TY  - JOUR
AB  - Recently, there has been increased concern about a risk of secondary malignancies (SM) occurring in myelofibrosis (MF) patients receiving ruxolitinib (RUX). In polycythemia vera (PV), on the other hand, only limited data on the risk of SM under RUX treatment are available. To investigate the association between RUX therapy in PV and SM, we conducted a retrospective, single-center study that included 289 PV patients. RUX was administered to 32.9% (95/289) of patients for a median treatment duration of 48.0 months (range 1.0-101.6). Within a median follow-up of 97 months (1.0-395.0) after PV diagnosis, 24 SM occurred. Comparing the number of PV patients with RUX-associated SM (n = 10, 41.7%) with the 14 (58.3%) patients who developed SM without RUX, no significant difference (p = 0.34, chi square test) was found. No increased incidences of melanoma, lymphoma, or solid "non-skin" malignancies were observed with RUX (p = 0.31, p = 0.60, and p = 0.63, respectively, chi square test). However, significantly more NMSC occurred in association with RUX treatment (p = 0.03, chi-squared test). The "SM-free survival" was not significantly different by log rank test for all 289 patients (p = 0.65), for the patients (n = 208; 72%) receiving cytoreductive therapy (p = 0.48) or for different therapy sequences (p = 0.074). In multivariate analysis, advanced age at PV diagnosis (HR 1.062 [95% CI 1.028, 1.098]) but not administration of RUX (HR 1.068 [95% CI 0.468, 2.463]) was associated with an increased risk for SM (p = 0.005). According to this retrospective analysis, no increased risk of SM due to RUX treatment could be substantiated for PV.
AU  - Sekhri, R.*
AU  - Sadjadian, P.*
AU  - Becker, T.*
AU  - Kolatzki, V.*
AU  - Huenerbein, K.*
AU  - Meixner, R.
AU  - Marchi, H.
AU  - Wallmann, R.*
AU  - Fuchs, C.
AU  - Griesshammer, M.*
AU  - Wille, K.*
C1  - 62859
C2  - 51107
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
TI  - Ruxolitinib-treated polycythemia vera patients and their risk of secondary malignancies.
JO  - Ann. Hematol.
PB  - Springer
PY  - 2021
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - The FLAMSA reduced intensity (RIC) concept, also known as "sequential therapy", is a conceptual platform for the treatment of leukemia separated in several parts: induction therapy, a sequence of antileukemic and immunosuppressive conditioning for allogeneic stem cell transplantation, and immune restitution supported by donor lymphocyte transfusions. The antileukemic part consists of fludarabine, cytosine arabinoside, and amsacrine (FLAMSA); non-cross reactive agents like fludarabine and amsacrine have been successfully used in cases of refractoriness and relapse. Immunosuppressive conditioning and transplantation follow after only 3 days of rest. This way, the toxicity of allogeneic transplantation could be reduced and the anti-leukemia effects by using allogeneic immune cells could be optimized. This review summarizes available data on efficacy and toxicity of this approach. Further, possible strategies for improvements are discussed in order to provide better chances for elderly and frail patients and patients with advanced and high-risk disease. Among others, several new agents are available that target molecular changes of leukemia for induction of remission and allow for bridging the time after transplantation until adoptive immunotherapy becomes safe and effective.
AU  - Kolb, H.J.
AU  - Schmid, C.*
C1  - 59544
C2  - 48873
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 1979–1988
TI  - The FLAMSA concept-past and future.
JO  - Ann. Hematol.
VL  - 99
PB  - Springer
PY  - 2020
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Carlet, M.
AU  - Vergalli, J.
AU  - Heckl, B.
AU  - Schmidt-Supprian, M.*
AU  - Jeremias, I.
C1  - 55624
C2  - 46408
CY  - 233 Spring St, New York, Ny 10013 Usa
SP  - S24-S25
TI  - MCL1 plays an essential role for patients'AML, as shown by inducible knockdown in PDX models IN VIVO.
JO  - Ann. Hematol.
VL  - 98
PB  - Springer
PY  - 2019
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Ebinger, S.
AU  - Zeller, C.
AU  - Spiekermann, K.*
AU  - Vick, B.
AU  - Jeremias, I.
C1  - 55621
C2  - 46412
CY  - 233 Spring St, New York, Ny 10013 Usa
SP  - S31-S32
TI  - Long-term dormancy is reversible in patients' AML cells growing in mice.
JO  - Ann. Hematol.
VL  - 98
PB  - Springer
PY  - 2019
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Liu, W.-H.
AU  - Schwarzkopf, L.
AU  - Herold, T.
AU  - Jeremias, I.
C1  - 55619
C2  - 46413
CY  - 233 Spring St, New York, Ny 10013 Usa
SP  - S53-S53
TI  - Inducible re-expression of KLF4 impairs growth of patient derived acute lymphoma leukemia cells IN VIVO and sensitizes them towards chemotherapy.
JO  - Ann. Hematol.
VL  - 98
PB  - Springer
PY  - 2019
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Wange, L.E.*
AU  - Koehrer, S.*
AU  - Bagnoli, J.W.*
AU  - Oezdemir, E.
AU  - Janjic, A.*
AU  - Geuder, J.*
AU  - Mann, G.*
AU  - Jeremias, I.
AU  - Panzer-Gruemayer, R.*
AU  - Enard, W.*
C1  - 55623
C2  - 46409
CY  - 233 Spring St, New York, Ny 10013 Usa
SP  - S63-S64
TI  - Analyzing transcriptional profiles of childhood ALL at single cell resolution.
JO  - Ann. Hematol.
VL  - 98
PB  - Springer
PY  - 2019
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - Venous thromboembolism (VTE) is a major burden in patients with BCR-ABL-negative myeloproliferative neoplasms (MPN). In addition to cytoreductive treatment anticoagulation is mandatory, but optimal duration of anticoagulation is a matter of debate. In our single center study, we retrospectively included 526 MPN patients. In total, 78 of 526 MPN patients (14.8%) had 99 MPN-associated VTE. Median age at first VTE was 52.5years (range 23-81). During a study period of 3497years, a VTE event rate of 1.7% per patient/year was detected. 38.4% (38/99) of all VTEs appeared before or at MPN diagnosis and 55.6% (55/99) occurred at uncommon sites like splanchnic or cerebral veins. MPN patients with VTEs were significantly more female (p=0.028), JAK2 positive (p=0.018), or had a polycythemia vera (p=0.009). MPN patients without VTEs were more often CALR positive (p=0.023). Total study period after first VTE was 336years with 20 VTE recurrences accounting for a recurrence rate of 6% per patient/year. In 36 of 71 MPN patients with anticoagulation therapy after first VTE event (50.7%), prophylactic anticoagulation was terminated after a median time of 6months (range 1-61); 13 of those 36 patients (36.1%) had a VTE recurrence after a median of 13months (range 4-168). In contrast, only three of 35 (8.6%) patients with ongoing anticoagulation had a VTE recurrence (p=0.0127). Thus, termination of prophylactic anticoagulation was associated with a significantly higher risk of VTE recurrence. Our data suggest that in MPN patients with VTE, a prolonged duration of anticoagulation may be beneficial.
