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Luo ZY, Fan LQ, Guo WL, Yang JP, Li ZY, Huang YX, Jiang H, Zhang XH. Effect of tandem autologous stem cell transplantation on survival in pediatric patients with high-risk solid tumors in South China. World J Stem Cells 2025; 17:100621. [DOI: 10.4252/wjsc.v17.i2.100621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 12/06/2024] [Accepted: 02/12/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Despite advances in treatment, the prognosis for patients with high-risk pediatric solid tumors remains dismal. Tandem autologous stem cell transplantation (ASCT) offers promise for improving outcomes in these patients. This study aimed to examine the efficacy and prognostic factors of tandem ASCT in pediatric patients with high-risk solid tumors.
AIM To determine the survival outcomes and prognostic factors in pediatric patients with high-risk solid tumors undergoing tandem ASCT.
METHODS A total of 40 pediatric patients with high-risk solid tumors treated from March 2015 to August 2022 were included in this retrospective study. The diagnoses of the patients included neuroblastoma, germ cell tumors, atypical teratoid/rhabdoid tumor, medulloblastoma, and pineoblastoma. After induction chemotherapy, all patients received tandem ASCT and were allocated into two groups (group A and group B) based on high-dose chemotherapy regimens. Prognostic relevance was evaluated by examining patient characteristics, such as sex, age, lactate dehydrogenase levels, primary site, the number of metastatic sites, and bone marrow involvement.
RESULTS The median follow-up duration since the first ASCT was 24 months (range: 1-91 months), with 5-year overall survival (OS) and event-free survival (EFS) rates of 73% and 70%, respectively, for the entire cohort. The 3-year OS rates were 67% for group A and 87% for group B (P = 0.29), with corresponding 3-year EFS rates of 67% and 79% (P = 0.57). Among neuroblastoma patients, the 5-year OS and EFS were 69% and 63% (P = 0.23). Univariable analysis revealed a notable association of age ≥ 36 months and elevated lactate dehydrogenase level at diagnosis with poorer OS. Despite acute adverse effects, all patients demonstrated good tolerance to the treatment, with no occurrences of transplant-related mortality.
CONCLUSION Tandem ASCT demonstrates promising survival outcomes for patients with high-risk solid tumors, particularly neuroblastoma, with manageable toxicity and no transplant-related mortality.
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Affiliation(s)
- Zi-Yan Luo
- Division of Hematology and Oncology, Department of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510000, Guangdong Province, China
| | - Li-Qun Fan
- Division of Hematology and Oncology, Department of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510000, Guangdong Province, China
| | - Wen-Ling Guo
- Division of Hematology and Oncology, Department of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510000, Guangdong Province, China
| | - Jian-Ping Yang
- Division of Hematology and Oncology, Department of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510000, Guangdong Province, China
| | - Zhuo-Yan Li
- Division of Hematology and Oncology, Department of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510000, Guangdong Province, China
| | - Yong-Xian Huang
- Division of Hematology and Oncology, Department of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510000, Guangdong Province, China
| | - Hua Jiang
- Division of Hematology and Oncology, Department of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510000, Guangdong Province, China
| | - Xiao-Hong Zhang
- Department of Pediatric Hematology Oncology, Guangdong Women and Children Hospital, Guangzhou 510000, Guangdong Province, China
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Vahdatiyekta P, Yrjänä V, Rosqvist E, Cetó X, Del Valle M, Huynh TP. Electrochemical Behavior of Glassy Carbon Electrodes Modified with Electropolymerized Film of N,N'-bis (2-thienylmethylene)-1,X-diaminobenzene toward Homovanillic Acid and 4-Hydroxyphenylacetic Acid. Bioelectrochemistry 2025; 165:108944. [PMID: 40020284 DOI: 10.1016/j.bioelechem.2025.108944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 02/07/2025] [Accepted: 02/16/2025] [Indexed: 03/03/2025]
Abstract
This study evaluates different electrochemical behaviors of modified glassy carbon electrodes (GCEs) for detecting urinary biomarkers related to breast cancer, namely homovanillic acid (HVA) and 4-hydroxyphenylacetic acid (4HPA). The analysis was performed in the presence of common urinary interferents, creatinine and urea. Modification of bare GCEs was done through the electropolymerization of N,N'-bis (2-thienylmethylene)-1,X-diaminobenzene (X = 2, 3, 4) isomers, so-called BTMD. The formation and characteristics of these polymeric layers were investigated using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), atomic force microscopy (AFM), and scanning electron microscopy (SEM). Differential pulse voltammetry (DPV) was used to measure responses of the electrodes to HVA and 4HPA, assessing their sensitivity and selectivity. Results showed that the developed electrodes effectively detected both biomarkers, with peak currents increasing proportionally to biomarker concentrations and minimal interference from creatinine and urea. The modified electrodes exhibited better linearity at higher concentrations; however, saturation was observed for 4HPA at high concentrations with the p-BTMD/GCE. Each electrode displayed unique peak current, potential, and response profiles, highlighting their promise for cross-reactive sensing systems, such as electronic tongues, to analyze complex matrices such as urine.
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Affiliation(s)
- Parastoo Vahdatiyekta
- Laboratory of Molecular Science and Engineering, Åbo Akademi University, 20500 Turku, Finland
| | - Ville Yrjänä
- Laboratory of Molecular Science and Engineering, Åbo Akademi University, 20500 Turku, Finland
| | - Emil Rosqvist
- Laboratory of Molecular Science and Engineering, Åbo Akademi University, 20500 Turku, Finland
| | - Xavier Cetó
- Sensors and Biosensors Group, Department of Chemistry, Universitat Autònoma de Barcelona, Edifici Cn, 08193 Bellaterra, Spain
| | - Manel Del Valle
- Sensors and Biosensors Group, Department of Chemistry, Universitat Autònoma de Barcelona, Edifici Cn, 08193 Bellaterra, Spain
| | - Tan-Phat Huynh
- Laboratory of Molecular Science and Engineering, Åbo Akademi University, 20500 Turku, Finland.
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King E, Struck R, Piskareva O. The triad in current neuroblastoma challenges: Targeting antigens, enhancing effective cytotoxicity and accurate 3D in vitro modelling. Transl Oncol 2025; 51:102176. [PMID: 39489087 PMCID: PMC11565549 DOI: 10.1016/j.tranon.2024.102176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/05/2024] [Accepted: 10/29/2024] [Indexed: 11/05/2024] Open
Abstract
Neuroblastoma is an embryonic tumour originating from neural crest cells and accounts for nearly 15 % of all childhood cancer deaths. Despite the implementation of intense multimodal therapy for neuroblastoma, half of the high-risk cohort will relapse with metastatic foci resistant to conventional therapies. There is an urgent need for novel precision medicine approaches to improve patient survival and ensure healthy post-treatment lives for these children. Immunotherapy holds promise for such therapeutics; however, developing effective options has been disappointing despite decades of research. The immunosuppressive tumour-immune microenvironment presents a significant challenge amplified with low mutational burden in neuroblastoma, even with the new discovered tumour antigens. Innovative, practical, and comprehensive approaches are crucial for designing and testing immunotherapies capable of passing clinical trials. Replacing animal models with physiologically relevant in vitro systems will expedite this process and provide new insights into exploitable tumour-immune cell interactions. This review examines this three-pronged approach in neuroblastoma immunotherapy: tumour antigen discovery, immunomodulation, and 3D in vitro tumour models, and discusses current and emerging insights into these strategies to address neuroblastoma immunotherapy challenges.
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Affiliation(s)
- Ellen King
- Cancer Bioengineering Group & Tissue Engineering Research Group (TERG), Department of Anatomy and Regenerative Medicine, RCSI University of Medicine and Health Sciences, Dublin, Ireland; School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Ronja Struck
- Cancer Bioengineering Group & Tissue Engineering Research Group (TERG), Department of Anatomy and Regenerative Medicine, RCSI University of Medicine and Health Sciences, Dublin, Ireland; School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Olga Piskareva
- Cancer Bioengineering Group & Tissue Engineering Research Group (TERG), Department of Anatomy and Regenerative Medicine, RCSI University of Medicine and Health Sciences, Dublin, Ireland; School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland; Advanced Materials and Bioengineering Research Centre (AMBER), RCSI University of Medicine and Health Sciences and Trinity College Dublin, Dublin, Ireland.
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4
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Meng Y, Wang S, Lv X, Huang X, Zhang W, Wu X, Schipper D, Yang X. Rapid and sensitive detection of vanillylmandelic acid based on a luminescent fourteen-metal Tb(III) planar nanocluster. Chem Commun (Camb) 2024; 60:14240-14243. [PMID: 39535599 DOI: 10.1039/d4cc03667k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
A 14-metal Tb(III) nanocluster with four CO32- anions as templates was constructed for the quantitative and qualitative detection of vanillylmandelic acid (VMA) with high sensitivity and selectivity. The luminescence response time to VMA is less than ten seconds, and the limit of detection is as low as 0.32 nM in CH3CN.
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Affiliation(s)
- Yanheng Meng
- College of Chemistry and Materials Engineering, College of life and environmental science, Wenzhou University, Key Lab of Biohealth Materials and Chemistry of Wenzhou, Wenzhou 325035, China.
| | - Shiqing Wang
- College of Chemistry and Materials Engineering, College of life and environmental science, Wenzhou University, Key Lab of Biohealth Materials and Chemistry of Wenzhou, Wenzhou 325035, China.
| | - Xiaoli Lv
- College of Chemistry and Materials Engineering, College of life and environmental science, Wenzhou University, Key Lab of Biohealth Materials and Chemistry of Wenzhou, Wenzhou 325035, China.
| | - Xianfeng Huang
- College of Chemistry and Materials Engineering, College of life and environmental science, Wenzhou University, Key Lab of Biohealth Materials and Chemistry of Wenzhou, Wenzhou 325035, China.
| | - Weibin Zhang
- College of Chemistry and Materials Engineering, College of life and environmental science, Wenzhou University, Key Lab of Biohealth Materials and Chemistry of Wenzhou, Wenzhou 325035, China.
| | - Xiaojun Wu
- Department of Neurosurgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Desmond Schipper
- The University of Texas at Austin, Department of Chemistry and Biochemistry, 1 University Station A5300, Austin, Texas, 78712, USA
| | - Xiaoping Yang
- College of Chemistry and Materials Engineering, College of life and environmental science, Wenzhou University, Key Lab of Biohealth Materials and Chemistry of Wenzhou, Wenzhou 325035, China.
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Y KN, Arjunan A, Maigandan D, Dharmarajan A, Perumalsamy LR. Advances and challenges in therapeutic resistant biomarkers of neuroblastoma: A comprehensive review. Biochim Biophys Acta Rev Cancer 2024; 1879:189222. [PMID: 39577750 DOI: 10.1016/j.bbcan.2024.189222] [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: 06/06/2024] [Revised: 11/11/2024] [Accepted: 11/14/2024] [Indexed: 11/24/2024]
Abstract
Therapeutic resistance is one of the significant challenges in Neuroblastoma. Owing to its molecular diversity, the therapeutic resistance mechanisms of Neuroblastoma are highly complicated. The traditional chemo and radio therapeutics fail to provide adequate solutions to the treatment resistance, demanding in-depth research to improvise the existing prognostic and therapeutic regimens. To address this knowledge gap, several investigations are being employed, such as unravelling the molecular signalling mechanisms involved in drug resistance at genomics and proteomics levels, development of biomarkers for assessing the therapeutic success, development of novel drug targets for cancer stem cells, targeted immunotherapy and combination therapies. This review collates the ongoing research efforts to address the challenges faced in Neuroblastoma treatment resistance and uncovers the importance of transitioning biomarker discoveries into clinical practice.
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Affiliation(s)
- Krithicaa Narayanaa Y
- Department of Biomedical Sciences, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, India.
| | - Amrutha Arjunan
- Department of Biomedical Sciences, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, India.
| | - Devi Maigandan
- Department of Biomedical Sciences, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, India.
| | - Arun Dharmarajan
- Sri Ramachandra Faculty of Clinical Research, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, India; Curtin Health Innovation Research Institute, Curtin University, Bentley, 6102 Perth, Western Australia, Australia; Curtin Medical School, Curtin University, Perth, Western Australia, Australia; School of Human Sciences, The University of Western Australia, Nedlands, Western Australia, Australia.
| | - Lakshmi R Perumalsamy
- Department of Biomedical Sciences, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, India.
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Vercouillie N, Ren Z, Terras E, Lammens T. Long Non-Coding RNAs in Neuroblastoma: Pathogenesis, Biomarkers and Therapeutic Targets. Int J Mol Sci 2024; 25:5690. [PMID: 38891878 PMCID: PMC11171840 DOI: 10.3390/ijms25115690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 05/18/2024] [Accepted: 05/21/2024] [Indexed: 06/21/2024] Open
Abstract
Neuroblastoma is the most common malignant extracranial solid tumor of childhood. Recent studies involving the application of advanced high-throughput "omics" techniques have revealed numerous genomic alterations, including aberrant coding-gene transcript levels and dysfunctional pathways, that drive the onset, growth, progression, and treatment resistance of neuroblastoma. Research conducted in the past decade has shown that long non-coding RNAs, once thought to be transcriptomic noise, play key roles in cancer development. With the recent and continuing increase in the amount of evidence for the underlying roles of long non-coding RNAs in neuroblastoma, the potential clinical implications of these RNAs cannot be ignored. In this review, we discuss their biological mechanisms of action in the context of the central driving mechanisms of neuroblastoma, focusing on potential contributions to the diagnosis, prognosis, and treatment of this disease. We also aim to provide a clear, integrated picture of future research opportunities.
