Childhood Brain Tumors Research Articles

True state and outcome of diffuse intrinsic pontine glioma in Japan: a retrospective questionnaire survey to evaluate the clinical factors affecting the prognosis of rare pediatric brain tumors by the Study Group of “Nationwide Multicenter Studies to establish Standard Treatment for Childhood Brain Tumors” in the Japan Children’s Cancer Group (JCCG) financed through a grant from the Japan Agency for

True state and outcome of diffuse intrinsic pontine glioma in Japan: a retrospective questionnaire survey to evaluate the clinical factors affecting the prognosis of rare pediatric brain tumors by the Study Group of “Nationwide Multicenter Studies to establish Standard Treatment for Childhood Brain Tumors” in the Japan Children’s Cancer Group (JCCG) financed through a grant from the Japan Agency for

40. The role of copy number alterations in predicting survival and influencing treatment of childhood brain tumors

Brain and central nervous system tumors are the most common form of solid tumor cancers among children. While many advances have been made in understanding the genomics of childhood brain tumors, the role of copy number alterations (CNAs) has not been fully characterized. Although the genomes of childhood brain tumor patients are generally considered to be relatively stable diploid genomes, analysis of a subset of pretreatment diagnostic samples from a cohort of 84 deceased patients from Washington University revealed widespread alterations, suggesting CNAs may play a larger role in the progression and prognosis of childhood brain tumors than originally thought.

A Rare Case of Adult Medulloblastoma Associated with Multiple Sclerosis: Case Report and Literature Review

Medulloblastomas are the most common primary malignant brain tumors in childhood. They are responsible for around 20–40% of all brain tumors in children. They rarely occur in adulthood, but here they only make up less than 1% of all brain tumors. The standard therapy consists of an operation in combination with radiation and chemotherapy, which are individually determined for the patient. In this article, we discuss a case of 47 years old female patient diagnosed with primary progressive multiple sclerosis since 1 year. After 3 months of the diagnosis, she deteriorated and became unable to walk. MRI showed a large patchy enhancing midline cerebellar mass with evolving hydrocephalus. Tumor expressed positive reaction with synaptophysin immunohistochemical stain rendering medulloblastoma diagnosis.

High Prevalence of Early Endocrine Disorders After Childhood Brain Tumors in a Large Cohort.

Endocrine complications are common in pediatric brain tumor patients. We aimed to describe the endocrine follow-up of patients with primary brain tumors. This is a noninterventional observational study based on data collection from medical records of 221 patients followed at a Pediatric Endocrinology Department. Median age at diagnosis was 6.7 years (range, 0-15.9), median follow-up 6.7 years (0.3-26.6), 48.9% female. Main tumor types were medulloblastoma (37.6%), craniopharyngioma (29.0%), and glioma (20.4%). By anatomic location, 48% were suprasellar (SS) and 52% non-suprasellar (NSS). Growth hormone deficiency (GHD) prevalence was similar in both groups (SS: 83.0%, NSS: 76.5%; P = 0.338), appearing at median 1.8 years (-0.8 to 12.4) after diagnosis; postradiotherapy GHD appeared median 1.6 years after radiotherapy (0.2-10.7). Hypothyroidism was more prevalent in SS (76.4%), than NSS (33.9%) (P < 0.001), as well as ACTH deficiency (SS: 69.8%, NSS: 6.1%; P < 0.001). Early puberty was similar in SS (16%) and NSS (12.2%). Hypogonadotropic hypogonadism was predominant in SS (63.1%) vs NSS (1.3%), P < 0.001, and postchemotherapy gonadal toxicity in NSS (29.6%) vs SS (2.8%), P < 0.001. Adult height was lower for NSS compared to target height (-1.0 SD, P < 0.0001) and to SS patients (P < 0.0001). Thyroid nodules were found in 13/45 patients (28.8%), including 4 cancers (4.8-11.5 years after radiotherapy). Last follow-up visit BMI was higher in both groups (P = 0.0001), and obesity incidence was higher for SS (46.2%) than NSS (17.4%). We found a high incidence of early-onset endocrine disorders. An endocrine consultation and nutritional evaluation should be mandatory for all patients with a brain tumor, especially when the tumor is suprasellar or after hypothalamus/pituitary irradiation.

