bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment Outcome of Aggressive Lymphoma with CyclOBEAP (CHOP-Like + Etoposide and Bleomycin): Results of Multicenter Trial.
Authors: Okamoto Masataka , Niitsu Nozomi , Aoki Sadao , Kuraishi Yasunobu , Okumura Hirokazu , Hirano Masami 
Published: October 2019

Abstract
Introduction: To improve treatment outcome in aggressive lymphoma, a CHOP-like regimen with added etoposide and bleomycin was studied.
Patients and Methods: Between April 1997 and March 2003, 126 consecutive patients (pts) with aggressive lymphoma of low-intermediate to high risk disease according to the age adjusted International Prognostic Index (IPI), age<61 years, and performance status(ECOG)<3 were treated with CyclOBEAP. MCL and ATL/L were excluded from this study. CyclOBEAP was a weekly protocol for a total period of 12 weeks. It consisted of doxorubicin 50mg/m2 given every 2 weeks in combination with either cyclophosphamide 1,000mg/m2 (weeks 1, 5, 9) or etoposide 70mg/m2 qd x4 (weeks 3, 7, 11). During the alternative weeks non-myelosuppressive vincristine 1.4mg/m2 (max. 2.0mg/body) was given either with bleomycin 10mg/m2 (weeks 2, 6, 10) or alone (weeks 4,8,12). Prednisolone 40mg/m2 was administered daily for 14 days during weeks 1–2, 5–6, and 9–10. Protocol dose intensity relative to that of CHOP was 1.5 for DXR, VCR and 1.0 for CPA. G-CSF was prophylactically used. Pts who had had a bulky disease at presentation received 40Gy of local irradiation after chemotherapy.
Results: One hundred twenty-six pts were enrolled and 5 were excluded from analysis; 3 due to change of diagnosis ( ATL/L, Hodgkin lymphoma, germ cell tumor), 1 due to PS4 and the other due to drop out. In 121 eligible pts (DLBCL 94, PTCL 11, ALCL 7, nasal NK/T 4, others 5), 7 pts did not complete the full course of the treatment because of pneumonia (3), liver damage (1), intrathoracic hemorrhage (1), and PD response at 8th week (2). Relative given dose intensity was 0.94 for DXR, 0.95 for CPA, 0.86 for VCR, 0.94 for VP16, and 0.96 for BLM. All pts were evaluated. CR (including cCR) was obtained in 106 (88%), PR in 11 and NC/PD in 4. No treatment related death was observed. With a median follow-up of 56 months, 5yr overall survival (OS) rate is 72% and progression-free survival (PFS) rate is 62%. The 5yr OS and PFS within the subgroups defined by IPI and in pts with DLBCL and PTCL are not significantly different (data shown in the table). WHO grade 4 neutropenia was observed in 91 pts and thrombocytepenia in 13 pts. 66 pts required 2 or more units of red cell transfusions (2 – 66 units). Liver damage of grade 3 to 4 was seen in 3 pts.
Conclusions: Addition of etoposide and bleomycin to CHOP drugs may enhance the effect of CHOP for aggressive lymphoma, encouraging comparative study between the two treatments.
n CR (%) 5yr OS 5yr PFS *OS:Log-Rank 0.578; Wilcoxson 0.616 *PFS:Log-Rank 0.552; Wilcoxson 0.573 #OS:Log-Rank 0.049; Wilcoxson 0.059 #PFS:Log-Rank 0.122; Wilcoxson 0.146 All 121 106 ( 88) 72 % 62 % IPI: L-I* 41 37 ( 90) 69 65 IPI: H-I* 62 56 ( 90) 71 55 IPI: H* 18 13 ( 72) 82 43 DLBCL# 94 82 ( 87) 70 58 PTCL# 11 11 (100) 100 82
Combination Therapy with CC-5013 (Lenalidomide; Revlimid™) Plus Dexamethasone (Rev/Dex) for Newly Diagnosed Myeloma (MM).
Authors: Rajkumar S. Vincent , Hayman Suzanne R. , Lacy Martha Q. , Dispenzieri Angela , Hoering Antje , Geyer Susan M. , Zeldenrust Steven R. , Greipp Philip R. , Fonseca Rafael , Lust John A. , Russell Stephen J. , Kyle Robert A. , Witzig Thomas E. , Gertz Morie A. 
