bluuebunny/crossref_metadata_2025_split huggingface dataset:
Specific Intensive Chemotherapy Plus Rituximab for Advanced Burkitt’s Lymphoma or Leukemia in HIV-Positive and Negative Adult Patients.
Authors: Ribera Josep-Maria , Oriol Albert , Esteve Jordi , Bergua Juan , Larregla Santiago , Brunet Salut , delPotro Santiago , Escoda Lourdes , Moreno-Rico Maria-Jose , Jimenez Javier Lopez , Feliu Evarist 
Published: October 2019

Abstract
A previous PETHEMA protocol (PETHEMA ALL3/97) proved that HIV-positive patients with Burkitt’s lymphoma (BL) and Burkitt-like acute lymphoblastic leukemia (ALL3) had similar outcome than HIV-negative patients (Haematologica2003; 88:445–53). We aimed to study the impact of the addition of rituximab to our previous protocol in terms of toxicity and efficacy, with special attention to HIV-positive patients. Consecutive patients between 18 and 55 years and diagnosed with advanced stage (stage III-IV or bulky stage II) BL/ALL3 between July 2003 and August 2006 received induction therapy including a pre-phase with cyclophosphamide (CPM) and prednisone (PDN), followed by cycle A (rituximab, iphosphamide, VCR, dexamethasone -DXM-, HD-MTX, ARA-C and VM-26), cycle B (rituximab, VCR, HD-MTX, CPM, DXM and doxorubicin) an cycle C (rituximab, DXM, VDN, HD-MTX, HD-ARAC and VP-16) up to six cycles (A1,B1,C1,A2,B2,C2) followed by two additional rituximab doses. CNS prophylaxis consisted of IT MTX+ARA-C+DXM given twice in cycles A and once in cycles B for a total of 8 doses.
Results: 36 patients (17 HIV-negative and 19 HIV-positive) were included. Both groups of patients were comparable for age, gender, ECOG score, BM and CNS involvement, bulky disease, LDH and albumin serum levels. Fifteen patients had bone marrow infiltration of whom 3 reached ALL3 criteria. Four out of 19 HIV positive patients begun treatment with HAART at the time of diagnosis and 15 were already under treatment. Median follow-up was 1.7 years (range 0.8–4.1). Main results of therapy are summarized in table 1. No significant differences in CR, DFS or OS were observed between HIV-positive and negative patients. Grade 4 neutropenia and thrombocytopenia were almost constant and lasted a median of 7 and 5 days respectively (range 0 – 39). Other frequent grade 3–4 toxicities were hepatic (5% of cycles), mucositis (18%) and infectious (18%). Episodes of grade 3–4 extrahematological toxicity were more frequent in HIV-positive patients (77% of episodes of mucositis, p=0.04 and 72% of infections). Treatment delays >7 days due to toxicity of previous cycle were also more frequent in HIV-positive patients (41% vs 24%, p= 0.04). In conclusion, our results prove that the addition of rituximab to a specific BL/ALL3 treatment is also feasible and highly effective for HIV-positive patients with similar results to HIV- negative patients in terms of efficacy although with higher toxicity.
Total (%) (n=36) HIV+ (%) (n=19) HIV- (%) (n=17) CR after two cycles 30 (83) 15 (79) 15 (88) Toxic death (1st 2 cycles) 5 (14) 3 (16) 2 (12) Resistance 0 0 0 Toxic death in CR 2 (6) 2 (11) 0 Relapses during treatment 1 (3) 0 1 (6) Relapses off treatment 0 0 0 Project. 1-year prob. DFS 90% 87% 93% Project. 1-yr prob. OS 78% 73% 82%
Preliminary Results of a Phase II Study of HCVIDDoxil Alternated with Methotrexate-Cytarabine in Patients with Newly Diagnosed T-Cell Lymphoma.
Authors: Pro Barbara , Fayad Luis , Romaguera Jorge , Fanale Michelle , Younes Anas , Hagemeister Fredrick B. , Samaniego Felipe , McLaughlin Peter , Rodriguez M.A. , Kwak Larry , Dang Nam H. 
Published: October 2019

Background The prognosis of patients with T-cell lymphoma (TCL) remains poor with conventional chemotherapy regimens and innovative approaches are needed. We evaluated the efficacy and safety of the regimen HCVIDDoxil, with pegylated doxorubicin substituting doxorubicin in the HCVAD regimen, alternated with MTX-Ara-C in patients with newly diagnosed TCL.