Development of Training in Problem Solving for Caregivers of Childhood Brain Tumor Survivors.

Family management (FM) challenges of maternal caregivers of young adult survivors of childhood brain tumors are well documented, but there are no evidence-based caregiver interventions to improve FM. The aims of this study were to (1) generate the knowledge necessary for developing a caregiver intervention (stage 0) and (2) modify an existing, efficacious intervention by engaging stakeholders (stage 1). Stages 0 and 1 of the National Institutes of Health Stage Model for Behavioral Intervention Development and the FM Styles Framework were used in this study. In stage 0, families with condition-focused FM patterns were identified as at risk for poor problem solving. The 12-item Condition Management Ability scale of the FM Measures was selected as the screener to identify condition-focused maternal caregivers. Problem solving was identified as a potential mechanism for promoting behavior change. In stage 1, Bright IDEAS for Everyday Living was modified by integrating the FM Styles Framework creating Training in Problem Solving for Caregivers of Young Adult Survivors of Childhood Brain Tumors. Qualitative and quantitative assessments of feasibility and acceptability by maternal caregivers were excellent and used to improve selected areas of concern. Feedback from stakeholders indicates that Training in Problem Solving is a promising approach to shifting FM patterns and improving the functioning of caregivers, young adult survivors, and families. When developing interventions, the use of systemic methods can provide both clinically based and scientifically acceptable solutions. Those interventions based on both problem solving and FM are potentially promising but need further testing.

MTORC1 promotes malignant large cell/anaplastic histology and is a targetable vulnerability in SHH-TP53 mutant medulloblastoma.

Medulloblastoma (MB), one of the most malignant brain tumors of childhood, comprises distinct molecular subgroups, with p53 mutant sonic hedgehog–activated (SHH-activated) MB patients having a very severe outcome that is associated with unfavorable histological large cell/anaplastic (LC/A) features. To identify the molecular underpinnings of this phenotype, we analyzed a large cohort of MB developing in p53-deficient Ptch+/– SHH mice that, unexpectedly, showed LC/A traits that correlated with mTORC1 hyperactivation. Mechanistically, mTORC1 hyperactivation was mediated by a decrease in the p53-dependent expression of mTORC1 negative regulator Tsc2. Ectopic mTORC1 activation in mouse MB cancer stem cells (CSCs) promoted the in vivo acquisition of LC/A features and increased malignancy; accordingly, mTORC1 inhibition in p53-mutant Ptch+/– SHH MB and CSC-derived MB resulted in reduced tumor burden and aggressiveness. Most remarkably, mTORC1 hyperactivation was detected only in p53-mutant SHH MB patient samples, and treatment with rapamycin of a human preclinical model phenocopying this subgroup decreased tumor growth and malignancy. Thus, mTORC1 may act as a specific druggable target for this subset of SHH MB, resulting in the implementation of a stringent risk stratification and in the potentially rapid translation of this precision medicine approach into the clinical setting.

Childhood Malignant Brain Tumors: Balancing the Bench and Bedside.

Simple SummaryBrain tumors remain the most common childhood solid tumors, accounting for approximately 25% of all pediatric cancers. They also represent the most common cause of cancer-related illness and death in this age group. Recent years have witnessed an evolution in our understanding of the biological underpinnings of many childhood brain tumors, potentially improving survival through both improved risk group allocation for patients to provide appropriate treatment intensity, and novel therapeutic breakthroughs. This review aims to summarize the molecular landscape, current trial-based standards of care, novel treatments being explored and future challenges for the three most common childhood malignant brain tumors—medulloblastomas, high-grade gliomas and ependymomas.Brain tumors are the leading cause of childhood cancer deaths in developed countries. They also represent the most common solid tumor in this age group, accounting for approximately one-quarter of all pediatric cancers. Developments in neuro-imaging, neurosurgical techniques, adjuvant therapy and supportive care have improved survival rates for certain tumors, allowing a future focus on optimizing cure, whilst minimizing long-term adverse effects. Recent times have witnessed a rapid evolution in the molecular characterization of several of the common pediatric brain tumors, allowing unique clinical and biological patient subgroups to be identified. However, a resulting paradigm shift in both translational therapy and subsequent survival for many of these tumors remains elusive, while recurrence remains a great clinical challenge. This review will provide an insight into the key molecular developments and global co-operative trial results for the most common malignant pediatric brain tumors (medulloblastoma, high-grade gliomas and ependymoma), highlighting potential future directions for management, including novel therapeutic options, and critical challenges that remain unsolved.

