bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mortality during Treatment of Patients with Advanced Hodgkin’s Lymphoma Undergoing Dose Escalated BEACOPP Chemotherapy: An Analysis of the German Hodgkin Study Group (GHSG).
Authors: Fuchs Michael , Franklin Jeremy , Klimm Beate , Josting Andreas , Pfistner Beate , Engert Andreas , Diehl Volker 
Published: April 2020

Abstract
Introduction: Due to substantial clinical progress over the past decades, the outcome of patients with Hodgkin’s Lymphoma (HL) has improved with a long-term disease free survival of nearly 80%. Even patients with advanced-stage HL show a five year freedom from treatment failure (FFTF) of 87% and overall survival (OS) of 91% when treated with 8 cycles of BEACOPPescalated (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbacine, prednisone). However, BEACOPPescalated has been associated with some acute and long-term treatment related mortality (TRM). We thus analysed the incidence, clinical features and risk factors for TRM of patients treated with BEACOPPescalated in the HD12 multicenter trial of the GHSG performed between 1998 and 2002. The HD12 was conducted for advanced HL patients (Stage IIB with large mediastinal mass and/or extranodal involvement, stage III/IV). All patients received 8 cycles of chemotherapy either 8x BEACOPPescalated (Arm A/B) or 4xBEACOPPescalated + 4xBEACOPPbaseline (Arm C/D) +/− 30Gy radiation on bulk and residual tumor.
Results: In this study, 43 patients (3.1%) from a total of 1392 included died from TRM. 5 patients were excluded from this analysis because of various reasons (change of fist-line therapy due to toxicity, TRM in BEACOPPbaseline) 38 patients were eligible for this analysis. 30 patients (79%) had infectious complications, 6 (16%) cardiac events such as arrhythmia or heart failure, 1 patient died due to bleomycin-related toxicity and 1 case remained unclear. 25 patients (66%) were older than 50 years in contrast to the whole HD12 study population with only 17% of patients being older than 50. There was no statistical difference between those cases with treatment related mortality and the whole study population in terms of other clinical risk factors such as gender, B-symptoms, extranodal involvement, stage of disease, large mediastinal mass or elevated ESR. There was also no difference between the 4 study arms. Most events occurred during the first 4 courses of BEACOPPescalated (79%) with the majority during the first cycle (n = 12; 32%). 23/26 (89%) of patients who died during cycles 2 – 8 had prior WHO grade III/IV leucopenia or infection.
Conclusion: Patient age and toxicity in previous cycles are the most obvious risk factors for TRM in patients with advanced HL undergoing BEACOPPescalated chemotherapy. In the HD12 study, the use of G-CSF was mandatory and most patients received their treatment on an outpatient basis. Thus, possible measures to reduce toxicity with this treatment include the prophylactic use of antibiotics as well as treating those with risk factors at least for the first course as inpatients.
A Prospective Study of Combined m-BACOD Chemotherapy and Radiotherapy for Aggressive Nasal NK/T-Cell Lymphoma.
Authors: Lei Kenny I.K. , Yu Brian K.H. , Hui Edwin P. , Zee Benny C.Y. , Chan Anthony T.C. 
Published: April 2020

Abstract
Purpose: Primary nasal NK/T-cell lymphoma is a highly aggressive tumor associated with poor response to therapy, frequent relapse, and a short median survival of 7–12 months. Moreover, the optimal treatment has not yet been established as most published studies were retrospective in nature. We performed a prospective study to evaluate the efficacy of combined m-BACOD chemotherapy and involved field radiotherapy (RT) for patients with previously untreated or relapsed nasal NK/T-cell lymphoma.
Methods: Between January 1998 and December 2004, all previously untreated or relapsed patients (pts), aged &gt; 18 years, with biopsy proven nasal NK/T-cell lymphoma, ECOG performance status &lt; 2, and adequate marrow, cardiac, liver and renal functions were included in this study. Previously untreated pts were treated with m-BACOD (iv methotrexate 200mg/m2 D8, D15 with leucovorin rescue, iv bleomycin 4mg/m2 D1, iv doxorubicin 45mg/m2 D1, iv cyclophosphamide 600mg/m2 D1, and iv vincristine 1mg/m2, and dexamethasone 6mg/m2 D1-5 PO) every 3 weeks for 6 cycles, followed by involved field RT (54 Gy in 27 daily fractions over 5.4 weeks). Relapsed pts with prior anthacycline-based chemotherapy were treated with 3 cycles of m-BACOD, followed by RT. Stage I/II pts with static response (SR) after 3 cycles m-BACOD were treated with early RT. Young pts (&lt;60 years) who achieved complete remission (CR) with m-BACOD were offered a course of high-dose therapy BEAM before RT. Endpoints were objective response (OR), treatment tolerability, progression-free-survival (PFS), and overall survival (OS).