Published: October 2019

Abstract
Background: Increasingly thalidomide (Thal) plus dexamethasone (Dex) is being used as initial therapy for multiple myeloma (MM), but there is a need to minimize non-hematologic toxicity with this regimen. CC-5013 (lenalidomide; Revlimid™) is a more potent analog of thalidomide with significantly fewer non-hematologic toxicities that has shown promising results in relapsed refractory myeloma. We report the initial results of the first phase II trial using the combination of CC-5013 plus Dex (Rev/Dex) as initial therapy for newly diagnosed MM.
Methods: The trial is designed to accrue 31 eligible patients; 13 patients (pts) (11 male and 2 female) were analyzed in this interim report. Patients were enrolled between February 2004 and July 2004. CC-5013 was given orally at a dose of 25 mg daily on days 1–21 of a 28-day cycle. Dex was given orally at a dose of 40 mg daily on days 1–4, 9–12, 17–20 of each cycle. Patients also received an aspirin once daily as thrombosis prophylaxis. Response was defined as a decrease in serum monoclonal (M) protein by 50% or higher and a decrease in urine M protein by at least 90% or to a level less than 200 mg/24 hours. Responses were assessed on an intent to treat basis.
Results: The median age was 61 years (range, 32–78). 8 patients (62%) had Stage III myeloma. 11 of the 13 patients achieved an objective response yielding a response rate of 85% within 1–2 months of therapy. So far 6 patients have experienced grade 3 adverse events. These include one episode each of CD4-count < 200/mm3, anemia, neutropenia, increased liver enzymes, muscle weakness, agitation, hyperglycemia, cardiac arrhythmia, pneumonitis, and colonic perforation (underlying diverticulitis and dexamethasone suspected). No deep vein thrombosis or grade 4 or higher adverse events have been observed so far.
Conclusions: Rev/Dex appears active and well tolerated in the treatment of newly diagnosed MM and is a potential alternative to Thal/Dex. However, these results are preliminary and responses are still being evaluated and need to be confirmed in the final analysis of this trial. A large randomized trial using Rev/Dex as initial therapy for MM is expected to be activated by the Eastern Cooperative Oncology Group later this year.
Thrombopoietin Protects Against Cardiotoxicity Induced by Doxorubicin.
Authors: Sung Rita Y.T. , Huang Wei Zhe , Yang Mo , Pong Nga Hin , Lee Shuk Man , Chan Wood Yee , Wong Yeuk Oi , Xiao Da Wei , To Man Yin , Li Karen K.H. 
Published: October 2019

Abstract
Doxorubicin (DOX), an anthracycline drug, is the key component of various chemotherapy regimens. However, it exerts severe cardiotoxicity including cardiomyopathy and congestive heart failure. Thrombopoietin (TPO) is an established cytokine for promoting early hematopoietic progenitor cells, the megakaryocytic/platelet lineage and angiogenesis. In this study, we investigated effects of TPO on the protection against cardiotoxicity induced by DOX in a mouse model. Male Balb/c mice at 10 weeks of age were randomly divided into 3 groups (each N=6): Normal control (saline), DOX (20mg/kg, single dose i.p., Day 0) and TPO+DOX treatment (12.5μg/kg TPO at Days −1, +1 and +3). Transthoracic echocardiography (Sonos 7500) was performed using a high frequency transducer (15L6) at baseline (Day −1) and Day +5 on animals maintained at a conscious state. Our results demonstrated that DOX exerted cardiotoxicity in DOX-treated animals, indicated by significant reductions in heart weight, heart rate and fraction shortening (Table). Treatment with TPO significantly increased these heart function parameters. Effects of TPO were confirmed by the morphology of heart tissues, which demonstrated extensive cytoplasmic vacuolization (mean±SD = 20.0±3.30%) and myofibrillar loss (42.0±5.90%) in DOX-treated animals. These damages were significantly reduced in TPO+DOC-treated mice (8.00±1.60% and 21.0±3.30% respectively, p<0.05). The possible direct effects of TPO on rat cardiomyocytes were further investigated by in vitro studies on cell line and primary cells. The MTT assay on the H9C2 cell line demonstrated that DOX (5μg/ml, 24h) significantly reduced cell viability by 26.2±1.09% (n=4, p<0.01). These cells responded to TPO at a dose-dependent manner and cell viability was recovered to 85.6±4.43% (100ng/ml TPO, p<0.01). DOX (0.58μg/ml) inhibited primary neonatal cardiomyocytes in culture (48h) by reducing their beating rates to 9.25±11.1% of those recorded before DOX treatment (n=8, p<0.01). TPO and the cardioprotective drug dexrazoxane (5.8μg/ml) increased the beating rates of these cardiomyocytes to 47.8±12.7% and 34.5±11.5%, respectively (p<0.01). We also detected the expression of TPO receptors (c-mpl) by RT-PCR in mouse heart tissues. Our study demonstrated that TPO has cardioprotective effects against DOX toxicity and could be further developed for clinical applications.
