bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum Ferritin Is an Independent Predictive Marker for Stem Cell Mobilization Efficacy in Patients with Hematologic Malignancy.
Authors: Kim Soo-Jeong , Lee Hye Won , Yoon Sul Hee , Park In-Hae , Kim Yuri , Kim Jin Seok , Cheong June-Won , Min Yoo-Hong 
Published: October 2019

Abstract
Autologous stem cell transplantation has been performed to support high-dose chemotherapy in hematologic malignancy. A good mobilization is mainly achieved with several mobilization chemotherapies followed by granulocyte colony stimulating factor (G-CSF). Although the complex mechanism of mobilization of hematopoietic stem cell (HSC) is not fully understood, it may be the results of interactions between hematopoietic stem cell and microenvironment of bone marrow. So, severe accumulation of iron in bone marrow due to frequent transfusions may have some negative effect on not only HSC engraftment but also HSC mobilization. We evaluated 30 patients, 6 (20%) with multiple myeloma, 16 (53%) with malignant lymphoma and 8 (27%) with acute leukemia in order to assess the impact of serum ferritin and CD34+ HSC mobilization. All patients treated with high dose chemotherapy and G-SCF (5-10ug/kg) before HSC collecting procedure. Serum ferritin, iron, C-reactive protein levels were measured at the first peripheral blood HSC collection. By evaluating the efficacy of CD34+ HSC harvest, 20/30 patients (66%) were considered good mobilizer patients, defined as patients with a CD34+ cells collection of >1*106 CD34+cells/kg/day, and a subset (5/30, 16.7%) as very poor mobilizer (<0.5*106 CD34+cells/kg/day), 5 patients between 0.5 and 1*106 CD34+cells/kg/day as poor mobilizer. There was no significant difference between 3 groups in age, diagnosis, disease status and previous treatment but notable statistical difference was found in serum ferritin level (median 1322 ng/mL in very poor group, 1068 ng/mL in poor group, 625 ng/mL in good group, P=0.027). The number of CD34+ cells/uL in the peripheral blood on the first day of apheresis was a surrogate marker of the efficacy of stem cell harvest (P<0.005) and it showed a strong correlation with serum ferritin (P=0.003). Especially serum ferritin over 1,000 ng/mL was significant correlated with poor mobilization efficacy (P=0.004). Age, diagnosis, disease status and previous chemotherapy had no correlation with mobilization efficacy in our study. In conclusion, severe accumulation of iron, measured by serum ferritin after repeated transfusion was adverse effect on HSC mobilization and serum ferritin might be independent predictive marker for mobilization efficacy.
Targeted Gene Delivery in CD30+ Hodgkin Lymphoma Cells Using Lentiviral Vectors.
Authors: Luong Quang T. , Morizono Kouki , Chen Irvin S.Y. , de Vos Sven 
Published: October 2019

Abstract
Despite the success of combination chemotherapy for the treatment of Hodgkin lymphoma (HL), chemotherapy-resistant disease still remains an unresolved problem with most patients eventually dying due to progression. HL is an ideal disease for targeted therapy. CD30 is a 120-kDa transmembrane glycoprotein belonging to the tumor necrosis factor (TNF)-receptor superfamily and strongly expressed in HL Reed-Sternberg cells. We hypothesize that specific, antibody-mediated, CD30-directed delivery of lentiviral vector constructs, encoding for a lethal cellular toxin, will be an effective anti-lymphoma strategy. However, gene delivery based therapy is limited by the transduction of non-target cells. The technology developed by Morizono et al. [Cell Cycle2005: 4: p854; Nature Medicine2005: 11: p346] demonstrates that lentiviruses can be specifically and effectively directed to target cells by conjugation of an antibody to a modified ZZ SINDBIS viral envelope (m168). In this study, we have used HL cell lines (CD30+: L591, L428, Hs445, RPMI6666) and Burkitt lymphoma (BL) cell lines (CD20+/CD30−: Raji, Ramos). We show that conjugation of an anti-CD30 antibody to m168 (m168anti-CD30), permits specific targeting and transduction of CD30+ Hodgkin lymphoma cells while avoiding CD30− Raji and Ramos cells [range 11–83% for HL cells versus 1–4% for BL cells]. Similarly, targeting of CD20+ cells can be achieved. Several of our HL cell lines (L591, Hs445 and RPMI6666) are CD30+/CD20+ [range 11–25% by flow cytometry] and we show that we can equally transduce these cells with an anti-CD20 antibody conjugated to our lentivirus [range 11–30% for CD20+ HL cells; 3% for L428 cells; 40–47% for BL cells]. In addition, we show in L591 cells, that the re-targeted viruses can transduce a greater percentage of target cells than an unmodified virus [83% for m168anti-CD30 versus 43% for VSVG]. These results demonstrate that the efficacy and specificity of targeted therapy can be greatly enhanced and lay the foundation for the development of more stable anti-CD30 directed lentiviral constructs expressing cellular toxins.
