bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prophylactic Colony-Stimulating Factors in Pediatric Patients Receiving Myelosuppressive Chemotherapy: A Meta-Analysis of Randomized Controlled Trials.
Authors: Wittman Brenda , Horan John T. , Lyman Gary H. 
Published: October 2019

Abstract
Background: The colony-stimulating factors (CSFs) are widely utilized to prevent neutropenic complications in both adults and children, but randomized controlled trials in the pediatric setting have varied considerably in size, methodology and patient population. A systematic review and meta-analysis was conducted to more definitively assess the impact of prophylactic CSFs on the risk of febrile neutropenia (FN) in pediatric oncology patients. The rates of documented infection (DI) and duration of severe neutropenia (ANC <500), hospitalization and antibiotic use were also evaluated.
Methods: MEDLINE and EMBASE were searched and identified references were hand-searched through July 2004 for randomized controlled trials (RCTs) of prophylactic G-CSF or GM-CSF in pediatric oncology patients. Both parallel and crossover studies were included. Of the 625 articles identified, 16 studies were included. Ten studies evaluated children with acute leukemia or high-grade lymphoma, and 6 evaluated those with solid tumors. Study objectives, quality, and outcomes were extracted by 2 independent reviewers. Weighted summary estimates of relative risks (RR) for FN and DI were calculated by the method of Mantel-Haenszel using a fixed effects model. Mean differences in durations (days) were estimated by the method of Cohen using a random effects model due to significant heterogeneity. An economic analysis based on cost minimization was calculated from the results of this analysis and a recent cost study.
Results: Among the 12 reporting RCTs, FN occurred in 68% of 400 controls and 59% of 404 CSF patients. Estimated RR was 0.88 [.81–.97; P=.01] favoring the CSFs for leukemia and high grade lymphoma studies and 0.71 [.51–.97; P=.03] for solid tumor studies. RR estimates were 0.85 [.78–.94; P<.001) for G-CSF and 0.83 [.47–1.49; P=.54] for GM-CSF. In 9 reporting studies, DI occurred in 25% of controls and 20% of CSF patients for an estimated RR of 0.80 [.61–1.06; P=.12]. The mean decrease in duration of neutrophils <500 in 13 reporting studies was 3.5 days [2.2–4.7; P<0.0001). Mean decreases favoring CSF use were also observed for hospital stay of 1.7 days [0.9–2.5] in 13 reporting RCTs (P<.01) and antibiotic use of 2.0 days [0.4–3.6; P=.02] in 10 RCTs. Baseline estimates based on the economic model provide incremental cost savings with CSF of $3,824 per subject and a cost saving FN risk threshold of 24%.
Conclusions: This analysis reveals that prophylactic CSFs significantly decrease the incidence of FN and the durations of severe neutropenia, hospitalization, and antibiotic use in pediatric patients receiving myelosuppressive chemotherapy. Differences in rates of documented infection were not statistically signficant. The economic analysis supports guidelines for CSF prophylaxis above a risk of 20%.
Quantitative PCR Predicts Early Relapse in Patients with Chronic Lymphocytic Leukemia (CLL) Submitted to Autologous Stem Cell Transplantation. The Case for Early Clinical Intervention.
