bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unrelated Donor Marrow Transplantation for Acute Lymphoblastic Leukemia in Japan. A Japan Marrow Donor Program Experience between 1993 and 2003.
Authors: Tsuchida Masahiro , Sao Hiroshi , Sakamaki Hisashi , Kawa Keisei , Kanda Yoshinobu , Kato Koji , Hara Masamichi , Ishii Mutsuo , Kikuchi Akira , Okamura Jun , Maruta Atsuo , Takaue Yoichi , Kasai Masaharu , Yabe Hiromasa , Morishima Yasuo , Kato Shunichi , Kodera Yoshihisa 
Published: October 2019

Abstract
From 1993 to 2003, 1223 patients, 0 to 61 year old, with high risk acute lymphoblastic leukemia underwent their first bone marrow transplantation through Japan Marrow Donor Program. Most transplants were performed between HLA serologically matched Japanese pairs with a few exceptions.
Of all, 520 patients underwent transplantation in the first complete remission (1CR: median follow up 488 days), and their probability of 5 year overall survival (OS) by Kaplan Meier analysis was 58.4(standard error; SE 2.8) %. The 281 patients in the 2CR (452 days) showed OS 49.4(3.7) %, 75 at the third or further CR (249 days), OS 29.5(5.9) %, and 333 at relapse or non CR(162 days), OS 16.4(2.6) %. The outcome of the younger tended to be the better except that the oldest group 51–61 year of age did fair. The GVHD prophylaxes were cyclosporine and short term methotrexate (sMTX) in 681 patients, and tacrolimus plus sMTX in 461. Among the 1CR patients, the 5 year OS of 276 patients in cyclosporine group was 52.0% (SE.3.7%) and 217 tacrolimus group showed significantly better OS, 66.5% (SE 5.7%, P=0.03). The grade II to IV, or III to IV acute GVHD developed in 47.3% or 19.1% respectively without any age difference. Acute GVHD grade I might solely favor the patients in 1CR at 5 years or earlier post-transplant, and the survival of those in 2CR was minimally affected by grade 0 to III acute GVHD. On the other hand, the presence of chronic GVHD did not improve the survival rate of the patients in 1CR, whereas the patients in 2CR achieved better survival if they had limited or extensive chronic GVHD. The importance of HLA class I DNA type matching in Japanese population has been published (N Engl J Med. 1998 Oct 22). Patients with ALL did poorly between the pairs with DNA A-locus mismatch in 1CR and 2CR, B-locus mismatch in 2CR, DRB1-locus mismatch in 2CR.
We concluded that, the unrelated donor marrow transplantation in Japan provided as good chance of survival for the patients with ALL as related donors did, despite poorer risk group they belong to. GVHD prophylaxis with tacrolimus might attain better outcome in 1CR patients, and chronic GVHD seemed to improve the OS for the patients in 2CR, but not for 1CR patients.
Expression and Modulation of Carbohydrate-Binding Protein Galectin-3 in Multiple Myeloma Cells by Combined Treatment with GCS-100 and Dexamethasone.
Authors: Chauhan Dharminder , Chang Yan , He Deli , Hideshima Teru , Podar Klaus , Tao Florence , Neri Paola , Schlossman Robert , Schindler Joanne , Carver Bradley , Richardson Paul , Anderson Kenneth C. 
Published: October 2019

