC REMOVAL OF MICROORGANISMS FROM HYDROCARBON FUELS
- Author
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Ruhnke, L. H., primary, Will, E., primary, and Pederson, P., primary
- Published
- 1965
- Full Text
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15. Functional interaction between local anaesthetics and calcium antagonists in guineapig myocardium: 1. Cardiodepressant effects in isolated organs
- Author
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HERZIG, S., primary, RUHNKE, L., additional, and WULF, H., additional
- Published
- 1994
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16. Effect of sample freezing on the isolation of Mycoplasma spp. from the clitoral fossa of the mare
- Author
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Bermudez, V, Miller, R B, Johnson, W, Rosendal, S, and Ruhnke, L
- Subjects
Mycoplasma ,Freezing ,Animals ,Female ,Horse Diseases ,Mycoplasma Infections ,Horses ,Vulvar Diseases ,Clitoris ,Research Article ,Specimen Handling - Abstract
The growth of Mycoplasma equigenitalium and Mycoplasma subdolum from specimens collected from the clitoral fossa of each of four Standardbred mares was not diminished by freezing of the specimens in liquid nitrogen (-196 degrees C) for up to 30 days when compared to samples cultured immediately.
- Published
- 1988
17. Phase identification of dental amalgam using transmission electron microscopy.
- Author
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Consani, Simonides, Ruhnke, Luiz Antonio, Silva, Darcy Martins, Consani, S, Ruhnke, L A, and da Silva, D M
- Published
- 1976
- Full Text
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18. Gemtuzumab ozogamicin plus midostaurin in combination with standard '7 + 3' induction therapy in newly diagnosed AML: Results from the SAL-MODULE phase I study.
- Author
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Röllig C, Schliemann C, Ruhnke L, Fransecky L, Heydrich BN, Hanoun M, Noppeney R, Schäfer-Eckart K, Wendelin K, Mikesch JH, Middeke JM, Reimann M, Fiebig F, Zukunft S, Wermke M, Serve H, Platzbecker U, Müller-Tidow C, Baldus CD, and Bornhäuser M
- Subjects
- Humans, Male, Middle Aged, Female, Aged, Adult, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized adverse effects, Induction Chemotherapy, fms-Like Tyrosine Kinase 3 genetics, Aminoglycosides administration & dosage, Aminoglycosides therapeutic use, Staurosporine analogs & derivatives, Staurosporine administration & dosage, Staurosporine therapeutic use, Staurosporine adverse effects, Gemtuzumab administration & dosage, Gemtuzumab therapeutic use, Leukemia, Myeloid, Acute drug therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage
- Abstract
We conducted a phase I trial in newly diagnosed acute myeloid leukaemia (AML) to investigate the combination of two novel targeted agents, gemtuzumab ozogamicin (GO) and midostaurin, with intensive chemotherapy in FLT3-mutated AML and CBF leukaemia. Three dose levels of midostaurin and one to three sequential doses of 3 mg/m
2 GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m2 GO on Days 1 + 4 and 100 mg midostaurin on Days 8-21 can be safely combined with IC in newly diagnosed AML., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)- Published
- 2024
- Full Text
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19. MDS-PB13 Score - Blood based detection of aberrancies by flow cytometry in patients with suspected and confirmed Myelodysplastic Neoplasms.
- Author
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Oelschlaegel U, Winter S, Sockel K, Epp K, Schadt J, Röhnert MA, Krüger T, Ruhnke L, Bornhäuser M, Platzbecker U, Kroschinsky F, and von Bonin M
- Subjects
- Humans, Flow Cytometry, Immunophenotyping, Neoplasms, Myelodysplastic Syndromes diagnosis
- Published
- 2024
- Full Text
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20. Germ line variant GFI1-36N affects DNA repair and sensitizes AML cells to DNA damage and repair therapy.
- Author
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Frank D, Patnana PK, Vorwerk J, Mao L, Gopal LM, Jung N, Hennig T, Ruhnke L, Frenz JM, Kuppusamy M, Autry R, Wei L, Sun K, Mohammed Ahmed HM, Künstner A, Busch H, Müller H, Hutter S, Hoermann G, Liu L, Xie X, Al-Matary Y, Nimmagadda SC, Cano FC, Heuser M, Thol F, Göhring G, Steinemann D, Thomale J, Leitner T, Fischer A, Rad R, Röllig C, Altmann H, Kunadt D, Berdel WE, Hüve J, Neumann F, Klingauf J, Calderon V, Opalka B, Dührsen U, Rosenbauer F, Dugas M, Varghese J, Reinhardt HC, von Bubnoff N, Möröy T, Lenz G, Batcha AMN, Giorgi M, Selvam M, Wang E, McWeeney SK, Tyner JW, Stölzel F, Mann M, Jayavelu AK, and Khandanpour C
- Subjects
- Humans, Mice, Animals, Temozolomide, DNA Damage, DNA Repair, Germ Cells metabolism, DNA, Transcription Factors genetics, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
Abstract: Growth factor independence 1 (GFI1) is a DNA-binding transcription factor and a key regulator of hematopoiesis. GFI1-36N is a germ line variant, causing a change of serine (S) to asparagine (N) at position 36. We previously reported that the GFI1-36N allele has a prevalence of 10% to 15% among patients with acute myeloid leukemia (AML) and 5% to 7% among healthy Caucasians and promotes the development of this disease. Using a multiomics approach, we show here that GFI1-36N expression is associated with increased frequencies of chromosomal aberrations, mutational burden, and mutational signatures in both murine and human AML and impedes homologous recombination (HR)-directed DNA repair in leukemic cells. GFI1-36N exhibits impaired binding to N-Myc downstream-regulated gene 1 (Ndrg1) regulatory elements, causing decreased NDRG1 levels, which leads to a reduction of O6-methylguanine-DNA-methyltransferase (MGMT) expression levels, as illustrated by both transcriptome and proteome analyses. Targeting MGMT via temozolomide, a DNA alkylating drug, and HR via olaparib, a poly-ADP ribose polymerase 1 inhibitor, caused synthetic lethality in human and murine AML samples expressing GFI1-36N, whereas the effects were insignificant in nonmalignant GFI1-36S or GFI1-36N cells. In addition, mice that received transplantation with GFI1-36N leukemic cells treated with a combination of temozolomide and olaparib had significantly longer AML-free survival than mice that received transplantation with GFI1-36S leukemic cells. This suggests that reduced MGMT expression leaves GFI1-36N leukemic cells particularly vulnerable to DNA damage initiating chemotherapeutics. Our data provide critical insights into novel options to treat patients with AML carrying the GFI1-36N variant., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
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21. Secondary-type mutations do not impact outcome in NPM1-mutated acute myeloid leukemia - implications for the European LeukemiaNet risk classification.