Authors: Moreno Carol , Villamor Neus , Colomer Dolors , Esteve Jordi , Bosch Francesc , Lopez-Guillermo Armando , Campo Elias , Montserrat Emili 
Published: October 2019

Abstract
Autologous stem cell transplants (auto-SCT) are increasingly performed in patients with CLL. Although this procedure results in a high complete response (CR) rate, most patients eventually relapse. The median time to relapse is around 5 years. Increasing levels of minimal residual disease (MRD), detected by PCR or flow cytometry (FC) are associated with clinical relapse. The early detection of patients likely to relapse shortly after SCT may be useful in the management of these patients. With this background, we analyzed the levels of MRD and its correlation with the risk of relapse and clinical outcome in 19 patients with CLL submitted to auto-SCT. MRD was assessed by FC and quantitative real time PCR of the IgH region using allele-specific oligonucleotides (ASO-PCR) in peripheral blood and/or bone marrow DNA samples obtained before SCT and at different time points thereafter. After SCT, 17 patients achieved CR and 2 partial response. A continuous pattern of relapses was observed and, after a median follow-up of 48 months (range, 11–101), 11/19 patients have progressed. The median number of CLL cells detected prior to SCT was 2.4x10−2 decreasing to 5.31x10−4 at 3–6 months after auto-SCT. No further decrease was observed beyond that point. At 3–6 months after auto-SCT, only 3/17 patients in CR had undetectable levels of disease. Patients with a MRD level >10−3 at this time point (3–6 months after transplant) had a significantly higher risk of progression than those who had less than 10−3 CLL cells. All but one patients with MRD>10−3 have relapsed (7/8) whereas only 4/9 with MRD<10−3 did so. As shown in the figure, median time to progression was significantly shorter in those patients with a higher MRD level (16 vs. 55 months; p=0.003)
Figure Figure
In conclusion, quantification of MRD within the first 6 months after auto-SCT allows the identification of CLL patients with a high risk of early clinical relapse. These data provide background to investigate whether early treatment, before clinically overt relapse occurs, might be useful in patients with high risk of relapse after SCT.
Acquirement of Rituximab Resistance in Lymphoma Cell Lines Is Associated with Structural Changes in the Internal Domain of CD20 Regulated at the Post-Transcriptional Level.
Authors: Czuczman Myron S. , Olejniczak Scott , Gowda Aruna C. , Starostik Petr , Hernandez-Ilizaliturri Francisco J. 
Published: October 2019

Abstract
The acquirement of resistance to rituximab has been observed in lymphoma patients. To further define the molecular basis for rituximab-resistance we have developed various rituximab-resistant cell lines (RRCL) and studied changes in CD20 structure at the protein and gene level, membrane reorganization, and signaling events following rituximab exposure. RRCL were generated by chronic exposure of Raji cells to escalating doses of rituximab alone (2R) or concurrently with human complement (4RH). Functional assays were performed to demonstrate decrease in rituximab-associated CMC and ADCC. Changes in the structure of CD20 were determined by Western blotting using various antibodies recognizing epitopes located in the internal (GST77 and 1439) and external domain (B1) of CD20. Sequencing of the CD20 gene from Raji parental and RRCL was performed to determine differences. Following rituximab treatment, lipid raft domains were extracted from Raji and RRCL to determine changes in polarization. Redistribution of CD20 antigen were evaluated by Western blotting. No significant changes were observed in the expression of the external domain of CD20 antigen between rituximab-sensitive and RRCL as demonstrated by flow cytometric analysis and Western blotting. However, significant changes in the internal domain of CD20 were observed in RRCL. Specifically, changes in the N-terminal, and to a lesser degree the C-terminal region of the internal domain of CD20 were observed in RRCL. The CD20 gene sequence was found to be identical between Raji cells and RRCL, suggesting a post-transcriptional regulatory mechanism is responsible for the changes in the structure of CD20. Redistribution of CD20 into the lipid raft domains was more evident in Raji parental cells when compared to RRCL, and a decrease in p38 activation was observed following exposure of RRCL to rituximab. In conclusion, our data strongly suggests that the acquirement of rituximab-resistance is associated with significant changes in the structure of the internal domain of the CD20 antigen. The abnormal production of truncated forms of the CD20 antigen, while not affecting external rituximab binding resulted in changes in the redistribution of CD20 antigen into lipid raft domains and a decrease in signaling events. Post-transcriptional events leading to the acquirement of truncated forms of CD20 may impair signaling activation, thus contributing to rituximab-resistance seen in RRCL.
Induction of Potent Anti-B-Cell Lymphoma CTL Responses by the Same Immunoglobulin Variable Region Subfamily Framework-Derived Peptides.
