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Ekici A, Ayan B, Kazancı EG, Kuşku ZB, Orcan CG, Havalı C, Dorum S, Metin T, Orhaner BB. Central nervous system complications during treatment in childhood acute leukemia. Acta Neurol Belg 2025; 125:77-88. [PMID: 39192159 DOI: 10.1007/s13760-024-02602-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 07/11/2024] [Indexed: 08/29/2024]
Abstract
OBJECTIVE Central nervous system (CNS) complications can be seen in patients with leukemia, depending on the disease itself and the chemotherapeutic agents used. This study focused on CNS complications during treatment in children with acute leukemia in a single pediatric institution. METHODS CNS complications were evaluated retrospectively in 115 patients with ALL and AML. Patients with CNS leukemia infiltration at the time of diagnosis or during a neurological event, late-onset encephalopathy, peripheral neuropathy, or a previous history of neurological abnormalities were excluded from the study. RESULTS A total of 115 children's clinical records with acute leukemia over a four-year period were reviewed. Acute CNS complications developed in 23.1% of acute myeloid leukemia (AML) patients and in 13.5% of acute lymphoblastic leukemia (ALL) patients. CNS complications developed most frequently during the induction phase of the treatment (66.7%). Seizures were the most common symptom (9 patients, 50%), followed by hemiparesis (4 patients, 22.2%) and headache (4 patients, 22.2%). Six patients (33.3%) had chemotherapy-induced toxic leukoencephalopathy, two (11.1%) had Wernicke's encephalopathy, and one patient (5.6%) each had sinus vein thrombosis, posterior reversible encephalopathy syndrome, and CNS infection. Sequelae occurred in three patients (16.7%), and only one patient (5.6%) died due to a CNS complication. CONCLUSION A wide variety of symptoms can be observed in childhood leukemia, depending on the disease itself, the chemotherapeutic agents used and a lot of other conditions such as nutritional problems. Our research shows that several CNS complications might manifest with similar symptoms; differentiated diagnosis between the underlying etiological reasons can be made by neuroimaging.
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Affiliation(s)
- Arzu Ekici
- Department of Pediatrics, Division of Neurology, Bursa Yuksek Ihtisas Training and Research Hospital, Mimar Sinan Avenue, Yıldırım, Bursa, Turkey.
| | - Bilgen Ayan
- Department of Pediatrics, Division of Hematology, Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey
| | - Elif Güler Kazancı
- Department of Pediatrics, Division of Hematology, Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey
| | - Zeynep Beyza Kuşku
- Department of Pediatrics, Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey
| | - Cengiz Gökhan Orcan
- Department of Radiology, Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey
| | - Cengiz Havalı
- Department of Pediatrics, Division of Neurology, Bursa Yuksek Ihtisas Training and Research Hospital, Mimar Sinan Avenue, Yıldırım, Bursa, Turkey
| | - Sevil Dorum
- Department of Pediatrics, Division of Metabolism, Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey
| | - Taha Metin
- Department of Pediatrics, Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey
| | - Betül Biner Orhaner
- Department of Pediatrics, Division of Hematology, Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey
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Newman J, Leelatian N, Liang J. Characterization of pediatric non-hematopoietic tumor metastases to the central nervous system: A single institution review. J Neuropathol Exp Neurol 2024; 83:268-275. [PMID: 38350468 DOI: 10.1093/jnen/nlae012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2024] Open
Abstract
Central nervous system (CNS) metastases represent a small portion of pediatric CNS neoplasms and data surrounding this condition with high morbidity is scarce. Single institutional archival institutional pathology records between 1999 and 2022 were searched for patients over 21 years old and younger with CNS, dura, cranial nerve, CSF, or leptomeningeal metastases; 41 cases were identified. We documented primary tumor types and locations, metastasis locations, types of invasion (direct extension vs distant metastasis), times from imaging or pathologic diagnosis to CNS involvement, and outcomes. Distant metastasis was the most common mechanism of metastasis (n = 32, 78%). Interval times to CNS metastasis varied by both tumor type and primary tumor location. In this cohort, osteosarcoma portended the shortest survival following CNS metastasis. This study highlights the diverse mechanisms and locations of CNS involvement in pediatric CNS metastases and illuminates a need for varied monitoring strategies when considering primary tumor type and anatomic location.
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Affiliation(s)
- John Newman
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Nalin Leelatian
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jiancong Liang
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
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A Comprehensive Review of Neuropsychologic Studies Supports the Concept That Adequate Folinic Acid Rescue Prevents Post Methotrexate Neurotoxicity. J Pediatr Hematol Oncol 2023; 45:1-11. [PMID: 36598958 DOI: 10.1097/mph.0000000000002604] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 11/08/2022] [Indexed: 01/05/2023]
Abstract
PURPOSE To review all studies providing evidence of the correlation between folinic acid (FA) rescue inadequacy and long-term cognitive damage in neuropsychological studies of children with acute lymphoblastic leukemia or osteogenic sarcoma treated under protocols using high-dose methotrexate and FA rescue. METHODS A comprehensive literature search was performed of all databases of the Web of Science Citation Index, during 1990-2020, for the terms: neuropsychological, neurocognitive, and cognitive, together with acute lymphoblastic (and lymphocytic) leukemia and osteogenic sarcoma. English-language peer-reviewed articles on neuropsychological assessments of children who had been treated with high-dose methotrexate without irradiation, and which included details of methotrexate and FA schedules, were selected. In addition, a personal database of over 500 reprints of articles from over 130 journals was reviewed on the subjects of methotrexate and FA and their side effects. RESULTS Three groups of studies were found and analyzed, with (1) no evidence of cognitive deterioration, (2) evidence of cognitive deterioration, and (3) more than 1 protocol grouped together, preventing separate analysis of any protocols, Protocols without cognitive deterioration reported adequate FA rescue, and those with cognitive deterioration reported inadequate FA rescue. CONCLUSION Neuropsychological evaluation supported inadequate FA being the cause of neurocognitive damage after high-dose methotrexate and that adequate FA rescue prevents this complication.
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Meena JP, Makkar H, Gupta AK, Bakhshi S, Gupta R, Thakral D, Chopra A, Tanwar P, Upadhyay AD, Pathak N, Seth R. A comprehensive analysis of cytogenetics, molecular profile, and survival among pediatric acute myeloid leukemia: a prospective study from a tertiary referral center. AMERICAN JOURNAL OF BLOOD RESEARCH 2022; 12:177-189. [PMID: 36742278 PMCID: PMC9890188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 11/15/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The objectives of this study were to investigate the cyto-molecular profile and survival of pediatric acute myeloid leukemia (AML). METHODS This prospective study was carried out in a tertiary care hospital from October 2018 to December 2020. Karyotype and cytogenetics analyses were done to identify chromosomal aberrations in pediatric AML. The targeted molecular panel utilized the polymerase chain reaction (PCR), reverse transcription-polymerase chain reaction (RT-PCR), and fragment analysis. RESULTS A total of 70 patients of AML with aged ≤18 years were enrolled in this study. The cytogenetic analyses revealed abnormal/recurrent cytogenetic abnormalities (CA) in 64.3% of patients and normal cytogenetics (CN) in 35.7% of patients. FAB M2 subtype showed frequent aberrant expression of the CD19 marker. CD7, CD11b, and CD36a were significantly present in the absence of molecular markers. Common chromosomal abnormalities were t(translocation) (8;21) (55%), monosomy/deletion 7 (13%), monosomal karyotype (5%) and complex karyotype (3%). The fusion transcripts RUNX1-RUNX1T1 [t(8;21)] (41%) and CBFB-MYH11 [t(16;16)] (3%) were detected by RT-PCR and FLT3-TKD D835 mutation (1.5%) by allele-specific oligo PCR. Fragment analysis revealed NPM1 (8%) mutation and FLT-ITD (9.5%) mutations. Complete remission was achieved in all evaluable patients. The median follow-up period of our patients was 225 days (IQR 28; 426 days). The median event-free survival (EFS) in all patients was 11.9 months (95% CI, 5-12.6 months). The forty months overall survival probability (pOS) was 58% in all patients. CONCLUSION The majority of patients had abnormal/recurrent cytogenetics abnormalities. FAB M2 subtype showed frequent aberrant expression of the CD19. The absence of molecular markers may suggest the presence of CD7, CD11b, and CD36a expression. The overall survival has increased considerably in LMIC.
