bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hospital Resource Utilization in Acute Invasive Aspergillosis (AIA) Patients (Pts) Treated with Voriconazole (VOR) or Amphotericin B (CAB).
Authors: Wingard John R. , Herbrecht Raoul , Marciniak Anne , Roberts Craig S. 
Published: October 2019

Abstract
Background: Treatment of AIA typically involves prolonged hospitalization and substantial use of intensive care (ICU) resources. This study compared consumption of hospital resources by AIA pts receiving initial treatment with either VOR or CAB.
Methods: Data were collected prospectively as part of a clinical trial comparing VOR to CAB in AIA of immunocompromised pts, where VOR showed a significant improvement in success and a relative survival benefit (Herbrecht R et al, NEJM2002; 347: 408–15). Pts in the modified-intent-to-treat population with completed resource utilization data were included. Total days of hospitalization, days of ICU, and hospitalization-free survival days during 12 weeks following initiation of therapy were compared. The impact of survival on resource consumption was explored.
Results: There were 143 and 131 pts in the VOR and CAB arms, respectively, with resource utilization data. Resource utilization data are presented in the Table.
Resource Utilization by Treatment Arm
VOR Mean (SD) CAB Mean (SD) Difference (95% CI) Total Hospital Days 27.8 (22.7) 27.7 (20.8) 0.1 (−5.1, 5.3) Total Hospital Days (survivors) 30.2 (24.2) 33.3 (22.2) −3.1 (−10.3, 4.0) ICU Days 5.6 (10.7) 8.1 (14.4) −2.5 (−5.5, 0.5) ICU Days (survivors) 4.0 (10.9) 8.1 (14.6) −4.1 (−7.9, −0.2) Hospitalization-free survival (days) 40.3 (29.8) 28.4 (28.5) 11.9 (4.9, 18.8)
Conclusion: VOR pts had significantly longer hospitalization-free survival and had a trend toward fewer ICU days than CAB pts. Improved survival with less hospital resource utilization and lower total drug acquisition costs (Lewis JS et al, ICAAC 2003, A1359) support the economic benefit of using VOR for primary therapy for AIA.
High Dose Therapy with Autologous Blood Stem Cell Transplantation (ASCT) for Follicular Lymphoma: Long-Term Outcome According to Histologic Grade.
Authors: Pohlman Brad , Jin Tony , Summers Kristie , Kuczkowski Elizabeth , Kalaycio Matt , Sobecks Ronald , Andresen Steven , Bernhard Laura , Cherni Kelly , Baker Janet , Bates Jennifer , Bolwell Brian J. 
Published: October 2019

Abstract
Follicular lymphoma is generally an indolent disease with a relatively long natural history requiring multiple therapies over many years. The optimal combination and sequence of these therapies continue to evolve. Despite substantial supporting evidence (including a recently published, randomized study), the role of high dose therapy with ASCT in follicular lymphoma has been questioned. Therefore, we reviewed the Cleveland Clinic experience to determine the long-term outcome of follicular lymphoma patients according to histologic grade. Between June 1991 and June 2004, 105 patients with relapsed, grade 1–3, follicular lymphoma (without histologic transformation) received high dose CBV (n=9) or BuCyVP (n=96) and ASCT at the Cleveland Clinic. The median follow-up among survivors is 4.4 (0.1–11.4) years.
