bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes after HLA-Matched Sibling Transplants or Chemotherapy in Children with Acute Lymphoblastic Leukemia in a Second Remission after an Isolated Central Nervous System Relapse.
Authors: Eapen Mary , Zhang Mei-Jie , Raetz Elizabeth , Devidas Meenakshi , Carroll William L. , Ritchey Arthur K. , Barredo Julio C. , Godder Kamar , Grupp Stephan A. , Lewis Victor A. , Davies Stella , Camitta Bruce 
Published: April 2020

Abstract
The optimal treatment for children with acute lymphoblastic leukemia (ALL) in second remission after an isolated central nervous system relapse is unknown. To address this question, we compared outcomes in 149 patients enrolled on Pediatric Oncology Group chemotherapy trials 9061 (n=79) and 9412 (n=70) and HLA-matched sibling transplant recipients (n=60) reported to the Center for International Blood and Marrow Transplant Research. Patients received treatment between 1990 and 2000. Median follow-up was 8 years and 9 years after chemotherapy and transplantation, respectively. Groups were similar with respect to sex and leukocyte count at diagnosis. Chemotherapy recipients were younger at diagnosis (5 vs. 7 years) and more likely to have had a longer duration of first remission (duration of first remission ≥18 months: 70% vs. 48%). All transplant recipients received bone marrow grafts and 83% received a total body irradiation containing preparatory regimen. The median time to transplantation after achieving a second remission was 2.5 months (range, &lt;1 – 8). To adjust for time-to transplant bias, we used left-truncated Cox regression models to examine treatment outcomes. Risks of a subsequent leukemia relapse were similar in both treatment groups. As expected, risks of a subsequent leukemia relapse were significantly higher in older patients (11–17 years; relative risk [RR] 2.63, p=0.004) and those with a short duration of first remission (&lt;18 months; RR 4.22, p&lt;0.001) regardless of type of treatment. Relative to chemotherapy recipients, risks of treatment-related mortality (RR 4.29, p=0.001), treatment failure (RR 2.37, p=0.003) and overall mortality (RR 2.68, p=0.002) were significantly higher within the first 2 years after achieving a second remission in recipients of HLA-matched sibling transplants. Among transplant recipients who survived the first two years, subsequent mortality and treatment failure risks did not differ by treatment group. In both treatment groups, recurrent leukemia was the commonest cause of death (60% and 56% after chemotherapy and transplantation, respectively). The 8-year probabilities of leukemia-free survival (adjusted for age and duration of first remission) were 66% and 58% after chemotherapy and transplantation, respectively. These data support use of chemotherapy alone for patients with ALL and isolated central nervous system relapse who achieve a second remission regardless of duration of first remission.
Diagnostic Usefulness of JAK2 Mutation in Manistest or Latent Polycythemia Vera and Secondary Polycythemia.
Authors: Bang Soo-Mee , Nam Eun Mi , Ahn Jeong Yeal , Lee Jae-Hoon , Kim Bong-Seog , Nam Seung-Hyun , Chi Hyun-Sook , Cho Young Uk , Kim Hyo Jung , Zang Dae Young , Park Moo-Rim , Shim Hyeok , Lee Jong Seok , Won Jong-Ho , Oh Doyeun ,   Korean MPD Working Party
Published: April 2020

