Malignant Tumors In Children Research Articles

Zarys problemu nowotworów żeńskich narządów płciowych u dziewcząt i młodych kobiet – aspekty ginekologii wieku rozwojowego i medycyny rodzinnej

Family doctors play a huge role in the holistic care of patients, including oncological prophylaxis also in the context of gynecology of developmental age. In the prevention of neoplastic diseases, for example, all activities in the field of family medicine are very important, and regarding pro-health education from an early age: providing patients with knowledge about the harmful effects of smoking, alcohol consumption, the role of physical activity and diet. Although cases of malignant neoplasms in children are not frequent, the specific gravity of the problem makes this issue particularly important in the context of gynecology of developmental age and family medicine. These issues discussed in the paper are also important in the context of developmental medicine. It is a branch of clinical and theoretical medicine dealing with tracking the regularities and disorders of human somatic and mental development from the moment birth until the end of the puberty process. Unfortunately, health problems, including oncological diseases, also occur in the developmental period.

Wilms' Tumor: Long-Term Effect of Multimodal Treatment on Renal Function

Patients with Wilms' tumor, a common malignant childhood tumor, have an excellent survival rate. The treatment protocol, which consists of a combination of surgery, chemotherapy, and irradiation, may induce both short- and long-term systemic effects. This paper addresses concerns regarding the effects of treatment on long-term renal function in the survivors of Wilms' tumor. In a retrospective study, the charts of 36 patients treated at the Children's Hospital of Western Ontario were analyzed with respect to the epidemiology and parameters of renal function. It was determined that patients with Stage I disease maintained normal renal function over five years. However, those with Stage III and IV disease exhibited decreased renal function immediately after treatment but regained normal renal function within five years. This investigation clearly establishes the need for future prospective studies of long-term renal function of the remaining kidney in children who have undergone treatment for Wilms' tumor.

Survival and prognostic factors for childhood malignant liver tumors: analysis of harmonized clinical data

BackgroundDespite overall striking advances in survival of childhood liver tumors, outcomes remain poor for specific patient segments. We aimed to assess overall survival (OS) of this rare disease and evaluate the generalizability of prognostic variables included in international collaborative systems using, for the first time, harmonized clinical data from two geographically different cohorts (Greece and Moscow). MethodsData for children (0-14 years) with liver tumors were retrieved from two Southern-Eastern European areas (Greece; 2001-2019 and Moscow; 2012-2019). Kaplan-Meier curves were constructed, and OS values were derived from Cox proportional models controlling for study variables. ResultsA total of 171 newly diagnosed cases (54.4% males) were included. The OS5-year exceeded 80% in patients <5 years, reaching 85% among 133 patients with hepatoblastoma (HBL). By contrast, children with other than HBL histology, especially hepatocellular carcinoma (HCC) had significantly worse prognosis (hazard ratio [HR] HCC: 7.09, 95% confidence intervals [CI]: 2.56-19.65; HR other liver tumors: 5.18; 95%CI: 2.15-12.49). The OS5-year was poorer (40%-60%) in patients with extensive local, metastatic or relapsed disease. By contrast, a significantly lower risk of death was shown in case of microscopically margin-negative resection (HR: 0.06, 95%CI: 0.02-0.17) and liver transplantation (HR: 0.12, 95% CI: 0.02-0.63) compared to the non- operated group. ConclusionsOutcomes of patients with liver tumors registered in two SEE areas were comparable to those reported by major collaborative trials. Ongoing clinical cancer registration could facilitate comparison of outcomes between different study groups in order to shape state of the art of treatment.

EPID-26. CLINICAL AND HISTOLOGICAL CHARACTERIZATION OF PRIMARY CENTRAL NERVOUS SYSTEM SARCOMA IN PEDIATRICS. A SINGLE INSTITUTION EXPERIENCE IN A MIDDLE-INCOME COUNTRY