Global molecular alterations involving recurrence or progression of pediatric brain tumors.

BackgroundWe aimed to identify molecular changes in recurrent or progressive pediatric brain tumors, as compared to the corresponding initial tumors from the same patients, using genomic, transcriptomic, and proteomic data from a unique and large cohort of 55 patients and 63 recurrent or progressive tumors from the Children's Brain Tumor Tissue Consortium, representing various histologic types.MethodsWe carried out paired analyses for each gene between recurrent/progressive and initial tumor groups, using RNA-sequencing and mass spectrometry-based proteomic data. By whole-genome sequencing (WGS) analysis, we also examined somatic DNA events for a set of cancer-associated genes.ResultsOf 44 patients examined by WGS, 35 involved at least one cancer-associated gene with a somatic alteration event in a recurrent or progressive tumor that was not present in the initial tumor, including genes NF1, CDKN2A, CCND2, EGFR, and MYCN. By paired analysis, 68 mRNA transcripts were differentially expressed in recurrent/progressive tumors with p<0.001, and these genes could predict patient outcomes in an independent set of pediatric brain tumors. Gene transcript-level associations with recurrence or progression were enriched for protein-level associations. There was a significant overlap in results from pediatric brain tumors and results from adult brain tumors from The Cancer Genome Atlas. Unsupervised analysis defined five subsets of recurrent or progressive tumors, with differences in gene expression and overall patient survival.ConclusionsOur study uncovers genes showing consistent expression differences in recurrent or progressive tumors. These genes may provide molecular clues as to processes or pathways underlying more aggressive pediatric brain tumors.

The risk of childhood brain tumors associated with delivery interventions: A Danish matched case-control study

BackgroundHead trauma has been associated with increased brain tumor risk in adults. Instrument assisted delivery can be a cause of head trauma in newborns. The goal of this study was to determine if instrument-assisted deliveries influenced the odds of childhood brain tumors in Denmark. MethodsWe conducted a matched case-control study of childhood (<20 years) brain tumors in Denmark born between 1978 and 2013 and diagnosed 1978–2016. A total of 1678 brain tumor cases were identified and 25 controls were matched to each case based on the child’s sex and birth date (N = 40,934). Conditional logistic regression was used to estimate effects (odds ratios (OR) and 95% confidence intervals (95%CI)) for variables of interest. ResultsCompared to children birthed by spontaneous vaginal delivery, children who later developed ependymomas (N = 118) had a greater likelihood of having experienced vacuum assisted deliveries (OR=1.74, 95% CI 1.02–2.96). Forceps use was low, and declined across the study period. We did not observe an overall increase in all CNS tumors (combined) with either vacuum delivery (OR=0.99, 95% CI 0.84–1.18) or forceps delivery (OR=1.26, 95% CI 0.78–2.03). ConclusionOur findings suggest an association between vacuum assisted deliveries and ependymomas.

Novel diarylamides and diarylureas with N-substitution dependent activity against medulloblastoma.

Medulloblastoma - highly aggressive and heterogeneous tumours of the cerebellum - account for 15-20% of all childhood brain tumours, and are the most common high-grade childhood embryonal tumour of the central nervous system. Herein, potent invitro anticancer activity against two established medulloblastoma cell lines of the sonic hedgehog subgroup, namely DAOY (p53 mutant) and ONS-76 (p53 wild type), has been achieved. A number of first-generation diarylamides and diarylureas were evaluated and activity is likely to be, in-part, conformation-dependent. The most active compound from this first-generation set of compounds, 1-naphthyl derivative 4b, was selected and a second-generation of compounds were optimised and tested for activity against the medulloblastoma cell lines. This process resulted in drug-like compounds with up to sixty times the activity (sub-micromolar) of the first-generation - thus providing potent new leads for further study.