Effects of TPO on Heart Weight and Functions of DOX-Treated Mice
Heart Weight (mg) Heart Rate (beats/min) Fraction Shortening (%) Mean±S.D.; * p<0.01 (DOX vs Control); # p<0.05 (DOX vs TPO+DOX at Day+5); ** p<0.05 (Day-1 vs Day+5) Control (Day-1) - 551±41.0 57.0±4.30 Control (Day+5) 118±15.3 581±40.0 60.7±2.80 DOX (Day-1) - 605±37.3 58.7±1.53 DOX (Day+5) 79.2±8.17* 410±45.2** 39.5±4.93** TPO+DOX (Day-1) - 575±40.0 60.2±3.55 TPO+DOX (Day+5) 92.7±6.94# 515±67.0# 56.3±7.66#
Myeloablative Treosulfan as Preparative Regimen for Allogeneic Haematopoietic Stem Cell Transplantation: A Single-Centre Experience.
Authors: Trenschel Rudolf , Ditschkowski Markus , Elmaagacli Ahmet , Steckel Nina K. , Hlinka Michal , Peceny Rudolf , Ottinger Helmut , Koldehoff Michael , Biersack Harry , Flasshove Michael , Beelen Dietrich W. 
Published: October 2019

Abstract
Treosulfan (TREO), a water-soluble bifunctional alkylating agent, has demonstrated strong immunosuppressive and antileukemic activity as well as profound stem cell toxicity in animal studies. Due to the advantageous clinical toxicity profile lacking significant non-hematologic organ toxicities, high-dose TREO in combination with cyclophosphamide (CY) has recently been evaluated in patients (pts) with an increased risk for organ toxicities precluding standard myeloablative conditioning regimens before allogeneic stem cell transplantation (SCT). Between 8/00 and 10/03, we treated 52 patients (pts) not eligible for conventional therapy with TREO in order to reduce toxicity in a myeloablative setting. Diagnoses were AML (n=14), ALL (n=11), MM (n=8), NHL (n=7), MDS (n=5), CML (n=4) and aplastic syndromes (n=3). 18 patients were grafted in early disease (1st or 2nd complete remission, chronic phase, or incipient first relapse (BM blasts < 10%). The remaining pts were classified as having advanced disease. Donors were identical siblings (n=24), non-identical family members (n=l), matched unrelated (n=14) or mismatched unrelated (n=13) donors. Conditioning regimen consisted of TREO 36g/qm (n=19) or 42g/qm (n=28) and CY 120mg/kg BW, 5 pts received TREO 42g/qm and fludarabine 150mg/qm. GvHD prophylaxis consisted of CSA alone (n=l) or in combination with short course MTX (n=25), alemtuzumab (n=22) or ATG (n=4). ANC > 500/μl and platelets > 20000/μl were reached at day 15 and 16 respectively. Acute GvHD grade II - IV occurred in 31% of pts and chronic GvHD in 60% of pts. Overall (OS) and disease free survival (DFS) were closely related to disease status. OS and DFS was 93% and 82,9% after a median of 18 months (range 0,9–38,5 months) for pts with early disease. In advanced disease the OS was 57,4% and the DFS 47,9% after a median of 4,8 months (range 0,3 – 22,9 months), respectively. In early disease, a single patient died of invasive aspergillosis associated with grade IV aGvHD. Another patient developed a relapse of CML which was successfully treated with DLI. Clinical relevant adverse events occurred in patients with advanced disease: MOF (n=7), VOD (n=2), infectious problems associated to GvHD grades II – IV (n=4), and pulmonary embolism (n=l). TREO as part of a myeloablative regimen seems to be effective and safe even in pts not eligible for conventional myeloablative therapy.
