bluuebunny/crossref_metadata_2025_split huggingface dataset:
Arsenic Trioxide in Mantle Cell Lymphoma.
Authors: Kwong Yok Lam , Chow Chit , Kumana Cyrus R. , Srivastava Gopesh , Au Wing Yan 
Published: April 2020

Abstract
Background. Mantle cell lymphoma (MCL) is incurable for many patients. Arsenic trioxide (As2O3) has activity in vitro against lymphoid malignancies. The effects of As2O3 on MCL in vitro and in patients with refractory disease were investigated.
Materials and methods. Mantle cell lymphoma (MCL) lines (Jeko-1, Granta-519) were treated with As2O3, in combination with mitoxantrone (MTZ) and ascorbic acid (AA). Consenting patients with refractory MCL were treated with oral-As2O3 (10 mg/day), AA (1 g/day) and chlorambucil (4 mg/day) as outpatients until maximum response or the disease judged refractory. Responses were defined by standard NCI criteria. In patients showing an initial response, vincristine (2 mg intravenously) and prednisolone (30 mg/day) might also be added. After achievement of maximum response, patients were maintained with As2O3 (10 mg/day) and AA (1 g/day) for two weeks every month, for a planned two years.
Results. As2O3 and MTZ but not AA induced a dose dependent apoptosis in the MCL lines, as shown by flow cytometry and MTT assays. As2O3, MTZ and AA were tested in various combinations in MTT assays. Synergistic interactions were observed only in the combinations As2O3 (1 uM) + MTZ (0.2 mg/L), and As2O3 (1 uM) + MTZ (0.2 mg/L) + AA (100 uM). Western blotting showed that As2O3-induced apoptosis was associated with a dose and time dependent down-regulation of cyclin D1. However, quantitative polymerase chain reaction showed no change in cyclin D1 gene transcription during As2O3-induced apoptosis. Eleven patients (10 men, 1 women) at a median age of 69 (51–70) years with refractory MCL were studied, at a median of 33 (8–85) months from diagnosis. At the time of As2O3 treatment, they had already had a median of 2 (1 – 4) relapses managed with a median of 2 (1 – 6) previous chemotherapeutic regimens. Eight of eleven patients were evaluable (for the other three, one died after 4 days of treatment, and the two were still receiving therapy). At a median follow up of 9 (4 – 20) months, 4 patients had reached complete remission (CR) or probable CR (CRu), two were in good partial remission, and two had died with progressive disease.
Conclusion. As2O3 induced apoptosis of MCL cells by post-transcription down-regulation of cyclin D1. Synergistic interactions were observed with AA and cytotoxics. Oral-As2O3, AA and chlorambucil were an active regimen for relapsed and therapy-refractory MCL, and treatment results compared favorably with other salvage regimens. This entirely oral regimen has several attractions, including outpatient treatment, low toxicity and cost.
A Human Anti-CD1a Monoclonal Antibody for Targeted Immunotherapy in Langerhans Cell Histiocytosis and Hematologic Malignancies.
Authors: Bechan Gitanjali , Lee David W. , Egeler R. Maarten , Arceci Robert J. 
Published: April 2020

Abstract
Langerhans Cell Histiocytosis (LCH) is characterized by the clonal proliferative of immature Langerhans cells resulting in a disorder with a wide variety of clinical manifestations and outcomes. Current therapies are based on the use of chemotherapeutic and immunosuppressive agents, usually in combination. Treatments are relatively non-specific, associated with significant adverse side effects and are ineffective in a significant number of patients. More effective and less toxic treatments are therefore needed. The selective expression of the nonclassical MHC protein, CD1a, on the lesional Langerhans cells in LCH makes this antigen an excellent immunotherapeutic target. To this end, we have generated a completely human monoclonal antibody (Mab) that specifically binds to a native, external epitope of CD1a using a human spleen phage display library. Epitope binding regions were selected for recognition of external domains of native CD1a and sequences showing specific binding were cloned into a human IgG1 backbone. The anti-CD1a Mab, termed 2113, shows high affinity and specificity for CD1a and is internalized after binding to the surface of CD1a expressing cells. The 2113 Mab also demonstrates significant complement dependent lysis (CDC) and antibody dependent cell cytotoxicity (ADCC) against CD1a expressing cells. No direct antibody mediated apoptosis was observed for 2113 binding to CD1a. A preclinical murine CD1a positive tumor model is being used to test the 2113 Mab for selective localization and tumor cytotoxicity. This Mab should provide an excellent reagent for therapeutic targeting of LCH and CD1a positive hematologic malignancies as well as possibly having application in the treatment of autoimmune disorders, prevention of graft-versus-host disease and augmenting cancer vaccines through direct antigen delivery to Langerhans cells.