Changes in executive function in pediatric brain tumor survivors.

Pediatric oncology survivors are at risk for executive function (EF) and working memory (WM) deficits, which can be measured via performance-based measures or rating scales. Previous studies have shown these measurement methods to be weakly correlated. This study aimed to describe parent-rated EF and performance-based WM (PBWM) in pediatric brain tumor (BT) survivors, examine change in EF and PBWM across time, and investigate the relationship between parent-rated WM and PBWM. The sample included 56 patients diagnosed with a BT in childhood (Mage =6.94years; SD=4.05) seen twice for clinical neuropsychological evaluation. PBWM was examined via the auditory WM scale from a Wechsler intelligence measure or Differential Ability Scales-II. Parents completed the Behavior Rating Inventory of Executive Function (BRIEF)/BRIEF-P/BRIEF-2 as a measure of global EF (Global Executive Composite [GEC]), metacognitive skills (Metacognitive Index/Cognitive Regulation Index [MI/CRI]), behavioral regulation (Behavior Regulation Index [BRI]), and emotional regulation (Emotion Regulation Index [ERI]). GEC, MI/CRI, and ERI at Time 1 were significantly above the mean (p<.01); BRI and PBWM did not differ from the normative mean. All measures were significantly higher than the normative mean at Time 2 (p<.05). PBWM was both clinically and statistically elevated (p<.001). There was a significant change across time in PBWM (p<.05), but not GEC, MI/CRI, ERI, or BRI. PBWM was weakly correlated with the BRIEF WM subscale at Time 1 and Time 2 (all p>.05). Multiple measures of EF should be considered when providing diagnoses and recommendations for pediatric BT survivors. Furthermore, given declines across time, findings document need for continued monitoring and reassessment of survivors as they get further out from treatment.

Parental Pesticide Exposure and Childhood Brain Cancer: A Systematic Review and Meta-Analysis Confirming the IARC/WHO Monographs on Some Organophosphate Insecticides and Herbicides.

Background: Brain tumors are the second most common neoplasm in the pediatric age. Pesticides may play an etiologic role, but literature results are conflicting. This review provides a systematic overview, meta-analysis, and IARC/WHO consideration of data on parental exposure to pesticides and childhood brain tumors. Methods: We searched PubMed, SCOPUS, and Google Scholar for literature (1 January 1966–31 December 2020) that assessed childhood brain tumors and parental exposure to pesticides. We undertook a meta-analysis addressing prenatal exposure, exposure after birth, occupational exposure, and residential exposure. A total of 130 case-control investigations involving 43,598 individuals (18,198 cases and 25,400 controls) were included. Results: Prenatal exposure is associated with childhood brain tumors (odds ratio, OR = 1.32; 95% CI: 1.17–1.49; I2 = 41.1%). The same occurs after birth exposure (OR = 1.22; 95% CI: 1.03–1.45, I2 = 72.3%) and residential exposure to pesticides (OR = 1.31; 95% CI: 1.11–1.54, I2 = 67.2%). Parental occupational exposure is only marginally associated with CBT (OR = 1.17, 95% CI: 0.99–1.38, I2 = 67.0%). Conclusions: There is an association between CBT and parental pesticides exposure before childbirth, after birth, and residential exposure. It is in line with the IARC Monograph evaluating the carcinogenicity of diazinon, glyphosate, malathion, parathion, and tetrachlorvinphos.

The development of a cognitive rehabilitation and psycho-social group programme for teenage and young adult survivors of brain tumours: A feasibility study.

Treatment for childhood and adolescent brain tumours is often intensive, with significant neurocognitive and psycho-social late effects (Zeltzer et al., 2009). This feasibility Study aimed to inform the development of a cognitive rehabilitation and psycho-social group intervention for Teenage and Young Adult (TYA) survivors of brain tumours. A group-based intervention incorporated ideas from the current evidence base, including psychoeducation and compensatory strategy training, with a focus on real-life goals and improving quality of life. Participants (N = 19, 13-24 years) were recruited from the University College London Hospital TYA Oncology Service. Participants had received treatment for a malignant brain tumour and had completed their treatment at least 1 year prior to participation. Four group-based, whole-day interventions ran every 3 months throughout a year. Feasibility criteria were established to answer questions about acceptability of the intervention and recruitment. Qualitative and quantitative feedback from all four groups demonstrated acceptability and suitability of the intervention with regards to the content, structure and delivery. Recruitment presented more of a challenge with 35% fewer referrals than expected. Feedback suggests that the intervention is suitable and acceptable, whilst limitations include numbers of referrals and referral pathways. Future directions are discussed.