- Author
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Eckardt JN, Bill M, Rausch C, Metzeler K, Spiekermann K, Stasik S, Sauer T, Scholl S, Hochhaus A, Crysandt M, Brümmendorf TH, Krug U, Wörmann B, Hiddemann W, Görlich D, Sauerland C, Steffen B, Einsele H, Neubauer A, Burchert A, Schäfer-Eckart K, Berdel WE, Schliemann C, Krause SW, Hänel M, Hanoun M, Kaufmann M, Fransecky L, Braess J, Ruhnke L, Schetelig J, Middeke JM, Serve H, Baldus CD, Platzbecker U, Müller-Tidow C, Bornhäuser M, Herold T, Thiede C, and Röllig C
- Subjects
- Humans, Mutation, Nuclear Proteins genetics, Prognosis, Leukemia, Myeloid, Acute genetics
- Published
- 2023
- Full Text
- View/download PDF
22. Impact of BMI on patient outcome in acute myeloid leukaemia patients receiving intensive induction therapy: a real-world registry experience.
- Author
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Enßle JC, Wolf S, Scheich S, Weber S, Kramer M, Ruhnke L, Schliemann C, Mikesch JH, Krause S, Sauer T, Hanoun M, Reinhardt HC, Kraus S, Kaufmann M, Hänel M, Fransecky L, Burchert A, Neubauer A, Crysandt M, Jost E, Niemann D, Schäfer-Eckart K, Held G, Kaiser U, Wass M, Schaich M, Müller-Tidow C, Platzbecker U, Baldus CD, Bornhäuser M, Röllig C, Serve H, and Steffen B
- Abstract
Background: Acute myeloid leukaemia (AML) is treated with intensive induction chemotherapy (IT) in medically fit patients. In general, obesity was identified as a risk factor for all-cause mortality, and there is an ongoing debate on its impact on outcome and optimal dosing strategy in obese AML patients., Methods: We conducted a registry study screening 7632 patients and assessed the impact of obesity in 1677 equally IT treated, newly diagnosed AML patients on the outcome (OS, EFS, CR1), comorbidities, toxicities and used dosing strategies., Results: Obese patients (BMI ≥ 30) displayed a significant inferior median OS (29.44 vs. 47.94 months, P = 0.015) and CR1 rate (78.7% vs. 84.3%, P = 0.015) without differences in median EFS (7.8 vs. 9.89 months, P = 0.3) compared to non-obese patients (BMI < 30). The effect was predominantly observed in older (≥60 years) patients. Obesity was identified as an independent risk factor for death, and obese patients demonstrated higher rates of cardiovascular or metabolic comorbidities. No differences for OS, EFS, CR1 or treatment-related toxicities were observed by stratification according to used dosing strategy or dose reduction., Conclusions: In conclusion, this study identifies obesity as an independent risk factor for worse OS in older AML patients undergoing curative IT most likely due to obesity-related comorbidities and not to dosing strategy., (© 2023. The Author(s).)
- Published
- 2023
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23. Midostaurin in addition to intensive chemotherapy in acute myeloid leukemia with t(8;21) and KIT and/or FLT3 - ITD mutations: results of the SAL MIDOKIT trial.
- Author
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Ruhnke L, Röllig C, Herold S, Sauer T, Brandts CH, Steffen B, Schäfer-Eckart K, Krause SW, Hänel M, Reichle A, Scholl S, Neubauer A, Mikesch JH, Schetelig J, Stölzel F, Kramer M, Haake A, Frimmel J, Krämer A, Schlenk R, Platzbecker U, Serve H, Baldus CD, Müller-Tidow C, Aust D, Bornhäuser M, Ehninger G, and Thiede C
- Subjects
- Humans, Staurosporine therapeutic use, Mutation, fms-Like Tyrosine Kinase 3 genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Published
- 2023
- Full Text
- View/download PDF
24. Intensified cytarabine dose during consolidation in adult AML patients under 65 years is not associated with survival benefit: real-world data from the German SAL-AML registry.
