Tumor Of Childhood Research Articles

Consensus guidelines for the management of posterior fossa tumour for low- and middle-income countries.

The posterior fossa is a limited compartment therefore lesions compressing its structures can result in devastating outcomes. It can cause significant neurological deficit due to mass effect on critical structures and hydrocephalus. Due to the nature of the infratentorial region, urgent surgical intervention is often the first-line option. Surgical neuro-oncologists guide patients and caregivers through the course of this disease and to inform them about the various options for management and long-term outcome optimisation. There is currently conflicting data; however, institutional experiences can guide us towards achieving improvements in surgical outcomes and quality of life. Advances in molecular classifications coupled with highdose radiation treatment improve our capacity for improving overall survival in these patients. Common childhood tumours are ependymomas, medulloblastomas, and juvenile pilocytic astrocytomas, while adults often present with metastases, and less commonly, cerebellar haemangioblastomas and gliomas. This paper outlines management strategies with consideration for multidisciplinary care and resourcelimited settings.

AF1q is a universal marker of neuroblastoma that sustains N-Myc expression and drives tumorigenesis

Neuroblastoma is the most common extracranial malignant tumor of childhood, accounting for 15% of all pediatric cancer deaths. Despite significant advances in our understanding of neuroblastoma biology, five-year survival rates for high-risk disease remain less than 50%, highlighting the importance of identifying novel therapeutic targets to combat the disease. MYCN amplification is the most frequent and predictive molecular aberration correlating with poor outcome in neuroblastoma. N-Myc is a short-lived protein primarily due to its rapid proteasomal degradation, a potentially exploitable vulnerability in neuroblastoma. AF1q is an oncoprotein with established roles in leukemia and solid tumor progression. It is normally expressed in brain and sympathetic neurons and has been postulated to play a part in neural differentiation. However, no role for AF1q in tumors of neural origin has been reported. In this study, we found AF1q to be a universal marker of neuroblastoma tumors. Silencing AF1q in neuroblastoma cells caused proteasomal degradation of N-Myc through Ras/ERK and AKT/GSK3β pathways, activated p53 and blocked cell cycle progression, culminating in cell death via the intrinsic apoptotic pathway. Moreover, silencing AF1q attenuated neuroblastoma tumorigenicity in vivo signifying AF1q’s importance in neuroblastoma oncogenesis. Our findings reveal AF1q to be a novel regulator of N-Myc and potential therapeutic target in neuroblastoma.

Revealing Orbital Tumors: A 2-Year Evaluation in Clinical Profile, Histopathological Features and Surgical Technique

Abstract
 Introduction & Objectives : Incidence of orbital tumors is relatively low, but the delay in diagnosis, even if benign, can lead to vision loss and deformity. This study aims to review clinical and demographic information of orbital tumors in Sardjito General Hospital, Yogyakarta.
 Methods : We retrospectively reviewed clinical data of 138 patients who diagnosed with orbital tumors during July 2021 - March 2023. Data extracted included clinical characteristics, operative procedures, and histopathologic characteristics of orbital tumors.
 Results : There were 138 orbital tumors managed at hospital during a 2-year period. Among 138 patients, 82 patients (59%) were female and 56 patients (40%) were male. Twenty-one patients (15%) were in childhood age and 117 patients (84.8%) were in adulthood age. The common clinical manifestations were proptosis (83.3%) and decreased vision (10.4%). The main procedure used was anterior orbitotomy (54.34%). Eighty-eight patients (63.7%) have primary tumors and 51.4% of the orbital tumors were malignant. The most common orbital tumor in childhood age was a cyst (15%). On the other hand, in adult patients, the most common orbital tumor was meningioma (18%) and Non- Hodgkin Lymphoma (15.7%). There was an overall 8% complication rate after orbitotomy tumor removal, including decrease in vision (3.3%), ptosis (2.6%), and strabismus (1.3%).
 Conclusion : Orbital tumors are challenging group of tumors with proptosis become the most frequent clinical characteristic that found. The orbital tumors in childhood and adulthood differ significantly in their incidence and tumor type with the percentage of malignant tumors increasing with age.