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Affiliation(s)
- Niels Vercouillie
- Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium; (N.V.); (Z.R.); (E.T.)
| | - Zhiyao Ren
- Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium; (N.V.); (Z.R.); (E.T.)
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium
- Cancer Research Institute Ghent, 9000 Ghent, Belgium
| | - Eva Terras
- Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium; (N.V.); (Z.R.); (E.T.)
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium
- Cancer Research Institute Ghent, 9000 Ghent, Belgium
| | - Tim Lammens
- Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium; (N.V.); (Z.R.); (E.T.)
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium
- Cancer Research Institute Ghent, 9000 Ghent, Belgium
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Nakatani N, Win KHN, Mon CY, Fujikawa T, Uemura S, Saito A, Ishida T, Mori T, Hasegawa D, Kosaka Y, Inoue S, Nishimura A, Nino N, Tamura A, Yamamoto N, Nozu K, Nishimura N. Distinct Expression Profiles of Neuroblastoma-Associated mRNAs in Peripheral Blood and Bone Marrow of Non-High-Risk and High-Risk Neuroblastoma Patients. BIOLOGY 2024; 13:345. [PMID: 38785826 PMCID: PMC11117621 DOI: 10.3390/biology13050345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 05/03/2024] [Accepted: 05/11/2024] [Indexed: 05/25/2024]
Abstract
Non-high-risk (non-HR) neuroblastoma (NB) patients have excellent outcomes, with more than a 90% survival rate, whereas HR NB patients expect less than a 50% survival rate. Metastatic disease is the principal cause of death among both non-HR and HR NB patients. Previous studies have reported the significant but limited prognostic value of quantitative PCR (qPCR)-based assays, measuring overlapping but different sets of neuroblastoma-associated mRNAs (NB-mRNAs), to detect metastatic disease in both non-HR and HR patient samples. A droplet digital PCR (ddPCR)-based assay measuring seven NB-mRNAs (CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNAs) was recently developed and exhibited a better prognostic value for HR patient samples than qPCR-based assays. However, it remained to be tested on non-HR patient samples. In the present study, we employed the ddPCR-based assay to study peripheral blood (PB) and bone marrow (BM) samples collected at diagnosis from eight non-HR and eleven HR cases and characterized the expression profiles of NB-mRNAs. The most highly expressed NB-mRNAs in PB and BM differed between non-HR and HR cases, with the CRMP1 mRNA being predominant in non-HR cases and the GAP43 mRNA in HR cases. The levels of NB-mRNAs in PB and BM were 5 to 1000 times lower in non-HR cases than in HR cases. The PB to BM ratio of NB-mRNAs was 10 to 100 times higher in non-HR cases compared to HR cases. The present case series suggests that non-HR and HR NB patients have the distinct expression profiles of NB-mRNAs in their PB and BM.
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Affiliation(s)
- Naoko Nakatani
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (N.N.); (T.F.); (S.I.); (A.N.); (A.T.); (N.Y.); (K.N.)
| | - Kaung Htet Nay Win
- Department of Public Health, Kobe University Graduate School of Health Science, Kobe 654-0142, Japan; (K.H.N.W.); (C.Y.M.)
| | - Cho Yee Mon
- Department of Public Health, Kobe University Graduate School of Health Science, Kobe 654-0142, Japan; (K.H.N.W.); (C.Y.M.)
| | - Tomoko Fujikawa
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (N.N.); (T.F.); (S.I.); (A.N.); (A.T.); (N.Y.); (K.N.)
| | - Suguru Uemura
- Department of Hematology/Oncology, Kobe Children’s Hospital, Kobe 650-0047, Japan; (S.U.); (A.S.); (T.I.); (T.M.); (D.H.); (Y.K.); (N.N.)
| | - Atsuro Saito
- Department of Hematology/Oncology, Kobe Children’s Hospital, Kobe 650-0047, Japan; (S.U.); (A.S.); (T.I.); (T.M.); (D.H.); (Y.K.); (N.N.)
| | - Toshiaki Ishida
- Department of Hematology/Oncology, Kobe Children’s Hospital, Kobe 650-0047, Japan; (S.U.); (A.S.); (T.I.); (T.M.); (D.H.); (Y.K.); (N.N.)
| | - Takeshi Mori
- Department of Hematology/Oncology, Kobe Children’s Hospital, Kobe 650-0047, Japan; (S.U.); (A.S.); (T.I.); (T.M.); (D.H.); (Y.K.); (N.N.)
| | - Daiichiro Hasegawa
- Department of Hematology/Oncology, Kobe Children’s Hospital, Kobe 650-0047, Japan; (S.U.); (A.S.); (T.I.); (T.M.); (D.H.); (Y.K.); (N.N.)
| | - Yoshiyuki Kosaka
- Department of Hematology/Oncology, Kobe Children’s Hospital, Kobe 650-0047, Japan; (S.U.); (A.S.); (T.I.); (T.M.); (D.H.); (Y.K.); (N.N.)
| | - Shotaro Inoue
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (N.N.); (T.F.); (S.I.); (A.N.); (A.T.); (N.Y.); (K.N.)
| | - Akihiro Nishimura
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (N.N.); (T.F.); (S.I.); (A.N.); (A.T.); (N.Y.); (K.N.)
| | - Nanako Nino
- Department of Hematology/Oncology, Kobe Children’s Hospital, Kobe 650-0047, Japan; (S.U.); (A.S.); (T.I.); (T.M.); (D.H.); (Y.K.); (N.N.)
| | - Akihiro Tamura
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (N.N.); (T.F.); (S.I.); (A.N.); (A.T.); (N.Y.); (K.N.)
| | - Nobuyuki Yamamoto
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (N.N.); (T.F.); (S.I.); (A.N.); (A.T.); (N.Y.); (K.N.)
| | - Kandai Nozu
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; (N.N.); (T.F.); (S.I.); (A.N.); (A.T.); (N.Y.); (K.N.)
| | - Noriyuki Nishimura
- Department of Public Health, Kobe University Graduate School of Health Science, Kobe 654-0142, Japan; (K.H.N.W.); (C.Y.M.)
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Horvat S, Kos J, Pišlar A. Multifunctional roles of γ-enolase in the central nervous system: more than a neuronal marker. Cell Biosci 2024; 14:61. [PMID: 38735971 PMCID: PMC11089681 DOI: 10.1186/s13578-024-01240-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 04/27/2024] [Indexed: 05/14/2024] Open
Abstract
Enolase, a multifunctional protein with diverse isoforms, has generally been recognized for its primary roles in glycolysis and gluconeogenesis. The shift in isoform expression from α-enolase to neuron-specific γ-enolase extends beyond its enzymatic role. Enolase is essential for neuronal survival, differentiation, and the maturation of neurons and glial cells in the central nervous system. Neuron-specific γ-enolase is a critical biomarker for neurodegenerative pathologies and neurological conditions, not only indicating disease but also participating in nerve cell formation and neuroprotection and exhibiting neurotrophic-like properties. These properties are precisely regulated by cysteine peptidase cathepsin X and scaffold protein γ1-syntrophin. Our findings suggest that γ-enolase, specifically its C-terminal part, may offer neuroprotective benefits against neurotoxicity seen in Alzheimer's and Parkinson's disease. Furthermore, although the therapeutic potential of γ-enolase seems promising, the effectiveness of enolase inhibitors is under debate. This paper reviews the research on the roles of γ-enolase in the central nervous system, especially in pathophysiological events and the regulation of neurodegenerative diseases.
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Affiliation(s)
- Selena Horvat
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia
| | - Janko Kos
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia
- Department of Biotechnology, Jožef Stefan Institute, Jamova Cesta 39, 1000, Ljubljana, Slovenia
| | - Anja Pišlar
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
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Feng L, Zhang S, Lu X, Yang X, Kan Y, Wang C, Zhang H, Wang W, Yang J. An Optimal Radiomics Nomogram Based on 18F-FDG PET/CT for Identifying Event-Free Survival in Pediatric Neuroblastoma. Acad Radiol 2023; 30:2309-2320. [PMID: 37393177 DOI: 10.1016/j.acra.2023.06.004] [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: 04/18/2023] [Revised: 05/13/2023] [Accepted: 06/02/2023] [Indexed: 07/03/2023]
Abstract
RATIONALE AND OBJECTIVES To investigate whether the 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) radiomics features that combine tumor and bone marrow can more accurately identify event-free survival (EFS) in pediatric neuroblastoma. MATERIALS AND METHODS A total of 126 patients with neuroblastoma were retrospectively included and randomly divided into the training and validation cohorts (7:3 ratio). Radiomics features were extracted to develop a tumor- and bone marrow-based radiomics risk score (RRS). The Kaplan-Meier method was used to evaluate the effectiveness of RRS in EFS risk stratification. Univariate and multivariate Cox regression analyses were used to determine independent clinical risk factors and construct the clinical models. The conventional PET model was constructed based on conventional PET parameters, and the noninvasive combined model integrated the RRS and the noninvasive independent clinical risk factors. The performance of the models was evaluated using C-index, calibration curves, and decision curve analysis (DCA). RESULTS A total of 15 radiomics features were selected to build the RRS. According to Kaplan-Meier analysis, there was a significant difference in EFS between the low-risk and high-risk groups as defined by the value of RRS (P < .05). The noninvasive combined model combining RRS and the International Neuroblastoma Risk Group stage achieved the best prognostic prediction of EFS, with a C-index of 0.810 and 0.783 in the training and validation cohorts, respectively. The calibration curves and DCA indicated that the noninvasive combined model had good consistency and clinical utility. CONCLUSION The 18F-FDG PET/CT-based radiomics of neuroblastoma allows a reliable evaluation of EFS. The performance of the noninvasive combined model was superior to the clinical and conventional PET models.
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Affiliation(s)
- Lijuan Feng
- Department of Nuclear Medicine, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, Beijing 100050, China (L.F., S.Z., X.L., X.Y., Y.K., W.W., J.Y.)
| | - Shuxin Zhang
- Department of Nuclear Medicine, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, Beijing 100050, China (L.F., S.Z., X.L., X.Y., Y.K., W.W., J.Y.)
| | - Xia Lu
- Department of Nuclear Medicine, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, Beijing 100050, China (L.F., S.Z., X.L., X.Y., Y.K., W.W., J.Y.)
| | - Xu Yang
- Department of Nuclear Medicine, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, Beijing 100050, China (L.F., S.Z., X.L., X.Y., Y.K., W.W., J.Y.)
| | - Ying Kan
- Department of Nuclear Medicine, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, Beijing 100050, China (L.F., S.Z., X.L., X.Y., Y.K., W.W., J.Y.)
| | - Chao Wang
- SinoUnion Healthcare Inc., Beijing, China (C.W.)
| | - Hui Zhang
- Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, China (H,Z,)
| | - Wei Wang
- Department of Nuclear Medicine, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, Beijing 100050, China (L.F., S.Z., X.L., X.Y., Y.K., W.W., J.Y.)
| | - Jigang Yang
- Department of Nuclear Medicine, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, Beijing 100050, China (L.F., S.Z., X.L., X.Y., Y.K., W.W., J.Y.).
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10
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Shi Y, Qu XL, Lu QL, Zhao J, Ma QC, Sun W, OuYang GX, Fu W, Tao X, Huang DS. Stable Lanthanide-Organic Frameworks: Crystal Structure, Photoluminescence, and Chemical Sensing of Vanillylmandelic Acid as a Biomarker of Pheochromocytoma. Inorg Chem 2023; 62:6934-6947. [PMID: 37098153 DOI: 10.1021/acs.inorgchem.3c00109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/27/2023]
Abstract
Several isostructural lanthanide metal-organic frameworks, viz. [Ln(DCHB)1.5phen]n (Ln-MOFs, where Ln = Eu for 1, Tb for 2, Sm for 3 and Dy for 4), are successfully synthesized through the hydrothermal reactions of 4'-di(4-carboxylphenoxy)hydroxyl-2, 2'-bipyridyl (H2DCHB) and lanthanide nitrates as well as chelator 1,10-phenantroline (phen). These structures are characterized by single-crystal X-ray diffraction, and the representative Ln-MOF 1 is a fivefold interpenetrated framework with the uncoordinated Lewis base N sites form DCHB2- ligands. The photoluminescence research studies reveal that Ln-MOFs 1-4 exhibit characteristic fluorescent emissions from ligand-induced lanthanide Ln(III) ions, while the single-component emission spectra of Ln-MOF 4 are all located in a white region under different excitations. The absence of coordinated water and the interpenetration property of the structures are conducive to the structure rigidity, and the results display that Ln-MOF 1 has high thermal/chemical stabilities in common solvents and a wide pH range as well as the boiling water. Notably, luminescent sensing studies reveal that Ln-MOF 1 with prominent fluorescence properties can perform in highly sensitive and selective sensing of vanillylmandelic acid (VMA) in aqueous systems (KSV = 562.8 L·mol-1; LOD = 4.6 × 10-4 M), which can potentially establish a detection platform for the diagnosis of pheochromocytoma via multiquenching mechanisms. Moreover, the 1@MMMs sensing membranes comprised of Ln-MOF 1 and a poly(vinylidene fluoride) (PVDF) polymer can also be facilely developed for VMA detection in aqueous media, suggesting the enhanced convenience and efficiency of practical sensing applications.
