Tumor Of Infancy Research Articles

Cardiac Rhabdomyomas Presenting with Critical Cardiac Obstruction in Neonates and Infants: Treatment Strategies and Outcome, A Single-Center Experience.

Cardiac rhabdomyomas are the most common benign pediatric heart tumor in infancy, which are commonly associated with tuberous sclerosis complex (TSC). Most rhabdomyomas are asymptomatic and spontaneously regress over time. However, some cases especially in neonates or small infants can present with hemodynamic instability. Surgical resection of the tumor, which has been the gold standard in alleviating obstruction, is not always possible and may be associated with significant morbidity and mortality. Recently, mammalian target of rapamycin inhibitors (mTORi) have been shown to be safe and effective in the treatment of TSC. We present the outcomes of neonates and an infant who received treatment for symptomatic rhabdomyomas at a tertiary cardiology center. Medical records were reviewed to obtain clinical, demographic, and outcome data. Six patients received interventions for symptomatic rhabdomyomas, median age at presentation was 1 day old (range from 1 to 121 days old), and 67% of the patients had a pathogenic mutation in TSC gene. One patient underwent surgical resection of solitary tumor at right ventricular outflow tract (RVOT) successfully. In the four patients with left ventricular outflow tract (LVOT) obstruction, two patients received combined therapy of surgical debulking of LVOT tumor, Stage I palliation procedure, and mTORi and two patients received mTORi therapy. One patient with RVOT obstruction underwent ductal stenting and received synergistic mTORi. Four of the five patients had good response to mTORi demonstrated by the rapid regression of rhabdomyoma size. 83% of patients are still alive at their latest follow-up, at two to eight years of age. One patient died on day 17 post-LVOT tumor resection and Hybrid stage one due to failure of hemostasis, in the background of familial factor VII deficiency. Treatment of symptomatic rhabdomyoma requires individualized treatment strategy based on the underlying pathophysiology, with involvement of multidisciplinary teams. mTORi is effective and safe in inducing rapid regression of rhabdomyomas. A standardized mTORi prescription and monitoring guide will ensure medication safety in neonates and infants with symptomatic cardiac rhabdomyoma. Although the majority of tumors responded to mTORi, some prove to be resistant. Further studies are warranted, ideally involving multiple international centers with a larger number of patients.

Paratesticular Rhabdomyosarcoma: About 3 Cases and Literature Review

Paratesticular rhabdomyosarcoma is a rare and highly aggressive embryonal tumor in infancy and childhood. The tumor is intrascrotal, localized in the spermatic cord, the epididymis, or in the tunica vaginalis. Multimodality treatment should involve surgery, radiotherapy and chemotherapy, which are indicated according to risk groups. Prognosis is excellent for localized tumors, survival rates exceed 90%. We report three cases of embryonal paratesticular rhabdomyosarcoma treated in our institution.

Osmundacetone Inhibits Angiogenesis of Infantile Hemangiomas through Inducing Caspases and Reducing VEGFR2/MMP9.

This study aims to explore the potential of Osmundacetone (OSC) as a new treatment for infantile hemangiomas (IH), the most common benign tumors in infancy. Currently, propranolol serves as the primary treatment for IH, but its effectiveness is limited, and it poses challenges of drug resistance and side effects. Therefore, there is a pressing need to identify alternative therapies for IH. The effects of OSC on the proliferation and apoptosis of HemECs (endothelial cells from hemangiomas) were assessed using CCK-8 assay, colony formation assay, HOCHEST 33342 staining, and flow cytometry. Western blot analysis was performed to investigate OSC's influence on Caspases and angiogenesis-related proteins. Animal models were established using HemECs and BALB/c mice, and histological and immunohistochemical staining were conducted to evaluate the impact of OSC on mouse hemangiomas, VEGFR2, and MMP9 expression. OSC treatment significantly reduced HemECs' viability and colony-forming ability, while promoting apoptosis, as indicated by increased HOCHEST 33342 staining. OSC upregulated the protein expression of Bax, PARP, Caspase9, Caspase3, AIF, Cyto C, FADD, and Caspase8 in HemECs. In animal models, OSC treatment effectively reduced hemangioma size and improved histopathological changes. OSC also suppressed VEGFR2 and MMP9 expression while elevating Caspase3 levels in mouse hemangiomas. OSC demonstrated promising results in inhibiting HemECs' proliferation, inducing apoptosis, and ameliorating pathological changes in hemangiomas in mice. Moreover, it influenced the expression of crucial caspases and angiogenesis-related proteins. These findings suggest that OSC holds potential as a novel drug for clinical treatment of IH.