- Author
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Hanoun M, Ruhnke L, Kramer M, Hanoun C, Schäfer-Eckart K, Steffen B, Sauer T, Krause SW, Schliemann C, Mikesch JH, Kaufmann M, Hänel M, Jost E, Brümmendorf TH, Fransecky L, Kraus S, Einsele H, Niemann D, Neubauer A, Kullmer J, Seggewiss-Bernhard R, Görner M, Held G, Kaiser U, Scholl S, Hochhaus A, Reinhardt HC, Platzbecker U, Baldus CD, Müller-Tidow C, Bornhäuser M, Serve H, and Röllig C
- Subjects
- Adult, Humans, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cytarabine therapeutic use, Remission Induction, Retrospective Studies, Adolescent, Middle Aged, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute drug therapy
- Abstract
Purpose: Higher doses of cytarabine appear to improve long-term outcome in acute myeloid leukemia (AML), in particular for younger patients. To this end, the optimal dosage of single-agent cytarabine in consolidation therapy remains elusive. Here, we assessed the impact of different dosages of cytarabine consolidation after 7 + 3 induction on outcome in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry., Methods: Patients between 18 and 64 years of age, registered between April 2005 and September 2020, who attained complete remission after intensive induction and received at least one consolidation cycle with intermediate (IDAC) or high-dose cytarabine (HiDAC) were selected. To account for differences in patient and disease characteristics between both groups, the average treatment effect was estimated by propensity score weighting., Results: Six-hundred-forty-two patients received HiDAC consolidation with median dosage of 17.6 (IQR (interquartile range), 16.5-18.0) g/m
2 for a median number of 3 cycles (IQR, 2-3), whereas 178 patients received IDAC consolidation with 5.9 (IQR, 5.7-8.6) g/m2 for a median of 2 cycles (IQR, 1-3). Both groups differed significantly in some important characteristics (age, sex, cytogenetic risk group, ECOG performance status, disease status, HCT-CI, number of induction cycles). After propensity score weighting for differences in patient and disease characteristics, relapse-free survival after 2 years was comparable between HiDAC-treated (55.3%) and IDAC-treated (55.6%) patients (HR = 0.935, p = 0.69). Moreover, no significant differences in overall survival were observed after 2 years (84.7 vs. 80.6%, HR = 1.101, p = 0.65). Notably, more patients treated with IDAC received allogeneic hematopoietic cell transplantation in first remission (37.6 vs. 19.8%, p < 0.001). Censoring for allogeneic hematopoietic cell transplantation in first remission revealed no significant survival difference with regard to cytarabine dosage. Considering only of European LeukemiaNet (ELN) favorable-risk AML patients, there was no significant difference in outcome. Of note, significantly more patients treated with HiDAC suffered from ≥ 3 CTCAE infectious complications (56.7 [95%-CI 52.8-60.6%] vs. 44.1% [95%-CI 36.6-51.7%]; p = 0,004). The rate of other ≥ 3 CTCAE non-hematological toxicities and secondary malignancies was comparable in both treatment groups., Conclusions: This retrospective analysis suggests no significant benefit of high-dose cytarabine compared to intermediate dosages in consolidation for AML patients under 65 years of age, independent of ELN risk group., Trial Registration: NCT03188874., (© 2022. The Author(s).)- Published
- 2023
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25. Acute severe non-A-E-hepatitis of unknown origin in children - A 30-year retrospective observational study from north-west Germany.
- Author
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Leiskau C, Tsaka S, Meyer-Ruhnke L, Mutschler FE, Pfister ED, Lainka E, and Baumann U
- Subjects
- Humans, Child, Pandemics, Acute Disease, Germany epidemiology, COVID-19 complications, COVID-19 epidemiology, Hepatitis epidemiology, Liver Failure, Acute etiology, Hepatitis A complications, Hepatitis A epidemiology
- Abstract
Background & Aims: The etiology of the current acute severe non-A-E hepatitis epidemic in children remains unclear. We aimed to describe the occurrence and outcomes of acute severe hepatitis in pediatric patients in North-West Germany over a period of more than 30 years and in the context of the current epidemic., Methods: We analyzed all cases of acute severe hepatitis in childhood, as defined by the World Health Organization, at Hannover Medical School from 1990 and at the University Hospital of Essen from 2009 to 16 May 2022. We separated cases into a historic cohort (1990-2018) and a COVID-19 era cohort (2019-2022)., Results: After application of exclusion criteria, 107 patients with acute severe hepatitis were identified (2.32 cases/center/year). Annual incidence per center rose significantly from 2.2 (historic cohort until 2018) to 4.25/center/year (from 2019, p = 0.002). Of all cases, 75.7% presented with jaundice, while 53.3% had clinical signs of infection. Two cases of adenovirus were proven (2004/2016), other pathogens detected were HHV-6 (4), CMV, HSV, EBV(3). Sixty-nine patients (64.5%) met the criteria of pediatric acute liver failure, with 44 requiring liver transplantation. In the current cohort, patients with infection, gastrointestinal symptoms and higher alanine aminotransferase had a better chance of transplant-free survival, whereas hepatic encephalopathy, higher international normalized ratio and bilirubin predicted a poor outcome. Twenty-five patients developed hepatitis-associated aplastic anemia and 19 patients (17.8%) died., Conclusions: Acute non-A-E-hepatitis in children is a rare but severe entity, often leading to acute liver failure. Clinical presentation in our current cohort resembles 2022 NAEH cases, with improved outcomes compared to historic controls. The rising incidence of NAEH in our centers since 2019, in the absence of adenoviral infection, indicates other potential triggers of similar NAEH cases., Impact and Implications: As the current epidemic of severe acute non-A-E-hepatitis cases in children highlights our limited understanding in the field, we aim to describe current cases, characterizing the presentation over time, and defining similarities and discrepancies before and during the COVID-19 pandemic. Our data show a rising incidence of non-A-E-hepatitis cases since the beginning of the COVID-19 pandemic. These cases were not associated with adenoviral infections, suggesting that the recently described accumulation of adenovirus infections in relationship to hepatitis is a new trigger for a known phenomenon, rather than a new disease entity. Therefore, the role of protective isolation and subsequent lack of contact with trivial infections in children during the pandemic should be the subject of further examinations. We expect our data to contribute to a better understanding of severe acute hepatitis in childhood, increased vigilance for this potentially lethal disease beyond the current epidemic, and ultimately improved clinical diagnosis and care., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
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26. [Novel Strategies to Treat Acute Myeloid Leukemia].