Etodolac Inhibits EBER Expression and Induces Bcl-2-Regulated Apoptosis in Burkitt’s Lymphoma Cells.
Authors: Kobayashi Miki , Nakamura Satoki , Shibata Kiyoshi , Sahara Naohi , Shigeno Kazuyuki , Shinjo Kaori , Naito Kensuke , Ohnishi Kazunori 
Published: April 2020

Abstract
Cyclooxygenase-2 (COX-2) is reported to be an important cellular target for therapy in malignancies. The growth inhibitory effects of COX-2 inhibitors on malignancies have been demonstrated to be through not only COX-2 dependent, but also independent mechanisms. In this study, we showed that etodolac, COX-2 inhibitor, induced apoptosis via COX-2 independent pathway, and investigated the molecular details of etodolac-induced apoptosis in Burkitt’s lymphoma cells. In Daudi and Raji Burkitt’s lymphoma cell lines, which expressed no COX-2 enzyme, etodolac more strongly induced apoptosis compared to meloxicam. Moreover, Etodolac did not induce apoptosis to normal B lymphocytes. For the pathway of etodolac-induced apoptosis, reduction of anti-apoptotic bcl-2 mRNA and Bcl-2 protein, activation of Caspase-9 and -3, down-regulation of caspase inhibitors, c-IAP-1 and Survivin were involved. Moreover, EBER-1 and -2 expression in EBV positive Daudi and Raji cells were reduced to result in down-regulation of Bcl-2 by treatment with etodolac. It has been reported that etodolac has stereoisomers, R- and S- etodolac. We found that racemate of etodolac more strongly induced apoptosis in Daudi and Raji cells compared to R- or S- etodolac. In conclusion, our findings indicated etodolac inhibited EBERs expression and induced apoptosis via a Bcl-2-regulated pathway. Moreover, racemate of etodolac more effectively induced apoptosis than R- and/or S- etodolac. Therefore, these activities of etodolac potentially extend to the treatment of patients with Burkitt’s lymphoma resistant to chemotherapy.
BCR/ABL Induces Expression of Histidine Decarboxylase and Synthesis of Histamine in CML Cells.