Epidemiological characteristics and survival outcomes of children with medulloblastoma treated at the National Cancer Institute (INCA) in Rio de Janeiro, Brazil.

Medulloblastoma (MB),the most common malignant brain tumor of childhood has survival outcomes exceeding 80% for standard-risk and 60% for high-risk patients in high-income countries (HICs). These results have not been replicated in low- and middle-income countries (LMICs), where 80% of children with cancer live. This is a retrospective review of 114 children aged 3-18years diagnosed with MB from 1997 to 2016 at National Cancer Institute (INCA). Sociodemographic, clinical, and treatment data were extracted from the medical records and summarized descriptively. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. The male-to-female ratio was 1.32 and the median age at diagnosis was 8.2years. Headache (83%) and nausea/vomiting (78%) were the most common presenting symptoms. Five-year OS was 59.1% and PFS was 58.4%. The OS for standard-risk and high-risk patients was 69% and 53%, respectively. The median time to diagnosis interval was 50.5days and the median time from surgery to radiation therapy initiation was 50.4days. Patients who lived >40km from INCA fared better (OS=68.2% vs. 51.1%, p=.032). Almost 20% of families lived below the Brazilian minimum wage. Forty-five patients (35%) had metastatic disease at admission. Gross total resection was achieved in 57% of the patitents. Although there are considerable barriers to deliver effective MB treatment in countries like Brazil, the OS seen in the present study demonstrates that good outcomes are not only feasible but can and should be increased with appropriate interventions.

QOLP-30. LONG-TERM UNMET SUPPORTIVE CARE NEEDS OF TYA CHILDHOOD BRAIN TUMOUR SURVIVORS AND THEIR CAREGIVERS: A CROSS-SECTIONAL SURVEY

Abstract INTRODUCTION The supportive care needs of long-term childhood brain tumour survivors, now teenagers and young adults (TYAs), and their caregivers are largely unknown. TYAs are a unique patient cohort with specific challenges and vulnerabilities differing from children or older adults. We aimed to describe their supportive care needs and explore associations between needs and quality of life (QoL).This is the first study to collect quantitative data about needs in this survivorship group. METHODS Participants were recruited from long-term follow-up clinics (in three National Health Service Trusts in England) and online. Participants included childhood brain tumour survivors, ≥ 5 years from diagnosis, currently aged 13-30, and their primary caregivers. Survivors completed the Supportive Care Needs Survey (SCNS) Short-Form and Paediatric Functional Assessment of Cancer Therapy – Brain (Peds-FACT-Br). While caregivers completed the SCNS-Partners and Caregivers (SCNS-P&amp;C) and the Caregiver Quality of Life Index–Cancer (CQOLC). RESULTS In total, 112 individuals (69 survivors/43 caregivers) participated. Survivors reported on average 9.4 (±8.5) unmet needs. Needs were greatest in the psychological domain, with anxiety (60.3%), uncertainty about the future (50.7%) and feeling down and depressed (48.5%) most commonly reported. Caregivers reported on average 12.4 (±12.3) unmet needs. Again, the greatest number of unmet needs were observed in the psychological domain. Many caregivers also reported information needs around financial support/government benefits (42.9%) and possible survivor fertility problems (42.9%). Multivariable linear regression analysis showed that female survivors, unemployed survivors, survivors further away from diagnosis, and single caregivers were more likely to report unmet needs. More unmet needs were significantly associated with poorer QoL in survivors and caregivers. CONCLUSION This research provides leads to improving supportive care and long-term follow-up services. Psychological support appears to be the biggest gap in care. Understanding unmet needs and recognising what services are required is critical to improving quality of long-term survival.

