Childhood Malignancies Research Articles

Global Impact of Monoclonal Antibodies (mAbs) in Children: A Focus on Anti-GD2.

Monoclonal antibodies (mAbs), as the name implies, are clonal antibodies that bind to the same antigen. mAbs are broadly used as diagnostic or therapeutic tools for neoplasms, autoimmune diseases, allergic conditions, and infections. Although most mAbs are approved for treating adult cancers, few are applicable to childhood malignancies, limited mostly to hematological cancers. As for solid tumors, only anti-disialoganglioside (GD2) mAbs are approved specifically for neuroblastoma. Inequities of drug access have continued, affecting most therapeutic mAbs globally. To understand these challenges, a deeper dive into the complex transition from basic research to the clinic, or between marketing and regulatory agencies, is timely. This review focuses on current mAbs approved or under investigation in pediatric cancer, with special attention on solid tumors and anti-GD2 mAbs, and the hurdles that limit their broad global access. Beyond understanding the mechanisms of drug resistance, the continual discovery of next generation drugs safer for children and easier to administer, the discovery of predictive biomarkers to avoid futility should ease the acceptance by patient, health care professionals and regulatory agencies, in order to expand clinical utility. With a better integration into the multimodal treatment for each disease, protocols that align with the regional clinical practice should also improve acceptance and cost-effectiveness. Communication and collaboration between academic institutions, pharmaceutical companies, and regulatory agencies should help to ensure accessible, affordable, and sustainable health care for all.

Antifungal Drug-Drug Interactions with Commonly Used Pharmaceutics in European Pediatric Patients with Acute Lymphoblastic Leukemia.

Leukemia is one of the leading childhood malignancies, with acute lymphoblastic leukemia (ALL) being the most common type. Invasive fungal disease is a concerning problem also at pediatric hemato-oncology units. Available guidelines underline the need for antifungal prophylaxis and give recommendations for proper treatment in various clinical scenarios. Nonetheless, antifungal agents are often involved in drug-drug interaction (DDI) occurrence. The prediction of those interactions in the pediatric population is complicated because of the physiological differences in adults, and the lack of pharmacological data. In this review, we discuss the potential DDIs between antifungal agents and commonly used pharmaceutics in pediatric hemato-oncology settings, with special emphasis on the use of liposomal amphotericin B and ALL treatment. We obtained information from Micromedex® and Drugs.com® interaction checking databases and checked the EudraVigilance® database to source the frequency of severe adverse drug reactions that resulted from antifungal drug interactions. Several major DDIs were identified, showing a favorable safety profile of echinocandins and liposomal amphotericin B. Interestingly, although there are numerous available drug interaction checking tools facilitating the identification of potential serious DDIs, it is important to use more than one tool, as the presented searching results may differ between particular checking programs.

A practical nomogram and risk stratification system for predicting survival outcomes in neuroblastoma patients: a SEER population-based study

BackgroundNeuroblastoma (NB) is a childhood malignancy with marked heterogeneity, resulting in highly variable outcomes among patients. This study aims to establish a novel nomogram and risk stratification system to predict the overall survival (OS) for patients with NB.MethodsWe analyzed neuroblastoma patients from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The nomogram was constructed using independent risk factors for OS, identified through univariate and multivariate Cox regression analyses. The accuracy of this nomogram was evaluated with the concordance index, receiver operating characteristic curve, calibration curve, and decision curve analysis. In addition, we developed a risk stratification system based on the total score of each patient in the nomogram.ResultsA total of 2185 patients were randomly assigned to the training group and the testing group. Six risk factors, including age, chemotherapy, brain metastases, primary site, tumor stage, and tumor size, were identified in the training group. Using these factors, a nomogram was constructed to predict 1-, 3-, and 5-year OS of NB patients. This model exhibited superior accuracy in the training and testing groups, exceeding traditional tumor stage prediction. Subgroup analysis suggested worse prognosis for retroperitoneal origin in the intermediate-risk group and adrenal gland origin in the high-risk group compared to other sites. Additionally, the prognosis for high-risk patients significantly improved after surgery. We also developed a web application to make the nomogram more user-friendly in clinical practices.ConclusionThis nomogram demonstrates excellent accuracy and reliability, offering more precise personalized prognostic predictions to clinical patients.