REVEALING ORBITAL TUMORS: 2-YEAR EVALUATION IN CLINICAL PROFILE, HISTOPATHOLOGICAL FEATURES AND SURGICAL TECHNIQUE

Introduction: Incidence of orbital tumors is relatively low, but the delay in diagnosis, even if benign, can lead to vision loss and deformity. Purposes: This study aims to review clinical and demographic information of orbital tumors in Sardjito General Hospital, Yogyakarta. Method: We retrospectively reviewed clinical data of 138 patients who diagnosed with orbital tumors during July 2021 - March 2023. Data extracted included clinical characteristics, operative procedures, and histopathologic characteristics of orbital tumor. Result: There were 138 orbital tumors managed at hospital during 2-year period. Among 138 patients, 82 patients (59%) were female and 56 patients (40%) were male. Twenty-one patients (15%) were in childhood age and 117 patients (84.8%) were in adulthood age. The common clinical manifestations were proptosis (83.3%) and decreased vision (10.4%). The main procedure used was anterior orbitotomy (54.34%). Eighty-eight patients (63.7%) have primary tumors and 51.4% of the orbital tumors were malignant. The most cases in children were benign tumors (61.9%) meanwhile in adults were malignant (54.7%). The main orbital tumor in childhood age was a Non-Hodgkin Lymphoma (NHL) (19%) and cyst (14.3%). On the other hand, in adult patient, the most common orbital tumor was meningioma (18%) and NHL (15.7%). Conclusion: Orbital tumors are challenging group of tumors with proptosis become the most frequent clinical characteristic that found. The orbital tumors in childhood and adulthood differ significantly in their incidence and tumor type with the percentage of malignant tumors increasing with age.

How to improve initial diagnostic accuracy of kidney tumours in childhood?-A non-invasive approach.

Non-invasive differentiation of paediatric kidney tumours is particularly important in the SIOP-RTSG protocols, which recommend pre-operative chemotherapy without histological confirmation. The identification of clinical and tumour-related parameters may enhance diagnostic accuracy. Age, metastases, and tumour volume (TV) were retrospectively analysed in 3306 patients enrolled in SIOP/GPOH 9, 93-01, and 2001 including Wilms tumour (WT), congenital mesoblastic nephroma (CMN), clear cell sarcoma (CCSK), malignant rhabdoid tumour of the kidney (MRTK), and renal cell carcinoma (RCC). WT was diagnosed in 2927 (88.5%) patients followed by CMN 138 (4.2%), CCSK 126 (3.8%), MRTK 58 (1.8%) and RCC 57 (1.7%). CMN, the most common localized tumour (71.6%) in patients younger than 3 months of age, was diagnosed earliest and RCC the latest (median age [months]: 0 and 154, respectively) both associated with significantly smaller TV (median TV [mL]: 67.2 and 45.0, respectively). RCC occurred in >14% of patients older than 120 months or older than 84 months with TV <100 mL. Receiver operating characteristic analyses discriminated WT from CMN, RCC and MRTK regarding age (AUC = 0.976, 0.929 and 0.791) and TV (AUC = 0.768, 0.813 and 0.622). MRTK had the highest risk of metastasis (37.9%) despite young age, whereas the risk of metastasis increased significantly with age in WT. Age and TV at diagnosis can differentiate WT from CMN and RCC. MRTK must be considered for metastatic tumours at young age. Identification of CCSK without histology remains challenging. Combined with MRI-characteristics, including diffusion-weighted imaging, and radiomics and liquid biopsies in the future, our approach allows optimization of biopsy recommendations and prevention of misdiagnosis-based neoadjuvant treatment.