FDG-PET in Peripheral T-Cell Lymphoma.
Authors: Quigley Joanna M. , Bishu Shrinivas , Hankins Jordan H. , Armitage James O. 
Published: October 2019

Abstract
The sensitivity and specificity of fluorine-18 fluoro-deoxy-glucose positron emission tomography (PET) in the evaluation of peripheral T cell lymphomas (PTCL) is not well established. In this abstract, we describe our experience utilizing PET in the diagnostic evaluation of PTCL.
A retrospective review of 2768 PET examinations conducted at our institutionbetween the years 1999–2006 produced twenty-six examinations among twenty-two patients with a biopsy proven diagnosis of PTCL. All patients underwent staging of their disease using both conventional diagnostic methods and PET. Their therapeutic status was also taken into consideration when interpreting PET examinations. PTCL were classified by World Health Organization (WHO) criteria and included: PTCL-unclassified (PTCL-U), anaplastic lymphoma kinase positive (+) and negative (−) anaplastic large cell lymphoma, gioimmunoblastic (AITL n=1), and natural killer T-cell nasal type (NK/T n=1). PET results for each patient were compared against a standard of reference, and the sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PET) of PET were calculated.
PET had an overall sensitivity of 55% and specificity of 100% in PTCL-U. PET had an overall sensitivity of 83% and specificity of 100% in ALCL. PET had an overall sensitivity of 13% and specificity of 0% in cutaneous PTCL. Among patients with non-cutaneous PTCL-U, the sensitivity and specificity were 83% and 100% respectively. Among patients with non-cutaneous ALCL, the sensitivity and specificity were 100% respectively. Excluding those patients with cutaneous PTCL, PET correlated with clinical outcome in 87% of PTCL-U 100% of ALCL patients. The average maximum standard uptake value (g/mL) of abnormal foci demonstrated greater intensity in patients with ALCL (13.1) than those with PTCL-U (8.87) (Figure 1). PET had excellent correlation with CT, physical examination and clinical follow-up at both nodal and extra-nodal sites, but poor correlation at cutaneous sites (Figure 2).
The PPV and NPV of restaging PET in PTCL-U were 75% and 100% respectively. In ALCL, the PPV and NPV of restaging PET were 66% and 100% respectively.
PET is useful for staging and restaging patients with nodal and non-cutaneous extra-nodal involvement in PTCL-U and ALCL. It demonstrates a comparatively low sensitivity in cutaneous PTCL.
Average Maximum SUV (gm/ml) of Abnormal Foci in PTCL-U and ALCL Average Maximum SUV (gm/ml) of Abnormal Foci in PTCL-U and ALCL Positivity (%) of PET vs. Site of Disease by CT, Physical Exam and/or Clinical Follow Up Positivity (%) of PET vs. Site of Disease by CT, Physical Exam and/or Clinical Follow Up
Health-Related Quality of Life of Patients Diagnosed with Indolent Lymphoma.
Authors: Mathias Susan D. , Cimms Tricia A. , Colwell Hilary H. , Reyes Carolina M. , Lubeck Deborah P. 