Results: Seventeen pts (14 untreated, 3 relapsed) were included. The median age was 49 years (range: 34–90) with a sex ratio of 1:1.1 (M:F). Fifteen pts had stage I disease, 1 had stage II and 1 had stage IV disease. A median of 5 cycles (range: 2–6) of m-BACOD were delivered to each pt. An OR was observed in 15 pts (88%) after m-BACOD induction with CR in 13 pts (76%), PR in 1 pt (6%) and SR in 1 pt (6%). Two pts (12%) had progressive disease during m-BACOD therapy. The two pts with PR and SR were converted to CR after RT, resulting in a final CR of 88%. Grade 3/4 adverse events were leukopenia (70%), thrombocytopenia (12%), infection, (24%), pneumonitis (12%). There was 1 (6%) therapy-related death. Only 5 pts opted for BEAM high-dose therapy. With a median follow-up of 49 months (range: 3–82), the median PFS and median OS were 31.5 months (range: 1.9–68.9) and 35.6 months (range: 2.9–81.6), respectively. The 5-year PFS and OS were 55% and 63%, respectively. These results appears superior than our historic control (5-yr OS: 33%, Clin Oncol 1999) and that reported by others (5-yr OS: 37.9%, Int J Radiat Oncol Biol Phys. 2002)
Conclusion: m-BACOD chemotherapy in combination with involved field RT is a highly active and well tolerated treatment for pts with aggressive nasal NK/T-cell lymphoma.
Figure Figure
Comparison of LIC Obtained from Biopsy, BLS and R2-MRI in Iron Overloaded Patients with β-Thalassemia, Treated with Deferasirox (Exjade®, ICL670).
Authors: Piga A. , Fischer R. , Harmatz P. , St. Pierre T. G. , Longo F. , Fung E. , Engelhardt R. , Perrotta S. , Galanello R. , Capra M. , Vichinsky E. , Janka-Schaub G. , Masera G. , Cianciulli P. , Coates T. , Janssen G. , Jeng M. , Lai M. E. , Salles G. , Cole P. , Alberti D. , Rosenkranz G. , Opitz H. 
Published: April 2020

Abstract
Chelation therapy for patients with transfusional hemosiderosis is guided by the degree of iron overload and ongoing transfusion requirements; liver iron concentration (LIC) is one tool for measuring current iron burden. During the clinical development of the novel oral iron chelator deferasirox, LIC was measured in subcutaneous liver biopsy samples, but also non-invasively by biomagnetic liver susceptometry (SQUID-BLS) and magnetic resonance imaging (R2-MRI: FerriScan®). These methods were compared in a substudy of a large, open-label, randomized Phase III study in 586 β-thalassemia patients with transfusional hemosiderosis; the study evaluated the efficacy and safety of long-term deferasirox and deferoxamine treatment.
48 patients (aged 17–35 yrs) gave informed consent for adding BLS and MRI assessments (baseline, 6 and 12 months) to the biopsy assessments (baseline and 12 months) of the main study. At baseline, 47 patients were assessed by BLS and biopsy, 45 by R2-MRI; at 6 months, 42 by BLS and R2-MRI; at 12 months, 41 by BLS and R2-MRI, 39 by biopsy. BLS was performed and evaluated locally at 3 centers in Hamburg, Turin and Oakland. MR images were recorded at 4 centers in Hamburg, Turin, Stanford and Los Angeles and were analyzed centrally. Data from BLS and R2-MRI remained blinded until study completion. LIC from biopsies was determined by AAS from extracted paraffin blocks in a central laboratory and used as the standardized reference method. LIC was expressed as mg/g dry weight for all methods: for BLS, a wet-to-dry weight conversion factor of 3.3 was applied, while MRI was calibrated against fresh freeze-dried liver biopsies. The relationship between BLS or R2-MRI with biopsy measurements was modeled by linear regression after log-transformation of the data. To account for the correlation between baseline and post-baseline measurements of the same patient, mixed-effects models were fitted.
