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  • 1
    Language: English
    In: Leukemia, 2018-11, Vol.32 (11), p.2316-2325
    Description: The survival of pediatric patients with multiply relapsed and/or refractory (R/R) B-cell acute lymphoblastic leukemia has historically been very poor; however, data are limited in the current era. We conducted a retrospective study to determine the outcome of multiply R/R childhood B-ALL treated at 24 TACL institutions between 2005 and 2013. Patient information, treatment, and response were collected. Prognostic factors influencing the complete remission (CR) rate and event-free survival (EFS) were analyzed. The analytic set included 578 salvage treatment attempts among 325 patients. CR rates (mean ± SE) were 51 ± 4% for patients with bone marrow R/R B-ALL who underwent a second salvage attempt, 37 ± 6% for a third attempt, and 31 ± 6% for the fourth through eighth attempts combined. For patients achieving a CR after their second, third, and fourth through eighth attempts, the 2 year EFS was 41 ± 6%, 13 ± 7%, and 27 ± 13% respectively. Our results showed slight improvement when compared to previous studies. This is the largest and most recent study to date that evaluates the outcome of this patient population. Our data will provide detailed reference for the evaluation of new agents being developed for childhood B-ALL.
    ISSN: 0887-6924
    E-ISSN: 1476-5551
    Source: Nature Open Access
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 2
    Language: English
    In: Leukemia, 2020-09, Vol.34 (9), p.2473-2478
    Subject(s): Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics ; Antibodies, Bispecific - therapeutic use ; Recurrence ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy ; Humans ; Adolescent ; Child, Preschool ; Female ; Male ; Antineoplastic Agents - therapeutic use ; Child ; Philadelphia Chromosome ; Pediatrics ; Health aspects ; Children ; Index Medicus ; Letter ; Acute lymphocytic leukaemia ; Cancer
    ISSN: 0887-6924
    E-ISSN: 1476-5551
    Source: Nature Open Access
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 3
    Language: English
    In: Pediatric blood & cancer, 2020-05, Vol.67 (5), p.e28112-n/a
    Description: Background In a multicenter phase 1 study of children with relapsed/refractory acute lymphoblastic leukemia (ALL), moxetumomab pasudotox, an anti‐CD22 immunotoxin, demonstrated a manageable safety profile and preliminary evidence of clinical activity. A phase 2 study further evaluated efficacy. Procedure This international, multicenter, phase 2 study enrolled children with relapsed/refractory B‐cell precursor ALL who received moxetumomab pasudotox 40 µg/kg intravenously every other day, for six doses per 21‐day cycle. The primary objective was to evaluate the complete response (CR) rate. Secondary objectives included safety, pharmacokinetics, and immunogenicity evaluations. Results Thirty‐two patients (median age, 10 years) were enrolled at 16 sites; 30 received study drug and were evaluable for safety; 28 were evaluable for response. The objective response rate was 28.6%, with three patients (10.7%) achieving morphologic CR, and five patients (17.9%) achieving partial response. Disease progression occurred in 11 patients (39.3%). Ten patients (33.3%) experienced at least one treatment‐related serious adverse event, including capillary leak syndrome (CLS; n = 6), hemolytic uremic syndrome (HUS; n = 4), and treatment‐related death (n = 1) from pulmonary edema. No differences were observed in inflammatory markers in patients who did or did not develop CLS or HUS. Conclusions Despite a signal for clinical activity, this phase 2 study was terminated at interim analysis for a CR rate that did not reach the stage 1 target. Preclinical data suggest enhanced efficacy of moxetumomab pasudotox via continuous infusion or in combination regimens; thus, further studies designed to optimize the efficacy and safety of moxetumomab pasudotox in pediatric ALL may be warranted.