AU  - Wille, K.*
AU  - Sadjadian, P.*
AU  - Becker, T.*
AU  - Kolatzki, V.*
AU  - Horstmann, A.*
AU  - Fuchs, C.
AU  - Griesshammer, M.*
C1  - 54222
C2  - 45297
CY  - 233 Spring St, New York, Ny 10013 Usa
SP  - 93-100
TI  - High risk of recurrent venous thromboembolism in BCR-ABL-negative myeloproliferative neoplasms after termination of anticoagulation.
JO  - Ann. Hematol.
VL  - 98
IS  - 1
PB  - Springer
PY  - 2019
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Bagnoli, J.*
AU  - Ziegenhain, C.*
AU  - Vieth, B.*
AU  - Parekh, S.*
AU  - Vick, B.
AU  - Jeremias, I.
AU  - Hellmann, I.*
AU  - Enard, W.*
C1  - 50878
C2  - 42587
CY  - New York
SP  - S59-S59
TI  - Transcriptional heterogeneity in AML - evolution of gene expression in patient derived xenografts.
JO  - Ann. Hematol.
VL  - 96
PB  - Springer
PY  - 2017
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Ebinger, S.
AU  - Liu, W.
AU  - Tiedt, S.
AU  - Alves, C.C.
AU  - Jeremias, I.
C1  - 50877
C2  - 42582
CY  - New York
SP  - S52-S52
TI  - A rare population of drug resistant, dormant stem cells exists in patients' acute lymphoblastic leukemia growing in mice.
JO  - Ann. Hematol.
VL  - 96
PB  - Springer
PY  - 2017
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Finkenzeller, C.
AU  - Carlet, M.
AU  - Vosberg, S.*
AU  - Neumann, M.*
AU  - Riecken, K.*
AU  - Cornils, K.*
AU  - Fehse, B.*
AU  - Baldus, C.D.*
AU  - Greif, P.A.*
AU  - Jeremias, I.
C1  - 50871
C2  - 42577
CY  - New York
SP  - S75-S75
TI  - Clones with and without sensitivity towards treatment in vivo co-exist within a single sample of a patient with ALL.
JO  - Ann. Hematol.
VL  - 96
PB  - Springer
PY  - 2017
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Heckl, B.
AU  - Carlet, M.
AU  - Grunert, M.
AU  - Vick, B.
AU  - Roolf, C.*
AU  - Junghanss, C.*
AU  - Spiekermann, K.*
AU  - Hiddemann, W.R.*
AU  - Jeremias, I.
C1  - 50875
C2  - 42581
CY  - New York
SP  - S71-S72
TI  - Primary adult acute lymphoblastic leukemic cells reliably engraft and grow in immunodeficient mice.
JO  - Ann. Hematol.
VL  - 96
PB  - Springer
PY  - 2017
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Koczian, F.*
AU  - Vomacka, J.*
AU  - Vick, B.
AU  - Hettich, B.*
AU  - Kazmaier, U.*
AU  - Sieber, S.A.*
AU  - Jeremias, I.
AU  - Vollmar, A.*
AU  - Braig, S.*
C1  - 50873
C2  - 42579
CY  - New York
SP  - S73-S73
TI  - Targeting the ER-mitochondrial interface of cell death sensitizes leukemia cells towards cytostatics.
JO  - Ann. Hematol.
VL  - 96
PB  - Springer
PY  - 2017
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Koehnke, T.
AU  - Rechkemmer, S.*
AU  - Buecklein, V.
AU  - Hiddemann, W.*
AU  - Spiekermann, K.*
AU  - Subklewe, M.
C1  - 50880
C2  - 42589
CY  - New York
SP  - S26-S28
TI  - Early detection and alternative gating strategies in flow MRD.
JO  - Ann. Hematol.
VL  - 96
PB  - Springer
PY  - 2017
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Krupka, C.
AU  - Lindl, B.
AU  - Kischel, R.*
AU  - Kufer, P.*
AU  - Lichtenegger, F.S.
AU  - Koehnke, T.
AU  - Augsberger, C.
AU  - Altmann, T.
AU  - Spiekermann, K.*
AU  - Hiddemann, W.*
AU  - Subklewe, M.
C1  - 50870
C2  - 42576
CY  - New York
SP  - S81-S82
TI  - Influence of cytoreductive and immunmodulatory drugs on bispecific T-cell engager-based approaches in AML.
JO  - Ann. Hematol.
VL  - 96
PB  - Springer
PY  - 2017
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Oezdemir, E.
AU  - Ziegenhain, C.*
AU  - Panzer-Gruenmayer, R.*
AU  - Enard, W.*
AU  - Jeremias, I.
C1  - 50876
C2  - 42586
CY  - New York
SP  - S74-S74
TI  - A preclinical PDX model for patients` minimal residual disease in ALL.
JO  - Ann. Hematol.
VL  - 96
PB  - Springer
PY  - 2017
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Valtierra-Gutierrez, I.A.*
AU  - Farre-Orteu, A.*
AU  - Richter, M.*
AU  - Greif, P.A.*
AU  - Ziegenhain, C.*
AU  - Jeremias, I.
AU  - Metzeler, K.*
AU  - Spiekermann, K.*
AU  - Enard, W.*
AU  - Hellmann, I.*
C1  - 50879
C2  - 42588
CY  - New York
SP  - S57-S57
TI  - Detection of single-nucleotide variants in acute myeloid leukemia (AML) from bulk and single-cell RNA sequencing.
JO  - Ann. Hematol.
VL  - 96
PB  - Springer
PY  - 2017
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Vergalli, J.
AU  - Carlet, M.
AU  - Hoffmann, T.*
AU  - Roth, M.*
AU  - Zuber, J.*
AU  - Jeremias, I.
C1  - 50872
C2  - 42578
CY  - New York
SP  - S74-S75
TI  - XIAP is an attractive therapeutic target for all as validated in innovative genetically rngineered patient-derived xenograft models.
JO  - Ann. Hematol.
VL  - 96
PB  - Springer
PY  - 2017
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Vick, B.
AU  - Holdt, L.M.*
AU  - Hiddemann, W.R.*
AU  - Spiekermann, K.*
AU  - Jeremias, I.