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Affiliation(s)
- Jagdish Prasad Meena
- Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical SciencesNew Delhi 110029, India
| | - Harshita Makkar
- Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical SciencesNew Delhi 110029, India
| | - Aditya Kumar Gupta
- Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical SciencesNew Delhi 110029, India
| | - Sameer Bakhshi
- Department of Medical Oncology, Dr. B.R.A. IRCH, All India Institute of Medical SciencesNew Delhi 110029, India
| | - Ritu Gupta
- Laboratory Oncology Unit, Dr. B.R.A. IRCH, All India Institute of Medical SciencesNew Delhi 110029, India
| | - Deepshi Thakral
- Laboratory Oncology Unit, Dr. B.R.A. IRCH, All India Institute of Medical SciencesNew Delhi 110029, India
| | - Anita Chopra
- Laboratory Oncology Unit, Dr. B.R.A. IRCH, All India Institute of Medical SciencesNew Delhi 110029, India
| | - Pranay Tanwar
- Laboratory Oncology Unit, Dr. B.R.A. IRCH, All India Institute of Medical SciencesNew Delhi 110029, India
| | - Ashish Datt Upadhyay
- Department of Biostatistics, All India Institute of Medical SciencesNew Delhi 110029, India
| | - Nivedita Pathak
- Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical SciencesNew Delhi 110029, India
| | - Rachna Seth
- Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical SciencesNew Delhi 110029, India
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Shalabi H, Nellan A, Shah NN, Gust J. Immunotherapy Associated Neurotoxicity in Pediatric Oncology. Front Oncol 2022; 12:836452. [PMID: 35265526 PMCID: PMC8899040 DOI: 10.3389/fonc.2022.836452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/20/2022] [Indexed: 11/30/2022] Open
Abstract
Novel immunotherapies are increasingly being employed in pediatric oncology, both in the upfront and relapsed/refractory settings. Through various mechanisms of action, engagement and activation of the immune system can cause both generalized and disease site-specific inflammation, leading to immune-related adverse events (irAEs). One of the most worrisome irAEs is that of neurotoxicity. This can present as a large spectrum of neurological toxicities, including confusion, aphasia, neuropathies, seizures, and/or death, with variable onset and severity. Earlier identification and treatment, generally with corticosteroids, remains the mainstay of neurotoxicity management to optimize patient outcomes. The pathophysiology of neurotoxicity varies across the different therapeutic strategies and remains to be elucidated in most cases. Furthermore, little is known about long-term neurologic sequelae. This review will focus on neurotoxicity seen with the most common immunotherapies used in pediatric oncology, including CAR T cell therapy, alternative forms of adoptive cell therapy, antibody therapies, immune checkpoint inhibitors, and tumor vaccines. Herein we will discuss the incidence, pathophysiology, symptomatology, diagnosis, and management strategies currently being utilized for immunotherapy-associated neurotoxicity with a focus on pediatric specific considerations.
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Affiliation(s)
- Haneen Shalabi
- National Cancer Institute, Pediatric Oncology Branch, National Institutes of Health, Bethesda, MD, United States
| | - Anandani Nellan
- National Cancer Institute, Pediatric Oncology Branch, National Institutes of Health, Bethesda, MD, United States
| | - Nirali N. Shah
- National Cancer Institute, Pediatric Oncology Branch, National Institutes of Health, Bethesda, MD, United States
| | - Juliane Gust
- Seattle Children’s Research Institute, Seattle, WA, United States
- Department of Neurology, University of Washington, Seattle, WA, United States
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Patel N, RIch BJ, Patel S, Watts JM, Benveniste R, Abramowitz M, Markoe A, Eichberg DG, Komotar RJ, De La Fuente M, Pasol J, Diwanji T. Emergent Radiotherapy for Leukemia-Induced Cranial Neuropathies Refractory to Intrathecal Therapy. Cureus 2021; 13:e15212. [PMID: 34178531 PMCID: PMC8221003 DOI: 10.7759/cureus.15212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Neurologic symptoms from leukemic infiltration of the central nervous system are an oncologic emergency, and expeditious treatment is required to preserve function. We report the case of a 44-year-old patient with relapsed acute myeloid leukemia (AML) who developed sub-acute cranial neuropathies refractory to treatment with intrathecal (IT) chemotherapy. The patient was therefore treated with an emergent course of whole-brain radiotherapy, resulting in immediate improvement and subsequent resolution of cranial neuropathies. This case illustrates that while central nervous system involvement by AML is rare, radiotherapy remains an effective modality to avoid long-term morbidity in patients failing to respond to systemic or IT chemotherapy.
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Affiliation(s)
- Nirav Patel
- Radiation Oncology, University of Miami Sylvester Comprehensive Cancer Center, Miami, USA
| | - Benjamin J RIch
- Radiation Oncology, University of Miami Sylvester Comprehensive Cancer Center, Miami, USA
| | - Shareen Patel
- Radiation Oncology, University of Miami Miller School of Medicine, Miami, USA
| | - Justin M Watts
- Hematology/Oncology, University of Miami Sylvester Comprehensive Cancer Center, Miami, USA
| | - Ronald Benveniste
- Neurological Surgery, University of Miami Miller School of Medicine, Miami, USA
| | - Matthew Abramowitz
- Radiation Oncology, University of Miami Sylvester Comprehensive Cancer Center, Miami, USA
| | - Arnold Markoe
- Radiation Oncology, University of Miami Sylvester Comprehensive Cancer Center, Miami, USA
| | - Daniel G Eichberg
- Neurological Surgery, University of Miami Miller School of Medicine, Miami, USA
| | - Ricardo J Komotar
- Neurological Surgery, University of Miami Miller School of Medicine, Miami, USA
| | | | - Joshua Pasol
- Ophthalmology, University of Miami Sylvester Comprehensive Cancer Center, Miami, USA
| | - Tejan Diwanji
- Radiation Oncology, University of Miami Sylvester Comprehensive Cancer Center, Miami, USA
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Egyed B, Kutszegi N, Sági JC, Gézsi A, Rzepiel A, Visnovitz T, Lőrincz P, Müller J, Zombori M, Szalai C, Erdélyi DJ, Kovács GT, Semsei ÁF. MicroRNA-181a as novel liquid biopsy marker of central nervous system involvement in pediatric acute lymphoblastic leukemia. J Transl Med 2020; 18:250. [PMID: 32571344 PMCID: PMC7310470 DOI: 10.1186/s12967-020-02415-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 06/15/2020] [Indexed: 12/16/2022] Open
Abstract
Background Refractory central nervous system (CNS) involvement is among the major causes of therapy failure in childhood acute leukemia. Applying contemporary diagnostic methods, CNS disease is often underdiagnosed. To explore more sensitive and less invasive CNS status indicators, we examined microRNA (miR) expressions and extracellular vesicle (EV) characteristics. Methods In an acute lymphoblastic leukemia (ALL) discovery cohort, 47 miRs were screened using Custom TaqMan Advanced Low-Density Array gene expression cards. As a validation step, a candidate miR family was further scrutinized with TaqMan Advanced miRNA Assays on serial cerebrospinal fluid (CSF), bone marrow (BM) and peripheral blood samples with different acute leukemia subtypes. Furthermore, small EV-rich fractions were isolated from CSF and the samples were processed for immunoelectron microscopy with anti-CD63 and anti-CD81 antibodies, simultaneously. Results Regarding the discovery study, principal component analysis identified the role of miR-181-family (miR-181a-5p, miR-181b-5p, miR-181c-5p) in clustering CNS-positive (CNS+) and CNS-negative (CNS‒) CSF samples. We were able to validate miR-181a expression differences: it was about 52 times higher in CSF samples of CNS+ ALL patients compared to CNS‒ cases (n = 8 vs. n = 10, ΔFC = 52.30, p = 1.5E−4), and CNS+ precursor B cell subgroup also had ninefold higher miR-181a levels in their BM (p = 0.04). The sensitivity of CSF miR-181a measurement in ALL highly exceeded those of conventional cytospin in the initial diagnosis of CNS leukemia (90% vs. 54.5%). Pellet resulting from ultracentrifugation of CNS+ CSF samples of ALL patients showed atypical CD63−/CD81− small EVs in high density by immunoelectron microscopy. Conclusions After validating in extensive cohorts, quantification of miR-181a or a specific EV subtype might provide novel tools to monitor CNS disease course and further adjust CNS-directed therapy in pediatric ALL.
