bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activating Transcription Factor 3 (ATF3) Is Overexpressed in Classical Hodgkin Lymphoma and Is Required for Survival of Hodgkin and Reed-Sternberg Cells in Response to Cellular Stress.
Authors: Janz M. , Hummel M. , Truss M. , Wollert-Wulf B. , Mathas S. , Hagemeier C. , Bommert K. , Stein H. , Dorken B. , Bargou R. C. 
Published: April 2020

Abstract
Hodgkin and Reed-Sternberg (HRS) cells display aberrant activity of several transcription factors, including nuclear factor kappa B (NF-kB) and members of the activator protein-1 (AP-1) family, that promote cytokine expression, cellular survival and proliferation. Using oligonucleotide microarrays, we set out to identify additional factors which are responsible for the malignant phenotype of HRS cells. Microarray analysis and subsequent Northern and Western blotting revealed that activating transcription factor 3 (ATF3), a member of the CREB/ATF family of transcription factors that is involved in the cellular response to stress signals, shows a strong constitutive expression in Hodgkin-derived cell lines. In contrast, ATF3 expression could not be detected in several Non-Hodgkin cell lines of distinct differentiation stages, ranging from pre-B cell lines to plasma B cell lines. To investigate the expression pattern of ATF3 in primary tumor cells, we performed immunohistochemistry on tissue microarrays. Immunohistochemistry confirmed a strong expression of ATF3 in primary HRS cells with a nuclear staining pattern. ATF3 expression was observed in almost all cases of classical Hodgkin lymphoma examined (69/71), whereas ATF3 expression was not detected in lymphocyte-predominant Hodgkin lymphoma. In addition, a significant number of anaplastic large cell lymphomas revealed a nuclear ATF3 staining pattern. In contrast, among all other B and T cell Non-Hodgkin lymphomas, ATF3 expression was observed only in rare cases (7/244), indicating that ATF3 expression is almost exclusively restricted to classical Hodgkin lymphoma and to a subset of anaplastic large cell lymphomas. To investigate the role of ATF3 for proliferation and survival of HRS cells, we generated vector-based siRNA constructs to downregulate ATF3 expression. Our vector system carries a puromycin-resistance gene thus allowing selection of siRNA expressing cells. Transfection of Hodgkin-derived cell lines with ATF3 siRNA constructs and subsequent selection of siRNA-expressing cells demonstrated a dramatic loss of viable cells. Our observations indicate that ATF3 is required for the survival of HRS cells exposed to the environmental stress imposed by antibiotic selection.
Proliferation Characteristics in Pediatric Hodgkin’s Disease Point to a Cell Cycle Arrest in G1 Phase.
Authors: Tiemann Markus , Claviez Alexander , Lueders Heike , Zimmermann Martin , Schellong Guenther , Doerffel Wolfgang , Parwaresch Reza 
Published: April 2020

Abstract
This study was undertaken to determine the prognostic value of proliferation rate in Hodgkin and Reed-Sternberg (HRS) cells in pediatric and adolescent patients with Hodgkin’s disease (HD).
231 paraffin-embedded biopsies were immunostained with proliferation associated monoclonal antibodies Ki-S5 (Ki-67 antigen) and Ki-S2 (repp86 antigen), which is characterized by an expression pattern restricted to G2, S and M phases. Results were compared with clinical data from 224 patients included in multicenter GPOH HD-90 and HD-95 trials.
High Ki-67 expression was a striking feature (median: 80%, range: 20–100%) in contrast to low Ki-S2 expression (median: 20%, range: 10–80%). Apoptosis was assessed in 133 patients by TUNEL method (median: 10%, range: &lt;10–70%). Proliferation rate was independent of histological subtype, stage, presence of B symptoms and allocation to treatment group. Probability of event-free and overall survival at 5 years was 91% and 98%, respectively with no significant differences in patients with low or high proliferation rate.
The difference between Ki-67 and repp86 expression in HRS cells points to a possible cell cycle arrest in G1 phase, which may explain the obvious paradoxon of a highly proliferating but slowly growing paucicellular tumor. High proliferation rate does not seem to be an adverse prognostic factor in pediatric patients with HD treated by effective chemoradiotherapy regimens.
Greater Area under the Hemoglobin Change Curve Is Associated with Improved Outcomes in Elderly Patients Receiving Epoetin Alfa for Chemotherapy-Related Anemia.
Authors: McKenzie Scott R. , Duh Mei S. , Lefevbre Patrick , Fastenau John M. , Piech Catherine Tak 
Published: April 2020