Impact of Zinc Supplementation in prevention of Chemotherapy Induced Oral Mucositis

Objective: To determine the impact of Zinc supplements in prevention of oral mucositis and its consequences in patients receiving chemotherapy. Study Design: Quasi experimental study Place and Duration: Department of Paediatric Oncology, Pakistan Institute of Medical Sciences (PIMS), Islamabad from 1st March, 2023 to 31 July, 2023. Methodology: A total of 60 patients (N) diagnosed of acute lymphoblastic leukemia planned for induction of treatment were included in the study. Patients were randomly divided into two groups of thirty patients each. Group-A received Zinc supplements while group-B received the usual standard of care without any additional supplement. At the end of four weeks of induction therapy, all patients were assessed for presence and severity of oral mucositis. They were also inquired about food intolerance and need for analgesics. Results: Mean age of patients included in the study was 4.723 ± 2.84 yrs. Males were34 (56.6%) and 26 (43.3%) were females. Severity of mucositis (p-Value is 0.017) and food intolerance (p-Value is 0.020) were markedly decreased in the group receiving zinc supplements. Analgesics were required by 21 (70%) patients in the group receiving zinc supplements and by 27 (90%) in the group not receiving zinc supplements. However, p-Value remained non-significant (0.104). Conclusion: Both, severity of oral mucositis and food intolerance are significantly reduced in patients prescribed zinc supplements during the induction phase of chemotherapy. Though, requirement of analgesics was also considerably reduced amongst patients taking zinc supplements, the difference was not statistically significant for this particular variable in our study. Keywords: Acute Lymphoblastic Leukemia, Zinc, Oral Mucositis, Chemotherapy, Childhood Malignancy How to Cite This: Tariq R, Manzoor R, Batool Z, Yasmeen N, Fatima SI, Ayub S. Impact of Zinc Supplementation in prevention of Chemotherapy Induced Oral Mucositis. Isra Med J. 2023; 15(1): 3-6. DOI: https://doi.org/10.55282/imj.oa1372 This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Differences in induction phase outcomes of acute lymphoblastic leukemia between well-nourished and malnourished pediatric patients

Background Leukemia is the most common malignancy in childhood. Malnutrition is the main nutritional disorder occurring in children with cancer. Nutritional supportive care is a medical modality that has been associated with improved tolerance to chemotherapy, survival, and quality of life, as well as decreased risk of infection in children undergoing cancer therapy.
 Objective To examine differences in induction phase outcomes in well-nourished and malnourished pediatric acute lymphoblastic leukemia (ALL) patients.
 Methods This prospective study was conducted in newly-diagnosed ALL patients aged 1 to 18 years who underwent induction phase chemotherapy at Haji Adam Malik General Hospital, Medan, North Sumatera. Mid-upper arm circumference (MUAC) was used to determine nutritional status. Patient characteristics such as complete blood count (CBC) at the time of diagnosis, occurrence of febrile neutropenia, duration of induction, length of hospital stay, and remission status were collected. We analyzed differences in CBC, frequency of febrile neutropenia, as well as duration of induction and hospital stay between well-nourished and malnourished patients. We also assessed the difference in remission attainment between the two groups.
 Results There were 21 subjects in each group. Compared to well-nourished subjects, malnourished ones had a higher median incidence of febrile neutropenia [1 (range 0 to 30) vs. 3 (range 0 to 4); P=0.04], longer mean induction duration [64.2 (SD 11.5) vs. 71.2 (SD 10.6) days; P=0.046], and longer median hospital stay [30 (range 19 to 56) vs. 36 (range 22 to 49) days; P=0.001] compared to well-nourished subjects. There was no significant difference in CBC parameters and remission status after induction between the two groups.
 Conclusion Malnourished pediatric ALL patients had a significantly higher incidence of febrile neutropenia, duration of induction phase, and duration of hospital stay compared to well-nourished ALL patients.