Abstract INTRODUCTION Primary central nervous system (CNS) sarcomas are rare mesenchymal non-meningothelial tumors accounting for less than 0.2% of intracranial lesions. Diagnosis and management are challenging due to the current lack of substantive clinical, histological and molecular data. METHODS We retrospectively identified all patients with diagnosis of primary CNS sarcoma at the Hospital Fundación Pediatrico la Misericordia (HOMI) in Bogota, Colombia. We collected patient demographics, disease characteristics, and outcomes for analysis. RESULTS Between 2008 and 2020, twenty-four consecutive patients were diagnosed at the HOMI representing 6% of all CNS tumors diagnosed over the same time period. The median age at presentation was 9.48 years (range:1.6–13.4). The median time of symptoms prior to diagnosis was 2 weeks (0.1–24). The most common presentation was headache (21/24- 89%) and vomiting (19/24- 79%). The frontal lobe was involved in 63% of patients (15/24) and only one patient presented with a cerebellar lesion. Histologically, these tumors were characterized by a pleomorphic spindle cell architecture and high mitotic activity. All samples lacked immunoreactivity to GFAP, CD34, EMA, and S100 and all samples had strong nuclear immunopositivity for TLE-1; BCL-2 was reactive in eighteen cases. Gross total resection was attained in fifteen patients, most patients received focal radiation therapy and ICE chemotherapy. Progression-free survival at 12 and 24 months was 57% and 31% respectively. Overall survival was 77% at 12 months and 39% at 24 months. Thirteen patients relapsed, 11 presented with local failures, and 2 with intracranial recurrences outside of the radiation field. CONCLUSION Our study identifies TLE-1 as a diagnostic marker of primary CNS sarcoma, a highly malignant supratentorial tumor of childhood. Further molecular studies are urgently needed to elucidate the biology of this disease and the unusually high incidence observed in the Colombian pediatric population.

Integrated Microarray to Identify the Hub miRNAs and Constructed miRNA-mRNA Network in Neuroblastoma Via Bioinformatics Analysis.

Neuroblastomas (NB) are childhood malignant tumors originating in the sympathetic nervous system. MicroRNAs (miRNAs) play an essential regulatory role in tumorigenesis and development. In this study, NB miRNA and mRNA expression profile data in the Gene Expression Omnibus database were used to screen for differentially expressed miRNAs (DEMs) and genes (DEGs). We used the miRTarBase and miRSystem databases to predict the target genes of the DEMs, and we selected target genes that overlapped with the DEGs as candidate genes for further study. Annotations, visualization, and the DAVID database were used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis on the candidate genes. Additionally, the protein-protein interaction (PPI) network and miRNA-mRNA regulatory network were constructed and visualized using the STRING database and Cytoscape, and the hub modules were analyzed for function and pathway enrichment using the DAVID database and BiNGO plug-in. 107 DEMs and 1139 DEGs were identified from the miRNA and mRNA chips, respectively. 4390 overlapping target genes were identified using the two databases, and 405 candidate genes which intersected with the DEGs were selected. These candidate genes were enriched in 363 GO terms and 24 KEGG pathways. By constructing a PPI network and a miRNA-mRNA regulatory network, three hub miRNAs (hsa-miR-30e-5p, hsa-miR-15a, and hsa-miR-16) were identified. The target genes of the hub miRNAs were significantly enriched in the following pathways: microRNAs in cancer, the PI3K-Akt signaling pathway, pathways in cancer, the p53 signaling pathway, and the cell cycle. In summary, our results have identified candidate genes and pathways related to the underlying molecular mechanism of NB. These findings provide a new perspective for NB research and treatment.

Treatment outcomes for hepatoblastoma children with pulmonary metastasis and extrapulmonary involvement: experience of 36 cases at a single institution.

BackgroundHepatoblastoma (HB) was the most common primary liver malignant tumor in children. In this study, we aimed to analyze the clinical characteristics and outcome in HB children with pulmonary metastasis and extrapulmonary involvement.MethodsThis retrospective study enrolled 36 HB children with pulmonary metastasis and extrapulmonary involvement from January 2010 to December 2017. Clinical characteristics, treatment and outcomes were collected and analyzed. Survival curves were calculated by Kaplan-Meier method.ResultsThirty-six patients (10 females and 26 males) were recruited, with a mean onset age of 2.13 years (range, 0.33–7.83). Four (11.11%) patients presented with single metastatic pulmonary nodules, 32 (88.89%) patients presented with multiple metastatic nodules in both lungs. There were 10 (27.78%) patients with extrahepatic abdomen involvement, 13 (36.11%) patients with brain metastasis, and 16 (44.44%) patients with vascular metastasis. All patients underwent liver tumorectomy and chemotherapy. The median chemotherapy cycle was 17 (range, 3–39). In addition, 19 (54.29%) patients underwent lung metastasectomy. The patients were followed up to December 2018, with a median follow-up of 32.5 months. At the study closing date, 9 patients were alive, 24 patients had died, and 3 patients were censored. Alpha fetoprotein (AFP) level, PRETEXT stage and distant metastases had significant impact on survival time (all P<0.05).ConclusionsThe common sites of extrapulmonary metastasis of HB were blood vessels, brain and extrahepatic abdominal organs. The overall prognosis of HB patients with lung metastasis and extrapulmonary involvement was poor, especially those with PRETEXT stage IV, high AFP level or distant metastases.