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Affiliation(s)
- Bálint Egyed
- 2nd Department of Pediatrics, Semmelweis University, 7-9 Tűzoltó Str, Budapest, 1094, Hungary.,Department of Genetics, Cell- and Immunobiology, Semmelweis University, 4 Nagyvárad Sqr, Budapest, 1089, Hungary
| | - Nóra Kutszegi
- 2nd Department of Pediatrics, Semmelweis University, 7-9 Tűzoltó Str, Budapest, 1094, Hungary
| | - Judit C Sági
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, 4 Nagyvárad Sqr, Budapest, 1089, Hungary
| | - András Gézsi
- MTA-SE Immune-Proteogenomics Extracellular Vesicle Research Group, Semmelweis University, 4 Nagyvárad Sqr, Budapest, 1089, Hungary.,Department of Measurements and Information Systems, Budapest University of Technology and Economics, 2 Magyar tudosok korutja, Budapest, 1117, Hungary
| | - Andrea Rzepiel
- 2nd Department of Pediatrics, Semmelweis University, 7-9 Tűzoltó Str, Budapest, 1094, Hungary
| | - Tamás Visnovitz
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, 4 Nagyvárad Sqr, Budapest, 1089, Hungary
| | - Péter Lőrincz
- Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, 1/c Pázmány Promenade, Budapest, 1117, Hungary
| | - Judit Müller
- 2nd Department of Pediatrics, Semmelweis University, 7-9 Tűzoltó Str, Budapest, 1094, Hungary
| | - Marianna Zombori
- Heim Pal National Pediatric Institute, 86 Üllői Str, Budapest, 1089, Hungary
| | - Csaba Szalai
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, 4 Nagyvárad Sqr, Budapest, 1089, Hungary.,Heim Pal National Pediatric Institute, 86 Üllői Str, Budapest, 1089, Hungary
| | - Dániel J Erdélyi
- 2nd Department of Pediatrics, Semmelweis University, 7-9 Tűzoltó Str, Budapest, 1094, Hungary
| | - Gábor T Kovács
- 2nd Department of Pediatrics, Semmelweis University, 7-9 Tűzoltó Str, Budapest, 1094, Hungary
| | - Ágnes F Semsei
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, 4 Nagyvárad Sqr, Budapest, 1089, Hungary.
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Direct Delivery of piggyBac CD19 CAR T Cells Has Potent Anti-tumor Activity against ALL Cells in CNS in a Xenograft Mouse Model. MOLECULAR THERAPY-ONCOLYTICS 2020; 18:37-46. [PMID: 32637579 PMCID: PMC7321814 DOI: 10.1016/j.omto.2020.05.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/22/2020] [Indexed: 12/29/2022]
Abstract
The anti-CD19 chimeric antigen receptor (CAR) T cells showed excellent effect against acute lymphoblastic leukemia (ALL) in bone marrow (BM) in clinical trials. However, it remains to be elucidated whether the CD19 CAR T cell therapy is effective for ALL cells in central nervous system (CNS) because the patients with isolated or advanced CNS disease were excluded from clinical trials of systemic intravenous (i.v.) delivery of CAR T cells. Therefore, the preclinical evaluation for the efficacy of CAR T cell therapy against ALL cells in CNS is essential for clinical application. We evaluated the effect and adverse reaction of CD19 CAR T cells against ALL in CNS using a xenograft mouse model by i.v. or intra-cerebroventricular (i.c.v.) delivery of CAR T cells. Injection of piggyBac CD19 CAR T cells by i.v. had partial effects, whereas all CAR T i.c.v.-delivered mice had eliminated ALL in CNS. Although some CAR T i.c.v.-delivered mice showed transient changes of clinical symptoms during the first few days after treatment, none of CAR T i.c.v.-delivered mice displayed fatal adverse events. In this study, we demonstrated that direct delivery into CNS of CAR T cells is a possible therapeutic approach with the xenograft mouse model.
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Srinivasan R, Thomas S. Rapid Weight Gain: An Unusual Presentation of Leukemia. Indian J Med Paediatr Oncol 2020. [DOI: 10.4103/ijmpo.ijmpo_241_18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
AbstractNeurological manifestations of leukemia can be due to direct effects of the malignancy or due to the indirect effects of infection or therapy. An 11-year-old boy presented with recent-onset weight gain with papilledema and a history of tuberculosis contact. Neuroimaging and initial microscopic examination of the cerebrospinal fluid (CSF) did not aid in the diagnosis of central nervous system leukemia. He was started on antitubercular treatment yet deteriorated. Repeat CSF analysis when subjected to cytospin and flow cytometry confirmed the diagnosis of B cell acute lymphoblastic leukemia (ALL). Although there have been reports of relapsed ALL presenting as obesity, isolated rapid changes in weight at initial presentation are a very rare and unusual manifestation of ALL. To the best of our knowledge, this is the first such report.
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Affiliation(s)
- Ranjini Srinivasan
- Department of Paediatrics, St John’s Medical College Hospital, Bengaluru, Karnataka, India
| | - Sarita Thomas
- Department of Paediatrics, St John’s Medical College Hospital, Bengaluru, Karnataka, India
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Zhou F, Wen Y, Jin R, Chen H. New attempts for central nervous infiltration of pediatric acute lymphoblastic leukemia. Cancer Metastasis Rev 2020; 38:657-671. [PMID: 31820149 DOI: 10.1007/s10555-019-09827-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The cure rate of acute lymphoblastic leukemia (ALL), the commonest childhood cancer, has been sharply improved and reached almost 90% ever since the central nervous system (CNS)-directed therapy proposed in the 1960s. However, relapse, particularly in the central nervous system (CNS), is still a common cause of treatment failure. Up to now, the classic CNS-directed treatment for CNS leukemia (CNSL) has been aslant from cranial radiation to high-dose system chemotherapy plus intrathecal (IT) chemotherapy for the serious side effects of cranial radiation. The neurotoxic effects of chemotherapy and IT chemotherapy have been reported in recent years as well. For better prevention and treatment of CNSL, plenty of studies have tried to improve the detection sensitivity for CNSL and prevent CNSL from happening by targeting cytokines and chemokines which could be key factors for the traveling of ALL cells into the CNS. Other studies also have aimed to completely kill ALL cells (including dormant cells) in the CNS by promoting the entering of chemotherapy drugs into the CNS or targeting the components of the CNS niche which could be in favor of the survival of ALL cells in CNS. The aim of this review is to discuss the imperfection of current diagnostic methods and treatments for CNSL, as well as new attempts which could be significant for better elimination of CNSL.