Pleural effusion due to lymphangiomatosis and the role of sirolimus: A case report

Introduction: Lymphangiomatosis is a rare abnormal proliferation of lymphatic vessels involving multiple organs like the brain, lung, heart, spleen, liver, and bones. Lymphangiomas constitute 5.6% of all benign tumors in infancy and adulthood. Case presentation: We report a case of a young lady who presented with constitutional symptoms and progressive dyspnea. Her medical history is significant for muco-cutaneous albinism, diffuse hemangiomas of the bone and viscera, and consumptive coagulopathy status post-splenectomy. After initial investigations, she was found to have right-sided pleural effusion. Pleural fluid analysis indicated chylothorax. She had multiple drainages of the pleural fluid done, and afterward, ligation of the right thoracic duct was performed with a trial of sirolimus, which improved her chylothorax. Clinical discussion: Several case reports have reported positive outcomes with sirolimus in the treatment of lymphangiomatosis. However, larger controlled studies are needed to confirm these findings. Conclusion: Sirolimus is promising as a medical treatment for diffuse pulmonary lymphangiomatosis.

1 Ototoxicity and Cognitive Outcomes among Children Treated for Brain Tumors in Infancy

Objective:Treatment of childhood central nervous system (CNS) tumors can lead to sensorineural hearing loss (SNHL), with prior research indicating associations between SNHL and cognitive difficulties. Infants (0-3 years) treated for CNS tumors are at particular risk for neurocognitive deficits due to increased vulnerability of the developing brain and missed developmental opportunities secondary to prolonged treatment. This study expands upon existing research by examining the association between treatment-related SNHL and later neurocognitive outcomes among infants.Participants and Methods:Serial audiology and neurocognitive assessments were conducted as part of a prospective, multisite, longitudinal trial (SJYC07). Children with newly diagnosed CNS tumors were treated with chemotherapy, with or without focal proton or photon radiation therapy (RT). SNHL was dichotomized based on hearing in the better ear as present versus not present (Chang grade ≥1a vs. <1a). Neurocognitive assessments included intellectual functioning (IQ), and parent ratings of executive functioning and behavioral functioning. Demographic and clinical variables investigated included: sex, age at diagnosis (years), treatment type (chemotherapy only vs. chemotherapy + RT), risk group (low vs. intermediate vs. high), and socioeconomic status (SES, continuous). Logistic regression models were used to identify factors associated with SNHL. Change point longitudinal models were used to examine the effect of each covariate individually and the potential impact of SNHL on trajectories of neurocognitive outcomes.Results:Of 135 patients (median age at diagnosis= 1.5 years), 67% had mild-to-severe SNHL as defined by Chang grade ≥1a at last follow-up. SNHL occurred early after treatment with a 1-year cumulative incidence 63.0% ±4.3%. SNHL was associated with age at diagnosis (p <.001) but not sex, treatment exposure or study risk arm (p >.10). At pretreatment baseline, IQ was associated with age at diagnosis (older age= higher IQ) and SES (higher SES= higher IQ) with a change in the trajectory of IQ after SNHL (stable prior to SNHL and declined 1.46 points/year after SNHL), which was impacted by tumor location (patients with supratentorial tumors stable prior to SNHL and declined 2.84 points/year after SNHL; whereas, patients with infratentorial tumors increased 1.93 points/year prior to SNHL and were stable after SNHL). At pre-treatment baseline, adaptive functioning was associated with age at diagnosis (older age= higher skills) with a change in adaptive functioning after SNHL that varied by age. There was a change in trajectory of attention problems (stable before SNHL and worsening 1.39 points/year after SNHL). SNHL was not associated with parent report of emerging executive functioning.Conclusions:Children with brain tumors experience SNHL and cognitive difficulties early in treatment that can worsen over time. Younger age at diagnosis is associated with greater risk for SNHL and cognitive difficulties. Analyses of the time course between the emergence of SNHL and cognitive late effects suggests even mild SNHL is associated with a clinically signficant decline in IQ and attention problems. These findings have notable implications with respect to refining monitoring guidelines, informing modifications to treatment, advocating for interventions, and helping educate parents, teachers, and providers about the significant impact of mild SNHL.