Abstract
Galectins belong to the family of mammalian lectins sharing an evolutionary conserved sequence in their carbohydrate recognition binding (CRD) domains and exhibit a characteristic affinity for beta-galactoside-sugars. Based on their structure and CRD, galectins have been categorized into three different categories: 1) Prototype (Gal-1, 2, 5, 7, 10, 11, 13, and 14), 2) Chimera type (Gal-3), and 3) Tandem repeat type (Gal-6, 8, 9, and 12). In particular, Galcetin-3 (Gal-3) is associated with growth, differentiation, adhesion, RNA processing, and apoptosis (Apoptosis, 2005, 10: 267–75). Previous studies show that Gal-3 is expressed on tumor cell surface and mediate the transformation and metastasis of tumor cells in vivo(Apoptosis, 2005, 10: 267–75). Here, we show that Gal-3 is differentially expressed in multiple myeloma (MM) cell lines and purified patient cells, as determined by both western blotting and polymerase chain reaction (PCR). Importantly, Gal-3 shares structural similarities with the anti-apoptotic protein Bcl-2: both proteins are rich in proline, glycine, and alanine amino acid residues in their NH-2-terminal domains and contain anti-death motif Asp-Trp-Gly-Arg (NWGR) in their C-terminal domains (Proc Natl Acad Sci USA, 1996, 93: 6737–42). Gal-3, like Bcl-2, is therefore a potential therapeutic target. In this context, modified citrus pectins (MCP) have been reported to bind and inhibit Gal-3-induced human umbilical endothelial cell migration and micro vessel tube formation (Am J Pathol.2000, 156:899–909) as well as block tumor growth and metastasis (J Natl Cancer Inst. 2002, 94:1854–62). GCS-100 is a MCP currently under clinical development. Here we show that GCS-100 binds to human recombinant Gal-3. In MM cells, GCS-100 triggers apoptosis and enhances anti-tumor activity of the conventional agent Dexamethasone. We examined whether GCS-100-, Dex- or GCS-100 + Dex-induced MM cell death modulates Gal-3 or Bcl-2 expression. Treatment of MM.1S cells with either GCS-100 or Dex alone does not alter Gal-3 or Bcl-2 expression. However, combined treatment of MM cells with sub-toxic concentrations of GCS-100 and Dex markedly attenuates Gal-3 expression, without any changes in Bcl-2 levels, suggesting that alterations in Gal-3 are specific. Previous studies showed that Gal-3 inhibits mitochondrial pro-apoptotic protein cytochrome-c (cyto-c), and our results show that GCS-100 + Dex triggers the release of cyto-c from mitochondria to cytosol. Together, these data suggest that the combination of GCS-100 + Dex overcomes the inhibitory effect of Gal-3 on cyto-c, thereby inducing apoptosis. Since Gal-3 is widely expressed in MM cells, its inhibition may augment the anti-tumor activity of therapeutic regimens.
The Effect of Repeated Administration of Cyclophosphamide on CYP2B1 and 2B2 in Rat.
Authors: Afsharian Parvaneh , Terelius Ylva , Lundgren Stefan , Hassan Moustapha 
Published: October 2019

Abstract
Cyclophosphamide is used in high doses as a part of the conditioning regimen prior to stem cell transplantation. It is usually given for two or four consecutive days, primarily to facilitate engraftment of donor cells. Cyclophosphamide is a prodrug that is activated in liver by a 4-hydroxylation reaction catalyzed by cytochrome P450 (CYP) enzymes. Several studies have shown that cyclophosphamide induces its own metabolism, which affects its pharmacokinetic parameters after repeated dose (Chang TK, Yu L et al. Cancer Res1997; 57:1946–54 and Schuler U, Ehninger G et al. Cancer Chemother Pharmacol1987; 20:248–52). In the present study, we aimed to investigate the effect of repeated doses of cyclophosphamide on the CYPs in rat. mRNA, protein, and enzyme activity levels were investigated. Animals received (200 mg/kg, i.v.) at time 0, 20, 48 h. Additionally another group of animals was treated at 0, 6, 20, 26, 48 and 54 h. At each time point three animals were killed 30 min after the administration (Xie H, Afsharian P et al. Xenobiotica2005; 35:239–51). mRNAs of CYP2B1 and 2B2 were significantly induced up to 458- and 8.3-fold at 6h, 983- and 102-fold at 26 h, and 342- and 33-fold at 54 h. CYP2B protein levels were increased and their peaks was observed at 20 and 48 h. Microsomal activity of CYP2B was determined at three different concentration of cyclophosphamide (1, 0.5, 0.1 mM) by measuring the formation rate of 4-hydroxy-cyclophosphamide (4-OH-CPA). The microsomal activity increased as reflected in an increase in cyclophosphamide 4-hydroxylation at all concentrations used using microsomes from rats treated at 6, 20 and 48 h. A significant increase of 4-hydroxylation of cyclophosphamide (0.1 mM) by 2.9-, 4.4- and 4.2- fold, respectively compared to the control rats. However, a decrease in the hydroxylation rate was observed using microsomes from rats treated at 26 and 54 h and in all concentrations used that might due to hepatotoxicity effect of cyclophosphamide when administered in short time period of repeated dose. A significant (p<0.05) decrease in CPA concentration and a significant (p<0.05) increase in its metabolite (4-OH-CPA) level in plasma were observed with repeated administration of CPA. In conclusion, an induction effect on CYP2B and a substantial up regulation of its mRNA expression were observed after repeated administration of CPA. This information can have a high clinical importance when a dosing schedule for cyclophosphamide considering the polymorphism of CYPs in cancer patient.
Results of Phase II Study of Lenalidomide (L) {Revlimid®} in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL).
Authors: Chanan-Khan Asher Alban , Miller Kena C. , DiMiceli Laurie , Padmanabhan Swaminathan , Lawrence David , Bernstein Zale P. , Takeshita Kenichi , Spaner David , Wallace Paul , Byrne Catriona , Crystal Cynthia , Czuczman Myron S. 
Published: October 2019

