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5. S108: PEDIATRIC T- ALL RELAPSE: CONSTITUTIONAL CANCER PREDISPOSITION AND HYPERMUTATATOR PHENOTYPES

Author

Richter-Pechanska, P., primary, Kunz, J., additional, Rausch, T., additional, Erarslan-Uysal, B., additional, Bornhauser, B., additional, Frismantas, V., additional, Assenov, Y., additional, Zimmermann, M., additional, Happich, M., additional, von Knebel-Doeberitz, C., additional, von Neuhoff, N., additional, Koehler, R., additional, Stanulla, M., additional, Schrappe, M., additional, Cario, G., additional, Escherich, G., additional, Kischner-Schwabe, R., additional, Eckert, C., additional, Avigad, S., additional, Pfister, S., additional, Muckenthaler, M., additional, Bourquin, J.-P., additional, Korbel, J., additional, and Kulozik, A., additional

Published
2022
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8. Molecular Measurable Residual Disease Assessment before Hematopoietic Stem Cell Transplantation in Pediatric Acute Myeloid Leukemia Patients: A Retrospective Study by the I-BFM Study Group

Author

Benetton, M., Merli, P., Walter, C., Hansen, M., Da Ros, A., Polato, K., Tregnago, C., Abrahamsson, J., Strocchio, L., Sonneveld, E., Fogelstrand, L., Von Neuhoff, N., Reinhardt, D., Hasle, H., Pigazzi, M., Locatelli, Franco, Locatelli F. (ORCID:0000-0002-7976-3654), Benetton, M., Merli, P., Walter, C., Hansen, M., Da Ros, A., Polato, K., Tregnago, C., Abrahamsson, J., Strocchio, L., Sonneveld, E., Fogelstrand, L., Von Neuhoff, N., Reinhardt, D., Hasle, H., Pigazzi, M., Locatelli, Franco, and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Hematopoietic stem cell transplantation (HSCT) is a curative post-remission treatment in patients with acute myeloid leukemia (AML), but relapse after transplant is still a challenging event. In recent year, several studies have investigated the molecular minimal residual disease (qPCR-MRD) as a predictor of relapse, but the lack of standardized protocols, cut-offs, and timepoints, especially in the pediatric setting, has prevented its use in several settings, including before HSCT. Here, we propose the first collaborative retrospective I-BFM-AML study assessing qPCR-MRD values in pretransplant bone marrow samples of 112 patients with a diagnosis of AML harboring t(8;21)(q22; q22)RUNX1::RUNX1T1, or inv(16)(p13q22)CBFB::MYH11, or t(9;11)(p21;q23)KMT2A::MLLT3, or FLT3-ITD genetic markers. We calculated an ROC cut-off of 2.1 × 10−4 that revealed significantly increased OS (83.7% versus 57.1%) and EFS (80.2% versus 52.9%) for those patients with lower qPCR-MRD values. Then, we partitioned patients into three qPCR-MRD groups by combining two different thresholds, 2.1 × 10−4 and one lower cut-off of 1 × 10−2, and stratified patients into low-, intermediate-, and high-risk groups. We found that the 5-year OS (83.7%, 68.6%, and 39.2%, respectively) and relapse-free survival (89.2%, 73.9%, and 67.9%, respectively) were significantly different independent of the genetic lesion, conditioning regimen, donor, and stem cell source. These data support the PCR-based approach playing a clinical relevance in AML transplant management.

Published
2022

11. Stellungnahme der Ad-hoc-Kommission In-vitro-Diagnostika der AWMF zur Umsetzung der Verordnung (EU) 2017/746 (IVDR) im Hinblick auf In-vitro-Diagnostika aus Eigenherstellung

Author

Hoffmüller, P, Brüggemann, M, Eggermann, T, Ghoreschi, K, Haase, D, Hofmann, J, Hunfeld, KP, Koch, K, Meisel, C, Michl, P, Müller, J, Müller, C, Rabenau, HF, Reinhardt, D, Riemenschneider, MJ, Sachs, UJ, Sack, U, Stenzinger, A, Streichert, T, von Neuhoff, N, Weichert, W, Weinstock, C, Zimmermann, S, Spitzenberger, F, Ad-hoc-Kommission In-vitro-Diagnostika der AWMF, Hoffmüller, P, Brüggemann, M, Eggermann, T, Ghoreschi, K, Haase, D, Hofmann, J, Hunfeld, KP, Koch, K, Meisel, C, Michl, P, Müller, J, Müller, C, Rabenau, HF, Reinhardt, D, Riemenschneider, MJ, Sachs, UJ, Sack, U, Stenzinger, A, Streichert, T, von Neuhoff, N, Weichert, W, Weinstock, C, Zimmermann, S, Spitzenberger, F, and Ad-hoc-Kommission In-vitro-Diagnostika der AWMF