Lysates from the probiotic bacterium Streptococcus thermophilus enhances the survival of T cells and triggers programmed cell death in neuroblastoma cells.

Neuroblastoma is the most common brain solid tumor in infancy. Despite the availability of numerous approaches like immunotherapy, surgery, chemotherapy, and radiotherapy, neuroblastoma frequently develops resistance and recurs. Immunotherapy is one of the most promising approaches and PD-L1 antibody blocking is the phenomena used to inhibit PD-1 receptors to increase and improve cytotoxic T cells toward cancer. Numerous studies underlined the critical role of probiotics on immune system development and modulation in addition to possible role in inducing apoptosis in cancer cells. In this study, a Streptococcus thermophilus strain, isolated from a local yogurt, was used as it is considered a potential probiotic due to its tolerance lower pH, bile acid, antibiotic suitability, and blood hemolysis. Our results showed that S. thermophilus lysates played as an immune checkpoint modulator at 25 µg/ml dose boosting PD-L1 transcripts and protein levels in SH-SY5Y neuroblastoma cell line. Interestingly, co-culture between SH-SY5Y and Jurkat T cells in the presence of blocking PD-L1 antibodies increased Jurkat T-cell viability compering to control without lysate. On the other hand, annexin-V/7-AAD, qPCR and western blot results showed that S. thermophilus lysates at 200 and 400 µg/ml decreased SH-SY5Y cell viability and increased apoptotic marker genes transcription and caspase-3 and caspase-9 protein expression.

Infantile Hemangioma: A Cross-Sectional Observational Study.

(1) Background: With an incidence of 4-10%, infantile hemangiomas (IH) are the most encountered benign tumors in infancy. Low birth weight (LBW), prematurity, female sex, multiple gestations, and family history of IH are some of the statistically proven risk factors for developing IH. The aim of our study was to evaluate the prevalence of IH in our clinic and its connection to maternal and perinatal factors. (2) Methods: We conducted a cross-sectional study, over three years (2020-2022), at the Clinical Hospital of Obstetrics and Gynecology, "Prof. Dr. P. Sârbu", in Bucharest, Romania. (3) Results: During this period, 12,206 newborns were born and we identified 14 infants with infantile hemangioma. In our study, the prevalence of infantile hemangioma was 0.11%. The prevalence of IH in pregnancies obtained through in vitro fertilization was 1%, in twin pregnancies it was 2.27%, and in those with placenta previa, it was 4.16%. (4) Conclusions: Our findings provide a solid image of the prevalence of IH in our country and underline that the development of IH is strongly connected to maternal and perinatal variables, such as: preterm newborns, in vitro fertilization, high blood pressure, anemia, hypothyroidism, placenta previa, and twin pregnancy.

SPCR-08 ACADEMIC READINESS AMONG CHILDREN TREATED FOR BRAIN TUMORS IN INFANCY

Abstract BACKGROUND Children treated for brain tumors are more likely to have academic difficulties, receive special education services, and experience lower educational attainment than peers. Infants receiving treatment are at highest risk due to increased vulnerability of the developing brain and missed early developmental opportunities. The current study is the first to examine the emergence of academic readiness in children treated for brain tumors in infancy. METHODS Children were treated on a prospective, longitudinal multisite study with chemotherapy, with or without focal proton or photon radiation therapy (SJYC07). Academic readiness was monitored with the Bracken School Readiness Composite (SRC), and once age-appropriate, academic skills were assessed with the Woodcock Johnson III (WJII) word reading and applied math subtests. A subset of patients (n=70; median age at treatment 1.7 years; 67% male; 79% White) who completed the SRC during at least 2 timepoints were included. RESULTS Linear mixed models revealed SRC scores decreased significantly over time (p=0.033). There was a main effect of socioeconomic status (SES) such that lower SES predicted lower SRC scores, irrespective of time since treatment (p<0.0001). Other demographic and clinical factors were not predictive (i.e., age at diagnosis, disease risk, resection extent, number of surgeries, chemotherapy vs photon irradiation vs proton irradiation, shunt status, tumor location; ps>0.05). At the most distal assessment timepoint (median time since treatment 5.96 years), 28.8% and 20.3% scored below average (less than one standard deviation) on WJIII word reading and applied math, respectively; the former was significantly greater than normative expectations (16%, p=0.007). CONCLUSIONS Treatment for brain tumors in infancy appears to slow development of academic readiness skills, with SES predictive of risk and a disproportionate number of long-term survivors performing below age expectations in reading. These findings suggest the need for monitoring and interventions targeting early academic skills in this population.