Authors: Aichberger Karl J. , Mayerhofer Matthias , Krauth Maria-Theresa , Vales Anna , Derdak Sophia , Pickl Winfried F. , Sillaber Christian , Valent Peter 
Published: April 2020

Abstract
Basophil numbers are typically elevated in patients with chronic myeloid leukemia (CML) and characteristically increase during disease progression. As a consequence, blood histamine levels are highly upregulated in CML. We examined the biochemical basis of production of histamine in CML cells and analyzed the effects of the CML-related oncoprotein BCR/ABL on the generation of this mediator. Expression of histamine and of histidine decarboxylase (HDC), the major enzyme involved in histamine synthesis, were examined in primary CML cells obtained from patients with chronic phase (CP) CML or accelerated phase (AP) CML with basophilia, in the CML-derived cell lines K562 and KU812, and in Ba/F3 cells inducibly expressing BCR/ABL on exposure to doxycycline (TonB.210-X cells). In all patients with AP-CML and basophilia, high levels of HDC mRNA and of histamine were detected, whereas in CP-CML cells only expressed low amounts of HDC and of histamine. HDC mRNA and histamine were detectable in the basophil-committed CML cell line KU812, but not in K562 cells. Exposure of primary CML cells or KU812 cells to the BCR/ABL tyrosine kinase inhibitors imatinib (1 μM; Novartis Pharma AG) or AMN107 (100 nM; Novartis Pharma AG) decreased the levels of histamine and expression of HDC in BCR/ABL-transformed cells. Moreover, BCR/ABL was found to promote the expression of HDC mRNA and to increase the levels of histamine in TonB.210-X cells. The BCR/ABL-induced synthesis of histamine in these cells was blocked by the PI3-kinase inhibitor LY294002, whereas neither the MEK inhibitor PD98059, nor the mTOR inhibitor rapamycin affected histamine levels. In conclusion, our data show that the CML-specific oncoprotein BCR/ABL induces expression of HDC and synthesis of histamine in leukemic cells through a pathway involving the PI3-kinase.
The Early Referral for Reduced-Intensity Stem Cell Transplantation in Patients with Ph1 (+) Chronic Myelogenous Leukemia in Chronic Phase in the Imatinib Era: Results of the Latin American Cooperative Oncohematology Group (LACOHG) Prospective, Multicenter Study.
Authors: Ruiz-Arguelles Guillermo J. , Gomez-Almaguer David , Morales-Toquero Amelia , Gutierrez-Aguirre Cesar H. , Vela-Ojeda Jorge , Garcia-Ruiz-Esparza Miriam A. , Manzano Carlos , Karduss Amado , Sumoza Abraham , de-Souza Carmino , Miranda Eliana , Giralt Sergio 
Published: April 2020

Abstract
Using a reduced intensity stem cell transplantation (RIST) schedule, 24 patients with Ph1 (+) chronic myelogenous leukemia (CML) in first chronic phase were prospectively allografted in four Latin American countries: Mexico, Brasil, Colombia and Venezuela, using HLA-identical siblings as donors. Median age of the patients was 41 years (range 10 to 71); there were 8 females. Patients received a median of 4.4 x 106/ Kg CD34 cells. Median time to achieve above 0.5 x 109/L granulocytes was 12 days, range 0–41, whereas median time to achieve above 20 x 109/L platelets was also 12 days, range 0–45. Twenty two patients are alive 81 to 830 (median 497) days after the RIST. The 830-day probability of survival is 92%, whereas median survival has not been reached, being above 830 days. Eleven patients (46%) developed acute graft versus-host disease (GVHD), whereas 7 of 23 (30%) developed chronic GVHD. Two patients died 43 and 210 days after the RIST, one as a result of sepsis and the other one of chronic GVHD. The 100-day mortality was 4.4 %, whereas the transplant-related mortality was 8%. RIST for patients with CML in chronic phase seems as an adequate therapeutic option.
Denaturing- HPLC and HR-1 Melter-Based Detection of ABL Mutations in Patients with Chronic Myelogenous Leukemia (CML).