Authors: Guo Xiaoling , Zhu Ping 
Published: October 2019

Abstract
The immunoglobulin variable region (IgHV) which also be called the idiotype (Id) is the best-characterized tumor antigen expressed in B-cell lymphoma. It can function as a target for T-cell-mediated immune responses. However, the usefulness of this approach is limited because vaccines must be patient-specific. IgHV gene can be divided into seven subfamilies, which share the same gene sequence within their framework regions (FR). Here, we choice some peptides derived from the different gene subfamily FRs, and tried to identify if these peptides were capable of inducing cytotoxic T-lymphocyte (CTL) responses, and if the special CTL had possibility to kill B-cell lymphoma cells that belonging to the same subfamily. Meantime we explore if the limitations could be overcome by using the FR-derived peptides. In our study, we amplified seven respective IgHV gene subfamilies by PCR and directly sequenced for 108 cases of acute lymphoblastic leukemias. Complete VHDJH rearrangements were identified in 71(66%)out of 108 cases with 34 (47.89%) monoallelic rearrangements, 30 (42.25%) biallelic rearrangements and 7 (9.86%) oligoclonal rearrangements. SYFPEITHI and BIMAS software databases were used to predict T-cell epitopes in the seven different IgHV subfamily’s FR, and to find that these peptides have the same sequence as their germ line gene. Using an antigen-specific T-cell expansion system in vitro, we stimulated the PBMC from the health HLA-A0201 donor by the IgHV1 peptide(QLVQSGAEV) loading APC every week, and demonstrated that the predicted peptides could generate peptide-specific CTL successfully in healthy donors. The frequency of CD8+ and IgHV1 peptide(QLVQSGAEV)/tetramer+ double positive cells in the gated lymphocyte population was 0.38% before stimulation and increased to 49.38 % after forth stimulation . The cytokine release assay and the cytotoxicity assay indicate that these CTLs are capable of killing the lymphoma cell line belonging to the same family in a peptide-specific, and MHC-restricted way. Furthermore, the CTL stimulated by the IgHV1 peptide cannot kill the target cell pulsing a different subfamily peptide, indicating that the cytotoxicity is family-specific. Using the RT-PCR method, TCRBV expression of the CTLs were analyzed and the PCR products were sequenced directly. We found after four stimulations, the TCRBV expression were skewed in several families, and all the clones were found to have identical nucleotide sequences. In conclusion, our results demonstrate that the family-specific peptides derived from the IgHV FR can successfully lead to the generation of peptide-specific CTLs in vitro. Such defined antigenic epitopes may not only serve as candidates for novel lymphoma immunotherapy strategies, but also may help in discovering the interaction between the B-cell and T-cell clones.
The Expression of the CD21 Antigen in Non-Hodgkin’s Lymphoma Is Involved in LFA-1 Expression and Tumor Survival.