Nutritional status and inflammatory markers as survival predictors in pediatric central nervous system tumors

Central nervous system tumors (CNS) are the second most common malignancies in childhood. Inflammation and changes in nutritional status play an important role and can be used as prognostic markers. Thus, this study aimed to evaluate the predictive ability of nutritional status and inflammatory markers on overall survival (OS) of pediatric patients with CNS. In this retrospective cohort study, 103 patients were followed for 5 years. Clinical, anthropometric, and hematological data were collected. Body mass index for age (BMI/A), neutrophil-to-lymphocyte ratio (NLR) and systemic inflammation response index (SIRI) were calculated. OS curves were calculated using the Kaplan Meier method and evaluated using the Log-Rank test. The Cox proportional hazards model was performed to identify independent variables associated with prognostic factors, generating hazard ratios (HR) and 95% confidence intervals (CI). Nutritional status did not significantly affect OS. However, patients with NLR ≥2.18 and SIRI ≥1249.18 had significantly lower OS in 5 years. Only treatment and high NLR were identified as independent prognostic factors for worse OS. Treatment with exclusive radiotherapy or chemotherapy (HR: 16.22, 95% CI: 2.19-120.07) and NLR (HR: 1.94, 95% CI: 1.02-3.69) were identified as independent prognostic factors for worse OS at 5 years. High pretreatment NLR was shown to be an independent prognostic factor for OS in pediatric patients with CNS.

Automatic retinoblastoma screening and surveillance using deep learning.

Retinoblastoma is the most common intraocular malignancy in childhood. With the advanced management strategy, the globe salvage and overall survival have significantly improved, which proposes subsequent challenges regarding long-term surveillance and offspring screening. This study aimed to apply a deep learning algorithm to reduce the burden of follow-up and offspring screening. This cohort study includes retinoblastoma patients who visited Beijing Tongren Hospital fromMarch 2018 to January 2022 for deep learning algorism development. Clinical-suspected and treated retinoblastoma patients from February 2022 to June 2022 were prospectively collected for prospective validation. Images from the posterior pole and peripheral retina were collected, and reference standards were made according to the consensus of the multidisciplinary management team. A deep learning algorithm was trained to identify "normal fundus", "stable retinoblastoma" in which specific treatment is not required, and "active retinoblastoma" in which specific treatment is required. The performance of each classifier included sensitivity, specificity, accuracy, and cost-utility. A total of 36,623 images were included for developing the Deep Learning Assistant for Retinoblastoma Monitoring (DLA-RB) algorithm. In internal fivefold cross-validation, DLA-RB achieved an area under curve (AUC) of 0.998 (95% confidence interval [CI] 0.986-1.000) in distinguishing normal fundus and active retinoblastoma, and 0.940 (95%CI 0.851-0.996) in distinguishing stable and active retinoblastoma. From February 2022 to June 2022, 139 eyes of 103 patients were prospectively collected. In identifying active retinoblastoma tumours from all clinical-suspected patients and active retinoblastoma from all treated retinoblastoma patients, the AUC of DLA-RB reached 0.991 (95% CI 0.970-1.000), and 0.962 (95% CI 0.915-1.000), respectively. The combination between ophthalmologists and DLA-RB significantly improved the accuracy of competent ophthalmologists and residents regarding both binary tasks. Cost-utility analysis revealed DLA-RB-based diagnosis mode is cost-effective in both retinoblastoma diagnosis and active retinoblastoma identification. DLA-RB achieved high accuracy and sensitivity in identifying active retinoblastoma from the normal and stable retinoblastoma fundus. It can be used to surveil the activity of retinoblastoma during follow-up and screen high-risk offspring. Compared with referral procedures to ophthalmologic centres, DLA-RB-based screening and surveillance is cost-effective and can be incorporated within telemedicine programs. This study was registered on ClinicalTrials.gov (NCT05308043).

