bluuebunny/crossref_metadata_2025_split huggingface dataset:
ThaDD-V Treatment for Patients with Relapsed/Refractory Multiple Myeloma: A Feasibility/Activity Study.
Authors: Offidani Massimo , Polloni Claudia , Corvatta Laura , Piersantelli Maria-Novella , Mele Anna , Catarini Massimo , Brunori Marino , Ferranti Mario , Amoroso Barbara , Leoni Pietro 
Published: October 2019

Abstract
ThaDD regimen has provided significant results in recurrent/relapsed multiple myeloma (MM) patients (Offidani et al, 2006). In order to further improve those results without significantly increasing toxicity, we decided to include Velcade, synergic as per activity but not toxicity with the other drugs of ThaDD regimen. ThaDD-V was scheduled as follows: Thalidomide 100 mg/day, pegylated liposomal Doxorubicin 30 mg/sm iv days 4; Dexamethasone 20 mg days 1–2, 4–5, 8–9, 11–12 and Velcade 1.3 mg/sm iv days 1, 4, 8, 11 every 28 days (induction therapy). Patients received bortezomib for alternate cycles as following: 1 mg/sm day 1, 8, 15 and dexamethasone 20 mg days 1–2, 8–9, 15–16 and thalidomide 100 mg/day and dexamethasone 40 mg/day for 4 days monthly for a total of six cycles as consolidation therapy. Then patients received thalidomide 100 mg/day until relapse (maintenance therapy). Actually 20 patients (7 M, 13 F; median age 62.5 yrs, range 31–75) are assessable for response and toxicity. Five pts (25%) showed WHO performance status (PS) > 1, 9 pts (45%) presented refractory disease, 8 pts (40%) were priorily administered ≥ 2 lines of a treatment and 14 patients (70%) were submitted to one previous autologous stem cell procedure. Seven patients (35%) had extramedullary disease and 7 had unfavourable cytogenetics. Twelve patients scored an ISS ≥ 2 and 11 (55%) were in first remission for ≤ 12 months median duration. No patients were previously treated with Velcade, whereas six patients had received short-term Thalidomide treatment. Response was assessed according to IMVG uniform response criteria. Seventeen of 20 patients responded after at least one chemotherapy cycle reporting 5 (25%) sCR, 3 CR (15%), 8 VGPR (40%) and 1 stable disease. Three patients (15%) had extramedullary progressive disease. In a median follow-up of 12 months, 2 (10%) patients progressed and 1 (5%) died from cardiac infarction. Time to progression and overall survival were 73% and 95% at 12 months. We observed 4 grade 3 thrombocytopenia, 2 grade 3 DVT, 1 grade 3 diarrhoea, 1 grade 3 asthenia, 1 grade 4 infection and 1 grade 3 dermatological toxicity. Six patients developed grade 2 peripheral neuropathy and other three grade 3. In conclusion, ThaDD-V is extremely active in advanced MM patients as demonstrated by the elevated precentage of high quality remission. Nevertheless, patients are at substantial risk of developing neurotoxicity so the protocol was amended as per Velcade dose intensity and Thalidomide dose.
Early Normalization of Serum Free Light Chain Is Associated with Prolonged Time to Progression Following Bortezomib ± Pegylated Liposomal Doxorubicin Treatment of Relapsed/Refractory Multiple Myeloma.
