Neuroblastoma (NB) is the most common extracranial solid tumor in children and has the features of high recurrence rate and low survival rate, and therefore, early diagnosis, treatment response evaluation, and recurrence monitoring are of great significance for NB patients. Liquid biopsy refers to the detection of cells and nucleic acids in fluid specimens, mainly blood. It is noninvasive and can overcome tumor heterogeneity, thus making it possible to achieve the early diagnosis and dynamic detection of NB. This review introduces the latest advances in clinical research on the application of liquid biopsy in NB.
Child ; Humans ; Liquid Biopsy ; Neuroblastoma/diagnosis*

Neuroblastoma is a major cause of cancer death in early childhood, and its timely and correct diagnosis is critical. Gene expression datasets have recently been considered as a powerful tool for cancer diagnosis and subtype classification. However, no attempts have yet been made to apply deep learning using gene expression to neuroblastoma classification, although deep learning has been applied to cancer diagnosis using image data. Taking the International Neuroblastoma Staging System stages as multiple classes, we designed a deep neural network using the gene expression patterns and stages of neuroblastoma patients. Despite a small patient population (n = 280), stage 1 and 4 patients were well distinguished. If it is possible to replicate this approach in a larger population, deep learning could play an important role in neuroblastoma staging.
Classification ; Dataset ; Diagnosis ; Gene Expression ; Humans ; Learning ; Neuroblastoma

BACKGROUND: Neurotrophin-3 (NT-3), a member of the NT family, has only been considered an ancillary compound that provides anti-apoptotic benefits by inactivating tropomyosin receptor kinase C (TrkC)-induced apoptotic signals. However, little is known about the clinical relevance of NT-3 expression itself in neuroblastoma. The purpose of this study was to assess NT-3 expression in patients with neuroblastoma and its relevance to clinicopathologic findings and treatment outcomes. METHODS: In this study, expression of NT-3 and TrkC was analyzed using immunohistochemistry in 240 patients with newly diagnosed neuroblastoma. RESULTS: The results of the study revealed that NT-3 expression was associated with older age at diagnosis, localized tumors, and more differentiated tumors but was not associated with early treatment response (degree of residual tumor volume after three cycles of chemotherapy) and progression-free survival (PFS). However, when analysis was confined to patients with MYCN amplified tumors, NT-3 expression was associated with better early treatment response with borderline significance (P = 0.092) and higher PFS (86.9% vs. 58.2%; P = 0.044). In multivariate analysis in patients with MYCN amplified tumors, NT-3 was independent prognostic factor (hazard ratio, 0.246; 95% confidence interval, 0.061–0.997; P = 0.050). In another subgroup analysis, the early treatment response was better if NT-3 was expressed in patients without TrkC expression (P = 0.053) while it was poorer in patients with TrkC expression (P = 0.023). CONCLUSION: This study suggests that NT-3 expression in neuroblastoma has its own clinical significance independent of TrkC expression, and its prognostic significance differs depending on the status of MYCN amplification and/or TrkC expression.
Diagnosis ; Disease-Free Survival ; Humans ; Immunohistochemistry ; Multivariate Analysis ; Neoplasm, Residual ; Neuroblastoma ; Phosphotransferases ; Tropomyosin

PURPOSE: Diagnostic I-131 MIBG scintigraphy is an important imaging modality for evaluation of patients with neuroblastoma (NB) especially in centers where I-123 MIBG is not available. Single photon emission computed tomography/computed tomography (SPECT/CT) could potentially improve lesion detection over planar scintigraphy, but studies regarding its usefulness as an add-on to diagnostic I-131 MIBG scintigraphy are limited. This study aimed to determine the usefulness and factors related to usefulness of SPECT/CT in diagnostic I-131 MIBG scintigraphy in NB patients.METHODS: Usefulness of SPECT/CT for lesion detection, lesion localization, resolving suspicious findings, and clarifying the nature of lesions on anatomical imaging were retrospectively reviewed in 86 diagnostic planar I-131 MIBG scintigrams with add-on SPECT/CT.RESULTS: SPECT/CT detected additional lesions in 23.2%(20/86), helped localize lesions in 21.1%(8/38), resolved suspicious findings in 85.7%(6/7), determined functional status of lesions on anatomical imaging in 94.4%(17/18), and changed diagnosis from a negative to a positive study in 19.5%(8/41). Independent predictors of SPECT/CT being useful included presence of suspicious findings on planar imaging (OR 99.08; 95% C.I. 6.99–1404.41; p = 0.001), positive findings on planar imaging (OR 4.61; 95% C.I. 1.05, 20.28; p < 0.001), and presence of structural lesions on anatomical imaging (OR 32.54; 95% C.I. 5.37–196.96; p < 0.001).CONCLUSION: SPECT/CT is a useful add-on to diagnostic planar I-131 MIBG scintigraphy. Predictors of usefulness of SPECT/CT include suspicious or positive findings on planar scintigraphy and the presence of structural lesions on anatomical imaging.
3-Iodobenzylguanidine ; Diagnosis ; Humans ; Neuroblastoma ; Radionuclide Imaging ; Retrospective Studies