Authors: Otsuka Masaki , Yakushijin Yoshihiro , Hamada Makoto , Hato Takaaki , Yasukawa Masaki , Fujita Sigeru 
Published: October 2019

Abstract
CD21/complement receptor type 2 is a membrane protein expressed on B lymphocytes, follicular dendritic cells, early thymocytes, and a subset of mature T lymphocytes. This major B cell antigen appears later than CD19 and CD20 in cell differentiation and is lost from the cell surface during the early stages of B cell activation. CD21 is characterized not only as a complement ligand but also as an adhesion molecule of the cell surface that is dependent on CD23 expression, suggesting that it may be involved in lymphocyte trafficking and several immune responses. Recently two groups have reported that CD21 expression is significantly negatively associated with mortality in diffuse large B cell lymphomas. From these reports and clinical observations, we have transfected the CD21 gene into a CD21/CD23-negative lymphoma cell line (Namalwa). Interestingly, all established CD21+ transfectants (six clones from different bulks) showed homotypic aggregation during in vitro cell culturing, and none of the anti-CD21 antibodies prevented this cell aggregation. Moreover, these CD21+ transfectants were easily rejected in vivo when they were injected in nude mice compared to vector-only transfectants and parental cells as controls. These observations suggest that other adhesion molecules may be involved in CD21-induced cell aggregation and reduced tumorgenesis in vivo. After the screening of several integrins, CD21+ transfectants highly expressed LFA-1 (CD11a/CD18) on their cell surfaces compared to vector-only transfectants and parental cells. CD21+ transfectants displayed tight adhesion when in contact with recombinant human ICAM-1, and cell aggregation of CD21+ transfectants was blocked by an anti-LFA-1 monoclonal antibody. Northern and Western analysis and confocal laser scanning microscopic analysis suggested that the CD21 expression made the transfer of LFA-1 from the cytoplasm to the cell surface. We conclude that the expression of the CD21 molecule is strongly associated with the LFA-1 expression on the cell surface, independent of the CD23 molecule, and this phenomenon may be involved in tumor survival in non-Hodgkin’s lymphoma in vivo.
Early Allogeneic Hematopoietic Cell Transplantation during Induction Chemotherapy in High-Risk Acute Myeloid Leukemia.
Authors: Ehninger Gerhard , Platzbecker Uwe , Thiede Christian , Illmer Thomas , Schuler Ulrich S. , Schaich Markus A. , Bornhaeuser Martin 
Published: October 2019

Objectives: In patients with acute myeloid leukemia and high-risk cytogenetic aberrations or minor response to the first cycle of induction chemotherapy (IC) the probability of achieving a sustained complete remission is low. Thus early treatment intensification may be warranted in order to achieve long-term disease control. We performed a prospective trial to evaluate whether reduced-intensity conditioning followed by allogeneic hematopoietic stem cell transplantation (HSCT) from related or unrelated donors can be performed during the aplastic phase of IC in patients with poor-risk AML.
Methods: Seventeen patients (n=17) aged between 17 and 63 years (median 45) with acute myeloid leukemia and high-risk cytogenetic aberrations (n=14, complex, inv3 or t(3;3), t(3;5), −7 or del 7q, +8) or more than 10 % marrow blasts on day 15 after the first cycle of IC (n=3) were included so far. During aplasia a median of thirteen days (range 7–35) after the first (n=8) or second (n=9) cycle of IC patients received 5 x 30 mg/m2 fludarabine i.v. combined with either 8 mg/kg busulfan p.o. (n=4) or 150 mg/m2 melphalan iv. (n=13) followed by allogeneic G-CSF mobilized peripheral blood stem cells (PBSC, n=16) or bone marrow (n=1) from related (n=7) or unrelated (n=10) donors. Nine out of seventeen patients were not in complete remission before conditioning therapy was started. Patients with unrelated grafts received antithymocyte globulin (4 x 10 mg/kg ATG Fresenius). GvHD prophylaxis was performed with cyclosporine A (CSP).
Results: All patients engrafted (ANC > 0.5 Gpt/l on day 11, range 8–19, platelets > 50 Gpt/l day 15, range 11–32) and went into remission. Acute GvHD grade II-IV occurred in 8 patients and extensive chronic GvHD was documented in 5 patients with a follow-up of > 100 days. Two patients died while being in remission from infectious complications associated with acute (n=1) or chronic (n=1) GvHD and two patients died during relapse eight and twelve months after PBSC. With a median follow-up of 15 months (range 1–65) thirteen out of seventeen patients (76 %) are alive and in remission.
Conclusion: Early allogeneic HSCT as part of primary induction therapy seems to be an effective strategy in AML patients with either poor risk karyotype or minor response to the first induction cycle.
Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Patients Aged 65 Years or Older with AML and MDS.