Ocular and orbital tumors in childhood

Pediatric tumors of the eye and orbit can be benign or malignant as well as congenital or acquired and are usually distinctively different than those seen in adults. Although most of these neoplasms are benign (eg, dermoid cyst, chalazion, molluscum), their location near and within a vital organ can result in serious dermatologic and ophthalmologic sequelae. Lesions discussed include vascular lesions, retinoblastomas (the most common primary pediatric intraocular malignancy), rhabdomyosarcoma (the most common primary pediatric orbital malignancy), Langerhans cell histiocytosis, and metastatic lesions to the orbit (neuroblastoma, Ewing sarcoma). Although cysts and ocular melanoma can occur within the pediatric population, these conditions are covered in other contributions in this issue of Clinics in Dermatology.

5-Hydroxymethylcytosine Profiling of Cell-Free DNA Identifies Bivalent Genes That Are Prognostic of Survival in High-Risk Neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor in childhood. We previously showed that circulating cell-free DNA (cfDNA) and tumor biopsy derived 5-hydroxymethylcytosime (5-hmC) profiles identified patients with neuroblastoma who experienced subsequent relapse. Here, we hypothesized that 5-hmC modifications selectively enriched in cfDNA compared with tumor biopsy samples would identify epigenetic changes associated with aggressive tumor behavior and identify novel biomarkers of outcome in patients with high-risk neuroblastoma. 5-hmC profiles from cfDNA (n = 64) and tumor biopsies (n = 48) were compared. Two neuroblastoma cell lines underwent chromatin immunoprecipitation followed by sequencing (ChIP-Seq) for H3K27me3, H3K4me3, and H3K27ac; kethoxal-associated single-stranded DNA sequencing; hmC-Seal for 5-hmC; and RNA-sequencing (RNA-Seq). Genes enriched for both H3K27me3 and H3K4me3 in the included cell lines were defined as bivalent. Using bivalent genes defined in vitro, a bivalent signature was established in three publicly available cohorts of patients with neuroblastoma through gene set variation analysis. Differences between tumors with high or low bivalent signatures were assessed by the Kaplan-Meier method and Cox proportional hazards models. In cfDNA compared with tumor biopsy derived 5-hmC profiles, we found increased 5-hmC deposition on Polycomb Repressive Complex 2 target genes, a finding previously described in the context of bivalent genes. We identified 313 genes that bore bivalent chromatin marks, were enriched for mediators of neuronal differentiation, and were transcriptionally repressed across a panel of heterogeneous neuroblastoma cell lines. In three distinct clinical cohorts, low bivalent signature was significantly and independently associated with worse clinical outcome in patients with high-risk neuroblastoma. Low expression of bivalent genes is a biomarker of worse outcome in patients with high-risk neuroblastoma.

Postoperative Intensity Modulated Radiotherapy for Acinic Cell Parotid Carcinoma in Childhood- A Clinical Case from our Practice with Literature Review

Malignant parotid tumors in childhood are extremely rarely diagnosed diseases. Due to the rare incidence, there is no consensus on their complex treatment, as well as on the application of postoperative radiation therapy (RT). We present a clinical case of acinic cell parotid carcinoma in a 12-year-old girl, against the background of which we emphasize the optimal complex therapeutic approach. Despite radical facial nerve-sparing parotidectomy in pT2N0 acinic cell parotid carcinoma, due to the two pathohistological negative factors/two foci with vascular tumor invasion and the close proximity of the resection line to the preserved facial nerve, we conducted postoperative adjuvant RT. Due to the risk of late radiation reactions of normal tissues and organs after RT in childhood, intensity modulated radiation therapy (IMRT) with lower radiation doses in the target volumes was performed. Active surveillance and follow-up imaging studies are required for early diagnosis of possible recurrence or distant metastases.

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.