Abstract

In view of the approaching application date of Regulation (EU) 2017/746 ("IVDR") and the resulting EU-wide, harmonized requirements for in vitro diagnostic medical devices (IVD) manufactured and used within European health institutions, the Ad hoc Commission IVD" of the German Association of the Scientific Medical Societies (AWMF) takes a national position on the details of the requirements and conditions related to the use of these IVD products.The Ad hoc Commission IVD emphasizes the relevance of examination procedures developed in medical laboratories, especially in the field of orphan diseases and new diagnostic markers. The IVDR sets an adequate regulatory framework for IVD manufactured and used within health institutions as long as these requirements are fulfilled with reliability and in accordance with the current state of the art in medical laboratory sciences. At the same time, the IVDR requirements have to be regarded under a pragmatic view and in accordance with the quality management systems approved within the diffferent EU Member States. On the one hand, the mandatory requirements of the RiLiBÄK play an essential role in Germany. On the other hand, elements of voluntarily applicable international standards may support the fulfilment of product requirements for safety and performance according to Annex I of the IVDR. Both the complexity and possible solutions for the implementation of the IVDR requirements are discussed on the basis of examples such as the required documentation, performance evaluation and software validation.The Ad hoc Commission IVD recommends that, while aiming at a preferably EU-wide harmonized interpretation of the IVDR requirements, the flexibility in medical laboratory diagnostics necessary for patient care, including the use of IVDs from in-house production, should be emphasized., Vor dem Hintergrund des nahenden Geltungsbeginns der Verordnung (EU) 2017/746 ("IVDR") und der damit EU-weit harmonisierten Anforderungen an In-vitro-Diagnostika (IVD) aus Eigenherstellung positioniert sich die Ad-hoc-Kommission In-vitro-Diagnostika der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) im Einzelnen zu den in der IVDR gestellten Anforderungen und Bedingungen zur Verwendung dieser Produkte.Die Ad-hoc-Kommission IVD hebt die Bedeutung von in medizinischen Laboratorien eigenentwickelten Untersuchungsverfahren für die Patientenversorgung vor allem im Bereich seltener Erkrankungen und neuer diagnostischer Marker hervor. Die IVDR bildet für die Entwicklung und Verwendung von IVD aus Eigenherstellung einen passenden regulatorischen Rahmen, sofern die Anforderungen zuverlässig entsprechend dem Stand der medizinischen Wissenschaft und Technik, aber zugleich pragmatisch und in Übereinstimmung mit den in den Mitgliedstaaten bewährten Qualitätsmanagementsystemen umgesetzt werden. In Deutschland sind hier einerseits die verpflichtenden Anforderungen der RiLiBÄK zu nennen. Andererseits können Elemente von freiwillig anzuwendenden internationalen Normen dazu dienen, die nach Anhang I der IVDR umzusetzenden Anforderungen an Sicherheit und Leistung für IVD aus Eigenherstellung zu erfüllen. Sowohl die Komplexität als auch Lösungskonzepte zur Umsetzung der Anforderungen werden u.a. am Beispiel der erforderlichen Dokumentation, der Leistungsbewertung und der ggf. durchzuführenden Softwarevalidierung aufgezeigt.Die Ad-hoc-Kommission empfiehlt, bei einer möglichst weitreichend harmonisierten Interpretation der Anforderungen gleichzeitig die für die Patientenversorgung notwendige Flexibilität in der labordiagnostischen Versorgung einschließlich der Verwendung von IVD aus Eigenherstellung zu gewährleisten.

Published
2021

12. Advisory opinion of the AWMF Ad hoc Commission In-vitro Diagnostic Medical Devices regarding in-vitro diagnostic medical devices manufactured and used only within health institutions established in the Union according to Regulation (EU) 2017/746 (IVDR)

Author

Hoffmüller, P, Brüggemann, M, Eggermann, T, Ghoreschi, K, Haase, D, Hofmann, J, Hunfeld, KP, Koch, K, Meisel, C, Michl, P, Müller, J, Müller, C, Rabenau, HF, Reinhardt, D, Riemenschneider, MJ, Sachs, UJ, Sack, U, Stenzinger, A, Streichert, T, von Neuhoff, N, Weichert, W, Weinstock, C, Zimmermann, S, Spitzenberger, F, AWMF Ad hoc Commision In-vitro Diagnostic Medical Devices, Hoffmüller, P, Brüggemann, M, Eggermann, T, Ghoreschi, K, Haase, D, Hofmann, J, Hunfeld, KP, Koch, K, Meisel, C, Michl, P, Müller, J, Müller, C, Rabenau, HF, Reinhardt, D, Riemenschneider, MJ, Sachs, UJ, Sack, U, Stenzinger, A, Streichert, T, von Neuhoff, N, Weichert, W, Weinstock, C, Zimmermann, S, Spitzenberger, F, and AWMF Ad hoc Commision In-vitro Diagnostic Medical Devices