Abstract
Background: Several measures have been used to assess the efficacy of erythropoietic agents in patients with chemotherapy-related anemia (CRA). Previous research has demonstrated the area under the 16-week hemoglobin (Hb) change curve (Hb AUC16) as a sensitive and comprehensive efficacy measure compared to traditional single time point or threshold-based measures. Higher Hb AUC16 values during epoetin alfa (EPO) therapy in patients with CRA are associated with reduced transfusion requirements, improved quality of life, increased hematologic response rates, and decreased EPO utilization. This subgroup analysis of elderly patients with CRA evaluates the clinical significance of higher Hb AUC16 values in this unique population.
Methods: Data from three, large, multicenter EPO clinical trials were evaluated. In EPO 1, patients received 10,000 Units TIW with potential escalation to 20,000 Units TIW. In EPO 2 and EPO 3 patients received 40,000 Units QW with potential escalation to 60,000 Units QW. Eligible patients for this analysis were &gt;/=65 years, had a baseline Hb &lt;/=11g/dL, had a non myeloid malignancy and received chemotherapy with or without radiotherapy (EPO 1: N=935: EPO 2: N=1,270; EPO 3: N=269). Hb AUC16 was calculated using sequential trapezoidal methodology based on the Hb change and was stratified into quartiles to assess trends in outcome measures. Trend tests were performed to determine if the following outcomes had significant linear trends across the Hb AUC16 quartiles: proportion of patients transfused, hematopoietic response (Hb rise &gt;/= 2 g/dL over baseline or Hb &gt;/= 12 g/dL during study), EPO utilization, and quality of life [assessed by the Linear Analogue Scale Assessment (LASA, all studies) and the anemia subscale of the FACT-An (EPO 1 and EPO 2)].
Results: Greater Hb AUC16 values had a strong linear association with a decreasing proportion of patients transfused (p&lt;.0001), increasing hematopoietic response rate (p&lt;.0001), decreasing average weekly EPO dose (p&lt;.0001), increasing LASA scores in all studies (p&lt;.001) and FACT-An scores in EPO 1 and EPO 2 (p&lt;.001).
Conclusions: In the elderly patient subset, greater Hb AUC16 values were associated with significant improvement in clinical outcomes including the percentage of patients transfused, hematopoietic response rates, QOL score improvements, and EPO utilization. Hb AUC16 is an objective and meaningful metric that summarizes hematologic response over the course of treatment and is associated with clinical benefits in elderly patients receiving erythropoietic therapy.
A Psychosocial Assessment of Patients before and after Autologous Stem Cell Transplantation.
Authors: Bolwell Brian J. , McLellan Linda , Foster Larry , Dabney Jane , Welsh Erin , Kuczkowski Elizabeth , Curtis Julie , Bell Kimberly , Baker Janet , Bernhard Laura , Cherni Kelly , Rybicki Lisa , Sekeres Mikkael A. 
Published: April 2020

Abstract
There are relatively few reports in the medical literature describing psychosocial assessment of bone marrow transplant patients; what data exists primarily focuses on allogeneic transplant recipients. We have begun to prospectively assess psychosocial parameters of patients undergoing autologous transplantation using the Functional Assessment of Cancer Therapy-BMT (FACT-BMT) tool. The general questions consist of four subscales developed and normed in cancer patients that measure; physical well-being; social/family well-being; emotional well-being; functional well-being; and a specific module to address BMT-specific concerns. Each subscale is positively scored, with higher scores indicating better functioning. A baseline survey is collected by the social worker pre-transplant and a follow-up survey is administered and collected approximately 6 weeks post-transplant by the Transplant Coordinator. 56 consecutive patients undergoing autologous stem cell transplant have FACT-BMT data both pre-transplant and approximately one month post-discharge. Median age was 50. 52% are male; underlying diagnoses include NHL (45%), Hodgkin’s disease (32%), myeloma (16%), AML (5%), testicular cancer (2%). 93% had chemosensitive disease at the time of transplant. All patients received peripheral blood progenitor cells (PBPCs), and all received a chemotherapy-only preparative regimen. All patients were hospitalized for approximately three weeks for the transplant. For most of the variables measured by the FACT-BMT tool, there was no significant difference in pre-transplant and post-transplant scores. The one variable that did change was emotional well-being: patients scored statistically significantly higher post-transplant as compared to the pre-transplant score (p&lt;0.001). We also have collected baseline FACT-BMT data on 42 consecutive allogeneic BMT recipients, as well as 12 recipients of non-myeloablative allogeneic BMT transplants. There is no significant difference in any pre-transplant variables measured by the FACT-BMT score between autologous recipients, ablative allogeneic recipients, and non-myeloablative allogeneic recipients. We conclude that patients undergoing an autologous stem cell transplant have a higher sense of emotional well-being after engraftment and hospital discharge. Presumably this reflects positive feelings about accomplishing this intensive treatment for their underlying malignancy, and suggests that emotional and physical recovery after auto-BMT is reasonably rapid. A larger dataset will hopefully allow a more detailed comparison of allo and auto BMT recipients.
A Randomized Trial of Short-Course Preemptive Ganciclovir Compared with Conventional Ganciclovir Therapy To Prevent Cytomegalovirus Infection after Allogeneic Stem Cell Transplantation.
Authors: Park Keun W. , Lee Jeeyun , Park Jinny , Ho Young Kim , Lee Mark H. , Lee Se-Hoon , Kang Jung H. , Kim Kihyun , Jung Chul W. , Kim Won S. , Park Joon O. , Im Young H. , Park Young S. , Kang Won K. , Park Keunchil 
Published: April 2020