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Affiliation(s)
- Fen Zhou
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuxi Wen
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Runming Jin
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Hongbo Chen
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Koyuncu I, Tülüce Y, Slahaddin Qadir H, Durgun M, Supuran CT. Evaluation of the anticancer potential of a sulphonamide carbonic anhydrase IX inhibitor on cervical cancer cells. J Enzyme Inhib Med Chem 2019; 34:703-711. [PMID: 30810431 PMCID: PMC6394301 DOI: 10.1080/14756366.2019.1579805] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
Cervical cancer is a common type of cancer. Carbonic anhydrase IX (CA IX) is an attractive target for tumour therapy, being overexpressed in many cancers. We investigated the anticancer properties of the aromatic sulphonamide S-1 as a CA IX inhibitor on cervical cancer cells (HeLa) positive for CA IX expression and normal prostate epithelial cell line (PNT1-A) negative for CA IX. We examined the cytotoxic, apoptosis, genotoxic, and oxidative stress activity of S-1 on HeLa and PNT1-A cell lines. S-1 induced significant reduction of cell viability, caused apoptosis, and up-regulated ROS production. This decrease in cell survival rate can be attributed to the high level of ROS and apoptosis, which has also been shown to arrest the cell cycle. Our findings indicated that S-1 is more effective on HeLa than PNT1-A. S-1 was able to induce apoptosis of cervical cancer cells and is a possible candidate for future anticancer studies.
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Affiliation(s)
- Ismail Koyuncu
- a Department of Biochemistry, Faculty of Medicine , Harran University , Sanliurfa , Turkey
| | - Yasin Tülüce
- b Department of Medical Biology, Faculty of Medicine , Van Yuzuncu Yil University , Van , Turkey
| | - Hewa Slahaddin Qadir
- b Department of Medical Biology, Faculty of Medicine , Van Yuzuncu Yil University , Van , Turkey
| | - Mustafa Durgun
- c Department of Chemistry, Faculty of Arts and Sciences , Harran University , Sanliurfa , Turkey
| | - Claudiu T Supuran
- d Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences , Università degli Studi di Firenze , Sesto Fiorentino (Florence) , Italy
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Kinjyo I, Bragin D, Grattan R, Winter SS, Wilson BS. Leukemia-derived exosomes and cytokines pave the way for entry into the brain. J Leukoc Biol 2019; 105:741-753. [PMID: 30702754 DOI: 10.1002/jlb.3a0218-054r] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 12/07/2018] [Accepted: 01/02/2019] [Indexed: 12/25/2022] Open
Abstract
Infiltration of acute lymphoblastic leukemia (ALL) blasts into the CNS remains as a major clinical problem, with high risk for chemotherapy-resistant relapse and treatment-related morbidity. Despite the common inclusion of CNS prophylaxis treatments in therapy regimens, there are significant gaps in understanding the mechanisms that mediate leukemia cell entry into the CNS as well as roles for resident cells in the brain. In this study, we employ a xenograft model of human B cell precursor (BCP)-ALL in immunocompromised mice. This model system recapitulates key pathological characteristics of leptomeningeal involvement seen in patients and provides insights into rare cases that involve parenchymal invasion. We examine the infiltration of engrafted leukemia blasts into brains of recipient mice and provide evidence that the interaction between blasts and brain resident cells causes aberrant activation of host cells in the brain microenvironment. BCP-ALL blasts also release multiple cytokines and exosomes containing IL-15 that bind and are internalized by astrocytes and brain vessel endothelial cells. Leukemic invasion is linked to production of VEGF-AA by astrocytes and disruption of the blood-brain-barrier (BBB) integrity. Knockdown of either IL-15 or IL-15Rα in the NALM6 cell line decreases CNS infiltration in engrafted mice. These results provide important insights into the multiple mechanisms by which lymphoblasts modulate the brain microenvironment to breach the BBB for metastatic invasion.
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Affiliation(s)
- Ichiko Kinjyo
- Department of Pathology, University of New Mexico, Albuquerque, New Mexico, USA
| | - Denis Bragin
- Department of Neurosurgery, University of New Mexico, Albuquerque, New Mexico, USA
| | - Rachel Grattan
- Department of Pathology, University of New Mexico, Albuquerque, New Mexico, USA
| | - Stuart S Winter
- Blood Diseases and Cancer Program, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA
| | - Bridget S Wilson
- Department of Pathology, University of New Mexico, Albuquerque, New Mexico, USA.,Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
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Zając-Spychała O, Pawlak M, Karmelita-Katulska K, Pilarczyk J, Jończyk-Potoczna K, Przepióra A, Derwich K, Wachowiak J. Anti-leukemic treatment-induced neurotoxicity in long-term survivors of childhood acute lymphoblastic leukemia: impact of reduced central nervous system radiotherapy and intermediate- to high-dose methotrexate. Leuk Lymphoma 2018; 59:2342-2351. [PMID: 29424258 DOI: 10.1080/10428194.2018.1434879] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The aim of the study was to evaluate the long-term neurodevelopmental consequences of currently applied acute lymphoblastic leukemia (ALL) therapy containing chemotherapy alone or combined with 12 Gy radiotherapy. Seventy-nine children aged 6.3-21.7 years diagnosed with ALL and treated according to ALL IC-BFM 2002 have been studied. The control group consisted of 23 children newly diagnosed with ALL. We assessed subcortical gray matter volume using automatic MRI segmentation and cognitive performance to identify differences between three therapeutic schemes and patients prior to treatment. Irradiated patients had smaller selected subcortical volumes than those treated with chemotherapy alone and than the controls, while the chemotherapy group had similar volumes as the control one. In neurocognitive assessment, irradiated children performed worse in major domains than the control group. There were no significant results for patients after high dose chemotherapy without radiotherapy. There was a significant relationship between full scale IQ together with verbal learning and volumes of hippocampus, amygdala, and pallidum. In all children treated for ALL, both decreased volume of selected subcortical structures and cognitive impairment were observed, especially in children who were irradiated.
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Affiliation(s)
- Olga Zając-Spychała
- a Department of Pediatric Oncology, Hematology and Transplantology , Poznan University of Medical Sciences , Poznan , Poland
| | - Mikolaj Pawlak
- b Department of Neurology and Cerebrovascular Disorders , Poznan University of Medical Sciences , Poznan , Poland
| | | | - Jakub Pilarczyk
- a Department of Pediatric Oncology, Hematology and Transplantology , Poznan University of Medical Sciences , Poznan , Poland
| | | | - Agnieszka Przepióra
- d Department of Pediatric Radiology , Poznan University of Medical Sciences , Poznan , Poland
| | - Katarzyna Derwich
- a Department of Pediatric Oncology, Hematology and Transplantology , Poznan University of Medical Sciences , Poznan , Poland
| | - Jacek Wachowiak
- a Department of Pediatric Oncology, Hematology and Transplantology , Poznan University of Medical Sciences , Poznan , Poland
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Abstract
The central nervous system (CNS) is an important site of involvement by acute lymphoblastic leukemia (ALL) in adults. The prevalence is sufficiently high that prophylactic treatment is routinely given to this sanctuary site in order to eradicate occult disease that might otherwise lead to a relapse. A lumbar puncture should be routinely performed in all newly diagnosed patients with ALL. The risks of CNS leukemia vary by phenotype and genotype. Preventive treatment of the CNS during post-remission therapy has become an integral part of all current ALL treatment protocols. Most treatment regimens combine multiple doses of intrathecal chemotherapy with high-dose systemic methotrexate and/or cytarabine. Cranial irradiation is less commonly used for prophylaxis but is still the most effective treatment for overt CNS leukemia. Recurrences within the CNS usually coincide with or predict soon afterwards for systemic relapse in the marrow and blood.