Assessment of Metabolic Syndrome and Kidney and Heart Function in Childhood Cancer Survivors

Background: The survivors of childhood cancer suffer from a number of long-term side effects. These include atherosclerosis and cardiovascular diseases (CVDs) that develop earlier in adulthood than in the rest of the population. The aim of this study was to identify prognostic factors of developing atherosclerosis before the development of symptomatic CVD. Methods: A total of 141 children that were 7–18 years old were examined; there were 116 survivors of childhood malignancies (hematopoietic and lymphoproliferative malignancies—52; neuroblastoma—22; Wilms tumor—24; other solid tumors—18) and 25 healthy controls. Anthropometric measurements, blood pressure measurements, ultrasonography of the abdomen, echocardiography, and laboratory tests were performed. Results: There were no significant differences in gender distribution, time from the end of the treatment, weight, BMI, prevalence of central obesity, blood pressure and resistive index of the renal arteries, lipid profile, or glucose and fibrinogen levels. Patients with solid tumors had a significantly lower height and worse renal function. Patients with hematological malignancies significantly presented the lowest shortening fraction of the left ventricle. The salusin β levels were significantly higher in the control group than among the patients. Conclusions: The type and severity of side effects are closely related to the type of neoplasm and the treatment that has been undergone. Careful observation and regular follow-up are necessary.

OTHR-12. LOCATION-RELEVANT GROWTH FACTOR DEPENDENCE ON THE FORMATION OF PEDIATRIC BRAIN TUMOR ORGANOIDS FROM PDOX MODELS AND PATIENT SAMPLES

Abstract Brain cancer constitutes the most common type of childhood malignancies and the leading cause of death in children. Despite recent advances in diagnostic methods, surgical techniques as well as chemo- and radio-therapeutic strategies; the survival rates in many types of malignant pediatric brain tumors remain dismal, with <25% of children with high grade glioma surviving five years after initial diagnosis and nearly all patients with diffuse intrinsic pontine glioma succumbing to the disease within 9-12 months. Moreover, even among brain tumor survivors, many patients are left with long-term cognitive and/or neuroendocrine sequalae. Therefore, more efficacious therapeutic modalities that can improve the patient’s quality of life and increase their survival are urgently needed. 3D organoid cultures have arisen as clinically relevant and molecularly accurate in vitro brain tumor model systems for preclinical drug testing. These models have demonstrated to faithfully recapitulate the genomic and phenotypic complexities of the original tumor and thereby, can reliably predict the patient response to treatment. Recognizing the impact of the tumor microenvironment and the brain developmental stage on brain tumor growth, we developed a novel protocol to evaluate the impact of tumor location-related niche factors on the development of brain tumoral organoids. Utilizing different growth factor combinations that are unique/selective to different regions of brain development, we were able to develop 39 PDOX-derived organoids from a total of 40 PDOX models tested (success rate: 97.5%) and 23 patient-derived organoids from a total of 29 patient samples tested (success rate: 79%). Furthermore, cellular characterization studies revealed the replication of an heterogenous cell population. Altogether, our study identifies differences on growth factor dependence for the formation of organoids from brain tumors of different locations and demonstrates that PDOX models are valuable tools for the development and optimization of protocols for organoid model establishment.

OTHR-08. MULTIDISCIPLINARY APPROACH TO PAEDIATRIC BRAIN CANCER BIO-BANKING IMPROVES ENROLLMENT, FACILITATES DISCOVERY RESEARCH, AND ENABLES BETTER ACCESS TO DIAGNOSTIC AND THERAPEUTIC STUDIES