Abstract
We studied the efficacy and safety of a short course of ganciclovir to prevent cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. In general, preemptive ganciclovir is administered twice daily for 1–2 weeks (induction phase) and then once daily until 6 days after cessation of viremia and antigenemia (maintenance phase). We randomly assigned allogeneic HSCT recipients who had positive shell vial culture for CMV or CMV antigenemia to receive preemptive ganciclovir therapy with or without induction phase (5 mg/kg body weight, twice a day for one week). 32 and 34 patients were randomized to the standard treatment arm and the short course arm, respectively. There were no statistically significant differences in patient characteristics such as age, sex, type of disease, type of transplantation, seropositivity of CMV antibody in donor, seropositivity of CMV antibody in recipient, type of conditioning regimen or GVHD prophylaxis regimen between two groups. The median time to clearance of CMV viremia and antigenemia was 7 d and 9 day, respectively (P = 0.333). Seven patients in the short course arm failed for viral clearance after preemptive therapy and were cross-overed to the standard preemptive therapy, which resulted in clearance of antigenemia and viremia in all patients. The toxicity profile was higher in the standard treatment arm with 5 neutropenia and 1 drug-induced hepatitis whereas there was only 1 neutropenia in the short-course arm. Of 5 patients who experienced neutropenia, 2 died of sepsis. This study shows that the preemptive ganciclovir therapy with maintenance phase alone may be equally effective to the standard treatment arm with less toxicity profile in prevention of CMV disease in allogeneic HSCT recipients. The omission of induction phase in CMV preemptive therapy may allow patients to avoid unnecessary hospital admissions.
Tinzaparin in Problem Pregnancy (TIPP): Retrospective Analysis of Therapeutic Outcomes in High-Risk Pregnant Patients Treated with Tinzaparin.
Authors: Andersen Judith C. ,   TIPP Participants MD
Published: April 2020

Abstract
BACKGROUND: Pregnancy represents a “physiologic” maternal thrombophilic state, with presumed evolutionary goals of ensuring secure fetal implantation, placental stability, and control of peripartum maternal bleeding. Specific pregnancy-induced maternal changes include increased activated Protein C resistance; decreased active Protein S; increased levels of vitamin K-dependent procoagulants, factor VIII, von Willebrand factor, and fibrinogen; and increased levels of plasminogen activator inhibitor (PAI-1). Superposition of pregnancy upon inherited or acquired thrombophilias may have untoward consequences for both mother and fetus. Venous thromboembolism (the leading cause of maternal morbidity and mortality in pregnancy) is five times more likely to occur in pregnant women than in nonpregnant women of similar age. Placental insufficiency and recurrent fetal loss are strongly associated with inherited and acquired thrombophilia, and antithrombotic interventions with aspirin, unfractionated heparin and low molecular weight heparins (LMWHs) have decreased maternal morbidity and improved fetal outcome. LMWHs offer decreased incidence of bleeding, heparin-induced thrombocytopenia with thrombosis (HITT), and osteoporosis, as well as predictable dosing efficacy. An industry sponsored series of roundtable discussions with US hematology and high-risk obstetrics practitioners revealed that a collective deterrent to use of tinzaparin (the most recently introduced LMWH with favorable pharmacokinetics and once-daily dosing) was the limited amount of published safety and efficacy data in this patient population.
STUDY DESIGN: Fifty pregnancies in women treated with tinzaparin between January 2003, and June 2004, in American maternal/fetal medicine programs for high risk from prior pregnancy-associated VTE, presence of high risk pre-existing thrombophilias, or recurrent fetal loss are undergoing retrospective analysis for maternal and fetal outcomes; safety; and compliance with therapy. A specific identifier-blind data collection tool will capture historical and examination data and diagnostic studies that establish and follow risk as well as tabulate antithrombotic and adjunctive medication/supplement regimens. “Live birth” and “fetal loss” questionnaires will capture maternal and fetal course, complications, anesthesia and delivery decisions, and tissue pathology, as appropriate.
RESULTS: Data analysis will be complete by late November 2004. In the absence of large randomized trials of efficacy and safety, such a study may provide guidelines for safe and effective use of tinzaparin in American high-risk pregnancy.
Outcome of Adults with Precursor B-Cell and Mature B-Cell (Burkitt-Cell) ALL/Lymphoma in a Large Inner City Hospital.
Authors: Mims Martha P. , Edwards Maria , Udden Mark M. 
Published: April 2020