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Affiliation(s)
- Richard A Larson
- a Department of Medicine, Section of Hematology/Oncology, and Comprehensive Cancer Center , The University of Chicago , Chicago , IL , USA
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15
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Levinsen M, Marquart HV, Groth-Pedersen L, Abrahamsson J, Albertsen BK, Andersen MK, Frandsen TL, Harila-Saari A, Pronk C, Ulvmoen A, Vaitkevičienė G, Lähteenmäki PM, Niinimäki R, Taskinen M, Jeppesen M, Schmiegelow K. Leukemic blasts are present at low levels in spinal fluid in one-third of childhood acute lymphoblastic leukemia cases. Pediatr Blood Cancer 2016; 63:1935-42. [PMID: 27447373 DOI: 10.1002/pbc.26128] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 05/30/2016] [Accepted: 06/08/2016] [Indexed: 12/22/2022]
Abstract
BACKGROUND Central nervous system (CNS) involvement is associated with relapse in childhood acute lymphoblastic leukemia (ALL) and is a diagnostic challenge. PROCEDURE In a Nordic/Baltic prospective study, we assessed centralized flow cytometry (FCM) of locally fixed cerebrospinal fluid (CSF) samples versus local conventional cytospin-based cytology (CC) for detecting leukemic cells and evaluating kinetics of elimination of leukemic cells in CSF. RESULTS Among 300 patients with newly diagnosed ALL, 87 (29%) had CSF involvement by FCM, while CC was positive in 30 (10%) of 299 patients with available CC data (P < 0.001). Patients with FCM+/CC+ had higher CSF leukemic blast counts compared to patients positive by FCM only (medians: 0.10 vs. 0.017 leukemic blasts/μl, P = 0.006). Patients positive by FCM had higher white blood cell counts in peripheral blood than patients negative by FCM (medians: 45 × 10(9) /l vs. 10 × 10(9) /l, P < 0.001), were younger (medians: 3 years vs. 4 years, P = 0.03), and more frequently had T-cell ALL (18/87 vs. 16/213, P = 0.001). At treatment day 15, five of 52 patients (10%) who had CSF positive by FCM at diagnosis remained so despite at least two doses of weekly intrathecal chemotherapy. CONCLUSIONS Longer follow-up is needed to clarify whether FCM positivity has prognostic significance and is an indicator for intensified CNS-directed therapy.
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Affiliation(s)
- Mette Levinsen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Hanne V Marquart
- Department of Clinical Immunology, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Line Groth-Pedersen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Jonas Abrahamsson
- Department of Pediatrics, Institution of Clinical Sciences, Sahlgrenska University Hospital, Gothenburg, Sweden
| | | | - Mette K Andersen
- Department of Clinical Genetics, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Thomas L Frandsen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Arja Harila-Saari
- Department of Pediatrics, Astrid Lindgrens Hospital, Stockholm, Sweden
| | - Cornelis Pronk
- Department of Pediatrics, Skåne University Hospital, Lund, Sweden
| | - Aina Ulvmoen
- Department of Pediatrics, Oslo University Hospital, Norway
| | - Goda Vaitkevičienė
- Centre for Pediatric Oncology and Hematology, University Children's Hospital, Vilnius, Lithuania
| | | | - Riitta Niinimäki
- Department of Pediatrics, Oulu University Hospital, Oulu, Finland
| | - Mervi Taskinen
- Children and Adolescents, Helsinki University Hospital, Helsinki, Finland
| | - Maria Jeppesen
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Kjeld Schmiegelow
- Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.
- Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
- Division of Pediatric Hematology/Oncology, Perlmutter Cancer Center, NYU Langone Medical Center, New York.
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Khalifa NM, Nour WFM, ElSaid NAE, El Ezz RZA, El-kiki HA. Role of MRI in the evaluation of postchemotherapy brain changes in childhood leukemia: An Egyptian study. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2016. [DOI: 10.1016/j.ejrnm.2016.05.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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17
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Hicks C, Sitthi-Amorn J, Douglas J, Ramani R, Miele L, Vijayakumar V, Karlson C, Chipeta J, Megason G. Molecular Analysis of Central Nervous System Disease Spectrum in Childhood Acute Lymphoblastic Leukemia. CLINICAL MEDICINE INSIGHTS-ONCOLOGY 2016; 10:5-15. [PMID: 26997880 PMCID: PMC4792199 DOI: 10.4137/cmo.s18180] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 01/04/2016] [Accepted: 01/07/2016] [Indexed: 11/05/2022]
Abstract
Treatment of the central nervous system (CNS) is an essential therapeutic component in childhood acute lymphoblastic leukemia (ALL). The goal of this study was to identify molecular signatures distinguishing patients with CNS disease from those without the disease in pediatric patients with ALL. We analyzed gene expression data from 207 pediatric patients with ALL. Patients without CNS were classified as CNS1, while those with mild and advanced CNS disease were classified as CNS2 and CNS3, respectively. We compared gene expression levels among the three disease classes. We identified gene signatures distinguishing the three disease classes. Pathway analysis revealed molecular networks and biological pathways dysregulated in response to CNS disease involvement. The identified pathways included the ILK, WNT, B-cell receptor, AMPK, ERK5, and JAK signaling pathways. The results demonstrate that transcription profiling could be used to stratify patients to guide therapeutic decision-making in pediatric ALL.
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Affiliation(s)
- Chindo Hicks
- Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA.; Department of Public Health Sciences, University of Lusaka, Lusaka, Zambia
| | - Jitsuda Sitthi-Amorn
- Children's Cancer Center, University of Mississippi Medical Center, Jackson, MS, USA
| | - Jessica Douglas
- Children's Cancer Center, University of Mississippi Medical Center, Jackson, MS, USA
| | - Ritika Ramani
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
| | - Lucio Miele
- Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Vani Vijayakumar
- Department of Radiology, University of Mississippi Medical Center, Jackson, MS, USA
| | - Cynthia Karlson
- Children's Cancer Center, University of Mississippi Medical Center, Jackson, MS, USA
| | - James Chipeta
- Department of Pediatrics and Child Health, University of Zambia, Lusaka, Zambia
| | - Gail Megason
- Children's Cancer Center, University of Mississippi Medical Center, Jackson, MS, USA
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18
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Saumet L, Haouy S, Daien V, Hillaire-Buys D, Roessler J, Sirvent N. [Isolated unilateral cranial nerve palsy during childhood acute lymphoblastic leukemia treatment: What does it mean?]. Arch Pediatr 2016; 23:415-6. [PMID: 26968305 DOI: 10.1016/j.arcped.2016.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 01/01/2016] [Indexed: 10/22/2022]
Affiliation(s)
- L Saumet
- Unité d'oncologie pédiatrique, CHU Arnaud-de-Villeneuve, avenue du Doyen-Gaston-Giraud, 34295 Montpellier cedex 5, France.
| | - S Haouy
- Unité d'oncologie pédiatrique, CHU Arnaud-de-Villeneuve, avenue du Doyen-Gaston-Giraud, 34295 Montpellier cedex 5, France
| | - V Daien
- Département d'ophtalmologie, CHU de Montpellier, 34090 Montpellier cedex 5, France
| | - D Hillaire-Buys
- Département de pharmacologie médicale et toxicologie, CHU de Montpellier, 34295 Montpellier cedex 5, France
| | - J Roessler
- Unité d'oncologie pédiatrique, CHU Arnaud-de-Villeneuve, avenue du Doyen-Gaston-Giraud, 34295 Montpellier cedex 5, France
| | - N Sirvent
- Unité d'oncologie pédiatrique, CHU Arnaud-de-Villeneuve, avenue du Doyen-Gaston-Giraud, 34295 Montpellier cedex 5, France
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19
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Central nervous system acute lymphoblastic leukemia: role of natural killer cells. Blood 2015; 125:3420-31. [PMID: 25896649 DOI: 10.1182/blood-2014-08-595108] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 03/17/2015] [Indexed: 02/06/2023] Open
Abstract
Central nervous system acute lymphoblastic leukemia (CNS-ALL) is a major clinical problem. Prophylactic therapy is neurotoxic, and a third of the relapses involve the CNS. Increased expression of interleukin 15 (IL-15) in leukemic blasts is associated with increased risk for CNS-ALL. Using in vivo models for CNS leukemia caused by mouse T-ALL and human xenografts of ALL cells, we demonstrate that expression of IL-15 in leukemic cells is associated with the activation of natural killer (NK) cells. This activation limits the outgrowth of leukemic cells in the periphery, but less in the CNS because NK cells are excluded from the CNS. Depletion of NK cells in NOD/SCID mice enabled combined systemic and CNS leukemia of human pre-B-ALL. The killing of human leukemia lymphoblasts by NK cells depended on the expression of the NKG2D receptor. Analysis of bone marrow (BM) diagnostic samples derived from children with subsequent CNS-ALL revealed a significantly high expression of the NKG2D and NKp44 receptors. We suggest that the CNS may be an immunologic sanctuary protected from NK-cell activity. CNS prophylactic therapy may thus be needed with emerging NK cell-based therapies against hematopoietic malignancies.