Abstract
Introduction: Lenalidomide (L) is a compound in a new group of drugs called ImiDs® which have Immunomodulatory properties and with anti-tumor activity reported in multiple myeloma and MDS. Although the exact mechanism of action of L is unknown, they are reported to affect the tumor microenvironment through modulation of critical cytokines such as TNF-a, VEGF and IL-6. These cytokines also play an important role in pathogenesis of CLL. Based on these properties we have investigated and previously reported on the anti-leukemic activity of thalidomide in CLL. We subsequently conducted a phase II study with L, to evaluate its clinical activity in pts with relapse (rel) or refractory (ref) CLL. Here we present the results of this study.
Patients and Methods: CLL pts with rel or ref disease were eligible. L was given at 25mg PO QD x 21 days followed by 7 days rest on a 28 day cycle. Absolute lymphocyte counts (ALC) were measured at Day 0, 7 and 30. Response was assessed at day 30 and monthly thereafter using the NCI-WG 1996 criteria. Pts with stable disease (SD) or better response were continued on therapy for a maximum of 12 months while those with progressive disease (PD) were to receive rituximab (R) (375mg/m2) added to L. Pts were considered evaluable for response if they completed at least 2 months of treatment. Target enrollment is 29 patients.
Results: Twenty nine pts, median age of 64 years (range: 47–75) were enrolled. All pts are available for toxicity and 17 out of 29 pts available for response evaluation. Three pts on treatment are too early for response assessment while 9 pts are off study (2 withdrew consent and 5 got < 2 months of therapy due to toxicity). Response is reported based on evaluable pts. Complete remission (CR) was noted in 2/17 (11.7%) pts while partial remission (PR) was noted in 9/17 (52.9%) pts. Additional 5/17 (29.4%) pts, currently on treatment, achieved stable disease (SD). ORR (CR+PR) in the intent to treat population is 42.3% (11/26, excluding pts currently too early for response assessment). To date only 1 pt has PD after 3 months of L and is on LR per protocol. Toxicity: Flare reaction (tender swelling of lymph nodes and/or rash) was the most common SE noted in almost all pts. Other important SE were tumor lysis syndrome (n=2); grade 3/4 hematologic toxicities (n=7) and febrile neutropenia (n=3).
Conclusion: This is the first study to report the clinical activity of L in pts with CLL. Our findings are encouraging and provide evidence of the anti-CLL activity of L. Although some of the pts did achieve a CR, longer follow-up will determine the durability of responses noted to date. Update results of this study along with toxicity profile of L in CLL will be presented at the meeting.
Patient Characteristics in CD 20+ and CD 20− Adult Acute Lymphoblastic Leukemia (ALL): A Single Institution Analysis.
Authors: Gladney Sara P. , Heffner Leonard T. , Langston Amelia , Holden Jeannine , Phillips Carol , Winton Elliott , Flowers Christopher R. , Lechowicz Mary Jo , Lonial Sagar , Waller Edmund , Khoury Hanna J. 
Published: October 2019

Abstract
Targeted therapy is increasingly incorporated into the chemotherapy regimens of adult ALL. While the prognosis of BCR/ABL + (Philadelphia) ALL is well recognized; the significance of CD 20 postivity is unknown. We report the characteristics of 76 patients treated at Emory University between January 1999 and March 2005, divided into 2 groups based on CD 20 expression, as determined by flow cytometry. The CD 20+ patients presented with a higher WBC count and LDH, and lower platelet counts (table). In the CD 20+ group, 65% had pre B cell ALL and 8% had high grade B cell leukemia/lymphoma, whereas the CD 20- group consisted of 30% pre B cell ALL, 24% T cell ALL, and 10% had high grade leukemia/lymphoma. Of the 35 Ph+ ALL patients, 27 were CD20+ (20%) and 18 CD20- (51%). Patients were treated on clinical trials L20, ALL2, and more recently with the Hyper-CVAD regimen (n=32). Only 5 of the CD 20+ patients received rituximab in addition to chemotherapy. With a median follow-up of 320 days, 46% of patients in each group are alive, 35% and 38% relapsed in the CD 20+ and CD 20- group, respectively. In summary, we found that CD 20+ ALL patients present with higher WBC count and LDH, and a lower platelet count; although, due to our small sample size, these differences were not significant. Further follow up is needed to provide mature results on survival and remission.
CD 20+ CD 20- p= Total numbers 26 50 Median Age (yrs) 45.2 (18–74) 44 (19–76) NS Median WBC (103/μl) 29.1 10 0.09 Median Platelet (103/μl) 35 65 0.11 Median LDH (IU) 894 500 0.05 Normal Cytogenetics 13 (50%) 21 (42%) NS Ph+ ALL 7 (26%) 18 (35%) NS CR within 60 days 20 (77%) 27 (54%) NS Primary Refractory 2 (8%) 6 (12%) 0.7 Relapse 9 (35%) 19 (38%) NS Alive at last follow up 12(46%) 23 (46%) NS Expired by d270 8 (36%) 11 (25%) NS
Simultaneous Detection of Major Fusion Transcripts in CML, ALL and AML Leukemias in a Multiplex Bead-Array Assay.
Authors: Ye Fei , Mire Brad , Wolf Ila , Lahey Cora , Hadd Andrew G. 
Published: October 2019