Colonic Intussusception Revealing a Cecal Adenocarcinoma Associated with Silent Crohn's Disease

Bowel intussusception is uncommon during adulthood and represents 1% to 5% of all bowel obstruction mainly involving the small bowel. Although most of small bowel intussusception during childhood remains idiopathic, malignant or benign tumors and post-operative complications are usually the underlined diagnosed beyond the intussusception for adults. Few cases reported bowel intussusception during Crohn’s disease without evidence of any association between the two conditions. We report the case of a colonic intussusception of a young adult secondary to a colorectal cancer revealing a silent Crohn’s disease.

Different Types of Clinical Presentations and Stages of Retinoblastoma Among Children.

IntroductionRetinoblastoma (Rb) is the most common intraocular malignant tumor of childhood. The different modes of Rb presentation comprise proptosis, anterior chamber inflammatory signs, spontaneous hyphema, secondary glaucoma, and strabismus. The primary aim of this study was to investigate the different clinical presentations and stages of Rb that may help in early detection and timely diagnosis to prevent the advancement of the disease and increase rates of survival in children. Materials and methodsThis was a descriptive cross-sectional study conducted between December 2019 and May 2020 over a period of six months at a tertiary care hospital in Karachi, Pakistan. The sample size included 68 eyes of children with lesions of Rb at the time of presentation to the hospital. Brightness scans (B-scans), computed tomography (CT) scans, and magnetic resonance imaging (MRI) were performed. The International Intraocular Retinoblastoma Classification (IIRC) was used to stage each eye. In case of enucleation (if necessary) of the eye, the biopsy was performed to evaluate the histological features of cancer. All statistical analysis was performed using Statistical Package for Social Sciences version 17.0 (IBM Corp., Armonk, New York).ResultsThe mean age of the children was 3.21 ± 1.75 years. Leukocoria was the most common clinical presentation observed in more than half (n = 35, 51.47%) of the sample population followed by proptosis reported in nearly two-fifths (n = 25, 36.76%), strabismus and phthisis bulbi observed in equal proportions (n = 3, 4.41%), and hypopyon documented in a minor proportion (n = 2, 2.94%) of patients. Regarding stages of the Rb disease, the most common stages were observed to be stage C and stage E. ConclusionsThis study concludes that the early detection of Rb is possible through a better understanding of presenting features of the disease. It can prevent the progression of the disease to the advanced stages and decrease morbidity and mortality. The early detection of Rb can be made possible through the examination of red reflex on the regular check-ups of children as leukocoria is the most common clinical presentation.

Atypical presentation of metastatic disease in patients with stage 4S neuroblastoma of the observation group: description of the clinical case

The most common extracranial solid malignant tumor of childhood – neuroblastoma (NB) is characterized by the presence of two metastatic forms (stages 4 and 4S). Stage 4S is described to have metastatic spread to the liver, skin, and minimal bone marrow invasion. Certain rare localisations of NB metastases (pleura, testicles, and others) may not worsen the prognosis in children of the first year of life in the absence of severe bone marrow invasion and metastases to the skeletal bones. The article describes a clinical case of retroperitoneal NB with atypical metastasis to the pleura in a child of the first months of life with a favorable outcome with a minimum amount of chemotherapy.

Identification of clinical molecular targets for childhood Burkitt lymphoma.