Pulmonary metastatectomy in pediatric cancer patients at National Cancer Institute, Egypt: prognostic factors and outcome

BackgroundMetastatic tumors account for 80% of all lung tumors in children. Wilms tumour and osteosarcoma are the most tumors of childhood that produce lung metastases. The aim of the current study is to assess the prognostic factors of pulmonary metastatectomy in pediatric solid tumours as age, number, size, site,laterality, resectability of pulmonary nodules, and number of Thoracotomies. Calculate overall survival among patients who underwent pulmonary metastatectomy.MethodsIt is a retrospective study including all pediatric patients with metastatic solid tumors to lungs treated at pediatric oncology department, National Cancer Institute, Cairo University from 2008 to 2014. Fifty-five patients were included, 43 (78.2℅) patients of them had Osteosarcoma.ResultsThirty (54.5℅)patients were male. The mean age was 15 years ranging from (4.5- 23) years. The site of primary disease was at lower limbs in 43 (78.2%) patients. All patients underwent complete surgical resection of the primary disease with negative margin, 22(51.1%) of the osteosarcoma patients did amputation with tumor necrosis less than 90%. All patients received chemotherapy and only 9 received radiation therapy. The patients were classified into four groups according to time of diagnosis of pulmonary metastasis: at time of diagnosis in 13 (21.8%) patients, within treatment in 16 (30.9%) patients, within first year follow up in 18 (32.7%) patients and detected late in 8 (14.5%) patients. Bilateral lung metastasis diagnosed by CT chest were detected in 42 (76.4%) patients. Size of metastatic nodules was ranging from (0.5 to 10 cm) with mean 3.4 cm. Number of metastatic nodules was ranging from (1 to 28) median 4.Metastatic complications were detected in 19 patients. 5-year OS was 74.8% in the study group, and 68% in osteosarcoma patients. Effect of prognostic factors as sex, time of respectability, laterality, tumor necrosis of the 1ry disease, Timing of lung metastasis, size and site of the primary, Surgical approach of metastatectomy, postoperative complications on overall survival of the studied patients was done with significant P-value of tumor necrosis of the 1ry disease and Timing of lung metastasis 0.017, 0.001 respectively.ConclusionResection of pulmonary metastases of pediatric solid tumours is a safe and effective treatment that offers better survival.

Comprehensive management of Pindborg tumor in childhood: a case report

Relevance. The calcifying epithelial odontogenic tumor, also known as Pindborg tumor, is a locally aggressive neoplasm characterized by strands and medullary formations of flat and clear cells, often accompanied by spherical calcifications and amyloid-stained hyaline deposits. The Pindborg tumor is rare, representing less than 1% of odontogenic tumors, and typically manifests in individuals aged 20 to 60 years. However, there is a growing incidence of neoplasms of diverse origins in childhood. This article presents a clinical case detailing the comprehensive multi-stage treatment of a pediatric patient with a Pindborg tumor, facilitating complete rehabilitation before reaching adulthood.Clinical case description. This article presents a clinical case detailing the comprehensive management of a patient with a Pindborg tumor. The individual initially sought treatment at the Department of Pediatric Maxillofacial Surgery of A.I. Evdokimov Moscow State Medical and Dental University in 2020, undergoing complete combined treatment until November 2023. Full rehabilitation was successfully achieved by the time of adulthood through a series of four consecutive surgeries, including dental implantation, followed by prosthetics utilizing a non-removable orthopedic structure in the final stage.Conclusion. Initiating comprehensive rehabilitation at an early stage, including dental implantation before reaching adulthood, facilitates complete social adaptation in society and contributes to the patient's harmonious development.

17q Gain in Neuroblastoma: A Review of Clinical and Biological Implications.