Abstract
Backgrounds: The discovery of Janus kinase 2 (JAK2) mutation make it easy to diagnose polycythemia vera (PV) in which the prevalence of this mutation is reported up to 96%. The latent PV is defined in patients who show the lower hemoglobin than WHO criteria at the time of diagnosis without any cause of secondary erythrocytosis; 17~18.5g/dL in male and 15 ~16.5g/dL in female. We investigated the mutational status of JAK2 in polycythemia vera either of latent or manifest type and secondary polycythemia.
Methods : We reviewed the clinical records of 182 patients from 8 centers, who underwent bone marrow (BM) examination with a suspicion of non-BCR/ABL myeloproliferative diseases (nMPD). JAK2 mutation was examined by allele-specific PCR in 110 patients.
Results : The positive rate of JAK2 mutation was 69% of 48 patients with PV, 54% in 41 patients with essential thrombocythemia (ET), 25% of 8 patients with chronic idiopathic myelofibrosis and 100% of 1 patient with unclassifiable MPD. JAK2 mutation was not detected in 7 patients with secondary polycythemia and 5 with reactive thrombocytosis. The number of patients with latent PV was eleven (23%) among the 48 PV patients. Nine of these 11 patients were positive for JAK2 mutation. Finally, sensitivity of JAK2 mutation was 69% (33/48) in all PV, 82% (9/11) in latent PV, and 65% (24/37) in manifest PV. The specificity of JAK2 mutation was 100% for secondary polycythemia. Among the 41 patients with ET, four patient had high hemoglobin met the latent PV criteria. Only one patient among them showed JAK2 mutation. The presence of a JAK2 mutation was closely correlated with the diagnosis of PV (p=0.006), leukocytosis (p=0.000), increased megakaryocytes (p=0.013), and decreased serum EPO (p=0.034) in 98 nMPD patients. In these patients, vascular events before or after the diagnosis and survival were not affected according to JAK2 status during the median follow-up of 25 months (range; 0~211).
Conclusions : The JAK2 mutation help diagnose PV with higher sensitivity in latent PV than manifest PV. This finding can be adopted in the diagnosis of PV in newly visited polycythemic patient whose hemoglobin were under the criteria and condition could be excluded for secondary erythrocytosis. Therefore, JAK2 mutation should be incorporated into the work-up of nMPD including PV for accurate diagnosis. In the meeting, we can present the additional JAK2 data of untested 72 patients.
A Phase II Study of Nilotinib, a Novel Tyrosine Kinase Inhibitor Administered to Patients with Hypereosiniphilic Syndrome (HES).
Authors: le Coutre Philipp , Hochhaus Andreas , Heim Dominik , Rafferty Teresa , Weitzman Aaron , Zheng Ming , Baskaynak Gökben , Verhoef Gregor 
Published: April 2020

Abstract
Idiopathic hypereosinophilic syndrome (HES) is a rare myeloproliferative disorder characterized by sustained overproduction of eosinophils and organ involvement that can lead to chronic eosinophilic leukemia. HES is a clonal disorder characterized in some patients by constitutive activation of FIP1L1-PDGFRA. There is currently no approved therapy for HES. Nilotinib is a novel aminopyrimidine which potently inhibits Bcr-Abl, as well as the PDGF-R and c-Kit kinases. This Phase II study was designed to evaluate the safety and efficacy of nilotinib administered at an oral dose of 400 mg twice daily to patients with specific HES disease related criteria and with a clinical indication for treatment. Preliminary data are available for 11 patients. The median age is 63 (range 25–77) years. There were 10 males and 1 female. Extramedullary involvement was present in 6 (55%) patients at baseline. Treatment is ongoing for 4 (36%) patients and 7 (64%) have discontinued; 2 (18%) for adverse events; 3 (27%) for disease progression, and 1 (9%) for an administrative reason. There was one patient death due to neutropenic sepsis and endocarditis. Overall, 5 (45%) patients had investigator documented stable disease, and 1 (9%) patient a 51 year old male had a CR. Grade 3 or 4 adverse events included one patient each with rash, decreased hemoglobin, myalgia, arthralgia, pruritis, and diabetes mellitus. In summary, these data suggest that nilotinib has clinical activity and an acceptable safety and tolerability profile in patients with HES.
PTK787/ZK 222584 (PTK/ZK), an Oral Tyrosine Kinase Inhibitor, Has Activity in Patients with Agnogenic Myeloid Metaplasia (AMM).
Authors: Giles Francis J. , Carroll Michael , List Alan , Ferrajoli Alessandra , Thomas Deborah , Cortes Jorge , Feldman Eric , Roboz Gail 
Published: April 2020

Abstract
Increased angiogenesis and vascular endothelial growth factor (VEGF) levels are prognostic in AMM. Agents with anti-VEGF activity including thalidomide (Thomas. Cancer 2006) and lenalidomide (Tefferi. Blood 2006) have activity in AMM. PTK/ZK, a novel oral aminophthalazine, is a small molecule inhibitor of VEGFR-2, PDGFR, c-kit and c-fms. Twenty-nine patients with angogenic myeloid metaplasia (AMM) were enrolled between June 2002 and November 2003 on a phase I/II study of PTK/ZK, administered orally on a continuous twice daily (BID) dosing schedule as follows: two (7%) patients received 750 mg BID and 27 (93%) patients received 500 mg BID. The age range was 42 to 78 (median 62), seventeen (59%) patients were male, and Karnofsky performance status was ≥ 70% in all (100%) patients. In twelve (41%) previously treated patients, the median number of prior regimens was 2.5 (range 1–6). Nine (31%) of the 29 patients had abnormal cytogenetics at the time of enrollment. The most commonly reported potentially PTK/ZK-related adverse events (AEs) were nausea, vomiting, dizziness, fatigue, thrombocytopenia and anorexia. One or more of these AEs occurred in &gt; 15% of patients. Five (17 %) patients achieved clinical improvement (CI), as determined by the International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia. Four CIs had improvement in splenomegaly and the fifth had improvement in hemoglobin. As had similarily been seen in patients with AML treated with PTK/ZK monotherapy, PTK/ZK exposure, both AUC and Cmin, showed decreases after multiple doses (Roboz.Leukemia.2006). PTK/ZK is an active, well tolerated agent in the treatment of AMM and warrants further investigation within combination regimens.
Atiprimod Inhibits the Growth of JAK2 Tyrosine Kinase Over-Expressing Cells “In Vitro” and “Ex Vivo”.
Authors: Nussenzveig Roberto , Manshouri Taghi , Kantarjian Hagop , Giles Francis , Cortes Jorge , Gaikwad Amos , Priebe Waldemar , Estrov Zeev , Verstovsek Srdan 
Published: April 2020