Abstract
Acute lymphoblastic leukemia is the most common acute leukemia in children, but accounts for only about 20% of adult acute leukemias. In children overall survival at 5 years is about 70% as a result of intensive treatment regimens. Application of such treatment regimens to adults has improved the 5 year survival to about 30–35% in large studies. We report here a retrospective analysis of all 18 cases which presented to our hospital during the last 2 1/2 years. All patients were treated with intensive chemotherapy regimens (primarily Hyper CVAD alternating with MTX/AraC) including maintenance therapy for patients with precursor B-cell ALL. The mean age of all patients was 39.6 ± 15.2 years., 11 patients were male and 7 female. Thirteen patients presented with precursor B-cell ALL (8 male/5 female); the mean age of these patients was 36.3 ± 16.1 years. Five patients presented with Burkitt-cell leukemia (3 male/2 female), the mean age of these patients was 48 ± 8.9 years; 4 patients were HIV positive. Overall, 7 of 18 patients are alive, 5 are in remission, 1 did not achieve remission and is being evaluated for stem cell transplant, and 1 is completing the first cycle of chemotherapy. The 7 surviving patients include 5 with precursor B-cell ALL (4 male/1 female) and 2 Burkitt-cell patients (both female, both HIV+, both with CD4 count &gt; 400). An analysis of high risk features in pre B-cell ALL patients showed only one patient older than 60, 1 with adverse cytogenetics (9:22 translocation), one with WBC count &gt;50,000/ml at presentation, and 2 who required more than 1 course to achieve CR. Positivity for CD20 has been reported by some to be an adverse prognostic factor in pre B ALL. In our study 8 of 13 pre B ALL patients were CD20 positive, 3 of these patients survive as compared to 2 of 5 CD20 negative patients. Women with pre B ALL had significantly poorer outcomes than men with only 1 of 5 surviving; all women with CD20 positive disease succumbed. Among the Burkitt-cell patients, the 2 survivors were HIV positive women with the highest CD4 counts. Three of 18 patients (16.6%) died during induction; 1 presented to our hospital in first relapse 3 years after first CR, 1 developed overwhelming fungal infection, and 1 suffered probable anaphylactic reaction. More than 75% of patients with pre B ALL were Hispanic, and while 3 are still living, only one has completed induction and consolidation and is still in remission. The reasons behind the poor survival of the Hispanic subgroup are not clear, however, it should be noted that all patients who were CD20 positive in this group have either died or failed to achieve remission. In this series 27% of patients had mature B-cell disease, which is much higher than the 5% estimated incidence in adults overall. Despite the preponderance of HIV positive patients, the survival of these patients compares favorably with that reported in the literature.
Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia: A Comparative Study of Flow Cytometry and Quantitative Real-Time Polymerase Chain Reaction (RQ-PCR).
Authors: Misra Ashish K. , Sartor Mary , Sutton Rosemary , Venn Nicola C. , Cross Shamira , Bradstock Ken , Norris Murray , Dalla-Pozza Luciano 
Published: April 2020