Table of patient, disease, ASCT characteristics, and outcome
Variable Grade 1 (n=45) Grade 2 (n=36) Grade 3 (n=24) p-value Age: median (range) 49(35–62) 51(33–58) 53(42–64) 0.042 Male sex: N (%) 23(51) 20(56) 12(50) 0.89 Years from diagnosis to ASCT: median (range) 3.0(0.4–15.7) 3.0(0.9–17.6) 2.3(0.6–15.2) 0.34 Prior # chemotherapy regimens: 2–3/>4, N (%) 36(80)/9(20) 32(89)/4(11) 19(79)/5(21) 0.49 Disease status at ASCT: CR/PR, N (%) 6(13)/33(73) 10(28)/22(61) 6(25)/15(63) 0.58 Bone marrow status at ASCT: +/−, N (%) 8(23)/27(77) 4(13)/28(88) 4(18)/18(82) 0.54 Prior radiation therapy: N (%) 14(31) 11(31) 5(21) 0.63 LDH > normal at ASCT: N (%) 28(62) 27(77) 13(54) 0.16 Tumor bulk >10 cm at ASCT: N (%) 8(18) 6(17) 5(21) 0.92 Disease progression: N (%) 20(44) 13(36) 11(46) – Death: N (%) 17(38) 11(31) 10(42) –
Kaplan-Meier freedom from progression and overall survival according to histologic grade are shown:
Figure Figure
By Cox proportional univariate analysis, male sex, ≥4 prior chemotherapy regimens, and elevated LDH predicted a higher risk of progression while prior radiation therapy and bone marrow involvement predicted a higher risk of death. By Cox proportional multivariate analysis, male sex and elevated LDH predicted a higher risk of progression while prior radiation therapy and tumor bulk predicted a higher risk of death. In conclusion, approximately half of all patients that receive high dose therapy and ASCT for relapsed follicular lymphoma of any histologic grade enjoy long-term remissions and survival. ASCT remains one of the most beneficial treatment options for many patients with relapsed follicular lymphoma.
Tandem Autologous Stem Cell Transplantation Following High Dose Chemotherapy for Transformed Low Grade and Refractory High Grade Lymphoma.
Authors: Dubruille Viviane , Morineau Nadine , Moreau Philippe , Guillaume Thierry , Mahe Beatrice , Chevalier Patrice , Luc Harouseau Jean , Noel Milpied 
Published: October 2019

Abstract
The results of autologous stem cell transplantation following high dose chemotherapy for transformed low grade, high grade refractory or relapsing early (<1 year) lymphoma are disappointing. We describe a tandem intensive chemotherapy followed by autologous stem cell transplantation in 37 patients between April 1996 and February 2004. The median age was 49 yo (33–63yo); 19 patients had a transformed low-grade lymphoma, 7 patients a high grade early (<1year) relapse and 11 patients had induction failure. Pre transplant therapy consisted of 2 to 4 courses of polychemotherapy with anthracycline or with cisplatine. The first intensive chemotherapy program consisted of mitoxantrone 45mg/m² at day 1 and cytarabine 1000mg/m² at days 1,2,3,4 followed by autologous stem cell transplantation at day 5. The second intensive treatment consisted of fractioned total body irradiation (12 Gy) and cyclophosphamide 60mg/m² for two days followed by autologous stem cell transplantation in 35 patients and of BEAM (carmustine 300mg/m² at day 1, cytarabine 200mg/m²/12hours at days 2,3,4,5; etoposide 400mg/m² at days 2,3,4,5; melphalan 140mg/m² at day 6) followed by autologous stem cell transplantation in 2 patients who previously received radiotherapy. The regimen was well tolerated with no treatment related death. With a median follow-up of 34.4 months from day 0 of the first intensive treatment, 22 patients are alive in complete remission. The 5y Kaplan Meyer probability of survival is 59%; 15 patients relapsed after a median of 10.6 months (1.9–30.1) and died. The 5y OS in each category is: transformed low grade lymphoma: 68%; high grade early relapse: 29%; induction failure: 64%. This tandem intensive chemotherapy is feasible, well tolerated and effective for transformed low grade lymphoma and induction failure but seems to be disappointing for high grade in early relapse and new therapeutic approaches need to be explored for this category.
Low Incidence of Complete Remission but Comparable Event-Free Survival(EFS) and Overall Survival (OS) with a History of Prior Monoclonal Gammopathy of Undetermined Significance (MGUS) or Smoldering Myeloma (SMM) among Patients Receiving Total Therapy 2 (TT 2).