Methods Previously untreated patients (pts) with Zubrod performance status 3 or less, age > 18 years, and adequate marrow, cardiac, liver and renal function were included in this study. Patients with ALK + anaplastic large cell lymphoma (ALCL), skin involvement alone, HIV positive serology, and evidence of CNS involvement were excluded. Patients received HCVIDDoxil (iv cyclophosphamide 300 mg/m2 iv Q 12 h X 6 doses days 1–3, mesna 600 mg/m2 iv daily over 24 hours by continuous infusion days 1–3, doxil 25 mg/m2/day iv on day 2, vincristine 1.4 mg/m2 (max. 2 mg) iv days 4 and 11, dexamethasone 40 mg iv or po daily X 4 days 1–4 and 11–14) alternated with MTX/Ara-C (MTX 200 mg/m2 iv over 2 hours on day 1, then 800 mg/m2 iv over 22 hours on day 1, Ara-C 3 g/m2 iv Q 12 hours X 4 doses on days 3–4). Courses were repeated every 3 weeks for a maximum of 8 cycles. Endpoints were response rate and progression-free survival.
Results Between October 2003 and July 2007, 38 patients (pts) were included, 20 pts with PTCL, 6 pts with ALCL-ALK-, 4 pts with NK-TCL, 4 pts with HSL, and 4 pts with AIL. Median age was 54 (range, 23–70). Thirty-three (86%) pts had stage III/IV, 5 stage I/ II. Twenty-five (65%) pts had extranodal disease, and 14 (36%) pts had bone marrow involvement. A median of 5 cycles were delivered. To date 32 pts are evaluable for response. The ORR was 87%, with CR in 19 pts (59%) and PR in 9 pts (28%). Common Grade ¾ adverse events were thrombocytopenia in 31 pts (96%), neutropenia in 24 (75%), anemia in 23 (71%), and febrile neutropenia in 7 (32%). Six of the complete responders progressed (31%, median TTP 188 days), and 13 of the responses are ongoing (+6-+36 months).
Conclusions In this high-risk population the regimen HCVIDDoxil alternated with MTX-Ara-C induced a high response rate. Further follow-up is needed to evaluate if the high response rate results in improved disease-free survival. As expected, the major toxicity was myelosuppression. Enrollment in this study continues.
Induction of Both CCAAT/Enhancer Binding Protein β and ε Are Required for All Trans Retinoic Acid-Induced Granulocytic Differentiation of Myeloid Leukemia Cells.
Authors: Lu Min , Xia Lijuan , Friedman Alan D. , Waxman Samuel , Jing Yongkui 
Published: October 2019

Abstract
All trans retinoic acid (ATRA) induces remission in patients with acute promyelocytic leukemia (APL) by induction of granulocytic differentiation. Since CCAAT/enhancer binding protein (C/EBP) α, β and ε play important roles in normal granulocytic differentiation we compared their expression and regulation in ATRA differentiation inducible NB4 and HL-60 cells to their ATRA differentiation resistant subclones R4 and HL-60/Res cells. All four cell lines robustly express C/EBPα but have low or absent C/EBPβ and ε expression. ATRA treatment increases the levels of C/EBPβ and ε protein in NB4 and HL-60 cells but not in the R4 and HL-60/Res cells which is correlated with the degree of differentiation induction. Knockdown of C/EBPβ or ε using shRNA decreases ATRA differentiation induction of HL-60 cells. HL-60 cells with BCR-ABL stable transfection lose expression of C/EBPα, and ATRA-induced differentiation and expression of C/EBPβ and ε are no longer seen. K562 cells which express BCR-ABL do not have detectable or inducible C/EBPα, β and ε after ATRA treatment and are resistant to ATRA differentiation induction. Ectopic expression of C/EBPα-estrogen receptor (ER) or C/EBPβ-ER, but not C/EBPε-ER, induces granulocytic differentiation in K562 cells after addition of estradiol or tamoxifen which activates these fusion factors. C/EBPα-ER or C/EBPβ-ER infected K562 cells is followed by induction of C/EBPε expression and knockdown of C/EBPε in C/EBPα-ER or C/EBPβ-ER infected K562 cells decreases induction of differentiation. The induction of C/EBPα, β, and ε expression by ATRA is investigated in ten additional myeloid leukemia cell lines and it is found that the expression of C/EBPβ and ε, but not C/EBPα, are induced in THP-1 and ML-1 cells which are responsive to ATRA differentiation induction. These results indicate that induction of C/EBPβ is required and C/EBPε plays a collaborative role with C/EBPβ in ATRA-induced differentiation of myeloid leukemia cells.