Burkitt lymphoma (BL) is a malignant tumor in children. Although BL is generally curable, early relapse and refractoriness may occur. Some molecular indicators have been recently suggested for BL diagnosis, but large heterogeneity still exists. This study aimed at providing clinical molecular targets and methods that may help improve diagnosis and treatment of childhood BL. Only children patients were included in the study, and targeted gene sequencing was conducted to identify tumor specific mutations. The mRNA and protein level expression of potential target genes were measured by real-time PCR and immunohistochemistry. The relationship between BL specific gene mutation and differential expression with clinical features was analyzed. The results showed that i) detailed analysis of c-MYC/BCL2/BCL6 gene loci alteration and gene expression would help in accurate diagnosis and treatment determination of childhood BL; ii) loss-of-function mutations in SOCS1 or CIITA gene might be used as malignant markers for BL diagnosis and prognosis; iii) specific mutations of CD79A, MYD88, KLF2, DNMT3A and NFKBIE genes often concurrently existed in BL and showed association with benign clinical outcomes; iv) the high expression of MYC, TCF3 and loss-of-function ID3 genes in tumor may be potential therapeutic targets and could be used for treatment monitoring; and v) four MYC-translocation negative cases were re-defined as high-grade B-cell lymphoma-not otherwise specified (HGBL-NOS) but showed similar clinical outcomes and molecular features to other BL cases in the study, suggesting more studies needed to explore the molecular mechanisms and clinical significance of this provisional tumor entity.

MYC-associated protein X binding with the variant rs72780850 in RNA helicase DEAD box 1 for susceptibility to neuroblastoma.

Neuroblastoma (NB) is one of the most common malignant tumors in children, with variable clinical behaviors and a 15% death rate of all malignancies in childhood. However, genetic susceptibility to sporadic NB in Han Chinese patients is largely unknown. To identify genetic risk factors for NB, we performed an association study on 357 NB patients and 738 control subjects among Han Chinese children. We focused on DEAD box 1 (DDX1), a putative RNA helicase, which is involved in NB carcinogenesis. The potential association of DDX1 polymorphisms with NB has not been discovered. Our results demonstrate that rs72780850 (NM_004939.2:c.-1555T>C) located in the DDX1 promoter region is significantly associated with higher expression of DDX1 transcript and increased NB risk (odds ratio=1.64, 95% confidence interval=1.03%-2.60%, P=0.004), especially in aggressive NB compared with ganglioneuroma and ganglioneuroblastoma in a dominant model (TC+CC vs. TT). Furthermore, the MYC-associated protein X (MAX) transcription factor showed stronger binding affinity to the DDX1 rs 72780850 CC allele compared with the TT allele, explaining the molecular mechanism of the increased NB risk caused by the rs72780850 polymorphism. Our results highlight the involvement of regulatory genetic variants of DDX1 in NB.

Anti-progressive Effects of a Series of Glycinyl and Alaninyl Triazolyl-oxazolidinones on Kelly Neuroblastoma Cell Line.

Neuroblastoma (NB), the most common extracranial malignant childhood tumor accounts for about 15% of cancer-related deaths in children. Despite the intensive treatment of patients with high-risk scarification of NB, clinical outcomes indicate tumor recurrence greater than 50% and late severe adverse effects. Oxazolidinones are 5-membered heterocyclic compounds with antibacterial activity against resistant bacterial strains. Structural modifications around the oxazolidinone moiety have resulted in derivatives with anti-cancer properties against proliferation, motility, and invasion of breast cancer cells. This study aimed to examine the anti-cancer potential of novel oxazolidinones against a model of a neuroblastoma cell line. Newly synthesized and characterized triazolyl-oxazolidinone derivatives were incubated with neuroblastoma Kelly cells. The anti-proliferation and anti-progression effects of the compounds were evaluated by MTT, and adhesion with migration assays. The 5-nitrofuroyl glycinyl-oxazolidinone containing 4-methyltriazolyl group demonstrated the most potent activity with an IC50=6.52 μM. Furthermore, the D-isomer of 5-nitrothiophenecarbonyl alaninyl containing derivative reduced the adhesion to fibronectin by 56.34%, while the D-isomer of 5-nitrofuroyl alaninyl derivative reduced the migration of Kelly cells by 29.14%. The presence of the 4-methyltriazolyl moiety seems to enhance the anti-proliferative property of triazolyl-oxazolidinone derivatives, as demonstrated by PH-145. There is little or no effect of the stereochemistry of the alanine side-chain on the antiproliferative effect, as demonstrated by the 5-nitrofuroyl D- and L-alaninyl containing derivatives with similar IC50 values. The observed differences in the inhibition of adhesion and migration by the oxazolidinones on Kelly cells provide a new therapeutic approach that needs further investigation.

Pediatric Hepatocellular Carcinoma.