Abstract

In view of the approaching application date of Regulation (EU) 2017/746 ("IVDR") and the resulting EU-wide, harmonized requirements for in-vitro diagnostic medical devices (IVD) manufactured and used within European health institutions, the Ad hoc Commission IVD of the German Association of the Scientific Medical Societies (AWMF) takes a national position on the details of the requirements and conditions related to the use of these IVD products.The Ad hoc Commission IVD emphasizes the relevance of examination procedures developed in medical laboratories, especially in the field of orphan diseases and new diagnostic markers. The IVDR sets an adequate regulatory framework for IVD manufactured and used within health institutions as long as these requirements are fulfilled with reliability and in accordance with the current state of the art in medical laboratory sciences. At the same time, the IVDR requirements have to be regarded under a pragmatic view and in accordance with the quality management systems approved within the different EU Member States. On the one hand, the mandatory requirements of the RiLiBÄK play an essential role in Germany. On the other hand, elements of voluntarily applicable international standards may support the fulfilment of product requirements for safety and performance according to Annex I of the IVDR. Both the complexity and possible solutions for the implementation of the IVDR requirements are discussed on the basis of examples such as the required documentation, performance evaluation and software validation.The Ad hoc Commission IVD recommends that, while aiming at a preferably EU-wide harmonized interpretation of the IVDR requirements, the flexibility in medical laboratory diagnostics necessary for patient care, including the use of IVD from in-house production, should be emphasized., Vor dem Hintergrund des nahenden Geltungsbeginns der Verordnung (EU) 2017/746 ("IVDR") und der damit EU-weit harmonisierten Anforderungen an In-vitro-Diagnostika (IVD) aus Eigenherstellung positioniert sich die Ad-hoc-Kommission In-vitro-Diagnostika der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) im Einzelnen zu den in der IVDR gestellten Anforderungen und Bedingungen zur Verwendung dieser Produkte.Die Ad-hoc-Kommission IVD hebt die Bedeutung von in medizinischen Laboratorien eigenentwickelten Untersuchungsverfahren für die Patientenversorgung vor allem im Bereich seltener Erkrankungen und neuer diagnostischer Marker hervor. Die IVDR bildet für die Entwicklung und Verwendung von IVD aus Eigenherstellung einen passenden regulatorischen Rahmen, sofern die Anforderungen zuverlässig entsprechend dem Stand der medizinischen Wissenschaft und Technik, aber zugleich pragmatisch und in Übereinstimmung mit den in den Mitgliedstaaten bewährten Qualitätsmanagementsystemen umgesetzt werden. In Deutschland sind hier einerseits die verpflichtenden Anforderungen der RiLiBÄK zu nennen. Andererseits können Elemente von freiwillig anzuwendenden internationalen Normen dazu dienen, die nach Anhang I der IVDR umzusetzenden Anforderungen an Sicherheit und Leistung für IVD aus Eigenherstellung zu erfüllen. Sowohl die Komplexität als auch Lösungskonzepte zur Umsetzung der Anforderungen werden u.a. am Beispiel der erforderlichen Dokumentation, der Leistungsbewertung und der ggf. durchzuführenden Softwarevalidierung aufgezeigt.Die Ad-hoc-Kommission empfiehlt, bei einer möglichst weitreichend harmonisierten Interpretation der Anforderungen gleichzeitig die für die Patientenversorgung notwendige Flexibilität in der labordiagnostischen Versorgung einschließlich der Verwendung von IVD aus Eigenherstellung zu gewährleisten.

Published
2021

23. Front-line imatinib treatment in children and adolescents with chronic myeloid leukemia: Results from a phase III trial