    Subject(s): CAT‐8015 ; pharmacokinetics ; moxetumomab ; safety ; pediatric
    ISSN: 1545-5009
    E-ISSN: 1545-5017
    Source: Alma/SFX Local Collection
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  • 4
    Language: English
    In: Journal of pediatric hematology/oncology, 2016-07, Vol.38 (5), p.329-333
    Description: Although regimens for induction therapy in children with acute lymphoblastic leukemia (ALL) are similar across the United States, typical practice with regard to inpatient length of stay (LOS) varies by institution. US children's hospitals were categorized by typical induction LOS; and readmissions, pediatric intensive care unit (PICU) admissions, and average adjusted charges were compared for the first 30 days from initial admission. Using Pediatric Health Information System data, we extracted ALL induction admissions from 2007 to 2013. We categorized hospitals into 3 categories based on median LOS: short (≤7 d), medium (8 to 15 d), or long (≥16 d). Median LOS varied from 5 to 31 days across hospitals. Thirty-day median inpatient costs per patient ranged from $32 K for short LOS, $40 K for medium LOS, and $47 K for long LOS. Compared with short LOS hospitals (n=14), medium LOS (n=8) and long LOS hospitals (n=8) had lower odds of PICU readmissions (odds ratio [OR], 0.68; P=0.0124 and OR, 0.31; P〈0.001, respectively), and long LOS hospitals had lower odds of any readmission (OR, 0.44; P〈0.0001). Average LOS for children with newly diagnosed ALL varies widely by institution. Children's hospitals that typically admit new ALL patients for 〉7 days have fewer PICU readmissions but substantial increase in total induction inpatient costs.
    Subject(s): Hospitals, Pediatric - statistics & numerical data ; United States ; Humans ; Child, Preschool ; Hospitalization - statistics & numerical data ; Induction Chemotherapy ; Infant ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - economics ; Young Adult ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy ; Adolescent ; Female ; Patient Readmission - statistics & numerical data ; Child ; Length of Stay - statistics & numerical data ; Hospitalization - economics ; Index Medicus
    ISSN: 1077-4114
    E-ISSN: 1536-3678
    Source: Hellenic Academic Libraries Link
    Source: EBSCOhost EJS
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 5
    Language: English
    In: Clinical cancer research, 2020-05-15, Vol.26 (10), p.2297-2307
    Description: Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution. We report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1-21) were treated in this trial. The most common grade 3-4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia ( = 1); seizure, somnolence, and delirium ( = 1); and pneumonitis, hypoxia, and hyperbilirubinemia ( = 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects. Despite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690.
    Subject(s): Decitabine - administration & dosage ; Prognosis ; Follow-Up Studies ; Mitoxantrone - administration & dosage ; Humans ; Child, Preschool ; Neoplasm Recurrence, Local - drug therapy ; Infant ; Male ; Neoplasm Recurrence, Local - pathology ; Young Adult ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy ; Vincristine - administration & dosage ; Adult ; Female ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology ; Child ; Doxorubicin - administration & dosage ; Dexamethasone - administration & dosage ; Survival Rate ; Polyethylene Glycols - administration & dosage ; Asparaginase - administration & dosage ; Pilot Projects ; Bortezomib - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Adolescent ; Vorinostat - administration & dosage ; Salvage Therapy - methods ; Index Medicus ; decitabine ; vorinostat ; relapse ; acute lymphoblastic leukemia ; epigenetic
    ISSN: 1078-0432
    E-ISSN: 1557-3265
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 6
    Language: English
    In: Blood, 2010-11-19, Vol.116 (21), p.2904-2904