Abstract
Approximately 25% of children with acute lymphoblastic leukemia (ALL) relapse after frontline therapy. Current stratification methods using clinical/biological criteria fail to identify a significant proportion of these children. Numerically more patients classified as standard/medium risk relapse than those with high-risk ALL. Early identification of this group with intensification of therapy may prevent this.
We compare two techniques, multi-parameter flow cytometry (FCM) and real-time polymerase chain reaction (RQ-PCR) to monitor minimal residual disease (MRD) in bone marrow after initial therapy in newly diagnosed patients. We report our initial experience in patients with B-lineage ALL from a single institution (CHW) treated on the ANZ Haematology-Oncology Group Study VIII protocol for ALL.
Multiparameter FCM was performed using two different four colour combinations of antibodies:
CD19APC/CD45PerCP/CD10FITC/CD20PE and CD19APC/CD45PerCP/CD34FITC/CD9PE. A series of dual parameter displays were generated to define normal B cell differentiation pathways and this allowed the discrimination of malignant precursor B cells. RQ-PCR used clone specific primers and Taqman probes selected after sequencing the immunoglobulin heavy chain and/or T cell receptor gene rearrangements detected in the diagnosis DNA. The RQ-PCR assays had greater sensitivity and were highly reproducible. The timepoints used for analysis were Day 33 (D33) and D79, following induction and consolidation respectively. Of 45 patients, 44 (98%) had informative RQ-PCR markers: 12 (27%) with high MRD levels at D33 (&gt;10−3) while 3 (6.7%) had high levels at D79. In contrast by FCM 5 (11.1%) had positive MRD (&gt;0.1%) on D33 compared with 7 (15.6%) on D79. The 3 with high MRD on RQ-PCR at D79 were also identified by FCM. 2 of these 3 patients had been classified as standard/medium risk by conventional criteria. These two techniques may be complementary in identifying patients with significant MRD. Only a proportion of patients were identified by both methods. Long term follow up and ongoing recruitment will help delineate the optimal surveillance/stratification strategy by correlating these findings with outcome.
Daunorubicin, Cytarabine and Fludarabine (DAF) for the Treatment of Relapsed/Refractory Acute Myeloid Leukemia. Phase II Study by the Polish Adult Leukemia Group (PALG).
Authors: Holowiecki Jerzy , Grosicki Sebastian , Krzemien Slawomira , Skotnicki Aleksander , Warzecha Krzysztof , Zdziarska Barbara , Stella-Holowiecka Beata , Krawczyk-Kulis Malgorzata , Kopera Malgorzata , Wojciechowska Maria 
Published: April 2020

Abstract
In 1992–93 a synergistic interaction of ribonucleotide reductase inhibitors (fludarabine, cladribine) and cytarabine (AraC) resulting in increase of Ara-CTP concentration in myeloblasts was proved. In the previous study by the Polish Adult Leukemia Group (PALG 1999 Study) we demonstrated that addition of cladribine to standard daunorubicin + cytarabine induction potentiates antileukemic activity of the regimen in acute myeloid leukemia (AML).
The goal of the current study was to assess the safety, tolerance and antileukemic activity of a new DAF regimen consisting of daunorubicin 60 mg/m2/d iv 1–3, AraC 200 mg/m2 ci 1–7, and fludarabine 25 mg/m2/d 1–5.
Twenty-five AML patients aged 40 (range 19–62) years with primary refractoriness 60% (n=15) or in relapse 40% (n=10) were included in the study between 2003–2004. DAF was administered as a second (n=24) or as a third line of induction treatment (n=1).
Twelve patients (48%) achieved complete remission (CR), 1 (4%) had partial remission (PR), and 10 (40%) did not respond (NR, leukemia regrowth). Two patients died in aplasia from infectious complications (8%).
All patients developed severe thrombocytopenia and granulocytopenia (WHO grade III or IV). Median time to neutrophil &gt;0.5 G/L recovery and platelet &gt;50 G/L recovery equaled 21 d. (11–30) and 20 d. (11–27), respectively.
Eleven (44%) patients exerienced severe (WHO grade III or IV) neutropenic infections (bacterial n=9, fungal n=2). Other serious adverse events were infrequent: vomiting 24% (n=6), mucositis 24% (n=6). Severe hepatotoxicity, nephrotoxicity and cardiotoxicity was not observed.
Median hospital stay lasted 28 (11–41) days. Patients required 5.5 (0–13) PRBC transfusions and 5.5 (1–14) platelet transfusions. Hematopoietic growth factors were not administered.
Results of this phase II study indicate that DAF is a relatively well-tolerated and safe regimen with high anti-leukemic potency in relapsed/refractory AML. Based on these findings a randomized, multicenter study comparing DAF to the standard DA induction has been designed for newly diagnosed AML patients.