On average, the LIC data obtained from BLS and biopsy were related by a factor of 0.46 (95% CI: 0.32, 0.67). With R2-MRI assessment of LIC vs biopsy, the factor was 0.72 (95% CI: 0.54, 0.97). BLS and R2-MRI measurements could not be related appropriately by a factor. Overall, LIC from biopsy was generally larger than that obtained from BLS; R2-MRI measurements fell in-between biopsy and BLS. Differences are caused in part by the variability in the wet-to-dry weight ratio relating in vivo with in vitro methods.
In conclusion, LIC data from 3 independent methods were correlated but not equivalent. It is therefore important that for an individual patient, a single method is consistently used under standardized conditions.
Identification of a Transcription Factor Potentially Involved in γ-Globin Gene Expression.
Authors: Grosso Michela , Amendola Giovanni , Petruzzelli Raffaella , Puzone Stella , Sessa Raffaele , Di Concilio Rosanna , D’Urzo Giovanna , Izzo Paola 
Published: April 2020

Abstract
The switch from fetal to adult globin gene expression occurs around birth when fetal hemoglobin (HbF) production gradually declines within a few months. Much effort is underway to clarify the molecular basis of this mechanism, since impaired hemoglobin switching leading to persistent expression of fetal globin genes in adults (HPFH) offers therapeutic potential for hemoglobinopathies (S.L. Thein. Br. J. Haematol2004; 124: 264–74).
In order to identify and study regulatory factors putatively involved in γ-globin gene expression, we examined the reticulocyte mRNAs differently expressed in three siblings (one brother, 54 years-old and two sisters 35- and 37-years old, respectively). The eldest brother had been referred to Umberto I Hospital for evaluation of a severe condition of β-thalassemia intermedia on chronic transfusion therapy since 1990. Both of his sisters resulted clinically affected by a milder form of thalassemia intermedia, non-transfusion dependent, showing Hb values around 8.4 g/dL, Hb A2 levels from 6.0 to 7.9% and HbF ranging from 14.5 to 27.6%, values higher than those resulted in their brother (5.9% Hb A2 and 7.2% HbF). Molecular analysis was performed on DNA extracted from peripheral leucocytes and revealed the same β-globin gene cluster genotype for all these subjects who resulted homozygous for the β+ IVSI-6 (C→T) mutation associated to haplotype VI chromosomes. Different levels of HbF were thus presumably responsible of different clinical phenotypes. To investigate the possible causes of the variations in γ-globin gene expression, extensive sequence analysis was performed on putative regulatory regions within the β-globin gene cluster (Zhi-Hong Lu et al., Blood1996; 87: 1604–11). Results showed the same genetic background in all the siblings. It was thus supposed that genetic determinants external to the β-globin gene cluster were responsible of the different γ-globin gene expression. To explore this hypothesis, the reticulocyte transcriptome was analyzed by a differential mRNA display approach. Reticulocytes were isolated from peripheral blood and total RNA extracted for all family members. Our study revealed several bands differentially displayed in the sample from the more severely affected sibling respect to his sisters. Selected bands were cloned in a pGEM T-vector (Promega, WI) and sequenced. Comparative sequence searches were performed using the BLAST algorithm. Preliminary data gave, for two of the clones originated from bands with increased expression in the brother, a complete homology (greater than 95%) with the cDNA sequence of a cold shock domain protein, displaying features of a repressor factor for several hematopoietic genes (Horwitz M. et al. JBC1994; 269: 14130–39; P. Coles et al. Nucleic Acids Res1996; 12: 2311–17).
Pharmacogenomics of Deferiprone Metabolism.
Authors: Haverfield Eden V. , Weatherall David J. , Graber Andrea Yoder , Ramirez Jacqueline , Ratain Mark J. 
