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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: Journal of clinical oncology, 2011-08-20, Vol.29 (24), p.3293-3300
    Description: To assess the toxicity, pharmacokinetics, and pharmacodynamics of multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in children with relapsed/refractory leukemia. Twelve patients with acute leukemia (11 with acute myeloid leukemia [AML]) received sorafenib on days 1 to 7 and then concurrently with cytarabine (1 g/m(2)) and clofarabine (stratum one: 40 mg/m(2), n = 10; stratum two [recent transplantation or fungal infection]: 20 mg/m(2), n = 2) on days 8 to 12. Sorafenib was continued until day 28 if tolerated. Two sorafenib dose levels (200 mg/m(2) and 150 mg/m(2) twice daily) were planned. Sorafenib pharmacokinetic and pharmacodynamic studies were performed on days 7 and 8. At sorafenib 200 mg/m(2), two of four patients in stratum one and one of two patients in stratum two had grade 3 hand-foot skin reaction and/or rash as dose-limiting toxicities (DLTs). No DLTs were observed in six patients in stratum one at sorafenib 150 mg/m(2). Sorafenib inhibited the phosphorylation of AKT, S6 ribosomal protein, and 4E-BP1 in leukemia cells. The rate of sorafenib conversion to its metabolite sorafenib N-oxide was high (mean, 33%; range, 17% to 69%). In vitro, the N-oxide potently inhibited FLT3-internal tandem duplication (ITD; binding constant, 70 nmol/L) and the viability of five AML cell lines. On day 8, sorafenib decreased blast percentages in 10 of 12 patients (median, 66%; range, 9% to 95%). After combination chemotherapy, six patients (three FLT3-ITD and three FLT3 wild-type AML) achieved complete remission, two (both FLT3-ITD AML) had complete remission with incomplete blood count recovery, and one (FLT3 wild-type AML) had partial remission. Sorafenib in combination with clofarabine and cytarabine is tolerable and shows activity in relapsed/refractory pediatric AML.
    Subject(s): Hematologic and hematopoietic diseases ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Biological and medical sciences ; Medical sciences ; Tumors ; Niacinamide - analogs & derivatives ; Protein Kinase Inhibitors - pharmacokinetics ; Recurrence ; Pyridines - administration & dosage ; Drug Administration Schedule ; Humans ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Leukemia - drug therapy ; Drug Resistance, Neoplasm ; Male ; Phenylurea Compounds ; Benzenesulfonates - administration & dosage ; Cytarabine - administration & dosage ; Arabinonucleosides - pharmacokinetics ; Protein Kinase Inhibitors - administration & dosage ; Adenine Nucleotides - pharmacokinetics ; Arabinonucleosides - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Adolescent ; Leukemia, Myeloid, Acute - drug therapy ; Female ; Adenine Nucleotides - administration & dosage ; Child ; Hema7 ; Pedi18 ; Hema5 ; Hema6 ; Faze ; Original Reports ; Pedi3
    ISSN: 0732-183X
    E-ISSN: 1527-7755
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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  • 4
    Language: English
    In: Journal for immunotherapy of cancer, 2019-03-20, Vol.7 (1), p.81-81
    Description: Consolidation therapies for children with intermediate- or high-risk acute myeloid leukemia (AML) are urgently needed to achieve higher cure rates while limiting therapy-related toxicities. We determined if adoptive transfer of natural killer (NK) cells from haploidentical killer immunoglobulin-like receptor (KIR)-human leukocyte antigen (HLA)-mismatched donors may prolong event-free survival in children with intermediate-risk AML who were in first complete remission after chemotherapy. Patients received cyclophosphamide (Day - 7), fludarabine (Days - 6 through - 2), and subcutaneous interleukin-2 (Days - 1, 1, 3, 5, 7, and 9). Purified, unmanipulated NK cells were infused on Day 0, and NK cell chimerism and phenotyping from peripheral blood were performed on Days 7, 14, 21, and 28. As primary endpoint, the event-free survival was compared to a cohort of 55 patients who completed chemotherapy and were in first complete remission but did not receive NK cells. Donor NK cell kinetics were determined as secondary endpoints. Twenty-one patients (median age at diagnosis, 6.0 years [range, 0.1-15.3 years]) received a median of 12.5 × 10 NK cells/kg (range, 3.6-62.2 × 10 cells/kg) without major side effects. All but 3 demonstrated transient engraftment with donor NK cells (median peak donor chimerism, 4% [range, 0-43%]). KIR-HLA-mismatched NK cells expanded in 17 patients (81%) and contracted in 4 (19%). However, adoptive transfer of NK cells did not decrease the cumulative incidence of relapse (0.393 [95% confidence interval: 0.182-0.599] vs. 0.35 [0.209-0.495]; P = .556) and did not improve event-free (60.7 ± 10.9% vs. 69.1 ± 6.8%; P = .553) or overall survival (84.2 ± 8.5% vs. 79.1 ± 6.6%; P = .663) over chemotherapy alone. The lack of benefit may result from insufficient numbers and limited persistence of alloreactive donor NK cells but does not preclude its potential usefulness during other phases of therapy, or in combination with other immunotherapeutic agents. TRIAL REGISTRATION: www.clinicaltrials.gov , NCT00703820 . Registered 24 June 2008.