Solid Pseudopapillary Tumor of Pancreas in a 14-year-old Adolescent Presenting With Melena: A Case Report

Background: The incidence of pancreatic neoplasms in infants and children is 1.8 cases per 1000000. Three of children’s most common primary pancreatic neoplasms are pancreatoblastoma, solid pseudopapillary neoplasm of the pancreas, and pancreatic endocrine neoplasms. Solid pseudopapillary neoplasm of the pancreas is a low-grade malignant tumor. Solid pseudopapillary neoplasm in children is presented with a palpable mass (60%), followed by abdominal pain (33.3%). Although duodenal invasion frequently occurs in patients with pancreatic cancer, massive gastrointestinal bleeding is seldom encountered. The most helpful imaging technique is the CT scan. Surgical resection is the treatment of choice for solid pseudopapillary neoplasms. Case Presentations: A 14 years old male adolescent was presented to our pediatric emergency department with fatigue, dizziness, fever, vomiting, and tachycardia. He had melena 5 days before admission. Crystalloids, pantoprazole, and packed red blood cells were administered to stabilize the patient. As the initial resuscitation measures stabilized the patient, endoscopic gastroduodenoscopy was performed, and a vascular lesion measuring 60×70 mm was noted in the second part of the duodenum. CT scan of the abdomen with intravenous and oral contrast showed a mass with solid and cystic components measuring 75×52 mm between the head of the pancreas and gallbladder origination from the head of the pancreas. The patient underwent Whipple surgery. The diagnosis of the pathologic evaluation was a solid pseudopapillary tumor of the pancreas. Conclusions: Most pediatric pseudopapillary tumors of the pancreas present with a palpable mass and abdominal pain, and gastrointestinal bleeding is a rare presentation not mentioned in previous case reports.

Surgical treatment of rare benign right ventricular tumors in infants: two case reports

Objective: To describe rare clinical and morphological forms of right ventricular neoplasms (mesenchymal hamartoma, rhabdomyoma) in infants which required surgical treatment in infancy.Methods: We performed 2 radical operations to remove right ventricular neoplasms: neonatal mesenchymal hamartoma and infantile rhabdomyoma.Results: We confirmed the effectiveness of surgery for rhabdomyoma and mesenchymal hamartoma in infants based on an 11-year postoperative follow-up period. We followed a necessary search strategy to detect tuberous sclerosis complex often associated with rhabdomyoma.Conclusion: Surgical treatment of rare right ventricular neoplasms in infants demonstrated favorable long-term results. Received 29 December 2022. Revised 22 February 2023. Accepted 27 March 2023. Informed consent: The patients' mothers informed consent to use the records for medical purposes is obtained. Funding: The study did not have sponsorship. Conflict of interest: The authors declare no conflict of interest. Contribution of the authorsLiterature review: E.A. Enin, A.V. MishinDrafting the article: A.V. MishinCritical revision of the article: K.N. Kuatbekov, E.A. Enin, A.L. Egizekov, A.A. SarsembayevaSurgical treatment: K.N. Kuatbekov, A.V. MishinFinal approval of the version to be published: K.N. Kuatbekov, E.A. Enin, A.L. Egizekov, A.V. Mishin, A.A. Sarsembayeva

Global metabolomics study on the pathogenesis of pediatric medulloblastoma via UPLC- Q/E-MS/MS.