Abstract
Background:
A novel somatic single point non-synonymous mutation (1849 G to T) in the tyrosine kinase JAK2, rendering the enzyme constitutively active, has been reported in classical myeloproliferative disorders (MPD), specifically, in greater than 90% of patients with polycythemia vera (PV), and 50% of patients with essential thrombocythemia (ET) and myelofibrosis with myeloid metaplasia (MMM). Consequently, JAK2 tyrosine kinase has become a significant target for the development of specific inhibitors of its activity with possible therapeutic benefits for patients with classical MPD. We report here the results of a study using atiprimod, an anti-inflammatory and anti-cancer compound belonging to the azaspirane class of cationic amphiphilic drugs in JAK2 over-expressing cell lines and patient samples. In contrast to TKI inhibitors, this drug is causing downregulation of JAK2 protein by facilitating its degradation, possibly through the ubiquitin-proteosome pathway (Faderl, S. et al, Leukemia Research 2006 in press).
Methods and Results:
We have examined the growth inhibitory effect of atiprimod against two mouse FDCP cell lines transfected with erythropoietin receptor (Epo-R) and, either wild-type JAK2 (JAK2WT) or mutant JAK2 (JAK2V617F). Atiprimod growth inhibition, measured using 72 hours MTS assay, was significant against both mutant JAK2V617F cells (IC50 0.42μM) and wild-type JAK2WT cells (IC50 0.65μM). Atiprimod was found to induce apoptosis in cell lines as evidenced by an increase in the mitochondrial membrane potential and augmented annexin V positivity by flow cytometry. Mononuclear cells, isolated from peripheral blood of PV patients (JAK2V617F positive), were cultured in cytokine supplemented serum free media for expansion of erythroid progenitors. Expansion spanned a three week, three step sequential treatment of the erythroid progenitor cells with specific combinations of cytokines. Finally, treatment of expanded erythroid progenitor cells with atiprimod for 24 and 48 hours resulted in increased annexin V positive cells, in both, a dose and time dependent manner.
Conclusion:
Our preliminary pre-clinical results suggest that atiprimod might be a beneficial medication for MPD patients carrying the JAK2V617F mutation. Atiprimod is currently being tested in a phase I clinical study.
Study of the Expression of Angiogenic Factors and Dopaminergic Receptors: Correlation with ZAP70, CD38 and the Mutational State in Chronic Lymphocytic Leukaemia (CLL).
Authors: Eroles Pilar , Benet Isabel , Marugan Isabel , Teruel Ana Belen , Solano Carlos , Terol Maria Jose 
Published: April 2020