Authors: de Lima Marcos , Shahjahan Munir , Alamo Jorge , Williams Patricia , von Wolff Brigitte , Couriel Daniel , Khouri Issa , Rondon Gabriela , Wheeler Brandy , Estey Elihu , Ueno Naoto , Kebriaei Partow , Champlin Richard , Giralt Sergio 
Published: October 2019

Abstract
Allogeneic HSCT is a potentially curative treatment for AML/MDS, but aging is generally associated with poorer outcomes. The incidence of AML/MDS, however, increases after the 7th decade of life, and there is limited data with transplantation in this age group. Here we review our experience treating such patients.
Methods: Retrospective analysis of outcomes of patients aged 65 or older treated from 1996 to 2004 with allogeneic HSCT (n=40; median age 67 years, range 65–75 years). Diagnosis was MDS in 5 cases and AML in 35 patients. Cytogenetics were high-risk in 50% and intermediate risk in 50%; 80% of the patients had active disease at HSCT (n=32). All preparative regimens contained fludarabine 100–150 mg/m2, combined with cytarabine 4 gm/m2, and idarubicin 36 mg/m2 (n=12); or with busulfan (n=8); with melphalan 140 or 180 mg/m2 (n=12); and with melphalan 140 mg/m2 and Mylotarg 2 or 4 mg/m2 (n=8). ATG was added in unrelated donor (MUD) HSCT. All but 2 patients received tacrolimus and methotrexate for graft-versus host disease (GVHD) prophylaxis. Stem cell source was bone marrow in 11 cases and peripheral blood in the others. Donors were related in 27 cases and unrelated in 13 cases (33%).
Results: 35 patients engrafted (88%); complete remission (CR) rate was 72%, 6 patients died early and 3 did not respond. Eleven patients are alive at a median of 12.5 mo (range, 2.6–59 mo), 10 of them in CR. One-year overall survival was 30% for the whole group, 26% for recipients of MUD and 32% for recipients of related donor HSCT (MUD x sibling, P=NS). One-year event-free survival was 28%. Median survival and disease-free survival was 4.5 and 2.5 mo, respectively; 42% of the patients in CR post HSCT have relapsed (n=13). Acute and chronic GVHD rates were 45% and 48%, respectively. Non-relapse mortality (NRM) was 40%.
Figure shows survival of patients with and without circulating blasts at the time of transplant. Figure shows survival of patients with and without circulating blasts at the time of transplant.
Conclusions: Here we expanded our previous observations indicating that allogeneic HSCT is a treatment option for selected patients in this age range. In this cohort with advanced stage disease (80% with active disease at transplant), NRM was high, but survival after sibling and unrelated donor transplants was similar.
Varicella-Zoster-Virus-Specific CD4+ Cytotoxic T Cells as Tumor-Specific Effector Cells in Cancer Immunotherapy.
Authors: Landmeier Silke , Pscherer Sibylle , Eing Bodo , Rooney Cliona M. , Juergens Heribert , Rossig Claudia 
Published: October 2019

Abstract
Adoptive transfer of gene-engineered T cells expressing tumor antigen-specific chimeric receptors (chRec) is a promising tool in cancer immunotherapy. A major limitation is the failure of chRec to induce proliferative T cell responses, resulting in a rapid loss of function. To provide a strategy for reexpansion of tumor-reactive T cells in vivo, we generated dual-specific T cells that respond to varicella zoster virus while also possessing chRec-mediated tumor reactivity. We expanded VZV-specific cytotoxic T cell lines (VZV-CTL) from four seropositive donors by culturing peripheral blood-derived T cells with lysates extracted from VZV-infected fibroblasts. Repeated stimulation with VZV lysates resulted in efficient and continued expansion for 10–12 weeks. >1x109 T cells were routinely obtained from a starting number of 1x106 peripheral blood T cells. The T cells displayed a mainly CD3+CD4+ (90±5%) phenotype. ELISPOT assays showed specific, MHC class II-restricted IFN-γ release in response to CD40-activated B cells expressing the viral glycoproteins gE and IE62. VZV-CTL belong to a non-regulatory effector T cell subset, shown by their failure to exert antiproliferative effects against cocultured autologous T cells and lack of Foxp3 expression. Retroviral transduction with chRec recognizing the tumor ganglioside antigen GD2 (14.G2a-ζ) and the B cell lineage antigen CD19 (CD19-ζ) resulted in receptor surface expression on 29–74% and 39–45% of cells, respectively. Gene-modified VZV-CTL efficiently recognized antigen-expressing tumor targets in an MHC-independent manner, as demonstrated by antigen-specific secretion of IFN-γ in response to coincubation with GD2-expressing tumor targets. Furthermore, chRec-transduced VZV-CTL performed potent and antigen-specific tumor cytolysis. Antibody blocking experiments revealed that tumor cells were lysed in a granulysin-dependent manner. ChRec-transduced CD3+CD4+ cytolytic VZV-CTL may provide a source of highly potent tumor-reactive cells for adoptive immunotherapy cancer. Endogenous viral reactivations or administration of booster doses of varicella vaccine may lead to survival of these tumor-reactive T cells for prolonged periods of time in vivo.