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Affiliation(s)
- Yu Shi
- College of Materials Science and Engineering, Zhejiang University of Technology, Hangzhou 310014, China
| | - Xiang-Long Qu
- College of Health Management, Shangluo University, Beixin Street 10, Shangluo Shaanxi 726000, China
| | - Qi-Liang Lu
- Zhejiang Prov Peoples Hosp, Key Lab Tumor Mol Diag & Individualized Med Zheji, Affiliated Peoples Hosp, Hangzhou Medical College, Hangzhou 310000, P. R. China
| | - Jie Zhao
- Zhejiang Prov Peoples Hosp, Key Lab Tumor Mol Diag & Individualized Med Zheji, Affiliated Peoples Hosp, Hangzhou Medical College, Hangzhou 310000, P. R. China
| | - Qian-Cheng Ma
- Zhejiang Prov Peoples Hosp, Key Lab Tumor Mol Diag & Individualized Med Zheji, Affiliated Peoples Hosp, Hangzhou Medical College, Hangzhou 310000, P. R. China
| | - Wen Sun
- Zhejiang Prov Peoples Hosp, Key Lab Tumor Mol Diag & Individualized Med Zheji, Affiliated Peoples Hosp, Hangzhou Medical College, Hangzhou 310000, P. R. China
| | - Guang-Xiong OuYang
- Zhejiang Prov Peoples Hosp, Key Lab Tumor Mol Diag & Individualized Med Zheji, Affiliated Peoples Hosp, Hangzhou Medical College, Hangzhou 310000, P. R. China
| | | | - Xinyong Tao
- College of Materials Science and Engineering, Zhejiang University of Technology, Hangzhou 310014, China
| | - Dong-Sheng Huang
- Zhejiang Prov Peoples Hosp, Key Lab Tumor Mol Diag & Individualized Med Zheji, Affiliated Peoples Hosp, Hangzhou Medical College, Hangzhou 310000, P. R. China
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11
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Passudetti V, De Leo L, Maselli F, Pellegrino R, Brindisino F. Tumour Hidden behind Thoracic Spine Pain: A Rare Case of Neuroblastoma in a Young Mother-A Case Report. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:13448. [PMID: 36294024 PMCID: PMC9602929 DOI: 10.3390/ijerph192013448] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 10/14/2022] [Accepted: 10/16/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND Neuroblastoma (NB) is the most common form of paediatric malignancy, responsible for up to 15% of cancer deaths in children, whereas in adults, its onset is a rarer event, despite being characterized by greater lethality. The purpose of this case report was to describe the clinical presentation, physical examination, and clinical decision-making process in a patient with Neuroblastoma mimicking thoracic spine pain of musculoskeletal origin. METHODS a thirty-two-year-old mother complained of thoracic spine pain on her left vertebral side and in her left periscapular muscles; her pain was constant, deep, and worse at night; she also experienced pain during physical exertion of her upper limbs; the patient also reported pain in her left breast. RESULTS the physiotherapist's anamnesis and physical examination led him to suspect the need for an extra-expertise pathology and to refer his patient to another medical specialist; the subsequent investigations revealed a poorly differentiated Neuroblastoma ALK + (IIC) in the posterior mediastinum on the left; the patient underwent surgery excision after 4 months. CONCLUSIONS differential screening should be a physiotherapist's fundamental skill in their patients' clinical management, especially in direct access cases; the physiotherapist has an ethical and moral duty to conduct differential screening, in order to rule out extra-expertise pathologies-both when patients self-refer for rehabilitation assessment, and when they are referred by other practitioners.
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Affiliation(s)
- Valerio Passudetti
- Department of Clinical Sciences and Translational Medicine, Medicine and Surgery School, University of Roma “Tor Vergata”, 00133 Rome, Italy
| | - Luca De Leo
- Check-Up Center Private Practice, 73020 Lecce, Italy
| | - Filippo Maselli
- Department of Human Neurosciences, University of Roma “Sapienza”, 00185 Rome, Italy
- Sovrintendenza Sanitaria Regionale Puglia INAIL, 70126 Bari, Italy
| | - Raffaello Pellegrino
- Antalgic Mini-Invasive and Rehab-Outpatients Unit, Department of Medicine and Science of Aging, University “G. d’Annunzio” Chieti-Pescara, 66100 Chieti, Italy or
| | - Fabrizio Brindisino
- Department of Medicine and Health Science “Vincenzo Tiberio”, University of Molise C/da Tappino c/o Cardarelli Hospital, 86100 Campobasso, Italy
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12
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Shishkanova TV, Sinica A. Electrochemically deposited cobalt bis(dicarbollide) derivative and the detection of neuroblastoma markers on the electrode surface. J Electroanal Chem (Lausanne) 2022. [DOI: 10.1016/j.jelechem.2022.116674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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13
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Faridzadeh A, Salimi Y, Ghasemirad H, Kargar M, Rashtchian A, Mahmoudvand G, Karimi MA, Zerangian N, Jahani N, Masoudi A, Sadeghian Dastjerdi B, Salavatizadeh M, Sadeghsalehi H, Deravi N. Neuroprotective Potential of Aromatic Herbs: Rosemary, Sage, and Lavender. Front Neurosci 2022; 16:909833. [PMID: 35873824 PMCID: PMC9297920 DOI: 10.3389/fnins.2022.909833] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/31/2022] [Indexed: 11/13/2022] Open
Abstract
Hundreds of millions of people around the world suffer from neurological disorders or have experienced them intermittently, which has significantly reduced their quality of life. The common treatments for neurological disorders are relatively expensive and may lead to a wide variety of side effects including sleep attacks, gastrointestinal side effects, blood pressure changes, etc. On the other hand, several herbal medications have attracted colossal popularity worldwide in the recent years due to their availability, affordable prices, and few side effects. Aromatic plants, sage (Salvia officinalis), lavender (Lavandula angustifolia), and rosemary (Salvia Rosmarinus) have already shown anxiolytics, anti-inflammatory, antioxidant, and neuroprotective effects. They have also shown potential in treating common neurological disorders, including Alzheimer's disease, Parkinson's disease, migraine, and cognitive disorders. This review summarizes the data on the neuroprotective potential of aromatic herbs, sage, lavender, and rosemary.
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Affiliation(s)
- Arezoo Faridzadeh
- Department of Immunology and Allergy, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yasaman Salimi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hamidreza Ghasemirad
- Student Research Committee, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Meraj Kargar
- Student Research Committee, Afzalipour Faculty of Medicine Kerman University of Medical Sciences, Kerman, Iran
| | - Ava Rashtchian
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Golnaz Mahmoudvand
- Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Mohammad Amin Karimi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nasibeh Zerangian
- School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Negar Jahani
- Student Research Committee, Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Anahita Masoudi
- Student Research Committee, Jahrom University of Medical Sciences, Jahrom, Iran
| | - Bahare Sadeghian Dastjerdi
- Student Research Committee, Department of Midwifery, Faculty of Nursing and Midwifery, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Marieh Salavatizadeh
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamidreza Sadeghsalehi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Niloofar Deravi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- *Correspondence: Niloofar Deravi
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14
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Fathi E, Vandghanooni S, Montazersaheb S, Farahzadi R. Mesenchymal stem cells promote caspase-3 expression of SH-SY5Y neuroblastoma cells via reducing telomerase activity and telomere length. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:1583-1589. [PMID: 35317118 PMCID: PMC8917842 DOI: 10.22038/ijbms.2021.59400.13187] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 10/26/2021] [Indexed: 01/14/2023]
Abstract
OBJECTIVES The use of mesenchymal stem cells in malignancies has attracted much attention due to their ability to deliver anticancer agents to tumors, including cytokines, chemokines, etc. This study aimed to investigate the effect of MSCs on the neuroblastoma SH-SY5Y cells through proliferation/apoptosis, senescence assessment, telomere length, and telomerase activity in vitro. BAX and BCL2 were also examined as potential signaling pathways in this process. MATERIALS AND METHODS For this reason, two cell populations (MSCs and SH-SY5Y cells) were co-cultured on trans-well plates for 7 days. In a subsequent step, SH-SY5Y cells were harvested from both control and experimental groups and subjected to flow cytometry, ELISA, real-time PCR, PCR-ELISA TRAP assay, and Western blotting assay for Ki67/Caspase3 investigation, β-Galactosidase assessment, telomere length, and telomerase activity assay. Also, expression of genes and proteins through real-time PCR and Western blotting demonstrated the involvement of the aforementioned signaling pathways in this process. RESULTS It was found that MSCs contributed significantly to decrease and increase of Ki-67 and Caspase-3, respectively. Also, MSCs dramatically reduced the length of telomere and telomerase activity and increased the β-Galactosidase activity in a significant manner. In addition, significant increase and decrease were also seen in BAX and BCL2 gene and protein expressions, respectively. CONCLUSION These findings revealed that close interaction between MSCs and neuroblastoma cells causes inhibition of the SH-SY5Y cell proliferation and promotes cell senescence via BAX and caspase-3 cascade pathways.
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Affiliation(s)
- Ezzatollah Fathi
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Somayeh Vandghanooni
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Montazersaheb
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Raheleh Farahzadi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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15
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Liquid biomarkers for the management of paediatric neuroblastoma: an approach to personalised and targeted cancer therapy. JOURNAL OF RADIOTHERAPY IN PRACTICE 2021. [DOI: 10.1017/s1460396920000102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
AbstractBackground:Neuroblastoma is the most common extracranial solid tumour of infancy and accounts for about 6–10% of paediatric cancers. It has a biologically and clinically heterogeneous behaviour that ranges from spontaneous regression to cases of highly aggressive metastatic disease that could be unresponsive to standard therapy. In recent years, there have been several investigations into the development of various diagnostic, predictive and prognostic biomarkers towards personalised and targeted management of the disease.Materials and Methods:This paper reports on the review of current clinical and emerging biomarkers used in risk assessment, screening for early detection and diagnosis, prognostication and monitoring of the response of treatment of neuroblastoma in paediatric patients.Conclusions:Tumour markers can significantly improve diagnosis; however, the invasive, unpleasant and inconvenient nature of current tissue biopsies limits their applications, especially in paediatric patients. Therefore, the development of a non-invasive, reliable high accurate and personalised diagnostic tool capable of early detection and rapid response is the most promising step towards advanced cancer management from tumour diagnosis, therapy to patient monitoring and represents an important step towards the promise of precision, personalised and targeted medicine. Liquid biopsy assay with wide ranges of clinical applications is emerging to hold incredible potential for advancing cancer treatment and has greater promise for diagnostic purposes, identification and tracking of tumour-specific alterations during the course of the disease and to guide therapeutic decisions.
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16
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Uemura S, Lin KS, Mon Thwin KK, Nakatani N, Ishida T, Yamamoto N, Tamura A, Saito A, Mori T, Hasegawa D, Kosaka Y, Nino N, Nagano C, Takafuji S, Iijima K, Nishimura N. Limited correlation between tumor markers and minimal residual disease detected by seven neuroblastoma-associated mRNAs in high-risk neuroblastoma patients. Mol Clin Oncol 2021; 15:137. [PMID: 34055352 DOI: 10.3892/mco.2021.2299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 12/18/2020] [Indexed: 01/23/2023] Open
Abstract
Vanillylmandelic acid (VMA), homovanillic acid (HVA), neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) are classical tumor markers and are used as standard clinical evaluations for patients with neuroblastoma (NB). Minimal residual disease (MRD) can be monitored by quantifying several sets of NB-associated mRNAs in the bone marrow (BM) and peripheral blood (PB) of patients with NB. Although MRD in BM and PB has been revealed to be a strong prognostic factor that is independent of standard clinical evaluations, its interrelation with tumor markers remains uncharacterized. The present study determined the levels of tumor markers (VMA, HVA, NSE and LDH) and MRD (BM-MRD and PB-MRD) in 133 pairs of concurrently collected BM, PB and urine samples from 19 patients with high-risk NB. The patients were evaluated during the entire course of treatment, which included 10 diagnoses, 32 treatments, 36 post-treatment, 9 relapses and 46 post-relapse sample pairs. The level of BM-MRD and PB-MRD was determined by quantifying 7 NB-mRNAs (collapsin response mediator protein 1, dopamine beta-hydroxylase, dopa decarboxylase, growth-associated protein 43, ISL LIM homeobox 1, pairedlike homeobox 2b and tyrosine hydroxylase) using droplet digital PCR. In overall sample pairs, tumor markers (VMA, HVA, NSE and LDH) demonstrated weak but significant correlations (P<0.011) with BM-MRD and PB-MRD. In subgroups according to each patient evaluation, the degree of correlation between tumor markers and MRD became stronger in patients with adrenal gland tumors, BM metastasis at diagnosis and relapse/regrowth compared with overall sample pairs. In contrast, tumor markers demonstrated variable correlations with MRD in subgroups according to each sample evaluation (BM infiltration at sampling, collection time point and disease status). The results suggested that tumor markers may demonstrate limited correlation with MRD in patients with high-risk NB.