Pleitrophin Is Highly Expressed by Myeloma Cells, Elevated in the Serum of Myeloma Patients, and Is a New Autocrine Growth Factor for This B Cell Malignancy.
Authors: Chen Haiming , Zhu Daocheng , Campbell Richard A. , James Christine Pan , Li Sonia Guangxu , Santos Janice , Wang Cathy S. , Bonavida Benjamin , Berenson James R. 
Published: October 2019

Abstract
Pleitrophin (PTN) was originally described as a development regulatory cytokine. This protein regulates the growth of neuroectodermal and mesodermal cell lineages during early embryogenesis but becomes down-regulated during late phase of embryogenesis and shows a very restricted expression pattern in adult neural system. This protein has been recently shown to both induce angiogenesis and bind to syndecan. Thus, we determined whether this protein may be found in tumor cells from myeloma patients and its potential to influence their growth. First, we measured serum levels of PTN in myeloma (n=115) and age-matched controls (n=50) using an ELISA-based technique. PTN levels in the serum of myeloma patients were markedly elevated compared to the normal control group (P<0.02). The serum concentration of PTN in MM patients averaged 28 pg (range, 8 to 110 pg). In contrast, the control serum levels averaged only 12 pg (range, 0 to 20 pg. Interestingly, the PTN concentration in two patients with plasma leukemia was much higher than other multiple myeloma patients. Next, we analyzed the expression of PTN using RT-PCR on RNA from myeloma cell lines (RPMI8226, U266), and multiple myeloma patients’ and normal control bone marrow aspirates. Results showed that the PTN mRNA was strongly expressed in multiple myeloma cell lines, myeloma bone marrow samples but not in the normal control bone marrow specimens.
In order to determine whether PTN stimulates multiple myeloma growth, we further cloned a whole PTN sense or anti-sense sequencing DNA into the multiple myeloma cell lines RPMI8226 and U266. Cells transduced with sense PTN showed markedly increased proliferation compared to cells transduced with antisense or vector alone. The role of PTN in hematological malignancies has not been previously defined. Due to the restricted expression pattern of PTN in adults, PTN is suggested as a potential new target for treatment of multiple myeloma. Further investigations are defining the prognostic value of PTN serum levels and the mechanism by which this cytokine drives myeloma growth.
MTOR Inhibitors Activate the AKT Kinase in Multiple Myeloma Cells by Upregulating the IGF-1/IRS-1/PI-3 Kinase Cascade.
Authors: Shi Yijiang , Yan HuaJun , Frost Patrick , Hoang Bao , Gera Joseph , Lichtenstein Alan 
Published: October 2019

Abstract
MTOR inhibitors, such as rapamycin and CCI-779, have shown pre-clinical potential as therapy for multiple myeloma (MM). By inhibiting expression of cell cycle proteins, these agents induce G1 arrest. However, by also inhibiting an mTOR-dependent phosphorylation of insulin receptor substrate-1 (IRS-1), they may alter its subcellular localization and/or prevent its degradation which could enhance IGF-1 signaling and downstream PI3-kinase/AKT activation. This may be a particular problem in MM where IGF-1-induced activation of AKT is an important anti-apoptotic cascade. We, thus, studied PI3-kinase/AKT activation in MM cells treated with mTOR inhibitors. Rapamycin enhanced basal AKT activity, AKT phosphorylation and PI3-kinase activity in MM cell lines. Both PTEN-null as well as PTEN-wild type myeloma lines were similarly affected. Rapamycin also significantly prolonged activation of AKT induced by exogenous IGF-1. CCI-779, used in a xenograft model, also resulted in MM cell AKT activation in vivo. Blockade of IGF-1 receptor function prevented rapamycin’s activation of AKT. Furthermore, rapamycin prevented serine phosphorylation of IRS-1 and IRS-1 degradation. Though similarly blocking IRS-1 degradation, proteasome inhibitors did not activate MM cell AKT. Although rapamycin sensitized MM cells for dexamethasone-induced apoptosis, it protected against PS-341-induced apoptosis. Thus, mTOR inhibitors activate PI3-K/AKT in MM cells and activation depends on basal IGF-1/IGF-R signaling. As activated AKT may protect against apoptosis, future use of mTOR inhibitors in myeloma patients will have to carefully consider the types of anti-myeloma agents used in combination.