Published: April 2020

Abstract
Individuals with transfusion-dependent β-thalassemia can be affected by iron accumulation in the heart and liver, resulting in liver fibrosis, cardiomyopathy and eventual death. As a result, iron chelation treatment is a necessary concurrent therapy for many patients. Deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one) is currently the only orally active iron chelator approved outside the U.S. for the treatment of iron overload. Despite the efficacy of deferiprone in reducing serum ferritin levels and total body iron burden, not all patients respond to the drug, and serious adverse events can require discontinuation of therapy. The variability in drug response, combined with a high rate of side effects, indicate that there may be genetic factors that influence how the drug is metabolized. We have identified the uridine diphosphate glucuronosyltransferase (UGT) enzyme that metabolizes deferiprone. Utilizing human liver microsomes and insect cell supersomes, we have screened UGT 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15 and 2B17 enzymes for deferiprone glucuronidation. Deferiprone glucuronide was detected solely with UGT1A6. Previous reports of linkage disequilibrium between the UGT1A1*28 and UGT1A6*2 alleles (Kohle et. al., 2003; Peters et. al., 2003), combined with the association of the UGT1A1*28 allele with an increased risk of hyperbilirubinemia and gallstone formation in the hemoglobinopathies (Haverfield et. al., 2005), substantiate the importance of elucidating the pharmacogenomics of deferiprone metabolism. From this preliminary data, it will be possible to examine UGT1A6 genetic variation that may contribute to differences in drug efficacy and toxicity, and further delineate any additional enzymes involved in deferiprone metabolism.
Phosphorylation of AML1 (RUNX1) Controls Transcription, Nuclear Localization, and Is Regulated during DNA Damage.
Authors: Wang Suiquan , Zhang Youhong , Biggs Joseph R. , Zhang Dong-Er , Kraft Andrew S. 
Published: April 2020

Abstract
We demonstrate that AML1 (RUNX1) is phosphorylated on S276, S293, T300, S303 and S462 after phorbol ester treatment in K562 cells, and these phosphorylations control the transcriptional activity of this protein and regulate varied promoters including TCRb, GM-CSF, M-CSF receptor, and myeloperoxidase gene (JBC279: 53116–53125, 2004). In addition, we find that phosphorylation of the AML1 protein controls the binding of AML1 to the nuclear matrix, and regulates its degradation (MCR3: 391–401, 2005). We have now derived rabbit phosphopeptide antisera to S276, S303, and S462 in the AML1 protein. Using these antibodies, we find that in unsynchronized Jurkat T cells AML1 contain low levels of phosphorylation at all three sites. To examine whether this phosphoryaltion is cell cycle regulated, we blocked cells in G1/S with aphidicolin or in G2/M with nocodazole. In contrast to G1/S block that had no effect on phosphorylation, nocodazole treatment induces marked increases in phosphorylation of S276, S303, and S462. The nocodazole increase in phosphorylation was markedly inhibited by staurosporine, a PKC inhibitor, and to a lesser extent by the JNK inhibitor SP600125, and the p38 inhibitor, SB202190. Using elutriation to examine untreated Jurkat cells, we demonstrate increases in the level of AML1 protein as cells progress through the cell cycle to G2/M. However, the actual level of phosphorylated protein as judged by phospho303 and 462 antibodies decreases. Nocodazole treatment of Jurkat cells not only induces G2/M arrest, but also induces apoptosis. We are currently investigating the hypothesis that DNA damage causes phosphorylation of AML1 that regulates both its activity and location.
PU.l Immortalizes Hematopoietic Progenitors in a GM-CSF Dependent Manner.
Authors: Houston Isaac B. , Jennings Serena , Huang Kelly J. , DeKoter Rodney P. 