Anti-Apoptotic Proteins, HSP90 and Activated STAT3 Contribute to Busulfan Resistance of Myeloid Leukemia Cells.
Authors: Andersson Borje S. , Valdez Ben C. , Murray David , Ramdas Latha , de Lima Marcos , Jones Roy , Kornblau Steven , Champlin Richard E. 
Published: October 2019

Abstract
Busulfan(Bu)-based chemotherapy is a conditioning treatment prior to hematopoietic stem cell transplantation (HSCT) of patients with acute and chronic myelogenous leukemia (AML, CML). A major obstacle to successful HSCT is Bu resistance, which might be attributed to individual differences in drug pharmacokinetics and metabolism, or inherent resistance of cancer cells. We hypothesize that gene expression profiling of leukemia cells can be used to dissect the factors that contribute to their Bu resistance. Two Bu-resistant leukemia cell lines were established, characterized and analyzed by microarray and real-time RT-PCR techniques to identify differentially expressed genes. The CML B5/Bu2506 cells are 4.5-fold more resistant to Bu than their parental B5 cells. The AML KBM3/Bu2506 cells are 4.0-fold more Bu-resistant than KBM3 parental cells. Both resistant sublines evade Bu-mediated G2-arrest and apoptosis with constitutively up-regulated anti-apoptotic genes (BCL-XL, BCL2, BCL2L10, BAG3 and IAP2/BIRC3) and down-regulated pro-apoptotic genes (BIK, BNIP3, and LTBR).). Bu-induced apoptosis is partly mediated by activation of caspases; use of the inhibitor Z-VAD-FMK completely abrogated PARP1 cleavage and reduced apoptosis by ∼ 50%. Furthermore, Bu resistance in these cells may be attributed in part to up-regulation of HSP90 protein and activation of STAT3. Inhibition of HSP90 with geldanamycin attenuated phosphorylated STAT3 and made B5/Bu2506 and KBM3/Bu2506 more Bu-sensitive. Analysis of cells derived from patients classified as either clinically resistant or sensitive to high-dose Bu-based chemotherapy had alterations in gene expression that were analogous to those observed in the in-vitro model cell lines, confirming the potential clinical relevance of this model for Bu resistance. Our results suggest the important roles of apoptotic signaling mechanism, HSP90 and STAT3 and should be considered in the classification of AML patients who will likely benefit from busulfan-based pretransplant conditioning therapy and those who should be offered alternative treatment modalities.
Lenalidomide Displays Direct Anti-Non-Hodgkin’s Lymphoma (NHL) Cell Activity in Association with Enhanced SPARC Expression but Independent of Its Ability to Strongly Inhibit NHL Cell VEGF Production In Vitro.
Authors: Zhang Ling-Hua , Schafer Peter , Muller George , Stirling David , Bartlett J. Blake 
Published: October 2019

Abstract
Lenalidomide is an oral anti-angiogenic, anti-proliferative and immunomodulatory drug that is approved for the treatment of transfusion-dependent patients with anemia due to low- or intermediate-1-risk MDS associated with a del 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, and in combination with dexamethasone for the treatment of previously treated multiple myeloma patients. Encouraging early results suggest a potential for clinical efficacy in B cell non-Hodgkin’s lymphoma (NHL). We have previously shown that lenalidomide can directly inhibit the proliferation of NHL cells and synergize with dexamethasone in inducing cell cycle arrest at the G1/S transition leading to caspase activation and apoptosis. In this study we have studied the potential for lenalidomide mediated growth inhibition, apoptosis and inhibition of angiogenic factors in NHL. We have assessed proliferation, expression of p21 and SPARC tumor suppressor genes and the production of the angiogenic factor vascular endothelial growth factor (VEGF) in six established NHL cells lines in vitro. The effect of lenalidomide on NHL cells was determined after 1–3 days using 3H-thymidine incorporation, microbead array and real time PCR. We found that lenalidomide displays anti-proliferative effects on Namalwa, Jeko-1 and Rec-1 cells when used alone and in combination with dexamethasone. However, several NHL cell lines, such as Granta-519, DB, and JVM-2, appear to be resistant. We also found that lenalidomide strongly inhibited VEGF production (but not mRNA levels) by the three sensitive lines (but not the three resistant lines) at much lower concentrations than required for inhibitory effects on proliferation. Excess recombinant human VEGF or neutralizing anti-VEGF antibody had no effect on Rec-1 proliferation suggesting that there is no connection between these two effects. Lenalidomide strongly increased the expression of tumor suppressor genes, such as p21cip/kip and SPARC (secreted protein acidic and rich in cysteine). In particular, elevation of SPARC mRNA correlated with the anti-proliferative effect of lenalidomide and was not seen in the resistant cells, whereas elevated p21 was observed in both sensitive and resistant (DB) cells. The effect of SPARC gene silencing on lenalidomide-induced effects is being assessed in siRNA studies. In conclusion, lenalidomide demonstrates anti-proliferative activity against certain sensitive NHL cells, particularly in combination with dexamethasone. Potent anti-VEGF activity of lenalidomide appears to be independent of proliferation and supports its anti-angiogenic potential. Lenalidomide-induced up-regulation of SPARC mRNA appears to correlate with sensitivity and may have biomarker potential in NHL.