Abstract
INTRODUCTION: Accurate sub-classification of leukemia-associated chromosome translocations is essential for precise risk-stratified diagnosis and improvement of treatment outcomes. We have developed a rapid assay system to detect the nine most common chromosomal translocations covering three different leukemia disease groups: CML, ALL and AML. The purpose of our study was to confirm clinical detection of twelve translocation markers.
MATERIALS AND METHODS: The liquid bead array assay combined multiplex RT-PCR with signal readout in a 96-well plate format. RNA fusion transcripts of leukemia-associated chromosome translocations were reverse transcribed into cDNA and amplified by multiplex PCR using biotin-modified primers. An endogeneous control gene, GAPDH, was co-amplified in each sample and concurrently analyzed. A single-tube bead array contained 11 marker specific oligonucleotide probes with sequences complimentary to the fusion transcript splice junction for the following markers: b2a2, b3a2 for CML; e1a2, E2A-PBX1, TEL/AML1 and MLL/AF4 (e10/e4, e9/e5) for ALL; PML/RARa (long and short forms), AML1-ETO and inv(16) (A and D types) for AML. Biotinylated amplified products were hybridized to the array without intervening purification steps. After incubation with streptavidin-conjugated fluorophore, the reaction mixtures were analyzed by the Luminex platform.
RESULTS: RNA samples from translocation-positive cell lines and IVT products were detected with less than 10% CVs in approximately five hours. Long and short forms of PML-RARa and A and D types of inv(16) were specifically resolved. The assay can detect two MLL/AF4 subtypes: MLL/AF4 (e10/e4) or MLL/AF4 (e9/e5). Eighty-seven leukemia patient samples (RNAs extracted from peripheral blood and bone marrow) were screened and all translocations were correctly detected. A software system for selective readout based on disease class was implemented.
CONCLUSIONS: This multiplex array-based assay can be an effective and reliable tool in the clinical screening of leukemia patients for the presence of specific fusion transcripts with important diagnostic and prognostic implications.
Expression of Inhibitor-of-Apoptosis Protein (IAP) Livin in Pediatric Acute Lymphoblastic Leukemia (ALL) Cells.
Authors: Dasgupta Anindya , Gu Lubing , Alvarado Carlos S. , Zhou Muxiang , Findley Harry W. 
Published: October 2019

Abstract
Livin (ML-IAP, KIAP, BIRC7) is a recently identified member of the IAP family of anti-apoptosis proteins, and expression has been reported in melanoma, some types of carcinoma, and neuroblastoma. Additionally, we have detected expression of livin in leukemic cells from pediatric ALL cell lines and primary ALL cells. Livin was detected by RT-PCR in all 9 ALL lines tested, although expression varied markedly among lines: 3 of 9 lines showed strong expression of livin (equal to or greater than the melanoma line G361, which served as a positive control), while the remaining lines had a faint band. These livin-positive lines included both B-cell precursor ALL (BCP-ALL, 7 lines) as well as T-ALL (2 lines). We confirmed livin protein expression (by immunoblot) in 3 lines with high levels of livin RNA (EU-1 and REH, BCP-ALL; and CCRF-CEM, T-ALL); two other lines (EU-3 and EU-4, BCP-ALL) with low levels of livin RNA showed much less protein expression. These results are similar to those we have previously reported for neuroblastoma, which also shows variability in expression of livin among different cell lines. Similarly, livin was detected in primary ALL cells from all four patients tested to date (including three BCP-ALL and a T-ALL case) at either diagnosis or relapse. Again, livin expression varied significantly among cases; one of the two cases with elevated livin was in relapse, while the other two cases (at diagnosis) showed only faint expression. Livin expression in normal bone marrow mononuclear cells was also low (relative to G361 cells and high-expressing ALL cells). When resistance to doxorubicin was compared for lines with elevated livin vs those with low livin expression, increased resistance was noted in the former lines. To further evaluate the effect of livin on drug resistance, EU-4/ALL cells with low endogenous livin were stably transfected with a livin expression plasmid. A significant increase in resistance to doxorubicin was noted for livin-transfected cells at concentrations above 1ug/ml in a 48 hr cytotoxicity assay. Taken together, these results suggest that elevated livin expression contributes to drug resistance in some cases of pediatric ALL. We are currently evaluating the mechanism by which elevated livin expression protects leukemic cells from doxorubicin.
Hairy Cell Leukemia and Secondary Lymphoproliferative Disorders.
Authors: Chang Monique , Kujawa Jennifer , Garrison Michael , Hindenburg Alexander 
Published: October 2019