Published: October 2019

Abstract
Background Numerous treatment options are available for patients with indolent lymphoma (IL), including active treatment and active observation without initiation of therapy, watchful waiting; each is associated with unique, longer term therapeutic and health-related quality of life (HRQL) consequences. We sought to identify key HRQL domains of importance to patients with indolent lymphoma and whether HRQL varies by treatment.
Methods Five focus groups (n=33), supplemented by in-depth one-on-one telephone interviews (n=19) were conducted with IL patients across the US. Patients completed a questionnaire composed of five standard validated instruments related to physical well-being, social/family well-being, emotional well-being, functional well-being (FACT-G), additional concerns (FACT-Lym), physical appearance, psychosocial adaptation to illness (PAIS), and mental health (MHI-5). Questionnaire domains were scored on a 0–100 scale where higher scores indicate better functioning.
Results A total of 52 IL patients (65% female; mean age 53 years) completed the questionnaire. Participants belonged to one of the following treatment categories: Active Treatment (n=18), Previous Treatment (n=25) and Watchful Waiting (n=9). Similarities in FACT scores were found between the Previous Treatment and Watchful Waiting groups. The Watchful Waiting group scored the lowest on both the MHI-5 and the PAIS. Differences were found in Physical Well-Being between the Active Treatment and Previous Treatment groups (67.06 vs. 81.10, respectively, p=0.029). Differences were observed for the PAIS between the Active Treatment and Watchful Waiting groups (83.82 vs. 65.63, respectively, p=0.021) and between the Previous Treatment and Watchful Waiting groups (85.00 vs. 65.63, respectively, p=0.010).
Conclusions Preliminary findings suggest that differences were observed between patients on active treatment, those who have previously been treated and patients who have never been treated, watchful waiting. Further elucidation of these issues is needed to facilitate HRQL evaluation in future studies and more importantly better inform patients and providers of treatment decisions.
Table 1. Mean (Standard Deviation) HRQL Scores of all Patients and by Treatment Categories Domains All Patients (N=52) Active Treatment (N=18) Previous Treatment (N=25) Watchful Waiting (N=9) FACT-G 73.01 (15.56) 67.41 (15.82) 76.21 (14.12) 75.67 (17.30) FACT-Lym 71.35 (15.25) 67.63 (16.09) 73.11 (12.39) 75.02 (18.58) Physical Appearance 76.85 (29.36) 65.00 (31.62) 82.69 (27.74) 87.50 (25.00) PAIS 81.50 (18.77) 83.82 (16.40) 85.00 (18.40) 65.63 (18.60) MHI-5 69.08 (18.00) 69.33 (15.22) 71.36 (18.46) 62.22 (21.92)
Concomitant Intrathecal Liposomal Cytarabine and Prednisolone Is a Safe and Well Tolerated Treatment Option in Pediatric Leukemia and Neuroblastoma Patients.
Authors: Björgvinsdóttir Helga , Bekassy Albert N. , Toporski Jacek , Heldrup Jesper 
Published: October 2019

Abstract
Malignant leptomeningeal dissemination poses significant treatment challenges and is difficult to eradicate. The disadvantages of conventional chemotherapy and intrathecal anticancer agents are due to limited drug penetration through the blood-brain barrier, low cytotoxic concentrations in the cerebrospinal fluid (CSF), and rapid metabolism. DepoCyte is a new liposomal, slow-release preparation of cytarabine for intrathecal use that maintains cytotoxic concentrations for as long as 14 days or more and improves the distribution of free cytarabine in the CSF.
Here, we report our experience concerning thirteen pediatric patients age 1–13 years who received more than 40 treatment doses with liposomal cytarabine either as a therapeutic or prophylactic agent in doses of either 35 mg or 50 mg (children 11 years and younger or 12 years and older, respectively). There were four patients with refractory/relapsing neuroblastoma stage IV, two of whom had confirmed central nervous system (CNS) involvement; and nine patients with CNS- and/or refractory/recurrent leukemia, including ALL, AML and infant ALL. Todate, individual patients have been treated with one to ten liposomal cytarabine doses each (medium 3,1), and one patient has received therapy over a period of one year (ten doses).