Authors: Lee Il-Kwon , Yun Ju Hyun , Kim Nan Young , Choi Jeong-Hwa , Kim Yeo-Kyeoung , Kim Hee Nam , Park Kyeong-Soo , Lee Je-Jung , Shin Myung Geun , Choi Chan , Kook Hoon , Hwang Tai Ju , Park Moo Rim , Jo Deog Yeon , Won Jong Ho , Kim Hyeoung-Joon 
Published: April 2020

Abstract
Imatinib mesylate is the first line of drug for CML since its ability to induce durable remissions in most patients with Philadelphia-positive leukemias and cytogenetic responses in most patients with chronic-phase CML. Although Imatinib mesylate has revolutionized current chronic myeloid leukemia therapy the phenomenon of relapse because of the emergence of resistance were observed. There were well-known mutations in kinase domain that confer resistance despite continued Imatinib mesylate chemotherapy and number of resistance-conferring mutation is increasing. In this study we systematically scanned kinase domain-encoding exon 5, 7, 8, 9, 10 and 11 from genomic DNA of 79 patients with CML to identify novel mutation using denaturing high-performance liquid chromatography (dHPLC) and HR-1 melter (Idaho Technology). In total 15 mutations in the regions were identified and three mutations are found to be novel and two were located in the catalytic domain region (F359I and E374K). Since these two mutations were identified in patients with primary and secondary resistance respectively, it might be classified into resistance-conferring mutation conditional on further functional evaluation. Also we found P499L mutation in the C-terminus and interestingly we detected E478Q in six patients with CML. Analysis with dHPLC and HR-1 screening after PCR amplification proved to be accurate and effective methods to isolate mutation. In addition dHPLC and HR-1 more sensitive compared to PCR direct sequencing methods since two mutations which were not detected by direct sequencing were confirmed only after subcloning of PCR products and sequencing. Taken together, we designed six PCR amplicons encompassing the kinase domain of abl kinase and screened for novel mutations patients with CML. Out of fourteen mutations identified two novel mutations in the catalytic domain need further investigation to understand if they contribute to the acquirance of imatinib mesylate resistance
Elevated Expression of C/EBPα/ε and c-myb Is Required for Myeloid Differentiation in CML.
Authors: Kobayashi Shinichi , Kimura Fumihiko , Ikeda Takashi , Torikai Hiroki , Osawa-Nakata Yukiko , Sato Ken , Motoyoshi Kazuo 
Published: April 2020

Abstract
The BCR/ABL fusion protein transforms hematopoietic stem cells and causes chronic myeloid leukemia (CML). However, the mechanism leading to the expansion of mature myeloid cells in CML remains obscure. To investigate this mechanism, we compared the gene expression profile of CML neutrophils with that of normal neutrophils by microarray analysis. The genes upregulated in CML neutrophils include critical transcription factors that regulate granulocytic differentiation and proliferation, as well as genes encoding neutrophil granule proteins (Table 1). The protein levels of these upregulated genes were also elevated in the CML neutrophils. To investigate whether BCR/ABL regulates the expression of these upregulated genes, primary CML neutrophils were exposed to 1 μM imatinib (a BCR/ABL tyrosine kinase inhibitor) for 12–16 hours. C/EBPα protein expression was downregulated in primary CML neutrophils after treatment with imatinib, compared to control cultures. We further explored the function of these upregulated genes in KCL22 cells, which are derived from CML blastic crisis. To investigate the effect of C/EBPα or C/EBPε on myeloid differentiation, we established KCL22 cells in which C/EBPα or C/EBPε expression was inducible (KCL22/α or KCL22/ε, respectively). Overexpression of either C/EBP protein resulted in morphological changes, such as reduction of the nuclear to cytoplasmic ratio, more condensed nuclear chromatin, and segmented nuclei, as well as the expression of differentiation specific markers including the G-CSF receptor and macrophage adhesion molecule-1 (Mac-1). These data indicate that C/EBPα /ε expression is sufficient to induce myeloid differentiation in BCR/ABL positive CML cells. We examined whether BCR/ABL regulates the protein expression of c-Myb. The expression of c-Myb in KCL22 cells treated with 1 μM imatinib was downregulated and growth in these cells decreased in parallel. Knock-down of c-Myb expression with siRNA inhibited the growth of KCL22 cells and these data indicate that c-Myb expression is important for the growth of CML cells. To test the effect of c-Myb on differentiation of KCL22 cells, we knocked down c-Myb expression with siRNA in KCL22/α or KCL22/ε cells after induction of C/EBP protein. The knock-down of c-Myb in KCL22α /ε cells resulted in downregulation of differentiation specific genes, including G-CSF receptor and neutophil elastase. Morphologically, the fraction of KCL22α /ε cells with segmented nuclei decreased when c-Myb expression was knocked down. Our results suggest that elevated expression of C/EBPα /ε and c-Myb play a key role in proliferation and differentiation in CML cells.