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Affiliation(s)
- Suguru Uemura
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Kyaw San Lin
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Khin Kyae Mon Thwin
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Naoko Nakatani
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Toshiaki Ishida
- Department of Hematology and Oncology, Kobe Children's Hospital, Kobe, Hyogo 650-0047, Japan
| | - Nobuyuki Yamamoto
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Akihiro Tamura
- Department of Hematology and Oncology, Kobe Children's Hospital, Kobe, Hyogo 650-0047, Japan
| | - Atsuro Saito
- Department of Hematology and Oncology, Kobe Children's Hospital, Kobe, Hyogo 650-0047, Japan
| | - Takeshi Mori
- Department of Hematology and Oncology, Kobe Children's Hospital, Kobe, Hyogo 650-0047, Japan
| | - Daiichiro Hasegawa
- Department of Hematology and Oncology, Kobe Children's Hospital, Kobe, Hyogo 650-0047, Japan
| | - Yoshiyuki Kosaka
- Department of Hematology and Oncology, Kobe Children's Hospital, Kobe, Hyogo 650-0047, Japan
| | - Nanako Nino
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - China Nagano
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Satoru Takafuji
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Kazumoto Iijima
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Noriyuki Nishimura
- Department of Public Health, Kobe University Graduate School of Health Science, Kobe, Hyogo 654-0142, Japan
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17
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Yokota K, Uchida H, Sakairi M, Abe M, Tanaka Y, Tainaka T, Shirota C, Sumida W, Oshima K, Makita S, Amano H, Hinoki A. Identification of novel neuroblastoma biomarkers in urine samples. Sci Rep 2021; 11:4055. [PMID: 33603049 PMCID: PMC7892837 DOI: 10.1038/s41598-021-83619-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 02/03/2021] [Indexed: 12/12/2022] Open
Abstract
Urine is a complex liquid containing numerous small molecular metabolites. The ability to non-invasively test for cancer biomarkers in urine is especially beneficial for screening child patients. This study attempted to identify neuroblastoma biomarkers by comprehensively analysing urinary metabolite samples from children. A total of 87 urine samples were collected from 54 participants (15 children with neuroblastoma and 39 without cancer) and used to perform a comprehensive analysis. Urine metabolites were extracted using liquid chromatography/mass spectrometry and analysed by Metabolon, Inc. Biomarker candidates were extracted using the Wilcoxon rank sum test, random forest method (RF), and orthogonal partial least squares discriminant analysis (OPLS-DA). RF identified three important metabolic pathways in 15 samples from children with neuroblastoma. One metabolite was selected from each of the three identified pathways and combined to create a biomarker candidate (3-MTS, CTN, and COR) that represented each of the three pathways; using this candidate, all 15 cases were accurately distinguishable from the control group. Two cases in which known biomarkers were negative tested positive using this new biomarker. Furthermore, the predictive value did not decrease in cases with a low therapeutic effect. This approach could be effectively applied to identify biomarkers for other cancer types.
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Affiliation(s)
- Kazuki Yokota
- Department of Paediatric Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
| | - Hiroo Uchida
- Department of Paediatric Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan.
| | - Minoru Sakairi
- Hitachi, Ltd., R & D Group, Centre for Exploratory Research, Tokyo, 185-8601, Japan
- Department of Rare/Intractable Cancer Analysis Research, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Mayumi Abe
- Hitachi, Ltd., R & D Group, Centre for Exploratory Research, Tokyo, 185-8601, Japan
| | - Yujiro Tanaka
- Department of Paediatric Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
| | - Takahisa Tainaka
- Department of Paediatric Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
| | - Chiyoe Shirota
- Department of Paediatric Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
| | - Wataru Sumida
- Department of Paediatric Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
| | - Kazuo Oshima
- Department of Paediatric Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
| | - Satoshi Makita
- Department of Paediatric Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
| | - Hizuru Amano
- Department of Paediatric Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
| | - Akinari Hinoki
- Department of Paediatric Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan
- Department of Rare/Intractable Cancer Analysis Research, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
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18
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Hrdlička V, Barek J, Navrátil T. Differential pulse voltammetric determination of homovanillic acid as a tumor biomarker in human urine after hollow fiber-based liquid-phase microextraction. Talanta 2021; 221:121594. [PMID: 33076128 DOI: 10.1016/j.talanta.2020.121594] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/25/2020] [Accepted: 08/26/2020] [Indexed: 11/19/2022]
Abstract
Novel method for the determination of a tumor marker homovanillic acid (HVA) in human urine was developed. Combination of hollow fiber - based liquid-phase microextraction (HF-LPME) and differential pulse voltammetry (DPV) at a cathodically pre-treated boron doped diamond electrode (BDDE) was applied for these purposes. Optimum conditions were: butyl benzoate as supported liquid membrane (SLM) formed on polypropylene HF, 0.1 mol L-1 HCl as donor phase, 0.1 mol L-1 sodium phosphate buffer of pH 6 as acceptor phase, and 30 min extraction time. HF-LPME-DPV concentration dependence was linear in the range from 1.2 to 100 μmol L-1. Limits of quantification (LOQ) and detection (LOD) were 1.2 and 0.4 μmol L-1, respectively. The applicability of the developed method was verified by analysis of human urine. Standard addition method was used, found HVA concentration was 13.5 ± 1.3 μmol L-1, RSD = 9.3% (n=5).
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Affiliation(s)
- Vojtěch Hrdlička
- J. Heyrovský Institute of Physical Chemistry of the Czech Academy of Sciences, Dolejškova 2155/3, 182 23, Prague 8, Czech Republic; Charles University, Faculty of Science, Department of Analytical Chemistry, UNESCO Laboratory of Environmental Electrochemistry, Hlavova 2030/8, 128 43, Prague 2, Czech Republic
| | - Jiří Barek
- Charles University, Faculty of Science, Department of Analytical Chemistry, UNESCO Laboratory of Environmental Electrochemistry, Hlavova 2030/8, 128 43, Prague 2, Czech Republic
| | - Tomáš Navrátil
- J. Heyrovský Institute of Physical Chemistry of the Czech Academy of Sciences, Dolejškova 2155/3, 182 23, Prague 8, Czech Republic.
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Tamura A, Inoue S, Mori T, Noguchi J, Nakamura S, Saito A, Kozaki A, Ishida T, Sadaoka K, Hasegawa D, Kosaka Y, Miyanishi M. Low Multiplication Value of Absolute Monocyte Count and Absolute Lymphocyte Count at Diagnosis May Predict Poor Prognosis in Neuroblastoma. Front Oncol 2020; 10:572413. [PMID: 33123478 PMCID: PMC7566172 DOI: 10.3389/fonc.2020.572413] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 09/07/2020] [Indexed: 12/22/2022] Open
Abstract
Despite the growing evidences that immune dysfunction contributes to tumor progression, the prognostic value in patients with neuroblastoma regarding circulating immune blood cell counts has not been well characterized. To answer this, we conducted a retrospective study to evaluate the prognostic value of the circulating immune cell counts at diagnosis in a cohort of 55 patients with neuroblastoma. Based on a novel index by multiplying the absolute monocyte count (AMC)/μl and absolute lymphocyte count (ALC)/μl, we sub-grouped patients with AMC × ALC ≥ 1 × 106 (/μl)2 as high group and patients with AMC × ALC < 1 × 106 (/μl)2 as low group. In the entire cohort, the 4-year progression-free survival (PFS), and overall survival (OS) for high group (n = 38) vs low group (n = 17) was 81.7% (95%CI; 63.6-91.3%) and 90.7% (95%CI; 73.8-96.9%) vs 31.7% (11.6-54.1%) and 56.5% (29.7-76.4%; p < 0.001 for PFS and p = 0.015 for OS), respectively, suggesting that a low AMC × ALC is associated with poor prognosis. In the subgroup analysis for high-risk patients, the 4-year PFS and OS for high group (n = 17) vs low group (n = 13) was 59.8% (31.2-79.7%) and 79.8% (49.4-93.0%) vs 8.5% (0.5-31.7%) and 42.0% (15.4-66.8%; p < 0.001 for PFS and p = 0.089 for OS), respectively. Our data demonstrate that AMC × ALC at diagnosis is a cost-effective and easily measurable biomarker for predicting prognosis in neuroblastoma.
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Affiliation(s)
- Akihiro Tamura
- Department of Hematology and Oncology, Kobe Children's Hospital, Kobe, Japan.,Laboratory for Organismal Patterning, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
| | - Shotaro Inoue
- Department of Hematology and Oncology, Kobe Children's Hospital, Kobe, Japan
| | - Takeshi Mori
- Department of Hematology and Oncology, Kobe Children's Hospital, Kobe, Japan
| | - Jun Noguchi
- Department of Hematology and Oncology, Kobe Children's Hospital, Kobe, Japan
| | - Sayaka Nakamura
- Department of Hematology and Oncology, Kobe Children's Hospital, Kobe, Japan
| | - Atsuro Saito
- Department of Hematology and Oncology, Kobe Children's Hospital, Kobe, Japan
| | - Aiko Kozaki
- Department of Hematology and Oncology, Kobe Children's Hospital, Kobe, Japan
| | - Toshiaki Ishida
- Department of Hematology and Oncology, Kobe Children's Hospital, Kobe, Japan
| | - Kay Sadaoka
- Laboratory for Organismal Patterning, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
| | - Daiichiro Hasegawa
- Department of Hematology and Oncology, Kobe Children's Hospital, Kobe, Japan
| | - Yoshiyuki Kosaka
- Department of Hematology and Oncology, Kobe Children's Hospital, Kobe, Japan
| | - Masanori Miyanishi
- Laboratory for Organismal Patterning, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
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20
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van Veenendaal LM, Bertolli E, Korse CM, Klop WMC, Tesselaar MET, van Akkooi ACJ. The Clinical Utility of Neuron-Specific Enolase (NSE) Serum Levels as a Biomarker for Merkel Cell Carcinoma (MCC). Ann Surg Oncol 2020; 28:1019-1028. [PMID: 32529274 DOI: 10.1245/s10434-020-08656-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND No adequate biomarker for Merkel cell carcinoma (MCC) has been identified. Serum neuron-specific enolase (NSE) has been tested and is commonly used as a biomarker for several other small cell malignancies. However, the role of NSE in MCC is still unclear. The purpose of this study was to investigate the role of NSE as a biomarker in MCC. METHODS A prospective cohort of MCC patients was analyzed using Kaplan-Meier curves with log-rank test, ROC curves, Cox regression, and mixed models. A separate evaluation was performed for patients treated with immunotherapy. RESULTS Eighty-four patients were included [47 males, median age 71 years, stages I & II, III, and IV MCC in respectively 39 (46%), 42 (50%), and 4 (3%) patients at time of diagnosis] with 565 NSE samples (median 15; interquartile range 12.6-22 ng/ml). Baseline NSE had no association with prognosis. NSE correlated with extent of disease (P = 0.01) and increased with 15 ng/ml per class (no tumor load, localized MCC, regional or distant metastases, respectively). NSE was able to detect progression (AUC 0.89). A NSE of 18.2 ng/ml was considered the most optimal level for clinical use (sensitivity 91%, specificity 78%, PPV 48%, NPV 98%). During immunotherapy (N = 23; 248 NSE values), all complete responders (N = 10) had a normalized NSE (< 18.2 ng/ml), all partial responders (N = 5) had a decreasing NSE. In nonresponders (N = 8), all NSE levels remained elevated. CONCLUSIONS NSE could be a valuable biomarker in MCC. NSE correlates with extent of disease; it is able to rule out progression and distinguishes responders from nonresponders during immunotherapy.