Neuroblastoma (NB) is the most frequent extracranial solid childhood tumor. Despite advances in the understanding and treatment of this disease, the prognosis in cases of high-risk NB is still poor. 17q gain has been shown to be the most frequent genomic alteration in NB. However, the significance of this remains unclear because of its high frequency and association with other genetic modifications, particularly segmental chromosomal aberrations, 1p and 11q deletions, and MYCN amplification, all of which are also associated with a poor clinical prognosis. This work reviewed the evidence on the clinical and biological significance of 17q gain. It strongly supports the significance of 17q gain in the development of NB and its importance as a clinically relevant marker. However, it is crucial to distinguish between whole and partial chromosome 17q gains. The most important breakpoints appear to be at 17q12 and 17q21. The former distinguishes between whole and partial chromosome 17q gain; the latter is a site of IGF2BP1 and NME1 genes that appear to be the main oncogenes responsible for the functional effects of 17q gain.

Epidemiology of pediatric hematological malignancies in Kazakhstan: Data from Unified National Electronic Healthcare System 2014-2021.

Patients with ALL had a higher incidence rate than patients with AML. The incidence rate of HL and NHL was relatively similar. All-cause mortality rates for leukemia and lymphomas were quite stable during the study period. Younger age is significantly associated with increased all-cause mortality among AML patients. However, there is no significant association of age with all-cause mortality among ALL, HL and NHL. In order to obtain more reliable data and analysis on pediatric (hematological) malignancies, specific registries for childhood tumors (including detailed information on relapses, treatments, short and long-term side effects, and specific death causes) should be implemented. • Leukemias and lymphomas together account for around 45% of all pediatric malignancies. • Lymphoma accounts for 12% of all childhood malignancies; non-Hodgkin's lymphomas (NHL) are more frequent than Hodgkin's lymphomas (HL). • The incidence rate of ALL was higher than the incidence rate of AML throughout the whole study period, whereas all-cause mortality of ALL and AML was quite stable. • According to Cox PH analysis, younger age (0-5years old) was associated with a higher risk of death among AML children compared to older children, and no significant association of age was observed with all-cause mortality among ALL and lymphomas.

Single-cell transcriptomics enable the characterization of local extension in retinoblastoma

Retinoblastoma (RB) is the most prevalent ocular tumor of childhood, and its extraocular invasion significantly increases the risk of metastasis. Nevertheless, a single-cell characterization of RB local extension has been lacking. Here, we perform single-cell RNA sequencing on four RB samples (two from intraocular and two from extraocular RB patients), and integrate public datasets of five normal retina samples, four intraocular samples, and three extraocular RB samples to characterize RB local extension at the single-cell level. A total of 128,454 qualified cells are obtained in nine major cell types. Copy number variation inference reveals chromosome 6p amplification in cells derived from extraocular RB samples. In cellular heterogeneity analysis, we identified 10, 8, and 7 cell subpopulations in cone precursor like cells, retinoma like cells, and MKI67+ photoreceptorness decreased (MKI67+ PhrD) cells, respectively. A high expression level of SOX4 was detected in cells from extraocular samples, especially in MKI67+ PhrD cells, which was verified in additional clinical RB samples. These results suggest that SOX4 might drive RB local extension. Our study presents a single-cell transcriptomic landscape of intraocular and extraocular RB samples, improving our understanding of RB local extension at the single-cell resolution and providing potential therapeutic targets for RB patients.

Methylation regulation for FUNDC1 stability in childhood leukemia was up-regulated and facilitates metastasis and reduces ferroptosis of leukemia through mitochondrial damage by FBXL2.

Leukemia, the most common malignant tumor in childhood, can be categorized into acute leukemia and chronic leukemia. However, the role of FUNDC1 in childhood leukemia (CL) remains unknown. This study aims to investigate the effects of FUNDC1 on patients with CL and its underlying mechanism both in vivo and in vitro. The mRNA expression levels of FUNDC1 were found to be up-regulated in serum samples from CL patients as well as in leukemia cell lines. Furthermore, it was observed that the mRNA expression of FUNDC1 was lower in stage I-II CL patients compared to stage III-IV patients. The up-regulation of FUNDC1 was found to promote leukemia metastasis. Additionally, it was discovered that FUNDC1 up-regulation reduces ferroptosis by inhibiting mitochondrial damage. In a leukemia model, FUNDC1 up-regulation induces the expression of FBXL2. Moreover, FUNDC1 up-regulation reduces FBXL2 ubiquitination, thus maintaining FBXL2 protein expression in leukemia. By inducing FBXL2, FUNDC1 reduces ferroptosis in leukemia through the inhibition of mitochondrial damage. The stability of FUNDC1 is controlled by METTL3 methylation. Overall, this study sheds light on the role of FUNDC1 in CL and provides insights into its underlying mechanisms.