C1  - 50874
C2  - 42580
CY  - New York
SP  - S68-S68
TI  - Modeling AML standard induction chemotherapy in the PDX mouse model.
JO  - Ann. Hematol.
VL  - 96
PB  - Springer
PY  - 2017
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Carlet, M.
AU  - Vergalli, J.
AU  - Finkenzeller, C.
AU  - Grunert, M.
AU  - Jeremias, I.
C1  - 47720
C2  - 39768
SP  - S88
TI  - Knockdown of XIAP sensitizes B-ALL cells towards chemotherapy in an innovative, dual luciferase in vivo competition assay.
JO  - Ann. Hematol.
VL  - 94
PY  - 2015
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Carlet, M.
AU  - Finkenzeller, C.
AU  - Vergalli, J.
AU  - Ebinger, S.
AU  - Oezdemir, E.
AU  - Heckl, B.*
AU  - Schneider, K.*
AU  - Terzyiska, N.*
AU  - Tiedt, S.
AU  - Alves, C.*
AU  - Grunert, M.
AU  - Vick, B.
AU  - Jeremias, I.
C1  - 47722
C2  - 39766
SP  - S28-S30
TI  - Functional characterization ofacute leukemias.
JO  - Ann. Hematol.
VL  - 94
PY  - 2015
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Ebinger, S.
AU  - Mura, L.
AU  - Grunert, M.
AU  - Jeremias, I.
C1  - 47728
C2  - 39760
SP  - S88-S89
TI  - Drug sensitivity of patient-derived ALL tumor cells is impaired by co-culture with feeder cells mimicking the in vivo micro-environment.
JO  - Ann. Hematol.
VL  - 94
PY  - 2015
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - Germline polymorphisms in genes mutated in acute myeloid leukemia (AML) may have prognostic impact. Therefore, the relevance of the polymorphism IDH1G105 (IDH1105GGT minor allele) was evaluated in the context of concomitant molecular mutations in a cohort of 507 AML cases with intermediate-risk cytogenetics. In addition, a cohort of 475 healthy controls was analyzed for this polymorphism. IDH1105GGT minor allele was found in 10 % of AML patients and 9 % of healthy controls. While no differences were seen with regard to cytomorphology or cytogenetics, immunophenotyping revealed significantly reduced expression of the progenitor marker CD34 in AML cases harboring IDH1105GGT minor allele. Cases with IDH1105GGT minor allele as compared to those with the IDH1105GGC major allele had significantly longer event-free survival (EFS) (median 16 vs 11 months, p = 0.013) which was most pronounced in the age group >60 years (median 14 vs 9 months, p = 0.007) and in the NPM1 mutated/FLT3-ITD/FLT3wt ratio <0.5 group (median 61 vs 13 months, p = 0.012). However, this association is not independent of other prognostic parameters, and we conclude that IDH1105GGT minor allele has to be considered in the context of the genetic background of the individual AML analyzed.
AU  - Fasan, A.*
AU  - Haferlach, C.*
AU  - Eder, C.*
AU  - Alpermann, T.*
AU  - Quante, A.S.
AU  - Peters, A.
AU  - Kern, W.*
AU  - Haferlach, T.*
AU  - Schnittger, S.*
C1  - 46802
C2  - 37845
SP  - 1991-2001
TI  - Evaluation of IDH1G105 polymorphism as prognostic marker in intermediate-risk AML.
JO  - Ann. Hematol.
VL  - 94
IS  - 12
PY  - 2015
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Finkenzeller, C.
AU  - Carlet, M.
AU  - Jeremias, I.
C1  - 47726
C2  - 39762
SP  - S89
TI  - Single cell clones from a patient with all show different drug sensitivity and growth behavior in vivo.
JO  - Ann. Hematol.
VL  - 94
PY  - 2015
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Greif, P.A.
AU  - Hartmann, L.
AU  - Vosberg, S.
AU  - Metzeler, K.H.
AU  - Schumacher, D.*
AU  - Pastore, F.
AU  - Braeundl, K.*
AU  - Zellmeier, E.*
AU  - Ksienzyk, B.*
AU  - Konstandin, N.P.*
AU  - Schneider, S.*
AU  - Graf, A.*
AU  - Blum, H.*
AU  - Neumann, M.*
AU  - Baldus, C.D.*
AU  - Bohlander, S.K.*
AU  - Wolf, S.*
AU  - Wiemann, S.*
AU  - Hiddemann, W.
AU  - Spiekermann, K.
C1  - 47723
C2  - 39765
SP  - S51-S52
TI  - Genetic evolution in relapsed AML.
JO  - Ann. Hematol.
VL  - 94
PY  - 2015
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Köhnke, T.
AU  - Sauter, D.*
AU  - Sauerland, M.C.*
AU  - Schneider, S.*
AU  - Braess, J.*
AU  - Hiddemann, W.*
AU  - Spiekermann, K.*
AU  - Subklewe, M.
C1  - 47727
C2  - 39761
SP  - S30-S31
TI  - Flow cytometric analysis of minimal residual disease in acute myeloid leukemia.
JO  - Ann. Hematol.
VL  - 94
PY  - 2015
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Lichtenegger, F.S.
AU  - Schnorfeil, F.M.
AU  - Geiger, C.
AU  - Köhnke, T.*
AU  - Buecklein, V.*
AU  - Altmann, T.*
AU  - Wagner, B.*
AU  - Henschler, R.*
AU  - Bigalke, I.
AU  - Kvalheim, G.*
AU  - Hiddemann, W.*
AU  - Schendel, D.J.
AU  - Subklewe, M.
C1  - 47725
C2  - 39763
SP  - S53
TI  - Next-generation dendritic cells for immunotherapy of acute myeloid leukemia.
JO  - Ann. Hematol.
VL  - 94
PY  - 2015
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Reiter, K.
AU  - Meiser, A.*
AU  - Polzer, H.
AU  - Hiddemann, W.
AU  - Spiekermann, K.
AU  - Leonhardt, H.*
AU  - Greif, P.A.
C1  - 47719
C2  - 39769
SP  - S82
TI  - Visualization of AML-specific FLT3 mutants and differential downstream signaling.
JO  - Ann. Hematol.
