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  • 1
    Language: English
    In: The New England journal of medicine, 2018-02-01, Vol.378 (5), p.439-448
    Description: CD19-specific CAR T cells were produced centrally for a global study in young people with relapsed B-cell ALL. The overall remission rate was 81%, and patients with a response were negative for minimal residual disease. High-grade toxic effects were frequent but treatable.
    Subject(s): Humans ; Receptors, Antigen, T-Cell - therapeutic use ; Child, Preschool ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - mortality ; Receptors, Antigen, T-Cell - antagonists & inhibitors ; Remission Induction ; Young Adult ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy ; Antibodies, Monoclonal, Humanized - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Adolescent ; Survival Analysis ; Antigens, CD19 ; Female ; Infusions, Intravenous ; Child ; Treatment outcome ; Care and treatment ; Young adults ; Lymphocytic leukemia ; Research ; Children ; Comparative analysis ; Health aspects ; Flow cytometry ; Pediatrics ; Edema ; Medical research ; CD19 antigen ; Acute lymphatic leukemia ; Transplants & implants ; Hematology ; Leukemia ; Minimal residual disease ; Oncology ; Lymphocytes T ; Lymphatic leukemia ; Children & youth ; Studies ; Chimeric antigen receptors ; Lymphocytes B ; Stem cells ; Bone marrow ; Remission ; Cancer
    ISSN: 0028-4793
    E-ISSN: 1533-4406
    Source: Single 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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  • 2
    Language: English
    In: The New England journal of medicine, 2018-02-22, Vol.378 (8), p.731-739
    Description: Fusions involving tropomyosin receptor genes are noted in cancers affecting children and adults. The TRK inhibitor larotrectinib induced a response in 75% of patients, regardless of age, tissue of origin, or TRK fusion partner. Toxic effects were generally mild.
    Subject(s): Protein Kinases - genetics ; Pyrazoles - therapeutic use ; Protein Kinases - analysis ; Humans ; Middle Aged ; Kaplan-Meier Estimate ; Child, Preschool ; Infant ; Male ; Antineoplastic Agents - therapeutic use ; Neoplasms - drug therapy ; Oncogene Proteins, Fusion - analysis ; Young Adult ; Disease-Free Survival ; Neoplasms - chemistry ; Pyrimidines - therapeutic use ; Adolescent ; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors ; Adult ; Female ; Aged ; Child ; Antimitotic agents ; Treatment outcome ; Safety and security measures ; Analysis ; Dosage and administration ; Diagnosis ; Antineoplastic agents ; Cancer ; Medical research ; Inhibitor drugs ; Tropomyosin ; Oncology ; Survival ; Patients ; Cancer therapies ; Children & youth ; Antitumor activity ; Children ; Drug dosages ; Tumors ; Index Medicus ; Abridged Index Medicus
    ISSN: 0028-4793
    E-ISSN: 1533-4406
    Source: Single 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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  • 3
    Language: English
    In: Cancer, 2018-11-01, Vol.124 (21), p.4241-4247
    Description: Background The highly selective oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib has demonstrated significant activity in adult and pediatric TRK fusion cancers. In the current study, the authors describe the clinical course of children with locally advanced TRK fusion sarcoma who were treated preoperatively with larotrectinib and underwent subsequent surgical resection. Methods A total of 24 children were treated on a pediatric phase 1 trial of larotrectinib (ClinicalTrials.gov identifier NCT02637687). Five children who had a documented TRK fusion sarcoma and underwent surgical resection were included in the current analysis. Tumor response (Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1) and surgical outcomes were collected prospectively. Results A total of 5 patients (median age, 2 years; range, 0.4‐12 years) had locally advanced infantile fibrosarcoma (3 patients) or soft‐tissue sarcoma (2 patients). Four patients had