Authors: Orlowski Robert , Sutherland Heather , Bladé Joan , Miguel Jesús San , Hájek Roman , Nagler Arnon , Sonneveld Pieter , Spencer Andrew , Robak Tadeusz , Mundle Suneel , Luo Donghan , Zhuang Sen Hong , Harousseau Jean-Luc 
Published: October 2019

Abstract
Multiple myeloma (MM), like other monoclonal gammopathies, frequently causes impairment of the κ/λ serum free light chain (sFLC) ratio. Based on a short serum half-life of FLC as compared to the complete immunoglobulin (hours versus days), early normalization of κ/λ could predict for response to treatment. As part of a randomized, controlled study, we examined the association between normalization of the κ/λ ratio after one or two 21-day cycles of treatment with bortezomib (B) ± pegylated liposomal doxorubicin (PLD) among patients with relapsed/refractory multiple myeloma. Patients with ≥1 prior therapy were randomized to receive PLD 30 mg/m2 on day 4 and B 1.3 mg/m2 on days 1, 4, 8, and 11, or B alone for up to eight 21-day cycles, or at least 2 cycles beyond complete response (CR) or optimal response, unless disease progression or unacceptable toxicities occurred (Orlowski, JCO 2007). κ/λ measurements were carried out prior to the start of therapy and at the end of each cycle through the entire study period using an immunoassay (Freelite, The Binding Sites, Birmingham, UK). Serial sFLC κ/λ measurements were available on sera from 487 patients with baseline values out of a total of 646 study patients. At baseline, 458/487 patients (94%) had an abnormal κ/λ ratio (<0.26 or >1.65). The percentage of patients with normal κ/λ ratio increased from 6% at baseline to 12% after cycle 1, 17% after cycle 2 and 23% by the end of the study. Among patients with a normal κ/λ ratio after cycle 1 (n=54), the median time to progression (TTP) was 345 days compared to 225 days in patients with abnormal ratios (n=395, p=0.0005, HR=0.47 favoring normalization). Following cycle 2, TTP was 325 days vs. 224 days (p≤0.001) in patients with normal (n=72) vs. abnormal (n=348) ratios, respectively. Additionally, patients with normalized sFLC ratios showed significantly higher overall response rates as compared to those with persistently abnormal ratios (≥ partial response [PR] 73% vs. 47%, p=0.001 following cycle 1, and 77% vs. 48%, p<0.0001 following cycle 2, respectively). Similarly, CR + very good PR rates were significantly higher among patients with normalized sFLC ratios after cycles 1 and 2 (p<0.0001 and p<0.001 respectively). As reported previously, both treatments, B + PLD and B alone, were well tolerated (Orlowski, JCO 2007). Normalization of the sFLC ratio as early as after cycle 1 of B + PLD, or B alone, was associated with a prolonged TTP and higher response rates. Additional analyses are undertaken to evaluate whether Freelite data:
predict treatment outcome earlier than electrophoresis, and correlate with 24-hour urine M-protein.
USF1 Recruits hSET1 Complex and Is Important for Maintaining Active Chromatin Domains in the β-Globin Locus.
Authors: Li Xingguo , Hu Xin , Felsenfeld Gary , Huang Suming 
Published: October 2019

Abstract
The chicken β-globin insulator element acts as a barrier to the encroachment of chromosomal silencing. This barrier insulator prevents the spread of a 16 Kb domain of condensed chromatin which lies immediately upstream of the β-globin genes in the chicken genome. We have previously shown that the transcription factors USF1/2 mediate the barrier activity by binding to the 5′HS4 insulator element of the chicken β-globin locus and maintaining a local active chromatin structure. In the mouse β-globin locus, USFs also play a critical role in regulating the developmental stage-specific transcription of the β-major globin gene. To further understand the diverse roles of USF proteins, we undertook the biochemical isolation of USF1-containing multiprotein complexes. We found that USF1 associates with the hSET1 complex, which is an H3K4-specific methyltransferase. This complex exhibits histone H3 methyltransferase enzymatic activity. Consistent with the role of USF1 in recruiting histone modifying enzyme hSET1 to the 5′HS4 insulator, knockdown of USF1 expression in erythroid leukemia cell line 6C2 leads to the loss of histone H3K4 dimethylation at 5′HS4 of the chicken β-globin locus. In addition, USF1, hSET1, as well as H3K4 methylation are colocalized on HS2 of the locus control region (LCR) and the promoter of the β-major globin gene. Furthermore, the double ChIP analysis demonstrates that the histone methyltransferase hSET1 is recruited by transcription factor USF1 onto the mouse β-globin locus. The results suggest that hSET1 may play an important role in establishing H3K4 methylations on the active β-globin locus and reveal the mechanisms of USF and its associated proteins in maintaining the open chromatin domain and in regulation of globin gene transcription.
Pharmacokinetic and Toxicological Results of a 28-Day Multiple Dose Study of Starch-Conjugated Deferoxamine (S-DFO, 40SD02) in Iron-Loaded Dogs.
Authors: Grady Robert W. , Bakke James , Steinmetz Karen , Bishop Terry R. , Hedlund Bo E. 