VL  - 94
PY  - 2015
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - We retrospectively compared the incidence of virus infections and outcome in the context of immune reconstitution in two different HLA-haploidentical transplantation (haplo-HSCT) settings. The first was a combined T-cell-replete and T-cell-deplete approach using antithymocyte globulin (ATG) prior to transplantation in patients with hematological diseases (cTCR/TCD group, 28 patients; median age 31 years). The second was a T-cell-replete (TCR) approach using high-dose posttransplantation cyclophosphamide (TCR/PTCY group, 27 patients; median age 43 years). The incidence of herpesvirus infection was markedly lower in the TCR/PTCY (22 %) than in the cTCR/TCD group (93 %). Recovery of CD4+ T cells on day +100 was faster in the TCR/PTCY group. CMV reactivation was 30 % in the TCR/PTCY compared to 57 % in the cTCR/TCD group, and control with antiviral treatment was superior after TCR/PTCY transplantation (100 vs 50 % cTCR/TCD). Twenty-five percent of the patients in the cTCR/TCD group but no patient in the TCR/PTCY group developed PTLD. While 1-year OS was not different (TCR/PTCY 59 % vs cTCR/TCD 39 %; p = 0.28), virus infection-related mortality (VIRM) was significantly lower after TCR/PTCY transplantation (1-year VIRM, 0 % TCR/PTCY vs 29 % cTCR/TCD; p = 0.009). On day +100, predictors of better OS were lymphocytes >300/μl, CD3+ T cells >200/μl, and CD4+ T cells >150/μl, whereas the application of steroids >1 mg/kg was correlated with worse outcome. Our results suggest that by presumably preserving antiviral immunity and allowing fast immune recovery of CD4+ T cells, the TCR approach using posttransplantation cyclophosphamide is well suited to handle the important issue of herpesvirus infection after haplo-HSCT.
AU  - Tischer, J.*
AU  - Engel, N.*
AU  - Fritsch, S.*
AU  - Prevalsek, D.*
AU  - Hubmann, M.*
AU  - Schulz, C.*
AU  - Zoellner, A.-K.*
AU  - Bücklein, V.L.*
AU  - Reibke, R.*
AU  - Mumm, F.*
AU  - Rieger, C.T.*
AU  - Hill, W.*
AU  - Ledderose, G.*
AU  - Stemmler, H.J.*
AU  - Köhnke, T.*
AU  - Jäger, G.*
AU  - Kolb, H.J.*
AU  - Schmid, C.*
AU  - Moosmann, A.
AU  - Hausmann, A.*
C1  - 45331
C2  - 37286
CY  - New York
SP  - 1677-1688
TI  - Virus infection in HLA-haploidentical hematopoietic stem cell transplantation: Incidence in the context of immune recovery in two different transplantation settings.
JO  - Ann. Hematol.
VL  - 94
IS  - 10
PB  - Springer
PY  - 2015
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Vick, B.
AU  - Rothenberg, M.*
AU  - Sandhöfer, N.
AU  - Carlet, M.
AU  - Finkenzeller, C.
AU  - Krupka, C.
AU  - Grunert, M.
AU  - Trumpp, A.*
AU  - Corbacioglu, S.*
AU  - Ebinger, M.*
AU  - Andre, M.C.*
AU  - Hiddemann, W.*
AU  - Subklewe, M.
AU  - Schneider, S.*
AU  - Metzeler, K.H.
AU  - Spiekermann, K.
AU  - Jeremias, I.
C1  - 47721
C2  - 39767
SP  - S83-S84
TI  - In vivo imaging facilitates reliable and sensitive monitoring of preclinical in vivo treatment trials in the individualized xenograft mouse model of AML.
JO  - Ann. Hematol.
VL  - 94
PY  - 2015
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Vosberg, S.
AU  - Herold, T.*
AU  - Metzeler, K.H.*
AU  - Schneider, S.*
AU  - Ksienzyk, B.*
AU  - Graf, A.*
AU  - Krebs, S.*
AU  - Blum, H.*
AU  - Spiekermann, K.
AU  - Bohlander, S.K.*
AU  - Hiddemann, W.
AU  - Mansmann, U.*
AU  - Greif, P.A.
C1  - 47724
C2  - 39764
SP  - S84
TI  - Detection of chromosome 9q deletion in Acute Myeloid Leukemia (AML) patients using targeted sequencing data.
JO  - Ann. Hematol.
VL  - 94
PY  - 2015
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - The mammalian target of rapamycin (mTOR) is a protein kinase involved in the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway. It plays a pivotal role in the control of cell proliferation, survival, and angiogenesis with multiple and frequent dysregulations of this pathway in human tumors. Temsirolimus is an intravenous drug, specifically inhibiting the mTOR pathway. Bendamustine is well known for its clinical activity in indolent non-Hodgkin-lymphoma (NHL) and has lately shown clinical activity in mantle cell lymphoma (MCL). Here, we present a case report of temsirolimus in combination with bendamustine and rituximab leading to a CR in a pretreated male. In addition, our in vitro data underlines the additive and synergistic efficacy in cell growth reduction of temsirolimus combined with bendamustine in MCL cell lines and in DLBCL cell lines. Furthermore, as an underlying mechanism of this additive, effects on cell cycle inhibition and apoptosis induction could be identified.
AU  - Zoellner, A.K.*
AU  - Weiglein, T.
AU  - Hutter, G.
AU  - Zimmermann, Y.
AU  - Cieplik, H.C.
AU  - Hess, G.*
AU  - Dreyling, M.
C1  - 47540
C2  - 40651
CY  - New York
SP  - 403-407
TI  - Temsirolimus acts as additive with bendamustine in aggressive lymphoma.
JO  - Ann. Hematol.
VL  - 95
IS  - 3
PB  - Springer
PY  - 2015
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - We and others have shown that cytogenetically normal (CN)-AML patients with biallelic CEBPA gene mutations (biCEBPA) represent a molecularly distinct group with a favorable prognosis. Patients carrying a monoallelic CEBPA mutation (moCEBPA), however, show no different outcome compared to patients with wildtype CEBPA, and these mutations are frequently associated with mutated NPM1 or FLT3-ITD. So far, no molecular or clinical hallmark has been identified to prognostically distinguish moCEBPA patients from patients with wildtype CEBPA. Therefore, we used the data of 663 CN-AML patients treated within the AMLCG 1999 trial to explore the prognostic value of moCEBPA in the context of concomitant clinical and molecular markers (mutated NPM1, FLT3-ITD). Multiple Cox regression in 515 patients adjusting for all available potential confounders revealed that the NPM1 mutation modified the prognostic value of moCEBPA with respect to overall survival (OS, p = 0.017) and event-free survival (EFS, p = 0.011). MoCEBPA was beneficial in NPM1 mutated patients: adjusted OS-hazard ratio (HR) 0.09, 95% confidence interval (CI) 0.01-0.63, p = 0.016; EFS-HR (95% CI) 0.16 (0.04-0.65), p = 0.010. In contrast, moCEBPA had no prognostic impact in patients with wildtype NPM1: OS-HR (95% CI) 1.08 (0.59-1.97), p = 0.804; EFS-HR (95% CI) 1.12 (0.64-1.96), p = 0.682. We found no prognostic effect modification for moCEBPA by FLT3-ITD. The presence of a moCEBPA mutation was shown to be associated with prolonged survival in NPM1 mutated CN-AML patients. Confirmation of these results in larger studies will clarify whether an additional moCEBPA mutation influences the risk stratification of patients with an NPM1 mutated/FLT3-ITD positive genotype.