Arsenic trioxide induces ferroptosis in neuroblastoma by mediating GPX4 transcriptional inhibition.

Neuroblastoma (NB), the most common extracranial solid tumor in childhood, significantly contributes to cancer-related mortality, presenting a dearth of efficacious treatment strategies. Previously, our studies have substantiated the potent cytotoxicity of arsenic trioxide (ATO) against NB cells, however, the specific underlying mechanism remains elusive. Here, we first identified ATO as a novel GPX4 inhibitor, which could trigger the ferroptosis in NB cells. Invitro, ATO significantly inhibited the proliferation and migration ability of NB cells SK-N-AS and SH-SY5Y, and induced ferroptosis. Furthermore, the iron chelator deferoxamine reversed ATO-mediated intracellular reactive oxygen species accumulation and hindered the generation of the lipid peroxidation product malondialdehyde. Conversely, ferric ammonium citrate notably intensified its cytotoxic effects, especially on retinoic acid (RA)-resistant SK-N-AS cells. Subsequently, the quantitative real-time polymerase chain reaction results showed ATO significantly inhibited the transcription of GPX4 in NB cells. Remarkably, immunoblotting analysis revealed that MG132 exhibited a notable effect on elevating GPX4 levels in NB cells. Nevertheless, pretreatment with MG132 failed to reverse the ATO-mediated decrease in GPX4 levels. These findings suggested that ATO reduced the GPX4 expression level in NB cells by mediating GPX4 transcriptional repression rather than facilitating ubiquitinated degradation. In conclusion, our research has successfully indicated that ATO could induce ferroptosis and initiate lipid peroxidation by regulating the transcriptional repression of GPX4, and ATO holds promise as a potential anti-tumor agent in NB, specifically for patients with RA-resistant HR-NB.

Current trends and prospects of surgical techniques for hepatoblastoma.

Hepatoblastoma, a common extracranial malignant solid tumor in childhood, is often detected at an advanced stage and is difficult to treat surgically. Despite the availability of multiple comprehensive treatments that can be combined with surgery, hepatoblastoma treatment outcomes remain poor. Surgery is the main treatment strategy for hepatoblastoma, but it faces many challenges, including tumor attachment to surrounding tissues, tumor wrapping or invading of vital organs and tissues, the presence of giant or multiple tumors, distant metastasis, the formation of a tumor thrombus, and significant surgical trauma. In this review, we discuss recent research advances and propose potential strategies for overcoming these challenges. Such strategies may improve the rate of hepatoblastoma resection and local control in children, as well as reduce complications and trauma.

A novel approach to guide GD2-targeted therapy in pediatric tumors by PET and [64Cu]Cu-NOTA-ch14.18/CHO.