Abstract Despite the significant progress made in the multi-modal treatment of childhood malignancies over the last four decades with a concomitantly increased cure rates, the benefit is still largely limited to patients with leukemias, lymphomas and localized non-CNS solid tumors, leaving patients with high-risk non-CNS solid tumours and most CNS malignancies with minimal advancements. More research is critical to understand what drives these cancers and to investigate the best ways to deliver curative therapies. Translational research relies on patient-derived tissue samples, animal models and cell-cultures to understand the biological, genetic, and molecular mechanisms of disease. To facilitate patient care and outcomes it is becoming increasingly important that paediatric clinical trials include tissue availability as part of eligibility criteria, making collection and storage of patient tissue a mandate of personalized medicine and a pillar of modern paediatric cancer medicine. Monash Children’s Cancer Biobank was established in 2011. Since 2017, a total of 64 patients were diagnosed with CNS malignancies across all grades, with an overall 69% of patients’ tissues being bio-banked at the time of initial diagnosis. Through the combination of an educational forum, regular multi-disciplinary meetings, and the early involvement of medical oncology and biobank staff, with our neurosurgical and clinical pathology colleagues, as part of patient management planning, the tissue acquisition for bio-banking increased from 44% to 82% over the course of 5 years. This consequently led to a 100% enrollment to tissue-enabling studies allowing for banking of both fresh-frozen tissue and living cell-line models, facilitating discovery research efforts as part of the Victorian Paediatric Cancer Consortium’s molecular analysis pipeline (https://vicpcc.org.au/dashboard). This significantly improves opportunities for identification of targetable pathways, access to targeted therapies, enrollment onto treatment clinical trials and identification of patients with cancer predisposition syndromes.

MDB-45. SELECTIVE B7-H3 INHIBITORS NI1 AND NI4 REDUCE AGGRESSIVENESS OF GROUP 3 MEDULLOBLASTOMA

Abstract Medulloblastoma (MB) is a primary childhood malignancy of the central nervous system (CNS). Clinically heterogenous MB are sub-grouped into four molecular subgroups, i.e. Wingless (WNT), Sonic Hedgehog (SHH), Group 3, and Group 4. Among all, Group 3 MB (G3MB) is known to be the most aggressive form, with less than 50% five-year survival. G3MB are associated with large-cell/anaplastic (LCA) histology, distinctive methylation profile, amplification of MYC, and isochromosome 17q (i17q). Targeting these high-risk molecular features unique to G3MB has been challenging, necessitating alternative approaches to therapy for G3-MB. One innovative approach is immunotherapy, which is largely impeded by inhibitory immune checkpoints. B7 homolog 3 (B7-H3/CD276), an immunosuppressive immune checkpoint protein and member of B7 superfamily, is significantly enriched in pediatric malignancies of CNS including G3MB. The enhanced expression of B7-H3/CD276 has been associated with aggressive and metastatic potential. B7-H3/CD276 is also a primary target of miR-1253, a novel tumor suppressor gene silenced in G3MB. Using a structure-based drug discovery pipeline, we screened the ChemBridge library of compounds to discover selective B7-H3 small-molecule inhibitors. Selective B7-H3 inhibitors Ni1 and Ni4 exhibited strong binding scores, CNS penetrance, and oral bioavailability. In vitro, both compounds had appreciably low IC50 values of 3µM (Ni1) and 0.75µM (Ni4). Further, both compounds inhibited wound healing and colony formation. Ni1 shifted the thermostability of B7-H3, suggesting in vitro biding. Ni1 has also undergone PK/PD and MTD studies in vivo, showing stability in serum, good blood-brain barrier permeability, and a half-life of 8 hours. We are now elucidating B7-H3-activated downstream signaling through JAK2/STAT3 signaling and testing the in vivo efficacy for Ni1 against G3MB tumors in a murine model.

MDB-26. CDK8 IS AN ONCOGENE IN GROUP 3 MEDULLOBLASTOMA THAT IMPACTS PROTEIN TRANSLATION BY REGULATING THE TRANSCRIPTIONAL ACTIVITY OF RIBOSOMAL GENES