Pediatric hepatocellular carcinoma is rarely seen in childhood. It constitutes approximately 1% of childhood solid organ malignancies. Pediatric hepatocellular carcinoma is the second most common malignant liver tumor after hepatoblastoma in children. In this review, we aimed to review the diagnosis and treatment of pediatric hepatocellular carcinoma in the light of the latest literature. We reviewed the literature in terms of the diagnosis and treatment of pediatric hepatocellular carcinoma. Hepatocellular carcinoma (HCC) and hepatoblastoma constitute 0.5-1.5% of all childhood malignant tumors. HCC is responsible for 27% of all liver tumors and 4% of all pediatric liver transplantations. While 99.6% of HCC is seen in adults, only 0.4% of it is seen in pediatric patients. Etiological predisposition and biological behavior are different from adults. In a child with cirrhosis or liver disease, HCC should be suspected in the presence of a high level of AFP and an abnormal nodule on ultrasonography. Hepatoblastoma should be considered first in the differential diagnosis. Treatment of pediatric HCC is challenging. Complete surgical resection is essential for the cure. To this end, different neoadjuvant chemotherapy protocols have been designed to convert non-resectable tumors into resectable tumors. For tumors that cannot be resected, liver transplantation for each patient with childhood HCC should be decided individually.

Effect of complex therapy of medulloblastoma in childhood and adolescence on bone mineral density

Medulloblastoma is the most common childhood malignant tumor of the posterior cranial fossa. A comprehensive treatment approach, including surgery, polychemotherapy and radiation therapy, inevitably leads to the development of various long-term consequences from the endocrine system, including a negative impact on bone tissue. Reduced linear growth rate, low adult height and low peak bone mass are well-known long-term effects of treatment. Based on data from Russian and foreign researchers, as well as our own experience, this review presents the endocrine consequences of treatment of malignant tumors of the central nervous system in childhood and adolescence, and summarizes the risk factors for various endocrine system disorders, including a decrease in bone mineral density (BMD). The review pays special attention to the assessment of BMD in a group of patients who have had cancer in childhood and adolescence and have undergone complex treatment, as well as the prevention and treatment of osteoporosis in children.

SP8 Promotes an Aggressive Phenotype in Hepatoblastoma via FGF8 Activation.

Hepatoblastoma (HB) is the most common malignant liver tumor in childhood and it generally has a good prognosis. However, if associated with aggressive metastatic disease, outcome is still poor. The molecular mechanisms leading to metastatic spread in HB patients are still unknown. By combining RNA-sequencing and a genome-wide methylome analysis, we identified the transcription factor SP8 and the growth factor FGF8 among the most strongly upregulated genes in metastatic HB cases, with a concomitant robust demethylation of the respective promoter regions. Of note, high expression of both candidates was associated with the aggressive C2 subtype of the 16-gene signature and poor survival. Chromatin immunoprecipitation revealed a direct transcriptional regulation of FGF8 through binding of SP8 to the FGF8 promoter. Gain- and loss-of-function experiments proved promoting effects of SP8 on motility, self-renewal, migration, and the invasive potential of HB cells. Moreover, stable overexpression of SP8 in Hep3B cells resulted in the acquisition of a mesenchymal phenotype and a strong upregulation of epithelial-mesenchymal transition-associated genes. Using KRAB-mediated CRISPR-dCas9 interference directed against FGF8, we could show that FGF8 is essential for the SP8-mediated aggressive tumor behavior. Treatment of HB cell lines with the pan SP family inhibitor mithramycin A resulted in a significant inhibition of their clonogenic growth. In summary, we identified SP8 and FGF8 as key players in aggressive traits of HB and propose SP8 inhibiting drugs as a new effective treatment strategy especially for metastatic tumors.

Abstract 1374: Preclinical investigation of ATR inhibition alone and in combination with PARP inhibition in high risk neuroblastoma