disease that was refractory to standard therapy. All 5 patients achieved a partial response to larotrectinib by version 1.1 of RECIST and underwent surgical resection after a median of 6 cycles (range, 4‐9 cycles) of treatment. Surgical resections were R0 (negative resection margins with no tumor at the inked resection margin) in 3 patients, R1 (microscopic residual tumor at the resection margin) in 1 patient, and R2 (macroscopic residual tumor at the resection margin) in 1 patient. Three patients achieved complete (2 patients) or near‐complete (〉98% treatment effect; 1 patient) pathologic responses. These patients remained in follow‐up and were no longer receiving larotrectinib for a minimum of 7 to 15 months postoperatively. Two patients had viable tumor at the time of surgical resection and positive resection margins and continued to receive adjuvant larotrectinib. No patients experienced postoperative complications or wound healing issues. Conclusions Children with locally advanced TRK fusion sarcomas may proceed to surgical resection after treatment with the selective TRK inhibitor larotrectinib, thereby sparing them the potentially significant morbidity noted with current approaches. These results support the evaluation of larotrectinib as presurgical therapy in children with newly diagnosed TRK fusion sarcomas. Children with locally advanced tropomyosin receptor kinase (TRK) fusion sarcomas may proceed to surgical resection after neoadjuvant treatment with the selective oral TRK inhibitor larotrectinib, sparing them the potentially significant morbidity noted with current approaches. The results of the current study support the further evaluation of larotrectinib as neoadjuvant therapy in children with newly diagnosed TRK fusion sarcomas.
    Subject(s): larotrectinib ; sarcoma ; tropomyosin receptor kinase (TRK) fusion ; local control ; neurotrophic receptor tyrosine kinase (NTRK) ; infantile fibrosarcoma ; pediatric ; surgery ; Index Medicus ; Abridged Index Medicus ; Original
    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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  • 4
    Language: English
    In: Pediatric blood & cancer, 2018-01, Vol.65 (1), p.e26593-n/a
    Subject(s): Kidney Neoplasms ; Humans ; Nephroma, Mesoblastic ; Care and treatment ; Genetic disorders ; Index Medicus
    ISSN: 1545-5009
    E-ISSN: 1545-5017
    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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  • 5
    Language: English
    In: Paediatric drugs, 2020-02, Vol.22 (1), p.1-11
    Description: The development of cluster of differentiation (CD)-19-targeted chimeric antigen receptor (CAR) T cells for the treatment of pre-B-cell acute lymphoblastic leukemia (B-ALL) is an exciting new advancement in the field of pediatric oncology. Tisagenlecleucel and axicabtagene ciloleucel are the first US FDA-approved CD19-targeted CAR T cells. While various different CD19 CAR T cells are in development, tisagenlecleucel is the only CAR T cell approved for pediatric patients. The multicenter phase II trial that led to the approval of tisagenlecleucel demonstrated excellent responses in individuals with highly refractory disease. Other high-risk groups of patients with B-ALL who experience poor outcomes with standard therapy may also benefit from treatment with tisagenlecleucel. After receiving CAR T cells, patients must be closely monitored for unique toxicities, including cytokine release syndrome, neurotoxicity, and B-cell aplasia. The management of patients with relapsed or refractory disease after administration of CD19 CAR T cells can be challenging, and treatment options vary according to the characteristics of the disease present at relapse. In the many patients who experience a complete response, CAR T cells can lead to a durable remission. This review describes the current design and manufacturing of CAR T cells. Data in the selection and management of pediatric patients are highlighted, as are areas where further studies are needed.