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Gediga MHE, Middeke JM, and Ruhnke L
- Subjects
- Humans, Cytarabine therapeutic use, Gemtuzumab therapeutic use, Anthracyclines therapeutic use, Azacitidine therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
Background: While the "7+3" regimen of cytarabine + anthracycline has been the backbone of acute myeloid leukemia (AML) treatment for four decades, several novel drugs have been approved in the past five years. Despite these promising novel therapeutic options, treatment of AML remains challenging, given the biologically heterogenous character of the disease., Aim: This review provides an update on novel treatment strategies for AML., Material and Methods: This article is based on the current European LeukemiaNet (ELN) recommendations and the DGHO «Onkopedia» guideline on AML treatment., Results and Conclusion: The treatment algorithm is based on patient-related and disease-specific factors, such as patient age and fitness as well as AML molecular profile. Younger patients considered fit for intensive chemotherapy receive 1-2 courses of induction therapy ("7+3" regimen, eg. cytarabine/daunorubicin, or CPX-351 for patients with myelodysplasia-related AML or therapy-related AML). For CD33+ patients or those with evidence of an FLT3 mutation "7+3" in combination with Gemtuzumab-Ozogamicin (GO) or Midostaurin is recommended, respectively. For consolidation, patients receive either high-dose chemotherapy (± GO/± Midostaurin) or undergo allogeneic hematopoietic cell transplantation (HCT), based on ELN risk stratification. In some cases, maintenance therapy with oral azacytidine or FLT3 inhibitor is indicated. Patients experiencing relapse should receive chemotherapy-based re-induction therapy or, in case of an FLT3 mutation, Gilteritinib and subsequently undergo allogeneic HCT. For older patients or those considered unfit for intensive therapy, azacytidine in combination with Venetoclax is a promising novel treatment strategy. Although not yet approved by the European Medical Agency (EMA), for patients with IDH1 IDH1 or IDH2 mutations treatment with the IDH1 and IDH2 inhibitors Ivosidenib and Enasidenib should be considered., Competing Interests: Leo Ruhnke: Beigene, Inc., Reisekostenunterstützung Neovii Biotech GmbH, Reisekostenunterstützung Jan Moritz Middeke: Beratungstätigkeit: Janssen, Roche, Gilead, Abbvie, Jazz, Pfizer, Astellas, Novartis, AstraZeneca Honorare: Novartis, Roche, Janssen, Abbvie, Pfizer, Sanofi, Astellas Finanzierung wissenschaftlicher Untersuchungen: Janssen, Jazz, Astellas, (Thieme. All rights reserved.)
- Published
- 2023
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27. Next Generation Biobanking: Employing a Robotic System for Automated Mononuclear Cell Isolation.
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Fuchs YF, Brunner J, Weigelt M, Schieferdecker A, Morgenstern R, Sturm A, Winter B, Jambor H, Stölzel F, Ruhnke L, von Bonin M, Rücker-Braun E, Heidenreich F, Fuchs A, Bonifacio E, Bornhäuser M, Poitz DM, and Altmann H
- Subjects
- Biological Specimen Banks, Leukocytes, Cell Separation, Robotic Surgical Procedures
- Published
- 2023
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28. Biallelic TET2 mutations confer sensitivity to 5'-azacitidine in acute myeloid leukemia.
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Stölzel F, Fordham SE, Nandana D, Lin WY, Blair H, Elstob C, Bell HL, Mohr B, Ruhnke L, Kunadt D, Dill C, Allsop D, Piddock R, Soura EN, Park C, Fadly M, Rahman T, Alharbi A, Wobus M, Altmann H, Röllig C, Wagenführ L, Jones GL, Menne T, Jackson GH, Marr HJ, Fitzgibbon J, Onel K, Meggendorfer M, Robinson A, Bziuk Z, Bowes E, Heidenreich O, Haferlach T, Villar S, Ariceta B, Diaz RA, Altschuler SJ, Wu LF, Prosper F, Montesinos P, Martinez-Lopez J, Bornhäuser M, and Allan JM
- Subjects
- Humans, Mice, Animals, Azacitidine, Kaplan-Meier Estimate, Mutation, DNA-Binding Proteins genetics, Leukemia, Myeloid, Acute genetics, Dioxygenases genetics
- Abstract
Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5'-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5'-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.
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- 2023
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29. Spatial heterogeneity and differential treatment response of acute myeloid leukemia and relapsed/refractory extramedullary disease after allogeneic hematopoietic cell transplantation.
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Kunadt D, Herold S, Poitz D, Wagenführ L, Kretschmann T, Sockel K, Ruhnke L, Brückner S, Sommer U, Meier F, Röllig C, von Bonin M, Thiede C, Schetelig J, Bornhäuser M, and Stölzel F
- Abstract
Although extramedullary manifestations (EMs) are frequent in patients with acute myeloid leukemia (AML), they are often not detected during clinical workup and neither imaging- nor molecularly based diagnostic strategies are established to reveal their existence. Still, the detection of EM is essential for therapeutic decision-making, as EM present with aggressive and resistant disease and since mutational profiling might render patients within a different risk category, requiring personalized therapeutic strategies. Here, we report the case of an AML patient presenting with AML bone marrow (BM) infiltration and molecularly distinct EM at time of diagnosis followed by multiple EM relapses while undergoing several intensive chemotherapies including allogeneic hematopoietic cell transplantations (alloHCTs).
18 Fluorodesoxy-glucose positron emission tomography (18 FDG-PET)-imaging revealed EM sites in the mediastinum, duodenum, skin, and in retroperitoneal tissue, whereas recurrent BM biopsies showed continuous cytomorphologic and cytogenetic remission after alloHCT. To investigate the molecular background of the aggressive character of extramedullary disease and its differential treatment response, we performed amplicon-based next generation sequencing. An exon 4 (c.497_498insGA) frameshift RUNX1 mutation was exclusively found in all of the patient's EM sites, but not in the BM or in peripheral blood samples at time of EM reoccurrence. In addition, we detected an exon 13 (c.3306G>T) ASXL1 point mutation only in the retroperitoneal tumor tissue at the time of the fourth relapse. In contrast to the patient's intermediate-risk BM AML at diagnosis according to ELN2017, EM sites showed molecular adverse-risk features implicating intensified strategies like cellular therapies. Notably, disease relapse could only be detected by imaging throughout the course of disease. This case demonstrates both the necessity of continuous molecular profiling of EM to reveal differential molecular composition of EM and BM-derived AML, supposedly leading to divergent susceptibility to established therapies, as well as recurrent18 FDG-PET-imaging for detecting residual disease and assessment of treatment response in case of EM AML., Competing Interests: Competing interests: The authors declare that there is no conflict of interest. C.T. is the CEO and co-owner of AgenDix GmbH., (© The Author(s), 2022.)- Published
- 2022
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30. Using stroma-anchoring cytokines to augment ADCC: a phase 1 trial of F16IL2 and BI 836858 for posttransplant AML relapse.