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Affiliation(s)
- Linde M van Veenendaal
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Eduardo Bertolli
- Department of Surgical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.,Skin Cancer Department, AC Camargo Cancer Center, São Paulo, SP, Brazil
| | - Catharina M Korse
- Department of Clinical Chemistry, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - W Martin C Klop
- Department of Head and Neck Surgery, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Margot E T Tesselaar
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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21
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Fu B, Chen H, Yan Z, Zhang Z, Chen J, Liu T, Li K. A simple ultrasensitive electrochemical sensor for simultaneous determination of homovanillic acid and vanillylmandelic acid in human urine based on MWCNTs-Pt nanoparticles as peroxidase mimics. J Electroanal Chem (Lausanne) 2020. [DOI: 10.1016/j.jelechem.2020.114165] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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22
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Overman RE, Kartal TT, Cunningham AJ, Fialkowski EA, Naik-Mathuria BJ, Vasudevan SA, Malek MM, Kalsi R, Le HD, Stafford LC, Lautz TB, Many BT, Jones RE, Bütter A, Davidson J, Williams A, Dasgupta R, Lewis J, Troutt M, Aldrink JH, Mansfield SA, Lal DR, Xiao J, Meyers RL, Short SS, Newman EA. Optimization of percutaneous biopsy for diagnosis and pretreatment risk assessment of neuroblastoma. Pediatr Blood Cancer 2020; 67:e28153. [PMID: 32072730 DOI: 10.1002/pbc.28153] [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] [Received: 10/01/2019] [Revised: 11/22/2019] [Accepted: 12/11/2019] [Indexed: 01/14/2023]
Abstract
BACKGROUND Image-guided percutaneous core needle biopsy (PCNB) is increasingly utilized to diagnose solid tumors. The objective of this study is to determine whether PCNB is adequate for modern biologic characterization of neuroblastoma. PROCEDURE A multi-institutional retrospective study was performed by the Pediatric Surgical Oncology Research Collaborative on children with neuroblastoma at 12 institutions over a 3-year period. Data collected included demographics, clinical details, biopsy technique, complications, and adequacy of biopsies for cytogenetic markers utilized by the Children's Oncology Group for risk stratification. RESULTS A total of 243 children were identified with a diagnosis of neuroblastoma: 79 (32.5%) tumor excision at diagnosis, 94 (38.7%) open incisional biopsy (IB), and 70 (28.8%) PCNB. Compared to IB, there was no significant difference in ability to accurately obtain a primary diagnosis by PCNB (95.7% vs 98.9%, P = .314) or determine MYCN copy number (92.4% vs 97.8%, P = .111). The yield for loss of heterozygosity and tumor ploidy was lower with PCNB versus IB (56.1% vs 90.9%, P < .05; and 58.0% vs. 88.5%, P < .05). Complications did not differ between groups (2.9 % vs 3.3%, P = 1.000), though the PCNB group had fewer blood transfusions and lower opioid usage. Efficacy of PCNB was improved for loss of heterozygosity when a pediatric pathologist evaluated the fresh specimen for adequacy. CONCLUSIONS PCNB is a less invasive alternative to open biopsy for primary diagnosis and MYCN oncogene status in patients with neuroblastoma. Our data suggest that PCNB could be optimized for complete genetic analysis by standardized protocols and real-time pathology assessment of specimen quality.
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Affiliation(s)
- Richard E Overman
- Division of Pediatric Surgery, Department of Surgery, C. S. Mott Children's Hospital, The University of Michigan, Ann Arbor, Michigan
| | - Tanvi T Kartal
- Division of Pediatric Surgery, Department of Surgery, C. S. Mott Children's Hospital, The University of Michigan, Ann Arbor, Michigan
| | - Aaron J Cunningham
- Department of Surgery, Division of Pediatric Surgery, Oregon Health and Science University, Portland, Oregon
| | - Elizabeth A Fialkowski
- Department of Surgery, Division of Pediatric Surgery, Oregon Health and Science University, Portland, Oregon
| | - Bindi J Naik-Mathuria
- Department of Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas
| | - Sanjeev A Vasudevan
- Department of Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas
| | - Marcus M Malek
- Division of Pediatric General and Thoracic Surgery, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Ranjeet Kalsi
- Division of Pediatric General and Thoracic Surgery, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Hau D Le
- Division of Pediatric Surgery, American Family Children's Hospital, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Linda Cherney Stafford
- Division of Pediatric Surgery, American Family Children's Hospital, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Timothy B Lautz
- Division of Pediatric Surgery, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University, Evanston, Illinois
| | - Benjamin T Many
- Division of Pediatric Surgery, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University, Evanston, Illinois
| | - Rachel E Jones
- Division of Pediatric Surgery, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University, Evanston, Illinois
| | - Andreana Bütter
- Division of Pediatric Surgery, Children's Hospital, London Health Sciences Centre, Western University, London, Ontario, Canada
| | - Jacob Davidson
- Division of Pediatric Surgery, Children's Hospital, London Health Sciences Centre, Western University, London, Ontario, Canada
| | - Andrew Williams
- Division of Pediatric Surgery, Children's Hospital, London Health Sciences Centre, Western University, London, Ontario, Canada
| | - Roshni Dasgupta
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jana Lewis
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Misty Troutt
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jennifer H Aldrink
- Division of Pediatric Surgery, Department of Surgery, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, Ohio
| | - Sara A Mansfield
- Division of Pediatric Surgery, Department of Surgery, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, Ohio
| | - Dave R Lal
- Division of Pediatric Surgery, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, Wisconsin
| | - Jerry Xiao
- Division of Pediatric Surgery, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, Wisconsin
| | - Rebecka L Meyers
- Division of Pediatric Surgery, Primary Children's Hospital, University of Utah, Salt Lake City, Utah
| | - Scott S Short
- Division of Pediatric Surgery, Primary Children's Hospital, University of Utah, Salt Lake City, Utah
| | - Erika A Newman
- Division of Pediatric Surgery, Department of Surgery, C. S. Mott Children's Hospital, The University of Michigan, Ann Arbor, Michigan
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Ferraro S, Braga F, Luksch R, Terenziani M, Caruso S, Panteghini M. Measurement of Serum Neuron-Specific Enolase in Neuroblastoma: Is There a Clinical Role? Clin Chem 2020; 66:667-675. [DOI: 10.1093/clinchem/hvaa073] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/28/2020] [Indexed: 12/21/2022]
Abstract
Abstract
BACKGROUND
The measurement of neuron-specific enolase (NSE) in serum is frequently requested for diagnosis, risk stratification, and treatment monitoring of neuroblastoma (NB) in the pediatric population. However, authoritative clinical practice guidelines advise about the poor diagnostic performance of NSE.
Content
We critically appraised the available literature evaluating the diagnostic and prognostic value of NSE in the management of NB, paying special attention to the definition of appropriate threshold levels. In addition, we discuss the interfering conditions causing artifactual increases of NSE concentrations in serum and potentially influencing the clinical evaluation of patients with suspected NB.
Summary
No definitive evidence supports the use of serum NSE for diagnosis and monitoring of NB. The risk of obtaining false-positive NSE results associated with confounders (e.g., sample hemolysis) and other pathophysiologic conditions (e.g., inflammation) is remarkable and hampers the diagnostic value of this test. NSE may be helpful to define the risk of death of patients with NB, mainly in the advanced stages of disease. However, further studies validating currently marketed immunoassays and defining threshold values useful for this scope are warranted.
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Affiliation(s)
- Simona Ferraro
- Unità Operativa Complessa Patologia Clinica, ASST Fatebenefratelli-Sacco, Milano, Italy
| | - Federica Braga
- Unità Operativa Complessa Patologia Clinica, ASST Fatebenefratelli-Sacco, Milano, Italy
- Dipartimento di Scienze Biomediche e Cliniche, “Luigi Sacco,” Università degli Studi, Milano, Italy
| | - Roberto Luksch
- Struttura Complessa Pediatria Oncologica, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Monica Terenziani
- Struttura Complessa Pediatria Oncologica, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Simone Caruso
- Unità Operativa Complessa Patologia Clinica, ASST Fatebenefratelli-Sacco, Milano, Italy
| | - Mauro Panteghini
- Unità Operativa Complessa Patologia Clinica, ASST Fatebenefratelli-Sacco, Milano, Italy
- Dipartimento di Scienze Biomediche e Cliniche, “Luigi Sacco,” Università degli Studi, Milano, Italy
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Abstract
Neuroblastoma is the most common extracranial solid tumor of childhood with a median age of presentation of 17 months. A common theme in high-risk neuroblastoma is maintenance of telomeres, one mechanism for which involves alternate lengthening of telomeres (ALT) associated with ATRX gene mutations. Mutations are believed to result in loss of ATRX protein, and therefore immunohistochemistry is used to detect mutations. We screened 133 cases of neuroblastoma by ATRX immunohistochemistry, and found 9 cases with partial to total absence of ATRX. Sequencing for ATRX mutations detected a mutation in 1 of 9 cases, suggesting immunostaining was not reliable for detecting mutations. To correlate immunostaining with ALT, fluorescence in situ hybridization (FISH) for ALT was performed in 6 of these cases and 5 (from 4 patients) showed ALT, implying impaired ATRX protein function, despite the failure to identify a mutation. Two other cases with large deletions in the ATRX gene showed diffusely positive staining for ATRX protein but showed ALT by FISH. Four of the 6 patients with ALT-positive tumors were over 5 years old. Therefore, 29 additional patients 5 years old and above with ATRX-positive tumors were screened for ALT by FISH and 6 additional cases with ALT were detected, bringing the total to 29% (10/34) of children 5 years old and above, 70% of which showed positive ATRX immunohistochemistry. Patients with ATRX mutations in neuroblastoma tend to have a more chronic and progressive course of disease. Screening neuroblastoma tumors at diagnosis for ATRX mutations may help identify patients who might benefit from personalized therapy directed against ALT. However, relaying on negative immunohistochemistry for ATRX protein to identify ALT in neuroblastoma may miss a significant proportion of patients. The addition of FISH for ALT as part of the diagnostic workup, especially for older children (5 y old and above), would help ensure that patients are correctly identified for anti-ALT therapy.
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Fan H, Su Y, Duan C, Zhao Q, Wang X, Zhu S, Zhao W, Jin M, Ma X. Iron deficiency in children at the time of initial neuroblastoma diagnosis. Pediatr Investig 2020; 4:17-22. [PMID: 32851337 PMCID: PMC7331340 DOI: 10.1002/ped4.12156] [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: 04/09/2019] [Accepted: 07/23/2019] [Indexed: 11/25/2022] Open
Abstract
IMPORTANCE There is a high incidence of iron deficiency in children worldwide. Notably, however, while iron deficiency is the most common cause of anemia, little is known about the prevalence and different types of iron deficiency in neuroblastoma patients. OBJECTIVE The aim of the present study was to investigate the prevalence of iron deficiency in patients newly diagnosed with neuroblastoma. METHODS A total of 195 newly diagnosed neuroblastoma patients from November 2015 to January 2018 were analyzed retrospectively. The survival analysis was estimated by the Kaplan-Meier method. RESULTS Of the 195 neuroblastoma patients included in the study, 121 (62.1%) had iron deficiency, 55 (28.2%) had absolute iron deficiency, and 66 (33.9%) had functional iron deficiency. Being aged ≥ 18 months, tumor originating in the abdomen, International Neuroblastoma Risk Group Staging System M, high-risk neuroblastoma, lactate dehydrogenase ≥ 1500 U/L, neuron-specific enolase ≥ 100 U/L, unfavorable histologic category, MYCN amplification, chromosome 1p loss, and bone marrow metastasis were associated with significantly higher rates of functional iron deficiency (P < 0.05). INTERPRETATION Functional iron deficiency at the time of initial neuroblastoma diagnosis predicted lower event-free survival. Long-term effects of iron supplementation in neuroblastoma patients with different types of iron deficiency need to be further studied.
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Affiliation(s)
- Hongjun Fan
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Yan Su
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Chao Duan
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Qian Zhao
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Xisi Wang
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Shuai Zhu
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Wen Zhao
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Mei Jin
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Xiaoli Ma
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
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Yi ES, Son MH, Hyun JK, Cho HW, Ju HY, Lee JW, Yoo KH, Sung KW, Koo HH. Predictors of survival in patients with high-risk neuroblastoma who failed tandem high-dose chemotherapy and autologous stem cell transplantation. Pediatr Blood Cancer 2020; 67:e28066. [PMID: 31736249 DOI: 10.1002/pbc.28066] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 09/22/2019] [Accepted: 10/15/2019] [Indexed: 12/17/2022]
Abstract
OBJECTIVE This study aims to explore prognostic factors for high-risk neuroblastoma patients with response failure to tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT). METHODS Survival outcomes were compared according to characteristics at initial diagnosis, at relapse/progression, and after relapse/progression in patients who experienced relapse/progression after tandem HDCT/auto-SCT from 2006 to 2018. RESULTS Forty-nine patients experienced relapse/progression after tandem HDCT/auto-SCT during the study period: 43 received salvage treatment and 30 underwent allogeneic SCT (allo-SCT) after reinduction treatment. Although all six patients who did not undergo salvage treatment died, 13 of the 43 patients who did remain alive. The 3-year probabilities of event-free survival (EFS) and overall survival (OS) from initial relapse/progression among the 49 patients were 14.4% ± 5.2% and 21.2% ± 6.4%, respectively. A higher neuron-specific enolase (NSE) level (>24 ng/mL) at relapse/progression was an independent prognostic factor for worse OS. Nine of 30 patients who underwent allo-SCT remain alive, and the 3-year probabilities of EFS and OS from allo-SCT were 16.5% ± 7.2% and 21.6% ± 8.3%, respectively. A higher NSE level and no incorporation of high-dose 131 I-metaiodobenzylguanidine (HD-MIBG) treatment into allo-SCT were independent prognostic factors for worse EFS and OS after allo-SCT. CONCLUSION The results suggest that a higher serum NSE level at relapse/progression is a predictor of worse prognosis in patients with response failure to tandem HDCT/auto-SCT, and that incorporation of HD-MIBG treatment into allo-SCT may improve outcomes.