Patients were given arachnoiditis prophylaxis with either oral dexamethasone 0,15 mg/kg × 2 daily (max 4 mg per dose) for 5 days or intrathecal prednisolone in age-dependent doses (Precortalon Aquosum; 8 mg, 12,5 mg, and 15 mg for patients 1–2 years, 3–11 years, and 12 years and older, respectively). The intrathecal prednisolone that was given concomitantly with liposomal cytarabine in approximately half of the treatment doses. Was convenient and caused less side-effects than oral dexamethasone.
DepoCyte was well tolerated in most patients, but side-effects such as headache, nausea and vomiting occurred on four occasions. One patient had seizures in connection with high-dose intravenous cytarabine therapy.
We conclude, that intrathecal DepoCyte therapy in doses of 35 to 50 mg with concomitant oral or intrathecal steroids is a practical, safe, and well tolerated treatment for leptomeningeal malignant disease. Further research is needed to determine the long-term effects and side-effects.
Differences in Fetal Hemoglobin Induction in Sickle Cell Disease and beta-Thalassemia.
Authors: Fathallah Hassana , Taher Ali , Bazarbachi Ali , Atweh George F. 
Published: October 2019

Abstract
A number of therapeutic agents including hydroxyurea, butyrate and decitabine have shown considerable promise in the treatment of sickle cell disease (SCD). However, the same agents have shown less clinical activity in β-thalassemia. As a first step towards understanding the molecular basis of the different clinical responses to these agents, we have studied the mechanisms of induction of fetal hemoglobin (HbF) by butyrate in BFU-E derived cells from 5 patients with SCD and 9 patients with β-thalassemia intermedia. Exposure to butyrate resulted in a dose-dependent augmentation of γ-globin mRNA levels in erythroid cells from patients with SCD. In contrast, induction of γ-globin expression in erythroid cells from patients with β-thalassemia intermedia was only seen at a high concentration of butyrate. The increase in γ-globin mRNA levels in patients with SCD and β-thalassemia intermedia was associated with opening of the DNA structure as manifested by decreased DNA methylation at the γ-globin promoters. Interestingly, butyrate exposure had markedly different effects on the expression of the β- and α-globin genes in the two categories of patients. Butyrate decreased the level of β-globin mRNA in 4 out of 5 patients with SCD (P = 0.04), while in β-thalassemia the levels of β-globin mRNA did not change in 7 patients and decreased in 2 patients after butyrate exposure (P = 0.12). Thus in patients with SCD, the effects of the induction of the γ-globin gene on the γ/(β+γ) mRNA ratios were further enhanced by the butyrate-mediated decreased expression of the β-globin gene. As a result, γ/(β+γ) mRNA ratios increased in all patients with SCD, with a mean increase of 31% (P = 0.002). In contrast, butyrate increased γ/(β+γ) mRNA ratios only in 4 out of 9 patients with β-thalassemia, with a more modest mean increase of 12% (P = 0.004). Interestingly, the decreased β-globin expression in patients with SCD was associated with closing of the DNA configuration as manifested by hypermethylation of DNA at the promoter of the β-globin gene while methylation of the same promoter did not change following butyrate exposure in patients with β-thalassemia intermedia. More surprisingly, the expression of the α-globin genes increased following butyrate exposure in 4 out of 9 patients with β-thalassemia, while the levels of α-globin mRNA decreased in 4 out of 5 patients with SCD. As a result, the favorable effects of the butyrate-induced increase in γ-globin gene expression on the α: non-α mRNA imbalance in patients with β-thalassemia intermedia were partly neutralized by the corresponding increase in α-globin gene expression. These differences may explain, at least in part, the more favorable effects of inducers of HbF in SCD than in β-thalassemia. Further studies are necessary to fully understand the molecular bases of the different responses to agents that induce HbF in patients with these disorders.
Quantitative Assessment of Minimal Residual Disease Predicts Outcome of Patients of Acute Myeloid Leukemia with Nucleophosmin (NPM) Mutation.
