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Abstract Background Neuroblastoma (NB) is a highly heterogeneous tumor, and more than half of newly diagnosed NB are associated with extensive metastases. Accurately characterizing the heterogeneity of whole-body tumor lesions remains clinical challenge. This study aims to quantify whole-tumoral metabolic heterogeneity (WMH) derived from whole-body tumor lesions, and investigate the prognostic value of WMH in NB. Methods We retrospectively enrolled 95 newly diagnosed pediatric NB patients in our department. Traditional semi-quantitative PET/CT parameters including the maximum standardized uptake value (SUVmax), the mean standardized uptake value (SUVmean), the peak standardized uptake value (SUVpeak), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured. These PET/CT parameters were expressed as PSUVmax, PSUVmean, PSUVpeak, PMTV, PTLG for primary tumor, WSUVmax, WSUVmean, WSUVpeak, WMTV, WTLG for whole-body tumor lesions. The metabolic heterogeneity was quantified using the areas under the curve of the cumulative SUV-volume histogram index (AUC-CSH index). Intra-tumoral metabolic heterogeneity (IMH) and WMH were extracted from primary tumor and whole-body tumor lesions, respectively. The outcome endpoints were overall survival (OS) and progression-free survival (PFS). Survival analysis was performed utilizing the univariate and multivariate Cox proportional hazards regression. The optimal cut-off values for metabolic parameters were obtained by receiver operating characteristic curve (ROC). Results During follow up, 27 (28.4%) patients died, 21 (22.1%) patients relapsed and 47 (49.5%) patients remained progression-free survival, with a median follow-up of 35.0 months. In survival analysis, WMTV and WTLG were independent indicators of PFS, and WMH was an independent risk factor of PFS and OS. However, IMH only showed association with PFS and OS. In addition to metabolic parameters, the International Neuroblastoma Staging System (INSS) was identified as an independent risk factor for PFS, and neuron-specific enolase (NSE) served as an independent predictor of OS. Conclusion WMH was an independent risk factor for PFS and OS, suggesting its potential as a novel prognostic marker for newly diagnosed NB patients.

Abstract Background Lymphatic leakage is one of the postoperative complications of neuroblastoma. The purpose of this study is to summarize the clinical characteristics and risk factors of lymphatic leakage and try to find effective prevention and treatment measures. Methods A retrospective study included 186 children with abdominal neuroblastoma, including 32 children of lymphatic leakage and 154 children of non-lymphatic leakage. The clinical information, surgical data, postoperative abdominal drainage, treatment of lymphatic leakage and prognosis of the two groups were collected and analyzed. Results The incidence of lymphatic leakage in this cohort was 14% (32 children). Through univariate analysis of lymphatic leakage group and non-lymphatic leakage group, we found that lymphatic leakage increased the complications, prolonged the time of abdominal drainage and hospitalization, and delayed postoperative chemotherapy (p

Abstract Objective To investigate the clinical features, treatment strategies, and prognosis of neuroblastoma with bilateral blindness. Methods The clinical data of five patients with bilateral blindness neuroblastoma admitted to Beijing Children’s Hospital from April 2018 to September 2020 were retrospectively collected to summarize their clinical characteristics. Results All patients were female and the median age at presentation was 25 (23, 41) months. The median intervention time from the onset of symptoms of bilateral blindness to the start of treatment was 10 (10, 12) days. All five cases were staged as stage M and grouped as high risk. Four cases were MYCN gene amplification and one case was MYCN acquisition. Five children were treated according to a high-risk neuroblastoma treatment protocol. Four children did not recover their vision after treatment, and one case improved to have light perception. All patients were effectively followed up for a median of 20 (12, 31) months, with three deaths, one tumor-free survival, and one recurrent tumor-bearing survival. Conclusion Neuroblastoma with bilateral blindness is rare in the clinic, mostly in children of young age, and is often associated with MYCN amplification and multiple metastases. Early hormone shock therapy and optic nerve decompression are beneficial for preserving the child’s vision. A joint multi-disciplinary treatment may help in the formulation of treatment decisions. Achieving a balance between good visual preservation and survival within the short optic nerve neurotherapeutic window is extremely challenging.

Abstract We report two children with hepatoblastoma (HB) with a history of neonatal necrotizing enterocolitis (NEC). Case 1 was diagnosed with HB at 5 months of age. Liver enlargement was found during the NEC operation at 3 months of age and then was clinically diagnosed by imaging. After six chemotherapy courses, a partial hepatectomy was performed. Three months after ceasing the chemotherapy, a chest computed tomography scan suggested that distant metastasis of the tumor should be considered, and the lesion was removed. However, 9 months after the operation, alpha‐fetoprotein concentrations were increased, and abdominal imaging showed a recurrence of the tumor in situ, resulting in a hepatectomy. Case 2 was diagnosed with NEC shortly after birth and underwent an intestinal resection and anastomosis 1 month later. He was diagnosed with HB at 3 years of age. Hepatectomy was performed after five courses of chemotherapy. Chemotherapy was stopped after 10 courses, and alpha‐fetoprotein concentrations were normal. At present, both children have survived and are in a healthy condition. Physicians should be aware of the possibility of HB and a history of NEC in children. Premature birth and low birth weight are common factors leading to the pathogenesis of HB and NEC. The association between these two diseases requires further study.

Abstract Recently, telomerase reverse transcriptase (TERT) gene rearrangements have been identified in neuroblastoma (NB), the typical pathological type of neuroblastic tumours (NTs); however, the prevalence of TERT rearrangements in other types of NT remains unknown. This study aimed to develop a practical method for detecting TERT defects and to evaluate the clinical relevance of TERT rearrangements as a biomarker for NT prognosis. A TERT break‐apart probe for fluorescence in situ hybridisation (FISH) was designed, optimised, and applied to assess the genomic status of TERT in Chinese children with NTs at the Beijing Children's Hospital from 2016 to 2019. Clinical, histological, and genetic characteristics of TERT‐rearranged NTs were further addressed. Genomic TERT rearrangements could be effectively detected by FISH and were mutually exclusive with MYCN amplification. TERT rearrangements were identified in 6.0% (38/633) of NTs overall, but 12.4% (31/250) in high‐risk patients. TERT rearrangements identified a subtype of aggressive NTs with the characteristics of Stage 3/4, high‐risk category, over 18 months old, and presenting all histological subtypes of NB and ganglioneuroblastoma nodular. Moreover, TERT rearrangements were significantly associated with elevated TERT expression levels and decreased survival chances. Multivariable analysis confirmed that it was an independent prognostic marker for NTs. FISH is an easily applicable method for evaluating TERT defects, which define a subgroup of NTs with unfavourable prognosis. TERT rearrangements would contribute to characterising NT molecular signatures in clinical practice.