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Berdel AF, Ruhnke L, Angenendt L, Wermke M, Röllig C, Mikesch JH, Scheller A, Hemmerle T, Matasci M, Wethmar K, Kessler T, Gerwing M, Hescheler D, Schäfers M, Hartmann W, Altvater B, Rossig C, Bornhäuser M, Lenz G, Stelljes M, Rueter B, Neri D, Berdel WE, and Schliemann C
- Subjects
- Antibodies, Monoclonal, Humanized, Antibody-Dependent Cell Cytotoxicity, Cytokines, Humans, Immunoglobulin Fc Fragments, Middle Aged, Recurrence, Interleukin-2 adverse effects, Leukemia, Myeloid, Acute pathology
- Abstract
Natural killer (NK) cells are key effectors in cancer immunosurveillance and posttransplant immunity, but deficiency of environmental signals and insufficient tumor recognition may limit their activity. We hypothesized that the antibody-mediated anchoring of interleukin-2 (IL-2) to a spliced isoform of the extracellular matrix (ECM) glycoprotein tenascin-C would potentiate NK-cell-mediated antibody-dependent cellular cytotoxicity against leukemic blasts. In this novel-novel combination, dose-escalation, phase 1 trial, we enrolled patients with posttransplant acute myeloid leukemia (AML) relapse to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of the antibody-cytokine fusion F16IL2 (10 × 106 to 20 × 106 IU IV; days 1, 8, 15, and 22 of each 28-day cycle) in combination with the anti-CD33 antibody BI 836858 (10-40 mg IV, 2 days after each F16IL2 infusion). Among the 15 patients (median [range] age, 50 [20-68] years) treated across 4 dose levels (DLs), 6 (40%) had received 2 or 3 prior transplantations. The most frequent adverse events were pyrexia, chills, and infusion-related reactions, which were manageable, transient and of grade ≤2. One dose-limiting toxicity occurred at each of DLs 3 (pulmonary edema) and 4 (graft-versus-host disease). Three objective responses were observed among 7 patients treated at the 2 higher DLs, whereas no responses occurred at the 2 starting DLs. Combination therapy stimulated the expansion and activation of NK cells, including those expressing the FcγRIIIA/CD16 receptor. ECM-targeted IL-2 combined with anti-CD33 immunotherapy represents an innovative approach associated with acceptable safety and encouraging biologic and clinical activity in posttransplant AML relapse. This trial was registered at EudraCT as 2015-004763-37., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2022
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31. Prevalence and variation of CHIP in patients with aggressive lymphomas undergoing CD19-directed CAR T-cell treatment.
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Teipel R, Kroschinsky F, Kramer M, Kretschmann T, Egger-Heidrich K, Krüger T, Ruhnke L, Herold S, Stasik S, Sockel K, Middeke JM, Trautmann-Grill K, Bornhäuser M, Thiede C, and von Bonin M
- Subjects
- Antigens, CD19, Clonal Hematopoiesis, Cytokine Release Syndrome, Humans, Prevalence, T-Lymphocytes, Lymphoma, B-Cell, Lymphoma, Non-Hodgkin, Neurotoxicity Syndromes, Receptors, Chimeric Antigen
- Abstract
Inflammation plays an important role in chimeric antigen receptor (CAR) T-cell therapy, especially in the pathophysiology of cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Clonal hematopoiesis of indetermined potential (CHIP) has also been associated with chronic inflammation. The relevance of CHIP in the context of CAR T-cell treatment is widely unknown. We evaluated the prevalence of CHIP, using a targeted deep sequencing approach, in a cohort of patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma before and after CAR T-cell treatment. The aim was to define the prevalence and variation of CHIP over time and to assess the influence on clinical inflammation syndromes (CRS/ICANS), cytopenia, and outcome. Overall, 32 patients were included. CHIP was found in 11 of 32 patients (34%) before CAR T-cell therapy. CHIP progression was commonly detected in the later course. Patients with CHIP showed a comparable response rate to CAR T-cell treatment but had an improved overall survival (not reached vs 265 days, P = .003). No significant difference was observed in terms of the occurrence and severity of CRS/ICANS, therapeutic use of tocilizumab and glucocorticosteroids, paraclinical markers of inflammation (with the exception of ferritin), or dynamics of hematopoietic recovery. CHIP is commonly observed in patients undergoing CD19-directed CAR T-cell therapy and is not associated with an inferior outcome., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2022
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32. Author Correction: Genome-wide association study identifies susceptibility loci for acute myeloid leukemia.
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Lin WY, Fordham SE, Hungate E, Sunter NJ, Elstob C, Xu Y, Park C, Quante A, Strauch K, Gieger C, Skol A, Rahman T, Sucheston-Campbell L, Wang J, Hahn T, Clay-Gilmour AI, Jones GL, Marr HJ, Jackson GH, Menne T, Collin M, Ivey A, Hills RK, Burnett AK, Russell NH, Fitzgibbon J, Larson RA, Le Beau MM, Stock W, Heidenreich O, Alharbi A, Allsup DJ, Houlston RS, Norden J, Dickinson AM, Douglas E, Lendrem C, Daly AK, Palm L, Piechocki K, Jeffries S, Bornhäuser M, Röllig C, Altmann H, Ruhnke L, Kunadt D, Wagenführ L, Cordell HJ, Darlay R, Andersen MK, Fontana MC, Martinelli G, Marconi G, Sanz MA, Cervera J, Gómez-Seguí I, Cluzeau T, Moreilhon C, Raynaud S, Sill H, Voso MT, Lo-Coco F, Dombret H, Cheok M, Preudhomme C, Gale RE, Linch D, Gaal-Wesinger J, Masszi A, Nowak D, Hofmann WK, Gilkes A, Porkka K, Milosevic Feenstra JD, Kralovics R, Grimwade D, Meggendorfer M, Haferlach T, Krizsán S, Bödör C, Stölzel F, Onel K, and Allan JM
- Published
- 2022
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33. The diagnostic red blood cell distribution width as a prognostic factor in acute myeloid leukemia.