AU  - Dufour, A.*
AU  - Schneider, F.*
AU  - Hoster, E.*
AU  - Benthaus, T.*
AU  - Ksienzyk, B.*
AU  - Schneider, S.*
AU  - Kakadia, P.M.*
AU  - Sauerland, M.C.*
AU  - Berdel, W.E.*
AU  - Büchner, T.*
AU  - Wörmann, B.*
AU  - Braess, J.*
AU  - Subklewe, M.*
AU  - Hiddemann, W.
AU  - Bohlander, S.K.
AU  - Spiekermann, K.
C1  - 7565
C2  - 29852
SP  - 1051-1063
TI  - Monoallelic CEBPA mutations in normal karyotype acute myeloid leukemia: Independent favorable prognostic factor within NPM1 mutated patients.
JO  - Ann. Hematol.
VL  - 91
IS  - 7
PB  - Springer
PY  - 2012
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - We determined the prevalence and progression rate of monoclonal gammopathy of undetermined significance (MGUS) and light-chain MGUS (LCMGUS) in Germany utilizing the biobank of the population-based Heinz Nixdorf Recall Study. The Heinz Nixdorf Recall Study comprises 4,814 men and women aged 45-75 years. To detect monoclonal proteins, standard serum electrophoresis was combined with parallel screening immunofixation using pentavalent antisera. Additionally, free light chains (FLC) were measured in all samples. Definition of MGUS included M-protein concentration, laboratory results, and disease history. LCMGUS was defined as abnormal FLC ratio, increase in FLC causing the abnormal ratio, and lack of intact immunoglobulin. One hundred sixty-five MGUS cases were identified among 4,702 screened samples (prevalence 3.5%, 95% confidence interval (CI) 3.0-4.1; median age 63 years, range 47-75 years; 103 (62%) male; IgG 59%, IgA 17%, IgM 17%, biclonal 4.8%, kappa 56%, and lambda 44%). Five cases progressed (0.6%/year, 95% CI 0.2-1.4). An abnormal FLC ratio was detected in 220 samples. Thirty-nine of these showed intact immunoglobulin. Thirty-four of the remaining met LCMGUS criteria (prevalence 0.7%, 95% CI 0.5-1.0). None of the LCMGUS cases progressed. We demonstrate a MGUS prevalence of 3.5% and a LCMGUS prevalence of 0.7% in the general population aged 45-75 years in Germany using a sensitive screening approach.
AU  - Eisele, L.*
AU  - Dürig, J.*
AU  - Hüttmann, A.*
AU  - Dührsen, U.*
AU  - Assert, R.*
AU  - Bokhof, B.*
AU  - Erbel, R.*
AU  - Mann, K.*
AU  - Jöckel, K.-H.*
AU  - Moebus, S.*
AU  - Heinz Nixdorf Recall Study Investigative Group (Löwel, H.)
C1  - 32421
C2  - 35019
SP  - 243-248
TI  - Prevalence and progression of monoclonal gammopathy of undetermined significance and light-chain MGUS in Germany.
JO  - Ann. Hematol.
VL  - 91
IS  - 2
PY  - 2012
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - Single-agent bortezomib, a potent, selective, and reversible inhibitor of the 26S proteasome, has demonstrated clinical efficacy in relapsed and refractory mantle cell lymphoma (MCL). Objective response is achieved in up to 45% of the MCL patients; however, complete remission rates are low and duration of response proved to be relatively short. These limitations may be overcome by combining proteasome inhibition with conventional chemotherapy. Rational combination treatment and schedules require profound knowledge of underlying molecular mechanisms. Here we show that single-agent bortezomib treatment of MCL cell lines leads to G2/M arrest and induction of apoptosis accompanied by downregulation of EIF4E and CCND1 mRNA but upregulation of p15(INK4B) and p21 mRNA. We further present synergistic efficacy of bortezomib combined with cytarabine in MCL cell lines. Interestingly this sequence-dependent synergistic effect was seen almost exclusively in combination with AraC, indicating that pretreatment with cytarabine, followed by proteasome inhibition, may be the preferred approach.
AU  - Hutter, G.
AU  - Rieken, M.*
AU  - Pastore, A.
AU  - Weigert, O.
AU  - Zimmermann, Y.
AU  - Weinkauf, M.
AU  - Hiddemann, W.*
AU  - Dreyling, M.
C1  - 8039
C2  - 29956
SP  - 847-856
TI  - The proteasome inhibitor bortezomib targets cell cycle and apoptosis and acts synergistically in a sequence-dependent way with chemotherapeutic agents in mantle cell lymphoma.
JO  - Ann. Hematol.
VL  - 91
IS  - 6
PB  - Springer
PY  - 2012
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - Prognosis of AML in elderly patients is poor due to adverse patient characteristics and comorbidities. In addition, disease-associated parameters reveal differences between older and younger patients with AML. Survival in normal karyotype AML (NK-AML) is influenced by different clinical and molecular markers. The aim of this work was to investigate the frequencies of molecular markers in patients with NK-AML with a focus on NPM1 mutations and FLT3-ITD in different age groups. In the present study, we analyzed the frequencies of mutations of NPM1 and FLT3-ITD in a cohort of 1,321 adult patients and 148 children with AML treated within the AMLCG99, the AML98, and AML04 trials and their distribution in different age groups. Additionally, the frequencies of mutations in CEBPA genes, FLT3-TKD, and MLL-PTD were analyzed in the cohort with NK-AML (n = 729). Our data show that the presence of mutations of NPM1 (from 60% to 40%) and FLT3-ITD (from 50% to 20%) significantly decreased with age in adult AML. Consequently, the proportion of NPM1-/FLT3-ITD- patients increased with age. The decreasing frequency of NPM1 mutations in elderly patients was paralleled by a reduced complete remission (CR) rate in the elderly of 55% compared to 80% in the younger patients. By contrast, the frequencies of other gene mutations, like FLT3-TKD and MLL-PTD, and mutations in CEBPA were not age-dependent. The decreasing frequency of the favorable NPM1 mutations with increasing age may partially explain the worse outcome in the elderly patients. Furthermore, the increasing amount of elderly patients without NPM1 mutations or FLT3-ITD suggests that other molecular and clinical risk factors may influence prognosis in this age group.
AU  - Schneider, F.*
AU  - Hoster, E.*
AU  - Schneider, S.*
AU  - Dufour, A.*
AU  - Benthaus, T.*
AU  - Kakadia, P.M.*
AU  - Bohlander, S.K.