Pediatric hepatoblastoma (HB) is the most common primary liver malignancy in infants and children. With great diversity and plasticity, tumor-infiltrating neutrophils were one of the most determining factors for poor prognosis in many malignant tumors. In this study, through bulk RNA sequencing for sorted blood and tumor-infiltrated neutrophils and comparison of neutrophils in tumor and para-tumor tissue by single-cell sequencing, we found that intratumoral neutrophils were composed of heterogenous functional populations at different development stages. Our study showed that terminally differentiated neutrophils with active ferroptosis prevailed in tumor tissue, whereas, in para-tumor, pre-fate naïve neutrophils were dominant and ferroptotic neutrophils dispersed in a broad spectrum of cell maturation. Gene profiling and in vitro T-cell coculture experiment confirmed that one of main functional intratumoral neutrophils was mainly immunosuppressive, which relied on the activation of ferroptosis. Combining the bulk RNA-seq, scRNA-seq data, and immunochemistry staining of tumor samples, CXCL12/CXCR4 chemotaxis pathway was suggested to mediate the migration of neutrophils in tumors as CXCR4 highly expressed by intratumoral neutrophils and its ligand CXCL12 expressed much higher level in tumor than that in para-tumor. Moreover, our study pinpointed that infiltrated CXCR4hi neutrophils, regardless of their differential distribution of cell maturation status in HB tumor and para-tumor regions, were the genuine perpetrators for immune suppression. Our data characterized the ferroptosis-dependent immunosuppression energized by intratumoral CXCR4 expression neutrophils and suggest a potential cell target for cancer immunotherapies.

Abstract Objective To summarize the clinical characteristics of children with adrenocortical carcinoma (ACC) and preliminarily explore the indications for and efficacy of neoadjuvant chemotherapy in certain patients. Methods The data of 49 children with adrenocortical tumors (ACT) in the past 15 years were retrospectively analyzed, and after pathology assessment using Weiss system grading, 40 children diagnosed with ACC were included. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and three-dimensional (3D) reconstruction of contrast-enhanced computed tomography data were used to evaluate the response to neoadjuvant chemotherapy. Results Forty patients (17 males, 23 females) with ACC were enrolled. Abnormal hormone levels were common in children with ACC (n = 31), and in terms of clinical presentation, sexual precocity was the most common (n = 14, 35.0%), followed by Cushing’s syndrome (n = 12, 30.0%). Seven of 40 children received neoadjuvant chemotherapy due to a maximum lesion diameter greater than 10 cm (n = 4), invasion of surrounding tissues (n = 2), intravenous tumor thrombus (n = 2), and/or distant metastasis (n = 2); 2 patients achieved partial response, and 5 had stable disease according to the RECIST 1.1 standard. Furthermore, 3D tumor volume reconstruction was performed in 5 children before and after neoadjuvant chemotherapy. Tumor volumes were significantly reduced in all 5 children, with a median volume reduction of 270 (interquartile range, IQR 83, 293) (range: 49–413) ml. After surgery with/without chemotherapy, the 5-year overall survival rate for all children was 90.0% (95% CI-confidence interval 80.0–100.0%), and the 5-year event-free survival rate was 81.5% (95% CI 68.0–97.7%). Conclusion In the diagnosis and treatment of pediatric ACC, a comprehensive endocrine evaluation is necessary to facilitate early diagnosis. Surgery and chemotherapy are important components of ACC treatment, and neoadjuvant chemotherapy should be considered for children with ACC who meet certain criteria, such as a large tumor, distant metastases, or poor general condition.

Introduction: Bilateral primary adrenal tumors are rare, and the majority of cases present the same histology. Bilateral adrenal tumors with different histology are extremely uncommon. Case presentation: A 6-month-old male presented with abdominal distension and excessive crying. Physical examination revealed a blood pressure (BP) of 108/80 mmHg, centripetal obesity, a “full moon” facial appearance, mild abdominal distension, tenderness to palpation, and no palpable masses. Bilateral adrenal tumors were found ultrasound. Contrast-enhanced computed tomography (CT) showed a soft tissue mass of 3.2 cm in diameter in the right adrenal gland and a mass of 2.1 cm in diameter in the left adrenal gland. Serum cortisol was 1563 nmol/L (normal: 96–551 nmol/L). After ruling out distant metastases, the patient underwent a right-sided adrenalectomy and a left adrenal tumor enucleation to preserve as much normal tissue as possible on the left adrenal gland. Pathology revealed a right adrenal cortical carcinoma and left adrenal poorly differenciated neuroblastoma. Post-surgery, the patient received hydrocortisone supplementation as needed and neuroblastoma-targeted chemotherapy. Hydrocortisone replacement was progressively reduced and eventually weaned off. No recurring lesions have been detected at 1 year of follow-up period. Conclusion: Bilateral adrenal tumors should never be assumed to be of similar type because, while extremely rare, bilateral tumors of different types are possible. All efforts should be made to preserve the normal adrenal tissue in cases of bilateral adrenal masses.

Abstract Objective To explore the criteria, safety and efficacy of laparoscopic surgery in pediatric neuroblastoma (NB). Methods A retrospective study of 87 patients with NB without image-defined risk factors (IDRFs) between December 2016 and January 2021 at Beijing Children’s Hospital was conducted. Patients were divided into two groups according to the surgical procedure. Results Between the 87 patients, there were 54 (62.07%) cases in the open surgery group and 33 (37.93%) cases in the laparoscopic surgery group. There were no significant differences between the two groups regarding demographic characteristics, genomic and biological features, operating time or postoperative complications. However, in terms of intraoperative bleeding (p = 0.013) and the time to start postoperative feeding after surgery (p = 0.002), the laparoscopic group was obviously better than the open group. Furthermore, there was no significant difference in the prognosis between the two groups, and no recurrence or death was observed. Conclusion For children with localized NB who have no IDRFs, laparoscopic surgery could be performed safely and effectively. Surgeons who are skilled in this can help children reduce surgical injuries, speed up postoperative recovery, and obtain the same prognosis as open surgery.