Authors: Fassas Athanasios , Barlogie Bart , Rasmussen Erik , Milner Teresa , Terry Julian , Zangari Maurizio , Talamo Giampaolo , Lee Choon-Kee , Thertulien Raymond , Crowley John , Tricot Guido 
Published: October 2019

Abstract
Symptomatic/progressive MM sometimes develops on the background of MGUS or progresses through a smoldering MM phase (SMM); other patients may have initially a solitary plasmacytoma of bone (SPC). This study examines the survival implications of pre-existing conditions such as MGUS (n=22), SMM (n=22) or SPC (n=20) among 668 enrolled in TT 2. TT 2 consists of intensive remission induction, melphalan-based tandem autotransplants; consolidation chemotherapy and interferon maintenance. 2 yr estimates of CR/near-CR (only IFE-positive) were similar in de novo MM (44%/67%) and in those with preceding SPC (46%/67%); both were higher than in case of preceeding SMM (24%/38%) or MGUS (17%/49%) (p=.009/p=.007). According to multivariate analysis, the time to CR was shorter in the presence of LDH > 190 U/L (HR 1.33, p=.003) and IgA isotype (HR 1.3, p=.08) but longer in the case of preceeding MGUS or SMM (HR 0.44, p=.02). Kaplan Meier plots of EFS and OS were similar for de novo MM and patients with the 3 precursor conditions. We conclude: (1) the low incidence of stringently defined CR among patients with preceeding MGUS or SMM does not negatively impact EFS or OS after initiation of therapy for symptomatic/progressive MM; (2) this lower incidence of CR may reflect the re-establishment of a stable precursor state due to the high level of drug resistance of these low proliferative activity conditions; (3) patients with de novo MM not achieving CR but having a prolonged EFS/OS may be those with a clinically unrecognized precursor condition; (4) measurements other than M protein-reduction must be identified to better assess minimal residual disease.
Figure Figure
Low Incidence of Cytogenetically-Defined MDS/AML among Newly Diagnosed Patients Treated According to Total Therapy 1 (TT 1) or Total Therapy 2 (TT 2).
Authors: Thertulien Raymond , Barlogie Bart , Sawyer Jeffrey , Bailey Clyde , Reiner Maureen , Rasmussen Erik , Fassas Athanasios , Zangari Maurizio , Tricot Guido 
Published: October 2019

Abstract
The leukemogenic potential of hematopoietic stem cell-toxic alkylating agents (melphalan, nitrosoureas) and of topoisomerase inhibitors are well established. We have previously reported, among 1,326 patients treated at our institution with melphalan-based tandem autotransplants, that the incidence of cytogenetically-defined MDS (CG-MDS) was directly related to the duration of prior alkylating agent therapy, patient age, and could be anticipated in those with poor stem cell mobilization. Using appropriate FISH probes applied to interphase nuclei, we have also reported that the MDS cytogenetic abnormality (MDS-CA) was usually already present in the cryopreserved PBSC. We have now examined the post-transplant incidence of MDS-CA among 195 patients receiving a first autotransplant as part of TT 1 and among 569 patients as part of TT 2. MDS-CA included del 20q11 in 4, t(1;7) (q10; p10) in 4, del 7q22/-7 in 4, del 13q in 3, del 5q22 in 3 and del 16q22 in 1 patient. 16 total events were observed, 10 on TT 1 and 6 on TT 2, with a low 5-yr estimate of MDS-CA of 1% with TT 2 and 4% with TT 1. Of these 16 patients, 3 have developed overt AML. Subsequent management included anthracycline/ara-C combination chemotherapy, as well as further autotransplant in 2 patients. 8 of the 16 patients have died, 2 due to AML, 3 due to progressive MM, and 3 to other causes. These findings indicate that limited exposure to chemotherapy and the use of non-genotoxic agents as induction treatment for myeloma reduce the risks of the potential development of t-MDS after autologous transplantation. Given the observed survival benefit for patients treated on these 2 protocols, these findings also support the notion of an aggressive approach to myeloma treatment using intensive, hematopoietic stem cell sparing induction and post-transplant consolidation therapy as administered in TT2.