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20
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Wu K, Fukuda K, Xing F, Zhang Y, Sharma S, Liu Y, Chan MD, Zhou X, Qasem SA, Pochampally R, Mo YY, Watabe K. Roles of the cyclooxygenase 2 matrix metalloproteinase 1 pathway in brain metastasis of breast cancer. J Biol Chem 2015; 290:9842-54. [PMID: 25691572 DOI: 10.1074/jbc.m114.602185] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Indexed: 01/19/2023] Open
Abstract
Brain is one of the major sites of metastasis in breast cancer; however, the pathological mechanism of brain metastasis is poorly understood. One of the critical rate-limiting steps of brain metastasis is the breaching of blood-brain barrier, which acts as a selective interface between the circulation and the central nervous system, and this process is considered to involve tumor-secreted proteinases. We analyzed clinical significance of 21 matrix metalloproteinases on brain metastasis-free survival of breast cancer followed by verification in brain metastatic cell lines and found that only matrix metalloproteinase 1 (MMP1) is significantly correlated with brain metastasis. We have shown that MMP1 is highly expressed in brain metastatic cells and is capable of degrading Claudin and Occludin but not Zo-1, which are key components of blood-brain barrier. Knockdown of MMP1 in brain metastatic cells significantly suppressed their ability of brain metastasis in vivo, whereas ectopic expression of MMP1 significantly increased the brain metastatic ability of the cells that are not brain metastatic. We also found that COX2 was highly up-regulated in brain metastatic cells and that COX2-induced prostaglandins were directly able to promote the expression of MMP1 followed by augmenting brain metastasis. Furthermore, we found that COX2 and prostaglandin were able to activate astrocytes to release chemokine (C-C motif) ligand 7 (CCL7), which in turn promoted self-renewal of tumor-initiating cells in the brain and that knockdown of COX2 significantly reduced the brain metastatic ability of tumor cells. Our results suggest the COX2-MMP1/CCL7 axis as a novel therapeutic target for brain metastasis.
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Affiliation(s)
- Kerui Wu
- From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157
| | - Koji Fukuda
- Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan
| | - Fei Xing
- From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157
| | - Yingyu Zhang
- Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, and
| | - Sambad Sharma
- From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157
| | - Yin Liu
- From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157
| | - Michael D Chan
- From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157
| | - Xiaobo Zhou
- From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157
| | - Shadi A Qasem
- From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157
| | - Radhika Pochampally
- Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, and
| | - Yin-Yuan Mo
- Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, and
| | - Kounosuke Watabe
- From the Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157,
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21
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Headache types, related morbidity, and quality of life in survivors of childhood acute lymphoblastic leukemia: a prospective cross sectional study. Eur J Paediatr Neurol 2014; 18:722-9. [PMID: 25030329 PMCID: PMC4253065 DOI: 10.1016/j.ejpn.2014.06.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Revised: 06/10/2014] [Accepted: 06/28/2014] [Indexed: 11/23/2022]
Abstract
BACKGROUND Increased headache prevalence was recently reported in survivors of childhood ALL. Headache sub types, related morbidity, and effect on quality of life has not been reported thus far. OBJECTIVE To study headache prevalence and type, related disability, and quality of life in a cohort of childhood acute lymphoblastic leukemia (ALL) survivors. METHODS Childhood ALL survivors in at least 1-year of remission and 5 years from diagnosis completed questionnaires and were evaluated by a neurologist. Disability was evaluated with Pediatric Migraine Disability Assessment scale and the Short Form-36 Health Survey assessed quality of life. RESULTS Thirty nine of 72 (54%) females and 37 of 90 (41%) males reported headaches. Median time from ALL diagnosis to first headache was 5.2 years and median age at headache onset was 10.1 years in 76 participants with headache. Migraine headaches were diagnosed in 51 (31%) and episodic tension-type headaches in 49 (30%); migraine and tension-type headaches co-existed in 24 (15%) and 18 (11%) participants had chronic daily headaches. Fatigue was associated with migraine headache while hypertension and female gender associated with tension type headache. Headache-related disability was mild in 22 (29%), moderate in 7 (9%), and severe in 5 (7%) survivors, and was absent in the remaining 42 (55%) survivors with headache. Both migraine and tension type headaches associated with reduced mental component scores, while headache related disability associated with a reduced physical component scores. CONCLUSIONS Headaches are common in ALL survivors but only a minority has significant disability or impairment of quality of life.
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22
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Tang YT, Jiang F, Guo L, Si MY, Jiao XY. Expression and significance of vascular endothelial growth factor A and C in leukemia central nervous system metastasis. Leuk Res 2013; 37:359-66. [PMID: 23137522 DOI: 10.1016/j.leukres.2012.10.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Revised: 10/03/2012] [Accepted: 10/12/2012] [Indexed: 02/05/2023]
Abstract
Metastasis to the central nervous system (CNS) is an obstacle for leukemia treatment, the mechanisms of which remain to be elucidated. VEGF-A and VEGF-C are suspected to participate in this process. Paired of cerebrospinal fluid (CSF) and serum samples were collected from leukemia and control cases. Levels of VEGF-A and VEGF-C in both CSF (VEGF-ACSF, VEGF-CCSF) and serum (VEGF-ASerum, VEGF-CSerum) were detected by ELISA. Our data show that higher levels of VEGF-ACSF are closely related to CNS leukemia (CNSL), and VEGF-ACSF may be a better predictor than the other risk factors elucidating the pathogenesis and development of CNSL.
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Affiliation(s)
- Yue-Ting Tang
- Department of Hematology Laboratory, First Affiliated Hospital of Shantou University Medical College, Guangdong, China
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23
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Gervasini G, Vagace JM. Impact of genetic polymorphisms on chemotherapy toxicity in childhood acute lymphoblastic leukemia. Front Genet 2012; 3:249. [PMID: 23189085 PMCID: PMC3504364 DOI: 10.3389/fgene.2012.00249] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Accepted: 10/26/2012] [Indexed: 11/19/2022] Open
Abstract
The efficacy of chemotherapy in pediatric acute lymphoblastic leukemia (ALL) patients has significantly increased in the last 20 years; as a result, the focus of research is slowly shifting from trying to increase survival rates to reduce chemotherapy-related toxicity. At the present time, the cornerstone of therapy for ALL is still formed by a reduced number of drugs with a highly toxic profile. In recent years, a number of genetic polymorphisms have been identified that can play a significant role in modifying the pharmacokinetics and pharmacodynamics of these drugs. The best example is that of the TPMT gene, whose genotyping is being incorporated to clinical practice in order to individualize doses of mercaptopurine. However, there are additional genes that are relevant for the metabolism, activity, and/or transport of other chemotherapy drugs that are widely use in ALL, such as methotrexate, cyclophosphamide, vincristine, L-asparaginase, etoposide, cytarabine, or cytotoxic antibiotics. These genes can also be affected by genetic alterations that could therefore have clinical consequences. In this review we will discuss recent data on this field, with special focus on those polymorphisms that could be used in clinical practice to tailor chemotherapy for ALL in order to reduce the occurrence of serious adverse effects.