Abstract Biliary atresia (BA) is a severe inflammatory and fibrosing neonatal cholangiopathy disease characterized by progressive obstruction of extrahepatic bile ducts, resulting in cholestasis and progressive hepatic failure. Cholestasis may play an important role in the inflammatory and fibrotic pathological processes, but its specific mechanism is still unclear. Necroptosis mediated by Z-DNA-binding protein 1 (ZBP1)/phosphorylated-mixed lineage kinase domain-like pseudokinase (p-MLKL) is a prominent pathogenic factor in inflammatory and fibrotic diseases, but its function in BA remains unclear. Here, we aim to determine the effect of macrophage necroptosis in the BA pathology, and to explore the specific molecular mechanism. We found that necroptosis existed in BA livers, which was occurred in liver macrophages. Furthermore, this process was mediated by ZBP1/p-MLKL, and the upregulated expression of ZBP1 in BA livers was correlated with liver fibrosis and prognosis. Similarly, in the bile duct ligation (BDL) induced mouse cholestatic liver injury model, macrophage necroptosis mediated by ZBP1/p-MLKL was also observed. In vitro, conjugated bile acid-glycodeoxycholate (GDCA) upregulated ZBP1 expression in mouse bone marrow-derived monocyte/macrophages (BMDMs) through sphingosine 1-phosphate receptor 2 (S1PR2), and the induction of ZBP1 was a prerequisite for the enhanced necroptosis. Finally, after selectively knocking down of macrophage S1pr2 in vivo, ZBP1/p-MLKL-mediated necroptosis was decreased, and further collagen deposition was markedly attenuated in BDL mice. Furthermore, macrophage Zbp1 or Mlkl specific knockdown also alleviated BDL-induced liver injury/fibrosis. In conclusion, GDCA/S1PR2/ZBP1/p-MLKL mediated macrophage necroptosis plays vital role in the pathogenesis of BA liver fibrosis, and targeting this process may represent a potential therapeutic strategy for BA.

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has inflicted immense damage to countries, economies and societies worldwide. Authorized COVID-19 vaccines based on different platforms have been widely inoculated in adults, showing up to 100% immunogenicity with significant efficacy in preventing SARS-CoV-2 infections and the occurrence of severe COVID-19. It has also greatly slowed the evolution of SARS-CoV-2 variants, as shown in clinical trials and real-world evidence. However, the total dosage of COVID-19 vaccines for children is much smaller than that for adults due to limitations from parental concern of vaccine safety, presenting a potential obstacle in ending the COVID-19 pandemic. SARS-CoV-2 not only increases the risk of severe multisystem inflammatory syndrome (MIS-C) in children, but also negatively affects children's psychology and academics, indirectly hindering the maintenance and progress of normal social order. Therefore, this article examines the clinical manifestations of children infected with SARS-CoV-2, the status of vaccination against COVID-19 in children, vaccination-related adverse events, and the unique immune mechanisms of children. In particular, the necessity and challenges of vaccinating children against SARS-CoV-2 were highlighted from the perspectives of society and family. In summary, parental hesitancy is unnecessary as adverse events after COVID-19 vaccination have been proven to be infrequent, comprise of mild symptoms, and have a good prognosis.

AimTo summarize systematically our six-year experience in the surgical treatment of postoperative bile leakage after liver tumor surgery in children, and explore its reoperation approach and treatment effect.MethodsThe clinical data of 6 patients with postoperative bile leakage cured by surgery from January 2016 to January 2022 were reviewed retrospectively.ResultsAmong the six pediatric patients with postoperative bile leakage cured by surgery, four were male (67%) and two were female (33%). All patients underwent complex segmentectomy. The median time to bile leakage was 14 days (range, 10 to 32), and the daily drainage volume was stable from 170 ml to 530 ml per day. After conservative treatment failed, four patients received biliary-enteric anastomosis (patients 1, 3, 4, and 6), and two patients received bilio-cholecyst anastomosis (patients 2 and 5). All six patients were successfully treated with reoperation, and five patients were alive and without recurrence, while one patient was lost to follow-up due to abandoned treatment.ConclusionOur study suggests that surgery is a reliable and effective treatment for postoperative intractable bile leakage in children undergoing complex segmentectomy. Bilioenteric anastomosis is the most common technique for bile leakage, and bilio-cholecyst anastomosis is a feasible and effective surgical approach. These findings have important implications for the management of postoperative complications in pediatric patients undergoing complex segmentectomy.

BackgroundIndocyanine Green (ICG) fluorescence imaging has been widely used in the surgical treatment of adult renal cancers, but its application in pediatric renal cancers has rarely been reported. This study aims to summarize the experience of ICG fluorescence imaging in pediatric renal cancers and explores its safety and feasibility.MethodsThe clinical features, surgical information, ICG administration regimen, near infrared radiography data in vivo and ex vivo and pathological results of children with renal cancers using ICG navigation were analyzed and summarized.ResultsThere were 7 cases of renal cancer, including 4 cases of Wilms tumor (WT), 1 case of malignant rhabdoid tumor of the kidney (MRTK) and 2 cases of renal cell carcinoma (RCC). By intraoperative intravenous injection of ICG from 2.5 to 5 mg (0.05–0.67 mg/kg), the tumors were visualized in 6 cases in vivo or ex vivo, and the tumor visualization failed in 1 case due to renal artery embolization before operation. By injecting 5 mg ICG into the normal renal tissue during the operation, 3 patients achieved fluorescent localization of sentinel lymph nodes. No ICG-related adverse reactions were found in any of the patients during or after operation.ConclusionsICG fluorescence imaging is safe and feasible for renal cancers in children. Intraoperative administration can achieve tumor and sentinel lymph node visualization which will facilitate the development of nephron sparing surgery (NSS). However, the technique is affected by ICG dose, anatomical conditions around the tumor, and renal blood flow. A proper dose of ICG and the complete removal of perirenal fat are helpful for the fluorescence imaging of the tumor. It has potential in the operation of renal cancer in children.