Molecular Transfer of Human CD40 and OX40 Ligands to Leukemic Human B-CLL Cells Extensively Expands Tumor-Reactive Cytotoxic T-Lymphocytes.
Authors: Biagi Ettore , Dotti Giampietro , Yvon Eric , Rousseau Raphael , Lee Edward , Gotschalk Stephen , Brenner Malcolm 
Published: October 2019

Abstract
CD40 ligand is an accessory signal for T-cell activation and can overcome T-cell anergy. The OX40-OX40 ligand pathway is involved in the subsequent expansion of memory T cells. We expressed both human CD40L and OX40L on B-Chronic Lymphocytic Leukemia (B-CLL) cells, by exploiting the phenomenon of molecular transfer from fibroblasts engineered to over-express both of these TNF-receptor superfamily members. We analyzed the effects of the modified B-CLL cells on the number, phenotype and cytotoxic function of autologous T cells in seven B-CLL patients. Transfer of CD40L and OX40L to B-CLL cells was observed in all patients (mean value from 1% pre to 76% post for CD40L; from 0.7% pre to 88% post for OX40L). Subsequent up-regulation of the costimulatory molecules CD80 (B7-1) and CD86 (B7-2) was obtained after engagement of the endogenous CD40 receptor on B-CLL by the transferred CD40L molecules (mean value from 8% pre to 64% post for CD80; from 36% pre to 95% post for CD86). Co-culture of modified and unmodified B-CLL cells with autologous T cells revealed profound differences in the immune responses they induced. With unmodified B-CLL cells, or cells expressing either CD40L or OX40L individually, less than a 10-fold expansion of autologous T cells was observed, with a <100-fold expansion in tumor reactive T cells (measured by IFN-gamma Elispot with autologous B-CLL cells as stimulators, and allogeneic B-CLL cells as controls). By contrast, co-culture with B-CLL cells expressing both CD40L and OX40L induced a >40 fold expansion of autologous T cells - including both CD8+ T cells and CD4+ T cells with a Th1 pattern of cytokine release - and a >2500-fold increase in leukemia-reactive T cells. These expanded T cells were also directly cytotoxic to B-CLL targets, producing a mean 48% B-CLL killing at an E:T ratio of 10:1. A proportion of these tumor-reactive CD8+ T cells were specific for survivin, a B-CLL associated tumor antigen. Hence the combination of CD40L and OX40L expression by B-CLL cells allows generation of potent immune responses to B-CLL, which may be exploitable either by using active immunization with CD40L/OX40L-modified tumor cells or by adoptive immunotherapy with CD40L/OX40L generated tumor-reactive T cells.
CD38 Ligation in B-Chronic Lymphocytic Leukemia Cells Induces Sequential Tyrosine Phosphorylation of ZAP70, PLC- γ2 and ERK1/2 Proteins.
Authors: Deaglio Silvia , Vaisitti Tiziana , Malavasi Fabio 
Published: October 2019

Abstract
CD38 is a negative prognostic marker in B-chronic lymphocytic leukemia (B-CLL). In a previous study we observed that CD38 and IL-2 cooperate in inducing proliferation and survival of B-CLL cells. Now attention is given to the signaling pathway ruled by CD38 in B-CLL cells. We show that CD38 ligation triggers a prominent tyrosine phosphorylation of the ZAP70 kinase in 6 out of 9 patients studied (2 representative shown in figure 1). ZAP70 activation is evident 1 minute after receptor cross-linking and tends to diminish within 5 minutes. Tyrosine phosphorylation of syk is undetectable in these conditions. A functional relationship between CD38 and ZAP70 was confirmed by the analysis of a panel of B cell lines. Indeed, CD38 ligation in Nalm-6, a pre-B cell line identified as ZAP70+, wais followed by ZAP70 tyrosine phosphorylation, with a kinetics overlapping the one observed with the B-CLL samples.