Abstract Medulloblastoma (MB) is one of the most common malignant childhood brain tumors. Single-cell RNA-seq analysis of human medulloblastoma patients revealed that Group 3 MBs are dominated by undifferentiated progenitor-like cells with elevated expression of ribosomal genes, suggesting that overactive ribosome biogenesis is a hallmark of Group 3 MB. Using CRISPR-Cas9 screen, we found that Cyclin-dependent kinase 8 (CDK8) is an essential gene for MYC MB viability. We showed that CDK8 facilitates MYC-driven transcriptional programs and is necessary for sustaining expression of MYC. Furthermore, the loss of CDK8 resulted in a reduction in the phosphorylation of RNA polymerase II CTD and caused significant changes in genome transcription. Using cut&run, we found CDK8 directly regulated ribosomal gene transcription activity. CDK8 inhibition impaired ribosome biosynthesis suppressed protein translation and led to a striking reduction in phospho-Pol II binding at the promoter regions and gene bodies of SE-associated genes. The combination of an mTOR inhibitor with CDK8 inhibitors showed remarkable synergy in suppressing ribosome biogenesis, decreasing cell viability and attenuating tumor growth in vitro and in multiple models of MB. This proposal outlines the mechanistic consequences of CDK8 inhibition on ribosome biogenesis and provides pre-clinical validation of CDK8 inhibitor treatment as a novel therapeutic approach in MYC MB.

MDB-05. HUMAN FETAL CEREBELLAR CELL ATLAS INFORMS MEDULLOBLASTOMA ORIGIN AND ONCOGENESIS

Abstract Medulloblastoma (MB) is the most common malignant childhood brain tumor, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella or human counterparts from frozen tissue nuclei5 have not fully defined the compositional heterogeneity of MBs. Here, we undertook an unprecedented single-cell profiling of freshly-isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group-3 and metastatic tumors. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group-3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin-loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group-3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group-3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs reveal potential cell populations predisposed to transformation and regulatory circuitries underlying tumor cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.

MDB-29. MEDULLOBLASTOMA SUBGROUP-SPECIFIC CHROMATIN STATES REVEAL NOVEL THERAPEUTIC VULNERABILITIES

Abstract Medulloblastoma (MB) is a highly malignant childhood brain tumor comprising a collection of molecularly and clinically distinct entities. Mutations in chromatin-modifying genes distribute across subgroups and account for nearly half of all MBs. However, the molecular consequences of chromatin modifier alterations remain poorly understood. Herein, we characterize the chromatin landscape of fifty-two primary MBs representing each MB subgroup using chromatin immunoprecipitation followed by sequencing (ChIP-seq) for six histone marks and perform multi-layered integration with somatic genetics, genome-wide DNA methylation, and transcriptomic datasets extracted from the same tumors. Analysis of differential chromatin states across MB subgroups identified significant enrichment of a bivalent enhancer state (EnhBiv) in Group 4 MB. Group 4-specific EnhBivs mapped to promoters of key neurodevelopmental genes and transcription factors and was associated with increased DNA methylation and reduced expression. In accordance with higher EnhBivs coverage in Group 4 MB, we found that KDM2B, a H3K4me3 and H3K36me2 demethylase, is highly expressed in Group 4 MBs and patient-derived xenografts (PDXs). KDM2B knockout mediated by CRISPR targeting suppressed growth of both Group 3 MB cell lines in vitro and Group 4 MB PDXs in vivo but had no effect on control SHH-MB cells, suggesting that KDM2B is a novel selective dependency in MB. Knockout of KDM2B in MB cells induced profound upregulation of PRC2 targets, genes regulated by bivalent histone marks, as well as genes involved in neuronal differentiation. Further biochemical and molecular studies demonstrated that KDM2B interacts with PRC2 complex subunits and occupies gene promoters associated with Group 4-specific EnhBiv chromatin. In summary, our comprehensive characterization of the MB chromatin landscape in a large cohort of primary tumors provides novel insights into the epigenetic basis of MB and implicates KDM2B as a novel Group 4 MB dependency that should be prioritized as a therapeutic target in this subgroup.