Background: The tumor-associated disialoganglioside GD2 is a bona fide immunotherapy target in neuroblastoma and other childhood tumors, including Ewing sarcoma and osteosarcoma. GD2-targeting antibodies proved to be effective in neuroblastoma and GD2-targeting chimeric antigen receptors (CAR)- expressing T cells as well as natural killer T cells (NKTs) are emerging. However, assessment of intra- and intertumoral heterogeneity has been complicated by ineffective immunohistochemistry as well as sampling bias in disseminated disease. Therefore, a non-invasive approach for the assessment and visualization of GD2 expression in-vivo is of upmost interest and might enable a more appropriate treatment stratification. Methods: Recently, [64Cu]Cu-NOTA-ch14.18/CHO (64Cu-GD2), a radiolabeled GD2-antibody for imaging with Positron-Emission-Tomography (PET) was developed. We here report our first clinical patients' series (n = 11) in different pediatric tumors assessed with 64Cu-GD2 PET/MRI. GD2-expression in tumors and tissue uptake in organs was evaluated by semiquantitative measurements of standardized uptake values (SUV) with PET/MRI on day 1 p.i. (n = 11) as well as on day 2 p.i. (n = 6). Results: In 8 of 9 patients with suspicious tumor lesions on PET/MRI at least one metastasis showed an increased 64Cu-GD2 uptake and a high tracer uptake (SUVmax > 10) was measured in 4 of those 8 patients. Of note, sufficient image quality with high tumor to background contrast was readily achieved on day 1. In case of 64Cu-GD2-positive lesions, an excellent tumor to background ratio (at least 6:1) was observed in bones, muscles or lungs, while lower tumor to background contrast was seen in the spleen, liver and kidneys. Furthermore, we demonstrated extensive tumor heterogeneity between patients as well as among different metastatic sites in individual patients. Dosimetry assessment revealed a whole-body dose of only 0.03 mGy/MBq (range 0.02-0.04). Conclusion: 64Cu-GD2 PET/MRI enables the non-invasive assessment of individual heterogeneity of GD2 expression, which challenges our current clinical practice of patient selection, stratification and immunotherapy application scheme for treatment with anti-GD2 directed therapies.

Solitary myofibroma in children: a report of two cases

Myofibromas are rare benign tumors of myofibroblasts, seen more commonly in children. These tumors typically involve soft tissues with a predilection for the head and neck. Malignant neoplasia is often suspected for these rapidly growing tumors in early childhood. Clinical and radiological findings are not typical, and histopathological examination makes the definitive diagnosis. This pathology requires the intervention of a multidisciplinary team and regular follow-up. We report our experience with two children with myofibromas, one in the right arm of a 5-year-old girl and the other in the right axilla of a 9-year-old boy. Tumors were totally resected in both children, who are under follow-up with no adjuvant treatment free of disease after surgery. Myofibroma should be considered in the differential diagnosis of pediatric soft tissue tumors. Surgical resection is sufficient for treatment and patients should be followed regularly for possible recurrences.

DNA methylation landscapes in DIPG reveal methylome variability that can be modified pharmacologically.

Diffuse intrinsic pontine glioma (DIPG) is a uniformly lethal brainstem tumor of childhood, driven by histone H3 K27M mutation and resultant epigenetic dysregulation. Epigenomic analyses of DIPG have shown global loss of repressive chromatin marks accompanied by DNA hypomethylation. However, studies providing a static view of the epigenome do not adequately capture the regulatory underpinnings of DIPG cellular heterogeneity and plasticity. To address this, we performed whole-genome bisulfite sequencing on a large panel of primary DIPG specimens and applied a novel framework for analysis of DNA methylation variability, permitting the derivation of comprehensive genome-wide DNA methylation potential energy landscapes that capture intrinsic epigenetic variation. We show that DIPG has a markedly disordered epigenome with increasingly stochastic DNA methylation at genes regulating pluripotency and developmental identity, potentially enabling cells to sample diverse transcriptional programs and differentiation states. The DIPG epigenetic landscape was responsive to treatment with the hypomethylating agent decitabine, which produced genome-wide demethylation and reduced the stochasticity of DNA methylation at active enhancers and bivalent promoters. Decitabine treatment elicited changes in gene expression, including upregulation of immune signaling such as the interferon response, STING, and MHC class I expression, and sensitized cells to the effects of histone deacetylase inhibition. This study provides a resource for understanding the epigenetic instability that underlies DIPG heterogeneity. It suggests the application of epigenetic therapies to constrain the range of epigenetic states available to DIPG cells, as well as the use of decitabine in priming for immune-based therapies.