Downstream events include the sequential activation of BTK and PLC-γ2, the latter likely responsible for the cytoplasmic Ca2+ mobilization, observed both in B-CLL and in the Nalm-6 cells. The signaling events culminate with the activation of ERK1/2, but not of SAP/JNK and p38 proteins. The results obtained with purified B-CLL cells from 2 representative patients are shown in figure 1.
Together, these data i) highlight for the first time a functional relationship between CD38 and ZAP70 in B cells and ii) identify crucial cytoplasmic steps in the signaling cascade promoted by CD38, thus providing a mechanistic base to explain why B-CLL patients with a CD38+/ZAP70+ clone are characterized by the most unfavourable clinical course. Selected bibliography
Figure. Figure.
Nurselike Cells in Chronic Lymphocytic Leukemia (CLL) Express Both BAFF and APRIL that Protect CLL B Cells from Spontaneous Apoptosis by Paracrine Manner.
Authors: Nishio Mitsufumi , Tsukada Nobuhiro , Ohata Junko , Zvaifler Nathan J. , Kipps Thomas J. 
Published: October 2019

Abstract
Large, adherent nurse-like cells (NLC) can differentiate from the blood mononuclear cells of patients with chronic lymphocytic leukemia (CLL) that, in turn, can support leukemia cell survival in vitro, and presumably in vivo. These cells differentiate in the context of CLL B cells and can be found in the secondary lymphoid tissues of patients with this disease. NLC express high levels of B cell activating factor belonging to the tumor necrosis factor (TNF) family (BAFF), a factor that can support normal and leukemia B cell survival in vitro. BAFF binds to three distinct members of TNF-receptor superfamily : TACI (transmembrane activator and CAML interactor), BCMA (B cell maturation antigen) and BAFF-R, the latter two of which are expressed by CLL B cells. We found that addition of saturating amounts of a recombinant BAFF-receptor-Fc fusion protein (BAFF-R:Fc) to cultures of NLC and CLL B cells failed to inhibit the protective effect(s) of NLC on CLL B cell survival in vitro. This suggested that another factor(s) made by NLC can contribute to the survival effect(s) of BAFF on CLL B cells. A candidate for this is a proliferation-inducing ligand (APRIL), another member of the TNF family that can interact with TACI and BCMA, but not BAFF-R. We found that, in contrast to CLL B cells or blood mononuclear cells, NLC express high-levels of APRIL mRNA and protein, as assessed by quantitative RT-PCR and immunoblot analyses. Furthermore, recombinant human APRIL also could support CLL B cell survival via mechanism similar to that used by recombinant BAFF. Consistent with the fact that APRIL and BAFF each can function to support CLL B cell survival, we found that a recombinant BCMA-Fc fusion protein could significantly inhibit the protective effects of NLC on CLL B cells in vitro. These data suggest that BCMA-Fc might be better suited than BAFF-R:Fc to inhibit the interactions between NLC and CLL B cells in vivo.
Tcl-1 Inhibits Nuclear Export of TR3 and Is Highly Expressed in ZAP70-Positive CLL B-Cells.
Authors: Pedersen Irene M. , Luciano Frederic , Zhang Xiao-kun , Croce Carlo M. , Kipps Thomas J. , Carson Dennis A. , Reed John C. 
Published: October 2019

Abstract
Chronic Lymphocytic Leukemia (CLL) is the most frequent leukemia afflicting the Western world. Unlike other more aggressive leukemias and lymphomas, CLL B-cells do not divide at a high rate and expansion of the malignant clone appears to be due to underlying defect in apoptosis.
