bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mabthera (Rituximab) Plus CVP Chemotherapy for First-Line Treatment of Stage III/IV Follicular Non-Hodgkin’s Lymphoma (NHL): Confirmed Efficacy with Longer Follow-Up.
Authors: Solal-Celigny Philippe , Imrie Kevin , Belch Andrew , Robinson Katherine Sue , Cunningham David , Rueda Antonio , Catalano John , Offner Fritz , Walewski Jan , Raposo João , Smith Paul , Marcus Robert 
Published: April 2020

Abstract
Design/Methods: We recently demonstrated in a phase III trial that the addition of rituximab to each of 8 cycles of CVP (R-CVP) chemotherapy significantly improves the clinical outcome of previously untreated patients with stage III/IV CD20 positive follicular NHL when compared to CVP alone (Marcus et al., Blood2005; 105: 1417–23). A multivariate Cox regression analysis of time to progression or death (TTP) showed a treatment benefit in all patient subgroups according to baseline risk factors, except for patients with a baseline hemoglobin level below normal. We now present an updated analysis of all major trial endpoints with 42 months follow-up (FU).
Results: A total of 321 patients (median age 53 years) were recruited (159 CVP, 162 R-CVP). Approximately half of the patients had high-risk disease according to the Follicular Lymphoma International Prognostic Index (FLIPI, score 3–5). The median TTP was more than doubled for patients receiving R-CVP compared to CVP alone (33.6 months vs 14.5 months, p&lt;0.0001). Median time to new lymphoma treatment or death (TNLT) was 12.3 months in the CVP group and nearly quadrupled to 46.3 months in the R-CVP group (p&lt;0.0001). Superior response rates for R-CVP were confirmed (CR+CRu rate 41% vs 11%, p&lt;0.0001) with a median response duration (DR) of 13.5 months in the CVP arm versus 37.7 months in the R-CVP arm. Median disease free survival (DFS) in complete responders was 44.8 months for patients receiving R-CVP and 20.5 months in patients receiving CVP alone (p=0.0005). Thirty-five patients in the CVP arm and 23 patients in the R-CVP arm have died. Kaplan-Meier estimates of 3-year OS rates were 81% in the CVP arm and 89% in the R-CVP (p=0.07). Importantly, significantly more patients receiving CVP died due to lymphoma progression compared to patients receiving R-CVP (25 vs 12 deaths, p=0.02). Subgroup analysis for TTP, ORR, DR and OS according to risk factors at baseline are ongoing and will be presented.
Conclusion: With longer FU, the combination of 8 cycles of rituximab with CVP chemotherapy continues to provide a major benefit as first line treatment for patients with advanced stage follicular NHL.
Kaplan Meier plot of time to death due to disease progression Kaplan Meier plot of time to death due to disease progression
Toxicity Profiles in Patients Using Bortezomib for Multiple Myeloma: Korean Multicenter Analysis.
Authors: Bang Soo-Mee , Lee Jae Hoon , Yoon Sung-Soo , Park Seonyang , Min Chang-Ki , Suh Cheolwon , Sohn Sang Kyun , Min Yoo-Hong , Lee Je-Jung , Kim Kihyun , Seong Chu-Myong , Yoon Hwi-Joong , Jo Deog-Yeon , Lee Kyung Hee , Lee Na-Ri 
Published: April 2020

Abstract
Introduction: The proteasome inhibitor bortezomib has demonstrated clinical activity in pts with MM. Its adverse effects including thrombocytopenia and peripheral neuropathy affected 30% to 60% of patients overall, and interrupted the therapy in 10% to 20%. There were no toxicity data in Asian pts using bortezomib for MM.
Methods: We reviewed the clinical records of MM pts from 24 centers in Korea using NCI Common Toxicity Criteria version 3.0. They were treated with bortezomib alone or in combination with other agents including thalidomide.
Results: 92 pts with MM were treated with a median age of 60yrs (range: 42–77). Median number of previous treatments was 3 (range: 1–10), 73% had been treated with three or more of the major classes of agents including thalidomide (67%) and autologous stem cell transplantation (51%). Regimens were bortezomib only in 36 (39%), bortezomib plus dexamethasone in 33 (36%), and bortezomib plus thalidomide-containing regimen in 23 (25%) pts. Analysis of response revealed CR +nCR in 31 (34%) and PR in 27 (30%), for an ORR of 64% in 90 evaluable pts. The most commonly reported adverse events were thrombocytopenia, sensory neuropathy, infection and fatigue (figure 1). Six therapy-related mortality (7%) were reported within 20 days after the last dose of bortezomib. Causes of death were infection in 3, disease progression in 2 and suicide in 1 patient. Twelve pts (13%) ceased the therapy due to toxicity; neuropathy in 7, infection in 4 and diarrhea in 1 pt. Neuropathy more than grade 2 were more frequent in pts who received thalidomide (11/23) when compared with those without thalidomide (17/69) (p=0.036). But preexisting neuropathy and number of prior regimens did not affect the neuropathy.
Conclusion: The incidence of thrombocytopenia and neurotoxicity were similar but the gastrointestinal toxicities were relatively low in Korean pts compared to that in western studies. Significant neuropathy was associated with the combination of thalidomide to bortezomib. This finding will give a useful message for the development of safe salvage regimen including bortezomib.
Figure Figure
Methylation of Progesterone Receptor Promoter-Associated CpG Island in Polycythemia Vera and Related Myeloproliferative Disorders.
Authors: Jelinek Jaroslav , Verstovsek Srdan , Bueso-Ramos Carlos E. , Prchal Josef T. , Issa Jean-Pierre J. 
Published: April 2020