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Affiliation(s)
- Eun Sang Yi
- Department of Pediatrics, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Meong Hi Son
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ju Kyung Hyun
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee Won Cho
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee Young Ju
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji Won Lee
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Keon Hee Yoo
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ki Woong Sung
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hong Hoe Koo
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Ahmad W, Ali A, Ali A, Khan S, Khan S, Husain I. Upcoming diagnostic biomarkers with promising prospects in neurological disorders. Clin Exp Pharmacol Physiol 2019; 47:347-356. [PMID: 31746003 DOI: 10.1111/1440-1681.13216] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 09/09/2019] [Accepted: 11/16/2019] [Indexed: 12/12/2022]
Abstract
An exponential increase in the prevalence of neurological disorders requires substantial steps to be taken for their prevention and treatment. Neurodiagnostic biomarkers are gaining momentum presently in order to enhance the diagnostic accuracy of neurodegenerative disorders, to precisely assess their advancement and to monitor the efficiency of therapeutic interventions. Therefore, the primary focus of the present review is the recent development in this field of neurodiagnostic biomarkers, and the current state of biomarker exploration in the context of various neurodegenerative diseases. This review encompasses an updated and detailed account of specific (β-Amyloid, Tau and Phospho-tau 181, Tar-DNA binding protein-43, Progranulin, a-synuclein, Clusterin, etc) and non-specific (genetic, synaptic, inflammatory and coagulation) neurodiagnostic biomarkers and the recent advances in this growing field. This comprehensive review also suggests the utilization of neurodiagnostic markers in network approaches and personalized medication that will eventually improvise the existing diagnostic and therapeutic complexities of neurodiagnostic biomarkers.
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Affiliation(s)
- Wasim Ahmad
- Department of Pharmacy, Mohammad Al-Mana College for Medical Sciences, Dammam, Saudi Arabia
| | - Abuzer Ali
- College of Pharmacy, Taif University, Taif, Saudi Arabia
| | - Amena Ali
- College of Pharmacy, Taif University, Taif, Saudi Arabia
| | - Sana Khan
- Department of Pharmacology, School of Pharmaceutical Education & Research, Jamia Hamdard, India
| | - Saba Khan
- Department of Pharmacology, School of Pharmaceutical Education & Research, Jamia Hamdard, India
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Quintero Escobar M, Maschietto M, Krepischi ACV, Avramovic N, Tasic L. Insights into the Chemical Biology of Childhood Embryonal Solid Tumors by NMR-Based Metabolomics. Biomolecules 2019; 9:biom9120843. [PMID: 31817982 PMCID: PMC6995504 DOI: 10.3390/biom9120843] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 11/30/2019] [Accepted: 12/02/2019] [Indexed: 01/19/2023] Open
Abstract
Most childhood cancers occur as isolated cases and show very different biological behavior when compared with cancers in adults. There are some solid tumors that occur almost exclusively in children among which stand out the embryonal solid tumors. These cancers main types are neuroblastoma, nephroblastoma (Wilms tumors), retinoblastoma and hepatoblastomas and tumors of the central nervous system (CNS). Embryonal solid tumors represent a heterogeneous group of cancers supposedly derived from undifferentiated cells, with histological features that resemble tissues of origin during embryogenesis. This key observation suggests that tumorigenesis might begin during early fetal or child life due to the errors in growth or pathways differentiation. There are not many literature data on genomic, transcriptomic, epigenetic, proteomic, or metabolomic differences in these types of cancers when compared to the omics- used in adult cancer research. Still, metabolomics by nuclear magnetic resonance (NMR) in childhood embryonal solid tumors research can contribute greatly to understand better metabolic pathways alterations and biology of the embryonal solid tumors and potential to be used in clinical applications. Different types of samples, such as tissues, cells, biofluids, mostly blood plasma and serum, can be analyzed by NMR to detect and identify cancer metabolic signatures and validated biomarkers using enlarged group of samples. The literature search for biomarkers points to around 20-30 compounds that could be associated with pediatric cancer as well as metastasis.
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Affiliation(s)
- Melissa Quintero Escobar
- Biological Chemistry Group, Department of Organic Chemistry, Institute of Chemistry, University of Campinas (UNICAMP), Campinas 13083-970, Brazil;
- Laboratory of Blood Coagulation, Department of Medical Physiopathology, Hemocentro, University of Campinas (UNICAMP), Campinas 13083-878, Brazil
| | - Mariana Maschietto
- Research Center, Boldrini Children’s Hospital, Campinas 13083-884, Brazil;
| | - Ana C. V. Krepischi
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo (USP), Sao Paulo 05508-0970, Brazil;
| | - Natasa Avramovic
- Institute of Medical Chemistry, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia;
| | - Ljubica Tasic
- Biological Chemistry Group, Department of Organic Chemistry, Institute of Chemistry, University of Campinas (UNICAMP), Campinas 13083-970, Brazil;
- Correspondence: ; Tel.: +55-19-3521-1106
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Duan K, Dickson BC, Marrano P, Thorner PS, Chung CT. Adult‐onset neuroblastoma: Report of seven cases with molecular genetic characterization. Genes Chromosomes Cancer 2019; 59:240-248. [DOI: 10.1002/gcc.22826] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 11/13/2019] [Accepted: 11/19/2019] [Indexed: 01/10/2023] Open
Affiliation(s)
- Kai Duan
- Department of Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario Canada
| | - Brendan C. Dickson
- Department of Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario Canada
- Department of Pathology and Laboratory Medicine Mount Sinai Hospital Toronto Ontario Canada
| | - Paula Marrano
- Division of Pathology The Hospital for Sick Children Toronto Ontario Canada
| | - Paul S. Thorner
- Department of Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario Canada
- Division of Pathology The Hospital for Sick Children Toronto Ontario Canada
| | - Catherine T. Chung
- Department of Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario Canada
- Division of Pathology The Hospital for Sick Children Toronto Ontario Canada
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Xie E, Zhang W, Xu H, Ling Y, Zhang Q, Pan S. Correction of serum NSE reference intervals includes the unidentified hemolysis sample: 1-year data analysis from healthcare individuals. J Clin Lab Anal 2019; 33:e22997. [PMID: 31402486 PMCID: PMC6868418 DOI: 10.1002/jcla.22997] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 07/16/2019] [Accepted: 07/17/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Reference intervals (RIs) are important for interpretation of laboratory results. Neuron-specific enolase (NSE) can be utilized to aid the diagnosis of various tumors. However, while red blood cells contain NSE αγ-isozymes, unrecognized slight hemolysis will result in increasing of NSE levels in serum. The aim of this study was to correct the NSE RIs from healthcare individuals results which may have unidentified microhemolysis. METHODS A total of 15 047 healthy individuals undergoing regular health care were recruited to redefine the NSE reference interval according to the CA28-A3 document. Volunteers with NSE level between 16.3 ng/mL and the upper limit of new RIs were performed venipuncture for NSE retest. Simultaneously, serum free hemoglobin (fHb) was performed with o-tolidine test. RESULTS Reestablishment of NSE RIs is 0-18.9 ng/mL, which is wider than 0-16.3 ng/mL provided by the manufacturer. Seventy-four volunteers with the NSE level between 16.3 and 18.9 ng/mL were performed venipuncture for NSE retest. The ratio of NSE level drop to normal is 85.1% (63/74) in the subsequent results; there are significant differences between the median NSE of two groups (18.15 vs 14.15 ng/mL). Subsequently, the fHb concentration of 22 healthy individuals from 74 individuals was measured; there are significant differences between the median fHb of two groups (58 vs 30 mg/L). CONCLUSIONS Some specimens with slightly elevated NSE may be attributed to the unrecognized slight hemolysis. The correction RIs may be expected to decrease the abnormal NSE results.
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Affiliation(s)
- Erfu Xie
- Department of Laboratory MedicineFirst Affiliated Hospital of Nanjing Medical UniversityNanjingChina
- National Key Clinical Department of Laboratory MedicineNanjingChina
| | - Wei Zhang
- Department of Laboratory MedicineFirst Affiliated Hospital of Nanjing Medical UniversityNanjingChina
- National Key Clinical Department of Laboratory MedicineNanjingChina
| | - Huaguo Xu
- Department of Laboratory MedicineFirst Affiliated Hospital of Nanjing Medical UniversityNanjingChina
- National Key Clinical Department of Laboratory MedicineNanjingChina
| | - Yun Ling
- Department of Laboratory MedicineFirst Affiliated Hospital of Nanjing Medical UniversityNanjingChina
- National Key Clinical Department of Laboratory MedicineNanjingChina
| | - Qiaodi Zhang
- Department of Laboratory MedicineFirst Affiliated Hospital of Nanjing Medical UniversityNanjingChina
- National Key Clinical Department of Laboratory MedicineNanjingChina
| | - Shiyang Pan
- Department of Laboratory MedicineFirst Affiliated Hospital of Nanjing Medical UniversityNanjingChina
- National Key Clinical Department of Laboratory MedicineNanjingChina
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31
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Newman EA, Abdessalam S, Aldrink JH, Austin M, Heaton TE, Bruny J, Ehrlich P, Dasgupta R, Baertschiger RM, Lautz TB, Rhee DS, Langham MR, Malek MM, Meyers RL, Nathan JD, Weil BR, Polites S, Madonna MB. Update on neuroblastoma. J Pediatr Surg 2019; 54:383-389. [PMID: 30305231 DOI: 10.1016/j.jpedsurg.2018.09.004] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 09/09/2018] [Accepted: 09/14/2018] [Indexed: 12/15/2022]
Abstract
Neuroblastoma is an embryonic cancer arising from neural crest stem cells. This cancer is the most common malignancy in infants and the most common extracranial solid tumor in children. The clinical course may be highly variable with the possibility of spontaneous regression in the youngest patients and increased risk of aggressive disease in older children. Clinical heterogeneity is a consequence of the diverse biologic characteristics that determine patient risk and survival. This review will focus on current progress in neuroblastoma staging, risk stratification, and treatment strategies based on advancing knowledge in tumor biology and genetic characterization. TYPE OF STUDY: Review article. LEVEL OF EVIDENCE: Level II.
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Affiliation(s)
- Erika A Newman
- C.S Mott Children's Hospital, The University of Michigan Medicine, Ann Arbor, MI.
| | | | | | - Mary Austin
- Memorial Hermann Texas Medical Center, Houston, TX
| | - Todd E Heaton
- Memorial Sloan Kettering Cancer Center, NY, New York
| | | | - Peter Ehrlich
- C.S Mott Children's Hospital, The University of Michigan Medicine, Ann Arbor, MI
| | | | | | - Timothy B Lautz
- Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL
| | | | - Max R Langham
- University of Tennessee Health Science Center and St. Jude Children's Research Hospital, Memphis, TN
| | - Marcus M Malek
- Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA
| | - Rebecka L Meyers
- Primary Children's Hospital, University of Utah, Salt Lake City, UT
| | | | - Brent R Weil
- Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA
| | | | - Mary Beth Madonna
- Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL
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32
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Johnsen JI, Dyberg C, Wickström M. Neuroblastoma-A Neural Crest Derived Embryonal Malignancy. Front Mol Neurosci 2019; 12:9. [PMID: 30760980 PMCID: PMC6361784 DOI: 10.3389/fnmol.2019.00009] [Citation(s) in RCA: 166] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 01/11/2019] [Indexed: 12/14/2022] Open
Abstract
Neuroblastoma is a neural crest derived malignancy of the peripheral nervous system and is the most common and deadliest tumor of infancy. It is characterized by clinical heterogeneity with a disease spectrum ranging from spontaneous regression without any medical intervention to treatment resistant tumors with metastatic spread and poor patient survival. The events that lead to the development of neuroblastoma from the neural crest have not been fully elucidated. Here we discuss factors and processes within the neural crest that when dysregulated have the potential to be initiators or drivers of neuroblastoma development. A more precise biological understanding of neuroblastoma causes and cell of origin is highly warranted. This will give valuable information for the development of medicines that specifically target molecules within neuroblastoma cells and also give hint about the mechanisms behind treatment resistance that is frequently seen in neuroblastoma.
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Affiliation(s)
- John Inge Johnsen
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet (KI), Stockholm, Sweden
| | - Cecilia Dyberg
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet (KI), Stockholm, Sweden
| | - Malin Wickström
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet (KI), Stockholm, Sweden
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33
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Baluchová S, Barek J, Tomé LI, Brett CM, Schwarzová-Pecková K. Vanillylmandelic and Homovanillic acid: Electroanalysis at non-modified and polymer-modified carbon-based electrodes. J Electroanal Chem (Lausanne) 2018. [DOI: 10.1016/j.jelechem.2018.03.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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34
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Nakagawara A, Li Y, Izumi H, Muramori K, Inada H, Nishi M. Neuroblastoma. Jpn J Clin Oncol 2018; 48:214-241. [PMID: 29378002 DOI: 10.1093/jjco/hyx176] [Citation(s) in RCA: 135] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Indexed: 02/07/2023] Open
Abstract
Neuroblastoma is one of the most common solid tumors in children and has a diverse clinical behavior that largely depends on the tumor biology. Neuroblastoma exhibits unique features, such as early age of onset, high frequency of metastatic disease at diagnosis in patients over 1 year of age and the tendency for spontaneous regression of tumors in infants. The high-risk tumors frequently have amplification of the MYCN oncogene as well as segmental chromosome alterations with poor survival. Recent advanced genomic sequencing technology has revealed that mutation of ALK, which is present in ~10% of primary tumors, often causes familial neuroblastoma with germline mutation. However, the frequency of gene mutations is relatively small and other aberrations, such as epigenetic abnormalities, have also been proposed. The risk-stratified therapy was introduced by the Japan Neuroblastoma Study Group (JNBSG), which is now moving to the Neuroblastoma Committee of Japan Children's Cancer Group (JCCG). Several clinical studies have facilitated the reduction of therapy for children with low-risk neuroblastoma disease and the significant improvement of cure rates for patients with intermediate-risk as well as high-risk disease. Therapy for patients with high-risk disease includes intensive induction chemotherapy and myeloablative chemotherapy, followed by the treatment of minimal residual disease using differentiation therapy and immunotherapy. The JCCG aims for better cures and long-term quality of life for children with cancer by facilitating new approaches targeting novel driver proteins, genetic pathways and the tumor microenvironment.