Authors: Chou Wen-Chien , Tang Jih-luh , Wu Shang-Ju , Yao Ming , Tien Hwei-Fang 
Published: October 2019

Abstract
Purpose: In patients of acute myeloid leukemia (AML) with mutations in Nucleophosmin (NPM), minimal residual disease (MRD) can be quantified by real-time polymerase chain reaction (qPCR). However, the validity of MRD detection by qPCR on a long-term basis and its prognostic significance remain undetermined.
Patients and Methods: We quantified NPM mutants by qPCR in genomic DNA of 202 bone marrow samples serially collected during a median follow-up of 21.9 months (range 2.5 to 204) from 40 AML patients bearing this mutation.
Results: With a relatively homogeneous number of mutants at diagnosis, induction chemotherapy resulted in a median of 2.78 logs of reduction (p<0.001). The mutant numbers determined by qPCR matched well with clinical courses: clinical relapse was accompanied by rise of mutants (p<0.001) and mutant numbers at morphological complete remission from patients without any subsequent relapse were significantly lower than others (p<0.001). Detection of mutant signals predicted relapse if no further chemotherapy was administered. Failure to achieve at least 2 logs of mutant reduction after consolidation led to shorter overall survival (OS) (11.3 months vs. not reached, p=0.01) and relapse-free survival (RFS) (3.8 months vs. 21.2 months, p=0.001). Patients with any rise of mutants during serial follow-up relapsed more frequently than those with persistently low or undetectable signals (p<0.001). Along serial follow-up, patients obtaining any mutant reduction to < 0.1% of internal control (INC) after treatment had longer OS (a median of 57.9 months vs. 20.2 months, p=0.002) and RFS (11.3 months vs. 4.0 months, p<0.001). On the other hand, detection of mutants above 1.5% of INC in any post-induction sample predicted a poorer outcome (a median of 22.1 months vs. not reached, p=0.002 for OS and 9.7 months vs. not reached, p<0.001 for RFS).
Conclusion: Quantification of MRD by qPCR on genomic DNA in AML bearing NPM mutation predicts outcomes of this group of patients.
A New Oral Aniticoagulant, Dabigatran Etexilate, Is Effective and Safe in Preventing Venous Thromboembolism after Total Knee Replacement Surgery (The RE-MODEL Trial).
Authors: Eriksson Bengt I. , Dahl Ola E. , van Dijk Cornelis N. , Frostick Simon P. , Kurth Andreas A. , Rosencher Nadia , Schnee Janet , Hettiarachchi Rohan , Christiansen Anita V. , Hantel Stefan , Büller Harry R. 
Published: October 2019

Abstract
BACKGROUND: Oral DVT prophylaxis not requiring monitoring is an advantage in orthopaedic patients. Dabigatran etexilate is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolic events (VTE) following orthopaedic surgery.
METHODS: In a phase III, multicenter, non-inferiority, double-blind study, patients undergoing total knee replacement were randomized to 3 treatments. The patients received 8±2 days of oral dabigatran etexilate, 150 or 220 mg once daily starting with a half dose (i.e.75 or 110 mg) 1–4 hours after surgery, or subcutaneous enoxaparin 40 mg once daily starting 12 hours prior to surgery. The primary efficacy outcome was the composite of total VTE and all causes of mortality during the treatment period. All efficacy and safety outcome events were adjudicated by blinded independent committees.
RESULTS: Efficacy could be evaluated for 1541 (75%) treated and operated patients. Total VTE and death occurred in 40.5%, 36.4% and 37.7% of patients assigned to dabigatran etexilate 150 or 220mg once daily or enoxaparin, respectively. Proximal DVT and/or PE occurred in 3.8%, 2.6% and 3.5% of patients receiving dabigatran 150 or 220mg or enoxaparin, respectively. Three deaths occurred during the treatment period, one in each of the treatment groups. Safety was evaluated for all 2076 patients receiving study treatment. The rate of major bleeding was 1.3%, 1.5% and 1.3% of patients receiving dabigatran 150 or 220mg or enoxaparin. Elevated LFTs (ALT >3xULN) occurred in 3.7%, 2.8% and 4.0% of the patients treated with 150 and 220 mg dabigatran or enoxaparin during the study. A late temporary rise in LFTs was observed in 6 patients (0.5%) who had received dabigatran.
