bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase II Trial of Dexamethasone, High-Dose Cytarabine, and Cisplatin (DHAP) in Combination with Rituximab as Salvage Treatment for Patients with Refractory or Relapsed Aggressive Non-Hodgkin’s Lymphoma.
Authors: Mey Ulrich J.M. , Strehl John W. , Orlopp Katjana S. , Flieger Dimitri , Birkmann J. , Ho Anthony , Kaiser U. , Neubauer Andreas , Glasmacher Axel G. , Schmidt-Wolf Ingo G.H. 
Published: April 2020

Abstract
Purpose: With commonly used salvage chemotherapy regimens like DHAP, response and overall survival rates are unsatisfactory. We designed a multicenter phase II trial to evaluate the safety and efficacy of the combination of rituximab with the DHAP regimen in patients who relapsed after or were resistant to a CHOP-like regimen.
Methods: 61 patients with relapsed or resistant aggressive B-cell NHL were included in this trial so far. The median age was 61,5 years. 39 patients were in first relapse; 21 had recurrence during the first 12 months after treatment. 5 patients had second or subsequent relapse, 17 had primary refractory disease. Treatment consisted of rituximab infusions (375 mg/m2 per dose) on day 1 followed by dexamethasone 40 mg d3–6 (d 3–5 in first cycle), cytarabine 2 x 2000 mg/m2 d 4 (2 x 1000 mg/m2 in first cycle), 2 x 1000 mg/m2 for patients &gt; 60 years of age (2 x 500 mg/m2 in first cycle), and cisplatin 25 mg/m2 d 3–6 (d3–5 in first cycle) for a maximum of 4 cycles. When hematological toxicity did not allow continuation of chemotherapy on day 22, rituximab was given as single agent on day 22 and the next cycle was postponed until day 29.
Results: The overall response rate in evaluable patients was 54.0%. 29.0% of patients achieved a complete response, 25% of patients had a partial response, 15.0% of patients had stable disease. 31.0% of patients showed progressive disease. Patients in first relapse achieved an overall response of 67.0 % as opposed to only 27.0% in patients with refractory disease. Grade 3/ 4 nausea and vomiting were the only severe toxicities attributed to rituximab in one patient. Main toxicities were neutropenia and thrombocytopenia. Grade 3/ 4 nephrotoxicity occured in 2 patients. Survival data will be presented at the meeting.
Conclusions: Interim analysis of the data suggests that the combination of rituximab with the DHAP regimen in the treatment of relapsed or refractory aggressive lymphoma is feasible and effective. In view of the unfavorable prognostic factors in our patient population, response rates (ORR = 54%) are encouraging and warrant further investigation.
Epstein-Barr Viral Load in Post Renal Transplant Lymphoproliferative Disease: Elevated EBV DNA Levels at Diagnosis and Clearence after Rituximab Therapy.
Authors: Baiocchi Otávio C.G. , Caballero Otávia L. , Vettore André L. , Bulgarelli Adriana , Franco Marcello F. , Alves Antonio C. , Pestana José O.M. , Colleoni Gisele W.B. , Bordin José O. 