    Subject(s): Cyclophosphamide ; Chemotherapy ; Killer cells ; Histocompatibility antigens ; Interleukins ; Immunotherapy ; HLA histocompatibility antigens ; Clinical trials ; Product development ; Children ; Health aspects ; Cancer ; Studies ; Antigens ; Survival analysis ; Transplants & implants ; Leukemia ; Neutrophils ; Ligands ; Cytotoxicity ; Patients ; Cancer therapies ; Index Medicus ; Clinical trial ; Natural killer cells ; Acute myeloid leukemia ; Child
    ISSN: 2051-1426
    E-ISSN: 2051-1426
    Source: BioMedCentral Open Access
    Source: PubMed Central
    Source: Directory of Open Access 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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  • 5
    Language: English
    In: Cancer, 2018-06-15, Vol.124 (12), p.2607-2620
    Description: BACKGROUND Central nervous system Langerhans cell histiocytosis (CNS‐LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH‐ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS‐LCH. METHODS Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS‐LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH‐ND patients, and the response to BRAF‐V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS Osteopontin was the only consistently elevated CSF protein in patients with CNS‐LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH‐ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH‐ND. Brain biopsies of patients with LCH‐ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+CD33+CD163+P2RY12‐) and associated osteopontin expression. Three of 4 patients with LCH‐ND treated with BRAF‐V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION In LCH‐ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH‐ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH‐ND. Cancer 2018;124:2607‐20. © 2018 American Cancer Society. While LCH‐associated neurodegeneration (LCH‐ND) has historically been considered to be an autoimmune or paraneoplastic phenomenon, identification of BRAFV600E+ myelo‐monocytic cells in peripheral blood and at sites of neurodegeneration is more consistent with a hematopoietic origin of LCH‐ND. A pathogenic role for these infiltrating BRAFV600E+ cells is supported by clinical and radiological responses of patients with LCH‐ND to BRAF‐V600E inhibition.
    Subject(s): neurodegeneration ; CNS neoplasms ; BRAF‐V600E ; Langerhans cell histiocytosis ; osteopontin ; Index Medicus ; Abridged Index Medicus ; BRAF-V600E
    ISSN: 0008-543X
    E-ISSN: 1097-0142
    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: Cancer, 2020-11-01, Vol.126 (21), p.4800-4805
    Description: Background Novel therapies are urgently needed for pediatric patients with relapsed acute myeloid leukemia (AML). Methods To determine whether the histone deacetylase inhibitor panobinostat could be safely given in combination with intensive chemotherapy, a phase 1 trial was performed in which 17 pediatric patients with relapsed or refractory AML received panobinostat (10, 15, or 20 mg/m2) before and in combination with fludarabine and cytarabine. Results All dose levels were tolerated, with no dose‐limiting toxicities observed at any dose level. Pharmacokinetic studies demonstrated that exposure to panobinostat was proportional to the dose given, with no associations between pharmacokinetic parameters and age, weight, or body surface area. Among the 9 patients who had sufficient (〉2%) circulating blasts on which histone acetylation studies could be performed, 7 demonstrated at least 1.5‐fold increases in acetylation. Although no patients had a decrease in circulating blasts after single‐agent panobinostat, 8 of the 17 patients (47%), including 5 of the 6 patients treated at dose level 3, achieved complete remission. Among the 8 complete responders, 6 (75%) attained negative minimal residual disease status. Conclusions Panobinostat can be safely administered with chemotherapy and results in increased blast histone acetylation. This suggests that it should be further studied in AML. The combination of panobinostat with fludarabine and cytarabine is safe and active in children with relapsed acute myeloid leukemia (AML). Panobinostat results in increased histone acetylation in leukemic blasts of children with relapsed AML.