Author

Suttorp, M, Schulze, P, Glauche, I, Göhring, G, Von Neuhoff, N, Metzler, M, Sedlacek, P, De Bont, E, Balduzzi, A, Lausen, B, Aleinikova, O, Sufliarska, S, Henze, G, Strauss, G, Eggert, A, Kremens, B, Groll, A, Berthold, F, Klein, C, Groß-Wieltsch, U, Sykora, K, Borkhardt, A, Kulozik, A, Schrappe, M, Nowasz, C, Krumbholz, M, Tauer, J, Claviez, A, Harbott, J, Kreipe, H, Schlegelberger, B, Thiede, C, Suttorp, Meinolf, Schulze, Philipp, Glauche, Ingmar, Göhring, Gudrun, Von Neuhoff, Nils, Metzler, Markus, Sedlacek, Petr, De Bont, Eveline S. J. M., Balduzzi, Adriana, Lausen, Birgitte, Aleinikova, Olga, Sufliarska, Sabina, Henze, Günter, Strauss, Gabriele, Eggert, Angelika, Kremens, Bernhard, Groll, Andreas H., Berthold, Frank, Klein, Christoph, Groß-Wieltsch, Ute, Sykora, Karl Walter, Borkhardt, Arndt, Kulozik, Andreas E., Schrappe, Martin, Nowasz, Christina, Krumbholz, Manuela, Tauer, Josephine T., Claviez, Alexander, Harbott, Jochen, Kreipe, Hans H., Schlegelberger, Brigitte, Thiede, Christian, Suttorp, M, Schulze, P, Glauche, I, Göhring, G, Von Neuhoff, N, Metzler, M, Sedlacek, P, De Bont, E, Balduzzi, A, Lausen, B, Aleinikova, O, Sufliarska, S, Henze, G, Strauss, G, Eggert, A, Kremens, B, Groll, A, Berthold, F, Klein, C, Groß-Wieltsch, U, Sykora, K, Borkhardt, A, Kulozik, A, Schrappe, M, Nowasz, C, Krumbholz, M, Tauer, J, Claviez, A, Harbott, J, Kreipe, H, Schlegelberger, B, Thiede, C, Suttorp, Meinolf, Schulze, Philipp, Glauche, Ingmar, Göhring, Gudrun, Von Neuhoff, Nils, Metzler, Markus, Sedlacek, Petr, De Bont, Eveline S. J. M., Balduzzi, Adriana, Lausen, Birgitte, Aleinikova, Olga, Sufliarska, Sabina, Henze, Günter, Strauss, Gabriele, Eggert, Angelika, Kremens, Bernhard, Groll, Andreas H., Berthold, Frank, Klein, Christoph, Groß-Wieltsch, Ute, Sykora, Karl Walter, Borkhardt, Arndt, Kulozik, Andreas E., Schrappe, Martin, Nowasz, Christina, Krumbholz, Manuela, Tauer, Josephine T., Claviez, Alexander, Harbott, Jochen, Kreipe, Hans H., Schlegelberger, Brigitte, and Thiede, Christian

Abstract

A total of 156 patients (age range 1.3-18.0 years, median 13.2 years; 91 (58.3%) male) with newly diagnosed CML (N = 146 chronic phase (CML-CP), N = 3 accelerated phase (CML-AP), N = 7 blastic phase (CML-BP)) received imatinib up-front (300, 400, 500 mg/m 2 , respectively) within a prospective phase III trial. Therapy response, progression-free survival, causes of treatment failure, and side effects were analyzed in 148 children and adolescents with complete data. Event-free survival rate by 18 months for patients in CML-CP (median follow-up time 25 months, range: 1-120) was 97% (95% CI, 94.2-99.9%). According to the 2006 ELN-criteria complete hematologic response by month 3, complete cytogenetic response (CCyR) by month 12, and major molecular response (MMR) by month 18 were achieved in 98, 63, and 59% of the patients, respectively. By month 36, 86% of the patients achieved CCyR and 74% achieved MMR. Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response or intolerance (N = 9). In all, 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N = 3) or SCT-related complications (N = 2). This large pediatric trial extends and confirms data from smaller series that first-line imatinib in children is highly effective.

Published
2018

30. Graft–versus-Leukemia effect after allogeneic stem cell transplantation and transduced donor leukocyte transfusion

Author

Weissinger EM, Borchers S, Provasi E, Morgan M, Silvani A, Radrizzani M, Benati C, Gallo Stampino C, Dammann E, Krons A, Kontsendorn J, Schmidtke J, Kuehnau W, von Neuhoff N, Kolb HJ, Stadler M, CICERI, FABIO, Ganser A, Hertenstein B., BONINI , MARIA CHIARA, Weissinger, Em, Borchers, S, Provasi, E, Morgan, M, Silvani, A, Radrizzani, M, Benati, C, Gallo Stampino, C, Dammann, E, Krons, A, Kontsendorn, J, Schmidtke, J, Kuehnau, W, von Neuhoff, N, Kolb, Hj, Stadler, M, Ciceri, Fabio, Bonini, MARIA CHIARA, Ganser, A, and Hertenstein, B.

Published
2011

31. Graft-versus-leukaemia with little graft-versus-host disease? A clinical phase I/II study using transfusion of transduced donor T-cells for donor leukocyte transfusion

Author

Weissinger EM, Borchers S, Provasi E, Radrizzani M, Bennati C, Stampino CG, Dammann E, Schiffer E, Kontsendorn J, Jorg S, Kuehnau W, von Neuhoff N, Kolb HJ, Stadler M, Ganser A, Hertenstein B., CICERI , FABIO, Weissinger, Em, Borchers, S, Provasi, E, Radrizzani, M, Bennati, C, Stampino, Cg, Dammann, E, Schiffer, E, Kontsendorn, J, Jorg, S, Kuehnau, W, Ciceri, Fabio, von Neuhoff, N, Kolb, Hj, Stadler, M, Ganser, A, and Hertenstein, B.