Published: April 2020

Abstract
The imbalance between EBV load and host immunological status is the trigger for post transplant lymphoproliferative disease (PTLD) development. Thus, monitorization of EBV load can be a useful tool in the management of these patients. In order to evaluate this issue in a renal transplant center, we studied eleven PTLD cases between January 2001 and December 2003. The diagnosis of PTLD was established according to WHO classification and confirmed by in situ hybridization (ISH) for EBV. Real-time PCR (LightCycler System, Roche, USA) and primers for amplification of EBV’s EBNA-1 gene were used to evaluate EBV viral load in peripheral mononuclear cells (PBMC) of PTLD cases. Samples were collected at diagnosis and 1, 3, 6 and 9 months after therapy. Median time from renal transplant to PTLD onset was 36 months. Eight (73%) were classified as diffuse large B-cell lymphoma, one as lymphoplasmocytoid lymphoma, one as polymorphic hiperplasia and one as Hodgkin’s lymphoma. All PTLD cases presented positive IgG and negative IgM antibodies, indicating remote EBV infection. All patients had their immunosuppression reduced (n=11), 5 received chemotherapy and 6 received monotherapy with Rituximab. Six patients (54%) achieved complete remission (CR), interestingly those with IPI &lt;=2, with a median follow-up of 20.5 months. Six (54%) patients died (four of PTLD and two of sepsis). At diagnosis, median EBV viral load of PTLD cases was 17,400 copies/106 PBMC (range 1,000 to 227,590). All six patients who achieved CR cleared their viral load one month after therapy initiation, independent of EBV levels at diagnosis and kept it undetectable during follow-up. Five out of six patients who received Rituximab achieved CR. We conclude that clearance of EBV load occurs early after therapy start and that its maintenance probably depends on restoration of T-cell defense after immunosuppression reduction. We also concluded that Rituximab monotherapy may be a reasonable therapy with a low toxicity profile in this group of patients.
Proteasome Inhibitors Can Induce Caspase-3 Activation and Apoptosis in Human CML Cell Lines.
Authors: Kim Byung-Su , Kim Chang Up , Kim Young-Ju , Bae Eun Kyung , Kim Jinhee , Ahn Kwang-Sung , Park Seonyang , Kim Byoung Kook , Yoon Sung-Soo 
Published: April 2020

Abstract
The proteasome is a multi-enzyme complex that provides the ubiquitin-dependent degradation of many cytoplasmic and nuclear proteins involved in cell cycle progression and apoptosis. Inhibition of the proteasome represents a promising approach for the treatment of cancer because it can lead to cell cycle arrest and activation of caspases in tumor cells. There are several proteasome inhibitors that have been reported to induce apoptosis in various tumors. However, the effect of proteasome inhibition in human myeloid leukemia has not been reported so far. In this study, we tested two peptide-aldehyde proteasome inhibitors (MG115, MG132) on two human CML cell lines (K562, KCL22). At first, we treated both cell lines for 24, 48 and 72 hours with different doses of MG115 and MG132 and cell viability was tested by MTT assay. It showed substantial time and dose dependent cytotoxicity in both CML cell lines. Acridine orange staining also revealed DNA fragmentation. We then performed caspase-3 colorimetric assay after treating both cell lines for 6, 12 and 24 hours with 0.78μM of MG115, MG132. K562 showed the continuous rising of caspase-3 activity, while KCL22 exhibited the initial increase and subsequent mild decrease of caspase-3 activity. In addition, western blot analysis showed the reduction of procaspase-3 expression. The expression of Bcl-2 and Bcl-XL was reduced by western blot. p21 expression was slightly increased and that of cyclin D1 was decreased. Additionally, the treatment of proteasome inhibitor in CML cell lines initially induced phosphorylation of Jun kinase. We next examined the expression of heat shock proteins (Hsp70, Hsp90) after treating for 6, 12, 24 hours with the same proteasome inhibitors. Western blot analysis results indicated that expression patterns were different between MG115 and MG132. MG115 induced the slight increase of Hsp70 and Hsp90 in K562, but the reduction of both in KCL22. Meanwhile, MG132 produced the decrease of Hsp70 and Hsp90 in both K562, KCL22. In summary, our work supports that a proteasome inhibitor can induce apoptosis in human CML cell lines. We are currently focusing on the combined effect of proteasome inhibitor and Hsp90 inhibitor on CML.
IC50 of Proteasome Inhibitors
Cell line Proteasome Inhibitor 24hr 48hr 72hr K562 MG115 3.01 μM 1.14 μM 0.59 μM K562 MG132 μ 2.13 M 1.03 μM 0.57 μM KCL22 MG115 156.92 μM 1.36 μM 0.73 μM KCL22 MG132 1.56 μM 0.93 μM μ 0.75 M
A New Abl Kinase Inhibitor (AMN107) Has In Vitro Activity on CML Ph+Blast Cells Resistant to Imatinib.