    Subject(s): acute myeloid leukemia ; childhood ; relapse
    ISSN: 0008-543X
    E-ISSN: 1097-0142
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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  • 7
    Language: English
    In: Journal of pediatric hematology/oncology, 2021-03-01, Vol.43 (2), p.e195-e197
    Description: Neurocutaneous melanocytosis (NCM) is a disorder characterized by multiple or large congenital nevi and excessive proliferation of melanocytes in the leptomeninges and brain parenchyma. The majority of NCM is a result of somatic mosaicism due to a single postzygotic mutation in codon 61 of NRAS. Patients with NCM are at high risk of developing leptomeningeal melanoma. The prognosis for leptomeningeal melanoma is poor with no known effective treatment options. We describe the clinical features, treatment, and outcome of 4 children with NCM and leptomeningeal melanoma and discuss the latest molecular findings and treatment options for this rare condition.
    Subject(s): 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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  • 8
    Language: English
    In: The Journal of experimental medicine, 2014-04-07, Vol.211 (4), p.669-683
    Description: Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207+ dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207+ DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c+ and CD14+ fractions and in bone marrow (BM) CD34+ hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207+ DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.
    Subject(s): Index Medicus
    ISSN: 0022-1007
    E-ISSN: 1540-9538
    Source: HighWire Press (Free Journals)
    Source: Rockefeller University Press
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: PubMed Central
    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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  • 9
    Language: English
    In: The Journal of experimental medicine, 2014-04-07, Vol.211 (4), p.669-683
    Description: Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207(+) dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207(+) DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c(+) and CD14(+) fractions and in bone marrow (BM) CD34(+) hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207(+) DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.
    Subject(s): Mannose-Binding Lectins - metabolism ; Antigens, CD34 - metabolism ; Histiocytosis, Langerhans-Cell - genetics ; Humans ; Child, Preschool ; Infant ; Male ; CD11c Antigen - metabolism ; Lectins, C-Type - metabolism ; Histiocytosis, Langerhans-Cell - pathology ; Antigens, Surface - metabolism ; Female ; Histocompatibility Antigens Class II - metabolism ; Cell Differentiation ; Child ; Dendritic Cells - metabolism ; Genetic Predisposition to Disease ; Risk Factors ; Treatment Outcome ; Hematopoietic Stem Cells - metabolism ; Mutation - genetics ; Cell Lineage ; Phenotype ; Animals ; Proto-Oncogene Proteins B-raf - genetics ; Bone Marrow - pathology ; Histiocytosis, Langerhans-Cell - blood ; Mice ; 302
    ISSN: 0022-1007
    E-ISSN: 1540-9538
    Source: HighWire Press (Free Journals)
    Source: Rockefeller University Press
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: PubMed Central
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  • 10
    Language: English
    In: Journal of pediatric hematology/oncology, 2018-05, Vol.40 (4), p.e198-e202
    Description: Rosai-Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy is a rare non-Langerhans' cell histiocytic disease resulting from the proliferation and accumulation of sinus histiocytes within lymph nodes. Extranodal involvement frequently occurs, which increases the morbidity and mortality of the disease. There is no clear consensus with regard to the most effective diagnostic and treatment modalities. This report will focus on the diagnostic imaging, treatment, and outcomes for 3 cases of Rosai-Dorfman disease. Imaging has typically utilized computed tomography (CT)/magnetic resonance imaging to detect extranodal involvement. However, the addition of fluorodeoxyglucose positron emission tomography/CT scans has shown value in identifying lesions unidentified or ambiguous on other modalities. Fluorodeoxyglucose positron emission tomography/CT detected disease involvement in 2 instances either not reported or not felt to be significant on correlative CT imaging. Areas of involvement included the stomach/liver in case 1, and the paranasal sinus in case 3. In addition, previously utilized chemotherapy regimens have not consistently displayed regression of the disease, which lends credence to the pursuit of more successful treatment. Notably, Clofarabine has shown promise in its use against histiocytic disorders. Our study concluded that Clofarabine demonstrates the ability to decrease lesion size and should be considered as an effective chemotherapeutic treatment method.
    Subject(s): Fluorodeoxyglucose F18 - administration & dosage ; Humans ; Child, Preschool ; Paranasal Sinuses - diagnostic imaging ; Tomography, X-Ray Computed ; Positron-Emission Tomography ; Liver - diagnostic imaging ; Clofarabine - administration & dosage ; Female ; Histiocytosis, Sinus - drug therapy ; Child ; Histiocytosis, Sinus - diagnostic imaging ; Stomach - diagnostic imaging ; Case studies ; Lymphadenopathy ; Care and treatment ; Diagnosis ; Histiocytosis ; 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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