Abstract Background:Neuroblastoma (NB) is the commonest extra-cranial malignant solid tumour of childhood and one of the most difficult to cure. DNA damage response (DDR) defects are frequently observed in high risk NB including allelic loss and loss of function mutations in key DDR genes, oncogene induced replication stress (RS) and cell cycle checkpoint dysfunction. Cancer cells with defective cell cycle checkpoint signalling and/or increased oncogene-driven RS are acutely dependent on the DNA damage sensor kinase ATR. This study aims to identify features of NB cell lines leading to ATR inhibitor sensitivity. As PARP inhibition causes RS through unrepaired single strand DNA breaks progressing to replication, we hypothesise that ATR inhibition will increase PARP inhibitor cytotoxicity. Aims: 1) To determine which molecular features lead to sensitivity to VE-821 (ATR inhibitor) in cell lines derived from high-risk NB tumours. 2) To assess synergism between PARP inhibition with olaparib and ATR inhibition in high risk NB cell lines and to measure RS. Materials and Methods: Cell proliferation in response to 72 hours treatment with VE-821 was assessed by XTT assay (Roche) in a panel of 11 NB cell lines and the effect of ATR inhibition on olaparib growth inhibition in 4 cell lines: SHSY5Y, SKNAS, NGP and N20_R1. CHK1S345 and H2AXS129 phosphorylation was assessed using Western blotting to determine ATR activity and RS respectively. RS was also measured by γH2AX foci formation using immunofluorescent microscopy. Results: VE-821 caused significantly more growth inhibition in MYCN amplified cell lines and cell lines with low ATM protein expression by XTT assay (p&amp;lt;0.05 Mann-Whitney U test). Olaparib (5 µM) treatment increased CHK1S345 and H2AXS129 phosphorylation after 24 hours treatment in all cell lines. H2AXS129 phosphorylation and foci number was further increased with the addition of VE-821 (1 µM). ATR inhibition prevented CHK1S345 phosphorylation. In cell proliferation assays, combination index analysis (Calcusyn) showed that ATR inhibition by VE-821 is synergistic with olaparib at sub lethal concentrations (&amp;lt;1 µM) (CI value 0.04-0.89). Conclusion: MCYN amplification and low ATM protein expression are determinants of ATRi sensitivity in NB cell lines. ATR inhibition by VE-821 is synergistic with olaparib at sub lethal concentrations (&amp;lt;1 µM) and further increases the replication stress caused by PARP inhibition. Citation Format: Harriet E. Southgate, Lindi Chen, Nicola J. Curtin, Deborah A. Tweddle. Preclinical investigation of ATR inhibition alone and in combination with PARP inhibition in high risk neuroblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1374.

Use of Immunohistochemistry in the differential diagnosis of Small Round Blue cell tumors.

Objectives: Objective of the study is to differentiate and sub-categorize malignant small round blue cell tumors by using immune-histochemistry. Study Design: Descriptive Observational study. Setting: Meezan Private Lab, Faisalabad, Pakistan. Period: 5 years, from July 2014 to June 2019. Material &amp; Methods: Sample Size: 126 cases of Round blue cells tumors. Sampling Technique: Non probability purposive sampling. Data Collection Procedure: 126 cases which fulfilled the inclusion and exclusion criteria were selected for the study. All these cases were subjected to immunohistochemistry. The IHC technique used was based on Peroxidase anti-peroxidase (PAP) method. Based on site and morphological clues, initially Leukocyte common antigen (LCA), Myogenin, Cytokeratin (CK), Desmin, chromogranin, Neuron specific enolase (NSE), S-100, Smooth muscle actine (SMA) and CD99 were used. Further immune stains panels were used afterwards, as and when needed like CD20, CD3, CD30, BCL2, CD117, Ki-67, Tdt, synaptophysin, SMA, CD56, Melan A, HMB45 and WT1. Results: Out of 126 cases of small round blue cell tumors, 35 (27.8 %) cases were diagnosed as diffuse large B cell lymphoma, 6 as Lymphoblastic lymphoma, 4 as Burkitt’s lymphoma, and 6 cases as NK/T cell lymphoma. Ewing’s sarcoma/PNET (12/126, 9.5%) was the 2nd highest in frequency, followed by Rhabdomyosarcoma, Synovial sarcoma, Malignant melanoma, and Germ cell tumor, which were all 9/126 each with 7.1 %. Conclusion: Immunohistochemistry is an important tool for appropriate and clear differential diagnosis of malignant small round blue cell tumors of childhood.

Echocardiography and Newer Imaging Techniques in Diagnosis and Long-Term Follow-Up of Primary Heart Tumors in Children