Abstract
Polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (MF) are clonal myeloproliferative disorders (MPD). A recently discovered activating mutation of JAK2 tyrosine kinase has been found in most patients with polycythemia vera (PV), in about half of those with essential thrombocythemia (ET) and myelofibrosis (MF), and in 10–20% patients with chronic myelomonocytic leukemia, Philadelphia-negative CML, atypical or unclassified MPD and megakaryocytic leukemia. It is not known what other factors determine the disease phenotype of PV, MF, and other MPD, and what factors other than JAK2 lead to disease progression. Very little is known about epigenetic changes in PV. DNA methylation of promoter-associated CpG islands is a well-recognized mechanism of epigenetic silencing used by tumors for evasion from regulatory mechanisms, and it is an alternative to genetic lesions in cancer causation. Using a genome-wide screen for differentially methylated CpG islands, we found methylation of progesterone receptor promoter region (PGR) in PV granulocytes. We then developed pyrosequencing assays for quantitative detection of PGR methylation in bisulfite-treated PCR-amplified DNA. The PGR methylation above normal control levels was observed in ET (2/12 patients, 17%), PV (10/22 patients, 45%), MF (8/12 patients, 67%), and patients with acute myeloid leukemia and antecedent PV (6/7 patients, 86%). We compared the levels of PGR methylation in MPD with the mutation status of JAK2. The 1849G&gt;T JAK2 mutation was present in 16/27 (59%) MPD patients with unmethylated PGR and 21/26 (80%) patients with methylated PGR; the difference not statistically significant; p=0.135. The role of progesterone receptor signaling in hematopoiesis is not known. Using real time quantitative RT-PCR assay for progesterone receptor expression we found detectable levels in granulocytes from 4/5 normal individuals while the expression in granulocytes from 5/5 PV patients was not detectable. To assess the functional significance of progesterone receptor silencing, we explored the effect of mifepristone, a progesterone receptor antagonist, on the response of BFU-E progenitors to erythropoietin. Mifepristone increased the sensitivity of BFU-E progenitors from normal blood to low concentrations of erythropoietin (60–250 mU/ml) suggesting that disabling of progesterone receptor may increase the response of hematopoietic cells to proliferative stimuli. In conclusion, our data show that PGR methylation is present in half of PV patients and it is even more frequent in MF and PV transformed to AML. Silencing of progesterone receptor by methylation may be an epigenetic change contributing to MPD phenotype and transformation to leukemia.
The Jak2V617F Oncogene Associated with Polycythemia Vera Regulates G1/S-Phase Transition.
Authors: Sattler Martin , Walz Christoph , Crowley Brian J. , Gramlich Jessica L. , King Kendra L. , Podar Klaus , Griffin James D. 
Published: April 2020