Safety, Tolerability, and Pharmacology of Bortezomib in Cancer Patients with Renal Failure Requiring Dialysis: Results from a Prospective Phase 1 Study.
Authors: Mulkerin Daniel , Remick Scot , Takimoto Chris , Ivy Percy , Karol Michael , Eton Omar 
Published: October 2019

Abstract
Background: Bortezomib (btz; VELCADE®) is a specific, reversible proteasome inhibitor approved for the treatment of patients (pts) with multiple myeloma (MM) and mantle cell lymphoma following at least one prior therapy. Retrospective analyses of phase 2/3 studies and case series have shown btz alone or in combination is active and tolerable in MM pts with various degrees of renal impairment, including pts on dialysis. We previously reported clinical and pharmacologic data from the first prospective, dose-escalating study of btz in adult cancer pts with various degrees of renal impairment (ASCO 2006, abstract 2032). Here we present updated safety and tolerability data for dialysis-dependent patients.
Methods: Pts with advanced cancer were stratified by renal function into controls and four groups ranging from mild impairment to dialysis dependence. Pts received btz on d 1, 4, 8, and 11 of a 21-day cycle; dose escalation (0.7, 1.0, 1.3 mg/m2) proceeded in cohorts of 3 pts based on dose limiting toxicities (DLTs) observed in cycle 1. Blood samples were taken on d 1 and 8 of cycle 1 for pharmacokinetic (PK) and pharmacodynamic (PD) analysis. Adverse events (AEs) were evaluated using NCI CTC v2.0. DLTs were grade 4 neutropenia for ≥7 d or neutropenic fever, grade 4 thrombocytopenia for ≥7 d, grade 4 hemoglobin for ≥7 d, and grade ≥3 non-hematologic toxicity.
Results: To date, 59 pts have been treated, including 16 controls, 34 pts with mild-to-severe impairment, and 9 dialysis pts. Among dialysis pts: 3 were treated at 0.7, 2 at 1.0, and 4 at 1.3 mg/m2; median age was 62 y (range: 42–74); tumor types were MM (n=4), follicular lymphoma (n=1), and solid tumors (n=4). Median number of treatment cycles received was 2 in controls and across renal impairment groups. Dialysis pts received a median of 2 treatment cycles (range: 1–4); 1 pt remains on therapy. Dose escalation was well tolerated, with no DLTs, in pts with mild-to-severe renal impairment. There were no DLTs in cycle 1 in dialysis pts. Toxicities were generally mild in all groups. Among dialysis pts, no unexpected toxicities were seen. One grade 4 treatment-related AE (elevated creatinine) has been reported; grade 3 treatment-related AEs include platelets/thrombocytopenia (3 pts), diarrhea, hemoglobin, leukopenia, lymphopenia, packed red blood cell transfusion, sensory neuropathy, and vomiting (1 pt each). The overall AE profile in dialysis pts was similar to that in controls and in pts with mild-to-severe impairment, although renal and metabolic AEs appeared more common in dialysis pts.
Conclusions: Btz at doses up to 1.3 mg/m2 on this schedule was well tolerated in pts with advanced malignancies with mild-to-severe renal impairment and dialysis dependence. PK and PD analyses for dialysis pts treated at 1.3 mg/m2 will be reported. Btz is a viable treatment option for pts requiring dialysis.
MEL1 at 1p36.3 Is Fused to Several Partner Genes Including HOXA9 Located at Different Chromosomal Bands from 3q21.3 in t(1;3)(p36.3;q21.3)-Leukemia.