    Subject(s): Antigens ; Pediatrics ; Young adults ; Cytokines ; Leukemia ; Cytotoxicity ; FDA approval ; Vectors (Biology) ; Lymphoma ; Cell growth ; Chemotherapy ; Lymphocytes ; Immunotherapy ; Immune system
    ISSN: 1174-5878
    E-ISSN: 1179-2019
    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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  • 6
    Language: English
    In: Magnetic resonance in medicine, 2015-10, Vol.74 (4), p.1095-1102
    Description: Purpose Because existing magnetic resonance thermometry techniques do not provide temperature information within bone, high‐intensity focused ultrasound (HIFU) exposures in bone are monitored using temperature changes in adjacent soft tissues. In this study, the potential to monitor temperature changes in cortical bone using a short TE gradient echo sequence is evaluated. Methods The feasibility of this proposed method was initially evaluated by measuring the temperature dependence of the gradient echo signal during cooling of cortical bone samples implanted with fiber‐optic temperature sensors. A subsequent experiment involved heating a cortical bone sample using a clinical MR‐HIFU system. Results A consistent relationship between temperature change and the change in magnitude signal was observed within and between cortical bone samples. For the two‐dimensional gradient echo sequence implemented in this study, a least‐squares linear fit determined the percentage change in signal to be (0.90 ± 0.01)%/°C. This relationship was used to estimate temperature changes observed in the HIFU experiment and these temperatures agreed well with those measured from an implanted fiber‐optic sensor. Conclusion This method appears capable of displaying changes related to temperature in cortical bone and could improve the safety of MR‐HIFU treatments. Further investigations into the sensitivity of the technique in vivo are warranted. Magn Reson Med 74:1095–1102, 2015. © 2014 Wiley Periodicals, Inc.
    Subject(s): thermometry ; cortical bone ; MR‐HIFU ; Temperature ; Bone and Bones - physiology ; Magnetic Resonance Imaging - methods ; High-Intensity Focused Ultrasound Ablation - instrumentation ; Bone and Bones - surgery ; Equipment Design ; Feasibility Studies ; Animals ; Image Processing, Computer-Assisted ; Cattle ; Signal Processing, Computer-Assisted ; High-Intensity Focused Ultrasound Ablation - methods ; Thermometry - methods ; Temperature measurements ; Sensors ; Index Medicus ; MR-HIFU
    ISSN: 0740-3194
    E-ISSN: 1522-2594
    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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  • 7
    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
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  • 8
    Language: English
    In: Bone marrow transplantation (Basingstoke), 2019-05-15, Vol.54 (11), p.1868-1880
    Description: On August 30, 2017, the U.S. Food and Drug Administration (US-FDA) approved tisagenlecleucel (KYMRIAH, Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor-T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring and disease assessments. To address these issues, experts representing the American Society for Blood and Marrow Transplant (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), the International Society of Cell and Gene Therapy (ISCT), and the Foundation for the Accreditation of Cellular Therapy (FACT), formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.
    Subject(s): Index Medicus
    ISSN: 0268-3369
    E-ISSN: 1476-5365
    Source: Nature Open Access
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: Alma/SFX Local Collection
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  • 9
    Language: English
    In: Pediatric blood & cancer, 2020-12, Vol.67 (12), p.e28639-n/a
    Description: Background Malignant peripheral nerve sheath tumor (MPNST) is an aggressive form of soft‐tissue sarcoma (STS) in children. Despite intensive therapy, relatively few children with metastatic and unresectable disease survive beyond three years. RAS pathway activation is common in MPNST, suggesting MEK pathway inhibition as a targeted therapy, but the impact on clinical outcome has been small to date. Procedure We conducted preclinical pharmacokinetic (PK) and pharmacodynamic studies of two MEK inhibitors, trametinib and selumetinib, in two MPNST models and analyzed tumors for intratumor drug levels. We then investigated 3′‐deoxy‐3′‐[18F]fluorothymidine (18F‐FLT) PET imaging followed by 18F‐FDG PET/CT imaging of MPNST xenografts coupled to short‐term or longer‐term treatment with selumetinib focusing on PET‐based imaging as a biomarker of MEK inhibition. Results Trametinib decreased pERK expression in MPNST xenografts but did not prolong survival or decrease Ki67 expression. In contrast, selumetinib prolonged survival of animals bearing MPNST xenografts, and this correlated with decreased pERK and Ki67 staining. PK studies revealed a significantly higher fraction of unbound selumetinib within a responsive MPNST xenograft model. Thymidine uptake, assessed by 18F‐FLT PET/CT, positively correlated with Ki67 expression in different xenograft models and in response to selumetinib. Conclusion The ability of MEK inhibitors to control MPNST growth cannot simply be predicted by serum drug levels or drug‐induced changes in pERK expression. Tumor cell proliferation assessed by 18F‐FLT PET imaging might be useful as an early response marker to targeted therapies, including MEK inhibition, where a primary effect is cell‐cycle arrest.