AU  - Braess, J.*
AU  - Heinecke, A.*
AU  - Sauerland, M.C.*
AU  - Berdel, W.E.*
AU  - Buechner, T.*
AU  - Woermann, B.J.*
AU  - Feuring-Buske, M.*
AU  - Buske, C.*
AU  - Creutzig, U.*
AU  - Thiede, C.*
AU  - Zwaan, M.C.*
AU  - van den Heuvel-Eibrink, M.M.*
AU  - Reinhardt, D.*
AU  - Hiddemann, W.
AU  - Spiekermann, K.
C1  - 6622
C2  - 28987
CY  - Berlin
SP  - 9-18
TI  - Age-dependent frequencies of NPM1 mutations and FLT3-ITD in patients with normal karyotype AML (NK-AML).
JO  - Ann. Hematol.
VL  - 91
IS  - 1
PB  - Springer
PY  - 2012
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - Mantle cell lymphoma (MCL) is a distinct subentity of non-Hodgkin lymphoma, characterized by the chromosomal translocation t(11;14)(q13;q32) leading to an overexpression of cyclin D1 in virtually all cases. However, additional cytogenetic aberrations are apparent in the vast majority of MCL. Applying LOH analysis in 52 MCL patient samples, we confirmed frequent alterations in 9p21 (28.6%) and p53 (28.9%) but also detected allelic losses in 1p21, 9q21, 13q13-14, 13q31-32, 17p13.1, and 17p13.3 in 28–45% of cases and allelic gains in 3q27-28 and 19p13.3 in 14–22% of cases. In addition, losses in the 2p23 and 7q22-35 genomic regions not previously described to be altered in MCL were identified in up to 20% of cases. Applying multivariate analysis, a cluster of genomic aberrations including 1p21, 3q27, 7q22-36, 6p24, 9p21, 9q31, and 16p12 alterations was identified which was closely associated to cell proliferation as determined by Ki67 immunostaining. This proliferation-dependent network of oncogenic alterations complements the previously identified proliferation expression signature described by RNA expression profiling in MCL.
AU  - Hutter, G.
AU  - Scheubner, M.
AU  - Ott, G.*
AU  - Zimmermann, Y.
AU  - Huebler, K.*
AU  - Roth, S.*
AU  - Stilgenbauer, S.*
AU  - Kalla, J.*
AU  - Stoecklein, H.*
AU  - Hiddemann, W.
AU  - Dreyling, M.
C1  - 47051
C2  - 40529
SP  - 821-828
TI  - Allelic genotyping reveals a hierarchy of genomic alterations in mantle cell lymphoma associated to cell proliferation.
JO  - Ann. Hematol.
VL  - 88
IS  - 9
PY  - 2009
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Göttlicher, M.
C1  - 4323
C2  - 21846
SP  - 91-92
TI  - Valproic acid: An old drug newly discovered as inhibitor of histone deacetylases.
JO  - Ann. Hematol.
VL  - 83
PY  - 2004
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - Gene silencing of DNA repair genes hMLH1 and MGMT caused by aberrant promoter methylation has been detected in various solid tumors. However, in acute myeloid leukemia (AML) the frequency of hMLH1 and MGMT promoter methylation is not yet fully elucidated. To determine the methylation status and expression of hMLH1 and MGMT, we investigated 22 AML cases by methylation-specific polymerase chain reaction (MS-PCR) and reverse transcription PCR (RT-PCR). To exclude unspecific PCR amplifications DNA sequencing was performed. hMLH1 promoter methylation was detectable in 4 of 20 AML cases. However, DNA sequencing could only confirm a methylated hMLH1 promoter in one case. mRNA expression was absent in one case and reduced in another. However, these cases did not display aberrant promoter methylation. In contrast, MGMT promoter methylation was not detectable in the investigated AML patient samples. Accordingly, MGMT mRNA expression was found to be normal in all but one case. Aberrant promoter methylation of hMLH1 was detectable only in a small number of AML cases. Additionally, in two cases the promoter methylation detected by MS-PCR could not be confirmed by sequencing, clearly indicating the importance of controlling MS-PCR results by the more specific sequence analysis. Surprisingly, hMLH1 promoter methylation was not associated with gene silencing, suggesting monoallelic methylation or promoter methylation only in a small subpopulation of malignant cells. The reduced mRNA expression in additional samples may indicate an involvement of hMLH1 in the malignant transformation in a small subset of cases. In contrast, MGMT does not seem to be involved in the pathogenesis of AML.
AU  - Lenz, G.*
AU  - Hutter, G.
AU  - Hiddemann, W.
AU  - Dreyling, M.
C1  - 4424
C2  - 22153
SP  - 628-633
TI  - Promoter methylation and expression of DNA repair genes hMLH1 and MGMT in acute myeloid leukemia.
JO  - Ann. Hematol.
VL  - 83
IS  - 10
PY  - 2004
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - The monoclonal antibodies (MoAbs) alemtuzumab (anti-CD52) and rituximab (anti-CD20) produce objective clinical responses in patients with chronic lymphocytic leukemia (CLL). However, their mechanisms of action are not fully understood. Therefore, we investigated the mechanisms of lymphoma and CLL cell killing by two anti-CD20 antibodies (rituximab, B1) and by alemtuzumab. All antibodies induced complement-independent cell death in B-lymphoid cell lines Raji, Ramos, and Mec-1. The efficiency of cell killing was increased by the addition of human complement in Raji but not Ramos cells. Both alemtuzumab and rituximab also killed freshly isolated CLL cells, with a much stronger response for alemtuzumab (from eight of eight patients) compared to rituximab (from two of six patients). Cell morphology and Western blot analyses revealed that the antibody-induced cell death lacked some typical features of apoptosis such as chromatin condensation or poly-ADP-ribose polymerase (PARP) cleavage. Taken together, the results suggest that the tumor killing activity of these MoAbs is not only mediated by complement-mediated cytotoxicity (CDC) or antibody-dependent cytotoxicity (ADCC), but also by a nonclassic, caspase-independent apoptotic pathway.
AU  - Stanglmaier, M.
AU  - Reis, S.
AU  - Hallek, M.
C1  - 2127
C2  - 22399
SP  - 634-645
TI  - Rituximab and Alemtuzumab induce a nonclassic, caspase-independent apoptotic pathway in B-lymphoid cell lines and in chronic lymphocytic leukemia cells.
JO  - Ann. Hematol.