Medulloblastoma is one of the most frequent malignant brain tumors in infancy and childhood. Early diagnosis and treatment are quite crucial for the prognosis. However, the pathogenesis of medulloblastoma is still not completely clarified. High-resolution mass spectrometry has enabled a comprehensive investigation on the mechanism of disease from the perspective of metabolism. Herein, we compared the difference of metabolic profiles of serum between medulloblastoma (n = 33) and healthy control (HC, n = 16) by using UPLC-Q/E-MS/MS. Principal component analysis and orthogonal projections to latent structures discriminant analysis (OPLS-DA) intuitively revealed the significantly distinct metabolic profiles between medulloblastoma and HC (p < 0.01 for permutation test on OPLS-DA model). Total of 25 significantly changed metabolites were identified. ROC analysis reported that six of them (Phosphatidic acid (8:0/15:0), 3'-Sialyllactose, Isocoproporphyrin, Acetylspermidine, Fructoseglycine and 3-Hydroxydodecanedioate) showed high specificity and precision to be potential diagnosis biomarkers (AUC > 0.98). Functional analysis discovered that there are four pathways notably perturbed for medulloblastoma. These pathways are related with the dysfunction of arachidonic acid metabolism, steroid hormone biosynthesis, and folate-related metabolism. The target intervention on these pathways may reduce the mortality of medulloblastoma.

Transorbital neuroendoscopy-assisted resection of a giant optic pathway glioma in a neonate.

Congenital giant orbital tumors in infancy are relatively rare, especially when the tumors are associated with significant intracranial extension. We describe the use of a transorbital neuroendoscopy-assisted resection of such a lesion. While this approach is increasingly gaining popularity for certain anterior and middle skullbase lesions in adults, this report represents the youngest patient reported on where this minimally invasive approach has been successfully used to resect the intracranial tumor. This surgical approach obviated the need for a separate craniotomy, with the additional benefit of minimizing blood loss.

Is there a Role for Combined Therapy with Oral Corticosteroids and Propranolol in Patients with Infantile Hemangioma? A Retrospective Cohort Study

Introduction: Infantile hemangioma (IH) is the most common benign tumor in infancy. Oral corticosteroids (OCs) still have an important role in the treatment of complex IH. In the present study, we provide our experience of oral propranolol + OCs treatment for IH. Materials and Methods: This was a retrospective cohort study of 26 IHs treated with propranolol, either alone or in combination with OCs, at the National Institute of Pediatrics, Mexico. Information on clinical and demographic data was collected. Data were summarized as mean (standard deviation) or median (minimum, maximum) or frequencies and proportions as needed. Comparative analysis between the group only treated with propranolol and the group treated with propranolol plus OCs was performed with Fisher’s exact test or Mann–Whitney U-tests. Results: All of our patients had a positive response to treatment. The comparison between both groups showed that the maximum and mean propranolol doses were significantly lower in the group of patients receiving combined treatment. Conclusions: Our findings support that the use of propranolol plus corticosteroids in IH allows the use of lower doses of both drugs for longer periods with less risk of adverse effects and fewer or no relapses.

Excellent Response of Infantile Hemangioma with Oral Propranolol: A Case Report

Background: Infantile hemangioma (IH) is the most common benign tumor in infancy. Most IHs resolve spontaneously and do not require treatment. Therapeutic intervention is necessary for life-threatening IH, tumors posing functional risks, ulceration, and severe anatomic distortion, especially on the face. Beta-blockers, most specifically propranolol, have been shown to induce involution of IH, which should be administered as early as possible to avoid potential complications. Purpose: To report a case of IH with visual impairment treated successfully using oral propranolol. Case: A 4-month-old girl weighing, 6.3 kg, with redness plaques on the right face since 3 weeks after birth. The lesions rapidly increased in size within 2 months, and the lesions on her right eyelid made it difficult to open her right eye. Dermatological examination showed erythematous plaques, compressible and varying in size and ptosis. The patient was diagnosed with periocular infantile hemangioma and was given oral propranolol therapy with an initiated dose 3x1 mg. The dose was increased gradually. The lesions were significantly decreased and she could open her right eye normally after 5 months of propranolol therapy. Discussion: Some cases of IH require early treatment. Early treatment is indicated for IH causing functional impairment. The use of propranolol in the management of IH is very effective in the reduction of the lesions and Has minimal side effects. Conclusion: Early diagnosis and intervention with propranolol for IH play an important role in determining the optimal outcomes.