    Subject(s): 18F‐FLT‐PET ; malignant peripheral nerve sheath tumor ; imaging‐based response biomarkers ; MEK inhibition ; Neurofibrosarcoma - diagnostic imaging ; Fluorodeoxyglucose F18 - pharmacokinetics ; Neurofibrosarcoma - pathology ; Cell Proliferation ; Radiopharmaceuticals - pharmacokinetics ; Humans ; ras Proteins - antagonists & inhibitors ; Mice, SCID ; Neurofibrosarcoma - drug therapy ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Tissue Distribution ; Xenograft Model Antitumor Assays ; Pyridones - administration & dosage ; Animals ; Benzimidazoles - administration & dosage ; Mice, Inbred NOD ; Neurofibrosarcoma - metabolism ; Mice ; Pyrimidinones - administration & dosage ; Tumor Cells, Cultured ; Apoptosis ; Positron Emission Tomography Computed Tomography - methods ; Index Medicus
    ISSN: 1545-5009
    E-ISSN: 1545-5017
    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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  • 10
    Language: English
    In: Pediatric blood & cancer, 2016-10, Vol.63 (10), p.1753-1760
    Description: Background Despite intensive therapy, children with metastatic and recurrent sarcoma or neuroblastoma have a poor prognosis. Magnetic resonance guided high intensity focused ultrasound (MR‐HIFU) is a noninvasive technique allowing the delivery of targeted ultrasound energy under MR imaging guidance. MR‐HIFU may be used to ablate tumors without ionizing radiation or target chemotherapy using hyperthermia. Here, we evaluated the anatomic locations of tumors to assess the technical feasibility of MR‐HIFU therapy for children with solid tumors. Procedure Patients with sarcoma or neuroblastoma with available cross‐sectional imaging were studied. Tumors were classified based on the location and surrounding structures within the ultrasound beam path as (i) not targetable, (ii) completely or partially targetable with the currently available MR‐HIFU system, and (iii) potentially targetable if a respiratory motion compensation technique was used. Results Of the 121 patients with sarcoma and 61 patients with neuroblastoma, 64% and 25% of primary tumors were targetable at diagnosis, respectively. Less than 20% of metastases at diagnosis or relapse were targetable for both sarcoma and neuroblastoma. Most targetable lesions were located in extremities or in the pelvis. Respiratory motion compensation may increase the percentage of targetable tumors by 4% for sarcomas and 10% for neuroblastoma. Conclusions Many pediatric sarcomas are localized at diagnosis and are targetable by current MR‐HIFU technology. Some children with neuroblastoma have bony tumors targetable by MR‐HIFU at relapse, but few newly diagnosed children with neuroblastoma have tumors amenable to MR‐HIFU therapy. Clinical trials of MR‐HIFU should focus on patients with anatomically targetable tumors.
    Subject(s): neuroblastoma ; hyperthermia ; sarcoma ; MR‐HIFU ; ablation ; Movement ; Humans ; Child, Preschool ; Infant ; Male ; Sarcoma - pathology ; Sarcoma - therapy ; Magnetic Resonance Imaging ; Adolescent ; Female ; Sarcoma - diagnostic imaging ; High-Intensity Focused Ultrasound Ablation - methods ; Child ; Infant, Newborn ; Chemotherapy ; Ionizing radiation ; Sarcoma ; Children ; Metastasis ; Health aspects ; Hyperthermia ; Fever ; Cancer ; Index Medicus
    ISSN: 1545-5009
    E-ISSN: 1545-5017
    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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