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Affiliation(s)
| | - Yuanyuan Li
- Laboratory of Molecular Biology, Life Science Research Institute, Saga Medical Center Koseikan
| | - Hideki Izumi
- Laboratory of Molecular Biology, Life Science Research Institute, Saga Medical Center Koseikan
| | | | - Hiroko Inada
- Department of Pediatrics, Saga Medical Center Koseikan
| | - Masanori Nishi
- Department of Pediatrics, Saga University, Saga 849-8501, Japan
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35
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Buller MC, Higbie CT, Tully TN, Crossland N, Wilson LD. Diagnostic Challenge. J Exot Pet Med 2018. [DOI: 10.1053/j.jepm.2017.10.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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36
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Rogasch JMM, Hundsdoerfer P, Furth C, Wedel F, Hofheinz F, Krüger PC, Lode H, Brenner W, Eggert A, Amthauer H, Schatka I. Individualized risk assessment in neuroblastoma: does the tumoral metabolic activity on 123I-MIBG SPECT predict the outcome? Eur J Nucl Med Mol Imaging 2017; 44:2203-2212. [PMID: 28808732 DOI: 10.1007/s00259-017-3786-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2017] [Accepted: 07/19/2017] [Indexed: 01/26/2023]
Abstract
PURPOSE Risk-adapted treatment in children with neuroblastoma (NB) is based on clinical and genetic factors. This study evaluated the metabolic tumour volume (MTV) and its asphericity (ASP) in pretherapeutic 123I-MIBG SPECT for individualized image-based prediction of outcome. METHODS This retrospective study included 23 children (11 girls, 12 boys; median age 1.8 years, range 0.3-6.8 years) with newly diagnosed NB consecutively examined with pretherapeutic 123I-MIBG SPECT. Primary tumour MTV and ASP were defined using semiautomatic thresholds. Cox regression analysis, receiver operating characteristic analysis (cut-off determination) and Kaplan-Meier analysis with the log-rank test for event-free survival (EFS) were performed for ASP, MTV, laboratory parameters (including urinary homovanillic acid-to-creatinine ratio, HVA/C), and clinical (age, stage) and genetic factors. Predictive accuracy of the optimal multifactorial model was determined in terms of Harrell's C and likelihood ratio χ 2. RESULTS Median follow-up was 36 months (range 7-107 months; eight patients showed disease progression/relapse, four patients died). The only significant predictors of EFS in the univariate Cox regression analysis were ASP (p = 0.029; hazard ratio, HR, 1.032 for a one unit increase), MTV (p = 0.038; HR 1.012) and MYCN amplification status (p = 0.047; HR 4.67). The mean EFS in patients with high ASP (>32.0%) and low ASP were 21 and 88 months, respectively (p = 0.013), and in those with high MTV (>46.7 ml) and low MTV were 22 and 87 months, respectively (p = 0.023). A combined risk model of either high ASP and high HVA/C or high MTV and high HVA/C best predicted EFS. CONCLUSIONS In this exploratory study, pretherapeutic image-derived and laboratory markers of tumoral metabolic activity in NB (ASP, MTV, urinary HVA/C) allowed the identification of children with a high and low risk of progression/relapse under current therapy.
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Affiliation(s)
- Julian M M Rogasch
- Department of Nuclear Medicine, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
| | - Patrick Hundsdoerfer
- Department of Pediatric Oncology/Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH), 10178, Berlin, Germany
| | - Christian Furth
- Department of Nuclear Medicine, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Florian Wedel
- Department of Nuclear Medicine, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Frank Hofheinz
- PET Center, Helmholtz Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
| | - Paul-Christian Krüger
- Institute for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany
| | - Holger Lode
- Department of Pediatric Oncology and Hematology, University Medicine Greifswald, Greifswald, Germany
| | - Winfried Brenner
- Department of Nuclear Medicine, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Angelika Eggert
- Department of Pediatric Oncology/Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Holger Amthauer
- Department of Nuclear Medicine, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Imke Schatka
- Department of Nuclear Medicine, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
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37
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Neuron-Specific Enolase Predicts Poor Outcome After Cardiac Arrest and Targeted Temperature Management: A Multicenter Study on 1,053 Patients. Crit Care Med 2017; 45:1145-1151. [PMID: 28426467 DOI: 10.1097/ccm.0000000000002335] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Outcome prediction after cardiac arrest is important to decide on continuation or withdrawal of intensive care. Neuron-specific enolase is an easily available, observer-independent prognostic biomarker. Recent studies have yielded conflicting results on its prognostic value after targeted temperature management. DESIGN, SETTING, AND PATIENTS We analyzed neuron-specific enolase serum concentrations 3 days after nontraumatic in-hospital cardiac arrest and out-of-hospital cardiac arrest and outcome of patients from five hospitals in Germany, Austria, and Italy. Patients were treated at 33°C for 24 hours. Cerebral Performance Category was evaluated upon ICU discharge. We performed case reviews of good outcome patients with neuron-specific enolase greater than 90 μg/L and poor outcome patients with neuron-specific enolase less than or equal to 17 μg/L (upper limit of normal). MEASUREMENTS AND MAIN RESULTS A neuron-specific enolase serum concentration greater than 90 μg/L predicted Cerebral Performance Category 4-5 with a positive predictive value of 99%, false positive rate of 0.5%, and a sensitivity of 48%. All three patients with neuron-specific enolase greater than 90 μg/L and Cerebral Performance Category 1-2 had confounders for neuron-specific enolase elevation. An neuron-specific enolase serum concentration less than or equal to 17 μg/L excluded Cerebral Performance Category 4-5 with a negative predictive value of 92%. The majority of 14 patients with neuron-specific enolase less than or equal to 17 μg/L who died had a cause of death other than hypoxic-ischemic encephalopathy. Specificity and sensitivity for prediction of poor outcome were independent of age, sex, and initial rhythm but higher for out-of-hospital cardiac arrest than for in-hospital cardiac arrest patients. CONCLUSION High neuron-specific enolase serum concentrations reliably predicted poor outcome at ICU discharge. Prediction accuracy differed and was better for out-of-hospital cardiac arrest than for in-hospital cardiac arrest patients. Our "in-the-field" data indicate 90 μg/L as a threshold associated with almost no false positives at acceptable sensitivity. Confounders of neuron-specific enolase elevation should be actively considered: neuron-specific enolase-producing tumors, acute brain diseases, and hemolysis. We strongly recommend routine hemolysis quantification. Neuron-specific enolase serum concentrations less than or equal to 17 μg/L argue against hypoxic-ischemic encephalopathy incompatible with reawakening.
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Ahmed AA, Zhang L, Reddivalla N, Hetherington M. Neuroblastoma in children: Update on clinicopathologic and genetic prognostic factors. Pediatr Hematol Oncol 2017; 34:165-185. [PMID: 28662353 DOI: 10.1080/08880018.2017.1330375] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Neuroblastoma is the most common extracranial solid tumor in childhood accounting for 8-10% of all childhood malignancies. The tumor is characterized by a spectrum of histopathologic features and a heterogeneous clinical phenotype. Modern multimodality therapy results in variable clinical response ranging from cure in localized tumors to limited response in aggressive metastatic disease. Accurate clinical staging and risk assessment based on clinical, surgical, biologic and pathologic criteria are of pivotal importance in assigning prognosis and planning effective treatment approaches. Numerous studies have analyzed the presence of several clinicopathologic and biologic factors in association with the patient's prognosis and outcome. Although patient's age, tumor stage, histopathologic classification, and MYCN amplification are the most commonly validated prognostic markers, several new gene mutations have been identified in sporadic and familial neuroblastoma cases that show association with an adverse outcome. Novel molecular studies have also added data on chromosomal segmental aberrations in MYCN nonamplified tumors. In this review, we provide an updated summary of the clinical, serologic and genetic prognostic indicators in neuroblastoma including classic factors that have consistently played a role in risk stratification of patients as well as newly discovered biomarkers that may show a potential significance in patients' management.
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Affiliation(s)
- Atif A Ahmed
- a Department of Pathology and Laboratory Medicine , Children's Mercy Hospital/University of Missouri , Kansas City , Missouri , USA
| | - Lei Zhang
- a Department of Pathology and Laboratory Medicine , Children's Mercy Hospital/University of Missouri , Kansas City , Missouri , USA
| | - Naresh Reddivalla
- b Department of Hematology-Oncology , Children's Mercy Hospital/University of Missouri , Kansas City , Missouri , USA
| | - Maxine Hetherington
- b Department of Hematology-Oncology , Children's Mercy Hospital/University of Missouri , Kansas City , Missouri , USA
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39
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Risk Stratification of Pediatric Patients With Neuroblastoma Using Volumetric Parameters of 18F-FDG and 18F-DOPA PET/CT. Clin Nucl Med 2017; 42:e142-e148. [PMID: 28072621 DOI: 10.1097/rlu.0000000000001529] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
PURPOSE This study determined the prognostic value of volumetric parameters derived from pretreatment F-FDG and F-DOPA PET/CT of neuroblastoma and their correlation with clinical and histopathologic features. PATIENTS AND METHODS A total of 25 children with neuroblastoma underwent pretreatment F-FDG and F-DOPA PET/CT within 4 weeks. The SUVmax of primary tumors on F-FDG and F-DOPA PET were recorded as SUVFDG and SUVDOPA, respectively. For volumetric parameters of primary tumors, 40% of SUVmax was used to generate volume of interest. If the 40% of SUVmax was below 2.5, an SUV threshold of 2.5 was used instead. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), dopaminergic tumor volume (DTV), and total lesion F-DOPA activity (TLDA) were recorded as F-FDG and F-DOPA volumetric parameters. All indices were compared between groups distinguished by survival status and clinical features, including bone marrow involvement, lymph node metastasis, amplification of the MYCN oncogene, invasive features on anatomic images, and risk categories. The Kaplan-Meier method and log-rank test were used to compare the survival curves between groups. RESULTS The median follow-up period was 28.2 months. Nonsurvivors (20%) tended to have lower SUVDOPA, DTV, and TLDA (P ≤ 0.05), and higher SUVFDG, MTV, and TLG (all P < 0.05). Lower F-DOPA uptake is associated with bone marrow and lymph node metastases (all P < 0.05). Higher F-FDG uptake is associated with MYCN amplification (all P < 0.05) and anatomic invasive features of tumors such as vascular encasement or adjacent organ invasion (TLG, P = 0.05). Only volumetric indices (DTV, TLDA, MTV, and TLG) significantly differed among risk groups (all P < 0.05). CONCLUSIONS Pretherapeutic F-DOPA and F-FDG PET provided complementary information, and both can be served for risk stratification. Volumetric indices of F-DOPA and F-FDG PET correlate more highly with risk grouping.
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40
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FX11 inhibits aerobic glycolysis and growth of neuroblastoma cells. Surgery 2016; 161:747-752. [PMID: 27919448 DOI: 10.1016/j.surg.2016.09.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 07/27/2016] [Accepted: 09/10/2016] [Indexed: 01/20/2023]
Abstract
BACKGROUND The MYC family of proteins promotes neuroblastoma tumorigenesis at least in part through the induction of aerobic glycolysis by promoting the transcription of key glycolytic enzymes, such as LDHA. FX11 is a selective inhibitor of LDHA that has demonstrated preclinical efficacy in adult cancers. Herein, we hypothesized that FX11 would inhibit aerobic glycolysis and block growth of neuroblastoma cells. METHODS We surveyed 3 MYCN-single copy and 5 MYCN-amplified neuroblastoma cell lines to correlate C-MYC/N-MYC protein levels with LDHA expression. Cell viability was measured with FX11 using a tetrazolium-based assay. Cell cycle analysis using propidium iodide with flow cytometry was performed to evaluate for growth arrest. Immunoblotting demonstrated PARP and Caspase 3 cleavage as evidence of apoptosis. RESULTS LDHA is frequently expressed in both MYCN--amplified and MYCN-single copy cell lines. N-MYC and C-MYC protein levels did not correlate with LDHA protein expression. FX11 inhibits aerobic glycolysis and growth in three MYCN-amplified and one MYCN-single copy neuroblastoma cell lines. FX11 induces modest G1 cell cycle arrest with selective induction of apoptosis. CONCLUSION Small molecule LDHA inhibition is capable of blocking aerobic glycolysis and growth of neuroblastoma cell lines in vitro and merits further in vivo evaluation of its preclinical efficacy in neuroblastomas.