Abstract The postoperative recurrence of neuroblastoma (NB) patients is an essential reason for the high mortality of NB due to the lack of early, non‐invasive, and dynamic strategies for monitoring NB recurrence. Therefore, whether the plasma circulating cell‐free MYCN gene as an indicator for monitoring of NB recurrence was systematically evaluated. The MYCN copy number and NAGK (reference gene) copy number (M/N) ratio in plasma and corresponding tumor tissues of NB patients was detected using an economical, sensitive, and specific single‐tube dual RT‐PCR approach developed in this study. The plasma M/N ratio of the MYCN gene amplification (MNA) group (N = 25, median M/N ratio = 4.90) was significantly higher than that of the non‐MNA group (N = 71, median M/N ratio = 1.22), p

Intelligent detection of locomotive signal lights and pedestrians on railway tracks is of great significance to the safe operation of locomotives, especially under bad illumination conditions. Due to the highly complicated operation environment of railway locomotives, it is relatively difficult to apply deep neural network-based object detection methods in the recognition of locomotive signal lights and railway pedestrians. This work, for the first time, proposes a real-time detection method based on improved YOLOv4 to recognize locomotive signal lights and railway pedestrians. In our method, the Region-of-Interest is introduced into the original network of YOLOv4 to improve the detection precision of pedestrians on railway tracks. Importantly, we establish a dataset called detection of locomotive signal lights and railway pedestrians (DLSLRP), which is dedicated to the training, testing, and validation of related convolutional neural networks. We evaluated the proposed detector on DLSLRP dataset, the experimental results suggest that our method can detect locomotive signal lights and railway pedestrians with high speed and accuracy under different illumination conditions. The mAP reaches 93.52%, and the detection speed achieves 25 FPS.

BackgroundPeritoneal malignant tumors in children are rare but commonly associated with disease progression and poor outcome. The successful treatment experience of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in adult peritoneal carcinoma has been applied to pediatric peritoneal malignancy in recent years. However, patients with desmoplastic small round cell tumor (DSRCT) accounted for the majority of patients treated with CRS and HIPEC in previous studies. The role of CRS and HIPEC remains controversial due to the rarity of the disease and the limited sample size of studies. Additionally, the cases using CRS and HIPEC except DSRCT were mainly small case reports with unclear outcomes. We present our experience in the treatment of pediatric peritoneal malignancies using CRS and HIPEC, with more emphasis on the safety, feasibility, and short-term outcome.MethodsA retrospective query from December 2019 to February 2022 identified 19 children with peritoneal malignancies who underwent CRS and HIPEC in our institution. Clinical characteristics, therapies, and outcomes were summarized and analyzed.ResultsThe median age of the patients was 6.4 years (range, 0.7–13.9 years). The histologic types included rhabdomyosarcoma (7), Wilms tumor (2), clear cell sarcoma of the kidney (2), undifferentiated sarcoma (2), immature teratoma (1), peritoneal serous carcinoma (1), malignant rhabdoid of the kidney (1), malignant germ cell tumor (1), neuroblastoma (1), and epithelioid inflammatory myofibroblast sarcoma (1). Seven patients underwent initial operation, and 12 patients received reoperation for tumor recurrence. The median peritoneal carcinomatosis index was 5 (range, 2–21). There were no perioperative deaths or life-threatening complications of CRS and HIPEC. Two patients had grade 3 complications of wound infection and wound dehiscence. With a median follow-up time of 14 months (range, 1.5–31 months), 14 patients were alive, and 5 died of tumor recurrence. Of the 14 patients who were alive, 2 relapsed after CRS and HIPEC and then received radiotherapy and molecular-targeted therapy or chemotherapy.ConclusionsCRS and HIPEC are safe and feasible in children, without increasing serious complications in the peri- and postoperative periods. The complication is acceptable. The short-term outcome shows possible effectiveness in pediatric peritoneal malignant tumors. The long-term effectiveness needs to be verified by additional cases and long-term follow-ups.

Abstract Background We admitted a child with a duplex kidney combined with preoperative rupture of nephroblastoma and used this case to discuss the clinical features and treatment of this disease. Case presentation We retrospectively analyzed the clinical data of a 5-year-old girl with preoperative duplex kidney rupture combined with inferior nephroblastoma who was admitted to the Fourth Hospital of Baotou. In addition, we reviewed the relevant literature. The patient’s details were as follows: weight, 17 kg; height, 108 cm; and body surface area, 0.7 m2. Abdominal ultrasound for abdominal pain revealed the presence of a left-sided renal mass; enhanced abdominal computed tomography further confirmed it to be a left-sided duplex kidney measuring approximately 6 × 5 × 5 cm, with a rupture originating from the lower kidney. The PubMed database was searched from 2010 to 2020 for the terms “Wilms’ tumor” and “Duplex” and “Wilms’ tumor” and “Rupture.” The treatment plan was preoperative chemotherapy (vincristine/dactinomycin, VA regimen) + left kidney tumor radical surgery + postoperative chemotherapy (actinomycin-D/VCR/doxorubicin, AVD regimen). Postoperative pathology revealed an International Society of Pediatric Oncology intermediate-risk stage-3 nephroblastoma (mixed type) in the left kidney. Literature review was performed with 71 cases meeting the set criteria with an aim to analyze and summarize the clinical characteristics and treatment of patients with ruptured nephroblastoma and duplex kidney combined with nephroblastoma. Conclusions To our knowledge, no previous studies have reported preoperative duplex kidney combined with nephroblastoma rupture. In patients with this condition, preoperative chemotherapy is recommended when the vital signs are stable and tumor resection can be performed after the tumor has shrunk to prevent secondary spread. If the patient’s vital signs are unstable, emergency exploratory surgery is needed. If the nephroblastoma rupture is old and limited, surgery can be performed when the tumor size is small.