Authors: Martinelli Giovanni , Martelli Alberto M. , Grafone Tiziana , Rosti Gianantonio , Mantovani Irina , Cappellini Alessandra , Tazzari Pier Luigi , Ottaviani Emanuela , Renzulli Matteo , Amabile Marilina , Poerio Angela , Soverini Simona , Terragna Carolina , Taccioli Cristian , Bassi Simona , Baccarani Michele 
Published: April 2020

Abstract
Imatinib mesylate (STI571), an inhibitor of the bcr/abl tyrosine kinase, is rapidly becoming the first-line therapy for chronic myeloid leukemia (CML). Imatinib has proved remarkably effective at reducing the number of leukemia cells in individual CML patients and promises to prolong life substantially in comparison with earlier treatments. However, the development of resistance to this drug is a frequent setback, particularly in patients in advanced phases of the disease. Therefore, new inhibitors of bcr/abl are needed. Very recently, a new bcr/abl inhibitor, AMN107, has been synthesized. We have tested AMN107 on leukemic cell lines and on blasts isolated from imatinib-resistant CML patients. Western blot analysis with phosphospecific antibodies revealed that in K562 cells AMN107 (10 nM) down-regulated phosphorylation of bcr/abl Tyr177, while the phosphorylation levels of Tyr412 were unaffected. This finding seems particularly important because recent evidence has demonstrated that the signaling pathway emanating from Tyr177 plays a major role in the pathogenesis of CML. Indeed, phosphorylated Tyr 177 forms a high-affinity binding site for the SH2 domain of the adapter protein Grb2. The main effectors of Brb2 are Sos and Ras, however Grb2 also recruits the scaffolding adapter protein Gab2 to bcr/abl via a Grb2,Gab2 complex. Which results in activation of the PI3K/Akt and Erk signalling networks.
In contrast, STI571, even if used at 200 nM, did not diminish phosphorylation of bcr/abl Tyr177. At 10 nM AMN107 blocked K562 cells in the G1 phase of the cell cycle. To obtain the same effect with imatinib, a 200 nM concentration was required. AMN107 did not affect cell cycle progression of bcr/abl-negative cell lines such as HL60 and NB4, even if the concentration was raised to 200 nM. AMN107 (5 μM for 24 h) significantly increased apoptosis rate in CML blasts isolated from patients resistant to the same concentration of imatinib. Therefore, AMN107 might represent a new bcr/abl selective inhibitor useful for overcoming imatinib resistance.
Two Pregnancies Resulting in a Healthy Newborn in a CML Patient Treated with Imatinib.
Authors: Sotiropoulos Damianos , Adamidou Despoina , Athanasiadou Anastasia , Goulis Dimitrios G. , Fassas Athanasios , Anagnostopoulos Achilles 
Published: April 2020

Abstract
Imatinib mesylate is the new molecular targeted therapy for Chronic Myeloid Leukemia (CML). Data on fertility and pregnancy are very limited. We report the case of a 27-year old female patient having two pregnancies during therapy with imatinib. CML was diagnosed in December 2001. At diagnosis the disease was in chronic phase with 100% Philadelphia-positive metaphases in bone marrow (BM). She started therapy with IFN/Ara-C and six months later she was still with 100% Ph-positive metaphases. As she had no related transplant donor, she was started on imatinib 400mg/day. Three months later, while in complete hematologic response (CHR), she became pregnant and despite doctor’s advice, she decided not to terminate the pregnancy. At that time she had 54% Ph-positive metaphases in BM. She continued receiving imatinib during the pregnancy without any adverse effects. Ultra-sound examination revealed two normal embryos and amniocentesis yielded normal karyotypes (male and female). In 24th week of gestation she was in CHR with 20% Ph-positive metaphases in BM. Two weeks later (26th week) she delivered two newborns who both died 48 hours later due to prematurity. Laboratory tests showed no abnormalities and all parameters were normal according to their age. Seven months later and while in CHR and complete cytogenetic remission (CCR) but being BCR-ABL positive, the patient became pregnant. Once again, she continued imatinib without any adverse effects. Ultrasound parameters were normal and amniocentesis showed a normal female karyotype. After 37 weeks of gestation she delivered a healthy female newborn. Two months postpartum the child is healthy, with normal laboratory tests. The patient is in CHR, CCR and BCR-ABL positive. In conclusion we report, the case of a woman with CML in whom fertility was not affected by imatinib. In addition, Imatinib caused no abnormalities to the embryos in both pregnancies and pregnancies did not affect the therapeutic effect of imatinib. However, it is under question whether imatinib has any implication in the preterm birth of the first pregnancy.