Published
2008

34. t(6;9)(p22; q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients

Author

Sandahl, JD, Coenen, Eva, Forestier, E, Harbott, J, Johansson, B, Kerndrup, G, Adachi, S, Auvrignon, A, Beverloo, Berna, Cayuela, JM, Chilton, L, Fornerod, M, de Haas, V, Harrison, CJ, Inaba, H, Kaspers, GJL, Liang, DC, Locatelli, F (Franco), Masetti, R, Perot, C, Raimondi, SC, Reinhardt, K, Tomizawa, D, von Neuhoff, N, Zecca, M, Zwaan, CM, Eibrink, Marry, Hasle, H, Sandahl, JD, Coenen, Eva, Forestier, E, Harbott, J, Johansson, B, Kerndrup, G, Adachi, S, Auvrignon, A, Beverloo, Berna, Cayuela, JM, Chilton, L, Fornerod, M, de Haas, V, Harrison, CJ, Inaba, H, Kaspers, GJL, Liang, DC, Locatelli, F (Franco), Masetti, R, Perot, C, Raimondi, SC, Reinhardt, K, Tomizawa, D, von Neuhoff, N, Zecca, M, Zwaan, CM, Eibrink, Marry, and Hasle, H

Published
2014

35. t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients

Author

Sandahl, J. D., primary, Coenen, E. A., additional, Forestier, E., additional, Harbott, J., additional, Johansson, B., additional, Kerndrup, G., additional, Adachi, S., additional, Auvrignon, A., additional, Beverloo, H. B., additional, Cayuela, J.-M., additional, Chilton, L., additional, Fornerod, M., additional, de Haas, V., additional, Harrison, C. J., additional, Inaba, H., additional, Kaspers, G. J. L., additional, Liang, D.-C., additional, Locatelli, F., additional, Masetti, R., additional, Perot, C., additional, Raimondi, S. C., additional, Reinhardt, K., additional, Tomizawa, D., additional, von Neuhoff, N., additional, Zecca, M., additional, Zwaan, C. M., additional, van den Heuvel-Eibrink, M. M., additional, and Hasle, H., additional

Published
2014
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38. Promoter methylation of PARG1, a novel candidate tumor suppressor gene in mantle cell lymphomas

Author

Ripperger, T., primary, von Neuhoff, N., additional, Kamphues, K., additional, Emura, M., additional, Lehmann, U., additional, Tauscher, M., additional, Schraders, M., additional, Groenen, P., additional, Skawran, B., additional, Rudolph, C., additional, Callet-Bauchu, E., additional, van Krieken, J. H.J.M., additional, Schlegelberger, B., additional, and Steinemann, D., additional

Published
2007
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42. Molecular Pathology, Abstract 1–24, Study Group

Author

Gaisa, N., primary, von Neuhoff, N., additional, Weber, A., additional, Grabsch, H., additional, Frank, P., additional, Schneider-Stock, R., additional, Sommerer, F., additional, Woenckhaus, M., additional, Schwark, T., additional, Kremer, M., additional, Laux, H., additional, Koenig, S., additional, Mathluothi, R., additional, Bloch, M., additional, Brabletz, T., additional, Hartmann, A., additional, Wild, P.J., additional, Stöhr, R., additional, Helms, M.W., additional, Pich, A., additional, Lehmann, U., additional, Bürger, H., additional, and Schlake, G., additional

Published
2003
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45. Structural and functional cellular changes induced by Burkholderia pseudomallei rhamnolipid.

Author

Häussler, S, Rohde, M, von Neuhoff, N, Nimtz, M, and Steinmetz, I

Abstract

In this study we report that extracellular Burkholderia pseudomallei rhamnolipid induced cytopathic changes characterized by retraction, rounding up, and, finally, detachment in phagocytic and nonphagocytic cell lines. These changes were due to a progressive reorganization of the F-actin network resulting in impaired cell cycle progression and a reduced phagocytic function of macrophages.