Table 1. Genes Upregulated in CML Neutrophils. Description Gene transcription factor C/EBP α transcription factor C/EBP ε transcription factor c-Myb neutrophil granule protein lactoferrin neutrophil granule protein neutrophil elastase neutrophil granule protein lysozyme
Hematologic Remission of Chronic Myelogenous Leukemia after Treatment with Imatinib Includes Normalization of the Red Cell Distribution Width.
Authors: Bessman Joel David , Montoya Maria 
Published: April 2020

Abstract
After treatment with imatinib, the majority of patients with chronic myelogenous leukemia (CML) achieve hematologic remission. This includes normalization of blood counts (red cells, white cells, and platelets) normalization of the white cell differential, and disappearance of abnormal immature cells from the peripheral blood. However, abnormal erythropoiesis may be more subtle than abnormal red cell counts. We reviewed two other indices of erythropoiesis, the mean cell volume (MCV) and the red cell distribution width (RDW). We studied 15 patients with a diagnosis of CML confirmed by BCR-ABL, in whom the first-line therapy was imatinib. Treatment dosage varied from 400 – 800 mg/day. Pre-treatment, all patients had an elevated white cell count, 14 of 15 had a low hemoglobin, and 11 of 15 had an abnormal high platelet count. None had an abnormal MCV (mean, 91.3, range 82 – 97), and 13 of 15 had an abnormal RDW (mean 16.2, range 14.1 – 19.2). After treatment was started, all 15 achieved a normal white cell count, hemoglobin, and platelet count within 3 months. All continued to have a normal MCV, with no apparent change (mean 92.1, range 82 – 98). However, after treatment 14 of 15 developed a normal RDW (mean 13.7, range 12.0 – 15.2). The RDW progressively declined during the first 3 months after treatment and reached an asymptote at that time. We conclude that hematopoiesis normalizes qualitatively as well as quantitatively after successful imatinib therapy of CML. Future study will determine whether an isolated elevated RDW will predict relapse or briefer duration of remission.
Addition of GM-CSF to Imatinib Results in Major Cytogenetic Response in Patient with Chronic Myeloid Leukemia (CML).
Authors: Connor Rebecca , Hurd David , Molnar Istvan 
Published: April 2020

Abstract
Imatinib mesylate, an inhibitor of BCR/ABL tyrosine kinase, has remarkable activity in CML resulting in up to 87% major cytogenetic response, but further treatment is needed for the remaining 13% of patients and others who progress on therapy. Studies suggest that hematopoietic growth factors (HGF) induce the selective terminal differentiation of CML progenitors at concentrations that allow optimal growth of normal progenitors. Treatment with HGF may be able to stop the expansion of BCR/ABL positive cells while promoting the expansion of non-leukemic myeloid cells, thereby encouraging a cytogenetic response. Initially, these HGF were used to improve the safety of chemotherapies but had not been studied specifically to improve cytogenetic response. Our institution has an open phase II study of GM-CSF in patients with chronic phase CML who have not achieved a complete cytogenetic remission after at least 9 months of therapy. Our first patient on study was a woman originally diagnosed in 4/1996 with a variant Philadelphia chromosome [t(9;9;22)] positive CML. She was initially started on hydroxyurea and was then switched to interferon-α for approximately 5 ½ years. When imatinib became available her interferon was discontinued and she was treated with imatinib at 400 mg daily. Bone marrow biopsy 5/2003 was morphologically normal but on cytogenetic analysis all cells contained the same aberrant karyotype. Her imatinib therapy was complicated by pancytopenia requiring frequent transfusions. She had received approximately 22 units of packed red blood cells over 11 months. Her white count had been running in the 1,500 to 2,500/μL range and her platelet count had dropped to 64,000/μL. She presented to us 1/2004 at the age of 56 and was evaluated for a reduced-intensity allogeneic transplant but did not have any donors available in her family. She was not felt to be a candidate for an unrelated donor transplant because of co-morbid risks. Given her continued cytogenetic abnormalities and lack of transplant candidacy she was enrolled in our GM-CSF trial March 2004. At the time of entry onto study she had been on imatinib for 2 1/2 years with no cytogenetic improvement. She began treatment with daily GM-CSF 100 μg/m2 in addition to her imatinib. Cytogenetic studies revealed a gradual increase in percentage of normal cells from start, 4 months, 9 months, and 15 months at 0%, 10%, 55%, and 85% respectively. She also had reversal of her pancytopenia and has not required transfusion of blood or platelets since enrollment. She developed an eosinophilia which we attribute to GM-CSF. Clinical studies have examined the use of GM-CSF in addition to interferon alpha. However, with imatinib becoming the new standard of care it is more relevant to examine the combined effect of imatinib and GM-CSF. The use of GM-CSF with imatinib in CML still needs more evaluation, but it appears to be a promising approach to improve cytogenetic response.