VL  - 83
IS  - 10
PY  - 2004
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - The conditioning regimen preceding hematopoietic stem cell transplantation (HSCT) causes a rapid decrease in the platelet count and signs of disseminated intravascular coagulation, possibly indicating platelet activation. As impacts during the conditioning regimen may predict later transplantation-associated complications, we investigated changes in platelet membrane glycoproteins (GP) and the liberation of microparticles. Platelet receptors and granules of 49 patients undergoing HSCT were evaluated by flow cytometric analysis before and after the different phases of the conditioning regimen [chemotherapy, total body irradiation (TBI), therapy with antithymocyte globulin (ATG)] and final transplantation. Following chemotherapy a high surface expression of CD62P, a low mepacrine staining, and a reduced surface expression of CD42b (part of the GP Ib/V/IX complex) were found, indicating an irreversible activation of platelets. In addition, elevated levels of circulating microparticles were observed, which may reinforce the thrombosis risk in these patients. Treatment with ATG leads to an elevated surface expression of PAC-1 epitopes, which are neoepitopes appearing after activation of GP IIb/IIIa. However, a significant degranulation was not detectable, which may be the consequence of inhibitory influences on platelets during ATG-induced cytokine release syndrome. TBI and transplantation itself had no influence on platelets. This study was able to demonstrate activating effects on platelets by certain phases of the conditioning regimen in patients receiving HSCT. Chemotherapy, in particular, leads to a strong and irreversible platelet activation and a generation of microparticles, which may cause an increased thrombosis risk. Our findings underline the impact of platelets on the pathogenesis of hemostatic complications during HSCT.
AU  - Pihusch, R.*
AU  - Höhnberg, B.*
AU  - Salat, C.*
AU  - Pihusch, M.*
AU  - Hiller, E.*
AU  - Kolb, H.-J.
C1  - 10366
C2  - 21133
SP  - 454-461
TI  - Platelet flow cytometric findings in patients undergoing conditioning therapy for allogeneic hematopoitic stem cell transplantation.
JO  - Ann. Hematol.
VL  - 81
IS  - 8
PY  - 2002
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - P-glycoprotein (P-gp) expression in mononuclear bone marrow cells was analyzed in 119 patients, including 60 with chronic myelogenous leukemia (CML), 48 with myelodysplastic syndromes (MDS), and 11 with acute myelogenous leukemia (AML). For P-gp measurement an immunocytological method using monoclonal antibodies C219, 4E3, and MRK 16 and the reverse transcription-polymerase chain reaction technique were applied. According to our results obtained in healthy volunteers using the immunocytological method, the limit for P-gp overexpression was set at ≥ 10% P-gp-positive mononuclear bone marrow cells and at ≥ 30% P-gp-positive mononuclear peripheral blood cells. All 42 CML patients in chronic phase had normal P-gp expression. P-gp overexpression was demonstrated in four of six patients in accelerated myelogenous blast cell phase and in four of 12 CML-BC patients. Of eight CML patients in blast crisis (BC) with normal P-gp expression, partial remission was achieved in three and minor response in five after prednisone/vindesine therapy. All four of the 12 CML-BC patients with P-gp overexpression did not respond to this therapy. Normal P-gp expression was seen in 41 (85.4%) of 48 untreated MDS patients. While P-gp overexpression did not develop during therapy in any of the myelodysplastic syndrome patients treated with low-dose ara-C alone, four of eight treated with low-dose ara-C plus GM-CSF and four of 11 treated with low-dose ara-C and IL-3 developed P-gp overexpression after therapy. Furthermore, 11 AML patients at primary diagnosis, including five AML patients with P-gp overexpression, who were treated with idarubicin, vepesid, and cytarabine V (ara-C) showed a complete remission. Additionally, one daunorubicin-cytarabine-pretreated refractory AML patient was treated with the oral form of the P-gp modulator drug dexniguldipine and achieved complete remission for a duration of 7 months. Our results suggest that in CML patients in BC, P-gp expression influences outcome after therapy. Further more, studies in a larger series of patients are necessary to prove the efficacy and toxicity of idarubicin/vepesid and cytarabine - or dexniguldipine-containing - therapy in relation to P-gp expression of AML patients.
AU  - Nüßler, V.
AU  - Pelka-Fleischer, R.
AU  - Zwierzina, H.H.
AU  - Nerl, C.H.
AU  - Beckert, B.
AU  - Gullis, E.
AU  - Gieseler, F.
AU  - Bock, S.
AU  - Bartl, R.
AU  - Petrides, P.E.
AU  - Wilmanns, W.
C1  - 33762
C2  - 38952
SP  - S25-S29
TI  - Clinical importance of P-glycoprotein-related resistance in leukemia and myelodysplastic syndromes - First experience with their reversal.
JO  - Ann. Hematol.
VL  - 69
IS  - 1
PY  - 1994
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - Biotin labeling of red cells was studied using different approaches to see if biotinylation is a useful label for determination of erythrocyte survival. Mouse red cells were labeled with biotin, either in vivo by injection or in vitro. In vivo labeled red cells were followed up in some mice without transfusing the labeled erythrocytes. Furthermore, in vivo labeled as well as in vitro labeled red cells were transfused into syngeneic mice. The biotin label allows an easy discrimination between labeled and unlabeled red cells during FACS analysis, and it is relatively stable for at least 50 days. All the three different approaches give similar results. Mean red cell life spans of in vivo or in vitro labeled red cells either transfused or followed up in vivo were between 44 and 52 days (T50 mean 23.9 days) when red cell destruction was assumed to be only a result of senescence. Mean red cell life spans were between 8 and 18 days (T50 mean 9.5 days) when a random destruction independent of red cell age was suggested. All the survival slopes are neither simple linear functions of time nor logarithmic functions, but they show an overlay of linear function by a logarithmic function where the components of both are unknown.
AU  - Hoffmann-Fezer, G.
AU  - Mysliwietz, J.
AU  - Mörtlbauer, W.
AU  - Zeitler, H.J.
AU  - Eberle, E.
AU  - Hönle, U.
AU  - Thierfelder, S.
C1  - 20560
C2  - 13766
SP  - 81-87
TI  - Biotin Labeling as an Alternative Non-Radioactive Approach for Determination of Red Cell Survival.
JO  - Ann. Hematol.
VL  - 67
IS  - 2
PY  - 1993
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - Biotin labeling of red cells was studied using different approaches to see if biotinylation is a useful label for determination of erythrocyte survival. Mouse red cells were labeled with biotin, either in vivo by injection or in vitro. In vivo labeled red cells were followed up in some mice without transfusing the labeled erythrocytes. Furthermore, in vivo labeled as well as in vitro labeled red cells were transfused into syngeneic mice. The biotin label allows an easy discrimination between labeled and unlabeled red cells during FACS analysis, and it is relatively stable for at least 50 days. All the three different approaches give similar results. Mean red cell life spans of in vivo or in vitro labeled red cells either transfused or followed up in vivo were between 44 and 52 days (T50 mean 23.9 days) when red cell destruction was assumed to be only a result of senescence. Mean red cell life spans were between 8 and 18 days (T50 mean 9.5 days) when a random destruction independent of red cell age was suggested. All the survival slopes are neither simple linear functions of time nor logarithmic functions, but they show an overlay of linear function by a logarithmic function where the components of both are unknown.