Abstract
The angiogenesis is a well known process implicate in the progression of CLL. In this disease has been described an increase of angiogenic and pro-angiogenic factors in serum and angiogenic receptors in B cells, mainly in advances stages. Recently had been known that the agonist of the dopaminergic receptor D2 can inhibit the tumour growth and a possible mechanism mediator is the internalization of VEGFR-2. The aim of this work had been to analyze the expression of the dopaminergic receptors (D1, D2, D3, D4 and D5), the angiogenic receptors and its correlation with the main biological factor implicated in the illness (ZAP-70, CD38 and the mutational status of IgVH/BCL-6). We had determinate the levels of the receptors VEGFR-1, VEGFR-2, VEGFR-3 and c-kit, the angiogenic factor bFGF and the dopaminergic receptors D1, D2, D3, D4 and D5 in B lymphocytes from peripheral blood of 29 patients with CLL in A stage (using positive selection and quantitative PCR), and we had analyzed the possible correlation with the values of CD38 and ZAP70 and the mutational status of IgVH/BCL-6 (using flow cytometry and direct sequenciation).
Results: The lymphocytes B-CLL show a significant increment of the expression of the receptors VEGFR-1, VEGFR-2 and c-kit versus normal lymphocytes B. The patients with positive ZAP70 (&gt; 20%) show a higher expression of all the factors studied except D1. The difference is statistically significant for D5, VEGFR-2 and c-kit (3 ×), D2 and bFGF (2 ×). The patients with positive CD38 show an increment in the expression of D2 (1,4x) and bFGF (1,9x) versus patients with negative CD38. The patients with both ZAP70 and CD38 positive present a higher expression of D2 and bFGF (2,2x and 1,9x) versus negatives ZAP70 and CD38, which show higher expression of D1 (4,8x). We had not found significant correlations between the studied factor and the mutational status of IgVH and BCL-6, only D1 shows a higher expression (3,6x) in patients with mutations IgVH versus unmutated independently of the BCL-6 status.
Conclusion: The lymphocytes B-CLL in stage A of Binet show high levels of expression of the angiogenic receptors VEGFR-1, VEGFR-2 and c-kit, the dopaminergic receptors D1 and D2, and the angiogenic factor bFGF that are significant higher that in normal lymphocytes B. The biological factor of bad prognostic (ZAP-70 and CD38) in patients in the initial A stage are associated with a higher expression of the receptors VEGF-R, c-kit, and D2 and the factor bFGF. Oppositely, negatives ZAP-70 and CD38 have correlation with the elevated expression of the receptor D1. This patron of differential expression can contribute to the tumoral progression of the patients in the initial stage of the illness.
Autoimmune Thrombocytopenic Purpura Complicating Chronic Lymphocytic Leukemia: Analysis of 60 Patients.
Authors: Visco Carlo , Stasi Roberto , Ruggeri Marco , Ambrosetti Achille , Fortuna Stefania , Frattini Francesco , Giaretta Ilaria , Zanotti Roberta , Madeo Domenico , Pizzolo Giovanni , Rodeghiero Francesco 
Published: April 2020

Abstract
Autoimmune thrombocytopenic purpura (AITP) represents the autoimmune condition most frequently associated with chronic lymphocytic leukemia (CLL) after autoimmune haemolytic anemia. However, the main characteristics and outcome of AITP in the course of CLL, as well as the impact of this complication in the natural history of the tumor remain unknown.
We identified 60 consecutive patients with CLL who developed AITP, representing 3,5% of CLL patients diagnosed in the three participating centers between 1995 and 2004. To be included in this study patients had to experience at least one episode of AITP, which was defined as the occurrence of acute and severe thrombocytopenia in the presence of normal or augmented number of megakariocytes in the bone marrow, without extensive lymphoid marrow infiltration, splenomegaly or recent cytotoxic treatment. A complete response (CR) to AITP treatment was defined by a platelet count &gt; or = 150×10(9)/L, and a partial response (PR) by a platelet count &gt; 50×10(9)/L or by an increase of at least twofold the initial level. Remaining patients were considered as no responders (NR).
Median age of our 60 patients was 65 years (range 48–83) and 40 were males. At CLL presentation RAI stage was 0 to 2 in 88%, time to CLL treatment was 13,8 months (range 0–120), while first line treatment for CLL consisted of Chlorambucile alone (Chl) in 73% of patients with 18% of patients that received no treatment for their malignancy. Median overall survival was 57 months. AITP occurred concomitantly to CLL diagnosis in 13 patients (22%), while median time to AITP for remaining 47 patients was 30 months (range 2–147). The median platelet count at AITP diagnosis was 23 × 10(9)/L(range, 1–81). Twenty-five patients (42%) presented with moderate bleeding signs at AITP diagnosis, while 4 patients (7%) experienced severe hemorrhagic episodes, requiring hospitalization and blood transfusions. Fifty-two of the 60 patients (87%) received at least one treatment for AITP: 32 patients received i.v.Ig alone or in combination with steroids, leading to a short-term NR in 66% (CR 19%, PR 15%); nine patients underwent splenectomy and 7 (78%) experienced a durable CR; patients who were treated with chemotherapy (Chl, COP, CVP) +/− steroids had at least a PR in 73% of cases. With a median follow-up from AITP onset of 35 months, 17 of the 52 treated patients are still NR (33%) and 13 of them are on treatment.
In our series of patients with CLL and AITP we observed an unexpectedly short survival regardless of a large prevalence of low RAI stages at diagnosis. Treatment of AITP with i.v. Ig +/− steroids leaded to a low rate of short-term responses, while splenectomy and chemotherapy seemed sufficiently adequate therapeutic approaches.
Involvement of the Tis11b/Berg36 Family in the Regulation of B-CLL Surivival and Differentiation.
Authors: Baou Maria , Murphy John , Yong Kwee L. , Carr Robert , Jewell Andrew P. 
Published: April 2020