Published: October 2019

Abstract
Starch-conjugated deferoxamine (S-DFO) is a long-acting, polymeric iron chelator designed to achieve iron balance in patients requiring frequent transfusions. Results from an ascending single dose study in 16 patients with beta-thalassemia showed that S-DFO is capable of achieving up to 7 days of iron balance (Br. J. Haematol. 138, 374–381, 2007). The multiple dose toxicology study described here was conducted to support extended clinical studies in patients with thalassemia and other iron overload disorders. The study was designed to evaluate physiological effects of S-DFO in iron-loaded animals;to seek evidence of cardiovascular side-effects;to find evidence of drug accumulation in plasma and other tissues; andto determine the No Observable Adverse Effect Level (NOAEL) following biweekly intravenous infusion for 4 weeks.
Iron loading was achieved by multiple biweekly infusions of iron-dextran so as to give a cumulative dose of 500 mg of iron/kg body weight. Equilibration of iron was then allowed to proceed for 10 weeks before initiation of treatment. The study included four groups of 10 iron-loaded animals (5M/5F):
saline controls; 210 and 420 mg/kg of deferoxamine (DFO) equivalents as S-DFO; 105 mg/kg of non-conjugated DFO;
and two groups of 10 normoferremic animals (5M/5F):
saline controls; and 210 mg/kg of DFO equivalents as S-DFO.
All animals received 8 doses of either S-DFO, DFO or saline over 28 days. Six animals in each group (3M/3F) were euthanized on Day 29 for histological examination, the remaining 4 animals in each group on Day 43. Safety parameters for cardiovascular pharmacology, hematology and clinical chemistry showed no changes attributable to S-DFO treatment. The polymeric chelator is cleaved/metabolized by serum amylase(s). While trough concentrations of S-DFO fragments prior to the final drug infusion on Day 25 showed some accumulation, there was no evidence of resulting pathological changes. Thus, the NOAEL is at least 420 mg/kg of DFO equivalents. The hepatic iron content of the iron-loaded animals was approximately 20 times greater than that of the normoferremic controls. Treatment with 420 mg/kg of DFO equivalents led to a 13% reduction in the liver iron content. Neither iron loading nor treatment with S-DFO had a significant effect upon the cardiac iron status. The lack of toxicity in normoferremic animals suggests that S-DFO may have applications in clinical situations where increased iron stores are not characteristic of the disease. Furthermore, the ability to safely infuse up to 420 mg/kg of DFO equivalents without concern for hypotension indicates that S-DFO may also be well suited for treatment of acute iron poisoning. Finally, these results support initiation of multidose studies of S-DFO in patients with thalassemia and other iron overload disorders.
Supported by NIDDK Contract Number N01-DK-32624.
The Early Treatment Response of the Clinically Challenging Group of Childhood T-ALL without NOTCH1 Mutations Is Signified by a Specific mRNA Gene Profile.
Authors: Kulozik Andreas , Breit Stephen , Pfister Stefan , Liu Shangyou , Stanulla Martin , Schrappe Martin , Ludwig Wolf-Dieter , Köhl Ulrike , Borkhardt Arndt , Kirschner-Schwabe Renate , Muckenthaler Martina U. 
Published: October 2019

Abstract
Activating mutations within the NOTCH1 gene occur in more than 50% of childhood precursor T-cell lymphoblastic leukemia (T-ALL, Weng et al. Science 2004). Our previous work has shown that in the context of the ALL-BFM 2000 treatment strategy, activating NOTCH1 mutations significantly correlate with a good early treatment response and specified a subgroup of patients with an exceptionally favorable long term outcome. By contrast, most of the relapses occurred in those patients without NOTCH1 mutations, which thus represents a clinically important and challenging subgroup (Breit et al., Blood 2006). We now aimed to further differentiate this subgroup without NOTCH1 mutations by analyzing the mRNA expression profile of primary pediatric T-ALL bone marrow samples. We first validated the biological significance of these analyses by comparing samples with and without activating NOTCH1 mutations and confirmed that the presence of activating NOTCH1 mutations correlates with differential expression of multiple downstream signaling pathways that are known to be activated by NOTCH1. Importantly, the comparison of patients without NOTCH1 mutations and good or poor prednisolone response revealed a specific gene signature that differentiates wild-type NOTCH1 T-ALL with a favourable from those with an unfavourable early treatment response. These discriminatory signatures significantly enrich for specific gene ontology categories (e.g. cell death, cellular growth and proliferation, and molecular transport), suggesting functional relevance of these differentially expressed genes. The specific comparison of different T-ALL subgroups thus reveals prognostic gene expression signatures particularly in the clinically difficult patients without NOTCH1 mutations.