AU  - Hoffmann-Fezer, G.
AU  - Mysliwietz, J.
AU  - Mörtlbauer, W.
AU  - Zeitler, H.J.
AU  - Eberle, E.
AU  - Hönle, U.
AU  - Thierfelder, S.S.
C1  - 40251
C2  - 40009
SP  - 81-87
TI  - Biotin labeling as an alternative nonradioactive approach to determination of red cell survival.
JO  - Ann. Hematol.
VL  - 67
IS  - 2
PY  - 1993
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - Perturbations of hematopoietic regulation ranging from transient granulocytopenia to rare cases of bone marrow failure are associated with infections due to hepatitis A virus (HAV). In an attempt to elucidate the pathogenetic mechanisms we had previously established that HAV has a direct suppressive effect on human bone marrow progenitors (CFU-GM, -GEMM, BFU-E). These studies were extended to long-term bone marrow cultures (LTBMC): Inoculation of bone marrow mononuclear cells with HAV did not interfere with the establishment of an adherent stromal layer, nor did the inoculation of already established layers cause any morphologically recognizable changes to the stroma. In contrast, a significant and progressive decline of the CFU-GM content in the culture supernatants was demonstrated. HAV antigen was detected by APAAP stain in a subpopulation of stromal cells, and sequential estimations of virus titers in the supernatants provided evidence for viral replication in primary bone marrow cultures. Interferon-gamma and tumor necrosis factor-alpha levels of infected cultures did not differ from those of uninfected controls. These findings argue for a direct suppression of (pre-) CFU-GM by HAV in a model system (LTBMC) lacking an immune defense which would limit viral replication.
      
      	 
AU  - Busch, F.W.
AU  - Kunst, A.
AU  - Flehmig, B.
AU  - Mergenthaler, H.-G.
AU  - Pawelec, G.
AU  - Vallbracht, A.
C1  - 20262
C2  - 13448
SP  - A132-A136
TI  - Myelopoiesis in Vitro is Suppressed by Hepatitis A Virus.
JO  - Ann. Hematol.
VL  - 64
PY  - 1992
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Reininger, C.B.
AU  - Reininger, A.J.
AU  - Steckmeier, B.
AU  - Hörmann, A.
AU  - Schramm, K.-W.
AU  - Schweiberer, L.
C1  - 20293
C2  - 13482
SP  - S. A6
TI  - Increased Platelet Activity in Postsurgical Patients.
JO  - Ann. Hematol.
VL  - 64 (Suppl.)
PY  - 1992
SN  - 0939-5555
ER  - 

TY  - JOUR
AU  - Hahn, J.
AU  - Kolb, H.-J.
AU  - Schumm, M.
AU  - Günther, W.G.
AU  - Ellwart, J.
AU  - Wilmanns, W.
AU  - Thierfelder, S.
C1  - 19153
C2  - 12209
SP  - 59-60
TI  - Positive Selection of Canine Hemopoietic Progenitor Cells.
JO  - Ann. Hematol.
VL  - 14
IS  - 2
PY  - 1991
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - Canine hematopoietic progenitor cells were characterized by separation with monoclonal antibodies. Depleted and enriched fractions were studied for growth of CFU-GM in semisolid agar and for repopulating capacity of lethally irradiated dogs. CFU growth was not reduced by depletion of marrow using monoclonal antibodies F 3-20-7 (anti-dog Thy-1), MT606 (anti-human CD6), and IOT2a (anti-human DR). CFU growth was variable following treatment with the anti-canine T-cell antibody MdT-P1 and immunomagnetic bead separation. It was regularly enriched when MdT-P1 treatment was followed by immunorosetting with staphylococcal protein A-loaded sheep red blood cells and density gradient separation. Lethally irradiated dogs were reconstituted by autologous marrow depleted of MdT-P1-positive cells using immunorosetting and density gradient centrifugation, whereas immunomagnetic bead-depleted marrow was ineffective. Fluorescence-activated cell sorting showed enrichment of hematopoietic progenitor cells in the weakly MdT-P1-positive fraction.
AU  - Hahn, J.
AU  - Kolb, H.J.
AU  - Schumm, M.A.
AU  - Beißer, K.
AU  - Ellwart, J.W.
AU  - Rieber, P.*
AU  - Maldacker, J.
AU  - Schwella, N.
AU  - Lösslein, L.K.
AU  - Holler., E.
AU  - Wilmanns, W.
AU  - Thierfelder, S.S.
C1  - 40800
C2  - 38720
SP  - 223-226
TI  - Immunological characterization of canine hematopoietic progenitor cells.
JO  - Ann. Hematol.
VL  - 63
IS  - 4
PY  - 1991
SN  - 0939-5555
ER  - 

TY  - JOUR
AB  - Direct in vivo labeling of erythrocytes with biotin is shown as a method for estimation of red cell survival as well as of enrichment of young or aged erythrocytes. Two succinimide esters (biotin-N-hydroxysuccinimide ester [BNHS], caproylamidobiotin-N-hydroxysuccinimide ester [C-BNHS] were used for biotin labeling of erythrocytes. With improved syntheses, pure BNHS (mp, 212°-214° C) and the spacered intermediate for C-BNHS, 6-(biotinylamide) hexanoate (mp, 225°-226° C) were obtained in an overall yield of 86%; the yield of C-BNHS (mp, 167°-169° C) was 68%. When three doses of 1 mg C-BNHS are injected intravenously into mice at 24-h intervals, all the red cells are biotin labeled. The rate of red cell production as well as the life span of red cells can be measured without any effect on erythropoiesis or damage by red cells in vitro. The survival curve seems to be linear, with 2.5%-3.3% disappearance of biotin labeled red cells daily. In mice, in vivo biotin labeling avoids damaging red cells by in vitro procedures and does not influence the steady state of erythropoiesis by hypertransfusion. Therefore, in vivo biotin labeling is a very useful method for determining red cell survival time in small animals.
AU  - Hoffmann-Fezer, G.
AU  - Maschke, H.
AU  - Zeitler, H.J.
AU  - Gais, P.
AU  - Heger, W.
AU  - Ellwart Thierfelder, J.S.
C1  - 40752
C2  - 38957
SP  - 214-217
TI  - Direct in vivo biotinylation of erythrocytes as an assay for red cell survival studies.
JO  - Ann. Hematol.
VL  - 63
IS  - 4
PY  - 1991
SN  - 0939-5555
ER  -