Abstract
Prolonged immunosuppression is generally associated with an increase in incidence of lymphoid cancers. Transplant recipients, primary or genetic immunodeficiencies and patients with the acquired immunodeficiency syndrome (AIDS) have a known increased incidence of lymphoproliferative disorders. Patients who develop hairy cell leukemia (HCL) also have impaired immune function at the T-cell level that is present before definitive therapy. The lack of T-cell responsiveness is due to a decrease in memory T helper cells, abnormal activation of spleen T lymphocytes that behave like tumor infiltrating cells, and selection of oligoclonal T-cell populations with a very restricted and skewed T-cell repertoire. Inadequate antigen presentation may also play a role due to monocytopenia and lack of CD 28 on T-cells. Treatment with purine analogs, particularly pentostatin and cladribine, targets both resting and proliferating lymphocytes. This further impairs immune function by producing a prolonged reduction of normal lymphocytes, mainly CD4 cells, for as long as two years. There are reports of lymphoproliferative disorders as a second malignancy after treatment for HCL. However, it is not clear if treatment with purine analogs can induce second malignancies due to immune suppression. We reviewed the literature for cases of secondary lymphoproliferative disorders in patients treated with and without purine analogues for HCL. Purine analogues do not appear to have an increased risk for a secondary lymphoproliferative disorder. However, a preexisting immunosuppressed state may exist that antecedes the treatment of HCL and predisposes some patients to secondary lymphoproliferative disorders.
Secondary Lymphoproliferative Disorders in Patients Treated for Hairy Cell Leukemia (HCL) Prior Treatment for HCL Non Hodgkin’s Lymphoma Hodgkin’s Lymphoma Waldenstrom’s Macroglobulinemia Multiple Myeloma Purine Analogues 16 3 2 1 Other Systemic Therapies 7 2 0 1 No Systemic Therapy 10 0 0 0 Unknown 3 1 0 0
Cytogenetics of Hispanics and Whites with Childhood Acute Lymphoblastic Leukemia in California.
Authors: Aldrich Melinda C. , Zhang Luoping , Wiemels Joseph L. , Ma Xiaomei , Loh Mignon , Selvin Steve , Feusner James , Smith Martyn T. , Buffler Patricia A. 
Published: October 2019

Abstract
Epidemiologic studies of childhood leukemia have made limited use of tumor genetic characteristics, which may be related to disease etiology. We characterized the cytogenetics of 543 childhood leukemia patients (0–14 years of age) enrolled in the Northern California Childhood Leukemia Study, an approximately population-based study comprised primarily of Hispanics (42%) and non-Hispanic whites (41%), and compared the cytogenetic profiles between these two ethnic groups. Subjects were classified by immunophenotypes, conventional cytogenetic characteristics, and fluorescence in situ hybridization findings. The abnormalities most frequently observed among all patients were pseudodiploidy and high hyperdiploidy (51–67 chromosomes) (27% and 25%, respectively). No ethnic differences in the frequency of 11q23/MLL rearrangements were observed between Hispanics and non-Hispanic whites. Among B lineage ALL patients without 11q23/MLL rearrangements, the percentage of TEL-AML1 translocations was significantly lower in Hispanics (13%) than in non-Hispanic whites (24%; P = 0.01). This is the first large study to compare frequencies of cytogenetic events of primarily Hispanic and non-Hispanic white childhood leukemia patients. Our data suggest some cytogenetic characteristics likely differ between non-Hispanic whites and Hispanics. The mechanistic basis for the two-fold variation in frequency of TEL-AML1 may be due to ethnic-specific risk factors or genetics and should be explored further. Owing to the heterogeneity of leukemia in children, it is possible that cytogenetic subgroups may have distinct etiologies and risk factors which otherwise would be overlooked with the broad leukemia subtypes (e.g. ALL, AML) presently used in epidemiologic analyses.