Shikonin reverses pyruvate kinase isoform M2-mediated propranolol resistance in infantile hemangioma through reactive oxygen species-induced autophagic dysfunction.

Infantile hemangioma (IH) is the most common benign tumor in infancy. Propranolol, a nonselective β-adrenergic receptor blocker, is now the first-line therapy for IH. Recently, low sensitivity to propranolol therapy has become one major reason for the failure of IH treatment. However, the exact underlying mechanisms are yet to be fully elucidated. Here, we reported that pyruvate kinase isoform M2 (PKM2), an essential glycolytic enzyme, played a critical role in regulating the progression of IH and the therapeutic resistance of propranolol treatment. Shikonin reversed the propranolol resistance in hemangioma-derived endothelial cells and in hemangioma animal models. Moreover, shikonin combined with propranolol could induce excessive reactive oxygen species (ROS) accumulation and lead to autophagic dysfunction, which is essential for the enhanced therapeutic sensitivity of propranolol treatment. Taken together, our results indicated that PKM2 has a significant role in hemangiomas progression and therapeutic resistance; it could be a safe and effective therapeutic strategy for those hemangiomas with poor propranolol sensitivity combined with shikonin.

Subglottic haemangioma treated with propranolol – a case report

Andrius Račiūnas1 1Royal London Hospital, Barts Health NHS Trust, Ear, Nose & Throat Department, London, United Kingdom Abstract: Introduction. Haemangioma is the most common tumour in infancy and can occur in about 10% of the population. They are categorized into two types: “infantile” and or rare “congenital”. In some uncommon cases, the haemangioma can appear in […]

Skin sequelae in patients with infantile hemangioma: a systematic review.

Infantile hemangioma (IH) is the most common vascular tumor in infancy. Although IHs can regress spontaneously, some problematic IHs still need treatment. However, either treated or untreated IHs may leave skin sequelae which can cause permanent disfigurement. Many studies evaluated the short-term efficacy of different kinds of treatment, but now, few studies are focusing on long-term skin sequelae. The objectives of our systemic review were to identify skin sequelae of IH thoroughly, determine specific factors associated with long-term IH sequelae, and learn how to improve these sequelae. We searched the following electronic databases: PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov. Three independent authors assessed the articles, and we reported this systemic review following PRISMA guidelines. Of 4448 articles initially identified, 62 underwent full-text review, and 17 met inclusion criteria. The overall rate of sequelae ranged from 5.3 to 93.5%. Factors associated with skin sequelae included patients' demographics, hemangioma characteristics, and treatment factors. What is Known: • Infantile hemangioma is the most common vascular tumor during infancy. •Infantilehemangiomas can regress spontaneously but either treated or untreated patients may leave permanent skinsequelae. What is New: •Skin sequelae in involuted Infantile hemangiomas are very common. •It is significant to prevent, recognize, and improve skin sequelae of infantile hemangiomas.

Apelin Receptor Can Act as a Specific Marker and Promising Therapeutic Target for Infantile Hemangioma

Infantile hemangioma (IH), the most common benign tumor in infancy, is generally sensitive to propranolol treatment. However, the challenge remains because resistance or recurrence could occur in some patients, and the mechanism or target of propranolol remains unknown. Therefore, advancement in the drug development is needed. In this study, we explored whether apelin receptor (APJ) can become a candidate target. We found that APJ is expressed only in endothelial cells of IH (HemECs) but not in other vascular anomalies, and its antagonist, ML221, can negatively regulate cellular viability and functions of HemECs. This inhibitory effect could be replicated in a murine hemangioma model. Importantly, invitro experiments also indicated that ML221 failed to affect the proliferation or angiogenesis of normal endothelial cells or APJ-knockout HemECs. Through analysis of the phosphoantibody microarray data, ML221 was revealed to have an inhibitory effect on HemECs by suppressing the activation of mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. These results verified the distinctive expression of APJ in IH and specific inhibition of HemEC activity caused by ML221. In addition, APJ was also detected in propranolol-resistant IH. Collectively, we propose that APJ can act as a specific marker and a promising therapeutic target for IH, which will facilitate further drug development.