Abstract
The V617F activating point mutation in Jak2 has recently been detected in a high proportion of patients with the myeloproliferative disorders polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. Using the Jak2V617F-mutant erythroid leukemia cell line HEL as a model, potential mechanisms that contribute to transformation were investigated. Inhibition of Jak2V617F with a small molecule kinase inhibitor reduced cell growth of HEL cells in a dose dependent manner with an IC50 of 300 nM. This inhibition of growth was associated with a G1 cell cycle arrest, with minimal or delayed apoptosis. The major Jak2 target in normal hematopoietic cells, STAT5, was found to be activated by Jak2V617F. Treatment of the cells with either a Jak2 kinase inhibitor, or with a Jak2-targeted siRNA, decreased STAT5 activation, and also resulted in decreased expression of cyclin D2 and increased expression of p27Kip. Of interest, we found that Jak2V617F induced high levels of reactive oxygen species (ROS), an activity associated with several other tyrosine kinase oncogenes. Expression of a constitutively active form of STAT5 by itself was capable reducing expression of p27Kip and increasing production of ROS, suggesting that each of these signaling events are downstream of STAT5. Additionally, treatment of HEL cells with the anti-oxidant N-acetylcystein increased expression of p27Kip, suggesting that Jak2V617F regulates cell cycle progression at least in part through STAT5 activation of ROS, and ROS regulation of p27Kip. Cell growth of HEL cells was found to be blocked by anti-oxidants. Overall, our results suggest that constitutive activation of Jak2 contributes to a transforming phenotype and therefore hints at novel targets for drug development that may aid traditional therapy.
Detection of Activated STAT5 in Neoplastic Mast Cells in Patients with Systemic Mastocytosis: Role of c-kit D816V.
Authors: Sonneck Karoline , Mayerhofer Matthias , Gleixner Karoline V. , Kerenyi Marc , Krauth Maria-Theresa , Fritz Richard , Sillaber Christian , Moriggl Richard , Valent Peter 
Published: April 2020

Abstract
Recent data suggest that activated STAT5 contributes to growth and differentiation of mast cells (MC) and that STAT5-knock out mice are MC-deficient. We have recently shown that constitutively activated STAT5 acts as a potent oncogenic signaling molecule in hematopoietic progenitor cells (Cancer Cell2005;7:87–99). In the present study, we examined the expression of activated STAT5 in neoplastic MC in systemic mastocytosis (SM) and asked whether the SM-related oncogene c-kit D816V is involved in STAT5-activation. For the immunohistochemical detection of activated tyrosine phosphorylated STAT5 (P-Y-STAT5), we used the specific monoclonal antibody AX1 (Advantex) which does not react with inactive STAT5. In all patients with SM tested (indolent SM, n=11; smouldering SM, n=2; aggressive SM, n=1; mast cell leukemia, n=1; all exhibiting c-kit D816V), MC were found to display P-Y-STAT5. Expression of activated STAT5 was also demonstrable in the c-kit D816V-positive mast cell leukemia-derived cell line HMC-1. The reactivity of HMC-1 cells with AX1 antibody was abrogated by a STAT5-specific blocking-peptide. To define the role of c-kit D816V in STAT5-activation, Ba/F3 cells with doxycycline-inducible expression of c-kit D816V (Ton.kit) were employed. In these cells, induction of c-kit D816V was followed by a massive increase in phosphorylated STAT5 as determined by a specific DNA-binding assay, whereas the total amounts of STAT5-mRNA and of the STAT5-protein showed only a slight increase or remained unchanged. In summary, these data show that neoplastic MC in SM express activated STAT5 (P-Y-STAT5), and that the transforming c-kit mutation D816V leads to persistent activation of STAT5 in these cells.
Heme Oxygenase-1 (HO-1): A Novel KIT D816V-Dependent Target in Neoplastic Human Mast Cells (HMC-1).
Authors: Kondo Rudin , Mayerhofer Matthias , Gleixner Karoline , Vales Anja , Krauth Maria-Theresa , Derdak Sophia , Gruze Alexander , Pickl Winfried , Sillaber Christian , Greish Khaled , Maeda Hiroshi , Valent Peter 
Published: April 2020