PAX5 Mutations Occur Frequently in Adult B-Cell Acute Lymphoblastic Leukemia (B-ALL) and Is Significantly Associated with BCR-ABL1 Fusion Gene.
Authors: Familiades Julien , Bousquet Marina , Dastugue Nicole , Lafage-Pochitaloff Marina , Marie-Christine Béné , Beldjord Kheira , Cayuela Jean-Michel , Grardel Nathalie , Preudhomme Claude , Cavé Hélène , Lhéritier Véronique , Delannoy André , Chalandon Yves , Ifrah Norbert , Pigneux Arnaud , Dombret Hervé , Macintyre Elizabeth A. , Huguet Françoise , Brousset Pierre , Broccardo Cyril , Delabesse Eric 
Published: October 2019

Abstract
PAX5 is a transcription factor central to B-cell differentiation, frequently mutated in pediatric B-ALL (38.9% in 192 B-ALL, Nature,2007;446:758). PAX5 mutations consist in whole or partial gene deletions or amplifications, fusion gene or point mutations. Adult B-ALL differs in many regards from pediatric B-ALL as demonstrated by differences in prognosis and genetic abnormalities (ETV6-RUNX1 almost absent from adult; BCR-ABL1 rare in children). We screened the occurrence of PAX5 mutations in a series of 119 adult patients with B-lineage ALL prospectively treated in the GRAALL-2003 (pediatric-like protocol for BCR-ABL1 negative patients) or GRAAPH-2003 (imatinib-containing protocol for BCR-ABL1 positive patients), with a median follow-up of 667 days. PAX5 copy number was evaluated using quantitative PCR of each exon performed in hexaplicate (10 exons). PAX5 point mutations of the paired and transactivation domains (exons 2, 3, 7, 8 and 9) were evaluated by sequence analysis. PAX5 rearrangement was evaluated by caryotype and FISH analysis. Globally, PAX5 mutations were identified in 35 cases (30%). Isolated complete deletion of 1 allele was found in 13 cases (11%). Hypomorphic PAX5 alleles were detected in 22 cases (19%) consisting either of partial deletion (13 cases), partial amplification (1), point mutations (7 cases, frequently associated with complete deletion of the remaining allele in 5 cases) or fusion gene (1 PAX5-ELN). In addition, 2 cases of whole PAX5 amplification were found (2%). The remaining 82 cases had two normal PAX5 alleles (68%). BCR-ABL1 fusion gene was significantly associated with PAX5 mutations (Pearson Chi2, p=0.045) occurring in 40% of patients with PAX5 mutations and 18.3% without. PAX5 mutations were rare in the early stages of B-ALL as estimated by the immunological EGIL classification (only 2/35 PAX5 mutant cases [5.7%] vs. 16/82 [19.5%] in normal PAX5 B-ALL cases blocked at the B-I stage). Frequencies of CD10+ and CD20+ blasts were significantly higher in PAX5 mutant cases (Mann-Whitney, p=0.022 and p=0.038, respectively). As PAX5 is essential to the immunoglobulin heavy chain DHJH to VHDHJH transition, we analyzed IGH rearrangement. No difference was detected regarding the frequency of IGH rearrangement (78% in normal vs. 74% in mutants) or the rearranged VH. Survival was not significantly different between the two groups of patients (log rank, p=0.45). In conclusion, PAX5 mutations were a frequent event in adult B-ALL, associated with BCR-ABL1 fusion gene but were not associated with a significant clinical evolution.
A Tamoxifen-Dependent Conditional Model of MYC-Induced T Cell Acute Lymphoblastic Leukemia in the Zebrafish.