Expression of Core-Binding Factor (CBF) Fusion Genes in Clonal Evolution of Chronic Myeloid Leukemia (CML).
Authors: Ravandi-Kashani Farhad , Kantarjian Hagop , Faderl Stefan , O’Brien Susan , Rios Mary B. , Cortes Jorge 
Published: April 2020

Abstract
A “2-hit” model of leukemogenesis has been proposed in which one class of mutations confers a proliferative or survival advantage to the cells and the second class serves primarily to interfere with hematopoietic cell differentiation. In support of this, FLT3 receptor mutations have been frequently reported in patients with t(8;21) and inv(16) acute myeloid leukemia (AML), otherwise known as core-binding factor (CBF) leukemias, whose fusion gene products (AML1-ETO and CBFB-MYH11) contribute to impaired differentiation of leukemic cells. In CML, enhanced kinase activity of BCR-ABL confers a proliferative and survival advantage to the leukemic cells and clonal evolution is a common event at the time of disease acceleration. However, the acquisition of CBF fusion genes has not been commonly reported during the clonal evolution of CML. We report 4 patients with CML who developed CBF type rearrangements [inv(16)(n=2) and t(8;21)(n=2)] at the time of disease progression. Patient #1, a 61 year old female, presented with myeloid blast phase disease with 46,XX,t(9;22)(q34;q11.2),inv(16)(p13q22) and was treated with imatinib achieving a hematological but not cytogenetic response. Patient #2, a 48 year old male, presented with chronic phase disease and received imatinib for 2 years, achieved a complete cytogenetic remission (CG CR) but progressed to blast phase with development of 46,XY,t(9;22)(q34;q11.2),inv(16)(p13q22). Both patients had elevated and abnormal marrow eosinophils at the time of clonal evolution. Patient #3, a 54 year old female, presented in chronic phase, received imatinib and achieved CG CR after 3 months. Blast transformation occurred after one year with 48, XX,+8,t(8;21)(q22;q22),t(9;22;19;10)(q34;q11;p13.1;q22),+der(22)t(9;22;19;10). Patient #4, a 47 year old male, presented with an extramedullary myeloid mass on his arm and features of chronic phase in the marrow examination. He was treated with troxacitabine with resolution of the mass. He was then treated with imatinib. Ten months later he developed a recurrent mass with cytogenetic studies of both the mass and marrow showing 47,XY,+8,t(8;21)(q22;q22),del(9)(q13q32),t(9;22)(q34;q11.2). To our knowledge, eleven other patients with CML with inv(16)(n=10) or with t(8;21)(n=1) have been previously reported in the literature, none treated with imatinib. Patients with inv(16) had features of AML with eosinophilia (FAB M4Eo) demonstrating dysplastic eosinophils in the bone marrow examination. Development of the CBF rearrangement was invariably associated with disease progression into the myeloid blast phase with the exception of one patient, reported to develop lymphoid blast phase, based on surface markers. CBF rearrngements occur rarely at the time of disease progression in CML and may contribute to disease transformation based on the “2-hit” hypothesis for leukemogenesis.
Flow Cytometry Applications in the Diagnosis of Myelodysplastic Syndrome (MDS): Analysis of 45 Cases.