Nephrotic syndrome in the first year of life, characterized by renal dysfunction and proteinuria, is associated with a heterogeneous group of disorders. These disorders are often related to genetic mutations, but the syndrome can also be caused by a variety of other diseases. We report an infant with nephrotic syndrome associated with a neuroblastoma. A 6-month-old girl was admitted with a 10% weight loss over 10 days and nephrotic-range proteinuria. She was ill-looking, and her blood pressure was higher than normal for her age. Her cystatin-C glomerular filtration rate was decreased, and levels of plasma renin, aldosterone, and catecholamines were elevated. Renal ultrasonography and abdominal computed tomography showed a retroperitoneal prevertebral mass encasing both renal arteries and the left renal vein. The mass was partially resected laparoscopically, and the pathologic diagnosis was neuroblastoma. Findings on a simultaneous renal biopsy were unremarkable. The patient was treated with chemotherapy and several anti-hypertensive drugs, including an alpha blocker. Two months later, the mass had decreased in size and the proteinuria and hypertension were gradually improving. In an infant with abnormal renin-angiotensin system activation, severe hypertension, and nephrotic-range proteinuria, neuroblastoma can be considered in the differential diagnosis.
Aldosterone ; Antihypertensive Agents ; Biopsy ; Blood Pressure ; Catecholamines ; Diagnosis ; Diagnosis, Differential ; Drug Therapy ; Female ; Glomerular Filtration Rate ; Humans ; Hypertension ; Infant ; Nephrotic Syndrome ; Neuroblastoma ; Plasma ; Proteinuria ; Renal Artery ; Renal Veins ; Renin ; Renin-Angiotensin System ; Ultrasonography ; Weight Loss

Spontaneous rupture with internal bleeding of solid tumors has rarely been described at the time of diagnosis or during chemotherapy. This rare event must be regarded as a life threatening condition. In these emergency situations, control of hemorrhage, which is life-saving, can be achieved by transcatheter arterial embolization (TAE) and/or surgical resection. This report describes two infants presenting with acute hemorrhagic shock due to spontaneous tumor rupture of hepatoblastoma and neuroblastoma during chemotherapy. TAE successfully arrested the tumor bleeding and a visibly reduced the tumor size in both children. Spontaneous rupture of solid tumors occur infrequently in children, but is a life threatening situation. Careful monitoring for the occurrence of this rare event especially in very young children presenting with a large tumor mass.
Child ; Diagnosis ; Drug Therapy ; Emergencies ; Hemorrhage ; Hepatoblastoma ; Humans ; Infant ; Neuroblastoma ; Rupture ; Rupture, Spontaneous ; Shock, Hemorrhagic

BACKGROUND: To evaluate the value of random urinary vanillylmandelic acid (VMA) as a surrogate marker for monitoring tumor response and predicting outcome in patients with neuroblastoma (NB). METHODS: Medical records of 91 patients newly diagnosed with NB at the Samsung Medical Center between June 2014 and August 2017 were reviewed. Clinical associations and other prognostic factors, including age at diagnosis, stage, pathologic subtype, MYCN amplification, and other cytogenetic aberrations, were analyzed. Furthermore, the significance of random urinary VMA level in predicting outcome and tumor response was also evaluated. RESULTS: The median random urinary VMA level at diagnosis was 27.9 (range: 1.7–600) mg/g creatinine. Abdominal primary site, male sex, advanced stage, less differentiated pathology (poorly differentiated, undifferentiated), 11q deletion, and high-risk tumor were associated with a higher VMA level at diagnosis. The VMA level decreased during chemotherapy (28.4%, 16.9%, and 9.6% of the VMA level at diagnosis after 3, 6, and 9 cycles of chemotherapy, respectively). A higher VMA level at diagnosis tends to be associated with a better overall survival in high-risk patients with borderline significance (58.3±18.6% vs. 76.5±13.4%, P=0.050). However, in the multivariate analysis, the VMA level was not a significant predictor of survival. A slower reduction in VMA level during chemotherapy was not associated with a worse overall survival. However, event free survival was significantly better in the rapid responder group. CONCLUSION: A higher VMA level was associated with high-risk features at diagnosis of NB. Random urinary VMA is a valuable marker for monitoring NB response during chemotherapy.
Biomarkers ; Chromosome Aberrations ; Creatinine ; Diagnosis ; Disease-Free Survival ; Drug Therapy ; Humans ; Male ; Medical Records ; Multivariate Analysis ; Neuroblastoma* ; Pathology ; Prognosis ; Vanilmandelic Acid*