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Vucinic V, Ruhnke L, Sockel K, Röhnert MA, Backhaus D, Brauer D, Franke GN, Niederwieser D, Bornhäuser M, Röllig C, Platzbecker U, Schwind S, and Jentzsch M
- Subjects
- Erythrocytes, Humans, Prognosis, Erythrocyte Indices, Leukemia, Myeloid, Acute diagnosis
- Published
- 2021
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34. Long-Term Mixed Chimerism After Ex Vivo / In Vivo T Cell-Depleted Allogeneic Hematopoietic Cell Transplantation in Patients With Myeloid Neoplasms.
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Ruhnke L, Stölzel F, Oelschlägel U, von Bonin M, Sockel K, Middeke JM, Röllig C, Jöhrens K, Schetelig J, Thiede C, and Bornhäuser M
- Abstract
In patients who have undergone allogeneic hematopoietic cell transplantation (HCT), myeloid mixed donor chimerism (MC) is a risk factor for disease relapse. In contrast, several studies found favorable outcome in patients with lymphoid MC. Thus far, most studies evaluating MC focused on a short-term follow-up period. Here, we report the first case series of long-term survivors with MC. We screened 1,346 patients having undergone HCT for myeloid neoplasms at our center from 1996 to 2016; 443 patients with data on total peripheral blood mononuclear cells (PBMC)/CD4
+ /CD34+ short tandem repeat (STR) donor chimerism (DC) and follow-up ≥24 months post-HCT were included. We identified 10 patients with long-term MC (PBMC DC <95% at ≥12 months post-HCT). Median follow-up was 11 years. All patients had received combined ex vivo/in vivo T cell-depleted (TCD) peripheral blood stem cells; none experienced ≥grade 2 acute graft-versus-host disease (GVHD). The mean total PBMC, CD4+ , and CD34+ DC of all patients were 95.88%, 85.84%, and 90.15%, respectively. Reduced-intensity conditioning (RIC) was associated with a trend to lower mean total DC. Of note, two patients who experienced relapse had lower CD34+ DC but higher CD4+ DC as compared with patients in continuous remission. Bone marrow evaluation revealed increased CD4+ /FOXP3+ cells in patients with MC, which might indicate expansion of regulatory T cells (Tregs ). Our results support known predictive factors associated with MC such as RIC and TCD, promote the value of CD34+ MC as a potential predictor of relapse, highlight the potential association of CD4+ MC with reduced risk of GVHD, and indicate a possible role of Tregs in the maintenance of immune tolerance post-HCT., Competing Interests: Author CT was employed by AgenDix GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ruhnke, Stölzel, Oelschlägel, von Bonin, Sockel, Middeke, Röllig, Jöhrens, Schetelig, Thiede and Bornhäuser.)- Published
- 2021
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35. Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers.
- Author
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Horak P, Heining C, Kreutzfeldt S, Hutter B, Mock A, Hüllein J, Fröhlich M, Uhrig S, Jahn A, Rump A, Gieldon L, Möhrmann L, Hanf D, Teleanu V, Heilig CE, Lipka DB, Allgäuer M, Ruhnke L, Laßmann A, Endris V, Neumann O, Penzel R, Beck K, Richter D, Winter U, Wolf S, Pfütze K, Geörg C, Meißburger B, Buchhalter I, Augustin M, Aulitzky WE, Hohenberger P, Kroiss M, Schirmacher P, Schlenk RF, Keilholz U, Klauschen F, Folprecht G, Bauer S, Siveke JT, Brandts CH, Kindler T, Boerries M, Illert AL, von Bubnoff N, Jost PJ, Spiekermann K, Bitzer M, Schulze-Osthoff K, von Kalle C, Klink B, Brors B, Stenzinger A, Schröck E, Hübschmann D, Weichert W, Glimm H, and Fröhling S
- Subjects
- Adult, Gene Expression Profiling, Genomics, Humans, Exome Sequencing, Neoplasms drug therapy, Neoplasms genetics, Transcriptome
- Abstract
The clinical relevance of comprehensive molecular analysis in rare cancers is not established. We analyzed the molecular profiles and clinical outcomes of 1,310 patients (rare cancers, 75.5%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. On the basis of 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved overall response and disease control rates (23.9% and 55.3%) compared with previous therapies, translating into a progression-free survival ratio >1.3 in 35.7% of patients. These data demonstrate the benefit of molecular stratification in rare cancers and represent a resource that may promote clinical trial access and drug approvals in this underserved patient population. SIGNIFICANCE: Rare cancers are difficult to treat; in particular, molecular pathogenesis-oriented medical therapies are often lacking. This study shows that whole-genome/exome and RNA sequencing enables molecularly informed treatments that lead to clinical benefit in a substantial proportion of patients with advanced rare cancers and paves the way for future clinical trials. See related commentary by Eggermont et al., p. 2677 . This article is highlighted in the In This Issue feature, p. 2659 ., (©2021 American Association for Cancer Research.)
- Published
- 2021
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36. Case Report: ANXA2 Associated Life-Threatening Coagulopathy With Hyperfibrinolysis in a Patient With Non-APL Acute Myeloid Leukemia.
- Author
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Ruhnke L, Stölzel F, Wagenführ L, Altmann H, Platzbecker U, Herold S, Rump A, Schröck E, Bornhäuser M, Schetelig J, and von Bonin M
- Abstract
Patients with acute promyelocytic leukemia (APL) often present with potentially life-threatening hemorrhagic diathesis. The underlying pathomechanisms of APL-associated coagulopathy are complex. However, two pathways considered to be APL-specific had been identified: 1) annexin A2 (ANXA2)-associated hyperfibrinolysis and 2) podoplanin (PDPN)-mediated platelet activation and aggregation. In contrast, since disseminated intravascular coagulation (DIC) is far less frequent in patients with non-APL acute myeloid leukemia (AML), the pathophysiology of AML-associated hemorrhagic disorders is not well understood. Furthermore, the potential threat of coagulopathy in non-APL AML patients may be underestimated. Herein, we report a patient with non-APL AML presenting with severe coagulopathy with hyperfibrinolysis. Since his clinical course resembled a prototypical APL-associated hemorrhagic disorder, we hypothesized pathophysiological similarities. Performing multiparametric flow cytometry (MFC) and immunofluorescence imaging (IF) studies, we found the patient's bone-marrow mononuclear cells (BM-MNC) to express ANXA2 - a biomarker previously thought to be APL-specific. In addition, whole-exome sequencing (WES) on sorted BM-MNC (leukemia-associated immunophenotype (LAIP)1: ANXA
lo , LAIP2: ANXAhi ) demonstrated high intra-tumor heterogeneity. Since ANXA2 regulation is not well understood, further research to determine the coagulopathy-initiating events in AML and APL is indicated. Moreover, ANXA2 and PDPN MFC assessment as a tool to determine the risk of life-threatening DIC in AML and APL patients should be evaluated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ruhnke, Stölzel, Wagenführ, Altmann, Platzbecker, Herold, Rump, Schröck, Bornhäuser, Schetelig and von Bonin.)- Published
- 2021
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37. New automatic quantification method of immunofluorescence and histochemistry in whole histological sections.