EXTH-34. ION CHANNELS AS A THERAPEUTIC TARGET IN PAEDIATRIC HIGH-GRADE GLIOMAS

Abstract Pediatric Glioblastoma Multiforme (GBM) is a leading cause of CNS cancer-related death in children. The scarcity of treatments for GBM has opened the field to new pathways in adults, such as tumour treating fields(TTF). Studies have identified the clinical benefit of electrotherapy in combination with chemotherapeutics, however the mechanistic action is unclear. Increasing evidence suggests that ion channels not only regulate electrical signalling of excitable cells, but are also crucial in the development/progression of brain tumours. Ion channels are essential in cell-cycle control, invasion and migration of cancer cells, therefore presenting as valuable therapeutic targets. Candidate ion channel genes(ICG) associated with high-grade glioma (HGG) were identified via analysis of inhouse and publicly available data sets. Expression patterns of selected ICGs were assessed along with clinician correlations.. Protein and RNA expression of target ICGs was assessed in pGBM cell lines/ TMAs. Finally, the Human ClariomTMS array was used for whole transcriptome gene expression analysis of paediatric GBM cell lines treated with tumour treating fields or low frequency electrical fields via deep brain stimulating electrodes. Paediatric brain tumour cells were exposed to genetic and pharmacological manipulation of CLIC1 and CLIC4 ion channels individually or in combination. We have shown that HGG exhibit increased expression of CLIC4 and CLIC1 at protein and RNA levels in both publically available data sets and inhouse cell lines / TMAs. Clinical correlation determined that high CLIC4 and CLIC1 expression was associated with poor overall survival. Further to this, DNA array analysis revealed a downregulation of CLIC1 and CLIC4 ion channels genes in KNS42 cells when treated with electrotherapy compared to untreated cells. Inhibition of CLIC1 and CLIC4 reduces Cl- flux across cell membranes and reduces cell proliferation. These data provide rationale that manipulation of ICGs will reduce the capacity of childhood brain tumours to proliferate and invade.

A prospective behavioral and imaging study exploring the impact on long-term memory of radiotherapy delivered for a brain tumor in childhood and adolescence

BackgroundPosterior fossa tumors represent two thirds of brain tumors in children. Although progress in treatment has improved survival rates over the past few years, long-term memory impairments in survivors are frequent and have an impact on academic achievement. The hippocampi, cerebellum and cerebellar-cortical networks play a role in several memory systems. They are affected not only by the location of the tumor itself and its surgical removal, but also by the supratentorial effects of complementary treatments, particularly radiotherapy. The IMPALA study will investigate the impact of irradiation doses on brain structures involved in memory, especially the hippocampi and cerebellum. Methods/designIn this single-center prospective behavioral and neuro-imaging study, 90 participants will be enrolled in three groups. The first two groups will include patients who underwent surgery for a posterior fossa brain tumor in childhood, who are considered to be cured, and who completed treatment at least 5 years earlier, either with radiotherapy (aggressive brain tumor; Group 1) or without (low-grade brain tumor; Group 2). Group 3 will include control participants matched with Group 1 for age, sex, and handedness. All participants will perform an extensive battery of neuropsychological tests, including an assessment of the main memory systems, and undergo multimodal 3 T MRI. The irradiation dose to the different brain structures involved in memory will be collected from the initial radiotherapy dosimetry. DiscussionThis study will provide long-term neuropsychological data about four different memory systems (working memory, episodic memory, semantic memory, and procedural memory) and the cognitive functions (attention, language, executive functions) that can interfere with them, in order to better characterize memory deficits among the survivors of brain tumors. We will investigate the correlations between neuropsychological and neuroimaging data on the structural (3DT1), microstructural (DTI), functional (rs-fMRI), vascular (ASL) and metabolic (spectroscopy) impact of the tumor and irradiation dose. This study will thus inform the setting of dose constraints to spare regions linked to the development of cognitive and memory functions. Trial registrationClinicalTrials.gov: NCT04324450, registered March 27, 2020, updated January 25th, 2021. Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT04324450.

Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancer.