Repurposing a plant alkaloid homoharringtonine targets insulinoma associated-1 in N-Myc-activated neuroblastoma

High-risk neuroblastoma (NB) is a heterogeneous and malignant childhood cancer that is frequently characterized by MYCN proto-oncogene amplification or elevated N-Myc protein (N-Myc) expression. An N-Myc downstream target gene, insulinoma associated-1 (INSM1) has emerged as a biomarker that plays a critical role in facilitating NB tumor cell growth and transformation. N-Myc activates endogenous INSM1 gene expression through binding to the E2-box of the INSM1 proximal promoter in NB. We identified a plant alkaloid, homoharringtonine (HHT), from a chemical library screening showing potent inhibition of INSM1 promoter activity. This positive-hit plant alkaloid exemplifies an effective screening approach for repurposed compound targeting INSM1 expression in NB cancer therapy. The elevated N-Myc and INSM1 expression in NB constitutes a positive-loop through INSM1 activation that promotes N-Myc stability. In the present study, the biological effects and anti-tumor properties of HHT against NB were examined. HHT either down regulates and/or interferes with the binding of N-Myc to the E2-box of the INSM1 promoter and the inhibition of PI3K/AKT-mediated N-Myc stability could lead to the NB cell apoptosis. HHT inhibition of NB cell proliferation is consistent with the INSM1 expression as higher level of INSM1 exhibits a more sensitive IC50 value. The combination treatment of HHT and A674563 provides a better option of increasing potency and reducing cellular cytotoxicity than HHT or A674563 treatment alone. Taken together, the suppression of the INSM1-associated signaling pathway axis promotes the inhibition of NB tumor cell growth. This study developed a feasible approach for repurposing an effective anti-NB drug.

Vincristine, doxorubicin and cyclophosphamide chemotherapy induced oral chronic hyperplastic candidiasis and xerostomia in a young patient with Ewing’s sarcoma: A case report

Abstract A common primary bone malignancy in childhood and adolescence is Ewing’s sarcoma. Here we report multidisciplinary approach in the management of chronic hyperplastic candidiasis and xerostomia secondary to chemotherapy with vincristine, doxorubicin and cyclophosphamide (VDC) in a pediatric male patient with Ewing’s sarcoma of Ethmoid sinus. The initial diagnosed oral lesion was treated with topical clotrimazole 1%w/v for two weeks and Sucralfate 1g/10mL oral rinse for one month. Upon subsequent VDC chemotherapy cycle, the patient developed grade IV oral mucositis, severe neutropenia and associated oesophageal candidiasis. Treatment included combination of topical clotrimazole 1%w/v and Fluconazole 300mg/day (IV for 5 days and Tablet for 14 days). To prevent caries risk, pit and fissure sealants were applied and topical fluoride therapy was given; patient was encouraged to have frequent sips of water and prescribed kids xylitol gum for 15 days to minimize xerostomia. At 5-week follow up, reduction in burning sensation and resolution of white lesion was noted.

Availability of cytotoxic medicines in the WHO essential medicine list used in treating childhood malignancies in low-income and lower-middle-income countries: a systematic review protocol

IntroductionCancer is a leading cause of death globally with childhood cancers accounting for around 5% of the total incidence. Almost 90% of childhood cancers are recorded from low-income and lower-middle-income...

INTRAMEDULLARY FIXATION OF DOUBLE-BARREL VASCULARIZED FIBULA GRAFTS WITH SUBSEQUENT LENGTHENING FOR RECONSTRUCTION OF THE DISTAL FEMUR IN PATIENTS WITH OSTEOSARCOMA