Augmented Hyper-CVAD in Acute Lymphoblastic Leukemia (ALL): The MDACC Experience with Intensified L-Asparaginase and Vincristine in Adult ALL Salvage.
Authors: Faderl Stefan , Thomas Deborah A. , Garcia-Manero Guillermo , Ravandi Farhad , Beran Miloslav , Rytting Michael , Koller Charles A. , Verstovsek Srdan , Borthakur Gautam , Andreeff Michael , Kornblau Steve , Vu Khanh , Jarmon Rita , Kantarjian Hagop M. 
Published: October 2019

Abstract
Prognosis has improved in newly diagnosed adult ALL using dose-intense multiagent regimens. Outcome of 185 patients (pts) treated with Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) showed 91% CR rate with 5-yr. survival of 39% and low induction mortality (Kantarjian et al. JCO 18:547, 2000). Outcome remains poor in ALL salvage. Following leads in pediatric ALL, we hypothesized that “augmentation” of hyper-CVAD (AHCVAD) with vincristine, dexamethasone, and L-asparaginase during induction and consolidation may improve prognosis in adult ALL salvage. To evaluate efficacy and safety of AHCVAD we conducted a phase II study, in which pts received up to 8 courses of HCVAD alternating with methotrexate/high-dose cytarabine. Each course was augmented by L-asparaginase 20,000 units i.v. and vincristine 2 mg i.v. at days 1, 8, and 15 each, and dexamethasone 80 mg i.v./p.o. on days 1–4 and 15–18. From June 2003 to June 2005, 29 pts with relapsed/refractory ALL were treated. Median age was 32 yrs (range 14–70). Twenty-two pts (76%) had pre-B ALL (1 isolated CNS disease), 6 (21%) T cell ALL (2 with isolated extramedullary disease), and 1 (3%) pt had mature B ALL. Karyotype was diploid in 11 (44%) and abnormal in 14 (56%) pts (1 Ph+ ALL). No information is available in 4 pts. Median number of prior regimens was 1 (1–4). Median remission duration to initial induction regimen was 9 mos (0–68). Three pts were primary refractory. Of 29 pts, 22 are evaluable for response (2 too early, 5 off study for toxicity or pt. choice). Eight pts (37%) achieved CR, 1 (5%) PR, and 2 (10%) hematologic improvement (HI) for an OR of 52%. Six pts were able to proceed with stem cell transplant (5 CR, 1 HI). Of 29 pts evaluable for toxicity, 5 (17%) died on study from infectious complications. Uncomplicated neutropenic fever was common. Three pts (10%) were intolerant to L-asparaginase and had to be taken off study early. In summary, AHCVAD has activity in ALL salvage. However, asparaginase-related toxicities and neutropenic complications remain frequent and may limit the usefulness of this approach to selected patient populations.