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Kessel F, Steglich A, Tschongov T, Gembardt F, Ruhnke L, Stumpf J, Behrendt R, Cohrs C, Kopaliani I, Todorov V, Gerlach M, and Hugo C
- Subjects
- Algorithms, Fluorescent Dyes pharmacology, Humans, Kidney diagnostic imaging, Fluorescent Antibody Technique methods, Kidney ultrastructure, Software, Staining and Labeling methods
- Abstract
Immunofluorescent staining is a widespread tool in basic science to understand organ morphology and (patho-) physiology. The analysis of imaging data is often performed manually, limiting throughput and introducing human bias. Quantitative analysis is particularly challenging for organs with complex structure such as the kidney. In this study we present an approach for automatic quantification of fluorescent markers and histochemical stainings in whole organ sections using open source software. We validate our novel method in multiple typical challenges of basic kidney research and demonstrate its general relevance and applicability to other complex solid organs for a variety of different markers and stainings. Our newly developed software tool "AQUISTO", applied as a standard in primary data analysis, facilitates efficient large scale evaluation of cellular populations in various types of histological samples. Thereby it contributes to the characterization and understanding of (patho-) physiological processes., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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38. Progenitor Renin Lineage Cells are not involved in the regeneration of glomerular endothelial cells during experimental renal thrombotic microangiopathy.
- Author
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Ruhnke L, Sradnick J, Al-Mekhlafi M, Gerlach M, Gembardt F, Hohenstein B, Todorov VT, and Hugo C
- Subjects
- Animals, Animals, Genetically Modified metabolism, Animals, Genetically Modified physiology, Endothelial Cells metabolism, Endothelial Cells physiology, Glomerular Mesangium metabolism, Glomerular Mesangium physiology, Glomerulonephritis metabolism, Glomerulonephritis physiopathology, Integrin alpha Chains metabolism, Kidney Glomerulus metabolism, Mesangial Cells metabolism, Mesangial Cells physiology, Mice, Podocytes metabolism, Podocytes physiology, Stem Cells metabolism, Thrombotic Microangiopathies metabolism, Cell Lineage physiology, Kidney Glomerulus physiology, Regeneration physiology, Renin metabolism, Stem Cells physiology, Thrombotic Microangiopathies physiopathology
- Abstract
Endothelial cells (EC) frequently undergo primary or secondary injury during kidney disease such as thrombotic microangiopathy or glomerulonephritis. Renin Lineage Cells (RLCs) serve as a progenitor cell niche after glomerular damage in the adult kidney. However, it is not clear whether RLCs also contribute to endothelial replenishment in the glomerulus following endothelial injury. Therefore, we investigated the role of RLCs as a potential progenitor niche for glomerular endothelial regeneration. We used an inducible tet-on triple-transgenic reporter strain mRen-rtTAm2/LC1/LacZ to pulse-label the renin-producing RLCs in adult mice. Unilateral kidney EC damage (EC model) was induced by renal artery perfusion with concanavalin/anti-concanavalin. In this model glomerular EC injury and depletion developed within 1 day while regeneration occurred after 7 days. LacZ-labelled RLCs were restricted to the juxtaglomerular compartment of the afferent arterioles at baseline conditions. In contrast, during the regenerative phase of the EC model (day 7) a subset of LacZ-tagged RLCs migrated to the glomerular tuft. Intraglomerular RLCs did not express renin anymore and did not stain for glomerular endothelial or podocyte cell markers, but for the mesangial cell markers α8-integrin and PDGFRβ. Accordingly, we found pronounced mesangial cell damage parallel to the endothelial injury induced by the EC model. These results demonstrated that in our EC model RLCs are not involved in endothelial regeneration. Rather, recruitment of RLCs seems to be specific for the repair of the concomitantly damaged mesangium., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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39. Activation of murine macrophages and lymphocytes by Ureaplasma diversum.
- Author
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Chelmonska-Soyta A, Miller RB, Ruhnke L, and Rosendal S
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- Animals, Cytokines biosynthesis, Female, In Vitro Techniques, Mice, Mice, Inbred C3H, Nitric Oxide biosynthesis, Spleen cytology, Lymphocyte Activation immunology, Macrophage Activation immunology, Ureaplasma immunology
- Abstract
Ureaplasma diversum is a pathogen in the bovine reproductive tract. The objective of the research was to study interactions with macrophages and lymphocytes which might elucidate aspects of pathogenetic mechanisms of this organism. We studied the activation of murine macrophages of C3H/HeN (LPS-responder) and C3H/HeJ (LPS-low-responder) genotype for TNF-alpha, IL-6, IL-1 and nitric oxide production and blastogenic response of C3H/HeJ splenocytes after Ureaplasma diversum stimulation. Live and heat-killed U. diversum induced TNF-alpha, IL-6 and IL-1 in peritoneal macrophage cultures of both C3H/HeN and C3H/HeJ mice in a dose dependent manner. Interferon-gamma modulated the cytokine production, by increasing the production of TNF-alpha, IL-6 and nitric oxide, but IL-1 secretion was only enhanced in C3H/HeJ macrophages stimulated by live ureaplasmas. Supernatant of U. diversum sonicate was mitogenic for murine spleen lymphocytes. The blastogenic response was dose dependent, and stimulation with both U. diversum and Concanavalin A seemed to have an additive effect. These results suggest that U. diversum, similar to other mycoplasmas, activates murine macrophages and lymphoid cells. The studies should be repeated with bovine cells in order to elucidate pathogenetic aspects of inflammation in cattle caused by U. diversum.