IntroductionThe use of vascularised fibula grafts is an accepted method for reconstructing the distal femur following resection of malignant childhood tumours. Limitations relate to the mismatch of the cross-sectional area of the transplanted fibula graft and thel ocal bone, instability of the construct and union difficulties. We present midterm results of a unique staged technique—an immediate defect reconstruction using a double-barrel vascularised fibula graft set in in A-frame configuration and a subsequent intramedullary femoral lengthening.Materials & MethodsWe retrospectively included 10 patients (mean age 10 y)with an osteosarcoma of the distal femur, who were treated ac-cording to the above-mentioned surgical technique. All patients were evaluated with regards to consolidation of the transplanted grafts, hypertrophy at the graft-host junctions, leg length discrepancies, lengthening indices, complications as well as functional outcome.ResultsThe mean defect size after tumour resection was 14.5 cm, the mean length of the harvested fibula graft 22 cm, resulting in a mean (acute) shortening of 4.7 cm (in 8 patients). Consolidation was achieved in all cases, 4 patients required supplementary bone grafting. Hypertrophy at the graft-host junctions was observed in78% of the evaluable junctions. In total 11 intramedullary lengthening procedures in 9 patients had been performed at the last follow up. The mean Muskuloskeletal Society Rating Scale(MSTS) score of the evaluable 9 patients was 85% (57% to 100%)with good or excellent results in 7 patients.ConclusionsA-frame vascularised fibula reconstructions showed encouraging results with respect to defect reconstruction, length as well as function and should therefore be considered a valuable option for reconstruction of the distal femur after osteosarcoma resection. The surgical implementation is demanding though, which is emphasized by the considerable high number of com-plications requiring surgical intervention, even though most were not serious.

Beijing Children's Hospital guidelines on the design and conduction of the first standardized database for medulloblastoma.

Medulloblastoma (MB) is one of the most common malignant childhood brain tumors (WHO grade IV). Its high degree of malignancy leads to an unsatisfactory prognosis, requiring more precise and personalized treatment in the near future. Multi-omics and artificial intelligence have been playing a significant role in precise medical research, but their implementation needs a large amount of clinical information and biomaterials. For these reasons, it is urgent for current MB researchers to establish a large sample-size database of MB that contains complete clinical data and sufficient biomaterials such as blood, cerebrospinal fluid (CSF), cancer tissue, and urine. Unfortunately, there are few biobanks of pediatric central nervous system (CNS) tumors throughout the world for limited specimens, scarce funds, different standards collecting methods and et cl. Even though, China falls behind western countries in this area. The present research set up a standard workflow to construct the Beijing Children's Hospital Medulloblastoma (BCH-MB) biobank. Clinical data from children with MB and for collecting and storing biomaterials, along with regular follow-up has been collected and recorded in this database. In the future, the BCH-MB biobank could make it possible to validate the promising biomarkers already identified, discover unrevealed MB biomarkers, develop novel therapies, and establish personalized prognostic models for children with MB upon the support of its sufficient data and biomaterials, laying the foundation for individualized therapies of children with MB.

Infertility Treatments Resulting in Twin Pregnancy: Does It Increase the Risk for Future Childhood Malignancy.

Background: Controversy exists in the literature regarding the possible association between infertility treatments in singleton pregnancies and long-term risk for childhood malignancy. Data regarding infertility treatments in twins and long-term childhood malignancies are scarce. Objective: We sought to investigate whether twins conceived following infertility treatments are at an increased risk for childhood malignancy. Study design: A population-based retrospective cohort study, comparing the risk for future childhood malignancy in twins conceived by infertility treatments (in vitro fertilization and ovulation induction) and those who were conceived spontaneously. Deliveries occurred between the years 1991 and 2021 in a tertiary medical center. A Kaplan-Meier survival curve was used to compare the cumulative incidence of childhood malignancies, and a Cox proportional hazards model was constructed to control for confounders. Results: During the study period, 11,986 twins met the inclusion criteria; 2910 (24.3%) were born following infertility treatments. No statistically significant differences were noted between the groups comparing the rate (per 1000) of childhood malignancies (2.0 in the infertility treatments group vs. 2.2 in the comparison group, OR 1.04, 95% CI 0.41-2.62; p = 0.93). Likewise, the cumulative incidence over time was comparable between the groups (log-rank test, p = 0.87). In a Cox regression model, controlling for maternal and gestational age, no significant differences in childhood malignancies were noted between the groups (adjusted HR = 0.82, 95% CI 0.49-1.39, p = 0.47). Conclusions: In our population, twins conceived following infertility treatments are not at an increased risk for childhood malignancies.