CONCLUSIONS: Non-inferiority for the primary efficacy endpoint was met for both doses of dabigatran etexilate compared to enoxaparin. There was no difference in bleeding rates between the treatment groups. Oral administration of dabigatran etexilate once daily, given early in the postoperative period, was effective and safe for the prevention of total VTE in patients undergoing total knee replacement surgery.
ZAP-70 Enhances IgM Signaling in Chronic Lymphocytic Leukemia Cells Independent of Its Tyrosine Kinase Activity.
Authors: Chen Liguang , Huynh Lang , Weiss Arthur , Kipps Thomas J. 
Published: October 2019

Abstract
We found that expression of the zeta-associated protein of 70 kD (ZAP-70) by chronic lymphocytic leukemia (CLL) B cells enhanced IgM-receptor signaling, even though such CLL cells also expressed a highly-related and more active tyrosine kinase, p72Syk. To investigate whether the kinase activity of ZAP-70 is necessary for this effect, we transfected ZAP-70-negative primary leukemia cells with expression vectors encoding either wild-type ZAP-70 or ZAP-70-KI, a mutant ZAP-70 that has an inactivating point mutation in the ATP-binding site (Lys369-Ala) and that lacks tyrosine kinase activity. We achieved high-level expression of ZAP-70 or ZAP-70-KI in transfected CLL cell samples and compared these cells with each other and with the same CLL cell samples that had been mock transfected with a control vector and that remained negative for expression of ZAP-70 (n = 7). To examine the B-cell-receptor (BCR) signaling potential of these cells we assessed the extent of tyrosine phosphorylation of p72Syk, B-cell linker protein (BLNK), and phospholipase C gamma (PLC-γ), and measured intracellular calcium flux ([Ca2+]I) before and 5–10 minutes after surface IgM ligation with F(ab)2 anti- μantibody. Treatment of control mock-transfected ZAP-70-negative CLL cells with anti-μ resulted in negligible-to-minimal increases in phosphorylation of these cytosolic proteins, with mean increases in phosphorylation of p72Syk, BLNK, and PLC-γ of only 46% ± 47% (S.D), 173% ± 112%, and 73% ± 76%, respectively. CLL cells engineered to express non-mutated ZAP-70 experienced significantly higher levels of protein tyrosine phosphorylation following treatment with anti-μ, with mean increases in phosphorylation of p72Syk, BLNK, and PLC-γ of 186% ± 102%, 490% ± 323%, and 722% ± 836%, respectively, as had been noted in earlier studies. Surprisingly, CLL cells made to express the tyrosine-kinase-defective mutant ZAP-70KI also experienced significantly higher levels of protein tyrosine phosphorylation following treatment with anti-μ than did the mock-transfected CLL cells, with mean increases in phosphorylation of p72Syk, BLNK, and PLC-γ of 172% ± 94%, 431% ± 261%, and 759% ± 637%, respectively. These values were similar to those noted for anti-μ treated CLL cells that expressed the wild-type ZAP-70 protein. These results were reflected also in the ([Ca2+]I) induced by anti-μ in each of the three groups of CLL cells. Whereas anti-μ treatment of mock-transfected CLL cells resulted in negligible-to-minimal increases in ([Ca2+]I) of 0.25 units ± 0.19, anti-μ treatment of ZAP-70-transfected or ZAP-70KI-transfected CLL cells resulted in increases in ([Ca2+]I) of 1.05 units ± 0.53 and 0.95 units ± 0.46, respectively. These values each were significantly higher than that noted for mock-transfected CLL cells. We conclude that the tyrosine-kinase activity of ZAP-70 is not required for ZAP-70 to enhance BCR signaling in CLL cells.