BackgroundIndocyanine green (ICG) navigation surgery has been used for hepatoblastoma (HB) in children but the technique has been reported for using in other childhood liver cancers were rare. This article summarizes the application experience of ICG in HB and other childhood liver cancers in children and explores the role of fluorescence intensity measurement in identifying tumors.MethodsTo summarize the clinical experience of children with liver cancer treated by ICG navigation surgery. The tumor and its surrounding tissue were photographed by near infrared during the operation. The fluorescence intensity of tumors, ICG (+) lesions and the normal liver was measured, and the Tumor-Background Ratio (TBR) was calculated.ResultsA total of 11 children with liver cancer were injected intravenously with ICG 1 day before operation. With the help of ICG fluorescence navigation, there was no residual tumor at the surgical margin for all the children. Total fluorescence was seen in 2 cases, rim fluorescence in 2 cases, and partial fluorescence in 7 cases. 19 ICG false-positive nodules were found on the resection stump or residual liver tissue in 5 cases, and the TBR value of tumors was higher than that of false- positive nodules. 10 children have survived without disease.ConclusionICG navigation surgery is safe and feasible for liver cancer in children, which can enhance the visualization of the tumor during operation and provide more information about the location and boundaries of the tumor. This technique also has limitations, which can be affected by chemotherapy, tumor location, ICG administration regimen, and equipment. TBR is an effective method to identify tumor and non-cancerous lesions.

BackgroundOvarian tissue cryopreservation (OTC) is the only method of fertility preservation (FP) in prepubertal girls, but the experience remains limited. This study investigates the effectiveness and feasibility of FP of OTC in children facing gonadotoxicity treatment in Chinese first ovarian tissue cryobank.ProcedureOTC and evaluation of 49 children ≤14 years old in the cryobank of Beijing Obstetrics and Gynecology Hospital, Capital Medical University, from July 2017 to May 19, 2022, were analyzed retrospectively. We compared children’s general characteristics, follicle numbers, and hormone levels with and without chemotherapy before OTC.ResultsThe age of 49 children at the time of OTC was 7.55 (1–14) years old. There were 23 cases of hematological non-malignant diseases, eight cases of hematological malignant diseases, four cases of gynecological malignant tumors, one case of neurological malignant tumors, one case of bladder cancer, five cases of sarcoma, three cases of mucopolysaccharidosis, one case of metachromatic leukodystrophy, two cases of dermatomyositis, one case of Turner’s syndrome. The median follicular count per 2-mm biopsy was 705. Age and AMH were not correlated (r = 0.084, P = 0.585). Age and follicle count per 2-mm biopsy was not correlated (r = −0.128, P = 0.403). Log10 (follicle count per 2-mm biopsy) and Log10 (AMH) were not correlated (r = −0.118, P = 0.456). Chemotherapy before OTC decreased AMH levels but had no significant effect on the number of follicles per 2-mm biopsy.ConclusionsOTC is the only method to preserve the fertility of prepubertal girls, and it is safe and effective. Chemotherapy before OTC is not a contraindication to OTC.

Abstract Importance Cancer is the main cause of death by disease in children. Children experience the highest incidence of cancer in the first year of life. However, there is no comprehensive registration system for children with tumors in China. Objective To summarize the diagnosis and treatment of infant cancer and analyze the status of standardized diagnosis and management among several treatment centers in Beijing, China, thereby providing evidence to guide further clinical research. Methods From January 1, 2010 to December 31, 2019, patients with newly diagnosed infantile malignant solid tumors were admitted to six large tertiary pediatric solid tumor diagnosis and treatment centers in Beijing. The epidemiology, clinical features, and therapeutic effects of tumors in these patients were analyzed retrospectively. All patients were followed up until March 31, 2020. Results In total, 938 patients were enrolled in this study. There were 530 boys (56.5%) and 408 girls (43.5%); the median age was 6.0 months (range, 0–12.0 months). The three most common tumors were retinoblastoma in 366 patients (39.0%), neuroblastoma in 266 patients (28.4%), hepatoblastoma in 133 patients (14.2%), and central nervous system tumors in 52 patients (5.5%). The estimated 5‐year overall survival rate was 81.3% ± 1.8%, and the 5‐year event‐free survival rate was 71.8% ± 2.9%. The 5‐year overall survival rates of non‐rhabdomyosarcoma soft tissue sarcoma, neuroblastoma, and retinoblastoma were 100%, 88% ± 2.2%, and 86.9% ±2.1%, respectively. The 5‐year event‐free survival rates were 81.1% ± 2.7% for neuroblastoma, 81.6% ± 9.8% for non‐rhabdomyosarcoma soft tissue sarcoma, and 72.7% ± 14.1% for extracranial malignant germ cell tumors. Interpretation The three most common infantile malignant solid tumors were retinoblastoma, neuroblastoma, and hepatoblastoma. Multidisciplinary combined diagnosis and treatment is needed for infantile tumors.

Abstract Importance Neuroblastoma is the most common extracranial malignant solid tumor in children. Multidisciplinary care is critical to improving the survival of pediatric patients with neuroblastoma. Objective To systematically summarize the clinical characteristics of children with neuroblastoma and evaluate their prognosis with multidisciplinary care provided in a single center. Methods This retrospective study analyzed the clinical data of 1041 patients with neuroblastoma who were diagnosed, treated, and followed‐up in the Hematology‐Oncology Center of Beijing Children’s Hospital from 2007 to 2019. Results The median age at diagnosis was 34 months; 80.8% of the patients were younger than 5 years of age. Notably, 243 patients (23.3%) were classified as low‐risk, 249 patients (23.9%) were classified as intermediate‐risk, and 549 (52.7%) were classified as high‐risk. Furthermore, 956 patients underwent surgical resections; 986 (94.7%) patients received chemotherapy; and 176 patients with high‐risk neuroblastoma received hematopoietic stem cell transplantation. The 5‐year event‐free survival (EFS) rate was 91.3% and 5‐year overall survival (OS) rate was 97.5% in low‐risk group; in the intermediate‐risk group, these rates were 85.1% and 96.7%, respectively, while they were 37.7% and 48.9% in the high‐risk group (P < 0.001 for both). The 5‐year EFS and OS rates were significantly higher in patients diagnosed between 2015 and 2019 than in patients diagnosed between 2007 and 2014 (P < 0.001). In total, 278 patients (26.7%) exhibited tumor relapse or progression; the median interval until relapse or progression was 14 months. Of the 233 patients who died, 83% died of relapse or progression of neuroblastoma and 4.3% died of therapy‐related complications. Interpretation The 5‐year OS rate was low in high‐risk patients, compared with low‐and intermediate‐risk patients. Multidisciplinary care is critical for improvement of survival in pediatric patients with neuroblastoma. Additional treatment strategies should be sought to improve the prognosis of patients with high‐risk neuroblastoma.