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Affiliation(s)
- Guillermo Gervasini
- Department of Medical and Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura Badajoz, Spain
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24
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Supuran CT. Inhibition of carbonic anhydrase IX as a novel anticancer mechanism. World J Clin Oncol 2012; 3:98-103. [PMID: 22787577 PMCID: PMC3394083 DOI: 10.5306/wjco.v3.i7.98] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2011] [Revised: 09/17/2011] [Accepted: 06/30/2012] [Indexed: 02/06/2023] Open
Abstract
Carbonic anhydrases (CA, EC 4.2.1.1) catalyze the interconversion bewteen carbon dioxide and bicarbonate with generation of protons. The carbonic anhydrase isozyme IX (CA IX) is highly overexpresed in hypoxic tumors and shows very restricted expression in normal tissues. CA IX is a dimeric protein possessing very high catalytic activity for the hydration of carbon dioxide to protons and bicarbonate. Its quaternary structure is unique among members of this family of enzymes, allowing for structure-based drug design campaigns of selective inhibitors. Inhibition of CA IX with sulfonamide and/or coumarin inhibitors was recently shown to lead to a potent retardation for the growth of both primary tumors and metastases. Some fluorescent sulfonamides were shown to accumulate only in hypoxic tumor cells overexpressing CA IX, and might be used as diagnostic tools for imaging of hypoxic cancers. Sulfonamide inhibitors were also more effective in inhibiting the growth of the primary tumors when associated with irrdiation. CA IX is thus both a diagnostic and therapeutic validated target for the management of hypoxic tumors normally non-responsive to classical chemio- and radiotherapy.
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Affiliation(s)
- Claudiu T Supuran
- Laboratorio di Chimica Bioinorganica, University of Florence, Polo Scientifico, Room 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
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25
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Jakola AS, Gulati S. An adolescent with suspected intracranial hypertension - ALL is not what it seems. Childs Nerv Syst 2012; 28:1103-8. [PMID: 22286200 DOI: 10.1007/s00381-012-1697-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2011] [Accepted: 01/10/2012] [Indexed: 11/27/2022]
Affiliation(s)
- Asgeir Store Jakola
- Department of Neurosurgery, St. Olavs University Hospital, 7006 Trondheim, Norway.
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26
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Vagace JM, de la Maya MD, Caceres-Marzal C, Gonzalez de Murillo S, Gervasini G. Central nervous system chemotoxicity during treatment of pediatric acute lymphoblastic leukemia/lymphoma. Crit Rev Oncol Hematol 2012; 84:274-86. [PMID: 22578745 DOI: 10.1016/j.critrevonc.2012.04.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Revised: 04/02/2012] [Accepted: 04/13/2012] [Indexed: 02/02/2023] Open
Abstract
In the last decades, increasing success rates are being obtained in the chemotherapy of pediatric leukemia and lymphoma. However, the cornerstone of this treatment is still formed by a reduced number of drugs with a highly toxic profile. In particular, central nervous system complications remain a challenging clinical problem, requiring rapid detection and prompt treatment to limit permanent damage. Furthermore, clinicians are often challenged to discriminate between CNS involvement by the disease, toxicity of drugs or infections. This clinically oriented review will help recognize and handle the main neurologic adverse effects induced by chemotherapy in pediatric patients with lymphoblastic leukemia/lymphoma. Different clinical entities and putative drugs involved are discussed in each chapter, with clinical cases illustrating the most relevant and challenging events. In addition, specific clinical-radiological patterns of some of these neurologic events are detailed. Finally, the role of pharmacogenetics, with special focus on those polymorphisms that could help explain the occurrence of neurotoxicity, is also discussed.
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Affiliation(s)
- Jose Manuel Vagace
- Service of Pediatric Hematology, Materno Infantil Hospital, Badajoz, Spain.
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Vázquez E, Delgado I, Sánchez-Montañez A, Barber I, Sánchez-Toledo J, Enríquez G. Side effects of oncologic therapies in the pediatric central nervous system: update on neuroimaging findings. Radiographics 2012; 31:1123-39. [PMID: 21768243 DOI: 10.1148/rg.314105180] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The need for early, accurate diagnosis of central nervous system (CNS) complications occurring during and after pediatric cancer treatment is growing because of the improvement in overall survival rates related to innovative and aggressive oncologic therapies. An elevated degree of suspicion is needed to recognize the radiologic features of these CNS complications. Radiologists need familiarity with the early and late side effects of cancer therapy in the pediatric CNS (eg, toxic effects, infection, endocrine or sensory dysfunction, neuropsychologic impairment, second malignancies), in order to accelerate the imaging diagnosis and minimize as much as possible the associated morbidity. Acquisition of knowledge about these complications will enable the development of more appropriate therapeutic trials and more effective patient surveillance and will lead to an improved quality of life by decreasing the long-term sequelae in survivors.
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Affiliation(s)
- Elida Vázquez
- Department of Pediatric Radiology and Pediatric Oncohematology, Universidad Autónoma de Barcelona, Barcelona, Spain.
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28
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Derwich K, Wachowiak J, Zając-Spychała O, Balcerska A, Balwierz W, Chybicka A, Kowalczyk JR, Matysiak M, Jackowska T, Sońta-Jakimczyk D, Szczepański T, Wysocki M. Long-term results in children with standard risk acute lymphoblastic leukaemia treated with 5.0 g/m2 versus 3.0 g/m2 methotrexate i.v. according to the modified ALL-BFM 90 protocol. The report of Polish paediatric Leukemia/lymphoma study group. MEMO-MAGAZINE OF EUROPEAN MEDICAL ONCOLOGY 2011. [DOI: 10.1007/s12254-011-0279-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Feng S, Cen J, Huang Y, Shen H, Yao L, Wang Y, Chen Z. Matrix metalloproteinase-2 and -9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins. PLoS One 2011; 6:e20599. [PMID: 21857898 PMCID: PMC3157343 DOI: 10.1371/journal.pone.0020599] [Citation(s) in RCA: 159] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Accepted: 05/05/2011] [Indexed: 12/31/2022] Open
Abstract
Central nervous system (CNS) involvement remains an important cause of morbidity and mortality in acute leukemia, the mechanisms of leukemic cell infiltration into the CNS have not yet been elucidated. The blood-brain barrier (BBB) makes CNS become a refugee to leukemic cells and serves as a resource of cells that seed extraneural sites. How can the leukemic cells disrupt this barrier and invasive the CNS, even if many of the currently available chemotherapies can not cross the BBB? Tight junction in endothelial cells occupies a central role in the function of the BBB. Except the well known role of degrading extracellular matrix in metastasis of cancer cells, here we show matrix metalloproteinase (MMP)-2 and -9, secreted by leukemic cells, mediate the BBB opening by disrupting tight junction proteins in the CNS leukemia. We demonstrated that leukemic cells impaired tight junction proteins ZO-1, claudin-5 and occludin resulting in increased permeability of the BBB. However, these alterations reduced when MMP-2 and -9 activities were inhibited by RNA interference strategy or by MMP inhibitor GM6001 in an in vitro BBB model. We also found that the disruption of the BBB in company with the down-regulation of ZO-1, claudin-5 and occludin and the up-regulation of MMP-2 and -9 in mouse brain tissues with leukemic cell infiltration by confocal imaging and the assay of in situ gelatin zymography. Besides, GM6001 protected all mice against CNS leukemia. Our findings suggest that the degradation of tight junction proteins ZO-1, claudin-5 and occludin by MMP-2 and -9 secreted by leukemic cells constitutes an important mechanism in the BBB breakdown which contributes to the invasion of leukemic cells to the CNS in acute leukemia.