Authors: Xinh Phan Thi , Anh Hoang , Tanaka Hideo , Fujisawa Shin , Taketazu Fumitoshi , Rowley Janet D. , Tokunaga Katsushi , Sato Yuko 
Published: October 2019

Abstract
In MDS/AML with t(1;3)(p36;q21), overexpression of MEL1 lacking PR domain (MEL1S) driven by the RPN1 promoter at 3q21.3 is reported to be closely associated with the pathogenesis. Previously, we have defined the 1p36.3 breakpoint (BP) in 5 patients and the 3q21.3 BP in 4 patients with BAC/PAC probes. The BPs at 1p36 were clustered within 3 BP regions (BR), spanning an approximately 200-kb area: BR-1, a 70-kb region in the first intron of MEL1 covered by RP1-163G9; BR-2, a 29-kb region in 5′ region of MEL1 covered by RP5-907A6; BR-3, a 68.5-kb region between the BR-1 and BR-2. On the other hand, the BPs at 3q21.3 were clustered within only one BR, a 108.9-kb region belonging to RP11–475N22, centromeric to RPN1, in which GR6 gene and the promoter region of GATA2 gene are included. Among 5 patients, 2 had the 1p36.3 BPs within the first intron of MEL1, suggesting the existence of MEL1 fusion genes. As expected, using 3′- and 5′-RACE, we have identified 10 MEL1 fusion genes including MEL1/HOXA9 among the 4 patients, not only in patients with the 1p36.3 BP within MEL1 but also in patients with the 1p36.3 BP outside MEL1. None of reciprocal fusion transcripts were detected. Using two normal bone marrow samples and HNT-34 cell line as control, no MEL1 fusion transcripts were detected with TA cloning analysis of 50 clones obtained from each sample. Surprisingly, none of these partner genes were located at band 3q21.3, suggesting that different mechanisms from chromosome translocation might be involved in generating these fusion transcripts. This is the first report showing that MEL1 is involved in the (1;3)(p36;q21)-leukemia not only by inappropriate expression but also by generation of fusion transcripts. Taken together, our findings suggest that in addition to overexpression of MEL1S, MEL1 fusion transcripts may play important roles in the pathogenesis of t(1;3)-leukemia.
In Vivo Activated CD103+CD4+ Regulatory T Cells Ameliorate Ongoing Chronic GVHD.
Authors: Zhao Dongchang , Zhang Chunyan , Yi Tangsheng , Lin Chia-Lei , Todorov Ivan , Kandeel Fouad , Forman Stephen , Zeng Defu 
Published: October 2019

Abstract
The αEβ7 integrin CD103 is an excellent marker for identifying in vivo activated CD4+ regulatory T (Treg) cells. CD103− naive Treg cells from donors are effective in prevention but ineffective in treatment of graft versus host disease (GVHD). It is unknown whether in vivo activated donor CD103+ Treg cells can effectively treat ongoing GVHD. We have recently reported a new chronic GVHD model, in which donor DBA/2 (H-2d) spleen cells were transferred to the irradiated BALB/c (H-2d) recipients. The recipients showed chronic GVHD-like syndrome with high-levels of serum autoantibodies, proteinuria, and hair-loss, and the disease induction required both donor CD4+ T and B cells in a cell dose dependent manner (Blood, 2006). In the current studies, we observed that the percentage of CD103+ cells among donor CD4+ T cells in the recipients without disease was up to 45% and was more than two fold higher than that of the recipients with disease. The CD103+CD4+ T cells were more than 97% FoxP3+, which was similar to natural CD25hi Treg cells, but the former expressed markedly higher levels of CCR5 as compared to the latter. The CD103+ Treg cells showed markedly stronger suppression capacity as compared to freshly isolated as well as in vitro anti-CD3-activated CD25hi natural Treg cells. When injected into ongoing chronic GVHD recipients with severe proteinuria, CD103+ Treg cells (1x106) reversed proteinuria and tissue damages in 92% (11/12) of the recipients, and the recipients survived for more than 100 days. In contrast, the in vitro activated natural Treg cells reversed disease in only 25% (2/8) of the recipients, and the freshly isolated CD25hi natural Treg cells reversed none (0/12), and the treated recipients died within 45 days, which was similar to control PBS treated recipients. Furthermore, we found that infusion of the CD103+ Treg cells significantly reduced CD138+ antibody-secreting plasma cells in spleen and reduced serum levels of autoantibodies; and that infusion of the CD103+ Treg cells also significantly reduced CD44loCD62LhiSCA-1hi post-mitotic CD4+ T memory stem cells in spleen as well as pathogenic IFN-γ+CD4+ T cells in liver and nephritogenic IFN-γ+IL-10+CD4+ T cells in kidney tissues. Our results indicate that, different from CD103− naive natural Treg cells that prevent GVHD via suppressing donor T cell activation and expansion, CD103+ Treg cells ameliorate ongoing chronic GVHD via reducing activated pathogenic T and B cells.