Abstract Background Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disease. Some children with OMS also have neuroblastoma (NB). We and others have previously documented that serum IgG from children with OMS and NB induces neuronal cytolysis and activates several signaling pathways. However, the mechanisms underlying OMS remain unclear. Here, we investigated whether nitric oxide (NO) from activated microglias and its cascade contribute to neuronal cytolysis in pediatric OMS. Methods The activation of cultured cerebral cortical and cerebellar microglias incubated with sera or IgG isolated from sera of children with OMS and NB was measured by the expression of the activation marker, cytokines, and NO. Neuronal cytolysis was determined after exposing to IgG-treated microglia-conditioned media. Using inhibitors and activators, the effects of NO synthesis and its intracellular cascade, namely soluble guanylyl cyclase (sGC) and protein kinase G (PKG), on neuronal cytolysis were evaluated. Results Incubation with sera or IgG from children with OMS and NB increased the activation of cerebral cortical and cerebellar microglias, but not the activation of astrocytes or the cytolysis of glial cells. Moreover, the cytolysis of neurons was elevated by conditioned media from microglias incubated with IgG from children with OMS and NB. Furthermore, the expression of NO, sGC, and PKG was increased. Neuronal cytolysis was relieved by the inhibitors of NO signaling, while neuronal cytolysis was exacerbated by the activators of NO signaling but not proinflammatory cytokines. The cytolysis of neurons was suppressed by pretreatment with the microglial inhibitor minocycline, a clinically tested drug. Finally, increased microglial activation did not depend on the Fab fragment of serum IgG. Conclusions Serum IgG from children with OMS and NB potentiates microglial activation, which induces neuronal cytolysis through the NO/sGC/PKG pathway, suggesting an applicability of microglial inhibitor as a therapeutic candidate.

Abstract Background Neuroblastoma (NB) tumor rupture is a rare oncology emergency with a poor prognosis. We aimed to evaluate patient clinical characteristics and risk factors for ruptured NB. Methods A retrospective study of 47 patients with confirmed NB rupture between January 2009 and January 2019 at Beijing Children’s Hospital was conducted. To identify tumor rupture risk factors in high-risk NB patients, we included 93 consecutive non-ruptured high-risk NB patients from January 2017 to January 2019. Results The median age at presentation was 29 months (adrenal and retroperitoneum origin) for 47 ruptured NB patients. Spontaneous tumor rupture occurred in 22 cases; 18 cases occurred during or after the first chemotherapy cycle, and 7 occurred after core needle biopsy. Five patients died of tumor rupture, and 17 patients’ parents refused further antitumor therapy. Among the 25 remaining patients, 6 survived without disease, 5 received ongoing treatment and achieved stable disease, and 14 died. According to multivariate logistic regression analysis, a maximum primary tumor diameter > 13.20 cm and MYCN gene amplification were independent risk factors for tumor rupture within high-risk NB. Conclusions Tumor rupture is an uncommon, life-threatening event for NB patients; these patients are most likely to have poor outcomes due to tumor recurrence or rapid progression. Several treatment modalities, including symptomatic support therapy and chemotherapy, are important for saving lives and for developing NB risk-based treatment in the future.

Abstract Background This study was performed to identify risk factors associated with recurrence of hepatoblastoma. Methods A retrospective study was conducted on 56 patients with hepatoblastoma from 2012 to 2015 in Beijing Children’s Hospital. Pretreatment extension stage (PRETEXT), serum alpha fetoprotein (AFP) value, change trend of tumors after treatment and some other clinical characteristics were collected and analyzed. The comparison of independent variables that were not distributed normally was performed with the log-rank test. Results Twenty-eight patients with tumour recurrence and 28 patients without recurrence were included in this study, and the median age at presentation was 46.5 (26, 71.5) months. There was a significant difference in the 3-year recurrence-free survival (RFS) probability between patients aged over 54 months and those younger than 54 months (p = 0.007). After neoadjuvant chemotherapy, the chance of recurrence in partial response (PR) patients was significantly lower than that in stable disease (SD) patients (p = 0.004). The 3-year RFS rate of patients with a reduction in AFP of more than 60% after neoadjuvant chemotherapy was significantly higher than that of patients with a reduction of less than 60% (p = 0.005). The postoperative follow-up revealed that patients whose postoperative AFP fell to normal levels within 6 months of the start of treatment had a 3-year RFS rate of 68.6%, which is higher than that of patients whose AFP fell below the normal range after 6 months (p = 0.0005). Finally, the multivariate analysis by Cox regression showed that AFP decreased by less than 60% and tumour size decreased by less than 50% after neoadjuvant chemotherapy were significant independent prognostic risk factors for the 3-year RFS rate. The other clinical features were not significantly associated with tumour recurrence in this study. Conclusions Through this study, we concluded that the prognosis of childhood HB is related to the age at presentation and the response of chemotherapy. The results of the multivariate analysis showed that AFP decreased by less than 60% and tumour size decreased by less than 50% after neoadjuvant chemotherapy were significant independent prognostic risk factors. These findings can be helpful to evaluate therapeutic effects and predict prognosis.