Inhibition of Wnt Pathway Signaling by Thalidomide and Revlimid: Studies in a Drosophila Model System.
Authors: Stewart A. Keith , Zhu Yuan Xiao , Yahyapour Maryan , Manoukian Armen , Scanga Sam E. 
Published: October 2019

Abstract
High throughput sequencing, gene expression profiling and protein biochemistry in myeloma have all consistently revealed elevated expression of wnt signaling pathways in malignant plasma cells. Indeed, downregulation of the Wnt pathway in myeloma cells has recently been shown to inhibit myeloma cellular proliferation. Preliminary pharmacogenomic studies have also suggested that hyperactivation of the wnt signaling antagonist DKK-1 is associated with response to the immunomodulators thalidomide and revlimid. The mechanism of action for these therapeutically active drugs is however by no means clear as multiple biologic consequences of treatment have been proposed. We report here use of a drosophila model to examine wnt signaling inhibition by these pharmaceuticals. We employed a unique drosophila larval imaginal disc culture system in which wnt pathway activity is monitored through control of LacZ expression by the distalless promoter. In this system 10uM of both thalidomide and revlimid reproducibly inhibit lacZ expression when compared with vehicle controls. Western blots of larva confirmed downregulation of expression of armadillo (the drosophila b-catenin homologue) by both drugs but particularly revlimid. Lithium Chloride is an inhibitor of the drosphila GSK3b homologue shaggy and thus mimics wnt signaling by stabilizing b-catenin. The effect of Lithium could not be overcome by thalidomide or revlimid indicating that the action of these drugs is upstream of shaggy (or GSK3). Next we employed a fly transgenic for wingless which is embryonic lethal. By adding either drug to larval culture medium the lethality of wingless expression was reversed. Indeed drosophila embryos fed thalidomide exhibited developmental plate abnormalities. We next sought evidence that similar effects were evident in revlimid treated human myeloma. As previously reported most myeloma cell lines studied expressed b-catenin and this protein was downregulated by revlimid treatment of human myeloma cell lines co-incident with inhibition of growth as measured by MTT assay. We sought, but failed to find evidence of up-regulation of the wnt signaling pathway antagonist DKK-1 using an ELISA assay on pre and post treatment serum samples in patients responding to thalidomide.The implications of wnt signaling inhibition as a primary or secondary readout of therapeutic efficiency in MM may be of substantial importance in subsequent design of drug therapies or combination therapies.
Cladribine Alone or in Combination with Cyclophosphamide or Cyclophosphamide and Mitoxantrone as First Line Treatment in Chronic Lymphocytic Leukemia: An Early Report of Prospective Randomized Study.
Authors: Robak Tadeusz , Blonski Jerzy Z. , Gora-Tybor Joanna , Kasznicki Marek , Dwilewicz-Trojaczek Jadwiga , Tomaszewska Agnieszka , Konopka Lech , Ceglarek Bernadeta , Kloczko Janusz , Sokolowski Jaroslaw , Dmoszynska Anna , Kowal Malgorzata , Zawilska Krystyna , Stella-Holowiecka Beata , Sulek Kazimierz , Kuliczkowski Kazimierz , Warzocha Krzysztof , Calbecka Malgorzata , Skotnicki Aleksander 
Published: October 2019

Abstract
The aim of the study was to determine the efficacy and toxicity of cladribine alone (2-CdA) and in combination with cyclophosphamide - CY (CC) or CY and mitoxantrone - MIT (CMC) in previously untreated patients with progressive or symptomatic chronic lymphocytic leukemia in a randomized, multicenter study. 2-CdA was given at a dose of 0.12 mg/kg/d in 2 h I.V. infusion for 5 consecutive days in monotherapy and for 3 days in combination. In CC and CMC programmes cyclophosphamide was administered at a dose of 650 mg/m2 I.V. on day 1 and additionally mitoxantrone 10 mg/m2 I.V. on day 1 in CMC. Courses were repeated at 28 day intervals or longer if myelosuppression and/or infection developed, for a maximum of 6 courses. The response criteria were those recommended by NCI sponsored Working Group. Minimal residual disease (MRD) were evaluated by flow cytometry if CR was achieved.