    Description: Abstract Abstract 2904 Survival has improved dramatically in acute lymphoblastic leukemia (ALL), but further gains are unlikely using conventional chemotherapy alone. Several recently discovered, novel cytogenetic lesions with adverse prognostic impact, JAK2 activating mutations and CRLF2 rearrangements, occur in up to 15% of adult and pediatric ALL. These lesions are associated with activation of Jak2 and Stat5, and hold promise as targets for novel therapies affecting these signaling pathways. We performed in vitro testing of a novel small molecule Stat inhibitor, C188-9, in B-lineage ALL cell lines and patient samples with and without JAK2/CRLF2 alterations. C188-9 treatment for one hour at 10 μM inhibited Stat3 and Stat5 phosphorylation in ALL cell lines with JAK2 and CRLF2 alterations, but not in cell lines with wild-type JAK2 and CRLF2, as measured by phospho-flow cytometry (Fig. 1A). Only the cell lines with JAK2 and CRLF2 alterations demonstrated basal Stat5 phosphorylation on Western blot analysis, and this was inhibited by C188-9 treatment (Fig. 1B). C188-9 demonstrated cytotoxicity in ALL cell lines regardless of JAK2/CRLF2 status, with IC50s in the low micromolar concentration range (Fig. 1C). While C188-9 is undergoing investigation currently as a potent inhibitor of Stat3 in acute myeloid leukemia (AML), it also merits further investigation as an agent with Stat5 inhibitory activity and cytotoxicity in ALL. Figure 1. Effects of C188-9 in ALL cell lines. A. Stat3 and Stat5 phosphorylation were determined by flow cytometry in the ALL cell lines MHH-CALL-4 (JAK2/CRLF2 mutated) and Reh (JAK2/CRLF2 wild-type). In each condition, cells were incubated in serum-free media for one hour, followed by incubation with C188-9 or vehicle for one hour, stimulation with vehicle or pervanadate 125 mM for 15 minutes, fixation, permeabilization, phospho-antibody staining for phospho-Stat3 and phospho-Stat5, and flow cytometric analysis. B. Western blot for phospho-Stat5 in K562 cell line (positive control); MHHCALL-4 treated for one hour with C188-9 at 0, 5, or 10 uM; and RS4;11 (JAK2/CRLF2 wild-type ALL cell line). C. IC50 determination by ATP assay for C188-9 in the ALL cell lines MHH-CALL-4 and RS4;11. Each experiment was performed in triplicate. Figure 1. Effects of C188-9 in ALL cell lines. A. Stat3 and Stat5 phosphorylation were determined by flow cytometry in the ALL cell lines MHH-CALL-4 (JAK2/CRLF2 mutated) and Reh (JAK2/CRLF2 wild-type). In each condition, cells were incubated in serum-free media for one hour, followed by incubation with C188-9 or vehicle for one hour, stimulation with vehicle or pervanadate 125 mM for 15 minutes, fixation, permeabilization, phospho-antibody staining for phospho-Stat3 and phospho-Stat5, and flow cytometric analysis. B. Western blot for phospho-Stat5 in K562 cell line (positive control); MHHCALL-4 treated for one hour with C188-9 at 0, 5, or 10 uM; and RS4;11 (JAK2/CRLF2 wild-type ALL cell line). C. IC50 determination by ATP assay for C188-9 in the ALL cell lines MHH-CALL-4 and RS4;11. Each experiment was performed in triplicate. Disclosures: No relevant conflicts of interest to declare.
    ISSN: 0006-4971
    E-ISSN: 1528-0020
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: American Society of Hematology
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  • 7
    Language: English
    In: Blood, 2015-12-03, Vol.126 (23), p.3760-3760
    Description: Abstract Introduction Remission induction rates after a second or greater relapse is a critical endpoint in phase II trials of childhood acute lymphoblastic leukemia (ALL). A robust benchmark is crucial for identification of novel multi-agent regimens worthy of further study. The Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) consortium previously reported the response rates of children with multiply relapsed and refractory (R/R) ALL treated between 1995 and 2004, which provided a benchmark for clinical trials. To define more recent treatment patterns and test the robustness of this benchmark, we performed a retrospective cohort review of children with R/R ALL who experienced second or greater treatment failure at TACL consortium sites between 2005 and 2013. Patients and Methods Eligible patients were identified at participating TACL institutions. This cohort was comprised