ObjectivesTo investigate the genetic variants that are responsible for peripheral neuroblastic tumors (PNTs) oncogenesis in one family case.Materials and MethodsOne family was recruited, including the healthy parents, sister affected by neuroblastoma (NB), and brother who suffered from ganglioneuroma (GN). Whole-genome sequencing (WGS) of germline DNA from all the family members and RNA-seq of tumor RNA from the siblings were performed. Mutants were validated by Sanger sequencing and co-IP was performed to assess the impact of the mutant on chemosensitivity in the SH-SY5Y cell line.ResultsA novel compound heterozygous mutation of BRCA2 was locked as the cause of carcinogenesis. One allele was BRCA2-S871X (stop-gain) from the siblings’ mother, the other was BRCA2-N372H (missense) from their father. This novel compound heterozygous mutations of the BRCA2 gene associated with PNTs by disordering DNA damage and response (DDR) signal pathway. Moreover, chemosensitivity was reduced in the NB cell line due to the BRCA2-N372H mutant.ConclusionIn summary, these results revealed a novel germline compound heterozygous mutation of the BRCA2 gene associated with familial PNTs.

Pediatric hepatoblastoma (HB) is the most common primary liver malignancy in infants and children. With great diversity and plasticity, tumor-infiltrating neutrophils were one of the most determining factors for poor prognosis in many malignant tumors. In this study, through bulk RNA sequencing for sorted blood and tumor-infiltrated neutrophils and comparison of neutrophils in tumor and para-tumor tissue by single-cell sequencing, we found that intratumoral neutrophils were composed of heterogenous functional populations at different development stages. Our study showed that terminally differentiated neutrophils with active ferroptosis prevailed in tumor tissue, whereas, in para-tumor, pre-fate naïve neutrophils were dominant and ferroptotic neutrophils dispersed in a broad spectrum of cell maturation. Gene profiling and in vitro T-cell coculture experiment confirmed that one of main functional intratumoral neutrophils was mainly immunosuppressive, which relied on the activation of ferroptosis. Combining the bulk RNA-seq, scRNA-seq data, and immunochemistry staining of tumor samples, CXCL12/CXCR4 chemotaxis pathway was suggested to mediate the migration of neutrophils in tumors as CXCR4 highly expressed by intratumoral neutrophils and its ligand CXCL12 expressed much higher level in tumor than that in para-tumor. Moreover, our study pinpointed that infiltrated CXCR4hi neutrophils, regardless of their differential distribution of cell maturation status in HB tumor and para-tumor regions, were the genuine perpetrators for immune suppression. Our data characterized the ferroptosis-dependent immunosuppression energized by intratumoral CXCR4 expression neutrophils and suggest a potential cell target for cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Purpose. Retinoblastoma and neuroblastoma are the most common malignant extracranial solid tumors in children. This study aimed to summarize the clinical features, especially the delayed diagnosis in children with retinoblastoma and neuroblastoma. Methods. In a single hospital-based case-control study, a retrospective cohort of 175 children with retinoblastoma and neuroblastoma diagnosed from January 2016 to January 2018 were reviewed. The state of enucleation in retinoblastomas and pathological prognosis in neuroblastomas were outcome indicators. Hereby, the patients were divided into two groups, and clinical features including age at presentation and delayed diagnosis were compared. Results. A total of 112 patients with retinoblastoma and 63 with neuroblastoma were included. In the retinoblastoma cohort, the median age at presentation was 17.2 months (0.3–110 months). The mean delay of diagnosis was 1.6 ± 2.3 months, and the rate of enucleation was 61.6%. Unilateral disease, the International Classification of Intraocular Retinoblastoma (IIRC) stage E, and delay of diagnosis over 2.5 months were independent risk factors of ocular outcomes. Notably, the risk of enucleation was increased by 474% when the delay was longer than 2.5 months. In the neuroblastoma cohort, the delay of diagnosis of the unfavorable histology (UH) group was longer than that of the favorable histology (FH) group (1.9 months vs. 1.4 months, P=.487). The levels of serum ferritin and neuron-specific enolase were higher in the UH group than in the FH group (P

Abstract Background Neuroblastoma (NB) is the most common malignant tumor originating from the extracranial sympathetic nervous system in children. The molecular mechanisms underlying this disease are complex, and not completely understood. Methods Quantitative real-time PCR (qRT-PCR) was applied to quantify the expression of miR-20a-5p and its target gene ATG7 in clinical NB tissues. The biological function of miR-20a-5p and ATG7 in SH-SY5Y cells was investigated through in vitro studies (Real-Time cell kinetic analyzer, colony formation assay, caspase-Glo 3/7 assay and western blotting). The luciferase reporter assay was conducted to verify the biological relationship between miR-20a-5p and ATG7. Results Here we found that miR-20a-5p expression was significantly downregulated whereas its target autophagy-related gene 7 (ATG7) was increased along with clinical staging of NB progression. Correlation analysis showed that miR-20a-5p had a negative correlation trend with ATG7. In SH-SY5Y cells, forced expression of miR-20a-5p suppressed ATG7 expression, autophagy initiation and cellular proliferation while promoted apoptosis, suggesting a potential association between miR-20a-5p and ATG7. Further bioinformatic target prediction combined with protein expression and luciferase reporter assay verified that miR-20a-5p inhibited ATG7 by directly binding to its 3′-UTR, confirming the involvement of miR-20a-5p in the regulation of ATG7 in NB. Conclusions These results clarified that miR-20a-5p inhibited cell proliferation and promoted apoptosis through negative regulation of ATG7 and thus autophagy suppression in SH-SY5Y cells. Therefore, defining the context-specific roles of autophagy in NB and regulatory mechanisms involved will be critical for developing autophagy-targeted therapeutics against NB. Both miR-20a-5p and ATG7 would be potential therapeutic targets for future NB treatment.

Abstract Background Previous studies have shown that γδ TFH cells are capable of modulating antibody production in immunized and infected mouse model. In recent studies, human γδ TFH cells are shown to contribute to the activation of humoral immunity and promote the maturation of B cells. However, little information is available on their involvement in neuroblastoma (NB) pathogenesis. Results In the present study, the frequency of γδ TFH cells in 74 NB patients was significantly higher compared with that in 60 healthy controls. Moreover, most γδ TFH cells in NB patients had a naive phenotype with up-regulation of CD25, CD69, HLA-DR and CD40L and down-regulation of ICOS. Importantly, γδ TFH cells in NB patients produced more IL-4 and IL-10 than those in healthy controls. Furthermore, serum total IgG level was significantly increased in NB patients compared with healthy controls. The expression of CD23 on B cells was up-regulated while CD80 expression was significantly down-regulated in NB patients. Further analysis of B cell compartment showed that the frequency of CD19+CD27hi plasma cells was enhanced in NB patients. Spearman’s correlation analysis revealed that the frequency of γδ TFH cells was positively correlated to serum total IgG level and CD19+CD27hi plasma cells in NB patients, but negatively correlated to CD19+ B cells. Conclusions We concluded that γδ TFH cells might promote B cell maturation and antibody production in NB patients.