Background: Primary heart tumors (PHTs) in the pediatric population are very rare and do not manifest any characteristic symptoms. Methods: A retrospective analysis of 61 cases was undertaken. Data from three centers for the years 2003–2018 were gathered. The tumors’ clinical course, location, number, hemodynamic, treatment, and follow-up were evaluated. Echocardiography was complemented with magnetic resonance imaging, computer tomography, and histopathological examination. Results: Out of 61 PHT diagnoses, 56 (91.8%) were circumstantial including all 16 (26.2%) prenatal tumors. The reasons for cardiological consultations were arrhythmia, syncopes, lowered physical performance, and murmurs. Only five patients (8.2%) were suspected of tumors based on previous symptoms of sclerosis tuberosa. Rhabdomyoma was the most frequently found PHT (60.7%). The tumors were predominantly located in the ventricles (49.1%) and intraventricular septum (14.9%) and tended to be single (70.5%). About 37.7% of patients suffered from coexistent multi-organ problems, two (3.28%) from congenital heart defects and one (1.64%) from Carney’s syndrome. Tumor resection was performed on 26 (42.7%) patients, of which 16 (61.5%) underwent total and 10 (38.5%) partial tumor resection. During the follow-up (mean 4.3 years), 54 patients (88.5%) have improved or were stable, while seven (11.5%) died. Conclusions: Primary pediatric heart tumors are diagnosed completely circumstantially, and the most common is rhabdomyoma, although arrhythmia may suggest fibroma. Diagnosis of a heart tumor in children is not synonymous with fatal prognosis, and most of them require only constant observation. Life-saving operation allows improvement, while the prognosis for malignant tumors in children is definitely unfavorable.

Development of hedgehog pathway inhibitors by epigenetically targeting GLI through BET bromodomain for the treatment of medulloblastoma

Medulloblastoma (MB) is a common yet highly heterogeneous childhood malignant brain tumor, however, clinically effective molecular targeted therapy is lacking. Modulation of hedgehog (HH) signaling by epigenetically targeting the transcriptional factors GLI through bromodomain-containing protein 4 (BRD4) has recently spurred new interest as potential treatment of HH-driven MB. Through screening of current clinical BRD4 inhibitors for their inhibitory potency against glioma-associated oncogene homolog (GLI) protein, the BRD4 inhibitor 2 was selected as the lead for further structural optimization, which led to the identification of compounds 25 and 35 as the high potency HH inhibitors. Mechanism profiling showed that both compounds suppressed HH signaling by interacting with the transcriptional factor GLI, and were equally potent against the clinical resistant mutants and the wild type of smoothened (SMO) receptor with IC50 values around 1 nmol/L. In the resistant MB allograft mice, compound 25 was well tolerated and markedly suppressed tumor growth at both 5 mg/kg (TGI = 83.3%) and 10 mg/kg (TGI = 87.6%) doses. Although further modification is needed to improve the pharmacokinetic (PK) parameters, compound 25 represents an efficacious lead compound of GLI inhibitors, possessing optimal safety and tolerance to fight against HH-driven MB.

Long Noncoding RNA HNF1A-AS1 Regulates Osteosarcoma Advancement Through Modulating the miR-32-5p/HMGB1 Axis.

Background: Osteosarcoma (OS) is a primary malignant tumor in children and adolescents. Long noncoding RNA HNF1A antisense RNA 1 (HNF1A-AS1) is connected with OS development. However, there are few reports on the role and mechanism of HNF1A-AS1 in OS. Materials and Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to assess the expression of HNF1A-AS1, miR-32-5p, and high-mobility group protein B1 (HMGB1). Western blot analysis was performed to detect the protein level of HMGB1. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, transwell, or flow cytometer assays were applied to determine the proliferation, migration, invasion, and apoptosis of OS cells. The interaction between HNF1A-AS1 and miR-32-5p or HMGB1 was predicted by the starBase database and confirmed by dual-luciferase reporter assay. Enzyme-linked immunosorbent assay was employed to analyze levels of HMGB1 in the OS cell supernatant. Results: HNF1A-AS1 and HMGB1 were upregulated, while miR-32-5p was downregulated, in OS tissues and cells. Functionally, HNF1A-AS1 depletion induced apoptosis and impeded proliferation, migration, and invasion of OS cells. Interestingly, HNF1A-AS1 bound to miR-32-5p to regulate the expression of HMGB1. Furthermore, miR-32-5p knockdown overturned the effects of HNF1A-AS1 knockdown on apoptosis, proliferation, migration, and invasion of OS cells. In addition, the effects of HNF1A-AS1 silencing on the malignant behaviors of OS cells were reserved by HMGB1 overexpression. In addition, HNF1A-AS1 regulated the HMGB1 level in the OS cell supernatant through the miR-32-5p/HMGB1 axis. Conclusion: Downregulation of HNF1A-AS1 blocked OS progression through the miR-32-5p/HMGB1 axis, which provides a possible target and prognostic biomarker for treatment of OS.