Published
2003

46. Krüppel-like zinc finger proteins in end-stage COPD lungs with and without severe alpha1-antitrypsin deficiency

Author

Koczulla A-Rembert, Jonigk Danny, Wolf Thomas, Herr Christian, Noeske Sarah, Klepetko Walter, Vogelmeier Claus, von Neuhoff Nils, Rische Johanna, Wrenger Sabine, Golpon Heiko, Voswinckel Robert, Luisetti Maurizio, Ferrarotti Ilaria, Welte Tobias, and Janciauskiene Sabina

Subjects
Alpha 1-antitrypsin, COPD, Gene expression, Krüppel-like zinc finger proteins, Affymetrix gene chips, Medicine
Abstract

Abstract Background Chronic obstructive pulmonary disease (COPD) is influenced by environmental and genetic factors. An important fraction of COPD cases harbor a major genetic determinant, inherited ZZ (Glu342Lys) α1-antitrypsin deficiency (AATD). A study was undertaken to investigate gene expression patterns in end-stage COPD lungs from patients with and without AATD. Methods Explanted lungs of end-stage ZZ AATD-related (treated and non-treated with AAT augmentation therapy) and “normal” MM COPD, and liver biopsies from patients suffering from liver cirrhosis with and without ZZ AATD were used for gene expression analysis by Affymetrix microarrays or RT-PCR. Results A total of 162 genes were found to be differentially expressed (p-value ≤ 0.05 and |FC| ≥ 2) between MM and ZZ COPD patients. Of those, 134 gene sets were up-regulated and 28 were down-regulated in ZZ relative to MM lung tissue. A subgroup of genes, zinc finger protein 165, snail homolog 1 (Drosophila) (SNAI1), and Krüppel-like transcription factors (KLFs) 4 (gut), 9 and 10, perfectly segregated ZZ and MM COPD patients. The higher expression of KLF 9 and KLF10 has been verified in the replication cohort with AATD-related end-stage lung emphysema and liver cirrhosis. Furthermore, higher expression of KLF9, SNAI1 and DEFA1 was found in ZZ COPD lungs without augmentation therapy relative to MM COPD or ZZ COPD with augmentation therapy. Conclusions These results reveal the involvement of transcriptional regulators of the zinc-finger family in COPD pathogenesis and provide deeper insight into the pathophysiological mechanisms of COPD with and without AATD.

Published
2012
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47. The differentiation/retrodifferentiation program of human U937 leukemia cells is accompanied by changes of VCP/p97

Author

Steinemann Doris, Skawran Britta, von Neuhoff Nils, Bertram Catharina, Schlegelberger Brigitte, and Hass Ralf

Subjects
Cytology, QH573-671
Abstract

Abstract Background Retrodifferentiation and regained proliferative capacity of growth-arrested human leukemic cells after monocyte-like differentiation requires proteolytic activities together with distinct regulatory factors. The AAA ATPase valosin-containing protein (VCP/p97) contributes to protein degradation and cell cycle regulation, respectively, and it was of interest to study a possible role of VCP/p97 during this myelomonocytic differentiation and retrodifferentiation. Results Separation of autonomously proliferating human U937 myeloid leukemia cells by centrifugal elutriation demonstrated unaltered VCP/p97 expression levels throughout distinct phases of the cell cycle. However, phorbol ester-induced G0/G1 cell cycle arrest in differentiating human U937 leukemia cells was associated with a significantly increased protein and mRNA amount of this AAA ATPase. These elevated VCP/p97 levels progressively decreased again when growth-arrested U937 cells entered a retrodifferentiation program and returned to the tumorigenic phenotype. Whereas VCP/p97 was observed predominantly in the cytosol of U937 tumor and retrodifferentiated cells, a significant nuclear accumulation appeared during differentiation and G0/G1 growth arrest. Analysis of subcellular compartments by immunoprecipitations and 2D Western blots substantiated these findings and revealed furthermore a tyrosine-specific phosphorylation of VCP/p97 in the cytosolic but not in the nuclear fractions. These altered tyrosine phosphorylation levels, according to distinct subcellular distributions, indicated a possible functional involvement of VCP/p97 in the leukemic differentiation process. Indeed, a down-modulation of VCP/p97 protein by siRNA revealed a reduced expression of differentiation-associated genes in subsequent DNA microarray analysis. Moreover, DNA-binding and proliferation-associated genes, which are down-regulated during differentiation of the leukemic cells, demonstrated elevated levels in the VCP/p97 siRNA transfectants. Conclusion The findings demonstrated that monocytic differentiation and G0/G1 growth arrest in human U937 leukemia cells was accompanied by an increase in VCP/p97 expression and a distinct subcellular distribution to be reverted during retrodifferentiation. Together with a down-modulation of VCP/p97 by siRNA, these results suggested an association of this AAA ATPase in the differentiation/retrodifferentiation program.