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Affiliation(s)
- Saran Feng
- Leukemia Research Unit, Jiangsu Institute of Hematology, 1st Affiliated Hospital, Soochow University, Key Laboratory of Thrombosis and Hemostasis Ministry of Health, Suzhou, China
- Department of Hematology, Xuzhou Central Hospital, Xuzhou, China
| | - Jiannong Cen
- Leukemia Research Unit, Jiangsu Institute of Hematology, 1st Affiliated Hospital, Soochow University, Key Laboratory of Thrombosis and Hemostasis Ministry of Health, Suzhou, China
| | - Yihong Huang
- Department of Hematology, Affiliated Hospital, Xuzhou Medical College, Xuzhou, China
| | - Hongjie Shen
- Leukemia Research Unit, Jiangsu Institute of Hematology, 1st Affiliated Hospital, Soochow University, Key Laboratory of Thrombosis and Hemostasis Ministry of Health, Suzhou, China
| | - Li Yao
- Leukemia Research Unit, Jiangsu Institute of Hematology, 1st Affiliated Hospital, Soochow University, Key Laboratory of Thrombosis and Hemostasis Ministry of Health, Suzhou, China
| | - Yuanyuan Wang
- Leukemia Research Unit, Jiangsu Institute of Hematology, 1st Affiliated Hospital, Soochow University, Key Laboratory of Thrombosis and Hemostasis Ministry of Health, Suzhou, China
| | - Zixing Chen
- Leukemia Research Unit, Jiangsu Institute of Hematology, 1st Affiliated Hospital, Soochow University, Key Laboratory of Thrombosis and Hemostasis Ministry of Health, Suzhou, China
- * E-mail:
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30
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Does VEGF secreted by leukemic cells increase the permeability of blood–brain barrier by disrupting tight-junction proteins in central nervous system leukemia? Med Hypotheses 2011; 76:618-21. [DOI: 10.1016/j.mehy.2010.12.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2010] [Revised: 12/01/2010] [Accepted: 12/03/2010] [Indexed: 01/03/2023]
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31
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Ness KK, Armenian SH, Kadan-Lottick N, Gurney JG. Adverse effects of treatment in childhood acute lymphoblastic leukemia: general overview and implications for long-term cardiac health. Expert Rev Hematol 2011; 4:185-97. [PMID: 21495928 PMCID: PMC3125981 DOI: 10.1586/ehm.11.8] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Survival of childhood acute lymphoblastic leukemia (ALL) is one of the greatest medical success stories of the last four decades. Unfortunately, childhood ALL survivors experience medical late effects that increase their risk of morbidity and premature death, often due to heart and vascular disease. Research has helped elucidate the mechanisms and trajectory of direct damage to the heart from treatment exposure, particularly to anthracyclines, and has also contributed knowledge on the influences of related chronic conditions, such as obesity and insulin resistance on heart health in these survivors. This article summarizes the key issues associated with early morbidity and mortality from cardiac-related disease in childhood ALL survivors and suggests directions for interventions to improve long-term outcomes.
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Affiliation(s)
- Kirsten K Ness
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Mail Stop 735, 262 Danny Thomas Place, Memphis, TN 38105, USA
| | - Saro H Armenian
- Outcomes Research, Population Sciences, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010-3000, USA
| | - Nina Kadan-Lottick
- Section of Pediatric Hematology–Oncology, Yale University School of Medicine, 333 Cedar Street, LMP-2073, New Haven, CT 06520-8064, USA
| | - James G Gurney
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Mail Stop 735, 262 Danny Thomas Place, Memphis, TN 38105, USA
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32
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Jeha S, Pui CH. Risk-adapted treatment of pediatric acute lymphoblastic leukemia. Hematol Oncol Clin North Am 2010; 23:973-90, v. [PMID: 19825448 DOI: 10.1016/j.hoc.2009.07.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Optimal use of antileukemic agents and stringent application of risk-directed therapy in clinical trials have resulted in steady improvement in the outcome of children with acute lymphoblastic leukemia, with current cure rates exceeding 80% in developed countries. The intensity of treatment varies substantially among subsets of patients, as therapy is designed to reduce acute and long-term toxicity in low-risk groups while improving outcomes in poor risk groups by treatment intensification. Recent advances in genome-wide screening techniques, pharmacogenomic studies, and development of molecular therapeutics are ushering in an era of more refined personalized therapy.
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Affiliation(s)
- Sima Jeha
- Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
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33
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Marwaha RK, Kulkarni KP, Bansal D, Trehan A. Central nervous system involvement at presentation in childhood acute lymphoblastic leukemia: management experience and lessons. Leuk Lymphoma 2009; 51:261-8. [DOI: 10.3109/10428190903470323] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Kadan-Lottick NS, Brouwers P, Breiger D, Kaleita T, Dziura J, Northrup V, Chen L, Nicoletti M, Bostrom B, Stork L, Neglia JP. Comparison of neurocognitive functioning in children previously randomly assigned to intrathecal methotrexate compared with triple intrathecal therapy for the treatment of childhood acute lymphoblastic leukemia. J Clin Oncol 2009; 27:5986-92. [PMID: 19884541 PMCID: PMC2793042 DOI: 10.1200/jco.2009.23.5408] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2009] [Accepted: 07/08/2009] [Indexed: 11/20/2022] Open
Abstract
PURPOSE For the majority of children with acute lymphoblastic leukemia (ALL), CNS prophylaxis consists of either intrathecal (IT) methotrexate or triple IT therapy (ie, methotrexate with both cytarabine and hydrocortisone). The long-term neurotoxicities of these two IT strategies have not yet been directly compared. PATIENTS AND METHODS In this multisite study, 171 children with standard-risk ALL, age 1 to 9.99 years at diagnosis, previously randomly assigned to IT methotrexate (n = 82) or to triple IT therapy (n = 89) on CCG 1952, underwent neurocognitive evaluation by a licensed psychologist at a mean of 5.9 years after random assignment. RESULTS Patients who received IT methotrexate had a mean Processing Speed Index that was 3.6 points lower, about one fourth of a standard deviation, than those who received triple IT therapy (P = .04) after analysis was adjusted for age, sex, and time since diagnosis. Likewise, 19.5% of children in the IT methotrexate group had a Processing Speed Index score in the below-average range compared with 6.9% in the triple IT therapy group (P = .02). Otherwise, the groups performed similarly on tests of full-scale intelligence quotient, academic achievement, attention/concentration, memory, and visual motor integration. The association of treatment with measures of cognitive functioning was not modified by sex or age at diagnosis. In the post-therapy period, there were no group differences in special education services, neurologic events, or use of psychotropic medications. CONCLUSION This study did not show any clinically meaningful differences in neurocognitive functioning between patients previously randomly assigned to IT methotrexate or triple IT therapy except for a small difference in processing speed in the IT methotrexate group.
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Affiliation(s)
- Nina S Kadan-Lottick
- Section of Pediatric Hematology-Oncology, Yale University School of Medicine, New Haven, CT, USA.
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35
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Ribeiro R, Pui CH. Treatment of acute lymphoblastic leukemia in low- and middle-income countries: Challenges and opportunities. Leuk Lymphoma 2009; 49:373-6. [DOI: 10.1080/10428190701882179] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Pui CH, Howard SC. Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Lancet Oncol 2008; 9:257-68. [DOI: 10.1016/s1470-2045(08)70070-6] [Citation(s) in RCA: 264] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Abstract
AbstractSurvival of children with acute lymphoblastic leukemia (ALL) is often described as the success story for oncology. The improvements in the treatment of ALL represent the work of cooperative groups at their best. Fifty years ago a pediatric oncologist would have never considered using the term “cure” in a discussion with a family whose child was diagnosed with ALL. Today the term is not only used in the initial discussion but referred to frequently thereafter. However, as we all know, cure is not assured and is not obtained without sequelae. This review will focus on the improvements in treatment for newly diagnosed ALL in children and adolescents according to risk group and some of the challenges that remain despite the improved outcome.
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