In conclusion, the results of our study indicate that 2-CdA combined with CY or CY+MIT as first line therapy give higher CR rate than 2-CdA alone. However, CMC is more toxic than 2-CdA or CC. We recommend CC combination for further studies.
Treatment 2-CdA CC CMC p value Entered pts 167 169 163 Evaluated pts 143 152 139 CR 37 (25.9%) 43 (28.3%) 55 (39.6%) 0.03 OR 106 (74.1%) 125 (82.2%) 110 (79.1%) 0.2 MRD 15 (46.9%) 22 (82.2%) 25 (56.8%) 0.7 Median OR duration (years) 1.67 1.81 1.43 0.1 Relapse 48 (45.3%) 45 (29.6%) 43 (30.9%) 0.2 AIHA 10 (7.0%) 10 (6.6%) 5 (3.6%) 0.4 Thrombocytopenia grIII/IV 25 (17.5%) 25 (16.4%) 32 (23.0%) 0.3 Neutropenia grIII/IV 27 (18.9%) 43 (28.3%) 52 (37.4%) <0.001 Infections 39 (27.3%) 47 (30.9%) 53 (38.1%) 0.07 Died 39 (27.3%) 30 (19.7%) 37 (26.6%) 0.4
FLT3 ITD and FLT3 Tyrosine Kinase Domain Mutants Induce Different Phenotypes in a Murine Bone Marrow Transplant Model.
Authors: Grundler Rebekka , Miething Cornelius , Thiede Christian , Peschel Christian , Duyster Justus 
Published: October 2019

Abstract
Activating mutations of FLT3 are frequent in patients with acute myeloid leukemia (AML). Two distinct types of FLT3 mutations are most common: Internal tandem duplication (ITD) of the juxtamembrane domain-coding sequence in approximately 30% of patients with AML and point mutations within the second tyrosine kinase domain (TKD) in about 7% of AML patients. Patients carrying the FLT3 ITD mutation seem to have a significantly worse prognosis, whereas the impact of TKD mutations on clinical outcome has not yet been determined. Recently, point mutations within the activation loop of FLT3 were also found in a significant percentage of infant and childhood acute lymhoblastic leukemia (ALL).
Previous studies demonstrate that mice receiving transplants of bone marrow retrovirally infected with FLT3 ITD develop a myeloproliferative disease. The effect of FLT3 TKD mutations in vivo has not yet been investigated.
To examine the transforming properties of FLT3 TKD mutants in primary hematopoietic cells, we used a bone marrow transplant model (BMT). Therefore we transduced bone marrow with retrovirus expressing either FLT3 D835Y or FLT3 I836M+R and transplanted it to lethally irradiated syngeneic recipient mice. As control we also transplanted mice with FLT3 WT and ITD infected bone marrow, respectively. We found that mice transplanted with FLT3 ITD developed a myeloproliferative disorder in mice, as previously described. In contrast, mice transplanted with FLT3 TKD mutants developed a lymphoid disease with distinct hematologic manifestation.
Most recipients of FLT3 TKD transduced bone marrow developed T lymphoma syndrome, characterized by massive enlargement of thymus and lymph nodes. Some mice developed a B lymphoid leukemia with splenomegaly and enlarged lymph nodes. Interestingly, the disease latency of 53 to 183 days (median 102 days) of FLT3 TKD mutants contrasted with FLT3 ITD mice, which succumbed myeloproliferative disease within 53 to 70 days (median 58 days).
The lymphoid manifestation and longer latency of FLT3 TKD in a murine BMT model together with the absent influence of FLT3 TKD mutations on clinical outcome of AML patients suggest differences in cell signaling between FLT3 TKD mutants and FLT3 ITD. The TKD mutants seem to require lymphoid cell context for full malignant transformation, whereas FLT3 ITDs transform myeloid cells.