Abstract
Systemic mastoyctosis is a myeloid neoplasm characterized by abnormal growth and accumulation of mast cells (MC). Most patients express the D816V-mutated variant of c-KIT, which mediates resistance against most available tyrosine kinase inhibitors. Therefore, current research is focusing on novel targets in MC. We analyzed expression and function of the survival factor heme oxygenase-1 (HO-1) in neoplastic MC. As assessed by Northern blotting and RT-PCR, the human MC line HMC-1 that exhibits KIT D816V, was found to express HO-1 mRNA. Expression of the HO-1 protein was demonstrable by immunocytochemistry and Western blotting. To examine the role of mutated KIT in expression of HO-1, Ba/F3 cells with doxycycline-inducible expression of c-KIT D816V were employed. In these experiments, KIT D816V was found to induce HO-1 promoter activity and expression of HO-1 mRNA and HO-1 protein in these cells. Moreover, the KIT-D816V-targeting compound PKC412 was found to downregulate expression of HO-1 in HMC-1 cells. The KIT D816V-induced upregulation of HO-1 in Ba/F3 cells was completely blocked by a combination of LY294002 (PI3-kinase inhibitor) and PD89059 (MEK inhibitor), but not by single agents, suggesting involvement of multiple signaling pathways. We next examined whether targeting of HO-1 is associated with decreased survival. As assessed by 3H-thymidine uptake, the pegylated HO-1 inhibitor zinc-protoporphyrin (PEG-ZnPP) reduced proliferation of HMC-1 cells in a dose-dependent manner (IC50: 5 μM). The PEG-ZnPP-induced inhibition of growth was found to be associated with induction of apoptosis (control: 1±0.6 vs PEG-ZnPP, 5 μM: 55±5% apoptotic cells, p&lt;0.05). The HO-1 inductor hemin (10 μM) increased the expression of HO-1 in HMC-1 cells and partly rescued these cells from PKC412-induced growth-inhibition (PKC412, 1 μM: 39±8% vs PKC412 + hemin: 23±11%). Finally, PKC412 and PEG-ZnPP were found to produce cooperative (additive) growth-inhibitory effects on HMC-1 cells. In summary, our data show that HO-1 is a novel survival factor and interesting target in neoplastic human MC exhibiting the D816V-mutated variant of KIT.
PKC412 Inhibits In Vitro Growth of Neoplastic Mast Cells Expressing the D816V-Mutated Variant of KIT: Comparison with AMN107 and Imatinib, and Evaluation of Drug-Interactions.
Authors: Gleixner Karoline V. , Mayerhofer Matthias , Aichberger Karl J. , Derdak Sophia , Sonneck Karoline , Boehm Alexandra , Samorapoompichit Puchit , Gruze Alexander , Pickl Winfried , Manley Paul , Fabbro Doriano , Sillaber Christian , Valent Peter 
Published: April 2020

Abstract
In most patients with systemic mastocytosis (SM) including aggressive SM and mast cell leukemia (MCL), neoplastic cells express the oncogenic c-KIT mutation D816V. KIT-D816V is associated with constitutive tyrosine kinase (TK) activity and thus represents an attractive target of drug therapy. However, most available TK inhibitors including STI571=imatinib, fail to block TK-activity of KIT D816V at pharmacologic concentrations. We provide evidence that the novel TK-targeting drugs PKC412 and AMN107 decrease TK-activity of D816V-mutated KIT and counteract growth of Ba/F3 cells with doxycycline-induced expression of KIT D816V as well as growth of the human mast cell leukemia cell line HMC-1 expressing this c-KIT mutation. PKC412 was found to be the superior drug with IC50 values of 50–250 nM and without differences seen between HMC-1 cells exhibiting or lacking KIT D816V. By contrast, AMN107 exhibited potent effects only in the absence of KIT D816V in HMC-1 cells. Corresponding results were obtained with Ba/F3 cells exhibiting wild-type or the D816V-mutated variant of KIT. Moreover, we found that PKC412 and AMN107 inhibit growth of primary neoplastic MC in a patient with KIT D816V+ SM. The growth-inhibitory effects of PKC412 and AMN107 on HMC-1 cells were associated with TK-inhibition of KIT and with induction of apoptosis. In addition, PKC412 was found to downregulate expression of CD2 and CD63, two cell surface antigens upregulated in SM. In co-incubation experiments, PKC412 was found to synergize with AMN107, imatinib, and 2CdA in producing growth inhibition in HMC-1 cells lacking KIT D816V, whereas in KIT D816V+ HMC-1 cells, drug-interactions were additive rather than synergistic. Together, PKC412 and AMN107 alone and in combination counteract growth of neoplastic mast cells. Both drugs may therefore be considered as novel promising agents for targeted therapy in patients with aggressive SM or MCL.
Chimeric Anti-CD20 Monoclonal Antibody (Rituximab;Mabthera) in Remission Induction and Maintenance Treatment of Relapsed /Resistant Follicular Non-Hodgkin’s Lymphoma: Final Analysis of a Phase III Randomized Intergroup Clinical Trial.
Authors: Van Oers Marinus H.J. , Van Glabbeke Martine , Teodorovic Ivana , Rozewicz Cynthia , Klasa Richard , Marcus Robert E. , Wolf Max , Kimby Eva , Hagenbeek Anton 
Published: April 2020