Aberrant activation of telomerase in human cancer is achieved by various alterations within the TERT promoter, including cancer-specific DNA hypermethylation of the TERT hypermethylated oncological region (THOR). However, the impact of allele-specific DNA methylation within the TERT promoter on gene transcription remains incompletely understood. Using allele-specific next-generation sequencing, we screened a large cohort of normal and tumor tissues (n = 652) from 10 cancer types and identified that differential allelic methylation (DAM) of THOR is restricted to cancerous tissue and commonly observed in major cancer types. THOR-DAM was more common in adult cancers, which develop through multiple stages over time, than in childhood brain tumors. Furthermore, THOR-DAM was especially enriched in tumors harboring the activating TERT promoter mutations (TPMs). Functional studies revealed that allele-specific gene expression of TERT requires hypomethylation of the core promoter, both in TPM and TERT WT cancers. However, the expressing allele with hypomethylated core TERT promoter universally exhibits hypermethylation of THOR, while the nonexpressing alleles are either hypermethylated or hypomethylated throughout the promoter. Together, our findings suggest a dual role for allele-specific DNA methylation within the TERT promoter in the regulation of TERT expression in cancer.

Update on Phototherapy and Childhood Cancer in a Northern California Cohort.

We aimed to reassess the relationship between phototherapy and cancer in an extended version of a previous cohort and to replicate a report from Quebec of increased cancer risk after phototherapy beginning at age 4 years. This cohort study included 139 100 children born at ≥35 weeks' gestation from 1995 to 2017, followed through March 16, 2019, in Kaiser Permanente Northern California hospitals who had a qualifying bilirubin level from -3 mg/dL to +4.9 mg/dL from the American Academy of Pediatrics phototherapy threshold; an additional 40 780 children and 5 years of follow-up from our previous report. The exposure was inpatient phototherapy (yes or no), and the outcomes were various types of childhood cancer. We used Cox proportional hazard models, controlling for propensity-score quintiles, and allowed for time-dependent exposure effects to assess for the risk of cancer after a latent period. Over a mean (SD) follow-up of 8.2 (5.7) years, the crude incidence of cancer per 100 000 person-years was 25.1 among those exposed to phototherapy and 19.2 among those not exposed (233 cases of cancer). After propensity adjustment, phototherapy was not associated with any cancer (hazard ratio [HR]: 1.13, 95% confidence interval [CI]: 0.83-1.54), hematopoietic cancer (HR: 1.17, 95% CI: 0.74-1.83), or solid tumors (HR: 1.01, 95% CI: 0.65-1.58). We also found no association with cancer diagnoses at age ≥4 years. We did not confirm previous, concerning associations between phototherapy and adjusted risk of any cancer, nonlymphocytic leukemia, or brain and/or central nervous systems tumors in later childhood.

Integrated computational analyses reveal novel insights into the stromal microenvironment of SHH-subtype medulloblastoma

Medulloblastoma is the most common malignant brain tumour of childhood. While our understanding of this disease has progressed substantially in recent years, the role of tumour microenvironment remains unclear. Given the increasing role of microenvironment-targeted therapeutics in other cancers, this study was aimed at further exploring its role in medulloblastoma. Multiple computational techniques were used to analyze open-source bulk and single cell RNA seq data from primary samples derived from all subgroups of medulloblastoma. Gene expression is used to infer stromal subpopulations, and network-based approaches are used to identify potential therapeutic targets. Bulk data was obtained from 763 medulloblastoma samples and single cell data from an additional 7241 cells from 23 tumours. Independent bulk (285 tumours) and single cell (32,868 cells from 29 tumours) validation cohorts were used to verify results. The SHH subgroup was found to be enriched in stromal activity, including the epithelial-to-mesenchymal transition, while group 3 is comparatively stroma-suppressed. Several receptor and ligand candidates underlying this difference are identified which we find to correlate with metastatic potential of SHH medulloblastoma. Additionally, a biologically active gradient is detected within SHH medulloblastoma, from “stroma-active” to “stroma-suppressed” cells which may have relevance to targeted therapy. This study serves to further elucidate the role of the stromal microenvironment in SHH-subgroup medulloblastoma and identify novel treatment possibilities for this challenging disease.