Published
2008
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48. Front-line imatinib treatment in children and adolescents with chronic myeloid leukemia : results from a phase III trial

Author

Arndt Borkhardt, Birgitte Lausen, Bernhard Kremens, Christian Thiede, Philipp Schulze, Angelika Eggert, Christina Nowasz, Adriana Balduzzi, Sabina Sufliarska, Olga Aleinikova, Petr Sedlacek, Gudrun Göhring, Gabriele Strauss, Frank Berthold, Günter Henze, Andreas H. Groll, Alexander Claviez, Brigitte Schlegelberger, Jochen Harbott, Ingmar Glauche, Hans Kreipe, Ute Groß-Wieltsch, Martin Schrappe, Josephine T. Tauer, Manuela Krumbholz, Eveline S. J. M. de Bont, Christoph Klein, Nils von Neuhoff, Markus Metzler, Andreas E. Kulozik, Karl Walter Sykora, Meinolf Suttorp, Suttorp, M, Schulze, P, Glauche, I, Göhring, G, Von Neuhoff, N, Metzler, M, Sedlacek, P, De Bont, E, Balduzzi, A, Lausen, B, Aleinikova, O, Sufliarska, S, Henze, G, Strauss, G, Eggert, A, Kremens, B, Groll, A, Berthold, F, Klein, C, Groß-Wieltsch, U, Sykora, K, Borkhardt, A, Kulozik, A, Schrappe, M, Nowasz, C, Krumbholz, M, Tauer, J, Claviez, A, Harbott, J, Kreipe, H, Schlegelberger, B, and Thiede, C

Subjects
Male, Cancer Research, medicine.medical_specialty, Adolescent, Medizin, Antineoplastic Agents, Blastic Phase, 03 medical and health sciences, 0302 clinical medicine, Bone Marrow, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Treatment Failure, Child, Protein Kinase Inhibitors, Survival rate, Neoplasm Staging, business.industry, Infant, Imatinib, Hematology, Prognosis, medicine.disease, Combined Modality Therapy, Transplantation, Clinical trial, Leukemia, Treatment Outcome, Imatinib mesylate, Oncology, Child, Preschool, 030220 oncology & carcinogenesis, Disease Progression, Imatinib Mesylate, Female, Neoplasm Grading, business, Complete Hematologic Response, Biomarkers, 030215 immunology, medicine.drug
Abstract

A total of 156 patients (age range 1.3-18.0 years, median 13.2 years; 91 (58.3%) male) with newly diagnosed CML (N = 146 chronic phase (CML-CP), N = 3 accelerated phase (CML-AP), N = 7 blastic phase (CML-BP)) received imatinib up-front (300, 400, 500 mg/m 2 , respectively) within a prospective phase III trial. Therapy response, progression-free survival, causes of treatment failure, and side effects were analyzed in 148 children and adolescents with complete data. Event-free survival rate by 18 months for patients in CML-CP (median follow-up time 25 months, range: 1-120) was 97% (95% CI, 94.2-99.9%). According to the 2006 ELN-criteria complete hematologic response by month 3, complete cytogenetic response (CCyR) by month 12, and major molecular response (MMR) by month 18 were achieved in 98, 63, and 59% of the patients, respectively. By month 36, 86% of the patients achieved CCyR and 74% achieved MMR. Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response or intolerance (N = 9). In all, 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N = 3) or SCT-related complications (N = 2). This large pediatric trial extends and confirms data from smaller series that first-line imatinib in children is highly effective.

Published
2018

49. t(6;9)(p22;q34)/DEK-NUP214 rearranged pediatric myeloid leukemia: an international study on 62 patients

Author

Jean Michel Cayuela, Daisuke Tomizawa, Jochen Harbott, Der Cherng Liang, Christine Perot, Valerie de Haas, Nils von Neuhoff, Anne Auvrignon, Hiroto Inaba, Susana C. Raimondi, C. Michel Zwaan, Gertjan J.L. Kaspers, Christine J. Harrison, Gitte Kerndrup, Franco Locatelli, Marco Zecca, Souichi Adachi, Julie Damgaard Sandahl, Erik Forestier, Riccardo Masetti, Katarina Reinhardt, Lucy Chilton, Bertil Johansson, Maarten Fornerod, Marry M. van den Heuvel-Eibrink, Henrik Hasle, Eva A. Coenen, H. Berna Beverloo, Sandahl JD, Coenen EA, Forestier E, Harbott J, Johansson B, Kerndrup G, Adachi S, Auvrignon A, Beverloo HB, Cayuela JM, Chilton L, Fornerod M, de Haas V, Harrison CJ, Inaba H, Kaspers GJ, Liang DC, Locatelli F, Masetti R, Perot C, Raimondi S, Reinhardt K, Tomizawa D, von Neuhoff N, Zecca M, Zwaan CM, van den Heuvel-Eibrink MM, Hasle H, Erasmus MC other, Clinical Genetics, Pediatrics, Pediatric surgery, and CCA - Innovative therapy