Hepatoblastoma (HB), a leading primary hepatic malignancy in children, originates from primitive hepatic stem cells. This study aimed to uncover the genetic variants that are responsible for HB oncogenesis. One family, which includes the healthy parents, and two brothers affected by HB, was recruited. Whole-genome sequencing (WGS) of germline DNA from all the family members identified two maternal variants, located within APC gene and X-linked WAS gene, which were harbored by the two brothers. The mutation of APC (rs137854573, c.C1606T, p.R536X) could result in HB carcinogenesis by activating Wnt signaling. The WAS variant (c.G3T, p.M1-P5del) could promote HB cell proliferation and inhibit T-cell-based immunity by activating PLK1 signaling and inactivating TCR signaling. Further analysis reflected that WAS deficiency might affect the antitumor activity of natural killer and dendritic cells. In summary, the obtained results imply that an APC mutant together with an X-linked WAS mutant, could lead to HB tumorigenesis by activating Wnt and PLK1 signaling, inhibiting TCR signaling, and reducing the antitumor activity of natural killer and dendritic cells.

Background: Soft-tissue sarcomas during infancy are rare and understudied. With no data on this specific condition, we performed a retrospective study of infant-onset sarcomas based on a multi-institutional cohort in Beijing, China, collected over the past decade. We reviewed infantile soft-tissue sarcomas' clinical characteristics, treatments, and outcomes. Materials and Methods: The patients with soft-tissue sarcoma diagnosed from 0 to 12 months in four primary children's hospitals in Beijing from January 2010 to December 2019 were evaluated. Results: Fifty-one patients were enrolled, including 31 males and 20 females. The median age at the diagnosis was five months (range, 0-12), and seven (13.7%) patients were diagnosed in the first month of their life. Histologically, twenty-five patients were diagnosed with rhabdomyosarcoma (RMS), six were diagnosed with extraosseous Ewing sarcoma (EES), and twenty were diagnosed with nonrhabdomyosarcoma soft-tissue sarcoma (NRSTS). The treatment principles and details of RMS focused on reference to the Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols. For EES and NRSTS, chemotherapy was prescribed according to children's oncology group protocols. The five-year EFS/OS rates of RMS were 26.4% ± 19.5%/56.2 ± 17.8%, the five-year EFS/ OS rate of EES was 50% ± 20.4%, and the five-year EFS/OS of NRSTS was 85.2% ± 9.8%/100%. Conclusions: Infant-onset soft-tissue sarcoma is heterogeneous. The primary location of the abdominal or pelvic cavity of RMS and EWS was at a later stage and had a poorer prognosis. Multimodal therapy resulted in successful disease control for the majority of patients. Standardization of treatment protocols will facilitate care for such challenging conditions. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is the most common extra-cranial solid tumor in children and the most frequently diagnosed cancer in the first year of life. Previous genome-wide association studies (GWAS) of Caucasian and African populations have shown that common single nucleotide polymorphisms (SNPs) in several genes are associated with the risk of developing NB, while few studies have been performed on Chinese children. Herein, we examined the association between the genetic polymorphisms in candidate genes and the risk of NB in Chinese children. In total, 127 SNPs in nine target genes, revealed by GWAS studies of other ethnic groups and four related lincRNAs, were genotyped in 549 samples (244 NB patients and 305 healthy controls). After adjustment for gender and age, there were 21 SNPs associated with NB risk at the two-sided P < 0.05 level, 11 of which were located in LMO1. After correction for multiple comparisons, only rs204926 in LMO1 remained significantly different between cases and controls (OR = 0.45, 95% CI: 0.31-0.65, adjusted P = 0.003). In addition, 16 haplotypes in four separate genes were significantly different between case and control groups at an unadjusted P value < 0.05, 11 of which were located in LMO1. A major haplotype, ATC, containing rs204926, rs110420, and rs110419, conferred a significant increase in risk for NB (OR = 1.82, 95% CI: 1.41-2.36, adjusted P < 0.001). The major finding of our study was obtained for risk alleles within the LMO1 gene. Our data suggest that genetic variants in LMO1 are associated with increased NB risk in Chinese children.

The FAS and FASL system plays a substantial role in apoptosis and immune escape of cells. Three polymorphisms located in the promoter regions of FAS (-1377G/A and -670A/G) and FASL (-844T/C) have been shown to alter the transcriptional activity of the genes, respectively. This study was conducted to evaluate the effects of these polymorphisms on the susceptibility of neuroblastoma in the Chinese population. A total of 203 patients with neuroblastoma and 411 controls were recruited in this case-control study. Polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) was applied for genotyping. Unconditional logistic regression was used to estimate cancer risk by calculating odds ratios (ORs) and their 95% confidence intervals (95% CIs). It was observed that significantly increased risks of neuroblastoma associated with FAS -1377G/A and FASL -844T/C polymorphisms, with ORs equal to 1.55 (95% CI, 1.10-2.20) for FAS -1377 A allele and 2.90 (95% CI, 2.04-4.12) for FASL -844CC genotype carriers compared with non-carriers, respectively. However, no association was found between the polymorphisms of FAS -670A/G and risk of neuroblastoma. In addition, the cumulative effect of FAS and FASL polymorphisms on risk of neuroblastoma was observed (P for trend = 2.502×10(-10)), with OR for the carriers of both FAS -1377A allele and FASL -844CC genotypes equaled to 3.95 (95% CI, 2.40-6.51). This work reveals that polymorphisms of FAS -1377G/A and FASL -844T/C but not FAS -670A/G are associated with risk of neuroblastoma in Chinese. These findings support the hypothesis that genetic polymorphism in FAS/FASL death system may influence individual susceptibility to neuroblastoma.