Results of a Phase 2 Trial of HGS-ETR1 (Agonistic Human Monoclonal Antibody to TRAIL Receptor 1) in Subjects with Relapsed/Refractory Non-Hodgkin’s Lymphoma (NHL).
Authors: Younes Anas , Vose Julie M. , Zelenetz Andrew D. , Smith Mitchell R. , Burris Howard , Ansell Stephen , Klein Jerry , Kumm Elizabeth , Czuczman Myron 
Published: April 2020

Abstract
Two death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5), expressed in a wide variety of cancer cell types including lymphoma, enable TRAIL (TNF related apoptosis inducing ligand), a member of the TNF ligand superfamily, to induce apoptosis. HGS-ETR1 (TRM-1, mapatumumab) is a fully human monoclonal antibody agonistic to TRAIL-R1 with preclinical evidence of anti-tumor activity in vitro and in vivo. We conducted a phase 2 multicenter study of HGS-ETR1 in 40 subjects with relapsed or refractory NHL. Patients were included on the study if they had relapsed/refractory NHL of any histologic subtype, irrespective of the number of previous treatment regimens. HGS-ETR1 was administered at 2 dose levels: 3 mg/kg (8 subjects) or 10 mg/kg (32 subjects) every 21 days in the absence of disease progression or prohibitive toxicity for up to 6 cycles. The primary endpoint was tumor response evaluated with the International Working Group Criteria after every third treatment. Responses were confirmed between 4 and 8 weeks after initial documentation of response. Secondary endpoints included safety and tolerability. The median age of subjects was 62 years (range 32–81) (24M:16F) with an ECOG performance status 0–2. Subjects had received up to 12 previous therapeutic regimens (69% received 3 or more prior regimens). Original histologic classification is presently available for 34 subjects (14 follicular, 7 diffuse large B-cell, 6 mantle cell, 1 small lymphocytic, 2 peripheral T-cell, 1 anaplastic large cell, 3 lymphomas not classified). Preliminary response data are available for all 40 subjects. 3 subjects (8%), all with follicular lymphoma, had clinical responses (1CR, 2PR). Additionally, 12/40 subjects (30%) had stable disease, and the remainder had progressive disease at the time of first evaluation. 8 subjects (7 follicular) remain on study without disease progression for &gt;5 to &gt;13 months. One subject with a PR (special permission) has continued to receive HGS-ETR1 (10 cycles to date). Subjects tolerated therapy well with no subjects discontinuing therapy due to toxicity related to drug. There have been 10 reported SAEs, 2 of which were considered possibly/probably related to HGS-ETR1 administration (shingles, fever). In conclusion, HGS-ETR1 can be safely administered to heavily treated NHL patients. Clinical responses were seen in 3/14 follicular lymphoma subjects to date. Final data for all subjects will be reported at the meeting. These data suggest that HGS-ETR1 has activity in heavily pretreated lymphoma patients and further studies in combination with agents active in lymphoma are justified.