Authors: Font Patricia , Subira Dolores , Martinez-Chamorro Maria C. , Castañon Susana , Lopez-Pascual Juan , Alonso Arancha , Perez-Saenz Maria A. , Gil-Fernandez Juan J. , Alaez Concepcion , Escudero Antonio , Tomas Jose F. , Fernandez-Rañada Jose M. 
Published: April 2020

Abstract
Flow cytometry is a widely used method to study most of the hematologic malignancies. The utility of bone marrow immunophenotyping for the evaluation of patients with myelodisplastic syndrome (MDS) is currently being evaluated but most of these studies are based on the analysis of a large number of monoclonal antibodies.
OBJECTIVE: To explore the potential contribution of flow cytometry to the diagnosis of MDS using a reduced panel of conjugated monoclonal antibodies (MoAb).
PATIENTS AND METHODS: 45 bone marrow specimens from patients with a diagnosis of MDS based on morphologic and cytogenetic parameters (17 RA, 12 RARS, 5 MMCL, 9 RAEB, 2 RAEB-t), were analyzed by flow cytometry. In addition, 25 samples of bone marrow obtained from patients with cytopenias, but no diagnosis of MDS, were also studied. The panel of MoAb used was designed to identify abnormalities in the differentiation pathways of erithroid (CD71 FITC/Gly A PE/CD45 PC5) and myeloid lineage (CD 16 FITC/CD11b PE/CD13 PC5) as well as the presence of specific aberrant features in the CD34+ myeloid cell population (TdT FITC/CD7 PE/CD34 PC5). All samples were analized by two independet observers. To establish the diagnosis of MDS by flow cytometry, it was necessary to describe either immunophenotypic abnormalities in both myeloid and erithroid lineages or abnormalities in only one lineage plus description of more than 5% of CD34+ cells or abnormalities in one lineage plus description of aberrant features in the CD34+ population, regardless of its percentage.
RESULTS: In 43 of the 45 samples analyzed, flow cytometric criteria of MDS were described. Only two cases (1 RARS with normal karyotype and 1 RA with complex cytogenetics) were considered normal according to the immunophenotypic criteria (95% sensivity). Regarding the cohort control, 4 samples had flow cytometric criteria of MDS; 11 samples showed isolated antigenic aberrancies in the erithroid differentiation and the 11 samples left were considered as normal.
CONCLUSIONS: Flow cytometry may be a useful tool in the diagnosis of MDS, even analysing only two hemopoietic cell lineages. The reduced panel of MoAb described here can be widely used, is easy to be applied and shows a high sensitivity and a low cost. However, the finding of isolated immunophenotypic abnormalities in some patients without cytologic data of MDS seems to negatively influence the specificity of the technique. Nevertheless, those cases presenting an abnormal immunophenotype and normal morphology should be carefully monitored during their ulterior follow-up.
Clinical Course and Prognosis in Mast Cell Proliferative Disorders: A 17 Year Experience in a Single Center.
Authors: Sperr Wolfgang R. , Wimazal Friedrich , Boehm Alexandra , Hauswirth Alexander W. , Florian Stefan , Fritsche-Polanz Robert , Foedinger Manuela , Valent Peter 
Published: April 2020

Abstract
In patients (pts) with mast cell (MC) proliferative disorders, the clinical course, prognosis, and outcome vary depending on age, organ-involvement, and the disease-variant. We have retrospectively analyzed the clinical course and outcome in 56 pts with MC disorders refered to the University of Vienna between 1987 and 2004. Using WHO criteria, pts were found to have cutaneous mastocytosis (CM, n=6), indolent systemic mastocytosis (ISM, n=35), aggressive SM (ASM, n=3), mast cell leukaemia (MCL, n=1), SM with associated clonal hematologic non-MC-lineage disease (SM-AHNMD, n=6), and myelomastocytic leukemia (MML, n=5). These groups differed from each other in serum tryptase levels, hemoglobin, platelet counts, and lactate dehydrogenase (p&lt;0.05). By contrast, no significant differences were found in white blood cells, eosinophils, monocytes, or presence of the c-kit mutation D816V. Most pts with ISM showed a stable clinical course without signs of progression or increase in serum tryptase even when monitored for more than a decade. By contrast, in all pts with ASM, MCL, SM-AHNMD, and MML, the neoplasm progressed after a latency period of several months. The median event-free survival was 3.7 months in pts with ASM/MCL, 22.8 months in SM-AHNMD, and 5.0 months in MML. In CM and ISM, the median survival was not reached. The differences in event-free survival among WHO groups were found to be significant (p&lt;0.05). Apart from high grade WHO categories, adverse prognostic variables concerning survival were i. absence of skin-lesions, ii. high percentage (&gt;5%) of MC in bone marrow smears, and iii. splenomegaly. Polychemotherapy resulted in complete remission in MML, but not in ASM or MCL. Interferon-alpha and 2CdA showed cytoreductive effects in some pts with ASM, but did not work in MCL. For the latter group of pts new therapies need to be developed.