Elevated levels of anti-apoptotic Bcl-2 are thought to be involved in the pathogenesis of CLL. The activity of Bcl-2 can be modulated my interactions with other cellular proteins. Recently, orphan nuclear receptor TR3 (nur77) was shown to exit the nucleus, bind Bcl-2, and convert Bcl-2 into a killer protein (Lin, et al., CELL, 116:527, 2004). We evaluated the expression of TR3 by immunoblotting in CLL B-cells specimens. High levels of TR3 protein were present in 8 of 8 CLL patient specimens. Subcellular fractionation studies showed predominately nuclear localization of TR3 in 2 of 2 CLL specimens examined. Because Akt is known to regulate TR3 activity in the nucleus (Pekarsky, et al., Proc. Natl. Acad. Sci.98:3690, 2001), we also examined the expression of the Akt regulator, Tcl-1. The Tcl-1 protein was expressed in the majority of CLL samples and at high levels in 8 of 16 CLL specimens, correlating with ZAP70-positivity. In gene transfection experiments using tumor cell lines, over-expression of Tcl-1 inhibited nuclear export of TR3, as determined by immunofluorescence confocal microscopy. We propose a model in which expression of the oncogene Tcl-1 in CLL B-cells (perhaps related to ZAP70 expression) modulates nuclear Akt activity, in turn suppressing TR3 function, and thus reducing activity of the TR3-mediated pathway for conversion of Bcl-2 from protector to killer. This hypothesis requires further experimental testing.
Gene Expression in CLL Cells Associated with Lymphadenopathy and Chromosome 11q23 Deletion.
Authors: Dickinson John D. , Joshi Avadhut , Gilmore Jamie , Bierman Philip J. , Warren Sanger , Joshi Shantaram S. 
Published: October 2019

Abstract
Previously we have demonstrated that peripheral blood samples with B-cell Chronic Lymphocytic Leukemia (CLL) have different gene expression profiles associated with chromosome aberrations detected by fluorescence in situ hybridization (FISH). In particular, the vast majority of differentially expressed genes were related to the presence of the 11q23 deletion. The 11q23 deletion has previously been shown to be correlated with shortened over-all survival and extensive/bulky lymphadenopathy. In this study we sought to identify genes whose expression may play role in the progression of CLL in patients that carry the 11q23 deletion. Gene expression from 10,700 human gene specific 50-mer oligos (MWG Biotech, Ebersberg, Germany) was compared between two groups of peripheral blood CLL samples. The first group consisted of CLL patients with the 11q23 deletion detected by FISH as well as with the presence of abdominal/mediastinal lymphadenopathy. The second group consisted of CLL patients without the 11q23 deletion and without the presence of known abdominal/mediastinal lymphadenopathy. The non-11q deletion group included CLL patients with the 13q14 deletion, trisomy 12, 17p13 deletion, as well as several without any detectable abnormality. Immunoglobulin heavy chain variable region (IgVH) mutational status was compared in CLL samples in both groups to ensure that resulting expression differences were not the result of this known prognostic marker. Median of ratios was compared between the two groups. Eighty-eight (87) genes had a p-value < 0.01. Gene function was classified at the European Molecular Biology Laboratory (EMBL) Bioinformatic Harvester website. Twenty of these differentially expressed genes were cell cycle/cell signaling related genes that were over-expressed in the 11q23 deletion group. Examples include: activating transcription factor 4, rho-associated coiled-coil containing protein kinase 2, fibroblast growth factor 21 precursor, signal transducing adaptor molecule 1, mad2-like 1, interferon receptor 1, pim-2 oncogene, and zw10 interactor. In comparison, using the same peripheral blood CLL samples, 78 genes were differentially expressed (p < 0.01) between those samples that had a mutated IgVH versus those that had an unmutated IgVH. Therefore, the presence of both the 11q23 deletion and bulky abdominal/mediastinal lymphadenopathy significantly alters the gene expression profile of peripheral blood CLL cells, particularly genes related to the cell cycle and cell signaling related processes. Biological roles of some of these genes may help further elucidate the basis of the clinical behavior of CLL patients