Abstract
Background. Last year we reported interim results of a randomised phase III trial in patients with relapsed/refractory stage III/IV positive follicular NHL, demonstrating that the addition of rituximab (R) to CHOP chemotherapy for remission induction as well as rituximab maintenance treatment significantly improves the clinical outcome (Blood2004;104:169a). Based on these interim results, randomisation to the induction part of the trial was halted and the protocol was amended.
Study design. Patients with stages III or IV follicular lymphoma at initial diagnosis and relapsed after or resistant to a maximum of two non-anthracycline containing systemic chemotherapy regimens, were randomized to remission induction with either 6 cycles of standard CHOP (once every 3 weeks) or CHOP + R (375 mg /m2 at day 1 of each cycle of CHOP). Those with a complete or partial remission after 6 cycles of therapy underwent a second randomization to no further treatment (observation) or maintenance treatment with R (375 mg/m2 once every 3 months) until relapse or for a maximum period of two years.
Results. At the time of the preplanned second interim analysis (February 2004) 461 patients had been included. Of these, 369 could be evaluated for response (188 CHOP; 181 R-CHOP). Both treatment arms yielded similar partial response rates (CHOP: 53.7% - R-CHOP: 52.5%), but highly significant different CR rates (CHOP: 18.1%; R-CHOP: 30.4%; p=0.0004). Of 319 patients randomized for maintenance treatment, 268 were evaluable (132 observation; 136 R maintenance). A highly significant advantage was observed in progression free survival in patients randomized to R maintenance, when compared with the observation arm (median PFS 38 vs.15 months; p&lt;0.0001). At that time there was no impact on OS: the observed difference (in favor of R maintenance) was not significant for an interim analysis. Toxicity of CHOP and R-CHOP induction was similar, and R maintenance was associated with minimal toxicity. These results of the planned second interim analysis showed that the formal criteria for stopping the trial had been met. It was concluded that this is the first trial to show that: 1) in patients with relapsed/resistant follicular lymphoma R-CHOP remission induction results in a highly significant increase in CR rate as compared to CHOP; 2) rituximab maintenance treatment significantly improves PFS in patients responding to induction treatment. The final analysis of the study results will be performed in September 2005, with an additional follow-up of at least 18 months. The final results will be presented at the meeting.
Shear Stress Directly Regulates Platelet αIIbβ3 Signaling.
Authors: Feng Shuju , Lu Xin , Resendiz Julio C. , Kroll Michael H. 
Published: April 2020

Abstract
Integrin mechanotransduction is a ubiquitous biological process. Mechanical forces are transduced by an integrin’s ligand-bound extracellular domain through its β subunit’s cytoplasmic domain connected to the cytoskeleton. This often culminates in the activation of tyrosine kinases directing cell responses. The delicate balance between hemostasis and thrombosis requires exquisitely fine-tuned integrin function, and balance is maintained in vivo despite that the major platelet integrin αIIbβ3 is continuously subjected to frictional or shearing forces generated by laminar blood flow. To test the hypothesis that platelet function is regulated by the direct effects of mechanical forces on αIIbβ3, we examined αIIbβ3/cytoskeletal interactions in human platelets exposed to shear stress in a cone-plate viscometer. We observed that α-actinin, myosin heavy chain and Syk co-immunoprecipitate with αIIbβ3 in resting platelets, and that 120 dynes/cm2 shear stress leads to their disassociation from αIIbβ3. Shear-induced disassociation of α-actinin and myosin heavy chain from the β3 tail is unaffected by blocking VWF binding to GpIb-IX-V but abolished by blocking VWF binding to αIIbβ3. Syk’s disassociation from β3 is inhibited when VWF binding to either GpIb-IX-V or αIIbβ3 is blocked. Shear stress-induced phosphorylation of SLP-76 and its association with tyrosine phosphorylated SLAP-130 are inhibited by blocking ligand binding to αIIbβ3 but not by blocking ligand binding to GpIb-IX-V. Chinese hamster ovary (CHO) cells expressing human αIIbβ3 demonstrate calcium and shear-dependent (1 and 10 dynes/cm2) attachment to glass cover slips coated with 20 μg/ml VWF. CHO cells expressing αIIbβ3 with β3 truncated of its cytoskeletal binding domains at C-terminal residue 716 demonstrate decreased VWF-dependent adhesion and cohesion in response to 1 dyne/cm2 shear stress. These results support the hypothesis that shear stress directly modulates αIIbβ3 function, and suggest that shear-induced αIIbβ3-mediated signaling regulates platelet aggregation by directing the release of α-actinin and myosin heavy chain from the β3 tail.