Subjects
Oncology, Male, medicine.medical_specialty, Myeloid, Adolescent, Oncogene Proteins, Fusion, Chromosomal Proteins, Non-Histone, medicine.medical_treatment, Hematopoietic stem cell transplantation, Translocation, Genetic, Bone Marrow, Recurrence, Internal medicine, hemic and lymphatic diseases, medicine, Humans, Cumulative incidence, Child, Poly-ADP-Ribose Binding Proteins, Oncogene Proteins, Hematology, business.industry, Myelodysplastic syndromes, Gene Expression Profiling, Childhood Acute Myeloid Leukemia, Hematopoietic Stem Cell Transplantation, Infant, Newborn, Myeloid leukemia, Infant, Articles, ACUTE NONLYMPHOCYTIC LEUKEMIA, TUMOR-SUPPRESSOR, GROWTH ARREST, PROTEIN DEK, FG REPEATS, PR DOMAIN, GENE, EXPRESSION, MALIGNANCIES, FUSION, medicine.disease, Nuclear Pore Complex Proteins, Leukemia, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Treatment Outcome, N/A, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Leukemia, Myeloid, Child, Preschool, Myelodysplastic Syndromes, Immunology, Chromosomes, Human, Pair 6, Female, business, Chromosomes, Human, Pair 9
Abstract

Acute myeloid leukemia with t(6;9)(p22;q34) is listed as a distinct entity in the 2008 World Health Organization classification, but little is known about the clinical implications of t(6;9)-positive myeloid leukemia in children. This international multicenter study presents the clinical and genetic characteristics of 62 pediatric patients with t(6;9)/DEK-NUP214-rearranged myeloid leukemia; 54 diagnosed as having acute myeloid leukemia, representing

Published
2014

50. Genetically modified donor leukocyte transfusion and graft-versus-leukemia effect after allogeneic stem cell transplantation

Author

Sylvia Borchers, Julia Kontsendorn, Bernd Hertenstein, Michael Stadler, Elena Provasi, Wolfgang Kuehnau, Chiara Bonini, Nils von Neuhoff, Joerg Schmidtke, Eva M. Weissinger, Annika Krons, Arnold Ganser, Marina Radrizzani, Fabio Ciceri, Anna Silvani, Claudia Benati, Elke Dammann, Borchers, S, Provasi, E, Silvani, A, Radrizzani, M, Benati, C, Dammann, E, Krons, A, Kontsendorn, J, Schmidtke, J, Kuehnau, W, von Neuhoff, N, Stadler, M, Ciceri, Fabio, Bonini, C, Ganser, A, Hertenstein, B, and Weissinger, Em

Subjects
Adult, Male, Proteomics, Graft-vs-Leukemia Effect, medicine.medical_treatment, Receptors, Antigen, T-Cell, alpha-beta, Genetic Vectors, CD34, Fusion Proteins, bcr-abl, Graft vs Host Disease, Graft vs Leukemia Effect, Hematopoietic stem cell transplantation, Biology, Chimerism, Thymidine Kinase, Transduction, Genetic, hemic and lymphatic diseases, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Genetics, medicine, Humans, Transgenes, Molecular Biology, Research Articles, Immunosuppression Therapy, Remission Induction, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, Immunosuppression, Middle Aged, medicine.disease, Tissue Donors, Transplantation, Leukemia, Myeloid, Acute, Leukocyte Transfusion, surgical procedures, operative, Retroviridae, Immunology, Molecular Medicine, Female, Stem cell, Chronic myelogenous leukemia
Abstract

Seven patients with acute myeloid leukemia (AML) and two patients with chronic myelogenous leukemia (CML) were transplanted from HLA-identical sibling donors with CD34(+) cell-enriched stem cells (HSCTs) without further immunosuppression. The myeloablative standard transplantation protocol was adapted to include transfusion of gene-modified donor T cells after HSCT. Donor T cells were transduced with the replication-deficient retrovirus SFCMM-3, which expresses herpes simplex thymidine kinase (HSV-Tk) and a truncated version of low-affinity nerve growth factor receptor (Delta LNGFR) for selection and characterization of transduced cells. Transduced T cells were detectable in all patients during follow-up for up to 5 years after transfusion. Proteomic screening for development of acute graft-versus-host disease (aGvHD) was applied to five of the seven patients with AML. No positivity for the aGvHD grade II-specific proteomic pattern was observed. Only one patient developed aGvHD grade I. To date, three of the patients with AML relapsed; one responded to three escalating transfusions of lymphocytes from the original donor and is in complete remission. Two were retransplanted with non-T cell-depleted peripheral blood stem cells from their original donors and died after retransplantation of septic complications or relapse, respectively. In one patient with CML, loss of bcr-abl gene expression was observed after an expansion of transduced cells. Seven of nine patients are alive and in complete remission.

Published
2010

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