Abstract
Tis11b/Berg36 is a member of a family of proteins involved in post-transcriptional gene regulation. Members of this family bind to AU rich elements in certain mRNA species and increase mRNA stability. mRNA that contain AU rich elements and can be regulated in this way include molecules involved in the regulation of apoptosis eg bcl-2 and several cytokines eg TNF, IL-2. We have recently shown that Tis11b/Berg36 is involved in the regulation of apoptosis following Rituximab treatment of CLL cells suggesting a pro-apoptotic role of this gene in CLL cells. Thus B-CLL were stimulated with IL-4, anti-CD40, anti-CD40+IL-4 and PMA. It was found that IL-4, CD40 and their combination significantly inhibited spontaneous apoptosis while PMA was able to inhibit spontaneous apoptosis in some but not all patients tested and the overall effect did not reached statistical significance. Unexpectedly Tis11b/Berg36 mRNA remained unchanged following IL-4 treatment, but expression was induced following anti-CD40 or PMA treatment. Because it was found that regulation of Tis11b/Berg36 mRNA following the latter two treatments was under the control of NF-κB pathway and not p38 (as found for Rituximab treatment) it was hypothesized that this gene may be involved in the regulation of cell cycle or differentiation of B-CLL cells. Indeed it was found that stimulation of B-CLL cells with either PMA or anti-CD40 resulted in increase in sIgM as a marker of B-CLL differentiation. CLL cells were also found to express high basal levels of two other members of this family, Tis11 and Tis11d. From these stimuli, IL-4 or anti-CD40 were found to downregulate the basal expression of Tis11 mRNA. These data suggest that members of the Tis11b/Berg36 family are involved in the regulation of apoptosis and differentiation in B-CLL cells.
Influence of MDM2 Single Nucleotide Polymorphism SNP309 on Disease Onset and Course in CLL.
Authors: Zenz Thorsten , Häbe Sonja , Bühler Andreas , Kröber Alexander , Denzel Tina , Döhner Hartmut , Stilgenbauer Stephan 
Published: April 2020

Abstract
Background: A SNP in the MDM2 promotor region (SNP309) has been shown to directly influence MDM2 transcript and protein levels with the subsequent attenuation of the p53 pathway. In addition, the GG and GT genotype have been linked to earlier age of onset in patients with different cancers. Because of the well documented prognostic role of p53 in patients with CLL and the potential involvement of MDM2 particularly in patients with trisomy 12, we studied the MDM2 SNP309 in patients with CLL.
Methods: We developed a Denaturing High-Performance Liquid Chromatography (DHPLC) assay as a high-throughput approach to efficiently type this polymorphism.
Results: We analysed 627 CLL patients and found a similar genotype distribution as described for a large German control population (CLL: GG 12,75%; GT 48.8%; TT 38.4% vs. control: GG 14.4%; GT 44.1%; TT 41.8%). There was an equal genotype distribution among women and men. We compared the median age at diagnosis of the different genotype groups in CLL patients and did not find differences (female: GG 62.3; GT 59.8 TT 60; male: GG 58; GT 56.2; TT 58) (figure 1). However as a hormone dependent difference for pre- and postmenopausal female patients with cancer has been described, we separated the patients according to age and found a overrepresentation of the GG phenotype in young female CLL patients (&lt;51 years) (25% GG vs 11% GG; p=0.04). In contrast, for older, female patients with the GG genotype there was a trend towards delayed onset of CLL (Figure1).
The overall survival among a subgroup of 483 patients was not influenced by the presence of a particular genotype (Median survival (months): GG 132.6; GT 134.1; TT 112.8). The mRNA expression levels of MDM2 and p53 were analysed by quantitative RT-PCR and correlated with the different genotypes.
Conclusion: The approach described can be used to rapidly type the MDM2-SNP309. Based on this study a role for the MDM2 polymorphism on disease predisposition of CLL is unlikely. The role of hormone dependent differences according to genotype in female patients warrants further investigation.
Figure 1 Figure 1.