- Published
- 1994
40. Canada. Arthritis caused by Mycoplasma hyosynoviae in grower pigs.
- Author
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Sanford SE, Fruhner L, and Ruhnke L
- Published
- 1992
41. The influence of casting methods on the surface microhardness and crystalline formation of aluminum-copper alloys.
- Author
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Veronesi GS, Consani S, and Ruhnke LA
- Subjects
- Acid Etching, Dental, Air, Crystallization, Dental Polishing, Electricity, Gases, Hardness, Materials Testing, Oxygen, Surface Properties, Aluminum chemistry, Copper chemistry, Dental Alloys chemistry, Dental Casting Technique
- Abstract
The influence of air/gas, oxygen/gas, and electric casting methods on the surface microhardness and crystalline formation of three aluminum-copper alloys was verified. The inclusion, wax elimination, and casting of the pattern were accomplished by using conventional techniques for thermal expansion investment. After metalographic polishing, the surface hardness analysis was verified with a penetrator. The penetrations were transformed in Knoop hardness with the conversion table, and computed by variance analysis. The test sample surfaces were then etched with a reactive solution composed of equal parts of hydrogen peroxide and ammonium hydroxide. The crystalline grains precipitated by solution were photographed with Kodak film 32 ASA. The results demonstrated that the surface microhardness of the alloys was modified according to the heat sources used, and the crystalline grain disposition was also adversely influenced by the heat sources, with the exception of Goldent alloy.
- Published
- 1992
- Full Text
- View/download PDF
42. [Retentive capacity of materials used for bracket fixation].
- Author
-
Martin Neto MC, Consani S, and Antonio Ruhnke L
- Subjects
- Acid Etching, Dental, Composite Resins, Dental Enamel ultrastructure, Fluorides, Topical pharmacology, Humans, Polycarboxylate Cement, Zinc Phosphate Cement, Dental Bonding, Dental Cements, Orthodontic Appliances
- Published
- 1983
43. Infiltration of a radioactive solution into joined silver-amalgam.
- Author
-
Consani S, Ruhnke LA, and Stolf WL
- Subjects
- Radioisotopes, Tensile Strength, Dental Amalgam, Dental Bonding, Silver
- Published
- 1977
- Full Text
- View/download PDF
44. Verification of the consistency, setting time, and dimensional changes of root canal filling materials.
- Author
-
Benatti O, Stolf WL, and Ruhnke LA
- Subjects
- Chemical Phenomena, Chemistry, Physical, Powders, Surface Properties, Time Factors, Viscosity, Zinc Oxide-Eugenol Cement, Root Canal Filling Materials standards
- Published
- 1978
- Full Text
- View/download PDF
45. [Photomicrographic aspects of the surface roughness of composite resins].
- Author
-
Ferrari JC, Consani S, and Ruhnke LA
- Subjects
- Matrix Bands, Surface Properties, Composite Resins, Dental Polishing instrumentation, Dental Polishing methods
- Published
- 1984
46. [Studies on the variations in efficiency of burs at high speed].
- Author
-
Consani S, Ruhnke LA, and Stolf WL
- Subjects
- Dental High-Speed Equipment
- Published
- 1974
47. [Behavior of Copal varnish used as cavity insulator].
- Author
-
Consani S, de Goes MF, and Ruhnke LA
- Subjects
- Dental Materials, Evaluation Studies as Topic, Humans, In Vitro Techniques, Resins, Plant, Dental Cavity Lining
- Published
- 1979
48. An explanation for the water distribution in a hygroscopic expansion technique.
- Author
-
Consani S and Ruhnke LA
- Subjects
- Chemical Phenomena, Chemistry, Physical, Models, Chemical, Scintillation Counting, Tritium, Dental Casting Investment, Dental Casting Technique, Water
- Abstract
The water distribution in a controlled water addition technique was investigated using a Liquid Scintillation Counter. The mix water arrangement varied in different sections of the investment mass. The water distribution seemed to be the result of the influence of added water and a sprue base.
- Published
- 1980
- Full Text
- View/download PDF
49. Mycoplasma felis as a cause of pleuritis in horses.
- Author
-
Ogilvie TH, Rosendal S, Blackwell TE, Rostkowski CM, Julian RJ, and Ruhnke L
- Subjects
- Animals, Horses, Mycoplasma isolation & purification, Mycoplasma pathogenicity, Mycoplasma Infections microbiology, Pleural Effusion microbiology, Pleurisy microbiology, Horse Diseases microbiology, Mycoplasma Infections veterinary, Pleurisy veterinary
- Abstract
Mycoplasma felis was the only organism recovered from the thoracic cavity of a horse with pleuritis. Large numbers of mildly degenerative neutrophils were in the pleural fluid. The horse developed a serologic response to M felis and recovered during hospitalization. Experimentally, a pony was inoculated in the thoracic cavity with a pure culture of the M felis isolate suspended in the pony's serum. A control pony was inoculated with serum only. Within 48 hours, the principal pony developed fever, increased respiratory rate, pleural effusion, and signs of pain. A highly cellular exudate with nondegenerative neutrophils and large numbers of M felis was recovered from the thoracic cavity. The control pony remained normal. The principal pony developed an antibody response to M felis. The control pony did not. Fourteen days after inoculation, both ponies were euthanatized. Necropsy revealed pleural inflammation in the principal pony. Pleural lesions were not found in the control pony.
- Published
- 1983
50. Temperature developed during the cutting of tooth tissue.
- Author
-
Consani S and Ruhnke LA
- Subjects
- Dental Instruments statistics & numerical data, Humans, Tooth analysis, Dental Cavity Preparation, Temperature
- Published
- 1976
Catalog
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