PURPOSE: The purpose of this study is to investigate the clinical significance of tyrosine hydroxylase (TH) expression in peripheral blood (PB) at diagnosis in patients with neuroblastoma. MATERIALS AND METHODS: TH mRNA expression in PB was measured by reverse transcription quantitative real-time polymerase chain reaction in 210 patients who were newly diagnosed with neuroblastoma from July 2005 to June 2015 and the clinical significance of TH expression in PB at diagnosis was evaluated. RESULTS: TH expression was positive in 60 patients (28.6%). Fifty of 60 TH-positive patients had metastatic tumors and the remaining 10 had localized tumors. TH expression was associated with high-risk features (i.e., advanced stage, older age, unfavorable pathology, and MYCN amplification) at diagnosis. Among TH-positive patients, higher TH expression level was observed in high-risk patients than in low- or intermediate-risk patients (p=0.035). The probability of 5-year progression-free survival (PFS) was lower in TH-positive patients than in TH-negative patients (63.8±6.9% vs. 94.7±2.1%, p < 0.001). In analysis confined to high-risk patients, the 5-year probability of PFS remained lower in TH-positive patients (55.7±8.2% vs. 89.6±5.8%, p < 0.001). Among TH-positive patients, a higher expression level of TH was associated with a worse outcome. In multivariate analyses, positive TH expression in PB at diagnosis was an independent poor prognostic factor for PFS. CONCLUSION: The treatment intensity should be tailored according to TH expression in PB at diagnosis.
Diagnosis* ; Disease-Free Survival ; Humans ; Multivariate Analysis ; Neuroblastoma* ; Pathology ; Polymerase Chain Reaction ; Real-Time Polymerase Chain Reaction ; Reverse Transcription ; RNA, Messenger* ; Tyrosine 3-Monooxygenase* ; Tyrosine*

We present a case of a fetal adrenal hemorrhage, a rare disease in fetal life, detected prenatally at 36 weeks' gestation by ultrasound. Routine ultrasound examination at 36 weeks' gestation by primary obstetrician showed a cyst on the fetal suprarenal area. Initially, the suspected diagnosis was a fetal adrenal hemorrhage, but we should diagnose differently from neuroblastoma. Subsequent ultrasound examination at 38 and 39 weeks' gestation showed increase of the cyst in size. A 3.34-kg-male neonate was born by spontaneous vaginal delivery at 39 weeks' gestation. The diagnosis of adrenal hemorrhage was confirmed by postnatal follow-up sonograms and magnetic resonance imaging. Course and sonographic signs were typical for adrenal hemorrhage and the neonate was therefore managed without surgical exploration.
Diagnosis ; Follow-Up Studies ; Hemorrhage* ; Humans ; Infant, Newborn ; Magnetic Resonance Imaging ; Neuroblastoma ; Pregnancy ; Prenatal Diagnosis* ; Rare Diseases ; Ultrasonography

A 3-year-old boy presented to our emergency department with a 3-week history of pain in the bilateral hip and abdomen that had persisted through antibiotic therapy based on diagnosis of acute osteomyelitis. At presentation, he had fever, anemia, and increased concentration of lactate dehydrogenase. After the identification of a left adrenal mass indicating neuroblastoma on computed tomography scan, he was admitted to the hospital by a pediatric oncologist. Subsequently, positron emission tomography and bone scintigraphy showed disseminated metastasis to the bone and bone marrow, and neuroblastoma was pathologically confirmed. This case highlights the importance of differential diagnosis of non-traumatic hip pain in toddlers considering the protean manifestations of neuroblastoma.
Abdomen* ; Anemia ; Bone Marrow ; Child ; Child, Preschool* ; Diagnosis ; Diagnosis, Differential ; Emergencies ; Emergency Service, Hospital ; Fever ; Hip* ; Humans ; L-Lactate Dehydrogenase ; Male* ; Neoplasm Metastasis ; Neuroblastoma* ; Osteomyelitis ; Positron-Emission Tomography ; Radionuclide Imaging