Discovery, evaluation and mechanism study of WDR5-targeted small molecular inhibitors for neuroblastoma.

Neuroblastoma is the most common and deadliest tumor in infancy. WDR5 (WD Repeat Domain 5), a critical factor supporting an N-myc transcriptional complex via its WBM site and interacting with chromosome via its WIN site, promotes the progression of neuroblastoma, thus making it a potential anti-neuroblastoma drug target. So far, a few WIN site inhibitors have been reported, and the WBM site disruptors are rare to see. In this study we conducted virtual screening to identify candidate hit compounds targeting the WBM site of WDR5. As a result, 60 compounds were selected as candidate WBM site inhibitors. Cell proliferation assay demonstrated 6 structurally distinct WBM site inhibitors, numbering as compounds 4, 7, 11, 13, 19 and 22, which potently suppressed 3 neuroblastoma cell lines (MYCN-amplified IMR32 and LAN5 cell lines, and MYCN-unamplified SK-N-AS cell line). Among them, compound 19 suppressed the proliferation of IMR32 and LAN5 cells with EC50 values of 12.34 and 14.89 μM, respectively, and exerted a moderate inhibition on SK-N-AS cells, without affecting HEK293T cells at 20 μM. Analysis of high-resolution crystal complex structure of compound 19 against WDR5 revealed that it competitively occupied the hydrophobic pocket where V264 was located, which might disrupt the interaction of MYC with WDR5 and further MYC-medicated gene transcription. By performing RNA-seq analysis we demonstrated the differences in molecular action mechanisms of the compound 19 and a WIN site inhibitor OICR-9429. Most interestingly, we established the particularly high synergy rate by combining WBM site inhibitor 19 and the WIN site inhibitor OICR-9429, providing a novel therapeutic avenue for neuroblastoma.

TREATMENT/MANAGEMENT OF OTHER HEPATIC TUMORS

Pediatric liver neoplasias are rare, comprising 1–4% of all solid childhood tumors. More than half of these masses are due to hepatoblastoma and hepatocellular carcinomas, making remaining various liver tumors much more rarer. Hepatic mesenchymal hamartoma (HMH) is a benign tumor observed in children less than five- year-old. It is located in the right lobe of the liver more often. It has a cystic structure, and AFP is generally normal or slightly elevated. The treatment is complete resection. In rare cases, HMH can transform into undifferentiated embryonal sarcoma. Focal nodular hyperplasia is a well-circumscribed benign lesion, which is usually discovered incidentally as well as with oral contraceptive use, postchemotherapy status, and hereditary hemorrhagic telengiectasia. Typical imaging finding is a central scar in the mass lesion, which might overlap with fibrolamellar hepatocellular carcinoma. Asymptomatic cases might be managed with an expectant approach by careful monitoring whereas symptomatic cases might be treated with surgery or ablation therapy. Infantile hemangioma is the most common benign hepatic tumor in infancy. Symptoms at admission may include abdominal distention due to hepatomegaly, congestive heart failure, feeding problems, anemia, thrombocytopenia and consumptive coagulopathy, jaundice. Many of these hemangiomas are discovered incidentally and are localized. In most cases, these lesions are small enough to be of no clinical significance. In severe cases, propranolol, corticosteroids, mTOR inhibitors or cytotoxic agents can be used for treatment. Undifferentiated embryonal sarcoma of the liver (UESL) is the third most common malignant liver tumor in children. The median age of diagnosis of UESL is 10,5 years, in comparison to that of liver rhabdomyosarcoma which is 3.6 years. UESL is an aggressive malignancy that should be treated with multimodal therapy. Most important prognostic factor is the completeness of the resection. The survival is reported to range between 70% and 90% in various case series. Rhabdomyosarcomas are observed in the biliary tract. The usual sign in admission is obstructive jaundice with or without abdominal mass. Treatment is multimodal therapy. With CWS protocols, the 5-year overall (OS) and event free survival (EFS) rates were 58% and 47%, respectively. Hepatic angiosarcoma is a rare but highly aggressive malignancy of endothelial cells, previously known as infantile hemangioendothelioma type 2. There is a girl predominance. Despite multiagent aggressive treatment approaches including liver transplantation, the overall prognosis is still poor.