Published: April 2020

Abstract
Leukemia arises as a result of a multistep progression of blood cells towards malignancy. Genetic blocks in cell development and uncontrolled proliferation are often key steps in leukemic transformation. PU.1 is a transcription factor that has several known roles in hematopoietic development. Knock-out studies of PU.1 demonstrate a requirement for PU.1 in the development of myeloid and lymphoid cells. In addition, PU.1 concentration can influence cell development in normal hematopoiesis. Low concentrations of PU.1 are required for lymphoid development, whereas high concentrations of PU.1 are required for myeloid development. Mice that have been genetically altered to express abnormally low concentrations of PU.1 develop acute myeloid leukemia (AML) due to a developmental block within the myeloid lineage. In contrast, abnormally high concentrations of PU.1 in mice are capable of inducing erythroleukemias. This can occur through Friend virus integration into the PU.1 gene, which leads to over-expression of PU.1, and the subsequent blocking of erythroid development due to PU.1’s ability to antagonize GATA-1 function. Here we report that ectopic expression of PU.1 is sufficient to immortalize hematopoietic progenitors in a GM-CSF-dependent manner. When fetal hematopoietic progenitors are infected with a PU.1 retrovirus and placed into culture with GM-CSF, a small fraction become immortalized. These PU.1-infected progenitors (PIP cells) are arrested in development and can grow for several months in culture. PU.1 Immortalized Progenitors (PIP) are GM-CSF restricted and dependent. In addition, PIP cells display blast-like morphology and express cell surface markers indicative of myeloid development. In contrast, gene expression analysis of clonal PIP cell lines demonstrates the expression of stem cell, myeloid, and erythroid specific genes. Finally, PIP cells display low levels of endogenous PU.1 production as shown by real-time PCR relative to wild-type cells. These observations support a model in which high levels of PU.1, in conjunction with signaling through the GM-CSF receptor, block cell differentiation at an early stage in hematopoiesis. This discovery provides new information into PU.1’s ability to control cell differentiation and its ability to induce leukemia.
Kinetics of Plasma-Cell Chimerism after Allogeneic Stem Cell Transplantation by Real-Time PCR and Its Value To Quantify Minimal Residual Disease in Patients with Multiple Myeloma.
Authors: Kroeger Nicolaus , Zagrivnaja Maria , Schwartz Sabine , Badbaran Anita , Zabelina Tatjana , Ayuk Francis , Zander Axel , Fehse Boris 
Published: April 2020

Abstract
To investigate lineage-specific chimerism of plasma cells after allogeneic transplantation by real-time PCR based on bi-allelic single-nucleotide polymorphism (SNP) or, in case of female-to-male transplantation, on the detection of the DFFRY-gene, 48 samples from bone marrow samples and peripheral blood from 34 non-myeloma patients were analyzed at different times after transplantation. Plasma cells and T-cells were obtained with CD138- or CD3-microbeads and MiniMACS columns. The median chimerism for T-cells at day +100 was &gt; 99.9 % and remained stable on day +180 and one year after transplantation. In contrast, the median donor-plasma-cell chimerism at day +100 was 95.5 %, at day +180 98,6 %, at day +360 99.8 %, and two or more years after transplantation &gt; 99.9 %. There was a trend for more patients with full donor-plasma-cell chimerism at day 180 who received standard conditioning in comparison to reduced-intensity conditioning (56 % vs. 28 %, p=0.3) and who experienced acute graft-versus-host disease (43 % vs. 18 %, p=0.2).
To evaluate whether the quantitative measurement of donor-plasma-cell chimerism after allogeneic stem cell transplantation for patients with multiple myeloma might be a useful tool to determine minimal residual disease, we investigated 48 samples from 21 myeloma patients at different times after allogeneic stem cell transplantation, and we compared it with immunofixation and, in some cases, with molecular methods by using patient-specific primers. All patients with molecular remission measured by patient-specific primers had a plasma-cell chimerism of more than 99.5 %. Furthermore, in all but one patient plasma-cell chimerism of more than 99.3 % was associated with a negative immunofixation. In six patients with positive immunofixation after allogeneic stem cell transplantation treatment with bortezomib or donor-lymphocyte infusion was started and monitored by plasma-cell chimerism and immunofixation. All patients experienced an increase of donor-plasma-cell chimerism with negative immunofixation if chimerism exceeded &gt; 99.3 %. Dilution experiments with the TIB-196 cell line showed sensitivity of 104 using real-time PCR and SNPs, 105 in case of Y-PCR and 105 for nested PCR with patient-specific primers. We conclude that plasma-cell chimerism after allogeneic stem cell transplantation is delayed in comparison to T-cell chimerism, suggesting a reduced graft versus hematopoiesis effect on plasma cells. Quantitative measurement of plasma cells after allogeneic stem cell transplantation with highly sensitive real-time PCR allows monitoring of residual host-tumor cells in patients with multiple myeloma and allows guiding adoptive immunotherapy strategies to enhance remission status and to prevent relapse.