Imatinib Mesylate for Patients (pts) with Hypereosinophilic Syndrome (HES) and Systemic Mastocytosis (SM): A Phase II Trial.
Authors: Jabbour Elias , Kantarjian Hagop , Verstovsek Srdan , Jones Dan , O’Brien Susan , Luthra Raja , Ravandi-Kashani Farhad , Wierda William , Giles Francis , Rios Mary Beth , Cortes Jorge 
Published: April 2020

Abstract
Imatinib is a potent inhibitor of the tyrosine kinases c-abl, c-kit, ARG, platelet-derived growth factor (PDGFR)-alpha and PDGFR-beta. We and others have reported on the clinical efficacy of imatinib in pts with HES and SM. We report here on 28 pts (16 HES, 12 SM) treated in a phase II study of imatinib. Pts with HES received imatinib at a starting dose of 100 mg daily with escalation to 400 mg if no response after 1 month (mo). Pts with SM were started at a dose of 400 mg with possible escalation to 800 mg. The median age was 52 years (yrs) (26–77 yrs). All pts had signs and symptoms of end-organ involvement with 10 (83%) of 12 pts with SM having skin involvement. 15 (53%) of 28 pts had received prior therapies. Imatinib was started within 34 mo from diagnosis (3–162 mo). Prior to the start of imatinib, the median eosinophil count for pts with HES was 2.2 x109/L (0.5–7 x109/L) and the median percentage of eosinophils in the bone marrow was 19% (5%–28%). 2 of the pts with SM had increased eosinophils, 9 pts have been evaluated for serum tryptase level; this was increased in 5 (0 HES, 5 SM). 6/16 (37%) pts with HES responded: 3 achieved a complete remission (CR) (defined by the disappearance of eosinophilia and signs and symptoms of disease) and 3 a partial response (PR) (defined by the reduction of eosinophilia and organomegaly by &gt; 50%). Two pts (1 CR, 1 PR) required dose escalation to 400 mg. The median duration of response was 11+ mo (1+ to 21+). One patient died in CR at 18 mo, 1 was lost to follow-up after 1 mo in CR; 2 have ongoing response (1 PR, 1 CR) 15+ and 21+ mo, respectively; and 2 lost PR after 3 and 10 mo, respectively despite dose escalation. 7/12 pts with SM (58%) responded. Six pts achieved a major response (MR) (defined by the complete resolution of at least one clinical finding and no progression in other clinical findings): 4 CRs, 1 PR (defined by the incomplete regression of one or more clinical finding(s) without complete regression and without progress in other clinical findings) (Leuk Res 27:635,2003). One pt (MR) required imatinib escalation to 800 mg. The median duration of response was 14+ mo (7+ to 36+). At the time of response, 2 pts had normalized their tryptase levels. Only one pt has lost response (PR) after 9 mo. Overall, treatment was well tolerated. 2 pts experienced grade 3 diarrhea; one of them required imatinib dose reduction. We conclude that therapy with imatinib for patients with HES and SM appears effective and well tolerated.