of patients with medullary R/R B-cell precursor ALL who experienced at least 2 treatment failures or relapsed after hematopoietic stem cell transplant. Patient demographic data and details of the initial and R/R disease characteristics were abstracted from medical records and entered into a central database. This study was approved by the IRB of each participating institution. Treatment failure was defined by the presence or re-emergence of circulating blasts, M2/M3 BM, or extramedullary (EM) disease despite therapy. Complete remission (CR) was defined as M1 marrow, no EM disease and evidence of peripheral count recovery. For the purpose of statistical analysis, patients who met these criteria without platelet recovery (CRp) or normal blood count recovery (CRi) were included as CR. Univariate and multivariate logistic regression were utilized to evaluate the risk of re-induction failure. Predictors included in this preliminary analysis were NCI risk criteria at diagnosis, duration of the prior remission, the treatment attempt number, and the EM and BM status at the start of each therapy attempt. Results This report includes 214 patients. Fifty-six percent were male. At initial diagnosis, 32% were at least 10 years old, 26% had initial white blood cell (WBC) counts over 50,000/µL, and 39% were classified as high risk by the NCI risk criteria (Table 1). Therapy involved various combinations of agents and ranged between 2 and 10 attempts. The CR rate was 42% for third treatment attempt and 24% for fourth and subsequent treatment attempts (Table 2). Treatment failures were significantly associated with increased number of treatment attempts (p 〈 0.001), shorter duration of previous CR (p 〈 0.001) and NCI risk category at diagnosis (p = 0.018). Conclusion This preliminary analysis found similar CR rates in patients with third treatment failure compared to the 1st TACL retrospective study of the prior decade (42% vs. 44%, Ko et al, 2010) and an Austrian report with a small cohort of patients (Reismüller et al, 2013). Further analysis will be performed in comparison to the initial TACL retrospective study cohort once enrollment to this study has been completed (approximately 400 patients). A robust, contemporary historical control may serve as an alternative to a randomized control when outcome with past therapies in unacceptably poor. Table 1. Patient Characteristics at Initial Diagnosis of Patients with ALL who received at least two treatment attempt (n = 214 patients) Characteristic No of patients % Age, years 〈 1 (infants) 18 8 1-9 126 59 10 and over 70 33 WBC count/uL 〈 50K 128 60 50K and over 56 26 Unknown 30 14 NCI risk criteria at diagnosis Non-infants, standard risk 82 38 Non-infants, high risk 84 39 Non-infants, unknown 30 14 Infants 18 8 Sex Female 94 44 Male 120 56 CNS disease Yes 42 20 No 148 69 Unknown 24 11 Karyotype1 Normal 68 30 11q23 (MLL gene) rearranged 19 8 Hypodiploidy 7 3 Hyperdiploidy 26 12 iAMP21 2 1 t(12;21) 6 3 t(1;19) 7 3 t(9;22) 15 7 Other 46 21 Unknown 28 12 1 Karyotype is available for 214 unique patients; 2 entries were reported for 7 patients, and 4 entries were reported for 1 patient. Table 2. Achievement of CR/CRp/CRi After Treatment of R/R ALL by Preceding Remission Duration and Treatment Attempt Third treatment attempt Fourth through tenth treatment attempt Duration of preceding CR Response Total % Response Total % Not achieved (refractory) 24 63 38 20 86 23 〈 18 months duration 28 78 36 11 49 22 18 to 36 months duration 9 15 60 3 5 60 ≥ 36 months duration 8 8 100 0 1 0 All patients combined 69 164 42 34 141 24 Disclosures Sun: Gateway for Cancer Researchy: Research Funding; Amgen: Research Funding. Wilkes:Healthcare Research and Quality: Research Funding; Alex's Lemonade Stand Foundation: Research Funding. Gaynon:Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Sigma Tau: Speakers Bureau; JAZZ: Speakers Bureau. Wayne:Medimmune: Honoraria, Other: travel support, Research Funding; NIH: Patents & Royalties; Kite Pharma: Honoraria, Other: travel support; Pfizer: Honoraria; Spectrum Pharmaceuticals: Honoraria, Other: travel support, Research Funding. Whitlock:Amgen: Honoraria.