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Newman EA, Nuchtern JG. Recent biologic and genetic advances in neuroblastoma: Implications for diagnostic, risk stratification, and treatment strategies. Semin Pediatr Surg 2016; 25:257-264. [PMID: 27955728 DOI: 10.1053/j.sempedsurg.2016.09.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Neuroblastoma is an embryonic cancer of neural crest cell lineage, accounting for up to 10% of all pediatric cancer. The clinical course is heterogeneous ranging from spontaneous regression in neonates to life-threatening metastatic disease in older children. Much of this clinical variance is thought to result from distinct pathologic characteristics that predict patient outcomes. Consequently, many research efforts have been focused on identifying the underlying biologic and genetic features of neuroblastoma tumors in order to more clearly define prognostic subgroups for treatment stratification. Recent technological advances have placed emphasis on the integration of genetic alterations and predictive biologic variables into targeted treatment approaches to improve patient survival outcomes. This review will focus on these recent advances and the implications they have on the diagnostic, staging, and treatment approaches in modern neuroblastoma clinical management.
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Affiliation(s)
- Erika A Newman
- Section of Pediatric Surgery, Department of Surgery, The University of Michigan, Ann Arbor, Michigan.
| | - Jed G Nuchtern
- Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
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42
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Marrano P, Irwin MS, Thorner PS. Heterogeneity of MYCN amplification in neuroblastoma at diagnosis, treatment, relapse, and metastasis. Genes Chromosomes Cancer 2016; 56:28-41. [PMID: 27465929 DOI: 10.1002/gcc.22398] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 07/24/2016] [Accepted: 07/25/2016] [Indexed: 12/14/2022] Open
Abstract
Amplification of the MYCN gene in neuroblastoma is associated with a poor prognosis and is considered to remain unchanged in post-treatment specimens and metastases. While heterogeneity of MYCN copy number in tumor cells has been reported, serial samples have only been studied in a limited way, and the biologic relevance of this finding is not well understood. We used in situ hybridization on paraffin sections of 102 specimens from 30 patients with MYCN-amplified neuroblastoma to determine MYCN copy number in the primary tumor, pre- and post-treatment, and in metastatic samples. Nineteen cases (63%) showed diffuse MYCN amplification in all samples tested. Nine cases (30%) showed a reduction in MYCN copy number: five cases with diffuse amplification subsequently showed focal amplification, one case with diffuse MYCN amplification showed MYCN gain after treatment, and three focally amplified cases were non-amplified in later specimens. In two cases (7%), focal amplification became diffuse in subsequent samples. Histology was not predictive of the temporal or spatial pattern of MYCN amplification for a particular tumor. If extent of amplification (focal vs. diffuse) is not considered, 26/30 (87%) of cases were consistently MYCN-amplified. However, our data suggest that MYCN status can be heterogeneous between tumor sites, during tumor progression or following treatment, challenging the notion that MYCN copy number does not change for a particular neuroblastoma. Assessing the biologic significance of MYCN heterogeneity will require larger studies of clinically annotated tumor samples, and will depend on interpreting heterogeneity in MYCN status in combination with other genetic changes. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Paula Marrano
- Department of Pediatric Laboratory Medicine, the Hospital for Sick Children, Toronto, Canada
| | - Meredith S Irwin
- Department of Pediatrics, the Hospital for Sick Children, Toronto, Canada.,Department of Pediatrics, University of Toronto, Toronto, Canada
| | - Paul S Thorner
- Department of Pediatric Laboratory Medicine, the Hospital for Sick Children, Toronto, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
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Sekula P, Pressler JB, Sauerbrei W, Goebell PJ, Schmitz-Dräger BJ. Assessment of the extent of unpublished studies in prognostic factor research: a systematic review of p53 immunohistochemistry in bladder cancer as an example. BMJ Open 2016; 6:e009972. [PMID: 27531721 PMCID: PMC5013379 DOI: 10.1136/bmjopen-2015-009972] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 06/20/2016] [Accepted: 07/05/2016] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVES When study groups fail to publish their results, a subsequent systematic review may come to incorrect conclusions when combining information only from published studies. p53 expression measured by immunohistochemistry is a potential prognostic factor in bladder cancer. Although numerous studies have been conducted, its role is still under debate. The assumption that unpublished studies too harbour evidence on this research topic leads to the question about the attributable effect when adding this information and comparing it with published data. Thus, the aim was to identify published and unpublished studies and to explore their differences potentially affecting the conclusion on its function as a prognostic biomarker. DESIGN Systematic review of published and unpublished studies assessing p53 in bladder cancer in Germany between 1993 and 2007. RESULTS The systematic search revealed 16 studies of which 11 (69%) have been published and 5 (31%) have not. Key reason for not publishing the results was a loss of interest of the investigators. There were no obviously larger differences between published and unpublished studies. However, a meaningful meta-analysis was not possible mainly due to the poor (ie, incomplete) reporting of study results. CONCLUSIONS Within this well-defined population of studies, we could provide empirical evidence for the failure of study groups to publish their results that was mainly caused by loss of interest. This fact may be coresponsible for the role of p53 as a prognostic factor still being unclear. We consider p53 and the restriction to studies in Germany as a specific example, but the critical issues are probably similar for other prognostic factors and other countries.
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Affiliation(s)
- Peggy Sekula
- Institute for Medical Biometry and Statistics, Faculty of Medicine and Medical Center – University of Freiburg,Freiburg, Germany
| | - Julia B Pressler
- Department of Urology, Schön-Klinik Nürnberg Fürth, Fürth, Germany
- KUNO University Children's Hospital, Regensburg, Germany
| | - Willi Sauerbrei
- Institute for Medical Biometry and Statistics, Faculty of Medicine and Medical Center – University of Freiburg,Freiburg, Germany
| | - Peter J Goebell
- Department of Urology, University Clinic of Erlangen, Waldkrankenhaus St. Marien, Erlangen, Germany
| | - Bernd J Schmitz-Dräger
- Department of Urology, Schön-Klinik Nürnberg Fürth, Fürth, Germany
- Department of Urology, University Clinic of Erlangen, Waldkrankenhaus St. Marien, Erlangen, Germany
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Gaiser MR, Daily K, Hoffmann J, Brune M, Enk A, Brownell I. Evaluating blood levels of neuron specific enolase, chromogranin A, and circulating tumor cells as Merkel cell carcinoma biomarkers. Oncotarget 2016; 6:26472-82. [PMID: 26299616 PMCID: PMC4694915 DOI: 10.18632/oncotarget.4500] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 06/18/2015] [Indexed: 12/15/2022] Open
Abstract
Background Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer. Although used to monitor MCC patients, the clinical utility of neuron-specific enolase (NSE) and chromogranin A (ChrA) blood levels is untested. EpCAM-positive circulating tumor cells (CTC) reflect disease status in several epithelial tumors. Here we investigate the use of NSE and ChrA blood levels and CTC counts as biomarkers for MCC disease behavior. Methods NSE and ChrA blood levels from 60 patients with MCC were retrospectively analyzed; 30 patients were additionally screened for CTC. Biomarker values were correlated to clinical parameters. Results Despite routine use by some physicians, NSE and ChrA blood levels did not correlate with progression free survival, disease specific survival, or MCC recurrence. We found CTC in 97% of tested MCC patients. CTC counts were elevated in patients with active disease, suggesting their potential use in monitoring MCC. Conclusion NSE and ChrA levels were not effective in predicting outcomes or detecting recurrences of MCC. In contrast, CTC counts have potential utility as a biomarker for MCC disease behavior.
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Affiliation(s)
- Maria Rita Gaiser
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
| | - Kenneth Daily
- Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jochen Hoffmann
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
| | - Maik Brune
- Department of Internal Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany
| | - Alexander Enk
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
| | - Isaac Brownell
- Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Parisi MT, Eslamy H, Park JR, Shulkin BL, Yanik GA. 131I-Metaiodobenzylguanidine Theranostics in Neuroblastoma: Historical Perspectives; Practical Applications. Semin Nucl Med 2016; 46:184-202. [DOI: 10.1053/j.semnuclmed.2016.02.002] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Vizin T, Kos J. Gamma-enolase: a well-known tumour marker, with a less-known role in cancer. Radiol Oncol 2015; 49:217-26. [PMID: 26401126 PMCID: PMC4577217 DOI: 10.1515/raon-2015-0035] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2015] [Accepted: 07/13/2015] [Indexed: 12/16/2022] Open
Abstract
Background Gamma-enolase, known also as neuron-specific enolase (NSE), is an enzyme of the glycolytic pathway, which is expressed predominantly in neurons and cells of the neuroendocrine system. As a tumour marker it is used in diagnosis and prognosis of cancer; however, the mechanisms enrolling it in malignant progression remain elusive. As a cytoplasmic enzyme gamma-enolase is involved in increased aerobic glycolysis, the main source of energy in cancer cells, supporting cell proliferation. However, different cellular localisation at pathophysiological conditions, proposes other cellular engagements. Conclusions The C-terminal part of the molecule, which is not related to glycolytic pathway, was shown to promote survival of neuronal cells by regulating neuronal growth factor receptor dependent signalling pathways, resulting also in extensive actin cytoskeleton remodelling. This additional function could be important also in cancer cells either to protect cells from stressful conditions and therapeutic agents or to promote tumour cell migration and invasion. Gamma-enolase might therefore have a multifunctional role in cancer progression: it supports increased tumour cell metabolic demands, protects tumour cells from stressful conditions and promotes their invasion and migration.
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Affiliation(s)
- Tjasa Vizin
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Janko Kos
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
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48
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Takamura S, Teraki Y. Case of clear cell sarcoma in the left buttock in which serum neuron-specific enolase was a useful marker for monitoring disease progression. J Dermatol 2015; 42:621-4. [DOI: 10.1111/1346-8138.12854] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Accepted: 02/09/2015] [Indexed: 11/30/2022]
Affiliation(s)
- Saori Takamura
- Department of Dermatology; Saitama Medical Center; Saitama Medical University; Saitama Japan
| | - Yuichi Teraki
- Department of Dermatology; Saitama Medical Center; Saitama Medical University; Saitama Japan
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49
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Angelini P, Baruchel S, Marrano P, Irwin MS, Thorner PS. The neuroblastoma and ganglion components of nodular ganglioneuroblastoma are genetically similar: evidence against separate clonal origins. Mod Pathol 2015; 28:166-76. [PMID: 25081755 DOI: 10.1038/modpathol.2014.90] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Revised: 04/18/2014] [Accepted: 04/19/2014] [Indexed: 12/12/2022]
Abstract
Nodular ganglioneuroblastoma is characterized by a macroscopic nodule of neuroblastoma within a ganglioneuromatous component. These two components have been considered to originate from separate clones, with the neuroblastoma clone accounting for the clinical behavior of nodular ganglioneuroblastoma. In order to investigate the clonal origin of the cellular components (neuroblasts, ganglion cells, and Schwann cells) of nodular ganglioneuroblastoma, paraffin-embedded tumor samples from eight cases were analyzed by single nucleotide polymorphism array and in situ hybridization. DNA was extracted separately from neuroblastomatous and ganglioneuromatous areas. By in situ hybridization, MYCN gain (4-10 gene copies/nucleus) was detected in 7/8 neuroblastoma samples. In ganglioneuromatous regions, gains were also detected in ganglion cells but not in Schwann cells. Single-nucleotide polymorphism array studies identified chromosome losses (11q and 14q) and gains (12, 13q, 17q and 18q) in the neuroblastoma component, whereas the ganglioneuromatous component showed fewer or no genetic alterations. There were no unique copy number changes distinguishing nodular ganglioneuroblastoma from other subtypes of neuroblastoma. By in situ hybridization, ganglion cells but not Schwann cells showed the same alterations detected in neuroblasts. Thus, neuroblasts and ganglion cells in nodular ganglioneuroblastoma are genetically related and may arise from the same clone. In contrast, the Schwann cells have a different origin and may be derived from a non-neoplastic neural crest precursor. Our results suggest that the clinical behavior of nodular ganglioneuroblastoma cannot be explained by the presence of separate clones with distinct genetic signatures.
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Affiliation(s)
- Paola Angelini
- Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Sylvain Baruchel
- 1] Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada [2] Department of Pediatrics, University of Toronto, University of Toronto, Toronto, ON, Canada
| | - Paula Marrano
- Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Meredith S Irwin
- 1] Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada [2] Department of Pediatrics, University of Toronto, University of Toronto, Toronto, ON, Canada
| | - Paul S Thorner
- 1] Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
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Abstract
Neuroblastoma (NB) is the third most common pediatric cancer. Although NB accounts for 7% of pediatric malignancies, it is responsible for more than 10% of childhood cancer-related mortality. Prognosis and treatment are determined by clinical and biological risk factors. Estimated 5-year survival rates for patients with non-high-risk and high-risk NB are more than 90% and less than 50%, respectively. Recent clinical trials have continued to reduce therapy for patients with non-high-risk NB, including the most favorable subsets who are often followed with observation approaches. In contrast, high-risk patients are treated aggressively with chemotherapy, radiation, surgery, and myeloablative and immunotherapies.
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