Authors: Gutierrez Alejandro , Feng Hui , Edward Prochownik , Kanki John , Look A. Thomas 
Published: October 2019

Abstract
The MYC oncogene plays a central role in the pathogenesis of human T cell acute lymphoblastic leukemia (T-ALL), and our laboratory has previously developed a zebrafish model of Myc-induced T-ALL. The primary strength of the zebrafish as a model system for human disease lies in is its suitability for unbiased forward genetic and small molecule screens. Our central hypothesis is that forward screens performed using our zebrafish model of MYC-induced T-ALL will lead to the identification of entirely novel genes and pathways that play critical roles in MYC-induced leukemogenesis. However, zebrafish from our original line develop rapidly progressive T-ALL prior to achieving reproductive maturity, making this line poorly suited for the performance of large-scale screens. Therefore, a conditional model was required. We have now generated a transgenic zebrafish line that expresses a human MYC-estrogen receptor fusion construct under the control of the zebrafish recombination activating gene 2 (Rag2) promoter, which is lymphocyte-specific. When mated against fish transgenic for a Rag2-GFP transgene, the development and progression of T-ALL can be readily tracked in live fish by fluorescent microscopy. Upon treatment with 4-hydroxytamoxifen (4HT), zebrafish from this line develop fully penetrant T-ALL, with a mean time to tumor onset of 8 weeks. Additionally, removal from 4HT invariably led to complete morphologic remission in leukemic zebrafish from this line, and all of these fish remained alive and were able to mate successfully for greater than 6 months after removal from 4HT. This conditional zebrafish model of MYC-induced T-ALL will now allow the successful performance of forward genetic and small molecule screens to identify known and novel genes and pathways that play critical roles in T-ALL leukemogenesis and MYC-induced transformation.
Figure Figure
Efficacy of Dasatinib in Patients with Philadelphia-Chromosome-Positive Acute Lymphoblastic Leukemia Who Are Resistant or Intolerant to Imatinib: 2-Year Follow-Up Data from START-L (CA180-015).
Authors: Porkka Kimmo , Simonsson Bengt , Dombret Herve , Martinelli Giovanni , Ottmann Oliver G. , Zhu Chao , Van Tornout Jan M.A. , Garzon Felix T. , Larson Richard A. 
Published: October 2019

Abstract
Patients with Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) generally have a rapid disease course and a poor overall prognosis that is compounded by resistance to imatinib. Dasatinib is a novel multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases, with in vitro potency some 325-fold greater than imatinib against BCR-ABL and proven efficacy in this patient population. START-L is an open-label, international, multicenter study in which patients with imatinib-resistant or -intolerant Ph+ ALL enrolled from January through July 2005 were treated with dasatinib 70 mg BID. Dose escalation to 100 mg BID and reduction to 50 or 40 mg BID were allowed for inadequate response and toxicity, respectively. At the time of this update, all 46 treated patients (median age 48 years; 59% male) had a minimum follow-up of 12 mo. 96% of patients were imatinib-resistant; 46% had received doses of imatinib >600 mg/d, and 52% had received imatinib therapy for >12 mo. Median time from the initial Ph+ ALL diagnosis was 18 mo (range 3–163) and 37% had undergone prior stem-cell transplantation (SCT). BCR-ABL mutations were present at baseline in 78% of patients. The overall major hematologic response rate (MaHR) was 41% with a complete HR rate of 33%. Major cytogenetic response (MCyR) was achieved in 57% of patients with a complete CyR attained in all but one of these patients (54%). Response rates were consistent irrespective of pre-existing BCR-ABL mutations. The median duration of MCyR was 6.9 mo. Median overall survival (OS) was 8.0 mo and 22% of patients remained alive and progression-free after 1 year of treatment. Outcome was favorable for patients with prior SCT: median OS of 9.0 mo (5.8 mo for patients without prior SCT). As expected in these pre-treated patients, grade 3–4 cytopenias were significant with 78% of patients experiencing severe thrombocytopenia and neutropenia. Non-hematologic side-effects included diarrhea in 33% of patients (grade 3–4 in 9%), pleural effusion in 24% (grade 3–4 in 7%), nausea in 22% (no grade 3-4), and pyrexia in 22% (grade 3–4 in 2%). The dose of dasatinib was reduced in 30% of patients and interrupted in 43%; this was primarily attributable to non-hematologic toxicities. This resulted in a median of the average daily dose of 143 mg. Dasatinib continues to show impressive efficacy in this poor-prognosis patient population with Ph+ ALL after the failure of imatinib. Updated analyses corresponding to a minimum follow-up of 2 years will be presented.