    ISSN: 0006-4971
    E-ISSN: 1528-0020
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: American Society of Hematology
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  • 8
    Language: English
    In: Leukemia, 2020, Vol.34 (9), p.2473-2478
    Subject(s): Letter ; Acute lymphocytic leukaemia ; Cancer
    ISSN: 0887-6924
    E-ISSN: 1476-5551
    Source: Nature Open Access
    Source: Alma/SFX Local Collection
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  • 9
    Language: English
    Description: Two decades of rapid urban growth and increasing per capita water consumption has left water providers in Northwest Arkansas concerned about their ability to meet future demand for water. Beaver Water District (BWD) is the largest of four regional water providers that draw from Beaver Lake, the only source of potable water in the region. Growth projections and per capita consumption patterns indicate that BWD could exhaust its raw water allocation as early as 2031. Municipal water customers served by BWD were surveyed about their stated priorities for water use, their water conservation behaviors, and their attitudes and perceptions about urban growth, water resources, and willingness to pay fees for future water availability. A logistic regression, or “logit” model was developed from the survey to identify the attitudes that affect willingness-to-pay (WTP) and estimate mean WTP for water. Logit models are commonly used to estimate mean WTP for an environmental good, but the parameter estimates generated in a logit model describe a global relationship between the dependent and independent variables. Because the independent variables often represent social processes that are spatially non-stationary, geographically weighted regression (GWR) provides a means to examine spatial variations in a model by calculating local parameter estimates for every data point. GWR was applied to the data to identify spatial variations in mean WTP and the attitudes that influence WTP. Using a logit model, mean WTP was estimated at $227 annually for the region, with subsets of the data by municipality showing WTP ranges from $209 to $245. Using GWR, mean WTP over the region was estimated at $229 annually, but actual WTP values calculated for each data point ranged from $67 to $442 per year, with a clear pattern of low values correlating to closer proximity to the water resource. Both the logit and the GWR models were successful in estimating mean WTP over a region, but GWR also illustrated important spatial patterns in the data that can enrich our understanding of the problem and lead to more successful long-term strategies and solutions for meeting the future needs of a rapidly-expanding population.
    Subject(s): Water Resource Management ; Environmental Studies ; Environmental economics
    ISBN: 1124485953
    ISBN: 9781124485959
    Source: ProQuest Dissertations & Theses Global
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 10
    Language: English
    In: Immunity (Cambridge, Mass.), 2015-12-15, Vol.43 (6), p.1053-1063
    Description: The high-mannose patch on the HIV-1 envelope (Env) glycoprotein is the epicenter for binding of the potent broadly neutralizing PGT121 family of antibodies, but strategies for generating such antibodies by vaccination have not been defined. We generated structures of inferred antibody intermediates by X-ray crystallography and electron microscopy to elucidate the molecular events that occurred during evolution of this family. Binding analyses revealed that affinity maturation was primarily focused on avoiding, accommodating, or binding the N137 glycan. The overall antibody approach angle to Env was defined very early in the maturation process, yet some variation evolved in the PGT121 family branches that led to differences in glycan specificities in their respective epitopes. Furthermore, we determined a crystal structure of the recombinant BG505 SOSIP.664 HIV-1 trimer with a PGT121 family member at 3.0 Å that, in concert with these antibody intermediate structures, provides insights to advance design of HIV vaccine candidates. [Display omitted] •X-ray and EM structures of inferred precursors of the PGT121 family were generated•The N137 glycan is a major factor in affinity maturation of the PGT121 family•The antibody approach angle differs in the two main branches of the PGT121 lineage•A 3.0 Å crystal structure of an HIV trimer with a PGT121 family member was determined Strategies for generating broadly neutralizing antibodies (bnAbs) against the high-mannose patch of the HIV envelope have not been defined. Wilson and colleagues find that affinity maturation of the potent PGT121 family of bnAbs is focused on accommodating or avoiding glycans. These findings provide insights to advance structure-based vaccine design.
    Subject(s): Microscopy, Electron, Transmission ; Mutagenesis, Site-Directed ; Somatic Hypermutation, Immunoglobulin ; env Gene Products, Human Immunodeficiency Virus - immunology ; Humans ; Antibody Affinity - genetics ; Antibody Affinity - immunology ; Antigens, Viral - chemistry ; Crystallography, X-Ray ; Polysaccharides - immunology ; HIV Antibodies - chemistry ; Epitopes - immunology ; Antigens, Viral - immunology ; Antibodies, Neutralizing - immunology ; HIV-1 - immunology ; HIV Antibodies - immunology ; Image Processing, Computer-Assisted ; X-Ray Diffraction ; Antibodies, Neutralizing - chemistry ; HEK293 Cells ; Calorimetry, Differential Scanning ; Viral Envelope Proteins - immunology ; Epitopes - chemistry ; International relief ; Polysaccharides ; AIDS vaccines ; HIV antibodies ; Vaccination ; Crystals ; Structure ; HIV (Viruses) ; Sugars ; Antigenic determinants ; Monosaccharides ; Index Medicus
    ISSN: 1074-7613
    E-ISSN: 1097-4180
    Source: Backfile Package - All of Back Files EBS [ALLOFBCKF]
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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